1

Chapter 1: Oxygen-Directed Hydroboration

1.1 The Versatility of Organoboranes
Organoboron species are among the most versatile functionalities in synthetic
chemistry. Aliphatic and alkenyl boranes can be oxidized to alcohols and carbonyl
groups, respectively.
1
Aliphatic boranes can also be converted to amines
2
and are well
known for undergoing one-carbon homologation chemistry, allowing for installation of
formyl groups, esters, and nitriles.
3-5
Transition metal catalysis greatly expands the
utiltity of organoboron chemistry. Palladium catalysis enables Suzuki cross-coupling
reactions with both aryl/vinyl
6
and alkyl
7,8
coupling partners as well as with carbon
monoxide,
9,10
while rhodium catalyzes addition of vinyl boranes to aldehydes.
11-13

Trifuoroborate salts are more robust than other organoboron species, as they resist
oxidation upon exposure to air and even by dimethyldioxirane (DMDO), enabling
R
BX
n
OH
R
NHBn
R
R
NaOOH
B
C
l
3 ,

B
n
N
3
R
h
0 ,

R
'
C
H
O
OH
R'
Pd
0
, CO,
ROH
R
CO
2
R
R
BX
n
O
Pd
0
,
X
R
LiCCl
2
OMe
R
O
H
R
N
ClCH
2
CN
D
M
D
O
Scheme 1A: The Synthetic Transformations of Organoborons
1A1
1A2
1A3
1A4
1A5
1A6
1A7
1A8

2

oxidation of olefins in the presence of boron.
14
What makes all of these boron species
even more attractive as synthetic intermediates is that they are all conveniently accessible
by hydroboration.
1.2 The Limitation of Steric and Electronic Influence on Intermolecular
Hydroboration Regioselectivity

Hydroboration is crucial for the synthesis of organoboranes, and involves the
syn-addition of a boron-hydrogen bond across a carbon-carbon multiple bond in a four-
membered transition state such as 1B2b.
15
Intermolecular hydroboration of simple
olefins is controlled by the steric environment of the olefin in concert with its electronic
properties to provide anti-Markovnikov selectivity. The steric component of
regioselectivity reflects the smaller bulk of hydride compared to a BR
2
moiety (R= alkyl
or H). Therefore, a borane (HBR
2
) preferentially approaches an olefin with boron at the

3

less hindered carbon. Electronic effects supplement the steric preference. The dipole of
a borane B-H bond provides the hydrogen with negative character and the boron with
positive character. The four-membered transition state features the hydride of the borane
forming a bond with the more substituted carbon, which favors having partial positive
character relative to the less substituted carbon.
16
(Scheme 1B). The combination of
steric and electronic effects leads to excellent selectivity (19:1) with terminal olefins even
when R=H. Good selectivity is also achieved with trisubstituted olefins (98:2) and
2,2-disubstituted olefins (99:1). However, achieving regioselective hydroboration of a
1,2-disubstituted olefin remains an unresolved issue in the hydroboration literature. The
following chapter presents the reports in the literature that discuss the possibility of
affecting regio- and stereoselectivity by directing hydroboration with oxygen-containing
functionalities.
1.3 Mechanistic Proposals of Brown (Dissociative) and Pasto (Associative)
It has been proposed that intermolecular hydroboration can occur via either a
dissociative pathway or an associative pathway. The work of H. C. Brown et al. supports
a mechanism requiring that an uncomplexed trivalent borane be generated via
dissociation from either its dimer 1C1 or a Lewis-base complex 1C2, in order to react
with an olefin (Scheme 1C).
17-20
There are several kinetic studies that report the
observation of first order (in dimer) and three-halves order (1/2 order in dimer) kinetics
for reactions of 9-BBN dimer with fast reacting and slow reacting olefins,
respectively.
17-19
Another study using disiamylborane provides similar kinetic evidence
that dialkylboranes participate in hydroborations via a dissociative pathway.
20

4

H
B
H
B
R
R
R
R
B
H R
R
LB
B H
R
R
LB
THF
BR
2
Scheme 1C: Brown's Dissociation Pathway for Hydroboration
17-20
BR
2
BR
2
1C1
1C2
1C3 1C4
1C5
1C5
H BR
2
1C5

Compared to monoborane (BH
3
), dialkylboranes are much easier reagents with
which to conduct kinetic studies. This is due to the fact that BH
3
reacts with alkenes to
form multiple alkylborane species R
X
BH
(3-X)
, rendering kinetic data unclear. Despite this
setback, Brown initiated Lewis base concentration studies involving dimethylsulfide-
borane (Me
2
S BH
3;
BMS) and triethylamine-borane (Et
3
N BH
3
).
21
A qualitative rate
reduction was observed upon increasing the concentration of excess Me
2
S and Et
3
N in
the reactions of their corresponding borane complex with 1-octene. This led Brown to
propose a dissociative mechanism for BH
3
, as

a rate reduction under such conditions
would not be expected if an associative mechanism were in effect.
Pasto has published an alternative associative hydroboration mechanism,
proposing that THF remains complexed to boron while an olefin complexes to the boron
atom of THF BH
3
1D1

and undergoes hydroboration (Scheme 1D).
22, 23
This mechanism
is supported by kinetic studies conducted with 2-methyl-2-butene and 1D1. In addition to
the observation of second order kinetics, first order in both olefin and borane, Pasto also
reports an entropy value of -27 1 eu.
22
The kinetic data support a mechanistic pathway
in which 1D1 is directly attacked by an olefin and the entropy value indicates that this
attack does not result in the displacement of THF. The mechanism has been supported by
5

several theoretical studies,
24,25
including work by Schleyer, which supports ethylene
complexation to R
2
O BH
3
occurring in a S
N
2-like fashion.
26

Scheme 1D: Pasto's Associative Mechanism for Hydroboration
22,23
O B
H
H
H O B
H
H
H
O B
H
H
H
O B
H
H
1D1 1D2 1D3 1D4


1.4 Defining Oxygen-Directed Hydroboration
In order to discuss oxygen-directed hydroboration (ODHB), one must first
establish what is meant by directed reaction. Whenever the incorporation of an oxygen
atom into a substrate affects the reactivity or selectivity of a transformation, one can
argue that the change is due to some form of oxygen direction. This is regardless of
whether the effect is due to the steric environment of oxygen or to an inductive or
resonance polarization effect the oxygen might impose upon the substrate.
For example, Brown refers to directive effects in the hydroboration of substituted
styrenes in a study reporting the effects of a methoxy group on regioselectivity
(Equation 1).
27
Due to the planar structure of the fully conjugated system that separates
oxygen from the alkene-borane complex in the transition state with five bonds, these

6

results are due to the electronic perturbation placed on the substrate by remote oxygen.
Directive Effects is also the terminology used by Brown to describe the inductive
effects that chloride and tosylate groups have on the regioselectivity of a proximal
terminal alkene (Equation 2).
28

For the purposes of providing a perspective on literature accounts of ODHB in the
following chapter, the definition of a directed reaction to be used will be that of Hoveyda,
Evans, and Fu:
29
Preassociation of the reacting partners either through hydrogen
bonding, covalent, or Lewis acid-base union is followed by the maintenance of this
interaction during the ensuing chemical transformation. This is not to indicate that all
reports of ODHB to be discussed share(d) the same definition, but to establish a point of
reference for the discussion herein.
1.5 Oxygen Directed Hydroboration in the Literature
1.5i Ether Directed Hydroboration
Narutis et al. have recognized contrasting results in hydroboration studies
conducted by Gassman and Brown.
30
Brown has reported that norbornene 1E5 provides
>99:1 exo-selectivity upon hydroboration/oxidation, while increasing steric bulk at C-7
via incorporation of a methyl group syn to the alkene (1E6) leads to 22:78 exo:endo
selectivity (Scheme 1E).
31
However, Gassman has reported that 7,7-dimethoxy-
norbornene 1E1 undergoes hydroboration with THF BH
3
to provide a 78:22 exo/endo
mixture of alcohol 1E2 upon oxidative workup.
32
This selectivity does not correspond
with Browns steric argument. Narutis attributes the contrast of the 7,7-dimethoxy-
norbornene result to the formation of ether-borane complex 1E3 but a proposed
mechanistic pathway is not specified.
30

7


Methyl ethers have also been reported as affecting the regioselectivity of the
hydroboration of E- and Z-methoxy-ene-ynes.
33
Zweifel et al. have reported that treating
Z-methoxy-ene-ynes 1F1 and 1F5 with dicyclohexylborane (chex
2
BH) in THF leads to
preferential delivery of the boron to the alkyne carbon proximal to the methoxy group.
On the other hand, treating the corresponding E-substrates 1F4 and 1F8 under the same
conditions results in an increased preference for boron delivery to the distal alkyne
carbon. The authors rationalize the change in regioselectivities by invoking a transition
state 1F9, which illustrates the Z-methyl ether maintaining an interaction with chex
2
BH
while the B-H bond is added across the carbon-carbon triple bond (Scheme 1F). It should
be noted that the olefin geometry equilibrates to trans under the oxidation conditions,
after the hydroboration events.
8

H
OMe
H
H
OMe
H
Si
MeO
H
H
MeO
H
H
Si
1.chex
2
BH
THF
2. NaOOH
MeO
H
H
O MeO
H
H O
MeO
H
H
O MeO
H
H O
MeO
H
H
Si
O
MeO
H
H
O
Si
MeO
H
H
Si
O
H
MeO
H
R
B
H
96 : 4
65 : 35
56 : 44
1 : 99
R'
R'
Scheme 1F: Anomalous Hydroboration Results on Methoxy Ene-Ynes
1F1 1F2 1F3
1F4 1F2 1F3
1F5 1F6 1F7
MeO
H
H
O
Si
1F6 1F7 1F8
1F9
1.chex
2
BH
THF
2. NaOOH
1.chex
2
BH
THF
2. NaOOH
1.chex
2
BH
THF
2. NaOOH
Results reported by Suzuki serve as evidence against ether complexation to a
hindered dialkylborane in an intramolecular hydroboration. In pursuit of avencolide,
Suzuki observed unexpectedly low anti-Markovnikov regioselectivity upon
hydroboration (THF BH
3
)/oxidation (NaOOH) of a monosubstituted olefin 1G1. The
expected terminal alcohol 1G3 was isolated in 39% yield while the regioisomeric
secondary alcohol 1G4 was isolated in 31% yield. The authors attributed this unusual
result to a six-membered transition state 1G2. Interestingly, using a hindered
dialkylborane (chex)
2
BH exclusively provides the expected terminal alcohol in 86% yield
9

after oxidative workup. The steric bulk of the dialkylborane is believed to be responsible
for making the corresponding 1G2-like complex unfavorable, thus providing the
regioselectivity one would expect from intermolecular hydroboration. Jung et al. have
also discussed the possibility of benzyl ether-directed hydroboration with 5-benzyloxy-2-
heptene 1G5, which provides a 65:35 regioselectivity in favor of the 3,5-disubstituted
product 1G6 upon hydroboration with THF BH
3
followed by oxidative workup (Equation
3). ODHB was dismissed because no diastereoselectivity was observed.
34





OBn
OBn OBn OH
OH
THFBH
3
NaOOH
(3)
65 : 35
1G5 1G6 1G7





10

1.5ii Acetate Directed Hydroboration
There is one example of acetate-directed hydroboration proposed in the literature.
In the pursuit of epiallogibberic acid, House and Melillo treated the tetracyclic acetoxy
olefin 1H1 with disiamylborane, generating cis-diol 1H3 after oxidative workup.
35
The
authors propose that the disiamylborane is solvated by the acetoxy group of the

substrate, which provides the diastereo- and regioselectivity (Scheme 1H). Jung et. al
have reported that hydroboration of 5-acetoxy-2-heptene 1H4 provides 3,5-diol 1H5 with
75:25 regioselectivity after oxidative workup (Equation 4), but ODHB was dismissed in
their report because no diastereoselectivity was observed.
34

OAc
OH OH OH
OH
THFBH
3
NaOOH
(4)
75 : 25
1H4 1H5 1H6



1.5iii Alcohol Directed Hydroboration
Several diastereoselective hydroboration results have been attributed to alcohol
direction. Results reported by Bryson in the pursuit of helenalin are the most intriguing.
36

Unsaturated alcohol 1I1 was treated with either THF BH
3
or thexylborane (ThxBH
2
),
generating respective 1:7 and 1:11 ratios of diastereomeric diols 1I3 and 1I4. On the
other hand, treating unsaturated iodide 1I5 with THF BH
3
generates a 4:1 ratio of
11

diastereomers 1I6 and 1I7. This reversal of diastereoselectivity was attributed to an
intermediate monoalkoxyborane that reacts via the bridged bicyclic transition state 1I2.
The proposal of an intramolecular hydroboration via a thexylalkoxyborane is supported
by the work of Cha et al., who have reported that such species are viable reagents for
intermolecular hydroboration, even of substrates even as hindered as 2,4,4-trimethyl-2-
pentene (Scheme 1I).
37


Ohloff et al. have reported an outstanding level of diastereoselectivity achieved by
the hydroboration of isopulegol 1J1 (Scheme 1J).
38
The authors attribute a 19:1 ratio of
1,4-diols 1J3 and 1J4 to an intramolecular transition state 1J2 involving a
dialkoxyborane intermediate. However, the dialkoxyborane intermediate was not
observed and the authors did not comment on the low reactivity of the known
dialkoxyboranes 1J5 and 1J6. They did show that the same product ratio was obtained
12

starting from the corresponding isopulegyl borate [(RO)
3
B] and diborane, evidence that a
disproportionation product is the species responsible for hydroboration.

A variant of the dialkoxyborane species invoked by Ohloff for intramolecular
hydroboration was also proposed by Panek et al. in an unconventional approach to
ODHB.
39
They reported a unique result involving diastereoselective hydroboration of
o-methoxy-|,-unsaturated esters with dimethylsulfide borane (BMS). The
hydroboration is accompanied by reduction of the ester functionality. Low temperature
studies revealed that ester reduction uncharacteristically precedes hydroboration, which
the authors attribute to an activating effect of the o-alkoxy group.
40
It was proposed that
the dialkoxyborane 1K2, generated from ester reduction, is the species that undergoes
subsequent intramolecular hydroboration to provide diastereoselectivity opposite to that
predicted by the Kishi model for intermolecular hydroboration.
41
Treating the alcohol
analog of 1K1 (1K4) with BMS resulted in neither regio- nor diastereoselectivity. Thus,
the entire o-alkoxy-homoallylic ester is apparently the requisite moiety for achieving
selectivity even though the hydroboration itself is proposed to be alkoxy-directed.
In pursuit of (+)-mikrolin 1L3, Smith et al. demonstrated that diastereoselective
hydroxyl-influenced hydroboration is not a consistent phenomenon. In an attempt to
13

synthesize diol 1L2, the homoallylic alcohol 1L1 was treated with an unspecified
hydroborating agent, but 1L2 was not formed (Scheme 1J).
42
This demonstrates that the
results reported by Bryson and Ohloff do not represent a general trend. Jung et al. points
out that an alcohol group influences the hydroboration of acyclic 5-hydroxy-2-heptene
1L4, which provides 3,5-diol 1L5 with 73:27 regioselectivity. However, no
diastereoselectivity was observed, which is consistent with Jungs ether and acetoxy
results in Equations 3 and 4, so ODHB was dismissed as before.
34


OH
OH OH OH
OH
THFBH
3
NaOOH
(5)
73 : 27
1L4 1L5 1L6


14

1.6 Discussion
Theoretically, ODHB can be broken down into three simple processes: 1) a Lewis
acid-base interaction forms an oxygen-borane complex 1M2, 2) an olefin tethered to the
boron-complexed oxygen forms a tcomplex to the borane 1M3, and 3) a B-H bond
adds to the C=C bond. There are multiple reactions with which it remains unclear how
an oxygen can affect the regio- and/or stereocontrol of the transformation without an
interaction with borane (Scheme 1M).

There are two important issues to consider in order to relate section 1.5 to Scheme
1M: 1) how feasible is the formations of each proposed borane species? and 2) how
viable an agent is each intermediate for its corresponding transformation to the next
stage? For each case, these issues revolve around the directing group in question and
how it relates to the mechanistic proposals of Brown and Pasto.

1.6i Intramolecular Hydroboration with Alkoxyboranes
Mechanistically, the proposed transitions states of Bryson (1I2) and and Ohloff
(1J2) are distinct from other oxygen-directed hydroborations. Each alcohol has reacted
with borane to generate an alkoxyborane that resembles Paneks transition state structure
1K2. Boranes are well known for reacting with alcohols to form alkoxyboranes, as
illustrated by the Cha results (Scheme 1L), so the formation of alkoxyboranes is not
controversial.
37
The important question in this context is whether the resulting species
15

have sufficient reactivity for intramolecular hydroboration, despite the covalent
interaction between boron and oxygen in these structures. Since a Lewis base-borane
complex is no longer the proposed hydroborating species, the mechanistic proposals of
Brown and Pasto no longer apply and there is no problem regarding transition state
bonding. On the other hand, the issue of boron electrophilicity and reactivity remains
critical.
Brysons proposed intramolecular reaction of a monoalkoxy-alkylborane 1I2 is
the most convincing example of an oxygen-directed internal hydroboration. One would
expect the intermediate monoalkoxyborane to have reactivity between that of BH
3
and a
dialkoxyborane, and Chas demonstration that alkenes are hydroborated by
thexylalkoxyboranes provides evidence that one alkoxy group does not reduce the
electrophilicity of boron sufficiently to prevent hydroboration.
37
Therefore, Brysons
proposal that an oxygen-directed hydroboration occurs with thexylborane is consistent
with the literature precedent.
Another study by Cha et al. investigated the reactivity of thexylalkoxyboranes
1I10 with simple alcohols.
43
Hydrogen evolution studies demonstrated that a
stoichiometric amount of various alcohols does not react quantitatively, and that
conversion correlates to the steric bulk of the alcohol used. While they state, it is best to
defer for the present consideration of the reason why the hydrogen evolution stops
beneath the stoichiometric point, there appears to be something unique involved with the
incorporation of the thexyl group on boron, considering that it is well known that treating
boranes with alcohols easily forms borates,
44
boronates,
45
and borinates.
46
If the thexyl
group is the key to forming monoalkoxyborane species, Chas work suggests that
16

diastereoselective reaction using THF BH
3
may reflect additional unknown factors that
influence the product ratio. However, this does not rule out participation by an
alkoxyborane 1I2 (R=H).
The case for internal hydroboration via dialkoxyboranes is less strong. As already
mentioned in connection with Scheme 1J, pinacolborane 1J5 and catecholborane 1J6, are
relatively unreactive, respectively requiring heating to 40 C and 80 C in order to
hydroborate olefins without metal catalysis.
47,48
This is due to two covalently bound
oxygens that donate electron density to the empty p-orbital of boron, rendering it pseudo-
tetravalent and less electrophilic. The behavior of 1J5 and 1J6 raises questions about the
feasibility of an intramolecular hydroboration via dialkoxyborane.
A plausible argument that one might be tempted to make in defense of a room
temperature intramolecular hydroboration with a dialkoxyborane is that the
intramolecular nature of the transformation could provide enough of an entropic
advantage to overcome the diminished electrophilicity of the dialkoxyborane. However,
if this were the governing principle behind such results, ODHB would be a more
common occurrence in the literature. If the entropic advantage of intramolecularity is
large enough, then the mono- and/or dialkoxyboranes generated upon treating unsaturated
alcohols such as Paneks 1K4 with BMS would result in regioselective hydroboration.
No such selectivity was observed (Scheme 1K). Additionally, work by Heathcock
indicates that not only is selectivity not achieved upon treating an unsaturated alcohol
with an equivalent of borane, but no reaction is even observed.
49
Evidently, other
unknown factors also play a role, culminating in results that are highly substrate
dependant.
17

1.6ii Ether and Acetoxy Direction
Ether/acetoxy directed hydroboration is a more difficult phenomenon to account
for compared with alkoxy direction. Compared with alkoxyboranes, ether-borane
complexes (1M2, R=alkyl) are more transient species in oxygenated solvents due to the
facile equilibrium with the solvent-borane complex. This disadvantage for an ensuing
intramolecular process is supplemented by the fact that there is no clear rationalization
that explains how an unsaturated ether-borane 1M2 can both 1) remain intact and 2) react
with alkene to provide selectivity in the product mixture 1M4. Despite this lack of
understanding, ODHB remains a tempting explanation for the results of Gassman,
Zweifel, and Suzuki, due to the absence of obvious controlling steric and/or electronic
factors.
Ether-borane complexes are well precedented species so there is no doubt that an
ether-containing substrate could form a complex to BH
3
. According to calculations
published by Rauk et al., dimethylether has a greater affinity than methyl acetate for
boron trifluoride (BF
3
) (71 kJ/mol vs. 58 kJ/mol).
50
This suggests that an acetoxy group
would form a weaker complex to borane than would an acyclic ether. The same study
reports an 82 kJ/mol affinity between THF and BF
3
. These affinity values raise a
question that challenges the proposals of Narutis, Zweifel, Suzuki, and House: how can
the complexes 1E3, 1F9, 1G2, and (the precursor to) 1H2 form when THF or diglyme is
being used as the reaction solvent?
The Brown or Pasto mechanisms are not consistent with an ensuing ODHB once
the ether-borane complex 1M2 is formed. Browns dissociative mechanism (Scheme 1C)
can account for the formation of t-complex 1M3, but not for any selectivity observed in
18

the subsequent hydroboration, as oxygen does not interact with boron in the transition
state. Pastos associative mechanism (Scheme 1D) cannot be applied because it is
constrained by the geometric requirements imposed upon intramolecular S
N
2-like
transformations, as reported by Beak
51
and Baldwin (Scheme 1N).
52

O
Me
R
B H
H
H
O B
H
H
H
Me
'5.5'-Endo-Tet
disfavored
R
O
Me
R
BH
2
O B
H
H
H
Me
Scheme 1N: Intramolecular variant of Pasto's Mechanism Conflicts with Geometric Restrictions
1N1 1N2 1N3 1N4

The reports by Zweifel (Scheme 1F) and Suzuki (Scheme 1G) include particularly
intriguing proposals of ODHB and steric effects cannot account for the surprising
regioselectivities. However, oxygen has been proposed to influence the selectivity of
hydroboration with a variety of effects, and alternative explanations are worth evaluating,
since ODHB has proven so difficult to rationalize in the context of ether-direction.
Inductive effects have been investigated in depth by Brown with acyclic allyl,
homoallyl, and crotyl derivatives (Table 1O).
28,53,54
Alcohols, ethers, chorides, triflates,
and trifluormethyl groups clearly reduce the anti-Markovnikov regioselectivity achieved
with propene, and increase delivery of borane to C-2 in the crotyl environment (R
1
=
CH
3
). The same substituents also work against the normal anti-Markovnikov
regioselectivity of the allylic examples (terminal alkene, R
1
= H). The extent of the effect
is related to the electron withdrawing capability of the X group, as the trifluoromethyl
group (o
m
= 0.46) effects selectivity more than chloride (o
m
= 0.37). In both the crotyl
and allyl systems, the allylic heteroatom promotes hydroboration at the nearest alkene
carbon relative to the all-carbon analogies. A similar trend is also reported with
substituted styrenes.
27
The same trends in the context of 3- and 4- methoxy-cyclohexanes
19

R
1
X R
1
X R
1
X
OH
OH
BH
3
THF
NaOOH
1O1 1O2 1O3
Table 1O:Inductive Effects of Allylic, Crotylic, and Homoallylic Groups on Hydroboration Regioselectivity

Entry R
1
X 1O2 : 1O3 Entry R
1
X 1O2 : 1O3
1 CH
3
CH
3
50 : 50 8 CH
3
OPh 86 : 14
2 H CH
3
6 : 94 9 H OPh 14 :86
3 H CH
2
CH
3
7 : 93 10 H CH
2
OPh 13 : 87
4 CH
3
OH 90 : 10 11 CH
3
Cl 100 : 1
5 H OH 22 : 72 12 H Cl 40 : 60
6 H CH
2
OH 14 : 86 13 H CH
2
Cl 18 : 81
7 H OTf 45 : 55 14 H CF
3
74 : 26

are shown in Table 1P, accompanied by anti-diastereoselectivity, which indicates no
complexation between borane and the heteroatom substituted styrenes.
27
The same trends
in the context of 3- and 4- methoxy-cyclohexanes are shown in Table 1P, accompanied
by anti-diastereoselectivity, which indicates no complexation between borane and the
heteroatom.
R
3
R
2
R
2
R
3
OH
R
2
R
3
OH
1P1 1P2 1P3
BH
3
THF
NaOOH
R
1
R
1
R
1
Table 1P: Allic vs. Homoallyic Effects in Cyclohexene Systems

Entry R1 R2 R3 1P2 : 1P3 trans- : cis- (1P2)
1
55
H H Cl 96 : 4 89 : 11
2
55
H H OMe 91 : 9 89 : 11
3
56
-C(O)N(Me)OMe H OMe 95 : 5 95 : 5
4
57
-CH2SO2Ph H OMe 88 : 12 99 : 1
5
55
H OMe H 56 : 44 61 : 39

Steric interactions provide negligible hindrance to the hydroboration directing
effect of allylic electron-withdrawing groups. Brown has reported that crotyl alcohols,
ethers, and chlorides direct boron delivery to the proximal alkene carbon with
20

dialkylborane reagents disiamylborane and 9BBN (Table 1Q, entries 1-5).
58
Gung et al.
have shown that the added bulk at the carbinol carbon of 1-tBu-crotyl alcohol does
nothing to prevent boron incorporation of either BH
3
or thexylborane at the proximal
carbon with complete regioselection (Table 1Q, entries 6&7).
59
Gung invokes transition
state 1Q4 to propose that hyperconjugation contributes to the excellent regioselectivity
reported, and this is consistent with the data. However, the consistent trend in allylic
examples is that regioselectivity is directly related to the electron withdrawing capability
of the substituent, which polarizes the double bond such that it resists steric preferences.
The same effect is seen in the homoallylic examples, although it is smaller. Cyclic
carbamates are also capable of inductively influencing hydroboration, according to a
report by Sibi, in which the regioselectivity is attributed to the electron withdrawing
capability of the allylic nitrogen (Equation 6).
60
There could also be a small contribution
from the homoallylic oxygen in Sibis system.







21

Me X Me X Me X
OH
OH
1.R
2
BH
2. NaOOH
1Q1 1Q2 1Q3
R
1
R
1
Table 1Q: Hydroboration of Allylic Derivatives vs. Reagent Steric Demand
R
1
OH
t-Bu
H
B H
R
R
o
o
1Q4

Entry X R
1
HB Reagent 1Q2 : 1Q3
1
58
OH H Sia
2
BH 87 : 13
2
58
OH H 9BBN 100 : 0
3
58
OMe H 9BBN 92 : 8
4
58
Cl H Sia
2
BH 100 : 0
5
58
Cl H 9BBN 100 : 0
6
59
OH tBu BH
3
100 : 0
7
59
OH tBu ThxBH
2
100 : 0

THFBH
3
NaOOH
1R6 X=Boc 20:1 regioselectivity, 16:1 anti-: syn-
1R7 X= H 15:1 regioselectivity, 3.4:1 anti-: syn-
C
14
H
29
NX O
O
1R4 X= H
1R5 X= Boc
C
14
H
29
NX O
O
OH
C
14
H
29
NX O
O
OH
(6)

Inductive effects are evident in acyclic substrates (Tables 1O & 1Q; Equation 3),
and cyclic systems (Table 1P), indicating that the conformational mobility is not crucial
for regioselective hydroboration. Keese et al. provide reinforcing evidence in a report on
the hydroboration of 1-substituted norborn-2-enes (Table 1S).
61
In this conformationally
locked system, allylic electron withdrawing groups, including methoxy (entry 5),
maintain a significant effect on hydroboration regioselectivity, and the authors point out
that these results indicate that conformational mobility does not play a dominant role in
achieving regioselectivity.


