Full Text 01

Asymmetric 1,3-Dipolar Cycloaddition
Reactions of Azomethine Ylides,

Thiocarbonyl Ylides, and Nitrones
Staffan Karlsson
Doctoral thesis
Akademisk avhandling som med tillstånd av Kungliga Tekniska Högskolan i

Stockholm framlägges till offentlig granskning för avläggande av filosofie
doktorsexamen i organisk kemi, fredagen den 23:e Maj 2003, kl. 12:30 i sal 0202,
Åkroken, Mitthögskolan, Sundsvall. Fakultetsopponent: Professor David Tanner,
Department of Chemistry, Organic Chemistry, Technical University of Denmark,
Building 201, Kemitorvet, DK-2800 Kgs., Lyngby, Denmark.
Publikationen kan beställas från:

Kungl Tekniska Högskolan
© Staffan Karlsson
Chemistry, Department of Natural and Environmental Sciences,

Mid Sweden University, SE-851 70 Sundsvall, SWEDEN
Organic Chemistry, Department of Chemistry,

Royal Institute of Technology (KTH), SE-100 44, Stockholm, SWEDEN
ISBN: 91-7283-475-7
ISRN KTH/IOK/FR--03/75--SE
ISSN 1100-7974
TRITA-IOK
Forskningsrapport 2003:75
Printed by Ekonomi-Print AB, 2003
ii
iii
Abstract
This thesis describes the development of methods for the preparation of chiral
non-racemic substituted pyrrolidines, tetrahydrothiophenes, and isoxazolidines.
This has been accomplished by using asymmetric intermolecular 1,3-dipolar
cycloaddition reactions of azomethine ylides, thiocarbonyl ylides and nitrones,
respectively, with various dipolarophiles.
The asymmetry in these reactions was introduced using two different
approaches: a diastereoselective approach (i.e. using dipolarophiles linked to
chiral auxiliaries and/or using enantiomerically pure ylides) and an
enantioselective approach (i.e. the reacting partners are achiral and the reaction is
catalysed by an enantiomerically pure catalyst). Thus, using the former approach,
3,4-disubstituted pyrrolidines and tetrahydrothiophenes were obtained in high
diastereofacial selectivities (up to 90:10 dr). Using the latter approach, bicyclic
fused isoxazolidines were obtained in up to 93% ee.
Some of the cycloadducts obtained from these reactions were transformed into
enantiopure known precursors of some biologically active compounds
{[(3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol and octahydrocyclopenta[c]pyrrol-
3a-ylmethylamine dihydrobromide} and an active stereoisomer of a sex
pheromone component of a pine sawfly [the acetate of (2S,3R,7R,9S)-3,7,9-
trimethyl-2-tridecanol]. The synthetic utility of these 1,3-dipolar cycloaddition
reactions was also demonstrated by the syntheses of some new enantiopure
organocatalysts which were found to be useful in some 1,3-dipolar cycloaddition
reactions of nitrones with α,β-unsaturated aldehydes.
iv
List of Publications
I. trans-3,4-Disubstituted pyrrolidines by 1,3-dipolar cycloaddition:
enantioselective approaches and their limitations. Karlsson, S.; Han, F.;
Högberg, H.-E.; Caldirola, P.* Tetrahedron: Asymmetry 1999, 10, 2605-
2616.
II. Diastereoselective addition of chiral azomethine ylides to cinnamoyl
moieties, attached to chiral auxiliaries. Karlsson, S.*; Högberg, H.-E.*
Tetrahedron: Asymmetry 2001, 12, 1975-1976.
III. Synthesis of enantiomerically pure 4-substituted pyrrolidin-3-ols via
asymmetric 1,3-dipolar cycloaddition. Karlsson, S.*; Högberg, H.-E.*
IV. Diastereoselective addition of chiral azomethine ylides to cyclic α,β-
unsaturated N-enoylbornanesultams. Karlsson, S.*; Högberg, H.-E.* J.
Chem. Soc. Perkin Trans.1 2002, 1076-1082.
V. Enantiomerically Pure trans-3,4-Disubstituted Tetrahydrothiophenes
from Diastereoselective Thiocarbonyl Ylide Addition to Chiral α,β-
Unsaturated Amides. Karlsson, S.; Högberg, H.-E.* Org. Lett. 1999, 1,
1667-1669.
VI. Pheromones of Pine Sawflies: Synthesis of a Pure (2S,3R)-3-
Methylalkan-2-ol Stereoisomer via an Asymmetric 1,3-Dipolar
Cycloaddition; Preparation of a Pheromone Component of Macro-
diprion nemoralis. Karlsson, S.*; Högberg, H.-E.* Synthesis 2000, 1863-
1867.
VII. Catalytic enantioselective 1,3-dipolar cycloaddition of nitrones to
cyclopent-1-enecarbaldehyde. Karlsson, S.*; Högberg, H.-E. Tetrahe-
dron: Asymmetry 2002, 13, 923-926.
VIII. Organocatalysts Promote Enantioselective 1,3-Dipolar Cycloadditions
of Nitrones with 1-Cycloalkene-1-carboxaldehydes. Karlsson, S.*;
Högberg, H.-E. Eur. J. Org. Chem., submitted.
This thesis is based mainly on papers I-VIII and referred to by their Roman
numerals. The papers were reprinted with kind permission from: Elsevier
Science Ltd., U.K. (papers I, II, III, and VII), Thieme Stuttgart · New York