22


Entry X 1R2 : 1R3
1 Cl 74 : 26
2 Br 68 : 32
3 I 65 : 35
4 CH
3
52 : 48
5 OMe 75 : 25
6 CH
2
OMe 54 : 46

Taking these reports into consideration, the Zweifel results remain fascinating
because two similar enyne substrates provide such contrasting results (Scheme 1F).
Inductive effect arguments do not apply because there is no difference in oxygen-olefin
tether length. Switching enol ether geometry could perturb the resonance interaction
between alkyne and methoxy, but one would expect effective electron donation from the
methoxy group in both geometries due to the planar, unhindered nature of the molecules.
Through-space oxygen-olefin orbital interactions have been invoked as a rationalization
for stereoselectivity of hydroboration,
34,62
but no report has been found in which it has
been invoked to explain regioselectivity. Browns work with ortho-methoxy-styrene
provides indirect evidence that a through space effect does not account for Zweifels
regioselectivity, because the o-methoxy group leads to increased delivery of boron to the
distal carbon in a Z-methoxy-ene system (Equation 7). This is attributed to the
resonance electron donating effect of oxygen.
23

X
THF BH
3
NaOOH
X X OH
OH
X=H 18 : 82
X=OMe 12 : 88
(7)

Inductive effects must contribute to the reduced anti-Markovnikov selectivity
reported by Suzuki with terminal alkene G1. Allylic and homoallylic electron
withdrawing functionalities consistently provide a preference for delivery of boron to the
proximal alkene carbon. While the influence of a homoallylic substituent is weaker, it can
still be significant. Table 1O, entry 14 shows that three homoallylic fluorines cause a
reversal in selectivity from 1:19 to 3:1 relative to 3 hydrogen atoms. Approximation
using the Boltzmann equation indicates that this is a ca. 2.4 kcal/mol perturbation in AG

,
meaning that each fluorine contributes a noteworthy ~0.8 kcal/mol. Homoallylic ethers
have been shown to influence regioselectivity by ca. 0.1-0.4 kcal/mol (Equation 3; Table
1O, entry 10; Table 1P, entry 5; Table 1S, entry 6) and bishomoallylic ethers, such as the
one in of G1, can also be expected to provide an influence. A Serratosa report also
indicates that a homoallylic acetonide, analogous to the one incorporated into G1,
provides an inductive effect (Equation 8),
63
which correlates with Jungs homoallylic
ether results (Equation 3). If excess borane is used, one could argue complexation of the
alkoxy groups may lead to greater inductive effects, but this cannot be corroborated by
the experimental details provided. Furthermore, complexation would be reversible, so at
least some of the uncomplexed alkoxy substrate would be present and react faster.
Regardless of these details, questions remain regarding the role of inductive effects, and
whether they alone can account for the reported product mixture.
24

R
R
R
R
HO
THFBH
3
NaOOH
1 : 1 R=R
1
=H
2 : 1 R,R
1
= -OCH
2
C(Me)CH
2
O-
R
1
R
HO
(8)

Whatever the phenomena responsible for ether direction, they are not well
understood and are most likely unique in each case. Through-space orbital interactions
cannot be ruled out completely, but their effect(s) on regioselectivity is as poorly
established as that of OHDB. Thus, there is no conspicuous conclusive evidence to
oppose the ODHB proposals of Zweifel and Suzuki, despite the fact that the mechanistic
pathway(s) remain a mystery. On the other hand, inductive effects cannot be dismissed
as a contributing factor, Zweifels methoxy-ene-ynes not-withstanding.

1.7 Summary of Uncatalyzed Oxygen-directed Hydroboration
Oxygen-directed hydroboration (ODHB) has been a casually invoked concept in
synthetic organic chemistry literature for rationalizing a variety of anomalous regio- and
stereochemical results. The reality is that, beyond some intriguing empirical indications,
there is underwhelming evidence to support a conclusion that ODHB has ever occurred in
any general sense. This does not eliminate the possibility that ODHB is, in fact,
responsible for some of the results presented, nor can it be said that the mechanistic
proposals of either Brown or Pasto provide conclusive insight into how such
transformations transpire.



25

1.8 Metal-Catalyzed Oxygen-Directed Hydroboration
Transition metal-catalyzed hydroboration is a relatively recent development in
hydroboration methodology that provides a mechanistically more straightforward
approach to achieving a directed hydroboration. The inability of the Brown and Pasto
mechanisms to account for oxygen-borane complexes undergoing intramolecular
hydroboration is not a concern in the context of metal catalysis. Transition metals can
insert into the B-H bonds of relatively unreactive dialkoxyboranes such as pinacolborane
and catecholborane.
64,65
An olefin can then complex to the metal rather than to boron.
The metal-hydride bond is added across the olefin, followed by reductive elimination to
form the C-B bond, thus achieving a net hydroboration (Scheme 1O). Several studies
have taken advantage of an oxygen atom tethered to the olefin in order to direct the M-H
addition across the olefin by complexing to the metal (Scheme 1T).



26

1.8i Transition Metal Catalysis of Directed Hydroboration
In 1988, Evans specifically targeted alcohol-directed hydroboration in the context
of transition metal catalysis.
66
While rhodium(I) successfully promotes the
hydroboration of olefins by catecholborane, alcohols are not viable substrates under such
conditions because they form borates with catecholborane, precluding the desired
transformation. A net hydroxyl-directed
67
variant was pursued in which the hydroxyl
groups were protected as diphenylphosphites and submitted to the reaction conditions,
resulting in excellent diastereoselectivity. The phosphites were cleaved upon oxidative
workup to generate diol products, which were assayed after acylation (Scheme 1U). The
major limitation of this work was that it required stoichiometric amounts of Wilkinsons
catalyst.


Evans et al. improved upon these results several years later by introducing the
first catalytic directed hydroboration using secondary amides as directing groups under
conditions requiring only 5 mol % of iridium catalyst.
67
Good diastereoselectivity (91:9)
was achieved on cyclic systems and excellent regioselectivity (99:1) was achieved on
homoallylic amides (Scheme 1V).

27




Fu developed a method in which catalytic rhodium is viable for benzyl ether-directed
hydroboration of a cyclic olefin. The key to this work is the exploitation of ring slippage
in the indenyl ligands on rhodium.
68
Ring slippage is a phenomenon observed with
cyclopentadienyl-type ligands in which there is interconversion between q
5
- and q
3
-
complexation to a metal. This conversion to q
3
-complexation creates an additional
coordination site on (Ind)Rh(C
2
H
4
)
2
, allowing the coordination of both benzyl ether and
olefin components of 4-benzyloxy-1-cyclohexene 1W1 to rhodium. Hydroboration
ensues and oxidative workup provides a mixture of 1W2 and 1W3 isomers, as illustrated
in Table 1W. A solvent study demonstrated that a less coordinating solvent improves
diastereoselectivity, as hexane and CH
2
Cl
2
provide respective diastereoselectivities of
82:18 and 79:21 (Entries 1 & 2) while THF provides only 62:38 diastereoselectivity
(Entry 3). The >10:1 ratios of cis-1,3- : cis-1,4-monoprotected diols in both hexane and
CH
2
Cl
2
are indicative of an ether-directed reaction. A screen of several cyclopentadienyl
28

ligands was also reported. Based on the idea that selectivity is directly proportional to a
ligands propensity for ring slippage, entries 4-7 illustrate that the indenyl ligand has the
best combination of q
5
- vs q
3
- binding and compatibility with other variables.

Entry Cp
X
(mol %) Solvent cis-1R2 cis-1R3 trans-1R2 trans-1R3
1 Indenyl (10) hexane 75 7 7 11
2 Indenyl (10) CH
2
Cl
2
74 5 8 13
3 Indenyl (10) THF 47 15 23 15
4 Indenyl (2.5) 75 7 8 11
5 1,2,3-Me
3
-indenyl (2.5) 65 10 12 13
6 Cp (2.5) 30 28 30 12
7 Cp* (2.5) 26 29 33 12

Recognizing that three electron donating methyl groups in the indenyl ligand
caused a decrease in selectivity in Fus work, Sowa Jr. et al. pursued increased selectivity
by investigating indenyl ligands incorporating electron withdrawing groups.
69
Entries
1-4 of Table 1X illustrate that both diastereo- and regioselectivity (of cis-isomers) are
improved upon using 1-trifluormethylindenyl, 2-trifluormethylindenyl, or
1,3-(bis)trifluoromethylindenyl ligands on rhodium. Corresponding iridium catalysts
were also screened with the same ligands, demonstrating superior selectivities. The best
selectivity was achieved using the most electron deficient indenyl ligand on Ir(COD)
(Entry 8). Coupled with the reports by the Evans group, these results show that iridium is
superior to rhodium in terms of reactivity and selectivity.
29


Entry M Cp
X
(mol %) cis-1R2 cis-1R3 trans-1R2 trans-1R3
1 Rh Indenyl 74 11 9 6
2 Rh 1-CF
3
-Indenyl 81 6 10 4
3 Rh 2-CF
3
-Indenyl 81 6 9 4
4 Rh 1,3-(CF
3
)
2
-Indenyl 84 3 8 5
5 Ir Indenyl 93 <1 5 2
6 Ir 1-CF
3
-Indenyl 96 <1 2 2
7 Ir 2-CF
3
-Indenyl 96 2 2 <1
8 Ir 1,3-(CF
3
)
2
-Indenyl 98 2 <1 <1

A report by Gevorgyan et al. adds esters to the list of oxygen-containing
functionalities that direct transition metal-catalyzed hydroboration, which already
includes phosphites, amides, and ethers. Using pinacolborane 1J5 and [Rh(COD)Cl]
2
,

>99:1 cis diastereoselectivity was achieved with 3,3-disubstituted cyclopropenes.
70

Adding (R)-BINAP to the reaction mixture provided excellent enantioselectivity (Table
1Y) .




Entry R R
1
cis/trans ee (%) abs. config Yield (%)
1 Me Me >99 : 1 94 1S,2R 94
2 Et TMS >99 : 1 97 1R,2R 99
3 Me Ph >99 : 1 92 1S, 2R 99

30

1.8ii Lanthanide Catalysis in Alcohol-Directed Hydroboration
The previous section has illustrated that a variety of oxygen-containing groups
can direct transition metal-catalyzed hydroboration. However, the only report in the
literature in which conditions compatible with free hydroxyl groups are reported requires
the use of a lanthanide. Evans et al. reported that samarium triiodide (SmI
3
) can catalyze
the hydroboration of olefins by catecholborane and this methodology was applied to a
homoallylic alcohol to test whether or not oxygen direction could be achieved.
71
This
method generated 1,3-pentane-diol with 11:1 regioselectivity from 3-penten-1-ol after
oxidative workup (Scheme 1Z) but the mechanism remains unclear. The authors
acknowledge that ODHB is not confirmed by this result and, as an alternative to the
mechanism one depicted in scheme 1T, they present activated catecholborane 1Z4 as a
potentially relevant species in the hydroboration event(s). No other substrates were
investigated.





31

1.8iii Copper Catalyzed Hydroboration
Hoveyda has reported interesting results with copper-catalyzed hydroboration of
oxygenated alkenes using N-heterocyclic carbene (NHC) complexes.
72
Using copper
complex 1AA2, delivery of pinacolatoboron to the |-carbon of a variety of oxygenated
styrenic olefins is achieved with >98:<2 regioselectivity (Table V). Using the chiral
NHC 1AA3 provides identical regioselectivity with enantioselectivities as high as 96%
ee. Applying this methodology to non-oxygenated substrates provides identical
regioselectivity, as do other metal-catalyzed hydroborations of styrenes.
73
Therefore,
these transformations need not be oxygen-directed and the authors do not propose that
they are. However, the compatibility with the alcohol substituent makes them unique
(entries 4 & 7) in that they might succeed where rhodium has failed
66
in providing a
method for directed hydroboration of aliphatic unsaturated alcohols


Entry Catalyst R
1
R
2
X Solvent Regioselectivity Yield (%) ee (%)
1 1AA2 H CO
2
Me Na THF >98 : <2 76 -
2 1AA2 H OAc Na THF >98 : <2 82 -
3 1AA2 Me Me Na THF >98 : <2 96 -
4 1AA2 H H Na toluene >98 : <2 80 -
5 1AA3 H Me K THF >98 : <2 75 96-R
6 1AA3 Me Me K THF >98 : <2 51 89-R
7 1AA3 H H K THF >98 : <2 74 96-R


32

1.9 Oxygen-Directed Hydroboration: A Mechanistic Enigma
Several examples of transition metal-catalyzed hydroboration have been presented
above. The mechanisms of these reactions are easily understood compared to the
mechanism(s) of the proposed uncatalyzed ODHB reactions discussed in sections 1.3-1.5.
On the other hand, while the net result of these catalyzed reactions is indeed
hydroboration, the directed aspect of the reaction is the hydrometalation step. Therefore,
it remains debatable whether or not any oxygen-directed hydroboration is well
understood.






























33

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50. Rauk, A.; Hunt, I. R.; Keay, B. A. Lewis Acidity and Basicity: An Ab Initio Study
of Proton and BF
3
Affinities of Oxygen-Containing Organic Compounds. J. Org.
Chem. 1994, 59, 6808.
51. Beak, P. Determinations of Transition-State Geometries by the Endocyclic
Restriction Test: Mechanisms of Substitution at Nonstereogenic Atoms. Acc.
Chem. Res. 1992, 25, 215.
52. Baldwin, J. E. Rules for Ring-Closure. J. Chem. Soc., Chem. Commun. 1976,
(18), 734-736.
53. Brown, H. C.; Unni, M. K. Hydroboration. 25. Hydroboration of 3-Butenyl
Derivatives Containing Representative Substituents. J. Am. Chem. Soc. 1968, 90,
2902.
54. Brown, H. C.; Gallivan, R. M. Hydroboration. 26. Hydroboration of 2-Butenyl
(Crotyl) and Related Derivatives Containing Representative Substituents.
Control of Elimination Reaction of |-Substituted Organoboranes. J. Am. Chem.
Soc. 1968, 90, 2906.
55. Pasto, D. J.; Hickman, J. Transfer Reactions Involving Boron. 16. The
Hydroboration of 3- and 4-Heterosubstituted Cyclohexenes. J. Am. Chem. Soc.
1968, 90, 4445.
56. Kocienski, P.; Stocks, M.; Donald, D.; Perry, M. A Synthesis of the C24-C34
Segment of FK 506. Synlett 1990, (1), 38.
57. Linde, R. G.; Egbertson, M.; Coleman, R. S.; Jones, A. B.; Danishefsky, S. J.
Efficient Preparation of Intermediates Corresponding to C22-C27 and C28-C34
of FK-506. J. Org. Chem. 1990, 55, 2771.
58. Brown, H. C.; Chen, J. C. Hydroboration. 57. Hydroboration with 9-
Borabicyclo[3.3.1]nonane of Alkenes Containing Representative Functional
Groups. J. Org. Chem. 1981, 46, 3978.
59. Gung, B. W.; Ohm, K. W.; Smith, D. T. Regiofacial and Diastereofacial selective
Hydroboration of Chiral Allylic Stannanes, Silanes, and Germanes. Synth.
Commun. 1994, 24, 167.
38

60. Sibi, M. P.; Li, B. Q. Regioselective and Stereoselective Hydroborations of Chiral
Allyl Amines- Synthesis of Amino Alcohols Tetrahedron Lett. 1992, 33, 4115.
61. Luef, W.; Vogeli, U. C.; Keese, R. Hydroboration and Oxymercuration of Some
1-Substitued Norborn-2-enes. Helv. Chim. Acta 1983, 66, 2729.
62. Houk, K. N.; Rondan, N. G.; Wu, Y. D.; Metz, J. T.; Paddon-Row, M. N.
Theoretical Studies of Stereoselective Hydroborations. Tetrahedron 1984, 40,
2257.
63. Carceller, E.; Castello, A.; Garcia, M. L.; Moyano, A.; Serratosa, F.
Regioselective Functionalization of Cis-Bicyclo[3.3.0]octenone Derivatives.
Oxymercuration/Reduction versus Hydroboration/Oxidation. Acetal Groups as
Regioselective and Stereoselective Control Elements. Chem. Lett. 1984, (5), 775.
64. Kono, H.; Ito, K.; Nagai, Y. Oxidative Addition of 4,4,6-Trimethyl-1,3,2-
dioxaborinane and Benzo[1,3,2]dioxaborole to
Tris(triphenylphosphine)halogenorhodium. Chem. Lett. 1975, (10), 1095.
65. Crudden, C. M.; Hleba, Y. B.; Chen, A. C. Regio- and Enantiocontrol in the
Room-temperature Hydroboration of Vinyl Arenes with Pinacol Borane. J. Am.
Chem. Soc. 2004, 126, 9200.
66. Evans, D. A.; Fu, G. C.; Hoveyda, A. H. Rhodium(I)-Catalyzed Hydroboration of
Olefins- The Documentation of Regiochemical and Stereochemical Control in
Cyclic and Acyclic Systems. J. Am. Chem. Soc. 1988, 110, 6917.
67. Evans, D. A.; Fu, G. C.; Hoveyda, A. H. Rhodium(I)-Catalyzed and Iridium(I)-
Catalyzed Hydroboration Reactions - Scope and Synthetic Applications. J. Am.
Chem. Soc. 1992, 114, 6671.
68. Garrett, C. E.; Fu, G. C. Exploiting q(5)- to q(3)-indenyl ring slippage to access a
directed reaction: Ether-directed, rhodium-catalyzed olefin hydroboration. J.
Org. Chem. 1998, 63, 1370.
69. Brinkman, J. A.; Nguyen, T. T.; Sowa, J. R. Trifluoromethyl-substituted indenyl
rhodium and iridium complexes are highly selective catalysts for directed
hydroboration reactions. Org. Lett. 2000, 2, 981-983.
70. Rubina, M.; Rubin, M.; Gevorgyan, V. Catalytic enantioselective hydroboration
of cyclopropenes. J. Am. Chem. Soc. 2003, 125, 7198.
71. Evans, D. A.; Muci, A. R.; Sturmer, R. Samarium(III)-Catalyzed Hydroboration
of Olefins with Catecholborane- A General Approach to the Synthesis of Boronate
Esters. J. Org. Chem. 1993, 58, 5307.
39

72. Lee, Y. M.; Hoveyda, A. H. Efficient Boron-Copper Additions to Aryl-Substituted
Alkenes Promoted by NHC-Based Catalysts. Enantioselective Cu-Catalyzed
Hydroboration Reactions. J. Am. Chem. Soc. 2009, 131, 3160.
73. Burgess, K.; Ohlmeyer, M. J. Transition-Metal Promoted Hydroborations of
Alkenes, Emerging Methodology for Organic Transformations. Chem. Rev. 1991,
91, 1179.





















40

Chapter 2: Metal-Free Oxygen-Directed Hydroboration
2.1 A New Approach to Heteroatom-Directed Hydroboration
Despite repeated efforts over many years and several tantalizing empirical results
that suggest oxygen-directed hydroboration (ODHB), definitive examples of this process
remain elusive.
1-13
Evans metal catalyzed reactions of catecholborane with several
unsaturated alcohols, phosphinites, and carboxamides are the only methods known to
date with established synthetic potential for a range of substrates.
2-5
Another case of
ODHB involving an o-methoxy-|,-unsaturated ester was encountered by Panek et al.
6,13

using Me
2
S BH
3
(BMS). This example approaches the regioselectivity of the Evans result
with a homoallylic alcohol (8:1 vs. 11:1), but appears to be a special case reflecting
unusual reactivity due to the combined presence of an ester and an alkoxy group in the
starting material. The other historical examples reveal interesting perturbations of
hydroboration stereoselectivity or regioselectivity by oxygen substituents,
7-12
but these
reactions generally do not give useful product ratios. The purpose of the work described
in this chapter is to demonstrate a mechanistically distinct version of ODHB using metal-
free conditions that provide regiocontrol in the hydroboration of generic homoallylic
alcohols.
The dissociative mechanism of hydroboration presented by Brown and widely
accepted by the chemical community suggests that heteroatom-directed hydroboration is
not possible, in that it requires a trivalent borane species to form via dissociation from a
Lewis base complex before it can react with an olefin (Scheme 2A).
14-19
On the other
hand, Pasto has reported an associative mechanism that involves an olefin complexing to
a borane and undergoing hydroboration while the borane maintains an interaction with a
41

Lewis base (Scheme 2B).
20,21
This lesser-known mechanistic proposal has received
support in the literature
22-24
and is one source of inspiration for the pursuit of
intramolecular hydroboration via activation of heteroatom-borane complexes.

Another source of inspiration is a study by Schleyer et al., who have supported an
S
N
2-like complexation of an olefin to a borane-Lewis base complex as the mechanism for
intermolecular hydroboration.
22
The simplest version of this reaction cannot occur
intramolecularly in a 5- or 6-membered cyclic transition state, based on the work of
Beak
25
and Baldwin,
26
because the 180 orbital geometry required to form the trigonal
bipyramidal S
N
2 transition state via 5-endo-tet and 6-endo-tet transition states is
disfavored. Therefore, the 5.5-endo-tet transition state 2C2 necessary to invoke an

42

intramolecular variant of Pastos mechanism is also disfavored. On the other hand,
5-exo-tet and 6-exo-tet processes are highly favored in contrast to the 5-endo-tet and 6-
endo-tet. Thus, if one could introduce an exo-leaving group on boron, then the concepts
put forth by Pasto and Baldwin would no longer be dissonant in the context of an
intramolecular hydroboration pathway (Scheme 2C). Previous work in the Vedejs group
investigated the effects of introducing such a leaving group into homoallylic amine-
borane systems with good results, as described below.
27,28

Homoallylic amine-iodoboranes 2D3 were generated by activating purified
amine-boranes 2D1 with iodine (I
2
) according to the work of Ryschkewitsch.
29
These
amine-iodoboranes, while designed to allow intramolecular olefin-borane complexation
via an S
N
2-like associative pathway, might also achieve the desired complex 2D5 via a
dissociative S
N
1 pathway (Scheme 2D), although no evidence for this was found. Once
the intramolecular t-complex 2D5 is formed, hydroboration can occur by either a fused-
(2D8) or bridged (2D7) bicyclic transition state to generate 1,3- and 1,4-aminoalcohols
2D11 and 2D10, respectively, upon oxidation. The kinetic advantage of 5-membered
ring formation, and the greater thermodynamic stability of the fused bicyclic transition
state 2D8, led to the prediction that 1,3-aminoalcohols 2D11 would predominate in the
product mixture. The expected selectivity was observed: up to >20:1 selectivity was
achieved with both E- and Z-1,2-disubstituted olefin substrates.
27,28
In the case of a
terminal olefin, anti-Markovnikov selectivity was drastically reduced from 1:19
(expected with THF BH
3
)
30
to 1:3. Furthermore, |-substituted styrene (R=Ph) provided a
2:1 preference for the 1,3-amino-alcohol 2D11 after oxidative workup, in contrast to the
typical 1:5 ratio expected for |-substituted styrene.
30

43



2.2 Regioselectivity via Metal-Free Alcohol-Directed Hydroboration
The goal of the work reported in the remainder of this chapter was to develop a
metal-free method for oxygen-directed hydroboration through application of the amine-
direction precedents to the hydroboration of homoallylic alcohols, alkoxides, and ethers.
The investigation began with a focus on alcohol-directed hydroboration.
While an analogous activation approach for alcohol-directed hydroboration using
a potentially exocyclic leaving group might appear to be facile (Scheme 2E), amine-
44

borane and alcohol-borane complexes are very different in terms of stability. This leads
to restrictions on the alcohol system that were of no concern in the amine system. While
many amine-boranes can be generated by stirring the amine with THF BH
3
and then
purified by chromatography or crystallization, these are not options for alcohol-boranes
in the context of ODHB. Alcohol-boranes spontaneously evolve hydrogen gas at or
below room temperature to generate the presumably undesired alkoxy boranes
RO
(3-n)
BH
(n)
, thereby eliminating the option of purification by chromatography.
Furthermore, generating an alcohol-borane in ethereal solvents commonly associated
with hydroboration is not practical for ODHB since the solvent would compete for

45

borane complexation. Thus, if alcohol-directed hydroboration is to occur in an analogous
fashion compared to the amine case, the alcohol-boranes must be generated and activated
in situ at low temperatures with no ethereal solvents present.
Dichloromethane (DCM) was a straightforward solvent choice based on work
from both the Brown and Vedejs groups.
27,31
Choosing a borane carrier was a more
delicate matter in that the ideal carrier must find a balance between the contrasting
properties of 1) forming a sufficiently strong complex with borane to minimize the
concentration of undesired Lewis base in solution and 2) forming a weak enough borane
complex to allow the substrate to complex to borane. Thioanisole was chosen based on a
study by Brown, which reported that borane dissolves in thioanisole with 3 M
concentration despite a relatively weak complex between PhSMe and BH
3
.
32
Such
solutions are not commercially available due to their instability over time, but are
relatively easy to generate in 10 mL batches by bubbling excess diborane gas through
neat PhSMe. This procedure consistently provided borane concentrations of 2.5 M.
The first investigations into the activated borane approach to ODHB were carried
out with 3-penten-1-ol in DCM and thioanisole-borane [Ph(Me)S BH
3
] activated by
iodine (Table 2F; Entries1-7). A favorable regioselectivity of 7:1 for 1,3-pentanediol was
achieved in the initial experiment in which the substrate/borane solution was activated at
-40 C and was then warmed to between -20 C and 0 C (Entry 1). Subsequent control
experiments demonstrated that unactivated Ph(Me)S BH
3
was capable of hydroborating
substrate at -40 C, resulting in a reduced 3:1 regioselectivity for 1,3-diol 2F2 (Entry 3)
due to undesired background reaction. Regioselectivities were dramatically improved by
introducing both Ph(Me)S BH
3
and iodine to the substrate solution at lower temperatures.
46


Entry R
1
R
2
Activator X (C) T
1
(h) T
2
(h) 1,3-: 1,4- Conversion
1 Ph Me I
2
-40 1 5 7 : 1 total
2 Ph Me - -20 6 n/a 3 : 1 total
3 Ph Me - -40 6 n/a 3 : 1 partial
4 Ph Me - -78 6 n/a - trace
5 Ph Me I
2
-60 1 5 13 : 1 total
6 Ph Me I
2
-78 1 5 18 : 1 total
7 Ph Me I
2
-78 5 n/a 18 : 1 trace
8 Me Me I
2
-78 1 10 4.4 : 1 partial
9 Me Me I
2
-78 1 19 4.4 : 1 total

Entries 5 and 6 display regioselectivities of 13:1 and 18:1 from activation temperatures
of -60 C and -78 C, respectively. Entry 7 shows that the reaction had to be warmed
from -78 C to proceed at an acceptable rate.
These results with Ph(Me)S BH
3
were an encouraging indication that ODHB
could be achieved in analogous fashion to the amine-directed methodology. However,
the short-lived nature of Ph(Me)S BH
3
solutions, coupled with safety concerns for its
generation, and its unenviable odor led to the pursuit of alternative borane sources for a
method viable on scale. Dimethylsulfide borane (BMS) was investigated because it is
commercially available. Its scent would be forgivable if it could provide comparable
regioselectivity to Ph(Me)S BH
3
. Not only did BMS fail to provide comparable
47

regioselectivity (4.4:1 vs. 18:1), it required longer reaction times to achieve total
conversion (Table 2F; Entries 8 & 9).
Previous statements pertaining to the characteristics of an ideal borane carrier are
perhaps misleading in that the most ideal borane carrier in the pursuit of ODHB is no
carrier at all. Therefore efforts were made to generate solutions of (di)borane in DCM.
A DCM BH
3
stock solution approach was studied by bubbling excess diborane gas
through DCM cooled to -78 C. Borane concentrations of 0.44M were generated in
DCM, but loss of borane was observed upon warming. Table 2G illustrates that stock
solutions of 1:1 PhSMe:BH
3
generated in situ from a variety of borohydrides were also
not viable as storable reagents. Sodium borohydride (NaBH
4
) failed to generate any
detectable borane due to the insolubility of NaBH
4
in DCM, but tetrabutylammonium
borohydride (nBu
4
NBH
4
) did give excellent initial concentrations of borane upon
treatment with iodine. It was hypothesized that replacing the sulfide carrier with an
alcohol substrate would allow borane retention in solution to achieve ODHB upon
activation with I
2
, but uncertainty would remain regarding the timescale for activation vs.
the timescale for reaction of the alcohol with borane to generate borates and H
2
gas.

% BH
3
in solution
R After 3 h After 15 h After 7 d
Na 0 0 0
n-Bu
4
N 90 66 50
Bn(Et)
3
N - 54 47

48

Conversion of the unsaturated alcohol substrate was achieved using in situ borane
generation from nBu
4
NBH
4
followed by iodine activation, but regioselectivity dropped
from 18:1 to ~ 2:1. To ensure that this decrease in selectivity was not due to the absence
of sulfide, PhSMe was added to the reaction solution. As no change in regioselectivity
was observed, it was concluded that presence of sulfide has no effect on the reaction
(Scheme 2H). On the other hand, replacing I
2
with triflic acid (TfOH) as the borane-
generating and activating reagent provided excellent >20:1 regioselectivity with 3-nonen-
1-ol under sulfide-free conditions (Scheme 2I). By itself, this result is significant in that
it confirms that sulfide is not necessary for achieving good regioselectivity. Considering
the impact that TfOH activation had on the eventual development of an ODHB method
for alcohols, this result proved to be absolutely critical.





49

The I
2
-activated Ph(Me)S BH
3
method that provided excellent selectivity on 3-
penten-1-ol (Table 2F; Entry 6) failed to provide comparable results on more complex
substrates. Even 3-hexen-1-ol failed to give good regioselectivities. Yields were also
too low to be synthetically practical. Fortunately, it was discovered that TfOH-activated
BMS achieved moderate to good yields on a variety of substrates with superior
regioselectivity than that of the I
2
-Ph(Me)S BH
3
conditions. Best results were achieved
when BMS was preactivated with TfOH before addition of substrate (Table 2J).
33

All alkyl-substituted substrates provided 1,3-diols with excellent
regioselectivities. Selectivity is not highly dependent on olefin geometry, although trans-
olefins provide a somewhat improved result, as 28:1 and 37:1 regioselectivities were
achieved on cis- and trans- 3-hexen-1-ol, respectively (Table 2J; Entries 2&3).
Branching at C-5 is directly related to regioselectivities as demonstrated by the secondary
cyclohexyl group and the tertiary tbutyl group, respectively, providing 56:1 and 82:1
regioselectivities (Entries 5&6).
Aromatic substituents have a strange and unexpected effect on substrate reactivity
that seemingly relates to their proximity to the olefin. The styrenic olefin in entry 7
underwent only trace conversion even after extended reaction times. While the styrene
system was of particular interest due to the electronic perturbation of the olefin by the
phenyl ring, it had been expected that this perturbation would be a challenge in terms of
regioselectivity rather than reactivity. In general, |-substituted styrenes undergo
intermolecular hydroboration to generate benzylic boranes with a 5:1 regioselectivity
preference due to the conjugative electronic effect of the phenyl ring. However, the
observed drop in reactivity in this case cannot be attributed only to conjugation, as
50

R
OH
R
OH
OH
1.
CH
2
Cl
2
, -78C
2.
3. MeOH, NaOOH
-78C to -20C, time
Me
S
Me
BH
3
, TfOH
Table 2J: Regioselectivities Achieved Under Optimized Conditions
R
OH
OH
2J1 2J2 2J3
a R= CH
3
b R= CH
2
CH
3
c R= Z-C
2
H
5
d R= nCH
5
H
11
e R= cC
6
H
11
f R= tC
4
H
9
g R= Ph
h R= Bn
i R= (CH
2
)
2
Ph

Entry Stg Time (h) Yield 2J2 : 2J3
1 2J1a 10 41% >20 : 1
2 2J1b 10 51% 37 : 1
3 2J1c 5 51% 28 : 1
4 2J1d 10 69% > 20 : 1
5 2J1e 5 80% 56 : 1
6 2J1f 5 56% 82 : 1
7 2J1g 20 < 3% n/d
8 2J1h 10 22% n/d
9 2J1i 5 59 % >20 : 1

inserting a methylene tether between the phenyl ring and olefin does not restore reactivity
comparable to that of the alkyl substrates (Entry 8). Not until a second methylene linker
is added to the phenyl-olefin tether does reactivity return to expected levels (Entry 9).
The styrenic system behaves well in the amine directed hydroboration. Therefore, a 1:1
substrate-borane complex would be expected to behave well in the alcohol system.
However, a 1:1 complex is not a realistic assumption to make with a single equivalent of
activated borane present, let alone the two equivalents present in the reaction mixture
(standard conditions). It is tentatively proposed that activated borane forms a t-complex
51

to the aromatic ring that inductively deactivates the olefin. Adding a methylene tether
reduces the inductive effect and a second methylene group renders it insignificant.
Having achieved excellent regioselectivity on a variety of homoallylic alcohols
the next goal for this work was to confirm that the regioselectivity was due to ODHB.
This was investigated by running competition experiments in the presence of excess
cyclohexene. Not only was no cyclohexanol observed upon oxidative workup of these
reactions, but the yield of the desired diols actually increased by 10 % (Table 2K). This
is believed to be due to the cyclohexene behaving as a scavenger of acidic species in
solution.

Entry R Regioselectivity Yield (without additive) Cyclohexanol Observed
1 Me >20 : 1 51% (41%) none
2 Et >20 : 1 66% (51%) none

These acidic species are responsible for catalyzing a cyclization side reaction that
went unobserved until special care was taken with the reaction mixture of 6-phenyl-4-
hexen-1-ol 2L1. 2-Phenethyltetrahydrofuran 2L3 was recovered in low yield due to its
surprising volatility (Scheme 2L), but its formation suggests that a similar side reaction
accounts for the moderate yields in Table 2J. Despite good conversion of the aliphatic
substrates in Table 2J, the moderate yields were initially baffling because the volatile
tetrahydrofurans have the same mass as the corresponding starting materials, rendering
52

assay of the crude reaction mixtures by nominal mass spectrometry ineffective. Thus the
missing mass balance is attributed to the volatile tetrahydrofuran side products.



The successful ODHB of homoallylic alcohols led to the investigation of other
unsaturated alcohol substrates. 4-Hexen-1-ol 2M1 was used to study a bis-homoallylic
alcohol with unexpected results. It was believed that good regioselectivity for 1,4-diols
would be achieved in such systems for the same kinetic and thermodynamic reasons that
one would expect to account for the formation of 1,3 diols from homoallylic systems.
However, 1,4-hexane-diol 2M2 was generated with a modest 4.4:1 regioselectivity
compared to 1.6: 1 using THF BH
3
(Scheme 2M).

OH OH
OH
OH
OH
1. THFBH
3
, THF, 0 C
2. NaOOH
1.6 : 1
OH OH
OH
OH
OH
1. BMS, TfOH, DCM
-78 to -20 C
2. NaOOH
4.4 : 1
Scheme 2M: Investigating Bishomoallylic Substrates
2M1 2M2 2M3
2M1 2M2 2M3


53

In 1972 Brown reported that intramolecular hydroboration of thexyl-4-
pentenylborane 2N1 favors the five membered ring 2N2. This must be due to a kinetic
preference for five-membered ring formation, considering the well known preference of
dialkylboranes to react with anti-Markovnikov selectivity.
34
On the other hand, in the
case of thexyl-5-hexenylborane 2N4, the kinetic preference for six-membered ring
formation does not begin to compete with the inherent preference of the dialkylborane for
anti-Markovnikov regioselectivity (Scheme 2N). Negligible regioselectivity was also

achieved upon I
2
activation of bishomoallylic amine-boranes 2O1 (Scheme 2O).
28
These
two reports, in addition to the results with 2M1 support the conclusion that regioselective
delivery of borane to an olefin from the c-position of a simple acyclic substrate is
inherently difficult, regardless of the element at the o-position, attached to boron.

Entry Olefin Geometry R Yield (%) 1,4- : 1,5-
1 E H 95 2 : 1
2 Z H 91 2 : 1
3 Z Bn 63 1.5 : 1
54

The results with the bishomoallylic alcohol precluded the study of longer olefin-
borane tethers so a shorter (allylic) tether was briefly evaluated using 2-hexen-1-ol.
However, the conditions used on the homoallylic substrates did not consume olefin in the
allylic system. The reduced reactivity is attributed to 1) the alcohol-borane complex
inductively deactivating the olefin and 2) the thermodynamically disfavored [2.2.0]
fused- 2P2 and [2.1.1]-bridged 2P5 bicyclic transition states through which an
intramolecular transformation would have to proceed (Scheme 2P).
OH
1. BMS, TfOH, DCM
-78 to -20 C
2. NaOOH
BMS,TfOH
BMS,TfOH
O
B
H H
OTf
H
O
B
H H
OTf
H
B O H
n-Pr
H
disfavored
disfavored
B
O
OH
OH
H
H
OTf
n-Pr
Scheme 2P: Allylic Alcohols are Not Viable Substrates
OTf
2P1 2P2
2P3 2P4
2P1 2P5


2.3 Pursuing Diastereoselectivity via Metal-Free Alcohol-Directed Hydroboration
Having developed a method capable of regiocontrol in the hydroboration of
homoallylic alcohols, the new procedure was applied to a variety of secondary alcohols to
investigate its utility in the context of diastereocontrol. Isopulegol 2Q1 was an ideal
initial substrate as it is commercially available and had been previously studied by Ohloff
55

(Scheme 2Q).
7
However, a background reaction run to confirm Ohloffs 19:1
diastereoselectivity did quite the opposite. Treating isopulegol with 1M THF BH
3

provided only 5:1 diastereoselectivity favoring 2Q2. The (unknown) reason for this
discrepancy compared to the literature result is of little importance because treating
TfOH-activated BMS with isopulegol followed by subsequent oxidative workup provided
superior diastereocontrol (>30 : 1) in the generation of 1,4-diols 2Q2 and 2Q3 (Scheme
2Q). This increase is tentatively attributed to ODHB, but the reaction proved
surprisingly complex.
OH
OH
H
OH
OH
H
OH
OH OH
OH
1.
CH
2
Cl
2
, -78C
2.
3. MeOH, NaOOH
-78C to -20C, 5h
Me
S
Me
BH
3
, TfOH
OH
OTf
H
2
O
O
H
BH
2
OTf
OTf
OH
OH
H
OH
OH
H
OH
1. THFBH
3
, THF
2. MeOH, NaOOH
95 %
5 : 1
32%
>30 : 1
18% 11%
Scheme 2Q: Diasteroselectivity Achieved on Isopulegol
2Q1 2Q2 2Q3
2Q1 2Q2 2Q3 2Q4 2Q5
2Q6 2Q7
OH
OTf
2Q8


Two side products were produced under ODHB hydroboration conditions.
Isolating the isomeric 1,3-diol 2Q4 in 18% yield presented the possibility that the
hydroxyl directing effect might overcome the strong preference for anti-Markovnikov
56

hydroboration. However, the identification of citronellol 2Q5 as the second byproduct
indicated that acidic side reactions were interfering. Since isopulegol can be prepared by
acid catalyzed cyclization of citronellal, the reverse transformation should also be
feasible under these conditions.
35
Protonating the olefin of isopulegol would lead to a
tertiary triflate 2Q6 that can undergo ring opening via carbocation 2Q7, to form
protonated citronellal 2Q8, which is envisioned as being reduced by an activated borane
species in solution to provide citronellol. Generation of 1,3-diol 2Q4 might come from
either 2Q6 or 2Q8 upon aqueous workup. Cyclohexene did not suppress these side
reactions.
Secondary homoallylic alcohols were submitted to TfOH-activated BMS
conditions to investigate diastereoselectivity. Although no mechanistic evidence for
ODHB had been obtained at this stage of the investigation, several speculative rationales
had emerged, one of which assumes the simplest version of alcohol-directed

57

hydroboration, shown in Scheme 2R. A priori, diastereoselectivity on E-substrates was
expected based on chair-like transition states 2R1 and 2R3. Syn-1,3-diols were expected
to be favored, as they would be derived from the transitions state 2R1, in which the olefin
is in the extended conformation. The alternative conformer 2R3 should be disfavored
due to the A-1,3 strain generated between the olefin and the pseudoaxial proton next to
oxygen. Contrary to these predictions, only negligible diastereoselectivity was observed
with 4-decen-2-ol 2R5 and 2,2-dimethyl-5-docecen-3-ol 2R6 (Scheme 2R).
It was hypothesized that using a Z-olefin would lead to increased
diastereoselectivity due to the drastic steric interaction between the alkyl substituent and
the psuedoaxial carbinol proton in the disfavored transition state 2S3. However, similarly
poor results were observed on Z-substrates despite incorporating t-butyl groups at the

58

carbinol and distal olefinic carbons (Scheme 2S). It is important to note that almost no
regioselectivity was observed in either the E- or Z- systems. Apparently, the steric
environment of the secondary alcohol had prevented a useful alcohol-borane interaction.
Since excellent regioselectivity had only been achieved with primary alcohols, an
experiment with 2-isopropyl-3-penten-1-ol 2T1 was designed. Moving the chiral center
from the carbinol carbon to C-2 would allow a better alcohol-borane interaction while
bulkiness of the isopropyl group should provide a stereochemical bias. Excellent
regioselectivity was restored by using the primary alcohol. However, the C-2 isopropyl
group provided no diastereoselectivity. This result indicates that the A-1,3 interaction of
both psuedoaxial olefin and carbinol proton in transition state 2T4 is insufficient to
provide a stereochemical preference over the psuedoequatorial transition state 2T3,
assuming that the cyclic mechanism has been presented correctly.

Another approach to achieving diastereoselectivity was taken in which a bulkier
hydroborating agent was investigated. TfOH-activated phenylborane was chosen because
the introduction of steric bulk is accompanied by delocalization of electron density
59

involving boron. Generation of the desired borane species was confirmed by forming its
N,N-dimethyl-4-amino-pyridine (DMAP) complex in two different routes. Treating
lithium phenylborohydride
36
with an equivalent of TfOH to generate phenylborane
followed by a second (activating) equivalent of TfOH and subsequent addition of an
equivalent of DMAP generated a species with a
11
B NMR signal at o= +5ppm. An
identical signal was observed upon treating DMAP-phenylborane complex with an
OH
OH
OH
22 : 1 regioselectivity
n-pentyl
OH
n-pentyl
OH
8 : 1 regioselectivity
1 : 1 diastereoselectivity
B
H
H
H
Li
B
H
H
H
Li
OH
B
OTf
H
DMAP
TMSCl
B
H
H
DMAP
B
H
H
DMAP
H
2
TfOH
11
B o: -4ppm
H
2
TfOH
LiOTf
B
H
H
TfOH
H
2
B
OTf
H
DMAP
11
B o: 5ppm
1.
CH
2
Cl
2
, -78C
2.
3. MeOH, NaOOH
-78C to -20C
, TfOH
B
H
H
H
Li
1.
CH
2
Cl
2
, -78C
2.
3. MeOH, NaOOH
-78C to -20C
, TfOH
Scheme 2U: Pursuing Diastereoselectivity with Phenyl(triflate)borane
2U1 2U2 2U3
2U4 2U5 2U6
2J1e
2J2e
2S7 2U9

60

equivalent of TfOH. Thus it was concluded that the signal at o= +5ppm represents the
DMAP complex of Ph(OTf)BH, which confirms generation of Ph(OTf)BH in the first
route (Scheme 2U).
Treating a solution of Ph(OTf)BH with 4-cyclohexyl-3-buten-1-ol 2J1e provided
1,3-diol 2J2e with 22:1 regioselectivity upon oxidative workup, demonstrating that the
new reagent was capable of ODHB. However, submitting both the E- and Z- isomers of
2,2-dimethyl-5-dodecen-3-ol 2S7 to the Ph(OTf)BH conditions provided moderate
regioselectivity and no diastereoselectivity. The resistance of acyclic homoallylic
alcohols towards diastereo-induction necessitates further consideration of the feasibility
of the proposed mechanism.
Intramolecular hydroboration in analogous hydrocarbon systems is known to
provide diastereoselectivity with three-to-five atom tethers between boron and an
olefin.
37-42
Still has reported diastereocontrol in the internal hydroboration step starting

61

from of diene and thexylborane. Dienes 2,5-dimethyl-1,4-hexadiene 2V1 and
2,7-dimethyl-2,7-octadiene 2V7 provide diastereo-enriched diol mixtures as expected
from sequential inter- and intramolecular transformations. Diols 2V5 and 2V6 were
generated in a 15:1 ratio upon treating E-2,6-dimethyl-1,4-heptadiene 2V4 under the
same conditions. The authors state only in the case of [2V4] is some ambiguity
involved, and this is presumably due to a steric interaction between the isopropyl and
thexyl substituents. The issue of intramolecular hydroboration is of particularl interest
in the case of 2V4, as the intermediate generated by monohydroboration is a hydrocarbon
analog for 2R5-borane and 2R6-borane complexes. A specific transition state was not
proposed for these substrates.
Chair-like transition states have been suggested, involving boranes 2W1,
generated by hydroboration of a diene precursor. Yokoyama proposes that intramolecular
hydroboration occurs via cyclic transitions states 2W2a and 2W2b.
41,42
The lack of A-
1,3 strain between R
3
and R
Z
in 2W2b is responsible for the selectivity. The steric bulk
of thexylborane is key, as THF BH
3
provides poor selectivity. Acyclic diastereocontrol is
clearly achievable via intramolecular hydroboration in the all-carbon substrates, based on
the results of Still and Yokoyama. The contrasting lack of diastereoselectivity with the
oxygen analogs (homoallylic alcohols of section 2.3) cannot be accounted for by
inserting oxygen into Yokoyamas proposed transition states. The poor selectivity with
the original activated borane conditions (Schemes 2R, 2S, & 2T) is perhaps less
confusing considering the result in entry 1 of Table 2V. On the other hand, the steric
bulk of the PhB(H)OTf reagent should provide improved selectivity, acting as a steric
62


entry R
1
R
2
R
3
R
E
R
Z
anti- : syn- reference
1 H H Me -(CH
2
)
5
- 76 : 24 41
2 H Thx Me -(CH
2
)
5
- 96 : 4 41
3 H Thx Me CH
2
OBn Me 96 : 4 42
4 H Thx Me Me CH
2
OBn >98 : <2 42

replacement for a thexyl group, but no improvement was observed. Thus, the mechanism
of the alcohol directed hydroboration is clearly more complicated than initially proposed,
based on these contrasts with the hydrocarbon analogy.

2.4 Mechanistic Investigations
Mechanistic studies were done with the intent of supporting an intramolecular
pathway. The first experiment investigated the activated borane reagent using
11
B NMR
spectroscopy. A -20 C solution of BMS 2X1 (
11
B: o= -20.7 ppm, q, J= 104 Hz) in
CH
2
Cl
2
was treated with slightly less than one equiv of TfOH to provide a
11
B triplet at
o= -1.6 ppm (J= 128 Hz), which is believed to represent the expected dimethyl sulfide
complex of triflate borane 2X2.
63

To investigate the reactivity activated borane 2X2 with alcohols without the
complication of olefin reactivity interfering, 2X2 was treated with ethanol at -78 C and
warmed to -20 C while monitoring by
1
H NMR spectroscopy. Interestingly, the proton
NMR spectra taken at -78 C and -20 C showed a temperature dependant signal shift. At
-78 C a single peak was observed for both the methylene (o= 3.76 ppm) and methyl (o=
1.2 ppm) protons of ethanol. As the sample warms, the methylene (o= 3.76; 3.94 ppm)
and methyl (o= 1.2; 1.29 ppm) protons appear as two signals. After 10 min at -20 C the
more downfield signal is dominant. This observation suggests that either 1) the alcohol
does not complex to the sulfide-complexed BH
2
OTf or 2) an ethoxyborane is forming at
the elevated temperature. The latter was addressed with hydrogen evolution studies.

Quantitative hydrogen evolution upon treating 2X2 with an alcohol would prove
that complex 2X3 is transitory under reaction conditions, which would eliminate the
possibility of the envisioned mechanistic pathway. Hydrogen evolution studies began
with a control experiment in which a -20 C DCM solution of Me
2
S BH
3
was treated
with ethanol, generating 9% of the theoretical amount of H
2
over 90 minutes (Equation
2). Boron NMR spectroscopy of the resulting mixture was complex but no
monoalkoxyborane was observed at the expected value (o= ~50 ppm). These results
indicate that ethoxyboranes are not formed under such conditions.
64

S
B
Me
Me
H
H
H
EtOH (0.51 mmol)
CH
2
Cl
2
-20 C, 90 min
H
2
9%
(2)
2X1
.6 mmol .05 mmol

A more intricate experiment was required to investigate the real reaction
conditions. The first stage of the experiment involved measuring the amount of hydrogen
evolved from the activation of 2X1 with TfOH. Treating a -78 C solution of 2X1 with
1 equivalent of TfOH led to the collection of >90% of the theoretical amount of H
2
.
Substrate was then added via addition funnel to the reaction mixture at -78 C. No gas
evolution was observed at -78C. Upon warming to -20 C, ca. 10% of the theoretical
volume of H
2
was collected (Scheme 2X). Assuming that complexes of the alcohol and
BH
2
OTf are the species observed at low temperature, then they appear not to decompose
to monoalkoxyboranes at -20C:
11
B NMR spectroscopy does not reveal
monoalkoxyborane peaks in the expected range (o= 50 to 55 ppm) amid complex signals
including maxima at o= -20.7 ppm, -8.43 ppm, -1.7 ppm, and +35.2 ppm. Broad signals
obscure the spectrum in the range of -18 ppm < o < +24 ppm.
S
B
Me
Me
H
H
H
TfOH
CH
2
Cl
2
, -78 C
S
B
Me
Me
H
H
OTf
H
2
>90%
OH
Et
CH
2
Cl
2
, -78 C
30 min
O
B
H
H
OTf
H
Et
" "
-78 to -20 C
45 min
H
2
10%
Scheme 2X: Hydrogen Evolution Studies
2X1 2X2
2X3

65

The requisite species for achieving intramolecular hydroboration, according to the
original mechanistic proposal, is the substrate-BH
2
OTf complex 2X3 (Scheme 2X). The
proton remaining on oxygen, along with the resulting positive charge, serves to activate
the tetravalent boron by making it more electrophilic. Hydrogen evolution studies
indicate that a small (ca. 10%) amount of 2X3 undergoes hydrogen evolution which
could form an alkoxyborane 2Y5, (Scheme 2Y) by reacting with an external hydride
source, or perhaps more plausibly, the corresponding trifluorosulfonyloxy analogue 2Y1
if hydrogen evolution involves the internal hydride of 2X3. While monoalkoxyboranes
are not confirmed as hydroborating species, formation of alkoxyborane 2Y5 should not
be taken to preclude ODHB. Similarly, formation of 2Y1 has not been detected nor does
it have any precedent in the literature, but that does not mean that 2Y1 can be ruled out as
one of the species capable of undergoing internal hydroboration.
The reaction conditions include two equivalents of activated borane. This enables
potentially unreactive intermediate 2Y5 (Scheme Y) to complex to another molecule of
activated borane, forming the bis-borane species 2Y6, which is analogous to 2Y3 where
the activating proton has been replaced by a Lewis acid. Thus, the transition state 2Y2
can still be achieved by all substrates regardless of any possible monoalkoxyborane
formation. Monitoring the reaction of trans-3-hexen-1-ol by
11
B NMR spectroscopy
provided very complex spectra, but no downfield species (o= 70-80 ppm) indicative of
trivalent 2Y1 or either of the borenium ions 2Y6 or 2Y7 was observed. The spectra do
not define a clear mechanistic picture, but the
11
B signal at o= -8.43 ppm (tetravalent
boron; buried triplet, J
BH
= ~128 Hz) lends support for the formation of complex 2X3.
Brown has reported the
11
B signal of a similar species BH
2
Cl OEt
2
as a triplet at o= -5
66

O
B
H
H
OTf
H
R
O
B
H
OTf
R
BH
2
O
R
OTf
H
2
B
O
R
X H
TfO
O
B
H
H
R
B
H
H
TfO
OH
R
OH
Scheme 2Y: Loss of Hydrogen Does Not Preclude ODHB
2Y1 2X3 2Y2 2Y3
2Y5 2Y4
- H
2
BH
2
O
R
TfO
X
2Y6
O
B
H
H
R
2Y7
Me
2
SBH
2
OTf

ppm with a J
BH
= 136 Hz.
43
Therefore, the originally envisioned mechanism, in which
2X3 forms complex 2Y3 via 2Y2, remains feasible.
2.5 Alkoxide-Directed Hydroboration
Acid-catalyzed side reactions are the main inconvenience of using alcohols to
direct hydroboration with triflate-activated borane as demonstrated by formation of
tetrahydrofuran 2L3 from 2L1, and 2Q4 and 2Q5 from isopulegol 2Q1. The alcohol-
borane complex 2X3 that is believed to be responsible for intramolecular delivery of
borane is also a species that could possibly generate TfOH, leading to catalysis of
undesired reaction pathways. Thus, undesired reactions might be unavoidable with
alcohols. Lithium alkoxide substrates were investigated for this reason.
The best substrate in the alcohol series was 4-cyclohexyl-3-buten-1-ol 2J1e; it
provided an 80% yield of diol with 9% of recovered starting material (RSM), while the
rest of the mass was presumably lost due to acid-catalyzed formation of a volatile
tetrahydrofuran. The corresponding lithium alkoxide 2AA1e was studied to see if better
mass balance could be obtained without losing regioselectivity. Almost quantitative
(98%) mass balance was achieved upon treating TfOH-activated BMS with 2AA1e,
67

followed by oxidation with NaOOH. Regioselectivity favoring 1,3-diol 2U8 remained
excellent (>20 : 1), however, a decrease in yield was observed (Scheme 2Z).

A detailed investigation of the alkoxide-directed hydroboration was initiated to draw
comparison to the alcohol series. Comparable regioselectivity was achieved on all
aliphatic substrates. The reactivity of phenyl-substituted substrates continued to suffer,
presumably due to the same inductive deactivation effects of arene-borane complexes
discussed in relation to Table 2J. Comparing diol yields from alcohols with those from
alkoxides reveals no consistent advantage. Substrates with little steric bulk at C-4
provide greater yields in the alkoxide experiments (Table 2AA, entries 1 & 2) while
substrates with bulkier C-4 substituents provide greater yields in the alcohol experiments.
The improved results with unhindered substrates are reminiscent of the results with
Ph(Me)S BH
3
/iodine conditions studied initially, which were only effective on
3-penten-1-ol (Table 2F). It appears that only substrates unhindered at C-5 benefit from
the alkoxide reaction conditions. The bis-homoallylic alkoxide of 2M1 (2X2) was also
investigated, and the selectivity was comparable to the selectivity for 2M1 (Equation 3).
68


Entry Stg Time (h) Yield Regioselectivity
1 2AA1a 5 70% >20 : 1
2 2AA1b 5 90% >20 : 1
3 2AA1d 5 38% > 20 : 1
4 2AA1e 5 60% >20 : 1
5 2AA1f 5 44% >20 : 1
6 2AA1g 20 < 3% n/d
7 2AA1h 20 28% n/d
8 2AA1i 5 42 % 16 : 1


Neither the alcohol nor alkoxide method is perfect. The
alcohol method generally provides greater yields but acid
catalyzed side reactions destroy some starting material. The
alkoxide method preserves material but, in addition to generally
low diol yields, the procedure is relatively inconvenient as it
requires a system that incorporates a cold-jacketed addition
funnel (Figure 2-1). However, the preservation of starting material in the alkoxide case
69

presented the possibility that conversion could be improved. The effect of TfOBH
2

stoichiometry on conversion was investigated in an effort to achieve higher conversion to
diol. Entries 1-4 of Table 2BB illustrate that diol yield does increase with additional
reagent, but starting material starts decomposing by an unknown pathway(s) with 4
equivalents of activated borane added (Entry 4). Yields never surpassed that which was
obtained in the alcohols series (Entry 7).

OR
OH
OH
1.
CH
2
Cl
2
, -78C
2.
3. MeOH, NaOOH
-78C to -20C, 5h
Me
S
Me
BH
3
, TfOH
Table 2BB: Alkoxide Conditions vs Alcohol Experiments
2J2e 2J1e R =H
2AA1e R =Li

Entry R Equiv BMSOTf Additive Regioselectivity Yield RSM
1 Li 1.1 - >20 : 1 16% 76%
2 Li 2 - >20 : 1 60% 38%
3 Li 3 - >20 : 1 65% 29%
4 Li 4 - >20 : 1 70% 7%
5 H 1.1 - >20 : 1 55% 23%
7 H 2 - >20 : 1 80% 9%

A search for a viable acid scavenger was undertaken in an attempt to suppress
acid catalyzed side reactions without the use of nbutyl lithium (nBuLi). With acidic
conditions providing the best reactivity, and alkoxide conditions preventing undesired
side reactions, it was hypothesized that using hindered amines as acid scavengers would
provide the benefits of both to provide optimal yield. Cyclohexene was included in the
study because of the results in Table 2K. This was an opportunity to confirm the
70

hypothesis that acid catalysis is responsible for the generation of 2Q4 and 2Q5 from
isopulegol 2Q1 under alcohol direction conditions.
Table 2CC illustrates that suppression of 2Q4 and 2Q5, accompanied by
increased yields and good diastereoselectivity, was achieved with diisopropylethylamine
(Hunigs base) or 2,6-di-tert-butyl-4-methyl-pyridine. However, the 1,3-diol was still
observed in the hindered amine experiments (Entries 3 & 4), while the lithium alkoxide
approach essentially eliminated this product (Entry 5). The total suppression of 1,3-diol
2Q4 and citronellol 2Q5 in the alkoxide experiment supports the hypothesis that both
2Q4 and 2Q5 are generated via acid-catalyzed side reactions that are not completely
avoidable with an amine acid scavenger. This does not discount the possibility that the
amine proton scavengers could be effective on other substrates, as 2,2-disubstituted
olefins are more inclined to undergo protonation than 1,2-disubstituted olefins like 2J1.
As mass balance was best with the hindered pyridine in Table 2BB, this additive was also
tested with 2J1e. However, oxidative workup revealed poor conversion to the 1,3-diol
with good regioselectivity (Equation 4).