(paper VI), American Chemical Society (paper V), the Royal Society of
Chemistry, U.K (paper IV) and Wiley-VCH, Germany (paper VIII).
Not Included:
(a) Sex Pheromone of the Pine Sawfly, Macrodiprion nemoralis. Stereoselective
Synthesis of the Sixteen Stereoisomers of 3,7,9-Trimethyl-2-tridecyl Acetate.
Karlsson, S.; Hedenström, E.* Acta Chem. Scand. 1999, 53, 620-630.
(b) ASYMMETRIC 1,3-DIPOLAR CYCLOADDITIONS FOR THE CONST-
RUCTION OF ENANTIOMERICALLY PURE HETEROCYCLES. A
REVIEW. Karlsson, S.; Högberg, H.-E. Org. Prep. Proced. Int. 2001, 33, 103-
172.
v
Abbreviations
Ac Acetyl
AcCl Acetyl chloride
AcOH Acetic acid
Ar Aromate
BINAP 2,2’-Bis(diphenylphosphino)-1,1’-binaphtyl
BINOL 1,1’-Bi-2-naphtol
Bn Benzyl
Bu Butyl
DBU 1,8-Diazabicyclo[5,4,0]undec-7-ene
DMF Dimethylformamide
DMPU 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
DMSO Dimethylsulfoxide
Dr Diastereomeric ratio
ee Enantiomeric excess
ent-X The enantiomer of compound X
Et Ethyl
EtOAc Ethyl acetate
GC Gas chromatography
HOMO Highest Occupied Molecular Orbital
iPr Isopropyl
LUMO Lowest Unoccupied Molecular Orbital
M Metal
Me Methyl
MS Mass spectrometry
NMR Nuclear magnetic resonance
NOE Nuclear Overhauser Effect
OTf Trifluoromethanesulfonate
Ph Phenyl
Ra-Ni Raney nickel
R.T Room temperature
Super-hydride Lithium triethylborohydride
TFA Trifluoroacetic acid
THF Tetrahydrofuran
TMEDA Tetramethylethylenediamine
X Halogen unless not specified
Xc Chiral auxiliary
∆x Reflux
∆G* Activation energy
[α]D Specific rotation at λ = 599.6 nm
* Stereogenic centre
vi
Contents
Abstract ................................................................................................................iv
List of publications................................................................................................v
Abbreviations .......................................................................................................vi
1. Introduction .....................................................................................................1
1.1 The 1,3-dipolar cycloaddition reaction....................................................1
1.2 The 1,3-dipole/ylide ...................................................................................1
1.3 The dipolarophile ......................................................................................2
1.4 Mechanistic aspects ...................................................................................3
1.5 Enantiomerically pure compounds ..........................................................6
1.6 Diastereoselective 1,3-dipolar cycloaddition reactions using
chiral auxiliaries, principle and origin of π-facial selectivity................6
1.7 Doubly diastereoselective 1,3-dipolar cycloaddition reactions
using chiral auxiliaries, matched versus mismatched case ...................8
1.8 Enantioselective 1,3-dipolar cycloaddition reactions using
chiral catalysts, principle and origin of π-facial selectivity...................9
2. 1,3-Dipolar cycloaddition reactions of azomethine ylidesI-IV .....................12
2.1 General aspects........................................................................................12
2.2 Diastereoselective reactions using chiral auxiliaries.............................12
2.3 Doubly diastereoselective reactions using chiral auxiliaries................19
2.4 Enantioselective reactions using chiral catalysts ..................................26
2.5 Applications .............................................................................................28
3. 1,3-Dipolar cycloaddition reactions of thiocarbonyl ylidesV,VI ...................33
3.1 General aspects........................................................................................33
3.3 Applications .............................................................................................35
4. 1,3-Dipolar cycloaddition reactions of nitronesVII,VIII .................................40
4.1 General aspects........................................................................................40
4.3 Enantioselective reactions using chiral catalysts ..................................41
4.4 Applications .............................................................................................60
5. Conclusions and outlook...............................................................................65
6. Acknowledgements........................................................................................66
vii
1. Introduction
1.1 The 1,3-dipolar cycloaddition reaction

The [3 + 2] 1,3-dipolar cycloaddition is a reaction where two organic
compounds, a dipolarophile, 1, and a 1,3-dipole (or ylide), 2, combine to form a
five membered heterocycle 3 (Figure 1.1). The reaction is related to the Diels-
Alder reaction where a diene and a dienophile form a six membered ring. From
simple starting materials, the 1,3-dipolar cycloaddition reaction can furnish very
complex heterocycles, containing multiple stereogenic centres. Therefore this
reaction is often used as a key step in the syntheses of many natural products and
pharmaceuticals. After its discovery in 1888,1 with diazoacetic ester as the 1,3-
dipole, various other 1,3-dipoles have been used in this type of reaction.2
+ A C
B A C
B
1 2 3
Figure 1.1.
The asymmetric variants of this reaction using either chiral auxiliaries or

chiral catalysts are relatively new research fields and have attracted a continually
growing interest. Although progress has been made in these fields, resulting in
valuable tools for the syntheses of enantiomerically pure heterocycles, there are
still some unexplored areas which need to be investigated, or already existing
methods that need to be improved. This is the reason why I began to study
asymmetric 1,3-dipolar cycloaddition reactions.
1.2 The 1,3-dipole/ylide

The 1,3-dipole, also known as an ylide, bears a positive and a negative charge
distributed over three atoms and has 4π electrons. The most common atoms
incorporated in the 1,3-dipole are nitrogen, carbon, oxygen or sulfur.
Representative examples of some 1,3-dipoles are shown in Figure 1.2, but other
types of 1,3-dipoles also exist.2 These are divided into two groups, the allyl anion
type which has a bent structure and the propargyl/allenyl anion type with a linear
structure as shown in Figure 1.2.2 Each of these dipoles has four resonance
structures as exemplified for the nitrone and the diazoalkane in Figure 1.2. The
ylide can, depending on the nature of the 1,3-dipole exist in an equilibrium
between an E-form and a Z-form. This can have consequences for the
diastereoselectivity in reactions with dipolarophiles. This topic is brought up to
discussion in section 1.4.
[1] Buchner, E.; Ber. Dtsch. Chem. Ges. 1888, 21, 2637-2647.
[2] Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York,
1984, Vol 1, 3-27.
1
R5
R4
R1 R4 1 R1 O R1 O
N R R3 N
S N
R2 R3 R2 R3 R2 R3
R2
Azomethine ylide Thiocarbonyl ylide Nitrone
R1 O R1 O
N N
R2 R3 R2 R3
Allyl anion type
R1 R1 R1
R1 N O N N N N N N N
R2 R2
Nitrile oxide Azide Diazoalkane
R1 R1
N N N N
R2 R2
propargyl/allenyl anion type
Figure 1.2. Examples of 1,3-dipoles.
1.3 The dipolarophile

The dipolarophile in a 1,3-dipolar cycloaddition is a reactive alkene moiety
containing 2π electrons. Thus, depending on which dipole that is present, α,β-
unsaturated aldehydes, ketones, and esters, allylic alcohols, allylic halides,
vinylic ethers and alkynes are examples of dipolarophiles that react readily
(dipolarophiles 4-7, Figure 1.3). It must be noted, however, that other 2π-
moieties such as carbonyls and imines also can undergo cycloaddition with
dipoles. The alkene moiety can be mono-, di-, tri- or even tetrasubstituted (only
monosubstituted ones are shown here). However, mostly due to steric factors, tri-
and tetrasubstituted ones often display very low reactivity in reactions with
dipoles.
O
O
X OMe
R1 R1
R1
4 4 5 6 7
s-cis s-trans
R1 = H, Me or OMe X = OH or halogen
Figure 1.3. Examples of dipolarophiles in 1,3-dipolar cycloaddition reactions.
2
It must be pointed out that dipolarophiles incorporating two conjugated
double bonds such as dipolarophile 4 can exist in two different main
conformations, s-cis and s-trans, respectively (Figure 1.3), where the s-cis/s-
trans descriptor refers to the single bond connecting the two double bonds. Such
s-cis/s-trans-isomerism can have a major impact on the outcome of an
asymmetric 1,3-dipolar cycloaddition reaction and is discussed more in section
1.6.
1.4 Mechanistic aspects