71

OR
OH
H
OH
OH
H
OH
OH
OH
additive
1.
CH
2
Cl
2
, -78C
2.
3. MeOH, NaOOH
-78C to -20C, 5h
Me
S
Me
BH
3
, TfOH
OH
Table 2CC: Investigating Alkoxide Conditions on Isopulegol
2Q1 2Q2 2Q3 2Q4 2Q5

Entry R additive Q2+Q3 Q2 : Q3 Q4 Q5 RSM
1 H - 32% >30 : 1 18% 11% 20%
2 H
(1 equiv)

30% >30 : 1 22% 4% 10%
3 H N
(1 equiv)

52% >20 : 1 2% 0% 18%
4 H

50% >20 : 1 9% 0% 28%
5 Li - 70% ND trace 0% 21%

OH OH
OH
1.
CH
2
Cl
2
, -78C
2.
3. MeOH, NaOOH
-78C to -20C, 5h
Me
S
Me
BH
3
, TfOH
2J2e 2J1e
N But tBu
Me
22% yield
>20 : 1
2J1e
63%
(4)

Lithium alkoxide experiments provided no discernable advantage in the context of
diastereoselectivity on acyclic substrates. Homoallylic secondary alkoxides generated
from trans- 5-decen-2-ol and trans-2,2-dimethyl-dodecen-2-ol provided nearly
identically poor regio- and stereoselectivity in comparison to the corresponding alcohols
(Equation 5). Because of these results and the more difficult alkoxide vs. alcohol
procedure, further investigation of secondary alkoxides was not pursued.
72



The one constant in the substrates used to probe acyclic diastereoselection is that
the functionality at the chiral center can easily occupy a pseudo-equatorial position of a
chair-like transition state. To ensure that a substituent occupies the psudeo-axial position
at the carbinol carbon of a chair-like transition state one must use a tertiary alcohol. Thus
lithium 1-allyl-cyclohexanoxide 2DD1 was treated with TfOH-activated BMS conditions.
Surprisingly, 1,3-diol 2DD2 was recovered in 33% yield with 10:1 Markovnikov
3:1 regioselectivity
12% yiled
OLi
BMS + TfOH 1.
CH
2
Cl
2
-78 to -20C
2. MeOH, NaOOH
H
H OH
O
B
H
H
H
O
B
H
H
H
Li Li
vs.
H
H
OTf
OTf
OLi
10:1 regioselectivity
33% yield
BMS + TfOH 1.
CH
2
Cl
2
-78 to -20C
2. MeOH, NaOOH
OH
OH
O
B
H
O
B
H
Li Li
vs.
H
H
OTf
OTf
Scheme 2DD: Effect of Psuedo-Axial Substituent at Carbinol Position
H
H
OH
2DD1
2DD2
2DD3 3DD4
2DD5 2DD6
2DD7 2DD8

73

regioselectivity. This was unexpected because of the 1:19 anti-Markovnikov selectivity
reported for terminal olefins under normal conditions. The selectivity is believed to be
due to destabilization of the [3.1.1] bridged bicylic transition 2DD4 required for anti-
Markovnikov hydroboration by a steric interaction between bridging hydride and the
pseudo-axial component of the cyclohexane ring. This conclusion is supported by the
fact that lithium 3-buten-1-oxide 2DD5 provides only 3:1 Markovnikov regioselectivity
(Scheme 2DD). Tertiary alkoxides were not investigated further because the reaction of
Me
2
S BH
2
OTf with 2DD1 led to a complex mixture of products. This is presumably due
to the tertiary center participating in transformation involving easily displaced species
upon interaction between alkoxide and excess activated borane
2.6 Ether-Directed Hydroboration

Ether-directed hydroboration was investigated in an effort to differentiate the
oxygens in the final products. The methyl ether of 4-cyclohexyl-3-butanol 2EE1 was
treated with standard preactivation conditions to provide 2EE2 in 20 : 1 regioselectivity.
In contrast to the alcohol substrates, an in situ method was better than the preactivation
procedure, providing monoprotected 1,3-diol 2EE2 with improved selectivity of 50 : 1 in
60% yield (Scheme 2DD).
OMe
1. BMS, TfOH
CH
2
Cl
2
, -78 to -20C
2. NaOOH, MeOH
OMe
OH
61% yield
50: 1 regioselectivity
OMe
1. BMS, TfOH
CH
2
Cl
2
, -78 to -20C
2. NaOOH, MeOH
OMe
OH
20: 1 regioselectivity
Preactivation Method:
In situ Method:
Scheme 2EE: Effect of Order of Addition on Homoallylic Ethers
2EE1 2EE2
2EE1 2EE2
OMe
OMe
OH
OH
2EE3
2EE3

74

This successful ether direction is mechanistically relevant (vide infra), but a
methyl group is not a synthetically convenient protecting group. Collaboration with Dr.
Guoqiang Wang and Ms. Sarah Breed led to the discovery that an allyl ether can
effectively direct hydroboration (Equation 6), providing a conveniently mono-protected
1,3-diol that can be manipulated without interference from the primary oxygen. In situ
activation provided mono-allyl protected 1,3-diol with 27 : 1 regioselectivity in 55%
yield while minimizing diol formation (<5%) and monohydroboration of the allyl group
(<5%) after oxidation. The poor reactivity of allylic substrates in the alcohol series
(Scheme 2P) sheds light on why the chemoselectivity is so good in this reaction.
Intramolecular hydroboration of the proximal (allylic) alkene is disfavored due to
strained transition states and inductive deactivation of the olefin upon oxygen-borane
interaction. Thus, the chemoselectivity supplements the regioselectivity of 27:1 as
support for an intramolecular reaction pathway.


2.7 Mechanistic Insights

This work provides the first transition metal free method for a substrate-directed
hydroboration using generic homoallylic alcohols, alkoxides, and ethers. However, the
mechanistic picture is not as clear as was hoped. Scheme 2FF illustrates that all three
categories investigated (alcohols; alkoxides; ethers) could follow simple and analogous
mechanistic pathways via 2Y2 to provide regioselectivity. As previously discussed,
75

alcohol-borane complexes 2X3 evolve substoichiometric quantities of H
2
gas,
presumably to form an alkoxyborane 2Y1 or derived species, but this is a minor pathway
below -20 C. Alkoxide-borane complexes 2FF1 could release lithium triflate in a
somewhat analogous fashion, providing the same alkoxyborane 2Y1. However, the
methyl ether-borane complex 2FF2 cannot evolve methane or methyl triflate and still
provide monoprotected diol upon oxidative workup. This demonstrates that the
alkoxyborane 2Y1 is not an obligatory intermediate for the ODHB to occur, which
supports the possibility that all three species 2X3, 2FF1, and 2FF2 follow the envisioned
pathway to form olefin boron complexes 2Y3 via an associative mechanism akin to the

76

pathway proposed by Pasto for intermolecular hydroboration. However,
diastereoselectivity has not been achieved on acyclic alcohol or alkoxide substrates,
demonstrating that the reaction mechanism(s) is not as straightforward as envisioned.
The striking contrast with the all-carbon intramolecular hydroboration is not understood,
although nearly all of our data were obtained using the unhindered reagents derived from
Me
2
S BH
2
OTf. The steric bulk of PhB(H)OTf did not provide a result analogous to the
thexylborane reactions previously reported with the all-carbon carbon substrates and no
diol products were observed attempts to generate the more closely analogous activated
reagent ThxB(H)OTf as described in the next section.

2.8 Testing Intramolecular Hydroboration of Thexylalkoxyboranes
Cha has reported thexylalkoxyboranes as viable intermolecular hydroboration
reagents
44
and Bryson has proposed a similar intermediate undergoing intramolecular
hydroboration to account for unexpected diastereoselectivity (Scheme 2GG).
45

Therefore, the hypothesis that thexylalkoxyboranes might undergo unactivated oxygen-
directed intramolecular hydroboration was investigated in the context of homoallylic

77

alcohols. A 1:1 solution of 3-penten-1-ol and ThxBH
2
was generated at -50 C to prevent
intermolecular hydroboration. Warming to 0 C led to the observation of bubbling and a
11
B NMR signal at o= +51 ppm, which correlates to Chas value for thexylethoxyborane
(o= +50.4 ppm). This indicates that the desired intermediate was formed. The
thexylalkoxyborane solution was stirred at rt for 12h and oxidized with NaOOH to
provide 1,3-diol 2F2 with only 2:1 regioselectivity and 40% yield. This demonstrates
that the unactivated thexylalkoxyborane approach to intramolecular hydroboration is not
viable for regioselective hydroboration of acyclic homoallylic alcohols (Scheme 2HH).
Triflic acid activated thexylborane ThxB(H)OTf was also investigated with the
notion that it could improve diastereoselectivity of ODHB. Treating ThxBH
2
with triflic
acid followed by 4-nonen-2-ol 2R5 at -78 C did not produce diol upon warming to -20
C and oxidation with NaOOH. Submitting the simpler substrate 3-octen-1-ol 2HH2 to
identical conditions did not produce diols 2HH3 (Scheme 2HH). This ended
investigation into ODHB with thexylborane.

OH
H
2
B
THF, -50 to 0C
O
BH
11
B o= +51 ppm
1. 0 C to rt, 12h
2. NaOOH
OH
OH
2F1 2F2
2 : 1
40% yield
2HH1
Scheme 2HH: Investigating Oxygen-Directed Hydroboration with Thexylborane
unactivated:
activated:
BH
2
1. , TfOH
2. NaOOH
CH
2
Cl
2
-78 to -20 C
OH
R
2HH2 R= H
2R5 R= Me
OH
R
OH
2HH3 R=H
2R8 R=Me

78


2.9 Summary
Described above is the investigation of an alternative mechanistic proposal for
ODHB, which has been derived from the work of Pasto,
20, 21
Schleyer,
22
Beak,
25
and
Ryschkewitsch.
29
This borane activation approach has proven applicable to heteroatom-
directed hydroboration in the context of homoallylic amines,
27, 28
and it was hoped that it
would provide some semblance of clarity to the topic of ODHB, discussed in the previous
chapter. Homoallylic alcohols, alkoxides, and ethers have now been shown to undergo
highly regioselective intramolecular hydroborations upon application of the borane
activation approach using triflic acid to generate TfOBH
2
or equivalent species.
However, a clear mechanistic picture remains elusive. Poor diastereoselectivity on chiral,
branched acyclic substrates demonstrates that the mechanism(s) of these transformations
is not straightforward, and argues against the simplest version of the mechanism that had
been our working model. Mechanistic studies have not provided significant clarity, and
have not resulted in a more convincing mechanistic proposal. Therefore, while generic
ODHB has now been achieved without the use of metal catalysts, the chemical
community still awaits mechanistic understanding of oxygen-directed hydroboration.












79

Experimental


Substrates 5b and 5c are commercially available, while 5a,
46
5d,
47
5e,
48
5f,
47
5g,
49
5h,
50

and 5i
51
have been reported in the literature. Alcohols 2J1d, 2J1e, and 2J1f were
prepared using methods reported by Kocienski et al.,
47
2J1g, 2J1h, and 2R5

were
prepared by the method of Maryanoff et al.,
49
and 2J1i was prepared using the method of
Negishi et al.
52
The following diols have been reported previously: 2J2a,
5
2J3a,
53
2J2b,
54

2J3b,
54
2J2d,
55
2J3d,
56
2J2e,
57
2J3e,
58
2J2f,
58
2J3f,
59
2J2g,
60
2J3g,
53
2J2h,
61
2J3h,
57

2J3i,
59
and 2DD2.
62


Preparation of borane-thioanisole complex (BH
3
SMePh)
The procedure combines features reported in prior work
32,63
as follows: NaBH
4
(4.56 g,
0.120 mol) was suspended in 60 mL of diglyme using a 250 mL rb flask fitted with an
addition funnel (nitrogen atmosphere throughout). To a separate flask at 0 C, connected
to the first using a gas dispersion tube, was added thioanisole (5.08 g, 0.040 mol). Iodine
(15.1 g, 0.060 mol) in 60 mL of diglyme was then added dropwise to the NaBH
4

suspension causing bubbling that indicated generation of diborane (B
2
H
6
). The gas was
passed into neat thioanisole via a gas dispersion tube and any diborane that was not
reacted was passed through a second outlet and quenched with acetone. Upon
completion of the iodine addition, a gentle nitrogen flow was used to push any remaining
diborane into the acetone-containing vessel. The BH
3
SMePh was then capped and
stored at -20 C. The determination of molarity was performed by measuring out 0.50
mL of BH
3
SMePh into a flask with 2.0 mL of CDCl
3
. The solution was cooled to 0 C
and an excess amount of dimethylbenzylamine (0.3-0.4 mL) was added dropwise. The
80

mixture was stirred for 30 min and analyzed by
1
H NMR. The ratio between the
downfield shifts of 4.0 ppm for the complexed amine and 3.4 ppm for uncomplexed
amine was used to calculate the concentration of BH
3
SMePh. Typically a range of 3-4
M was obtained.

ODHB of homoallylic alcohols; reaction of 2J1e with Me
2
S BH
3
/TfOH.
CH
2
Cl
2
(16 mL) in a 50 mL rb flask was cooled to -78 C. Neat Me
2
S BH
3
(BMS; 300
L, 3.03 mmol) was added followed by TfOH (270 L, 3.04 mmol) dropwise. Each drop
of TfOH initially froze on the surface, forming a white solid that dissipated after a few
seconds of stirring. Gas evolution was observed. This solution was stirred for 35 min
before dropwise addition of a solution of 2J1e (0.214 g, 1.39 mmol) in CH
2
Cl
2
(11 mL).
The clear solution was stirrred at -20 C for 10 h and was then treated slowly with a
solution of 20% NaOH (4.8 mL) in MeOH (5.2 mL). The mixture was stirred 30 min at -
20 C before being stirred vigorously at 0 C for slow dropwise addition of 35% H
2
O
2

(2.4 mL ) in MeOH (2.6 mL). This mixture was warmed to rt and stirred for 10 h before
transferring to a separatory funnel with 75 mL of Et
2
O. Brine (10 mL) was then added,
and the aqueous layer was extracted with Et
2
O (3x, 75 mL). The combined organic
layers were dried (MgSO
4
), concentrated (aspirator), and purified by flash
chromatography (silica gel) using 30% EtOAc in hexanes to give 0.194 g of 2J2e (80%)
as a 56:1 mixture with 2J3e according to the NMR assay described below. All other
substrates 2J1 reported in Table 2 were reacted under analogous conditions.


81

Derivatization with 2-(trifluoromethyl)benzoyl chloride for NMR assay of
regioselectivity.

A sample of 2J2e/2J3e ( 0.024 g, 0.136 mmol) was taken up in CH
2
Cl
2
(1 mL) and
cooled to 0 C in a 10 mL rb flask. Neat 2-(trifluoromethyl)benzoyl chloride (0.1 mL,
0.68 mmol) was added dropwise to the magnetically stirred solution followed by DMAP
(0.085 g, 0.69 mmol) in CH
2
Cl
2
(1 mL). The clear solution was treated with Et
3
N (0.08
mL, 0.57 mmol) and removed from the ice bath. The solution gradually became yellow-
orange over 6h at rt. The reaction was loaded directly onto a preparatory TLC plate and
was developed twice with 10% EtOAc/hexane. The UV active band with R
f
of 0.25 was
extracted with EtOAc. Concentration (aspirator) gave pure diaroylated product (0.069 g,
0.13 mmol) in 97% yield. Regioisomer ratios were established by comparing integrals
for carefully phased, expanded
1
H NMR spectra as follows:
2-(trifluoromethyl)benzoate from 2J2a/2J3a: The methyl triplet (0.90 ppm) from 2J3a
ester was compared to the methyl doublet of 2J3a ester (1.2 ppm).
2-(trifluoromethyl)benzoate from 2J2/2J3 b,c,d,e,i: The 3-CH(O) methine proton was
compared to the 4-CH(O) methine proton.
2-(Trifluoromethyl)benzoate from 2J2f/2J3f: The t-butyl singlet (0.90 ppm) from 2J3f
ester was compared to the
13
C satellite peaks of the t-butyl singlet (0.97 ppm by
1
H
NMR) from 2J2f ester.





82

Table 2II NMR Data and Ratios from Controls Using Excess BH
3
THF and ODHB
precursor
alcohols
ester from alcohol 2J2
o C(3)H (ppm)
ester from alcohol 2J3
o C(4)H (ppm)
2J3 : 2J3
(excess BH
3
)
a
2J3 : 2J3
(ODHB)
2J2a/2J3a m, 5.19-5.33 m, 5.19-5.33 4.3 : 1
b
>20 : 1
2J2b/2J3b m, 5.23-5.31 m, 5.04-5.11 2 : 1 37 : 1
2J2c/2J3c m, 5.23-5.31 m, 5.04-5.11 2 : 1 28 : 1
2J2d/2J3d m, 5.29-5.35 m, 5.17-5.23 2 : 1 >20 :1
2J2e/2J3e m, 5.42-5.49 m, 5.05-5.11 2.7 : 1 56 : 1
2J2f/2J3f N/A N/A 2 : 1 82 : 1
2J2i/2J3i m, 5.34-5.41 m, 5.25-5.29 2 : 1 >20 : 1
(a) Control experiments: see procedure from 2J1i to 2J2i/2J3i, below, THF BH
3
. (b) Me
2
S BH
3
in THF
instead of THF BH
3


Control experiments; hydroboration of 2J1i with THF BH
3
and characterization of
2J2i.

To a 0 C solution of 2J1i (0.059 g, 0.33 mmol) in THF (2 mL) was added excess
THF BH
3
(1 mL, 1 mmol). The solution was stirred for 4h before treating with premixed
20% NaOH (0.8 mL) and 35% H
2
O
2
(0.4 mL) dropwise. The reaction mixture was
transferred to a separatory funnel containing brine and extracted with Et
2
O. The organic
layers were combined, dried over MgSO
4
, and concentrated (aspirator). According to
NMR assay after derivatization as described above, the crude mixture gave a 2:1 ratio of
2J2i:2J3i. Purification via silica gel chromatography in 70% EtOAc in hexanes eluted
pure 2J2i: HRMS-ES
+
(m/z): [M + Na]
+
calcd for C
12
H
18
O
2,
217.120; found, 217.121.
1
H
NMR (400 MHz, CDCl
3
, o): 1.47-1.59 (m, 2H). 1.62-1.82 (m, 4H), 2.33 (br s, 1H), 2.41
(br, s, 1H). 2.64 (t, J= 8 Hz, 2H), 3.77-3.84 (m, 1H), 3.84-3.91 (m, 2H), 7.16-7.20 (m,
3H), 7.25-7.30 (m, 2H)
13
C NMR (100 MHz, CDCl
3
, o): 27.30, 35.80, 37.35, 38.28,
83

61.88, 72.162, 125.79, 128.32, 128.40, 142.24. IR (neat, cm
-1
): 3350 (br), 2950(s), 2860
(m). Regioisomer 2J3i was eluted in later fractions, and was identified by comparison
with literature data.
59

ODHB of 2J1b in the presence of cyclohexene.
CH
2
Cl
2
(60 mL) in a 250 mL rb flask was cooled to -78 C under nitrogen. Neat BMS
(1.1 mL, 11.11 mmol) was added followed by TfOH (1 mL, 11.26 mmol) dropwise.
Each drop of TfOH initially froze on the surface, forming a white solid that dissipated
after a few seconds of stirring. Gas evolution was observed but no temperature change
was detected by internal temperature monitoring. This stirred for 30 min before addition
of a solution of 2J1b (0.68 mL, 5.55 mmol) and cyclohexene (3.0 mL, 29.6 mmol) in
CH
2
Cl
2
(30 mL) over 45 min. The internal temperature rose 2-3 degrees during addition.
The clear solution was stirrred at -20 C for 10 h and was then treated slowly with a
solution of 20% NaOH (6.0 mL) in MeOH (6.0 mL). The mixture stirred 30 min at -20
C and was then stirred vigorously at 0 C for slow dropwise addition of 35% H
2
O
2
(3.0
mL ) in MeOH (3.0 mL). This mixture was warmed to rt, stirred for 20 h, and transferred
to a separatory funnel using 75 mL of Et
2
O and 8 mL of brine. The aqueous layer was
extracted with Et
2
O (4x, 75 mL) and the organic layers were combined, dried over
MgSO
4
, filtered, concentrated (aspirator), and purified via silica gel chromatography
using 50% EtOAc in hexanes to give 0.456 g of 2J2b as a >20:1 mixture with 2J3b. The
product was contaminated with 13% dimethylsulfone. A 62% yield of diols was
calculated based on the NMR ratio of sulfone and diol signals.


84

Hydroboration of isopulegol 2Q1 with TfOH-activated BMS.
A -78 C solution of BMS (490 L, 4.9 mmol) in CH
2
Cl
2
(16 mL) was treated with
TfOH (450 L, 4.9 mmol) under N
2
. The mixture became a solution as gas evolution
was observed. A solution of isopulegol 2Q1
7
(0.25 g, 1.6 mmol) was added over 30 min
to the -78 C solution. The reaction was stirred at -20 C for 10 h before adding a mixture
of 5 N NaOH (5.4 mL) and MeOH (6 mL), followed by 30% H
2
O
2
diluted with H
2
O (3
mL) over 30 min. The reaction stirred for 12 h at rt before transferring to a separatory
funnel containing satd K
2
CO
3
(8 mL) and Et
2
O (100 mL). The aqueous layer was
extracted with Et
2
O (4X 50 mL). The organic layers were combined, dried over Na
2
SO
4
,
filtered, concentrated (aspirator), and purified via silica gel chromatography using 10%
EtOAc in hexanes (500 mL), 30% EtOAc in hexanes (600 mL), and 35% EtOAc in
hexanes (400 mL) to give 0.051 g 2Q1
7
(20%), 0.028 g citronellol 2Q5
64
(11%), 0.0483 g
1,3-diol 2Q4
65
(17%), and 0.0923 g of 1,4-diols 2Q2
7
and 2Q3
7
(32%, >30 : 1
diastereoselectivity). The same conditions were used for entries 3 & 4 of Table 2CC,
except 1.12 equiv of the appropriate amine was introduced as part of the substrate
solution in CH
2
Cl
2
.
Monitoring the ODHB of 2J1b using
11
B and
1
H NMR spectroscopy.
CD
2
Cl
2
(3 mL) in a 10 mL rb flask was cooled to -78 C. Neat BMS (60 L, 0.61 mmol)
was added followed by TfOH (55 L, 0.62 mmol). Each drop of TfOH initially froze on
the surface, forming a white solid that dissipated after a few seconds of stirring (gas
evolution). This stirred for 30 min and was then treated with a solution of 5b (0.030 g,
0.3 mmol) in CD
2
Cl
2
(2 mL) dropwise. The solution was cannulated into an oven-dried,
N
2
-flushed, septum-capped NMR tube submersed in a -78 C bath and
11
B and
1
H spectra
85

were taken at -78 C. The sample was kept in a -78 C bath while the probe was warmed
to -20 C and
1
H spectra were then taken over 2.5 h once every 5 min for the first 45
min followed by one every 15 min. The first 3 spectra contained a signal at 12.5 ppm
that disappeared by the 20
th
min at -20 C. Olefin signals remained, but were nearly gone
after 2.5 h. Using the same sample,
11
B spectra were taken at 2 min, 5 min, 15 min, 45
min, 2 h, and 2.5 h after warming to -20 C. At 5 min signals appeared at -20.6 ppm
(residual BMS), -2.5 ppm (tentatively, TfOBH
2
), 7.5 ppm (broad) and -8 ppm (broad).
At 45 min all of the aforementioned signals were present but a new broad signal appeared
at 34 ppm. At 2.5 h the signals at 34 and 7.5 ppm had broadened to the point of almost
disappearing while the signal at -8 had sharpened slightly, appearing as a broadened
triplet. The signal at -2.5 ppm dominated all
11
B spectra and the signal and -20.6
diminished over time.
Attempt at non-catalyzed ODHB with thexyl-3-pentenoxyborane 2HH1
O
B
2HH1
H

A sample of 2,3-dimethyl-2-butene (0.25 mL, 2.1 mmol) was added to a 0 C solution of
0.95 M THF BH
3
(2.1 mL, 2 mmol) under N
2
. The reaction stirred for 3 h while
warming to rt. The solution was then cooled to -30 C and 3-pentenol (0.26 mL, 2.1
mmol) was added. After 75 min at -30 C
11
B NMR spectroscopy revealed a dominant
signal at o= +51 ppm, which is assigned as 2HH1. The reaction was then stirred for 12 h
at rt before adding premixed 20% NaOOH (1 mL) and 35% H
2
O
2
(0.4 mL) and stirring
for 7 h. The reaction mixture was transferred to a seperatory funnel containing brine (3
86

mL) and Et
2
O (40 mL). The aqueous layer was extracted Et
2
O (4X 40 mL). The organic
layers were combined, dried over MgSO
4
, filtered, concentrated (aspirator), and purified
via silica gel chromatography using 50% EtOAc in hexanes (300 mL), 60% EtOAc in
hexanes (200 mL), and EtOAc (200 mL) to give 0.037 g of 3-pentenol (18%) and 0.1 g of
a 2:1 mixture of 1,3- and 1,4-diols (40%).
Hydroboration of 2J1e using PhB(OTf)H 2U5
Lithium phenylborohydride 2U1 was prepared according to the report by Graham et al.
66

A -78 C suspension of 2U1 (0.10 g, 1 mmol) in CH
2
CL
2
(4 mL) was treated with TfOH
(160 L, 1.8 mmol) dropwise under N
2
. A solution of 2J1e (0.07 g, 0.46 mmol) in
CH
2
Cl
2
(2 mL) was added to the activated phenylborane solution, which was then
warmed to -20 C and stirred for 5 h. The reaction was treated with premixed 20%
NaOH (0.8 mL) and MeOH (1.5 mL) followed by 35% H
2
O
2
(0.4 mL) in MeOH (1.5
mL). The reaction was stirred for 10 h, then transferred to a seperatory funnel containing
brine (3 mL) and Et
2
O (40 mL). The aqueous layer was extracted Et
2
O (4X 40 mL). The
organic layers were combined, dried over MgSO
4
, filtered, concentrated (aspirator), and
purified via silica gel chromatography using 50% Et
2
O in hexanes (150 mL) and 70%
EtOAc in hexanes (300 mL), to give 0.016 g of diols 2J2e & 2J3e (20%). Derivatization
and NMR assay as described above showed 22:1 regioselectivity. Hydroboration of 2S7
using 2U5 was done in analogous fashion.
ODHB of 2J1e via the lithium alkoxide 2AA1e.
BMS (60 L, 0.61 mmol) was taken up in 3 mL of CH
2
Cl
2
placed in a 2-neck 25 mL rb
flask fitted with a cold-jacketed addition funnel containing a solution of 2J1e (0.045 g,
0.29 mmol) in 2 mL of CH
2
Cl
2
. Both flask and funnel were cooled to -78 C. TfOH (55
87

L, 0.62 mmol) was added dropwise to the rb flask. Each drop of TfOH initially froze on
the surface, forming a white solid that dissipated after a few seconds of stirring (gas
evolution observed). After stirring for 30 min, n-BuLi (2.11M, 150 L, 0.33 mmol) was
added dropwise to the addition funnel, swirling the apparatus after addition was
complete. The resulting alkoxide solution was then added dropwise into the activated
borane solution at -78 C, and the reaction was then warmed to -20 C and stirred for 5 h
before MeOH (1 mL at -20C) was added dropwise. This stirred vigorously at 0 C for
30 min followed by addition of premixed 20% NaOH (0.6 mL) and 35% H
2
O
2
(0.3 mL)
dropwise. This stirred for 12 h and was then transferred to a separatory funnel containing
1 mL of saturated K
2
CO
3
solution using 20 mL Et
2
O. The aqueous layer was extracted
with Et
2
O (4x, 20 mL). The organic layers were combined, dried over MgSO
4,
and
concentrated (aspirator). The crude product was diaroylated as described above to give
0.097 g of the 2-(trifluoromethyl)benzoate of 2J2e for NMR assay (64% over 2 steps;
63:1 mixture with the regioisomer from 2J3e).
Preparation of E-4-cyclohexyl-1-methoxy-3-butene (2EE1).
OMe
2EE1

Sodium hydride (0.151 g, 3.77 mmol) was supended in THF (4 mL) and cooled to 0 C in
a 25 mL rb flask. A solution of 5i (0.269 g, 1.75 mmol) in THF (2 mL) was added
dropwise and the reaction was allowed to warm to rt for 1 h. The suspension was cooled
to 0 C and neat MeI (0.23 mL, 3.71 mmol) was added dropwise. The reaction and
warmed to rt for 2 h, quenched with H
2
O, and stirred for 15 min. The mixture was
88

transferred to a separatory funnel with 20 mL of Et
2
O and extracted with Et
2
O (3x, 20
mL). The organic layers were combined, dried over MgSO
4
, concentrated (aspirator),
and purified via silica gel chromatography using 2% Et
2
O in hexanes to give 0.149 g of
13 (50%). HRMS-CI
+
(m/z): [M + H]
+
calcd for C
11
H
20
O
,
169.159; found, 169.159.
1
H
NMR (400 MHz, CDCl
3
, o): 0.99-1.31 (m, 5H), 1.57-1.74 (m, 5H), 1.85-1.96 (m, 1H),
2.26 (q, J= 6.8 Hz, 2H), 3.34 (s, 3H), 3.38 (t, J= 7.2 Hz, 2H) 5.23-5.49 (m, 2H).
13
C
NMR (100 MHz, CDCl
3
, o): 26.04, 26.16, 33.00, 33.03, 40.65, 58.52, 72.77, 123.48,
138.57. The sample contained 12% Z-isomer (quartet at 2.34 ppm and singlet at 3.35
ppm by
1
H NMR). IR (neat, cm
-1
): 2925(s), 2850 (m).
Control experiment hydroboration of 13; preparation of 4-cyclohexyl-3-hydroxy-1-
methoxy-butane (2EE2) and 4-cyclohexyl-4-hydroxy-1-methoxy-butane (2EE3).
OMe
OH
2EE2
OMe
OH
2EE3


To a 0 C solution of 13 (0.040 g, 0.26 mmol) in THF (1 mL) was added excess
THF BH
3
(1 mL, 1 mmol). The solution stirred for 2h before treating with premixed
20% NaOH (0.8 mL) and 35% H
2
O
2
(0.4 mL) dropwise. The reaction mixture was
transferred to a separatory funnel containing brine and extracted with Et
2
O. The organic
layers were combined, dried over MgSO
4
, and concentrated (aspirator). Crude
1
H NMR
showed a 1.4:1 ratio of 2EE2:3EE3. Silica gel chromatography with 15% EtOAc in
hexanes eluted 2EE2; HRMS-CI
+
(m/z): [M + H]
+
calcd for C
11
H
22
O
2,
187.170; found,
187.169.
1
H NMR (400 MHz, CDCl
3
, o): 0.80-1.00 (m, 2H), 1.08-1.31 (m, 4H), 1.37-
1.52 (m, 2H), 1.60-1.73 (m, 6H), 1.77-1.85 (m, 1H), 2.89 (br s, 1H), 3.35 (s, 3H), 3.51-
3.59 (m, 1H), 3.6-3.67 (m, 1H), 3.86-3.94 (br m, 1H).
13
C NMR (100 MHz, CDCl
3
, o):
89

26.16, 26.31, 26.56, 32.91, 33.87, 34.06, 36.80, 45.28, 58.82, 68.60, 71.69. IR (neat, cm
-
1
): 3420 (br), 2920(s), 2850 (m). Pure 15 was eluted in later fractions; HRMS-CI
+
(m/z):
[M + H]
+
calcd for C
11
H
22
O
2,
187.170; found, 187.170.
1
H NMR (400 MHz, CDCl
3
, o):
0.95-1.48 (m, 8H). 1.60-1.87 (m, 7H), 2.32 (br s, 1H), 3.35 (s, 4H, -OCH
3
+ -CH-O).
3.42 (dt, J= 1.2, 4.8 Hz, 2H).
13
C NMR (100 MHz, CDCl
3
, o): 26.19, 26.33, 26.48, 26.53,
27.95, 29.2, 31.49, 43.70, 58.56, 73.08, 75.85. IR (neat, cm
-1
): 3420 (br), 2920(s), 2850
(m).
In Situ activation method for ODHB of 2EE1.
13 (0.10 g, 0.59 mmol) was taken up in CH
2
Cl
2
(10 mL) and cooled to -78 C in a 25 mL
rb flask. Neat BMS (120 L, 1.21 mmol) was added dropwise and the resulting solution
was stirred for 30 min before being treated slowly with neat TfOH (105 L, 1.18 mmol)
dropwise. Each drop of TfOH acid initially froze on the surface, forming a white solid
that dissipated after a few seconds of stirring. Gas evolution was observed. The clear
solution was stirred at -20 C for 10 h and treated slowly with a solution of 20% NaOH
(0.6 mL) in MeOH (1.0 mL). The mixture stirred 10 min before being stirred vigorously
at 0 C for slow dropwise addition of 35% H
2
O
2
(0.3 mL ) in MeOH (0.7 mL). This
mixture was warmed to rt and stirred for 10 h before transferring it to a separatory funnel
containing 3 mL of brine using 30 mL of Et
2
O. The aqueous layer was extracted with
Et
2
O (3x, 25 mL) and the organic layers were combined, dried over MgSO
4
, concentrated
(aspirator), and purified via silica gel chromatography using 20% EtOAc in hexanes to
give 0.067 g of 2EE2 (61%) as 50:1 mixture with 2EE3 along with 16% of recovered 13.
A trace (<1%) of demethylated alcohol (2J1e) was observed, but demethylated products
2J2e or 2J3e were not detected.
90

Synthesis of trans-2,2-dimethyl-5-dodecen-3-ol 2R6
OH
2R6

2R6 was synthesized using the method of Negishi et al.
49
A 0 C solution of 1-heptyne
(2.36 mL, 18 mmol) in hexanes (40 mL) was treated with a solution of DIBAL-H (3.2
mL, 18 mmol) in hexanes (16 mL) under N
2
. The transfer of DIBAL-H was completed
with hexanes (2 mL). The reaction was stirred for 30 min at rt before warming to 55 C
for 4 h. The reaction was then cooled to rt and 1.42 M nBuLi (12.67 mL, 18 mmol) was
added dropwise. The reaction became a white sludge while stirring for 20 min before a
solution of tbutyl-oxirane (2.4 mL, 19.7 mmol) in hexanes (20 mL) was added via
cannulation under N
2
. The reaction was stirred for 24 h at rt before cooling to 0 C and
adding 3N HCl (10 mL), which stirred for 1 hwhile warming to rt. Satd Rochelles salt
(30 mL) was added to the reaction, which was then transferred to a separatory funnel.
The aqueous layer was removed and rinsed with hexanes (2X, 80 mL). The organic layer
were combined, dried over MgSO4, filtered, and concentrated (aspirator), and purified
via silica gel chromatography in 15% EtOAc in hexanes followed by kugelrohor
distillation to provide 2R6. Yield was not recorded. (
1
H NMR (500 MHz, CDCl
3
, o):
0.88 (t, J= 7.5 Hz, 3H). 0.91 (s, 9H), 1.22-1.40 (m, 6H), 1.65 (d, J= 3 Hz, 1H). 1.85-
1.94 (m, 1H), 2.02 (q, J= 7.5 Hz ,2H), 2.27-2.34 (m, 1H), 3.19 (dt, J= 11 Hz, 2.5 Hz,
2H), 5.39-5.47 (m, 1H), 5.52-5.59 (m, 1H).