The 1,3-dipolar cycloaddition reaction of a 1,3-dipole with a dipolarophile
involves the 4π electrons of the dipole/ylide and the 2π electrons of the
dipolarophile. The reaction mostly proceeds in a concerted manner, which means
that all bonds are created simultaneously, but not necessarily to the same extent
at a certain time. Consequently, the stereochemistry of the dipolarophile is
conserved in the final product. This is exemplified in Scheme 1.1 where trans-2-
butene 8 reacts with the hypothetical dipole 2 furnishing exclusively trans-9.
Starting from the cis isomer of 8 will thus yield the cis isomer of 9.
+ A C
B
A C A C
B B
8 2 trans-9
Scheme 1.1.
If, on the other hand, the reaction proceeds via a two step mechanism, the
stereochemistry of the starting dipolarophile is not necessarily conserved
throughout the whole reaction. This is exemplified in Scheme 1.2, where trans-2-
butene 8 reacts with the dipole 2 in a two step fashion furnishing the
diastereomer cis-9 via isomerisation of the starting dipolarophile.
+ A C
B A C A C A C
B B B
8 2 cis-9
Scheme 1.2.
Depending on the nature of the dipole and the dipolarophile, the 1,3-dipolar
cycloaddition reaction is controlled either by a LUMO(dipolarophile)-
HOMO(dipole)- or a LUMO(dipole)-HOMO(dipolarophile) interaction but in
3
some cases a combination of both interactions is involved.3 An example of a
LUMO(dipolarophile)-HOMO(dipole) controlled reaction is depicted in Scheme
1.3. The approach of the dipole (e.g. 10) to the dipolarophile (e.g. 11) can occur
in an endo or exo mode resulting in two diastereomeric endo/exo cycloadducts,
endo-12 and exo-12, respectively. An overview over both these approaches is
depicted in Scheme 1.3 where the endo approach is stabilised by small secondary
π-orbital interactions, contributing to the endo/exo selectivity of the reaction.
However, other factors such as steric ones can have a major influence on this
endo/exo selectivity and can often override this stabilising effect.
R1 O
R1
LUMO o
R1
R3 O B *
R3
A C R 2 *A C * R3
HOMO R2 HH B
R2
endo-12
endo-approach
R1
O 11 R3
B C
A
R2 10
R1
R1 O
LUMO o
R3 R1
O H 3
*
H A C R 2 *A C * R3
HOMO 2 R B
R B
R2
exo-12
exo-approach
Scheme 1.3. Example of an endo- and an exo approach of a LUMO(dipolarophile)-HOMO(dipole)
controlled reaction. Primary orbital interactions are indicated with double headed arrows and
secondary orbital interactions with dotted lines.
Moreover, depending on the substitution pattern of the ylide, this can exist in an
equilibrium between a Z-form and an E-form. Reaction of each of these isomers
with a dipolarophile, gives rise to diastereomeric cycloadducts, provided that the
approach of these (endo or exo) is the same. This is exemplified in Scheme 1.4
where ylides E-13 and Z-13 react with the dipolarophile 4 via an exo-approach
furnishing diastereomeric cycloadducts trans-14 and cis-14 respectively. The
cis/trans nomenclature for the description of the stereochemistry of the
cycloadducts is thus often used instead of the exo/endo one to avoid confusion
when ylides existing as an equilibrating mixture of Z/E isomers are used.
[3] (a) Rispens, M. T.; Keller, E.; Lange, B. d.; Zijlstra, R. W. J.; Feringa, B. L. Tetrahedron;
Asymmetry 1994, 5, 607-624. (b) Sustmann, R. Tetrahedron Lett. 1971, 2717-2720. (c)
Sustmann, R. Pure Appl. Chem. 1974, 40, 569-593. (d) Houk, K. N.; Sims, J.; Watts, C. R.;
Luskus, L. J. J. Am. Chem. Soc. 1973, 95, 7301-7315.
4
O O
C(O)R1
H R1
R1 *
A C 4
B Me Me
C H A C *Me
B
B
E-13 trans-14
A
exo-approach
O O
C(O)R1
Me 1
R R1
A C 4 *
B H H
C Me A C *Me
B
B
Z-13 A cis-14
exo-approach
Scheme 1.4. Reaction of two Z/E isomers of ylide 13 with dipolarophile 4 via an exo-approach.
In addition to the issues concerning diastereoselectivity discussed above,

regioselectivity related ones can also arise. Thus, when both the ylide and the
dipolarophile are nonsymmetric, regioisomeric adducts can be formed. This is
exemplified in Scheme 1.5, where the hypothetical ylide 2 reacts in two different
modes with dipolarophile 4, giving rise to the regioisomeric cycloadducts 15a
and 15b. Nitrones are examples of nonsymmetric ylides, which upon reaction
with nonsymmetric dipolarophiles sometimes furnish two regioisomeric
cycloadducts. Depending on electronic factors and the substitution pattern of the
ylide and the dipolarophile, both modes of addition of the ylide to the
dipolarophile can occur.4
O O
1
R R1
A C
O A C B
A C B
B + 15a
R1 or
2 4 O O
1
R R1
C A C A
B B
15b
Scheme 1.5. Two alternative approaches of a hypothetical ylide 2 to dipolarophile 4 giving rise to
regioisomers 15a and 15b.
[4] (a) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New
York, 1984, Vol 2, 89-95. (b) Silva, M. A.; Goodman, J. M. Tetrahedron 2002, 58, 3667-
3671. (c) Magnuson, E. C.; Pranata, J. J. Comput. Chem. 1998, 19, 1795-1804. (d)
DeShong, P.; Jr. Lander, S. W.; Leginus, J. M.; Dicken, C. M. In Advances in Cycloaddition,
Curran, D. P.; Ed.; JAI Press, London, 1988, vol 1, 93-95. (e) Torssell, K. B. G. Nitrile
Oxides, Nitrones, and Nitronates in Organic Synthesis; VCH: Weinheim, 1988, 25-35.
5
1.5 Enantiomerically pure compounds
Many of the organic compounds present in our environment are chiral, that is,
their respective mirror images are not identical. A compound and its
nonsuperimposable mirror image are called a pair of enantiomers. Almost all the
chemical and physical properties of enantiomers are the same. However, when
put in a chiral non-racemic environment, such as in biological tissues, the effects
of the enantiomers may differ considerably. Many examples of differences in
biological activity of enantiomers have been found and the most well known one
is probably that of the sedative drug neurosedyn (thalidomide in the US). Thus,
the (R)-enantiomer is an efficient sedative, while the (S)-enantiomer (Figure 1.4)
is a potent human teratogen (causing fetal abnormities).
O O
O O
H H
HN N N NH
O O O O
(R)-Thalidomide (S)-Thalidomide
Figure 1.4. The two enantiomers of thalidomide.
The knowledge that enantiomers can have different effects has given rise to a
demand to find methods to obtain the chiral drugs in enantiomerically pure
forms. This can be accomplished using different approaches:
1) Resolution of a racemic mixture, that is, separation of two enantiomers

through enzymatic or chemical methods.
2) Diastereoselective synthesis using chiral auxiliaries derived from

enantiomerically pure starting materials.
3) Enantioselective synthesis from achiral starting materials mediated by a chiral

non-racemic catalyst.
The two latter approaches will be considered in this thesis.
1.6 Diastereoselective 1,3-dipolar cycloaddition reactions using

chiral auxiliaries, principle and origin of π-facial selectivity
Dipolarophiles of type 16 (Figure 1.5) exist, as mentioned in section 1.3, in an
equilibrium between two different main conformations, s-cis and s-trans,
respectively. Furthermore, the alkene moiety of dipolarophiles has two faces, a
si-face and a re-face respectively, onto which dipoles can be added. This is
exemplified in Figure 1.5 by the acrylic acid 16, which upon reaction in the s-cis
or s-trans conformation with a dipole from the si-face (attack from the top face
and bottom face respectively) gives the same π-facial selectivity furnishing the
6
same compound 17. Thus, in order to favour approach of the dipole to only one
face (i.e. the si- or the re-face) of the dipolarophile, both the geometry of the
dipolarophile and the mode of addition of the dipole must be controlled. This is
the principle in asymmetric synthesis and can be accomplished by introducing
chiral auxiliaries (described below) or chiral catalysts (described in section 1.8).
B
C C
si-face re-face
O
O OH O
OH OH
s-cis-16 C C s-trans-16
B
17
re-face C C si-face
B
Figure 1.5. Approach of a dipole to the si-face of acrylic acid 16 adopting either an s-cis or an s-
trans conformation.
When an achiral compound, for example acrylic acid 16 (Scheme 1.6), is