91


Synthesis of cis-2,2,7,7-tetramethyl-5-octen-3-ol 2S6 and cis-2,2-dimethyl-5-dodecen-
3-ol 2S7.
OH
2S6
OH
2S7

To a -78 C solution of 3,3-dimethyl-1-butyne (3.7 mL, 30 mmol) in THF (30 mL) was
added 1.38 M nBuLi (21 mL, 29 mmol), under N
2
. The reaction stirred for 20 min at -78
C before neat tbutyl-oxirane (4 mL, 33 mmol) was added dropwise, followed by
BF
3
OEt
2
(3 mL, 24.3 mmol). The reaction stirred for 2.5 h at -78 C before 15 mL of
satd NaHCO
3
was added. The reaction warmed to 0 C over 10 h. The THF layer was
separated from the aqueous layer, which was then rinsed with Et
2
O (2X 40 mL). The
organic layers were combined, dried over MgSO
4
, filtered, and concentrated to provide
crude 2,2,7,7-tetramethyl-5-octyn-3-ol. To a 0 C solution of cyclohexene (9.8 mL, 97
mmol) in Et
2
O (30 mL) was added 10 M BMS (4.6 mL, 46 mmol) dropwise under N
2
.
The reaction stirred at 0 C for 3 h before the solvent was blown down with N
2
through
the septum followed by placing the white powder under high vac.
67
The white powder
was suspended in THF (20 mL) and cannulated into a 0 C solution of 2,2,7,7-
tetramethyl-5-octyn-3-ol (19.56 mmol) in THF (10 mL). The transfer was completed
with THF (2X 10 mL) and the reaction stirred for 14h at rt. The reaction was cooled to 0
C and AcOH (15 mL, 250 mmol) was added. The reaction was heated to 60 C for 90
min. Solvent was removed via rotovap and the residue was treated with 1:1 CH
2
Cl
2
: 4M
KOH (60 mL) and stirred for 40 h. The mixture was transferred to a separatory funnel
and the organic layer was removed from the aqueous layer, which was rinsed with
92

CH
2
Cl
2
(3X 30 mL). The organic layer were combined and rinsed with satd NH
4
Cl (3X
25 mL) and Brine (40 mL), dried over MgSO
4
, filtered, concentrated (aspirator), and
purified via silica gel chromatography using 2% Et
2
O in hexanes to give 1.5 g of cis-
2,2,7,7-tetramethyl-5-octen-3-ol 2S6 (42%): (
1
H NMR (400 MHz, CDCl
3
, o): 0.93 (s,
9H). 1.12 (s, 9H), 1.27 (br s, 1H), 2.32 (m, 2H). 3.23 (dt, J= 9.2 Hz, 4 Hz, 1H), 5.26 (m,
1H), 5.54 (dt, J= 12 Hz, 2 Hz, 1H). Analogous conditions were used with 1-heptyne or
methyloxirane to generate 2S5
68
and 2S7. (
1
H NMR (400 MHz, CDCl
3
, o): 0.89 (t, J=
6.8 Hz, 3H). 0.93 (s, 9H), 1.22-1.40 (m, 6H), 2.0-2.26 (m, 4H). 3.09 (dt, J= 10 Hz, 3.2
Hz, 1H), 5.4-5.49 (m, 1H), 5.54-5.63 (dt, J= 12 Hz, 2 Hz, 1H).

Synthesis of trans-2-isopropyl-3-pentenol 2T1
OH
2T1

To a -78 C solution of 3-pentenoic acid (0.2 mL, 1.93 mmol) in HMPA (2 mL) and THF
(8 mL) was added 1.28 M (3.92 mL, 5 mmol) under N
2
. The reaction stirred for 30 min
before addition of 2-iodopropane (0.24 mL, 2.4 mmol) in THF (2 mL). The reaction
stirred for 3 h, warming to 0 C. 1 N HCl (4 mL) was added to quench the reaction,
which was transferred to a separatory funnel containing Et
2
O (40 mL). The aqueous
layer was extracted with Et
2
O (4X 40 mL). The organic layers were combined, dried
over MgSO4, filtered, and concentrated. Reduction of the crude mixture with LAH (0.31
g, 11.2 mmol) followed by silica gel chromatography in 10% EtOAc in hexanes provided
0.072 g of synthesis of trans-2-isopropyl-3-pentenol 2T1 (29%).
1
H NMR (500 MHz,
93

CDCl
3
, o): 0.86 (d, J= 7 Hz, 3H). 0.89 (d, J= 7 Hz, 3H), 1.52 (br s, 1H), 1.62 (m, 1H).
1.72 (dd, J= 6.5 Hz, 1.5 Hz, 3H), 1.95 (m, 1H), 3.38 (t, J= 10 Hz, 1H), 3.63 (dd, J= 10.5
Hz, 5 Hz, 1H), 5.22 (m, 1H), 5.56 (dq, J= 15 Hz, 6.5 Hz, 1H).
13
C NMR (125 MHz,
CDCl
3
, o): 18.13, 19.58, 20.77, 28.89, 52.53, 64.09, 129.25, 130.53.
ODHB with 2T1
To a -78 C solution of 10.1 M BMS (60 L, 0.61 mmol) in CH
2
Cl
2
(3 mL) was added
TfOH (50 L, 0.55 mmol) dropwise under N
2
. This stirred for 30 min at -78 C before
adding a solution of 2T1 (0.141 g, 0.32 mmol) and cyclohexene (0.16 mL, 1.58 mmol) in
CH
2
Cl
2
(2 mL). The reaction mixture was then stirred for 10 h at -20 C before adding
20% NaOH (0.4 mL) in MeOH (0.6 mL) followed by 35% H
2
O
2
(0.2 mL). The reaction
mixture stirred for 12 h at rt before transferring it to a separatory funnel containing brine
(2 mL) and Et
2
O (25 mL). The aqueous layer was extracted with Et
2
O (4X, 25 mL). The
organic layers were combined, dried over Na
2
SO
4
, filtered, concentrated (aspirator), and
purified via silica gel chromatography in 20% EtOAc in hexanes to collect 0.016 g of one
1,3-diol diastereomer (35%) and 0.015 g of the other (32%). No 1,4-diol regioisomer
was observed. Top 1,3-diol diastereomer:
1
H NMR (400 MHz, CDCl
3
, o): 0.92 (d, J= 7
Hz, 3H). 0.96 (t, J= 7.6 Hz, 3H), 1.01 (d, J= 7 Hz, 3H), 1.18 (m, 1H). 1.56-1.65 (m, 2H),
1.97 (oct, J= 6.4 Hz, 1H), 2.66 (br s, 1H), 2.91 (br s, 1H), 3.81 (m, 1H), 3.88-3.98 (m,
1H). Bottom 1,3-diol diastereomer:
1
H NMR (400 MHz, CDCl
3
, o): 0.95 (d, J= 6.4 Hz,
6H). 1.03 (t, J= 7.2 Hz, 3H), 1.5-1.68 (m, 4H), 2.74 (br s, 2H). 13.74-3.89 (m, 3H).



94

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Structural Characterization of MnH-B Interactions in Solution and in the Solid.
Dalton Transactions 2005, 171.

100

67. Abiko, A. Dicyclohexylboron trifluoromethanesulfonate. Org. Synth. 2003, 1,
103-108.
68. Blum, A.; Hess, W.; Studer, A. Stereocontrolled Formation of Vinylsilanes via
Homolytic Substitution at Silicon. Synthesis 2004, 2226.





















101

Chapter 3: The Impact of Ipc
2
BH on Synthetic Organic Chemistry
The creation of chiral centers in asymmetric fashion is a cornerstone of organic
synthesis and a frontier whose limits will be pushed for generations to come. Almost
fifty years ago, hydroboration earned the distinction of being one of the first synthetically
practical, non-enzymatic methods for generating an asymmetric center. This was
achieved by H. C. Brown through the generation of a C2-symmetric boron environment
in diisopinocampheylborane (Ipc
2
BH). While Brown immediately recognized the
ground-breaking nature and potential of the asymmetric induction, the C2-symmetric
nature of the reagent was initially unheralded. The following chapter will illustrate the
impact of Browns discovery over the past half century in the context of 1) the evolution
of asymmetric hydroboration and 2) the development of C2-symmetric boron species as
enantioselective reagents for organic synthesis.
3.1: The Evolution of Asymmetric Hydroboration
3.1i: Diisopinocampheylborane
In 1961, just five years after hydroboration in ethereal solvents was first reported,
1

Brown and Zweifel discovered that hydroboration of the naturally abundant chiral
terpene o-pinene 3A1 stops at the dialkylborane stage to asymmetrically form the
C2-symmetric dialkylborane diisopinocampheylborane (Ipc
2
BH) (3A2). This is
attributed to the steric bulk of both 3A1 and 3A2 preventing further reaction.
Fortunately, further reaction of 3A2 occurs with less hindered substrates. Olefins such as
cis-2-butene, cis-3-hexene, and norbornene react with 3A2 to provide (R)-2-butanol (R)-
3A3, (R)-3-hexanol (R)-3A4, and (1R,2S)-exo-norborneol 3A5 with respective
enantiomeric purities of 87%, 91%, and 83% after oxidative workup (Scheme 3A).
2

102

NaBH
4
, BF
3
OEt
2
Diglyme
3A1
1. cis-2-butene
2. NaOOH
OH
90 % yield
87% ee
1.
2. NaOOH
H
OH
62% yield
83% ee
1. cis-3-hexene
2. NaOOH
OH
81% yield
91% ee
Scheme 3A: The First Reported Asymmetric Hydroborations with Ipc
2
BH
B
H
3A2 3A3
3A4 3A5
Obtaining (R)-3A4 with an enantiomeric purity of 91% is of particular importance: since
o-pinene was available in 90% purity, this indicates that the formation of 3A2 occurs
with complete enantioselectivity.
High enantioselectivity is elusive with a broader range of olefins. While
cis-1,2-disubstituted (Type II) olefins are excellent substrates for asymmetric
hydroboration with Ipc
2
BH (3A2), the more hindered trans-1,2-disubstituted (Type III)
and trisubstituted (Type IV) olefins lead to lower enantioselectivities and loss of pinene
from 3A2 via retrohydroboration during the reaction. In the case of trans-2-butene two
equivalents of substrate are consumed for every equivalent of pinene released in the
reaction, while only one equivalent of the more hindered 1-methyl-cyclopentene is
consumed for each equivalent of pinene released. Brown reports that the loss of pinene is
the result of the equilibrium between the Ipc
2
BH dimer 3B1 and
triisopinocampheyldiborane 3B2 (Ipc
3
B
2
H
3
), which then reacts with the substrate at the
103

less substituted boron.
3
In the case of 3-methyl-cyclopentene, the initial hydroboration
must lead to a species (presumably 3B5) with sufficient steric bulk to prevent a second
hydroboration. Conversely, the less hindered trans-2-butene can react a second time,
accounting for the different ratios of consumed substrate : recovered pinene (Scheme
3B). Also worthy of note is the fact that the low enantiomeric purities observed in these
cases were opposite to those predicted by Browns model for Ipc
2
BH.


Enantiomeric purities of alcohols derived from the hydroboration of 1,1-
disubstituted (Type I) olefins with Ipc
2
BH (A2) are also low. In the case of 2-methyl-1-
butene, Ipc
2
BH generates (R)-2-methyl-1-butanol (R)-C1 with 21% ee (Scheme 3C).
Brown noted that reduced selectivity is to be expected in cases where the boron does not
become directly attached to the stereogenic carbon,
4
and differentiating a methyl group
104

from an ethyl group presents a challenge for any asymmetric transformation. Increasing
the steric differentiation of the olefin substituents using 2,3-dimethyl-1-butene leads to
(R)-2,3-dimethyl-1-butanol (R)-3C2 with 30% ee after oxidative workup (Scheme 3C).
Partial loss of pinene (9 % and 7 %, respectively) is observed in these reactions,
suggesting, though not explicitly concluded by Brown, that Ipc
3
B
2
H
3
3B2 is contributing
to the results.



Almost twenty years after the discovery of 3A2, Brown published an improved
synthesis of the reagent, making it readily available in 99% enantiomeric purity from
92% enantio-enriched pinene.
5
This enables greater selectivity with type II olefins in
tetrahydrofuran (THF) at -25 C. The increased purity of the reagent and lower reaction
temperatures are necessitated by the switching of solvent from diglyme to THF leading to
increased formation of monoisopinocampheylborane 3F2 (IpcBH
2
), which interferes with
selectivity at room temperature. More hindered substrates require higher reaction
temperatures, which lead to the aforementioned loss of pinene, rendering the improved
3A2 less effective. A summary of the selectivities achieved with 3A2 is provided in
Table 3D.

105

Table 3D: Asymmetric Hydroboration with Diisopinocampheylborane
Type of Olefin Substrate ee of Alcohol (%)
II 2-butene 98 (R)
a

II 3-hexene 93 (R)
a

II norbornene 83 (1S,2S)
a

III 2-butene 13 (S)
b

IV 1-Me-cyclopentene 22 (S,S)
b

I 2-Me-1-butene 21 (R)
b

I 2,3-dimethyl-1-butene 30 (R)
b

a) Achieved with the 99% enantiopure 3 in THF @-25 C
5

b) Achieved with 92% enantiopure 3 in diglyme @ rt.
3, 4


3.1ii: Monoisopinocampheylborane
Ten years passed between the report that monoisopinocampheylborane 3F2
(IpcBH
2
) can be generated in situ from triisopinocampheyldiborane 3B2 and the report
introducing pure IpcBH
2
as a hydroborating reagent.
6
Synthesis of 3F2 cannot be
achieved by simply treating a single equivalent of pinene with a stoichiometric amount of
BH
3
THF because the reaction cannot be stopped at the monohydroboration stage.
7

Brown et al. circumvented this complication by generating IpcBH
2
triethylamine
complex 3E3 from thexylborane-triethylamine complex (ThxBH
2
NEt
3
) 3E1 and pinene
3A1 (Scheme 3E). The thexyl group serves as a protecting group for the borane: initially
preventing the formation of Ipc
2
BH NEt
3
before undergoing retro-hydroboration to
generate tetramethylethylene (TME) 3E2 and the desired complex 3E3. Hydroboration
studies were conducted by treating 3E3 with an equivalent of BH
3
THF to free the
IpcBH
2
, followed by 1-methyl-cyclopentene, 2-methyl-2-butene, or 1-methyl-
cyclohexene. Subsequent oxidation led to (1S,2S)-2-methyl-cyclopentanol (1S,2S)-3E4,
(S)-3-methyl-2-butanol (S)-3E6, and (1S,2S)-2-methyl-cyclohexanol (1S,2S)-3E5 with
55% ee, 53% ee, and 72% ee, respectively.
106




A revised synthetic route was developed before IpcBH
2
was presented as a
reagent for hydroborating other types of olefins. The convenience and optical purity
provided by the route displayed in Scheme 3E was surpassed by an approach involving
treatment of Ipc
2
BH 3A2 with N,N,N,N-tetramethylethylene-diamine (TMEDA) followed
by equilibration at 34 C to form the TMEDA 2BH
2
Ipc complex 3F1 with loss of pinene
(Scheme 3F). TMEDA 2BH
2
Ipc complex 3F1 can be formed with enantiomeric purity
approaching 100% from 94% ee pinene, and 3F1 releases IpcBH
2
(3F2) upon treatment
with BF
3
OEt
2
. The byproduct TMEDA 2BF
3
(3F3) precipitates from THF but 3F3 is
inert so its removal is not necessary for hydroboration to occur smoothly.
8




107


Scheme 3F: Improved Synthesis of IpcBH
2
3F1
B
H
3A2
BH
3
SMe
2 TMEDA
3A1
3F1
3F1
BF
3
OEt
2
B
H
H
F
3
B N
N BF
3
3F2
3F3
H
B
H
N
N B
H
H



Table 3G summarizes the results of a series of publications following this revised
synthesis of IpcBH
2
3F2, illustrating its synthetic utility.
9-11
It is important to note that
Ipc
2
BH (A2) and IpcBH
2
3F2 are complimentary in terms of substrate scope: while 3A2
only works well on Type II olefins, 3F2 works well on Types III and IV but poorly on
Type II olefins. It is also convenient that both of these reagents can generate either
desired enantiomer due to the commercial availability of both (+) and (-) o-pinene. Table
3P is provided for a direct comparison of asymmetric hydroboration reagents. Despite all
the advantages of Browns Ipc
2
BH (3A2) and IpcBH
2
(3F2), the only substrates that are
beyond optimization are 1-phenyl-cyclopentene and, arguably, Type II olefins. Every
other substrate provides opportunity for improvement, and Type I olefins in particular.







108

Table 3G: Enantioselective Hydroboration with Monoisopinocampheylborane
B
H
H
3F2
1. Substrate, THF
2. NaOOH
OH
Alcohol +


a) Result published using method from Scheme D
12






Substrate Product Yield
(%)
ee
(%)
Substrate Product Yield
(%)
ee
(%)
Ph

Ph
HO
1S, 2R


92

100


OH
S


NR
a


23.6
Ph

Ph
HO
1S, 2R


79

88

Et Et
Et Et
OH
S


NR
a


19.7

Ph


Ph
OH
2S, 3R


89

81


OH
S


73

73

Ph

Ph
OH
2S, 3S


91

82

Et
Et

Et
Et
OH
S



83

75

Ph
Et

Ph
Et
OH
2S, 3R


87

85

Ph

Ph
OH
R


72

75

Et
Ph

Et
Ph
OH
2S, 3S


95

85

109


3.1iii: Dilongifolylborane
Despite the complementary nature of Ipc
2
BH (3A2) and IpcBH
2
(3F2), Brown
pursued a reagent that could stereoselectively hydroborate both hindered and unhindered
olefins, proposing that the defining characteristic of such a reagent would be a steric
environment simultaneously more hindered than 3F2 and less hindered than 3A2. These
requirements were met by the hydroboration of the sesquiterpene (+)-longifolene 3H1 to
form dilongifolylborane 3H2.
13
The reagent is convenient to synthesize because the
hydroboration of 3H1 stops at the diakylborane stage, at which point 3H2 precipitates
from ether. While the bulkiness of 3H2 makes its steric requirement greater than that of
3F2, the fact that the C-B carbons are primary enables the steric requirement to be less
than that of 3A2. This does allow the use of 3H2 for hydroboration of a broader range of
olefins with good selectivity (Table 3H). However, Type I and Type II olefins are not
3H1
H
B
H
BH
3
SMe
2
Et
2
O
H
3H2
1. Substrate
2. NaOOH
H
2
O
2
H
HO
Alcohol
Table 3H: Enantioselective Hydroboration with Dilongifolylborane
3H3

Substrate Alcohol Yield (%) ee (%) Substrate Alcohol Yield (%) ee %


OH
R


71

78
Et

Et
OH
R

76 75

Et Et

Et Et
OH
R


81

71

HO
1R, 2R

83 63

OH
R


79

70
Et

Et
HO
1R, 2R

81 59
110

discussed in this report and the selectivities reported for type II and type IV olefins are
not as synthetically useful as those for 3A2 and 3F2.

3.1iv: Limonylborane
Jadhav synthesized limonylborane 3I3 from another naturally abundant terpene:
limonene 3I1. Treating 3I1 with monochloroborane etherate (BH
2
Cl OEt
2
) forms the
bicyclic chloroborane 3I2, which is converted to 3I3 by LiAlH
4
in the presence of the
alkene substrate. While 3I3 does provide reasonable enantioselectivities for all but type I
olefin substrates, the selectivities, once again, do not approach those achieved with
Ipc
2
BH 3A2 and IpcBH
2
2F2 (Table 3I).

B
Cl
BH
2
ClOEt
2
Alcohol +
HO
HO
Table 3I: Enantioselective Hydroboration with Limonylborane
LiAlH
4
B
H
3I1 3I2 3I3
1. Substrate
2. NaOOH
3I4


Substrate Alcohol Yield (%) ee (%) Substrate Alcohol Yield (%) ee (%)


OH
R


78

55

HO
R


75

5.2


OH
R


75

58.6

HO
1R, 2R


77

46

OH
R


70

66.5




111

3.1v: (R,R) and (S,S)-2,5-Dimethyl-borolane and Related Reports
Not until 1985 was Browns dominance in the field of asymmetric hydroboration
faced with strong competition. Foregoing the Brown approach of forming chiral (di)alkyl
boranes by hydroborating terpenes, but returning to a C2-symmetric species, Masamune
targeted (R,R)-2,5-dimethylborolane (R,R)-3J7 using an approach involving chiral
resolution via amino alcohol complexes.
14
The synthetic route, illustrated in Scheme 3J,
is quite arduous. The borolane ring is assembled as an aminodialkylborane 3J2 by
treating (diethylamino)dichloroborane with bis-Grignard reagent 3J1. After
methanolysis to methoxyborolane 3J3, multiple resolutions with aminoalcohols allow
isolation of enantio-enriched material. N,N-dimethylethanolamine preferentially
complexes to cis-3J3 to form 3J4, which precipitates from Et
2
O, allowing separation of
112

racemic trans-3J4 from the solution. (S)-Prolinol selectively forms complex 3J5 from
(R,R)-3J3, allowing for separation from its enantiomer (S,S)-3J3, which can be recovered
as an enriched complex to (S)-valinol (not pictured). Complex 3J5 undergoes
methanolysis to form (R,R)-3J3, which is reduced by LiAlH
4
to form the lithium
borohydride-etherate 3J6. Treating 3J6 with excess methyl iodide (MeI) abstracts a
hydride, allowing borolane dimer 3J7 to form.
15
One of the most impressive aspects of
the synthesis is that it was undertaken with the knowledge that 3J7 might dimerize and
then isomerize into 2,5,5,9-tetramethyl-1,6-diborocyclodecane, 3J8. The analogous
conversion occurs with the parent borolane, rendering it incapable of hydroboration.
16, 17

Fortunately, the isomerization is slow enough that 3J7 can be used as a reagent for
exceptionally enantioselective hydroboration with any generic prochiral olefin except
Type I (Table 3K). This work could have rendered Browns Ipc
2
BH 3A2 and IpcBH
2

3F2 obsolete if not for the incredibly challenging synthesis of 3J7. Masamunes work has
yet to be duplicated in any context reported in the literature but the proof of concept
provides a challenge to the chemical community to find a more synthetically viable
method of generating enantio-pure C2-symmetric hydroboration agents.





113

B
H
H
LiOEt
2
1. Substrate, MeI, Et
2
O
2. NaOOH
3J9
Alcohol +
OH
OH
Table 3K: Enantioselective Hydroboration with (R,R)-2,5-Dimethylborolane
4K1

Substrate Alcohol
Yield
(%)
ee
(%)
a

Substrate Alcohol
Yield
(%)
ee
(%)
a




OH
S

75 97.6

HO
(S,S)

89 100



OH
S

71 99.5

HO
(S,S)

60 95.6

Et Et


Et
Et
OH
S

83 99.9

OH
S

97 99.3

Et
Et


Et
Et
OH
S

83 99.5


OH
S

90 94.2

HO
H
S

85 1.5
a) adjusted to compensate for the slight cis-borolane impurity present during the reaction.
Hodgetts and coworkers tried to answer the challenge by targeting the more
hindered borolane, 2,5-diisopropyl-borolane 3L5.
18
Optimum conditions were developed
for diastereoselective hydroboration of 2,7-dimethyl-2,6-octadiene 3L1 to favor trans-
2,5-diisopropyl-borolane. Treating 3L1 with dimethylsulfide monobromoborane
(BH
2
Br SMe
2
) in carbon tetrachloride at 76 C provides 4 : 1 trans-selectivity in 70 %
overall yield. The undesired cis-borolane forms complex 3L3 upon treatment with
pyrrolidinoethanol, allowing purification of racemic trans-methoxyborolane via cannula
114

filtration and distillation to provide 3L4 in 63% yield. However, no further progress
towards an enantiopure hydroborating reagent was reported, leaving Masamunes legacy
unfulfilled (Scheme 3L). Despite taking Masamunes arduous aminoalcohol resolution
approach, the improved borolane ring synthesis via diastereoselective hydroboration
rather than bis-Grignard addition makes Hodgetts' work noteworthy, as it doubles the
yield of racemic-trans-borolane after separation from the undesired cis-isomer.
1.BH
2
BrSMe
2
CCl
4
, 76 C
2. MeOH
B
OMe
4 : 1 d.r.
70%
OH
N
hexanes, -78 C
B
OMe
racemic
B
H
(S,S) or (R,R)
B
N
O
3L1 3L2 3L4 3L5
3L3
Scheme 3L: Hodgett's Progress Toward Enantiopure 2,5-Diisopropylborolane


Knochel recognized the significance of C2-symmetry in asymmetric
hydroborating reagents and pursued what he refers to as pseudo-C2-symmetric
monoalkylboranes 3M1-3, in which C2-symmetric alkyl appendages are incorporated on
boron.
19
Considering the general difficulty in achieving chiral induction with Type I
olefins due to the spatial separation of the chiral boron environment from the prochiral
center of the substrate,
4
it is understandable that the enantioselectivity achieved with 3M2
is lower than that achieved with borolane 3J7 (Table 3M). Not only is the selectivity
low, but the syntheses of boranes 3M1 and 3M2 involve 9-10 steps and will not be
elaborated in this text. Psuedo-C2-symmetric boranes are clearly not worthy successors
to Masamunes borolane, as their syntheses are longer and their selectivities are inferior.