linked to an enantiomerically pure auxiliary exemplified by 18, one obtains a
new enantiomerically pure derivative, the dipolarophile 19, which is expected to
react in a diastereoselective manner (i.e. diastereomers are formed in unequal
amounts) with a reagent such as the hypothetical cyclic dipole 20. Because one
of the two faces of the alkene moiety in the dipolarophile 19 is sterically shielded
(i.e. the bottom face) from attack, whereas the other one is not, the attack of the
dipole occurs mainly from the top face leading to a diastereoselective reaction
(Scheme 1.6). Thus, this reaction pathway leads to the major diastereomeric
cycloadduct 21 whereas attack from the bottom face leads to the minor one 22.
This preference for one of the π-faces of the chiral dipolarophile is often referred
to as diastereofacial selectivity or π-facial selectivity and should not be confused
with the endo/exo diastereoselectivity described in section 1.4. It must be
remembered that dipolarophiles of type 19 exist in an equilibrium between an s-
cis and an s-trans conformation (s-cis the reactive conformer here) as described
above. Attack onto the s-trans conformer of 19 by the dipole 20 from the least
sterically hindered side would lead to the opposite diastereofacial selectivity (i.e.
preference for diastereomer 22).
7
O
A OH
B C X
H
X 23
O A Y
Y
+ B C *
OH *
16 18 21
Chiral auxiliary
major pathway
A C
B
X
A C
B X
Y
Y
* 20 *
19
A C
B
minor pathway
X
H
A Y
B C *
22
Scheme 1.6. Example of a general diastereofacial selective 1,3-dipolar cycloaddition reaction using a
chiral auxiliary.
Because diastereomers often have different properties such as polarity and

melting point, various standard techniques can be applied to separate these. After
separation of the major and the minor diastereomer (i.e. 21 and 22 respectively),
the chiral auxiliary of the individual major diastereomer can be removed,
furnishing the desired enantiomerically pure compound 23 and the recovered
chiral auxiliary 18. Because commercially available chiral auxiliaries are often
expensive, mild and efficient methods are needed in order to attach the chiral
auxiliary to the substrate and to remove it from the product. Of course it is
essential that no epimerisation of the newly created stereocentre(s) occurs in the
product in the removal step.
1.7 Doubly diastereoselective 1,3-dipolar cycloaddition reactions

using chiral auxiliaries, matched versus mismatched case
This approach is similar to the one described in section 1.6 with the exception
that both reacting partners are chiral and non-racemic. Compared with the singly
diastereoselective reactions described in section 1.6, one expects a doubly
diastereoselective reaction to proceed in higher diastereofacial selectivity,
8
provided that a matched pair of enantiomers are reacted with each other. In
contrast, a reaction between a mismatched couple of reactants will proceed with
lower diastereofacial selectivity. Thus, it is important to choose the appropriate
absolute configuration of the substrate and the reactant. Figure 1.6 gives you an
example of both a matched and a mismatched case in which the same
dipolarophile as in Scheme 1.6 (i.e. 19), in an exo-mode, reacts with the chiral
dipole 24 (matched case) and the enantiomer ent-24 (mismatched case)
respectively. Thus, in the matched case in Figure 1.6, attack of the dipole 24
from the bottom face, results in unfavourable interactions between the two
substituents of the dipole and the dipolarophile. Therefore attack occurs
preferentially from the top face, where such interactions are absent. In the
mismatched case, however, attack of the enantiomer ent-24 from both sides of
the π-bond of the dipolarophile 19, results in unfavourable interactions. Thus,
compared with the matched case, a lower degree of discrimination between the
two π-faces of the dipolarophile by the dipole is expected.
Matched case Mismatched case
A C
B
*
ent-24
A C
B
*
24 X 19 X 19
Y Y
* *
A C
B
A C
B *
*
24 ent-24
Figure 1.6. Example of a general doubly diastereoselective 1,3-dipolar cycloaddition reaction

including a matched case and a mismatched case respectively.
1.8 Enantioselective 1,3-dipolar cycloaddition reactions using chiral

catalysts, principle and origin of π-facial selectivity
Enantioselective 1,3-dipolar cycloaddition reactions have become a rapidly
growing field of research in organic chemistry. The reason for this is that this
approach allows the chirality in the product to be introduced in the presence of
only a catalytic amount of a chiral non-racemic derivative (i.e. a catalyst).
Moreover, in contrast to the diastereoselective reactions involving attachment
and removal of a chiral auxiliary, no such additional synthetic steps are
necessarily required.
9
When a catalyst is coordinating to the dipole or the dipolarophile, the frontier
molecular orbitals (FMO) of the dipole and/or the dipolarophile may change
resulting in either an increase or a decrease in the energy gap (∆E) between the
LUMO and the HOMO of the dipole and dipolarophile, respectively, or vice
versa.5 A lowered energy gap will result in a faster reaction compared with the
uncatalysed one. An example of a LUMO(dipolarophile)-HOMO(dipole)
controlled reaction is illustrated in Figure 1.7. Thus, when the catalyst (e.g. a
Lewis acid) coordinates to the carbonyl oxygen of the dipolarophile (e.g. 4) the
LUMO energy of the dipolarophile decreases, which leads to a smaller energy
gap between the LUMO of the dipolarophile and the HOMO of the dipole
resulting in an increased reaction rate compared with the uncatalysed reaction,
that is, ∆E* < ∆E. It must be noted that coordination of the catalyst to the dipole
also results in a faster reaction provided that the reaction is
HOMO(dipolarophile)-LUMO(dipole) controlled. After dissociation of the
catalyst from the product it is ready for another catalytic cycle (Figure 1.7).
M+ A C O
B
O M+
O R1
catalyst *
2 + M+
R1 R1 A C
B
4 25
no catalyst added catalyst added
dipole dipolarophile dipole dipolarophile
LUMO
Energy
∆E
∆E*
HOMO
Figure 1.7. The change in the LUMO (and the HOMO) energy of the dipolarophile 4 when a catalyst
is coordinating to the carbonyl oxygen of the former, resulting in an increased reaction rate upon
reaction with dipole 2, compared with the uncatalysed reaction.
[5] Gothelf, K. V.; Jørgensen, K. A. Acta Chem. Scand. 1996, 50, 652-660.
10
It is obvious that if the catalyst is chiral and non-racemic, one π-face of the
dipolarophile may be more shielded than the other one resulting in a
discrimination of one of the π-faces by the dipole (Figure 1.8). Thus an
enantioselective reaction is expected to occur giving rise to unequal amounts of
two enantiomeric products. As pointed out in section 1.3 and 1.6, dipolarophiles
of the types shown in Figure 1.8, can exist in both an s-cis and an s-trans
conformation and this isomerism can have a major influence on the π-facial
selectivity.
The catalyst is frequently a chiral non-racemic Lewis acid but can also be a
non-metal containing organic compound. The catalyst attaches to the dipole or
the dipolarophile either through chelation or through covalent bonds.
Furthermore, depending on the nature of the dipolarophile (and the dipole)
chelation of a Lewis acid to the dipolarophile (and the dipole) can occur through
single or multiple points of attachments. Examples of mono- and bidentate
binding of a chiral Lewis acid to a dipolarophile are depicted in Figure 1.8. This
includes also an example of attachment of a non-metal containing catalyst to a
dipolarophile (case C). Compared to case A, in which the dipolarophile contains
only one Lewis basic site, B describes a case, where the dipolarophile contains
two Lewis basic oxygens, which are expected to contribute to the formation of a
more stable chelated complex with the Lewis acid. Thus, in order to favour
binding of a catalyst to the dipolarophile rather than to the dipole, a dipolarophile
containing at least two Lewis basic sites can be used.
*M
*M
O O O *N
R1 R1 R1
A B C
Figure 1.8. Examples of different modes of attachment of a chiral catalyst to a dipolarophile. A:

Monodentate chelation of a chiral Lewis acid. B: Bidentate chelation of a chiral Lewis acid. C:
Covalently bonded non-metal containing catalyst. Due to steric shielding arising from the substituent
of the chiral catalysts, attack of a dipole occurs from the bottom face (i.e. the re-face).
11
2. 1,3-Dipolar cycloaddition reactions of azomethine
ylidesI-IV
2.1 General aspects