115

Table 3M: Enantioselective Hydroboration with Knochels boranes
Borane Substrate Yield
(%)
ee
(%)
Borane Substrate Yield
(%)
ee
(%)
Ph Ph
BH
2
3M1




59

38
Ph Ph
BH
2
3M1



68

38
BH
2
3M2




54

55
BH
2
3M2



67

64
Ph Ph
BH
2
3M3




57

29 Ph Ph
BH
2
3M3



66

52


3.1vi: B-H-9-Boracyclo[3.3.2]decanes
Less than two years ago, came a report of a reagent that improved upon the 30%
ee hydroboration with Type I olefins achieved by Brown in 1964. The Soderquist group
combined a version of Masamunes resolution technique with an ingenious homologation
approach to access chiral bicyclic boranes reminiscent of Jadhavs limonylborane 3I3.
20

Exploiting single carbon homologation capabilities of boron, B-methoxy-9-
borabicylco[2.2.1]nonane (B-MeO-9-BBN) 3N1 was converted into B-methoxy-10-
trimethylsilyl-9-borabicylco[3.3.2]decane 3N2a and B-methoxy-10-phenyl-9-
borabicylco[3.3.2]decane 3N2b using the appropriately substituted diazomethane
reagents. Each enantiomer is isolable by crystalization via sequential treatment with the
two enantiomers of pseudoephedrine (Scheme 3N).

116

B
OMe
RCHN
2
hexanes
reflux, 10 h
B
TMS
OMe
Ph Me
NHMe HO
racemic
B
TMS
Ph
Me
NHMe
O
MeCN
B
TMS
OMe
B
TMS
Ph
Me
MeHN
O
Ph Me
MeHN OH
3N2a R= TMS: 97 %
3N2b R= Ph: 90 %
3N3a(S): R= TMS: 38 %
3N3b(S): R= Ph: 39.5 %
Scheme 3N: Generation and Resolution of Soderquist's 9-Boracyclo[3.3.2]decanes
3N1
3N3a(R): R= TMS: 28 %
3N3b(R): R= Ph: 28 %
3N2


The enantiopure complexes 3N3a and 3N3b are reduced to their respective
borohydrides 3O1 and 3O2, followed by hydride abstraction with TMSCl to generate the
chiral reagent for hydroboration, similar to the approach of Masamune (Table 3O).
Enantioselectivities from 28 to 98% ee are achieved with Type I olefins, which sets this
work apart from its predecessors.
21
The 10-TMS- and the 10-Ph-9-borabicylco-
[3.3.2]decane reagents 3O1 and 3O2 are similar to Browns Ipc
2
BH 3A2 and IpcBH
2

3F2 in that neither is ideal for all four olefin types, although they complement each other
in terms of substrate scope. Table 3P has been compiled for convenient comparison of
asymmetric hydroborating agents. Soderquists reagents are clearly best for Type I
olefins and hold their own with Masamunes borolane with Type III olefins. Synthetic
route aside, Masamunes borolane is the best reagent for Type IV olefins and Type II
olefins, which also provide comparable enantioselectivities upon treatment with Browns
Ipc
2
BH 3A2.


117



Borane
Source
Substrate Alcohol Yield
(%)
ee
(%)
Borane
Source
Substrate Alcohol Yield
(%)
ee
(%)
3O1-R


OH
S

98 84 3O2-S


OH
S

90 32
3O1-R


OH
R

95 95 3O2-S


OH
S

90 96
3O1-R

HO
H
S


87

40
3O2-S
OH
S

79 74
3O1-R

HO
H
S


60

56
3O2-S

HO
H
R

84 92
3O1-R
Ph

Ph HO
H
S


83

66
3O2-S
D
Ph

Ph
D
HO
H
R

97 92
3O1-S

HO
H
R


82

52
3O2-S
Ph
Ph HO
H
R

95 78
3O1-S
D
Ph

Ph
D
HO
H
R


86

98
3O2-R

HO
H
S

83 28

3O2-R

HO
H
S

97 38


118


3.1vii: Summary of Asymmetric Hydroboration
In summary, the major breakthroughs in asymmetric hydroboration include
Browns terpene-hydroboration approach, Masamunes C2-symmetric borolane
approach, and Soderquists bicyclicborane approach. All three incorporate a resolution
of some kind: Browns IpcBH
2
from Ipc
2
BH are resolvable using TMEDA and both
Masamune and Soderquist use chiral aminoalcohols for resolving borane enantiomers.
Both the Brown ipc-derived reagents and the two Soderquist reagents 3O1 and 3O2
complement each other to allow good enantioselectivity with all four types of prochiral
alkene substrates. However, neither of those four reagents approach the versatility of
Masamunes C2-symmetric borolane, which provides both 1) a standard by which other
asymmetric hydroboration reagents are judged, and 2) an obvious indication as to how
said standard could be surpassed.



119


120

3.2 C2-Symmetric Boron Reagents in Organic Synthesis
The synthetic application of Browns C2-symmetric diisopinocampheylboron
(Ipc
2
B-) moiety is not limited to hydroboration. It has been used in a wide variety of
asymmetric transformations including ketone reductions, aldol reactions, and several
different variations of aldehyde allylation. It has also provided a model for implementing
new C2-symmetric boron species in the context of the aforementioned transformations
and others.
3.2i Asymmetric Aldol Reactions Using C2-Symmetric Borons as Lewis Acids
In 1984, Meyers used diisopinocampheylborane triflate (Ipc
2
BOTf) to investigate
an alternative to Evans chiral auxiliary approach to asymmetric aldol reactions.
Whereas Evans has achieved stereoselective aldol reactions by forming a boron enolate
from an enantio-enriched substrate 3Q1 with a racemic boron Lewis acid (Scheme 3Q),
22

Meyers proposed using a racemic substrate with an enantio-enriched boron Lewis acid.
23

Treating 2-ethyl-4,4-dimethyl-2-oxazoline 3R1 with Ipc
2
BOTf provides azaenolate 3R2,
which provides the threo-addition product 3R4 with 9 : 1 diastereoselectivity and 77%
ee after treatment with an aldehyde followed by subsequent oxidative workup with H
2
O
2

(Table 3R). While these selectivities do not eclipse those achieved by Evans it is clear
that the C2-symmetric boron environment generates significant enantioinduction.
O
SMe
N O
O
B
OTf
OB(nBu)
2
SMe
N O
O
H
O
THF
-78 C
O
SMe
N O
O
OH
>99 : 1 Erythro
96.8% ee
Scheme 3Q: Evans' Chiral Auxiliary Approach to Stereoselective Aldol Chemistry
3Q1 3Q2
3Q3

121

O
N
Ipc
2
BOTf
iPr
2
NEt
O
N
B(Ipc)
2
R H
O
Et
2
O, -78 C
O
N
Me
OH
R
threo-3R4
N
O
B
O
Ipc
Ipc
H
R
H
2
O
2
Table 3R: Stereoselectivity of Ipc
2
B Azaenolates in Aldol Reactions
3R1 3R2 3R3

Entry R Threo : Erythro ee (%)
1 Et 92 : 8 77
2 nPr 91 : 9 77
3 nPent 90 : 10 77
4 iPr 91 : 9 85
5 chex 95 : 5 84
6 tBu 94 : 6 79

Meyers success inspired Paterson to investigate a more traditional chiral enolate
equivalent using Ipc
2
BX species with ethyl and methyl ketones.
24,25
It was found that
treating an ethyl ketone 3S1 with Ipc
2
BOTf and Hunigs base in CH
2
Cl
2
at -78 C
provides a >97:3 preference for the Z-enolates 3S2. Treating the Z-enolate with an
aldehyde followed by oxidative workup provides excellent syn-diastereoselectivity and
enantioselectivity (Table 3S). Enolization of diethylketone with Ipc
2
BCl and Et
3
N occurs
with modest selectivity to generate a 4:1 E- : Z- mixture of enol borinates. Treating this
mixture with methacrolein followed by H
2
O
2
generates a 4:1 anti:syn aldol mixture,
which is to be expected. However, the corresponding anti-aldol product is generated in
<20% ee and the syn-aldol product is generated in 80% ee, which is 11% lower than the
result reported in entry 1 of Table 3S. Paterson et al. point out that enol
diisopinocampheylborinates with E configuration are unlikely to be useful for
asymmetric anti aldol reactions. Investigation of methylketone-derived enol borinates
led to the observation of good enantio-induction using either Ipc
2
BCl or Ipc
2
BOTf.
122

Interestingly, the enantiofacial selectivity of aldehydes with methyl ketone-derived enol
borinates (re-face) is the opposite of that for the ethyl ketone analogs (si- face).

Table 3S: Stereoselectivity of Enol Borinates in Aldol Reactions
R
1
O
Ipc
2
BOTf
iPr
2
NEt
CH
2
Cl
2
-78 C
R
1
OB(Ipc)
2
> 97 :3 Z-
R
2
H
O
O
B
O
Ipc
S
L
M
H
R
2
H
2
O
2
R
1
O
Me
OH
R
2
Major Isomer
3S1 3S2 3S3 3S4

Entry R
1
R
2
syn : anti ee (%) yield (%)
1 Et H
2
C=C(Me) 98 : 2 91 78
2 Et nPr 97 : 3 80 92
3 Et iPr 96 : 4 86 75
4 Et 2-furyl 96 : 4 80 84
5 Ph H
2
C=C(Me) 98 : 2 91 97
6 iPr H
2
C=C(Me) 95 : 5 88 99
7 iBu H
2
C=C(Me) 97 : 3 86 79

Masamune
26,27
and Reetz
28,29
have investigated asymmetric
aldol reactions with enol borinates generated from their respective
C2-symmetric borolanes. The Masamune reagent 3T5 was
generated from the borolane triflate 3T3 while the Reetz reagents
3T6 was done using borolane chloride 3T4. Table 3T illustrates that enolates generated
from either borolane consistently provide excellent enantioselectivity. Both groups
rationalize their enantioselectivities using a Zimmerman-Traxler model 3S5. While the
selectivities from Tables 3S and 3T cannot be directly compared, other work by Reetz
30

and Paterson
25
indicates that these 2,5-trans-disubstituted borolanes provide superior
enantio-induction compared to the Ipc
2
B moiety.
123

O
SC(Et)
3
R
1
3T1 R
1
= H
3T2 R
1
= Me
B
R
2
R
2
X
4T3 R
2
= Me, X= OTf
4T4 R
2
= Ph, X= Cl
SC(Et)
3
O
R
1
B
R
2
R
2
R
3
H
O
O
SC(Et)
3
R
1
R
3
OH
Table 3T: Comparing the Masamune and Reetz Borolanes in Aldol Reactions
3T5 R
2
= Me
3T6 R
2
= Ph
3T7

Entry R
1
R
2
R
3
anti- : syn- Yield of 3T7 (%) ee (%)
a

1 H Me nPr - 82 91.2
2 H Ph nHex - 78 95
3 H Me iPr - 81 91.5
4 H Ph iPr - 72 92
5 H Me cHex - 95 90.1
6 H Ph cHex - 87 95
7 Me Me nPr 33 : 1 91 97.9
8 Me Ph nHex >155 : 1 36 100
9 Me Me iPr 30 : 1 85 99.5
10 Me Ph iPr >155 : 1 82 99
11 Me Me cHex 32 : 1 82 98
12 Me Ph cHex >155 : 1 58 98.7
13 Me Me tBu 30 : 1 95 99.9
14 Me Ph tBu >155 : 1 68 94.3

Corey has also approached the problem of asymmetric aldol transformations by
application of a C2-symmetric five-membered boracycle to the formation of chiral
enolates.
31
N,N-disulfonyl-1,4-trans-diphenyl-2,5-diaza-borolanes 3U2 and 3U3 were
studied for convenient comparison to the work of Paterson, Reetz, and Masamune. The
enol borinate generated from diethylketone and 3U2 reacts with various aldehydes to
provide >94 : 6 syn-diasteroselectivity and excellent enantioselectivity (Table 3U, Entries
1-3). The diastereoselectivity indicates the formation of a Z-enol borinate and the
enantioselectivities surpass those achieved by Paterson et al. The enol borinate generated
from phenyl thioacetate and 3U2 reacts with aldehydes to provide enantioselectivities
similar to those reported by Reetz and Masamune (Table 3T, entries 4&5).
124

Bromoboracyle 3U2 is incapable of enolizing the phenylthio ester of propionic acid but
3U3 can. The resulting Z-enol borinate is an excellent complement to the E-enolates
reported by Reetz and Masamune (Table 3T), as it provides >94 : 6 syn-
diastereoselectivity and excellent enantioselectivities upon treatment with aldehydes
(entries 6 & 7).

O
R
1
R
2
N
B
N
Ph Ph
S S
O
O
Ar
O
O
Ar
Br
R
3
H
O
B
O
O
H
R
3
H
N
N
R
2
R
1
Ph
Ph
SO
2
O
2
S
Ar
Ar
O
R
1
R
2
R
3
OH
Table 3U: Aldol Reactions with B-Bromo-N,N'-disulfonyl-1,4-trans-diphenyl-2,5-diaza-borolanes
3U1
3U2: Ar= tol
3U3: Ar= pNO
2
-C
6
H
4
3U4 3U5


Entry R
1
R
2
R
3
Ar syn- : anti- yield (%) ee (%)
1 Et Me Et p-CH
3
-C
6
H
4
>98 : 2 91 >98
2 Et Me iPr p-CH
3
-C
6
H
4
98 : 2 85 95
3 Et Me Ph p-CH
3
-C
6
H
4
94.3 : 5.7 95 97
4 PhS H iPr p-CH
3
-C
6
H
4
- 82 83
a

5 PhS H Ph p-CH
3
-C
6
H
4
- 84 91
a

6 PhS Me iPr p-NO
2
-C
6
H
4
94.5 : 5.5 72 97
7 PhS Me Ph p-NO
2
-C
6
H
4
98.3 : 1.7 70 95
a) The isolated enantiomer is the opposite of the one illustrated

This section serves as a demonstration of both the versatility and influence of
Browns C2-symmetric Ipc
2
B moiety. Paterson and Meyers have made it clear that ipc
borane reagents have synthetic applications beyond hydroboration, as do the
C2-symmetric Masamune and Reetz borolanes. These borolanes participate in aldol
125

reactions to provide excellent diastereo- and enantioselectivities that surpass and/or
complement those achieved by Corey et al. with C2-symmetric 2,5-diazaborolanes. The
versatility of several of these chiral boron environments will be demonstrated further in
the following sections.


3.2ii Asymmetric Allylations Using C2-Symmetric Allyl-Boron Species
Brown et al. have extensively studied a variety of asymmetric allylations with
B-allyl-diisopinocampheylboranes (Table 3V).
32-36
Allylation of several o-branched
alkyl aldehydes provides secondary homoallylic alcohols with good enantioselectivity
(83-90% ee; entries 1-3).
32
Analogous methallylation
34
(entries 4-6) and isoprenylation
33

(entries 7 & 8) have also been achieved, (89-96% ee). Similarly, crotylation using either
E- or Z-crotyldiisopinocampheylborane generates highly diastereo-enriched alcohols with
excellent enantioselectivity (entries 9-14).
35,36
These high selectivities have been
attributed to six-membered transition states resembling erythro-3V3 and threo-3V3.
Corey has also applied his C2-symmetric B-allyl-N,N-disulfonyl-1,4-trans-
diphenyl-2,5-diaza-borolane 3W1 to the allylation of aldehydes. The enantioselectivities
(95% ee) meet if not exceed those previously reported (Table 3W).
37



126

Ipc
2
B
R
1
R
2
R
3
H R
4
O
R
1
R
2
R
3
R
4
OH
Table 3V: Enantioselectivity with Diisopinocampheylborane Allylation Reagents
O
B
CH
3
H
H
R
S
S
M
L
L
M
erythro-3V3
O
B
H
H
3
C
H
R
S
S
M
L
L
M
threo- 3V3 3V1 3V2

Entry R
1
R
2
R
3
R
4
Yield (%) threo- : erythro- ee (%) Configuration
1
a
H H H nPr 72 - 87 R
2
a
H H H iPr 86 - 90 S
3
a
H H H tBu 88 - 83 S
4
b
Me H H nPr 56 - 91 S
5
b
Me H H iPr 57 - 96 R
6
b
Me H H tBu 55 - 90 R
7
b
H Me Me nPr 79 - 92 S
8
b
H Me Me iPr 73 - 89 S
9
a
H Me H Et 70 >99 : 1 90 -
10
a
H Me H CH
2
=CH 65 >99 : 1 90 -
11
a
H Me H Ph 79 >99 : 1 88 -
12
a
H H Me Et 70 1 : 99 90 -
13
a
H H Me CH
2
=CH 63 1 : 99 90 -
14
a
H H Me Ph 72 1 : 99 88 -
(a) (+)-o-pinene was used. (b) (-)-o-pinene was used


Entry R ee (%) configuration
1 nPent 95 S
2 cHex 97 R
3 PhCH
2
=CH 97 R
4 Ph 95 R


127

The Roush group has also reported good enantioselectivities for the allylation of
simple aldehydes using 2-allyl-1,3,2-dioxaborolane-4,5-dicarboxylic esters derived from
tartrate esters 3X1.
38,39
These C2-symmetric reagents and their E-crotyl analogs have
also been investigated in the context of double asymmetric synthesis with the
o,|-dialkoxyaldehydes 3X2 and 3Y1. Roush et al. discovered that, when using aldehyde
3X2, the diastereoselectivity of alcohol formation can be reversed by simply switching
the enantiomer of diisopropyltartrate (DIPT) from which the reagent is generated. The
diastereoselectivies are not identical, which indicates that there is a matched vs.
mismatched effect, albeit a minor one. The anti-diastereoselectivity is good with either
enantiomer of the crotylating reagent (Table 3X).
O
O
O
H
O
B
O
CO
2
R
CO
2
R
O
O
OH
O
O
OH
R
1
R
1
Table 3X: Stereoselectivity with 2-Allyl-1,3,2-dioxaborolane-4,5-dicarboxylic Esters
3X1
3X2
3X3 3X4
R
1

Entry R
1
tartrate anti- : syn- 3X3 : 3X4 Yield (%)
1 H (+)-DIPT - 96 : 4 91
2 H ()-DIPT - 8 : 92 -
3 Me (+)-DIPT 96 : 4 87 : 9 87
4 Me (-)-DIPT 98 : 2 2 : 96 85

The aldehyde 3Y1 apparently creates a greater matched vs. mismatched effect in
the context of simple allylation. While the (-)-DIPT-derived reagent provides excellent
96% dr, the (+)-DIPT-derived reagent provides only 18% dr of the opposite
anti-enantiomer. Other (+)-tartrate esters were screened to find that the highest
selectivity that could be achieved was 24% dr, with (+)-diethyltartrate [(+)-DET] (Table
128

3Y, Entries 1-3). Interestingly, the corresponding crotylation provides comparable dr and
good anti-diastereoselectivities with both DIPT-derived boronate enantiomers (Entries 4-
5). While there are clearly mismatched scenarios that lead to poor selectivity in certain
cases, this methodology provides convenient access to a variety of acyclic
polyoxygenated moieties in a stereocontrolled fashion.

O
O
O
H
O
O
OH
O
O
OH
R
1
R
1
O
B
O
CO
2
R
CO
2
R
Table 3Y: Stereoselectivity with 2-Allyl-1,3,2-dioxaborolane-4,5-dicarboxylic Esters
3X1
3Y1
3Y2 3Y3
R
1

Entry R
1
tartrate anti- : syn- 3Y2 : 3Y3 Yield (%)
1 H (+)-DET - 68 : 32 63
2 H (+)-DIPT - 64 : 36 -
3 H ()-DIPT - 2 : 98 94
4 Me (+)-DIPT 97 : 3 93 : 4 88
5 Me (-)-DIPT 92 : 8 4 : 88 80

As with hydroboration and aldol chemistry, C2-symmetric boron species allow
significant progress in the field of asymmetric allylation of aldehydes. Again, Browns
Ipc
2
B moiety has provided a foundation upon which others have built: Coreys
diazaborolane provides improved selectivity for allylation while Roushs tartrate-derived
boronates have demonstrated significant allylation and crotylation applications in double
asymmetric synthesis.


129

3.2iii Asymmetric Reduction of Ketones with C2-Symmetric Boron Species
The final common application for Browns Ipc
2
B moiety is the reduction of
ketones by B-chloro-diisopinocampheylborane (Ipc
2
BCl or DIPCl). Aryl-alkyl ketones
are the best substrates for DIP-Cl, providing almost perfect enantioselectivity, while the
enantioinduction achieved on dialkyl ketones depends on o-substitution of one of the
alkyl functionalities. These trends are presented in Table 3Z: only 4% ee is achieved in
DIPCl reduction of 2-butanone (entry 1) but adding a 3-methyl group provides 32% ee
(entry 2) and adding another provides 93% ee (entry 3), which is almost as high as the
selectivity achieved on acetophenone and indanone (entries 5&6).
40, 41


Table 3Z: Reduction of Prochiral Ketones with (-)-Ipc
2
BCl
Entry Ketone ee (%) configuration
1 2-butanone 4 S
2 3-methyl-2-butanone 32 S
3 3,3-dimethyl-2-butanone 93 S
4 2,2-dimethylcyclopentanone 71 S
5 acetophenone 98 S
6 1-indanone 97.4 S


Masamunes borolane 3J9 is a complementary to DIP-Cl, in that it reduces
dialkyl ketones with excellent enantioselectivity.
42
Borolane 3AA1 by itself is not a
selective reducing reagent. However, in the presence of its corresponding mesylate
3AA2, which serves as a chiral Lewis acid,
15
superb enantioselectivity is achieved on a
variety of dialkylketones (Table 3AA). No aryl-alkyl ketones were studied. However,
the commercially available DIP-Cl is a much more convenient reagent for the asymmetric
reduction of aryl-alkyl ketones reduction due to the difficult synthesis of 3J9.

130

B H B OMs
MsOH
O
R
1
R
2
Table 3AA: Reduction of Ketones Using the Masamune Borolane
OH
R
1
R
2
B
H
H
LiOEt
2
3J9 3AA1 3AA2 3AA3

Entry R
1
R
2
yield (%) ee (%) configuration
1 Me Et 75 80.3 R
2 Me Bn 69 98.9 R
3 Me iPr 69 100 R
4 Me cHex 83 99.5 R
5 Me tBu 72 99.3 R
6 nBu iBu 72 96.8 R

Kagan has pursued asymmetric reduction of ketones using C2-symmetric
oxazaborolidine catalysts.
43
Treating acetophenone with 10 mol% of either 3BB2 or
3BB4 and stoichiometric THF BH
3
provides 1-phenyl-ethanols S-3BB3 and R-3BB3 in
65% ee and 38% ee, respectively (Scheme 3BB). These results are significant because of
the substoichiometric amounts of chiral species used. All of the other applications
discussed previously require stoichiometric amounts of asymmetric reagent(s).


131

3.2iv: C2-Symmetric Boron Species as Ligands
Kagan has also investigated asymmetric hydrogenation using C2-symmetric
phenylboronate 3CC5 derived from his (R,R)-DIOP ligand.
44
This chiral ligand was
designed to have a dual role. The phosphines are ligands for rhodium while the boronate
can participate in a Lewis-acid/base interaction with the substrate to be hydrogenated.
However, ligand 3CC5 provides reasonable selectivities on several substrates: N-acetyl
dehydrophenylalanine 3CC1 and ketopantolactone 3CC3 are both hydrogenated with
3CC5/(RhClCOD)
2
to yield 3CC2 and 3CC4 in 73% ee and 54% ee, respectively. The
boronate does not provide an advantage over the dimethyl acetal of DIOP, which
provides selectivities of 81% ee & 52% ee with 3CC1 and 3CC3, respectively.

Scheme 3CC: Asymmetric Hydrogenation with Boron Ananlog of DIOP Ligand
H Ph
N CO
2
H
H
O
H Ph
N CO
2
H
H
O
H
O
O
O
HO
O
O
H
(RhClCOD)
2
3CC5, H
2
3CC1 3CC2 3CC3 3CC4
(RhClCOD)
2
3CC5, H
2
H Ph
N CO
2
H
H
O
H Ph
N CO
2
H
H
O
H
O
O
O
HO
O
O
H
(RhClCOD)
2
DIOP, H
2
3CC1 3CC2 3CC3 3CC4
(RhClCOD)
2
DIOP, H
2
O
B
O
PPh
2
PPh
2
H
H
Ph
3CC5
O
O
PPh
2
PPh
2
H
H
DIOP
100% yield
73% ee
100% yield
54% yield
100% yield
81% ee
100% yield
52% ee



132


3.3: Summary
The C2-symmetric diisopinocampheylborane discovered by Brown in 1962 has
led to a multitude of breakthroughs in asymmetric synthesis, not only as a practical
asymmetric hydroboration reagent, but also as the starting point for enantioselective
allylation, reduction, and aldol reactions. In the realms of hydroboration, ketone
reduction, and aldol reactions, the standards for enantioselectivity set using the Ipc
2
B-
moiety have been surpassed by the Masamune trans-2,5-dimethyl-borolane.
Unfortunately, said borolane is inconvenient to synthesize. Coreys diazaborolane
moiety has proven to be a superior reagent for allylation and aldol reactions and is
conveniently produced. These results, in addition to the allylation studies published by
Roush, demonstrate that C2-symmetric (hetero)borolanes are effective boron species for
asymmetric synthesis.




















133

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25. Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.; McClure, C. K.;
Norcross, R. D. Enantio- and Diasteroselective Aldol Reactions of Achiral Ethyl
and Methyl Ketones with Aldehydes: The Use of Enol
Diisopinocampheylborinates. Tetrahedron 1990, 46, 4663.
26. Blanchette, M. A.; Malamas, M. S.; Nantz, M. H.; Roberts, J. C.; Somfai, P.;
Whritenour, D. C.; Masamune, S.; Kageyama, M.; Tamura, T. Synthesis of
Bryostatins. 1. Construction of the C(1)-C(16) Fragment. J. Org. Chem. 1989, 54,
2817.
27. Masamune, S.; Sato, T.; Kim, B. M.; Wollmann, T. A. Organoboron Compounds
in Organic Synthesis. 4. Asymmetric Aldol Reactions. J. Am. Chem. Soc. 1986,
108, 8279.
28. Reetz, M. T. Asymmetric C-C Bond Formation Using Organometallic Chemistry.
Pure Appl. Chem. 1988, 60, 1607.
29. Reetz, M. T.; Rivadeneira, E.; Niemeyer, C. Reagent Control in the Aldol
Addition of Chiral Boron Enolates Based of the 2,5-Diphenylborolane Ligand
System. Tetrahedron Lett. 1990, 31, 3863.
30. Reetz, M. T.; Kunisch, F.; Heitmann, P. Chiral Lewis-Acids for Enantioselective
C-C Bond Formation. Tetrahedron Lett. 1986, 27, 4721.
31. Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. Practical Enantioselective
Diels-Alder and Aldol Reactions Using a New Chiral Controller System. J. Am.
Chem. Soc. 1989, 111, 5493.
32. Brown, H. C.; Jadhav, P. K. Asymmetric Carbon-Carbon Bond Formation via B-
Allyldiisopinocampheylborane. Simple Synthesis of Secondary Homoallylic
Alcohols with Excellent Enantiomeric Purities. J. Am. Chem. Soc. 1983, 105,
2092.
33. Brown, H. C.; Jadhav, P. K. 3,3-Dimethylallyldiisopinocampheylborane: A NOvel
Reagent for Chiral Isoprenylation of Aldehydes. Synthesis of (+)- and (-)-
Artemisia Alcohol in Exceptionally High Enantiomeric Purity. Tetrahedron Lett.
1984, 25, 1215.

136

34. Brown, H. C.; Jadhav, P. K.; Perumal, P. T. Asymmetric Methallylboration of
Prochiral Aldehydes with Methallyldiisopinocamphenylborane - Synthesis of 2-
Methyl-1-alken-4-ols in Greater-Than 90% Enantiomeric Purities. Tetrahedron
Lett. 1984, 25, 5111.
35. Brown, H. C.; Bhat, K. S. Chiral Synthesis via Organoboranes. 7.
Diastereoselective and Enantioselective Synthesis or erythro- and threo-|-
Methylhomoallyl Alcohols via Enantiomeric (Z)- and (E)-Crotylboranes. J. Am.
Chem. Soc. 1986, 108, 5919.
36. Brown, H. C.; Bhat, K. S. Enantiomeric (Z)- and (E)-
Crotyldiisopinocampheylboranes. Synthesis in High Optical Purity of all Four
Possible Stereoisomers of |-Methylhomoallyl Alcohols. J. Am. Chem. Soc. 1986,
108, 293.
37. Corey, E. J.; Yu, C. M.; Kim, S. S. A Practical and Efficient Method for
Enantioselective Allylation of Aldehydes. J. Am. Chem. Soc. 1989, 111, 5495.
38. Roush, W. R.; Walts, A. E.; Hoong, L. K. Diastereo- and Enantioselective
Aldehyde Addition Reactions of 2-Allyl-1,3,2-dioxaborolane-4,5-dicarboxylic
Esters, a Useful Class of Tartrate Ester Modified Allylboronates. J. Am. Chem.
Soc. 1985, 107, 8186.
39. Roush, W. R.; Halterman, R. L. Diisopropyl Tartrate Modified (E)-
Crotylboronates: Highly Enantioselective Propionate (E)-Enolate Equivalents. J.
Am. Chem. Soc. 1986, 108, 294.
40. Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V. Highly Efficient
Asymmetric Reduction od o-Tertiary Alkyl Ketones with
Diisopinocampheylchloroborane. J. Org. Chem. 1986, 51, 3394.
41. Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V. Chiral Synthesis via
Organoboranes. 14. Delective Reductions. 41. Diisopinocampheylchloroborane,
an exceptionally Efficient Chiral Reducing Agent. J. Am. Chem. Soc. 1988, 110,
1539.
42. Imai, T.; Tamura, T.; Yamamuro, A.; Sato, T.; Wollmann, T. A.; Kennedy, R. M.;
Masamune, S. Organoboron Compounds in Organic Synthesis. 2. Asymmetric
Reduction of Dialkyl Ketones with (R,R)-2,5-Dimethylborolane or (R,R)-2,5-
Dimethylborolane. J. Am. Chem. Soc. 1986, 108, 7402.
43. Dubois, L.; Fiaud, J. C.; Kagan, H. B. Enantioselective Borane Reduction of
Acetophenone Catalyzed by Oxaborolidines Derived from Chiral
Diethanolamines. Tetrahedron: Asymmetry 1995, 6, 1097.
44. Borner, A.; Ward, J.; Kortus, K.; Kagan, H. B. A Boron Analog of DIOP:
Synthesis and Properties. Tetrahedron: Asymmetry 1993, 4, 2219.

137

Chapter 4: Asymmetric Hydroboration with N-Tosyl-(R,R)-2,6-diisopropyl-1,4-
borazinane

4.1 C2-Symmetric Boranes as Ideal Hydroborating Agents
Hydroboration holds the distinction of being the first practical, non-enzymatic,
enantioselective reaction in the annals of synthetic organic chemistry. Despite this head
start, the search continues for an ideal asymmetric hydroborating agent. Browns seminal
works with diisopinocampheylborane (Ipc
2
BH) and monoisopinocampheylborane
(IpcBH
2
) have stood the test of time, providing complementary species for the
asymmetric hydroboration of a variety of alkenes (Types II, III, & IV Equation 1).
1-8

Much more recently, Soderquists work with 9-boracyclo[3.3.2]decanes represents
dramatic progress in addressing the longstanding problem of asymmetrically
hydroborating Type I alkenes.
9
Despite the undeniable importance of these developments
it is Masamunes trans-2,5-dimethylborolane [(R,R)-4A1]
10,11
that serves as the closest
example of an ideal asymmetric hydroborating reagent in the literature.

Masamunes borolane (R,R)-4A1 could have rendered Browns Ipc
X
BH
(3-X)

reagents synthetically inconsequential if not for the staggering effort involved in its
synthesis. Type II, III, and IV alkenes undergo hydroboration with (R,R)-4A1 to provide
alcohols with >95% ee after oxidation.
11
No other single reagent can claim such
versatility, which falls short of perfection only in that <5% ee was observed with Type I
alkenes. Borolane (R,R)-4A1 is generated in seven air-sensitive steps from bis-Grignard
reagent 4A4, including a prolinol resolution that provides diastereo-enriched 4A3
138


(Equation 2) from the mixture of trans-2,5-dimethylborolane enantiomers. Perhaps more
courageous than the synthesis itself is that it was undertaken knowing that (R,R)-4A1
might irreversibly form an unreactive species 4A6 (Equation 2), as borolane 4A7 forms
1,6-diboradecane 4A9 at room temperature (Equation 4).
12,13

In pursuing an ideal hydroborating agent, it cannot be ignored that two of the
most significant asymmetric hydroborating reagents known, Masamune's (R,R)-4A1 and
Brown's Ipc
2
BH, both incorporate a C2-symmetric boron environment. While the
significance of (R,R)-4A1 has not gone unnoticed,
14-16
its legacy remains unfulfilled. In
an effort to expand upon what is known about cyclic C2-symmetric boranes, hopefully to
develop easier synthetic access, and perhaps also to improve upon (R,R)-4A1, we
targeted C2-symmetric borinanes and their symmetrical heteroatom-containing analogs as
described below.
Three proposed improvements to the Masamune protocol were investigated in the
pursuit of a six-membered trans-2,6-disubstituted-boracycle: 1) assemble the boracycle
with trans-diastereoselectivity, 2) increase the steric bulk of the chiral substituents by
139

incorporating isopropyl groups, and 3) use an amino acid as a complexing agent for
resolution of boracycle mixture. Diastereoselective ring assembly would conserve
material in comparison to racemic boracycle generation from 4A4. Increased steric bulk
of the isopropyl substituents vs. Masamune's methyl groups should help to maintain
enantioselectivity in case the more flexible borinane environment promotes a looser
hydroboration transition state compared to the borolane system. It is conceivable that the
isopropyl groups might even provide greater stereoinduction than methyl groups,
depending on conformational preferences of the borinane compared to the borolane.
Resolution of diastereomers as well as enantiomers with a single complexing reagent
would streamline the overall process and an amino acid complex should help suppress the
air-sensitivity issues that contribute to the inconvenience of the Masamune protocol by
forming a more stable complex with the cyclic borane.
4.2 Diastereoselective Assembly of trans-2,6-Diisopropyl-(4-hetero)borinanes
Diastereoselective assembly of C2-symmetric trans-2,6-diisopropyl-borinanes
and their 4-hetero-analogs was initially pursued by Mr. John Nelson. 2,8-Dimethyl-2,7-
nonadiene 4B1a was treated with I
2
-activated DMAP BH
3
(DMAP BH
2
I) or THF BH
3
in
an effort to achieve diastereoselective generation of trans-2,6-diisopropyl-borinane-
DMAP complex 4B4a. In the case of THF BH
3
, it was envisioned that the trisubstituted
alkenes would provide excellent anti-Markovnikov regioselectivity in an intermolecular
hydroboration step to provide intermediate 4B2a, which would undergo subsequent
intramolecular, anti-Markovnikov hydroboration to provide borinane 4B3a. Addition of
DMAP should then produce the complex 4B4a for convenient assay of
diastereoselectivity in the crude product by
1
H NMR spectroscopy. Alternatively, 4B4a
140

should be formed directly from 4B1a and DMAP BH
2
I, generated in situ from
DMAP BH
3
and iodine.
17-20
Given the differences in boron substituents at the
intramolecular hydroboration stage from 4B2a or from 4B7a, we expected to have
several options for fine-tuning hydroboration diastereoselectivity to favor the desired
trans-4B4a. However, the simpler reagent THF BH
3
proved to react with the best trans-
selectivity with all of the substrates.

Preliminary NMR assay of the product mixture left no doubt that the minor
product from 4B1a and THF BH
3
is the symmetrical DMAP complex cis-4B4a, and by
implication, supported the unsymmetrical structure trans-4B4a for the major complex.
However, both cis- and trans-4B4a were somewhat unstable upon silica gel
chromatography and could not be purified. To corroborate the NMR assays, the mixture
of hydroboration products was therefore converted into diols 4B5a and 4B6a in excellent
141

yield via standard oxidation conditions (Table 4C, entries 1&2). Both diols were
symmetrical as expected and could be assayed by HPLC. The DMAP BH
2
I conditions
afforded 4B5a and 4B6a in a ratio of 7.8:1, reflecting predominant cis-
diastereoselectivity in the internal hydroboration step from 4B7. On the other hand, the
THF BH
3
conditions provided a 1:1.9 ratio of 4B5a:4B6a, corresponding to modest
trans-diastereoselectivity from 4B2a.

Entry X Conditions
a
Time (h) Yield (%) 4B5:4B6
1
b
CH
2
A 0.5 99 7.8 : 1
2
b
CH
2
B 0.5 92 1 : 1.9
3
b
SO
2
A 18 88 4.0 : 1
4
b
SO
2
B 0.5 99 1 : 1.3
5

NTs A 14 90 5.8 : 1
6

NTs B 0.5 98 1 : 3.6
7
c
NTs B 24 NR 1 : 5.6
d

(a) Conditions A: DMAP BH
3
(1.2 equiv) was activated with I
2
(0.6 equiv)
in DCM at 0 C. After warming to rt, 10 was added, the solution was
stirred (time), and was quenched with NaOOH/MeOH. Conditions B:
A rt solution of 10 in THF was treated with 1.0 M THF BH
3
(1.2 equiv)
and stirred (time) prior to quenching with NaOOH/MeOH. (b) Assayed
as the dibenzoyl derivative. (c) Performed at -30 C. (d) Ratio
determined by NMR assay of crude diol.

It was hypothesized that the inductive effect of incorporating an electron
withdrawing group (EWG) at the 4-position of the borinane might sufficiently stabilize
the DMAP-boron complex, allowing for isolation. The same inductive effect might also
help to improve diastereoselectivity in the 4-hetero-borinane hydroborations. Studies
with diprenyl sulfone 4B1b confirmed the former hypothesis, as both cis- and trans-
142

DMAP complexes 4B4b were stable to silica gel chromatography despite being difficult
to separate from one another. However, improved diastereoselectivity was not observed;
lower cis diastereoselectivity (4:1) was found under DMAP BH
2
I

conditions

and marginal
trans diastereoselectivity (1:1.3) was observed using THF BH
3
(entries 3 & 4). Thus the
primary concern became achieving better diastereoselectivity without sacrificing stability
of the DMAP complex.
N,N-Diprenyl-4-toluenesufonamide 4B1c was investigated because the N-tosyl
group should stabilize the DMAP complex 4B4c by electron withdrawal and its tendency
to improve crystalinity might facilitate diastereomer separation and resolution of trans-
4B3c. As in the prior examples 4B1a and 4B1b, the DMAP BH
2
I conditions favored cis
diastereoselectivity with 4B1c (5.8:1), but THF BH
3
provided improved 1:3.6 trans
diastereoselectivity at rt. Selectivity was increased to 1:5.6 upon conducting the
hydroboration at -30 C (Table 4C, entries 5-7). The diastereomeric mixture 4B4c was
separable by silica gel chromatography, and both cis and trans diastereomers were
obtained in crystalline form. The structure of trans-4B4c was established by X-ray
crystallography, which also confirmed that the enantiomers were not resolvable by
recrystalization, as both enantiomers were contained in the unit cell of the crystals.
It is proposed that the diastereoselectivity of 4B3c is derived from boat-like
transition state 4D1
eq
with a pseudo-equatorial isopropyl group being favored over the
boat-like transition state 4D1
ax
, which is thermodynamically less stable due to the
pseudo-axial isopropyl group (Scheme 4D). A chair-like transition state is unlikely, as
one would expect a diequatorial conformation leading to cis-4B3c to dominate such a
143

transformation. Thus, a chair-like transition state correlates well with the DMAP BH
3

results.

N
H
i-Pr
H
H
Ts
N
B
H
N
B
H
N
B
H
trans-4B3c
cis-4B3c
Scheme 4D: Diastereoselective Formation of N-Tosyl-trans-2,6-diisopropyl-1,4-borazinane
4B1c
4D1
ax
4D1
eq
Ts
Ts
Ts
THFBH
3
-30C
favored
disfavored
5.6:1 diasteroselectivity
H
i-Pr
Ts
N
B
H
H H


4.3 Resolution of (R,R)-2,6-Diisopropyl-1,4-borazinane Ring with Alanine
No method exists for predicting an ideal amino alcohol for crystallographic
resolution of a given racemic borane species, and chromatographic separation of
diastereomers is precluded by the instability of amino alcohol-borane complexes. Thus,
it came as little surprise that alaninol, phenylalaninol, valinol, and ephedrine complexes
of 4B4c all failed to provide convenient crystallization conditions and decomposed on
silica gel. It was hypothesized that using an amino acid would provide a more stable
complex from 4B4c due to the greater electron demand of the carboxyl group, a factor
that might allow for chromatographic separation of the resulting diastereomeric mixture.

144

The separation of borazinane 4B3c diastereomers and resolution of racemic trans-
4B3c was investigated by Mr. John Nelson. Generating alanine complex 4E2 was
complicated by the poor solubility of alanine in THF. Heating borazinane 4B3c in the
presence of alanine was out of the question for fear of ruining the trans-diastereomeric
excess via retro-hydroboration/hydroboration pathways. To avoid this potential
complication, B-methoxy-1,4-borazinane 4E1 was generated by methanolysis of 4B3c at
-30 C. Heating the more stable 4E1 with l-alanine at 45 C generated complex 4E2
(Scheme 4E). Not only was chromatography viable for separating the diastereomers, but
the trans-4E2 diastereomers could be separated by crystallization. The (R,R)-
N
N
i-Pr i-Pr
Ts
B
1. BH
3
THF
-30 C, 20 h
2. MeOH,
-30 C to rt
Ts
OMe
N
i-Pr i-Pr
Ts
B
OMe
cis-4E1
4E1
1. l-Alanine, 45 C
2. recrystalization
B
N
i-Pr i-Pr
Ts
H
2
N
O
O
l-(R,R)-4E2
1. d-Alanine, 45 C
2. recrystalization
B
N
i-Pr i-Pr
Ts
H
2
N
O
O
d-(S,S)-4E2
1. l-Alanine, 45 C
2. chromatography
B
N
i-Pr i-Pr
Ts
H
2
N
O
O
l-(R,R)-4E2
B
N
i-Pr i-Pr
Ts
H
2
N
O
O
l-(S,S)-4E2
B
N
i-Pr i-Pr
Ts
H
2
N
O
O
l-cis-4E2
Scheme 4E: Separation of Diastereomers and Resolution of 1,4-Borazinane Enantiomers
N
i-Pr i-Pr
Ts
B
OMe
(S,S)-4E1 (R,R)-4E1
2.8 : 2.8 : 1
4B1c
63%

145

diastereomer (98:2 dr) was particularly easy to isolate, as it precipitated almost
immediately upon dissolving the crude product in methylene chloride. Two
crystalizations provided l-(R,R)-4E2 in 27% yield. Treating 4E1 with d-alanine
provided the d-(S,S)-4E2 enantiomer in similar fashion. On the other hand,
crystallization conditions for facile separation of the remaining mixtures have not been
elucidated. Silica gel chromatography can separate the three diastereomers (63% yield)
but yield must be sacrificed for separation or vice versa because 4E2 is not completely
stable on silica gel. While 4E2 is stable to air upon isolation it is not as robust in
solution. After several crystallizations the mixture undergoes
degradation. Oxidative pathways are at least partially responsible as
evidenced by the isolation of side product 4E3 and by the fact that
using deoxygenated solvents for crystallization suppresses
degradation.
4.4 Transforming l-(R,R)-4E2 into a Viable Asymmetric Hydroborating Agent
Having resolved the trans-diastereomers of alanine complex 4E2, conversion to
the corresponding lithium dialkyl borohydride 4F1 was investigated with a screen of
lithium hydride reagents: lithium aluminum hydride (LAH), lithium
trimethoxyaluminum hydride [Li(MeO)
3
AlH],
21
lithium monoethoxy-aluminum hydride
[Li(EtO)AlH
3
],
9
super hydride (LiEt
3
BH), and lithium tri-tert-butoxy-aluminum hydride
[Li(tBuO)
3
AlH]. The first two reagents produced a proton-coupled triplet by
11
B NMR at
o= -20 ppm, which is assigned as 4F1. However, these reductions also produced
undesired boron species [o= -35 ppm, -4.2 ppm (LAH); 2 to 10 ppm (Li(MeO)
3
AlH)].
Li(EtO)AlH
3
and super hydride generated multiple boron species, according to
11
B NMR
B O
N
MeO
Ts
4E3
146

spectroscopy. The only reagent found to cleanly generate the desired boron species was
Li(tBuO)
3
AlH.
The single drawback of using Li(tBuO)
3
AlH for the reduction of 4E2 was that the
resulting borohydride 4F1 could not be isolated from the non-boron-containing side
products. Therefore, an in situ approach was taken to investigate hydroboration. Treating
crude 4F1 with the hydride abstracting agents TMSCl or TMSOTf generated an unknown
tetravalent species 4F2 with a
11
B NMR signal at o= -10 ppm. This signal is too far
upfield to represent either the trivalent borazinane 4B3c or its dimer 4F3 (Scheme 4F)
according to a comparison with di-t-butyl-borane (o= 47 ppm), which is reported in a
mixture also containing
11
B signals at o= -20.1, -17.2, -13.6, -.02, 24, 51.7, 83 ppm,
22
and
the borolane dimer 4A5 (o= 31.5 ppm)
10
or diborane (B
2
H
6
; o= 18 ppm).
23
Isolation of
complex 4B4c upon treatment of 4F2 with DMAP confirmed that species 4F2 is a

147

relatively weak Lewis base complex of the borazinane 4B3c. The Lewis base remains
undefined but is probably a reduced alanine residue. Considering the tetravalent nature
of 4F2, it was no surprise that hydroboration was not observed upon treating 4F2 with 1-
octene.
It was proposed that potassium salts of the reduction residues would be more
convenient to remove due to their poorer solubilities, thus enabling generation of free
borazinane 4B3c. Soderquists activated potassium hydride (KH*) was used initially to
investigate the degree of substitution at boron in the reaction intermediates, but turned out
to be critical to the generation of borohydride 4G1 (Scheme 4G).
24,25
While precipitated

148

solids were observed throughout the KH* reduction, cannulation of the borohydride
solution away from the residues and subsequent hydride abstraction with TMSCl resulted
in a product that remained soluble in THF. However, the solution did not contain
borazinane 4B3c , the unknown complex 4F2, or dimer 4F3 according to
11
B NMR
monitoring. Instead, a more downfield signal (o= +11.5 ppm) of a new unknown species
4G2 was generated. Treating 4G2 with 1-octene followed by reductive workup with
KH* led to the observation of a proton-coupled doublet by
11
B NMR at o= -18.3 ppm (J=
79.1 Hz), which is assigned as the potassium trialkylborohydride 4G3 (Scheme 4G).
Subsequent oxidation with NaOOH and benzoylation provided octyl benzoate 4G4 in
22% yield, suggesting marginal hydroboration reactivity for the unknown species 4G2.
This marginal reactivity caused concern that the hydroboration observed might
possibly be due to formation of BH
3
from decomposition of 4G2. Therefore, the Type III
alkene ethylidene-cyclohexane was treated using identical hydroboration conditions to
probe for any enantioselectivity, which would confirm a chiral boron environment being
involved in the transformation (Scheme 4G). Reductive workup with KH* provided a
proton-coupled
11
B doublet at o= -18 ppm (J= 81.3 Hz), which is assigned as
potassium trialkylborohydride 4G5. Subsequent oxidation with NaOOH followed by
acylation gave the acetate 4G6 in low yield, but 19% ee was observed by GC assay on a
chiral support. In addition to the observation of trialkylborohydrides 4G3 and 4G5 from
the reductive workup of the hydroboration of 1-octene and ethylidenecyclohexane,
respectively, this enantioinduction provided further evidence that the borazinane ring
remains intact and participates in hydroboration. However, the tetravalent
11
B chemical
149

shift and marginal reactivity of 4G2 indicate that an unidentified Lewis base Y
interferes with reactivity by inhibiting dissociation to 4B3c.
The Lewis base reduction byproducts from the generation of lithium borohydride
4F1 or potassium borohydride 4G1 had to be addressed in order to accurately evaluate
the true potential of borazinane 4B3c. Solvent rinsing and crystallization attempts were
made to remove the undesired species but all were unsuccessful. A Lewis acid screen
including BF
3
OEt
2
, TMSOTf, Zn(OTf)
2
,

Cu(OTf)
2
, and LiOTf was done expecting to
achieve competitive complexation to the undesired Lewis base contaminants, thus freeing
trivalent 4B3c and/or dimer 4F3. However, no dominant boron species resembling 4B3c
or dimer 4F3 was observed by NMR in any case. A Lewis acid screen including
BF
3
OEt
2
, TMSOTf, Cu(OTf)
2
, Sc(OTf)
3
, AgOTf, (C
6
F
5
)
3
B, and MgBr
2
was undertaken
to investigate the possibility of competitive complexation of DMAP from complex 3B4c,
but this was also unsuccessful. It became evident that removing alanine from diastereo-
enriched alanine complex l-(R,R)-4E2 prior to reduction to the borohydride would be the
most efficient way of generating pure potassium borohydride (R,R)-4G1.
Masamune generated pure borohydride 4A2 from prolinol complex 4A3
(Equation 2) by methanolysis followed by distillation and reduction of the resulting
methoxyborolane.
11
However, a variety of methanolysis conditions were unsuccessful in
cleanly converting alanine complex 4E2 to B-methoxy-borazinane4 E1. On the other
hand, hydrolysis conditions reported by Burke et al. for unmasking boronic acids from
N-methyliminodiacetic acid complexes
26
were used with 4E2 to generate a single
11
B
NMR signal at o= +53 ppm (Scheme 4H). This shift corresponds to methyl borinates
(45 ppm < o < 54 ppm),
27
indicating the formation of the desired borinic acid (R,R)-4H1.
150

(2)
B
N
i-Pr i-Pr
Ts
OH
KH*
1. aq. NaOH
2. Na
3
PO
4
(R,R)-4H1
B
N
i-Pr i-Pr
Ts
H
2
N
O
O
(R,R)-4E2
11
B o = +53 ppm
B
N
i-Pr i-Pr
H H
Ts
K
(R,R)-4G1
alanine
B
N
i-Pr i-Pr
H H
Ts
K
(R,R)-4G1
TMSCl
THF
heterogeneous mixture;
no
11
B NMR signals
B
N
i-Pr i-Pr
nC
8
H
17
Ts
11
B o= +87 ppm (in Et
2
O)
4H3
N
i-Pr i-Pr
B
Ts
O H
11
B o= +17.9 ppm
TMSCl,
Et
2
O
N
i-Pr i-Pr B
H
Ts
(R,R)-4B3c
NaOOH
N
i-Pr i-Pr
OH OH
4B6c
+ nC
8
H
18
OH
Ts
+
N
i-Pr
OH
Ts
H
4H5 4H4
1-octene 1-octene
Scheme 4H: Alanine-Free Hydroboration
(R,R)-4H2

The corresponding borinic anhydride was not observed by mass spectrometry, but the
possibility that it is present in the crude product has not been eliminated. No distillation
was needed before reduction because
1
H NMR spectroscopy showed that no trace of
alanine remained after aqueous extraction. Soderquists KH* reduced (R,R)-4H1 into
(R,R)-4G1 very cleanly in THF according to
11
B NMR spectroscopy. Addition of
distilled hexanes to a concentrated THF solution of (R,R)-4G1 led to its precipitation as a
151

white sludge. Placing the ether-rinsed sludge under high vacuum formed a bubble of
amorphous solid, which disintegrated into a white powder upon agitation.
Treating a mixture of the isolated borohydride powder 4G1 in Et
2
O with TMSCl
resulted in a heterogeneous mixture with no soluble boron species observed by NMR.
However, upon addition of 1-octene, a trivalent
11
B signal was observed at o= +87 ppm,
which is assigned as B-octyl-borazinane 4H3 (Scheme 4H). Treating a THF solution of
4G1 with TMSCl provided a boron species with a clean
11
B signal at o= +17.9 ppm,
which is similar to the chemical shift of the bridged dimer B
2
H
6
(o= +18 ppm),
23
but is
too far upfield relative to the borolane dimer 4A5 (o= 31.5 ppm)
10
and other
dialkylborane dimers (o= 23-27 ppm)
27
to be assigned as a H-bridged dimer.
Calculations done by Mr. Aleksanders Prokofjevs predict a
11
B NMR shift of 27 3 ppm
for dimer 4F3. The possibility of a hydride-bridged [R
2
(H)B-H-
B(H)R
2
] species was eliminated based on the upfield shifts of NaB
2
H
7

(o= -25.3 ppm),
27
the intramolecularly bridged species 4H6 (-4.9
ppm),
28
and Li(Et
3
B)
2
H (o= +8.7 ppm).
29

Treating potassium borohydride (R,R)-4G1 with a solution of TMSCl in CH
2
Cl
2

provided shifts of o= +25 and +71 ppm by
11
B NMR spectroscopy, which are
respectively assigned as the dimer 4F3 and the monomer (R,R)-4B3c. The observation of
two species in CH
2
Cl
2
and a single (third) species in THF lead to the conclusion that the
11
B signal at +17.9 ppm in THF is the THF borazinane complex (R,R)-4H2. This
chemical shift value is downfield compared to the THF complex of 9-BBN (o= +14
ppm),
30
but 4H2 may be somewhat deshielded by the N-Ts subunit compared to the
9-BBN environment.
B B H H H
K
4H6
152

Addition of 1-octene to a solution of 4H2 resulted in the observation of a
11
B
NMR signal at o= +86.5 ppm (Scheme 4H). Oxidative workup of 1-octene
hydroborations in both Et
2
O and THF reactions provided 1-octanol,
13
diol (S,S)-4B6c (85-
91%), and the alcohol byproduct S-4H5 (<5%).
14
For unknown reasons, complex 4H2
was not observed by
11
B NMR upon treating the crude KH* reduction reaction mixture
with TMSCl. Thus, precipitating (R,R)-4G1 from THF-hexane in its powdered form is
absolutely crucial for achieving hydroboration in THF.
Developing conditions for hydroboration enabled comparisons between the
presumed source of 4B3c and Masamunes borolane 4A1 in terms of substrate scope and
enantioselectivity. Initial screening of the four alkene types was done specifically using
substrates that had been tested by Masamune et al.
3
Ether was used as the solvent due to
the volatility and low molecular weight of some of the alcohol products. At room
temperature enantioselectivity with 4B3c was good for the Type II alkene cis-3-hexene
(86.4% ee - Table 4I; entry 2), and moderate for Type IV alkene ethylidenecyclohexane
(44.6% ee entry 9). By comparison, the Masasmune borolane 4A1 provides 99.9% ee
with cis-3-hexene and 99.3% ee with ethylidenecyclohexane
3
while Browns ipc
2
BH
provides 93% ee with cis-3-hexene
5
and ca. 20% ee with Type IV alkenes.
3
However,
enantioselectivity with 4B3c was poor for the type I and type III alkenes 2-methyl-1-
butene (<5% ee entry 1) and trans-3-hexene (3.8% ee entry 7), respectively. By
comparison, Masamune borolane 4A1 provides 1.5% ee and 99.5% ee for the respective
substrates
3
while Browns Ipc
2
BH provides 21% ee with 2-methyl-1-butene
4
and ca. 13%
ee for Type III alkenes.
3

153

Ensuing optimization studies used the type II alkene cis-1,4-diphenyl-2-butene
due to advantages in assay and product recovery, and demonstrated that Et
2
O promotes
marginally better enantioselectivity (86.4% ee) than THF (85.2 % ee), toluene (84% ee),
and CH
2
Cl
2
(79.2% ee) in the generation of R-1,4-diphenyl-2-butanol R-4I2 (Table 4I;
entries 2-3, 5-6). In an attempt to improve enantioselectivity, the reaction was conducted
at -20 C in THF, a solvent that ensures reagent solubility at the lower temperature.
Instead of the expected outcome, a slight decrease in enantioselectivity was observed
(80.2% ee; entry 4). With solvent and temperature optimizations having no substantial
effect, the enantioselectivity trends of borazinane 4B3c remain more reminiscent of
Browns Ipc
2
BH than of the Masamune borolane 4A1.
Like ipc
2
BH, borazinane 4B3c works well specifically with type II alkenes, which
is attributed to uncanny structural similarity for the transition states. Brown proposed
transition state conformation 4J1/4J2 for ipc
2
BH and Houk provided support for this
geometry with theoretical studies.
3,31
Borazinane (R,R)-4B3c fits into this model
beautifully, assuming a chair conformation 4J3. According to Browns model, transition
state 4J4 would form upon approach of cis-1,4-diphenyl-2-butene (Scheme 4J).
Subsequent hydroboration and oxidation would provide (R)-4I2, which is the enantiomer
obtained in 86% ee. On the other hand, there is crystallographic evidence that both the
alanine complex l-(R,R)-4E2 and the DMAP complex 4B4c exist in a twist-boat
boracycle conformation in the solid state. Thus it is possible that non-bonded interactions
in (R,R)-4B3c may cause it to adopt more of a twist boat conformation 4J7. The reduced
versatility and enantioselectivity of 4B3c compared to 4A1 is consistent with
Masamune's proposal that monomeric borolane 4A1 prefers a trans-diaxial envelope
154


Entry Alkene Type Solvent Product ee (%)
1
b


I ether 4I1 < 5
2
c

Ph Ph

II ether 4I2 86.4
f,g

3
c

Ph Ph

II THF 4I2 85.2
g,h

4
c

Ph Ph

II THF 4I2 80.2
g,i

5
c

Ph Ph

II CH
2
Cl
2
4I2 79.2
g

6
d

Ph Ph

II Toluene 4I2 84
g

7
d


II ether 4I3 84.6


8
d


III ether 4I3 3.8
9
e


IV ether 4I4 44.6
j

(a) Procedure: To a stirred mixture of 23 at rt in solvent was added
alkene (4 equiv) followed by TMSCl (1 equiv). After stirring 20 h,
oxidation with NaOOH at 0 C gave alcohol products, which were
purified by chromatography prior to derivatization and/or assay. (b)
Assayed by GC. (c) Assayed by HPLC. (d) Assay after conversion to
TMS ether. (e) Assayed after acetylation. (f) R-4I2 recovered in 72%
yield. (g) R-enantio-selectivity. (h) R-4I2 recovered in 61% yield. (i) -
20 C. (j) S-enantioselectivity

conformation in solution,
11
a conformation that cannot be adopted by the isopropyl
groups of 4B3c. Transition state 4J8 illustrates that a (pseudo)diaxial relationship can be
achieve by the protons on C-2 and C-6, presenting the possibility that the reduced
enantioselectivity of 4B3c is due to less bulky diaxial substituents adjacent to boron
compared with 4A1.
1
H NMR decoupling experiments with DMAP complex (R,R)-4B4c
in THF have revealed two coupling constants of J=10.8 Hz and 11.2 Hz between the
155

methine and methylene protons of the ring, providing evidence against borazinane
(R,R)-4B3c existing in chair conformation 4J3 in solution.

The overall generation of borazinane 4B3c, already simplified by
diastereoselective ring assembly and stability of its alanine complex, was streamlined
further upon discovery that a one pot in situ reduction-hydroboration sequence was viable
in Et
2
O. A heterogeneous mixture of l-alanine complex l-(R,R)-4E2 and KH* (4 equiv)
was stirred in Et
2
O before addition of cis-1,4-diphenyl-2-butene and TMSCl (3 equiv).
Subsequent oxidative workup provided (R)-4I2 in 37% yield and 86% ee (Equation 5).
The low yield is attributed to the heterogeneity of the reduction step causing poor
conversion of (R,R)-4E2 to (R,R)-4G1 although this cannot be confirmed due to neither
species being soluble in Et
2
O. Diol (S,S)-4B6c was recovered in 95% yield, which, in
addition to the enantioselective formation of (R)-4I2, indicates that the borazinane ring is
not compromised throughout the reaction. Soderquists KH* proved essential once
again,
16
despite its insolubility, as attempted borane generation via a one-pot procedure
156

with ether-soluble Li(tBuO)
3
AlH failed to give alcohol (R)-4I2 after oxidative workup.
The yield provides room for improvement, but this development demonstrates that a one
pot procedure can replace three sensitive steps in the Masamune protocol (Equation 1) if
one uses an amino acid rather than an amino alcohol for chiral borane resolution and
diastereomer separation.

4.5 Other Applications for the N-Tosyl-(R,R)-2,6-diisopropyl-1,4-borazacycle
Borazinane (R,R)-4B3c was also tested to see if it could
achieve asymmetric reduction of ketones, as the Masamune borolane
4A1 is also an effective reagent for the asymmetric reduction of
ketones in the presence of its corresponding mesylateborane (R,R)-4J9.
Masamune has reported that treating a 4:1 mixture of borolane 4A1 and mesylate (R,R)-
4J9 in pentane with 1-phenyl-2-propanone provided (R)-1-phenyl-2-propanol (R)-4K2 in
98.9% ee.
10,32
The Lewis-acid 4J9 is necessary for stereoinduction, as <5% ee is
achieved without it. No reduction product 4K2 was observed upon treating a pentane
suspension of borohydride (R,R)-23 with 1.2 equiv of MsOH followed by 1-phenyl-2-
propanone, but switching the solvent to toluene provided (R)-4K2 in 35% ee (Scheme
4K). This result suggests that (R,R)-4K1 was generated, which raised interest in utilizing
157

the chiral boracycle of (R,R)-4B3c as a Lewis acid. This led to an investigation of
generating a chiral borenium species for Diels-Alder catalysis.
B
N
i-Pr i-Pr
H H
Ts
K
(R,R)-4G1
O
MsOH
(1.2 equiv)
solvent, rt
(R,R)-4K1
OH
(0.8 equiv) (0.2 equiv)
-20 C
Pentane: Not observed
Toluene: 35% ee
N
i-Pr i-Pr B
H
Ts
(R,R)-4B3c
N
i-Pr i-Pr B
OMs
Ts
4K2
Scheme 4K: Asymmetric Reduction with 4B3c and Corresponding Mesylate
1.
2. DMAP

There are several reports of borenium species acting as chiral catalysts for Diels-
Alder chemistry
33-38
but none of them are derived from DMAP-borane complexes.
DMAP complexes of several boranes of varying degrees of substitution were treated with
MsOH and monitored by
11
B NMR in order to investigate if the species would be tri- or
tetravalent in DCM. Treating DMAP BH
3
4L1, DMAP BH
2
Ipc 4L3, DMAP BH(chex)
2

4L5, and borazinane complex 4B4c with MsOH generated
11
B shifts of o= +0.6 ppm,
o= +6.6 ppm, o= +11.7 ppm, o= +9.7 ppm, respectively. These shifts are indicative of a
tetravalent species believed to be 4L2, 4L4, 4L6,and 4L7 (Scheme 4L). Increasing the
steric bulk at boron generates a more downfield
11
B signal, indicating a more trivalent
nature, which correlates to the mesylate interaction with boron being weakened by the
alkyl groups. In order to pursue a more reactive species, complex 4B4c was treated with
triflic acid to introduce a weaker complexing anion. This generated a
11
B NMR signal at
+15.8 ppm, which has been assigned as 4L8. Treating a -78 C solution of 4L8 (7 mol%)
in DCM with methacrolein (1 equiv) followed by cyclopentadiene (5 equiv) generated
cycloadduct 4L9 with 97:3 endo:exo diastereoselectivity and 41% ee in 64% yield. It is
interesting that 4L8 catalyzes the reaction at all considering its tetravalent nature. The
158

enantioselectivity and yield suggests that the borazinane not only remains intact under the
reaction conditions but turns over as a catalyst.




159



4.6 Summary
The synthesis of N-tosyl-(R,R)-2,6-diisopropyl-1,4-borazinane 4B3c incorporates
diastereoselective assembly of the boracycle via cyclic of diene 4B1c, resolution of
dialkylborane diastereomers via alanine complexation rather than amino alcohol
complexation, and the ability to achieve hydroboration from the amino acid complex in a
single pot process. Despite its synthetic advantages, the hydroboration and reduction
results with 4B3c stand as the latest affirmation of how impressive the Masamune
borolane 4A1 is in terms of its synthetic versatility. These studies have also revealed that
DMAP complexes of chiral dialkylboranes, while not useful for resolution/separation of
diastereomeric borane mixtures, can be stable precursors to borenium catalysts such as
4L8 for asymmetric Diels-Alder cycloadditions.
This work represents the first report of a six-membered boracycle with a
C2-symmetric 2,6-dialkylborane environment and it shows promise in multiple
applications. However, if the asymmetric induction of these borazinane species is
representative for six-membered boracycles, then future efforts toward C2-symmetric
asymmetric boracycles should focus on 5-membered rings rather than 6-membered rings.





160

Experimental

Compounds 4B1, 4B4, 4B5, 4B6, 4B1c, 4E1, 4E2, and 4E3 were prepared and
characterized in the unpublished work of Mr. John Nelson.
In Situ Generation of borohydride 4F1.
N
i-Pr i-Pr
B
H H
Li
Ts
4F1

A sample of trans-4E2 (0.0963 g, 0.24 mmol) was taken up in distilled, degassed THF (2
mL) under nitrogen and cooled to 0 C. A solution of Li(tBuO)
3
AlH (0.246 g, 0.97
mmol) in THF (2 mL) was cannulated dropwise into the cooled solution of 4E2. THF
(0.5 mL) was used to complete the transfer of Li(tBuO)
3
AlH. The reaction was allowed
to stir for 1 h at rt before an NMR sample was cannulated into an NMR tube.
11
B NMR
spectroscopy displayed a signal at o= -20 ppm (t, J
BH
= 78.9 Hz) which is assigned as
4F1.
Generating the unknown borazinane complex 4F2 and DMAP complex 4B4c
N
i-Pr i-Pr
B
H X
Ts
4F2
Li
N
i-Pr i-Pr
B
DMAP
H
Ts
trans-4B4c

A sample of trans-4E2 (0.1025 g, 0.25 mmol) was taken up in distilled, degassed THF (2
mL) under nitrogen and cooled to 0 C. A solution of Li(tBuO)
3
AlH (0.256 g, 1.0 mmol)
in THF (2 mL) was cannulated dropwise into the cooled solution of 4E2. THF (0.5 mL)
161

was used to complete the transfer of Li(tBuO)
3
AlH. The reaction was allowed to stir for
1 h at rt before distilled, degassed TMSCl (115 L, 0.9 mmol) was added dropwise to the
reaction. The reaction stirred for 15 minutes before an NMR sample was cannulated into
an NMR tube.
11
B NMR spectroscopy displayed a broad signal at o= -10 ppm with no
apparent B-H coupling, which is assigned as 4F2. DMAP (0.22 g, 1.87 mmol) was
dissolved in THF (4 mL). The resulting solution was added to the NMR sample (0.5 mL)
and the original reaction mixture (3.5 mL). The resulting mixtures were combined and
concentrated. Purification by column chromatography in 2:3 EtOAc:hexanes eluted
0.086g of 4B4c (77%), identified by comparing
1
H NMR spectra with authentic material.
In Situ hydroboration of 1-octene via borohydride trans-4G1
B
N
i-Pr i-Pr
Ts
H H
K
trans-4G1
B
N
i-Pr i-Pr
Ts
H
nC
8
H
17
K
4G3
B
N
i-Pr i-Pr
Ts
H
c-hex
Me
K
4G5
B
N
i-Pr i-Pr
Ts
H Y
4G2
K

KH in mineral oil *(0.21 g) was activated as described by Soderquist.
25
A sample of
trans-4E2 (0.10, 0.26 mmol) was taken up in distilled THF (3mL). The resulting solution
was cannulated into the KH* and stirred for 1 h. The resulting mixture was cannulated
into a culture tube under nitrogen and centrifuged. The supernatant solution was
cannulated into a re-sealable flask and degassed via freeze-pump-thaw. In a glove box,
an aliquot was transferred to an NMR tube and treated with TMSOTf. Monitoring by
11
B
NMR spectroscopy lead to the observation of a dominant signal at o= +11.5 ppm, which
is an unknown species 4G2. 1-octene (70 L, 0.44 mmol) was added to the reaction,
followed by TMSCl (40 L, 0.31 mmol). A second batch of KH* was generated from
162

KH in mineral oil (0.20 g). The hydroboration mixture was cannulated onto the second
batch of KH* under nitrogen and stirred for 30 min. An aliquot was cannulated into an
oven dried, N
2
-flushed, septumed NMR tube.
11
B NMR spectroscopy displayed a signal
at o= -18.3 ppm (d, J
BH
= 81.3 Hz), which is assigned as 4G3. The aliquot was combined
with the reaction mixture, then cannulated into a culture tube and centrifuged. The
supernantant solution was cannulated into a clean flask and treated with TMSCl (40 mL,
0.31 mmol) followed by premixed satd NaOH in MeOH (0.9 mL) and 35% H
2
O
2
(0.9
mL). The reaction mixture was transferred to a separatory funnel containing brine and
extracted with Et
2
O. The organic layers were combined, dried over MgSO
4
, and
concentrated (aspirator). The crude reaction mixture was taken up in CH
2
Cl
2
(3 mL) and
treated with Bz
2
O (0.25 g, 1.11 mmol), Et
3
N (0.3 mL, 2.15 mmol), and DMAP (0.07 g,
0.58 mmol). The benzoylation was quenched with water and transferred to a separatory
funnel. Ether (10 mL) was added and the organic layer was rinsed with 1 N HCl and satd
NaHCO
3
. Each water layer was back extracted with hexanes. The organic layers were
combined, dried over MgSO
4
, and concentrated (aspirator), and purified via silica gel
chromatography using 10% Et
2
O in hexanes to give 0.0131g of 4G4
39
(22%). The same
procedure was used to generate 4G5 [o= -18 ppm (J
BH
= 81.3 Hz)] and 4G6
40
was
generated using analogous hydroboration / reduction / oxidation conditions followed by
acylation. The enantioselectivity of 4G6 was assayed by GC on a Chrompack Chirasil
Dex (25m x 0.32 mm x 0.25 mm) column (90 C, 1 mL/min)
40
: (S)-11.3 min , (R)-15.4
min.


163

One-pot procedure for hydroboration with l-(R,R)-4E2
In a glove box, a sample of l-(R,R)-4E2 (0.10 g, 0.25 mmol) was
added to a flask containing KH*(0.04 g, 1.05 mmol) prepared as
before. This mixture was suspended in Et
2
O (10 mL) and stirred
vigorously for 20 h at rt before addition of cis-1,4-diphenyl-2-
butene (100 L, 0.48 mmol) followed by TMSCl (100 L, 0.78 mmol). The resulting
mixture was stirred for 20 h before cooling to -78 C for addition of premixed 20%
NaOH (2 mL) and 35% H
2
O
2
(1 mL). The mixture was warmed to rt and stirred for 8 h
before transferring it to a separatory funnel containing brine (5 mL). The aqueous layer
was extracted with Et
2
O (4 x 20 mL). The organic layers were combined, dried over
MgSO
4
, and concentrated (aspirator), and purified via silica gel chromatography using
10%, 15%, and 30% EtOAc : hexanes to give 0.022 g of alcohol 4I2 (37%),
40
0.082 g of
diol 4B6c (95%), and 0.003 g of the elimination side product 4H5 (3%). The
enantiomeric excess of 4I2 was assayed as described later in data for Table 4I.
Compound 4H5: ESMS m/z: 258.4 (M+1).
1
H NMR (400 MHz, CDCl
3
, o): 0.87 (d, J=
6.8 Hz, 3H, CH
3
), 0.91(d, J= 6.8 Hz, 3H, CH
3
), 1.65 (m, 1H, CH), 1.92 (br d, J= 4.4 Hz,
1H, OH), 2.43 (s, 3H, CH
3
), 2.81 (ddd, J= 4.4 Hz, 8.3 Hz, 12 Hz, 1H, CH
2
N), 3.13 (ddd,
J= 3.2 Hz, 8 Hz, 12 Hz, 1H, CH
2
N), 3.4 (m, 1H, CH-O), 4.88 (br s, 1H, NH), 7.32 (dd,
J= 8.8 Hz, 0.8 Hz, 2H, Ar H), 7.75 (d, J= 8.8 Hz, 2H, Ar H).
13
C NMR
(CDCl
3
, 100 MHz, o) 143.5, 136.7, 128.8, 75.4, 46.6, 31.9, 21.5, 18.5, 17.8.



N
i-Pr i-Pr
Ts
B
H
2
N O
O
(R,R)-4E2
164

Generating alanine free (R,R)-4G1
A sample of l-(R,R)-4E2 (1.02 g, 2.5 mmol) was converted to (R,R)-4H1 using the
method of Burke et al.
26
Thus, a solution of 4E2 in THF (3 mL) was treated with 1M
NaOH (0.8 mL) and stirred vigorously open to the air for 10 min. The reaction was then
treated with 0.5 M aq Na
3
PO
4
(3 mL) and Et
2
O (3 mL) and stirred for 30 min, adding
distilled H
2
O (~10 mL) to dissolve the white precipitate that formed. The reaction
mixture was poured into a separatory funnel and the organic layer collected. The water
layer was extracted with Et
2
O (1x 20 mL). Some extra water had to be added once more
to dissolve white precipitates upon addition of Et
2
O. The organic layers were combined,
dried over MgSO
4
, filtered, and concentrated (aspirator followed by High-Vac for 30
min).
11
B NMR spectrospocopy indicated a single boron species at o= +53 ppm, which is
tentatively assigned as borinic acid 4H1. Based on ESMS m/z = 259 amu for M-1+Na
(Calcd 260 amu). No m/z for the corresponding borinic anhydride or borinic acid was
observed but this does not eliminate the possiblility that borinic anhydride was present
and was hydrolytically cleaved under the ESMS conditions (H
2
O, MeOH, NaCl). The
crude product was taken up in distilled THF (20 mL) and cannulated into a flask
containing KH* (0.51 g, 12 mmol) under nitrogen at rt. The transfer was completed with
THF (5mL) and the reaction stirred for one hour at rt. The resulting mixture was
transferred to a culture tube and centrifuged. The supernatant liquid was cannulated into
a RB flask containing a magnetic stir bar and was blown down with N
2
until ~3 mL of
solution remained. This solution was stirred vigorously while hexane (2 mL) was added
dropwise. A white powder-like solid started to precipitate. As more hexanes (13 mL)
was added the powder congealed into a gum-like mass as the mixture was stirred. The
165

solvent was decanted via syringe, and the residual gum was then rinsed with hexanes (20
mL) and Et
2
O (20 mL). Residual solvent was blown off with N
2
and high vacuum was
applied, causing the gel to form an amorphous bubble, which disintegrated into 0.53 g of
powder (59%) upon agitation. This (R,R)-4G1 powder was stored and dispensed in a
glove box. (R,R)-4G1:
1
H NMR (500 MHz, THF-D8, o): 0.31 (br s, 2H, B-CH), 0.71(q,
J
BH
= 77 Hz, 2H, BH
2
), 1.00 (d, J= 6.5 Hz, 6H), 1.02 (d, J= 6.5 Hz, 6H), 1.59 (m, 2H, -
CHMe
2
), 2.49 (s, 3H, CH
3
), 2.92 (br s, 2H, -CH
2
N), 3.1 (br s, 2H, -CH
2
N), 7.37 (d, J= 8
Hz, 2H, Ar H), 7.69 (d, J= 8 Hz, 2H, Ar H).
Establishing Hydroboration yield by NMR internal standard
In the glove box, a sample of (R,R)-4G1 (0.1007 g, 0.28 mmol) was suspeneded in Et
2
O
(8 mL) under N
2
and stirred vigorously at rt as cis-1,4-diphenyl-2-butene (100 L, 0.48
mmol) was added followed by TMSCl (35 L, 0.27 mmol). The mixture was stirred for
20 h, removed from the glovebox, and cannulated into a 0 C mixture of 20% NaOH (2
mL), 35% H
2
O
2
(1.1 mL), and 1:1 MeOH:Et
2
O (3 mL). The mixture was warmed to rt
and stirred for 8 h before transferring it to a separatory funnel containing brine (5 mL).
The aqueous layer was extracted with Et
2
O (4 x 20 mL) and the organic layers were
combined, dried over MgSO
4
, and concentrated (aspirator). Ph
3
CH (0.205 g, 0.840
mmol) was added to the crude product mixture and an NMR spectrum was taken in
CDCl
3
. The methine proton of Ph
3
CH (o= 5.72 ppm) integrated to 3.91, the methyl
group of diol 4B6c (o= 2.54 ppm) integrated to 3.00, and the methylene group of alcohol
4I2 (o= 2.75 ppm) integrated to 1.88. This indicates that 0.215 mmol of 4B6c and 0.202
mmol of 4I2 (94% relative to 4B6c) were generated. Purification via silica gel
166

chromatography using 10%, 15%, and 30% EtOAc : hexanes gave 0.077 g 4B6c (0.223
mmol), and 0.046 g of 4I2 (0.204 mmol, 91.5% relative to 4B6c).


Generation of 4H2 and 4H3
N
i-Pr i-Pr
B
Ts
O H
(R,R)-4H2
B
N
i-Pr i-Pr
nC
8
H
17
Ts
4H3
d8

In a glovebox, a solution of (R,R)-4G1 (0.057 g, mmol) in THF (3 mL) was treated with
TMSCl (20 L, 0.15 mmol). An aliquot was transferred to a dry NMR tube and
11
B
spectroscopy revealed a single signal at o= +17.9 ppm. The species assigned as 4H2 also
appears to be present by
1
H NMR spectroscopy (500 MHz, THF-D8, o): 0.97-1.03 (m,
2H, B-CH), 1.03-1.09 (m, 12H, CH
3
), 2.02-2.13 (m, 2H, -CHMe
2
), 2.52 (s, 3H, CH
3
)
3.10-3.29 (m, 4H, -CH
2
N), 7.45-7.49 (m, 2H, Ar H), 7.75-7.79 (m, 2H, Ar H). Treating
the solution with 1-octene led to observation of a signal at +86.5 ppm, which has been
assigned as 4H3.






167

Hydroboration with 4F3 and 4B3 in Methylene Chloride
N
i-Pr i-Pr
B
Ts
N
i-Pr i-Pr B
Ts
H H
4F3
N
i-Pr i-Pr B
H
Ts
(R,R)-4B3c

In the glove box, a sample of (R,R)-4G1 (0.072 g , 0.2 mmol) in a dry culture tube was
treated with a solution of TMSCl (26 L, 0.2 mmol) in CD
2
Cl
2
(5 mL). The resulting
mixture was centrifuged, a precipitate-free aliquot was transferred to a dry NMR tube,
and
11
B spectroscopy revealed a signals at o= +71 ppm, +52 ppm, and +25 ppm in a ratio
of ca. 3:1:2. The peak at +52 ppm is attributed to partial oxidation of the sample, the
peak at +71 ppm is assigned as the monomer 4B3c and the peak at +25 ppm is assigned
as the dimer 4F3. The
1
H NMR spectrum in of this mixture in CD
2
Cl
2
is clean, but a
mixture is evident.
1
H NMR (400 MHz, CD
2
Cl
2
, o): 0.64 (qd, J
BH
= 34.8 Hz, J= 6.8Hz,
1H, B-H), 0.72-.96 (m, 12H, CH
3
), 1.72-1.78 (m, 2H, -CHMe
2
), 2.37 (s, 3H, CH
3
) 2.78-
3.03 (m, 2H, -CH
2
N), 3.03-3.16 (m, 2H, -CH
2
N), 3.63(m, 2H, B-CH), 7.20-7.32 (m, 2H,
Ar H), 7.48-7.61 (m, 2H, Ar H). The NMR sample was transferred back to the original
mixture, which was then treated with cis-1,4-diphenyl-2-butene (100 L, 0.48 mmol) and
stirred for 20 h, removed from the glovebox, and cannulated into a 0 C mixture of 20%
NaOH (2 mL), 35% H
2
O
2
(1.1 mL), and THF (3 mL). The mixture was warmed to rt and
stirred vigorously for 16 h before transferring it to a separatory funnel containing brine (5
mL). The aqueous layer was extracted with Et
2
O (3 x 20 mL). The organic layers were
168

combined, dried over MgSO
4
, concentrated (aspirator), and purified via silica gel
chromatography using 10%, 15%, and 30% EtOAc : hexanes to give 0.021 g of alcohol
4I2 (49%), 0.049 g of diol 4B6c (72%), and 0.003 g of the fragmentation side product
4H5 (4%).
Hydroboration procedure starting with (R,R)-4G1 powder (Table 4I)
In the glove box, a sample of (R,R)-4G1 (0.103 g, 0.28 mmol) was suspeneded in Et
2
O (8
mL) at rt and stirred vigorously as 1-octene (100 L, 0.62 mmol) was added followed by
TMSCl (35 L, 0.27 mmol) under nitrogen. The mixture was stirred for 20 h, and an
aliquot was removed.
11
B NMR spectroscopy showed a signal at o= +87 ppm (br s),
which is assigned as 4H3. The reaction mixture was removed from the glovebox and
cannulated into a 0 C mixture of 20% NaOH (2 mL), 35% H
2
O
2
(1.1 mL), and 1:1
MeOH:Et
2
O (3 mL). The mixture was warmed to room temp and stirred for 8 h before
transferring it to a separatory funnel containing brine (5 mL). The aqueous layer was
extracted with Et
2
O (4 x 20 mL) and the organic layers were combined, dried over
MgSO
4
, concentrated (aspirator), and purified via silica gel chromatography using 40%
Et
2
O : pentane to give 0.021 g of octanol (57%), 0.06 g of diol 4B6c (62%), and 0.003 g
of the fragmentation side product 4H5 (4%).
Table 4I Data
Each substrate in Table 4I was hydroborated using analogous hydroboration / and
oxidation conditions. The enantioselectivity of terminal alcohol 4I1 was assayed by GC
on a Chrompack Chirasil Dex (25m x 0.32 mm x 0.25 mm) column (90 C, 1 mL/min):
9.5 min, 9.7 min; as was the trimethylsilylether of 4I3
41
(90 C, 1 mL/min): (R)-13.8 min
(minor), (S)-14.45 min (major); and the acetate of 4I4 (90 C, 1 mL/min)
40
: (S)-11.3 min
169

(major) , (R)-15.4 min (minor). The ee of 4I2 was assayed by HPLC on a Chiralcel-OD
column (5% IPA: Hexanes, 1 mL/min): (S)-13 min (minor), (R)-19.6 min (major).
42
The
assignment of stereochemistry in table 4I is confirmed by the work of Blakemore
42
and
Stampfer.
40




Entry Alkene Type Solvent Product ee (%)
1
b


I ether 4I1 < 5
2
c

Ph Ph

II ether 4I2 86.4
f,g

3
c

Ph Ph

II THF 4I2 85.2
g,h

4
c

Ph Ph

II THF 4I2 80.2
g,i

5
c

Ph Ph

II CH
2
Cl
2
4I2 79.2
g

6
d

Ph Ph

II Toluene 4I2 84
g

7
d


II ether 4I3 84.6


8
d


III ether 4I3 3.8
9
e


IV ether 4I4 44.6
j

(a) Procedure: To a stirred mixture of 23 at rt in solvent was added
alkene (4 equiv) followed by TMSCl (1 equiv). After stirring 20 h,
oxidation with NaOOH at 0 C gave alcohol products, which were
purified by chromatography prior to derivatization and/or assay. (b)
Assayed by GC. (c) Assayed by HPLC. (d) Assay after conversion to
TMS ether. (e) Assayed after acetylation. (f) R-4I2 recovered in 72%
yield. (g) R-enantio-selectivity. (h) R-4I2 recovered in 61% yield. (i) -
20 C. (j) S-enantioselectivity


170

Asymmetric reduction of 1-phenyl-2-propanone
A sample of (R,R)-4G1 (0.099 g, 0.27 mmol) was suspended in toluene (3 mL) under
nitrogen, treated with MsOH (22 L, 0.34 mmol), and stirred vigorously for 2 h at rt.
The reaction was cooled to -40 C before 1-phenyl-2-propanone was added. The reaction
was stirred at -20 C for 48 h before quenching with a solution of DMAP (0.0361g, 0.3
mmol) in toluene (2 mL). The reaction was concentrated and purified by silica gel
chromatography using 40% Et
2
O in pentane to give 1-phenyl-2-propanol 0.002 g 4K2
(< 10%). The ee of 4K2 was assayed by HPLC with a Chiralcel OD-H column (1.5%
IPA: hexane, 0.5 mL/min): (S)-enantiomer:16.6 min (major); (R)-enantiomer:17.8 min
(minor)
43
to provide 35% ee.
Generating Mesylate Complexes of DMAP Borenium Cations
H
B
H
MsO B
MsO
i-Pr B
MsO
i-Pr
N
Ts
DMAP
DMAP
DMAP
B
H
MsO
DMAP
4L2 4L4 4L6 4L7

Complexes 4L2, 4L4, 4L6, and 4L7 were generated in situ by treating DCM solutions of
their DMAP-borane precursors with methanesulfonic acid in a glovebox. 4B4c (0.02 g,
0.2 mmol) in 1 mL of DCM was treated with MsOH (7 L, 0.1 mmol) to generate a new
species observed by
11
B NMR spectroscopy at o= +9.7 ppm, which is assigned as
tetravalent 4L7. Starting material was also evident by
11
B NMR spectroscopy (~1:1).
4L3
18
( 0.04 g, 0.15 mmol) in 1 mL DCM was treated with MsOH (7 L, 0.15 mmol) to
generate a new species observed by
11
B NMR spectroscopy at o= +6.6 ppm, which is
assigned as tetravalent 4L4. 4L1
18
( 0.02 g, 0.16 mmol) in 1 mL DCM was treated with
171

MsOH (10 L, 0.15 mmol) to generate a new species observed by
11
B NMR
spectroscopy at o= +0.6 ppm, which is assigned as tetravalent 4L2. Dicylcohexylborane
was generated as previously reported,
44
and was quenched with an equivalent of DMAP
and concentrated (aspirator, then high vacuum) to give crude 4L5 (
11
B o= +2.5 ppm).
Treating a solution of crude 4L5 (0.046 g, 0.015 mmol) with MsOH (10 L, 0.15 mmol)
generated a new species observed by
11
B NMR spectroscopy at o= +11.6 ppm, which is
assigned as tetravalent 4L6.

Asymmetric Diels-Alder catalysis with 4L8
A sample of (R,R)-4B4c (0.084 g, 0.19 mmol) was taken up in
CH
2
Cl
2
(8 mL). TfOH (10L, mmol) was added, causing gas
evolution.
11
B NMR spectroscopy enabled observation of a boron
species at o= +15.8, which is assigned as 4L8, and an unknown
species at o= -14 ppm. The reaction was stirred for 10 minutes
before cooling to -95 C and adding methacrolein (0.25 mL, 3.03
mmol) followed by cyclopentadiene (1.22 mL, 14.9 mmol).
33
The reaction stirred at -78
C for 10 h before quenching with a solution of DMAP (0.10 g, 0.83 mmol). The
solution was concentrated and purified by silica gel chromatography using 2% Et
2
O in
hexanes to give 0.3 g of 4L9 (64%). Enantioselectivity was assayed with by chiral GC
using Chrompack Chirasil Dex (25 m x 0.32 mm x 0.25 mm) column (1.3 mL/min, 100
C) after NaBH
4
reduction to the corresponding alcohol 2-methyl-bicyclo[2.2.1]hept-2-
ene-2-methanol.
45
Minor diastereomer: 33.6 min (minor) and 35.3 min (major): 25% ee.
Major diastereomer: 37.4 min (minor) and 38.7 min (major): 41% ee.
i-Pr B
TfO
i-Pr
N
N
N
Ts
4L8
172



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176


















Appendix

NMR Spectra
177



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