Azomethine ylides have the general structure 29 as depicted in Scheme 2.1 and
belong to the allyl anion type having four resonance structures as described in
section 1.2 (only one shown in Scheme 2.1). They are in general very reactive
short-lived species, and thus they have to be prepared from a stable precursor in
situ. Examples of ways to generate such species are acid catalysed decomposi-
tion of N-alkyl-N-methoxymethyl-N-(trimethylsilyl)methylamines 26, photolysis
of aziridines 27 and proton abstraction from imine derivatives 28 (Scheme 2.1).6
Me3Si N OMe H+
R1 - Me3SiOMe O
O
26
R2 3 4 5 R4 R5
R R R
hυ R 2
N 3
R 30 * *
N 3
R2 * N * R
R1 1
R or M
27 R1
Base 29 31
R2 N R3
MX
28
R2 = R3 = H
from 26
Scheme 2.1. Examples of generation of azomethine ylides 29 from stable precursors. Reaction with
an electron-deficient dipolarophile (i.e. 30) furnishes a pyrrolidine derivative 31.
In the presence of a dipolarophile such as an α,β-unsaturated acyl derivative (i.e.

30, Scheme 2.1) reaction readily occurs, furnishing a substituted pyrrolidine 31
containing up to four new stereogenic centres. The reactions of azomethine
ylides with dipolarophiles are in general HOMO(dipole)-LUMO(dipolarophile)
controlled.
2.2 Diastereoselective reactions using chiral auxiliaries

Since Padwa and co-workers performed the first diastereofacial selective 1,3-
dipolar cycloaddition reaction in 1985 using a chiral non-racemic azomethine
ylide,7 a number of other chiral azomethine ylides have been found to undergo
[6] (a) Vedejs, E. In Advances in Cycloaddition, Curran, D. P.; Ed.; JAI Press, London, 1988,
33-51. (b) Lown, J. W. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New
York, 1984, Vol 1, 653-670. (c) Harwood, L. M.; Vickers, R. J. In Synthetic Applications of
1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products; Padwa, A.;
Pearson, W. H., Eds.; John Wiley & Sons, Inc., New York, 2002, vol 59, 170-192.
[7] Padwa, A.; Chen, Y.-Y.; Chiacchio, U.; Dent, W. Tetrahedron 1985, 41, 3529-3535.
12
cycloaddition with dipolarophiles in varying degree of π-facial selectivity.8 The
chiral ylides can be prepared from amines such as phenylethylamine,
phenylglycinol and ephedrine, which are all commericially available in both
enantiomeric forms. When using such types of ylides (i.e. 33), one disadvantage
is that the original chiral centre in the starting amine (i.e. 32) is normally
destroyed upon removal of the N-substituent of the cycloadduct (Scheme 2.2).
Thus, the chiral amine, amine 32 is, via 33, 34, transformed into achiral 36 (and
pyrrolidine derivative 35). Therefore, such reactions should not be considered as
chiral auxiliary induced asymmetric cycloadditions. It must be noted, however,
that there are successful examples where chiral auxiliaries have been attached to
azomethine ylides and removed from the cycloadducts in a non-destructive
manner.8
NH2
R2 R1 chiral R2 R1 achiral
32 36
+
O O
O R5
R5
* *
R3 N R4 5
R * * reduction * *
R3 N R4 R3 N R4
R2 R1 H
R2 R1
33 34 35
Scheme 2.2. Example of a general diastereofacial selective reaction using a chiral ylide.
A number of asymmetric 1,3-dipolar cycloaddition reactions of azomethine

ylides, where the chirality instead resides in the dipolarophile are described in
the literature.8,9 Such chiral non-racemic dipolarophiles can be obtained via
linkage of an enantiomerically pure chiral auxiliary to an achiral dipolarophile
(Scheme 2.3). Thus, chiral dipolarophiles such as N-enoylderivatives (e.g. 41 and
42) are conveniently prepared from the corresponding acid chloride 38 (usually
obtained from the acid 37 after treatment with SOCl2) and chiral auxiliaries such
as camphorsultam 3910 and oxazolidinone derivatives 4011 after deprotonation of
these with a base such as MeMgBr (Scheme 2.3).
[8] (a) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863-909. (b) Karlsson, S.;
Högberg, H.-E. Org. Prep. Proced. Int. 2001, 33, 103-172.
[9] Gothelf, K. V.; Jørgensen, K. A. In Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products; Padwa, A.; Pearson, W. H., Eds.;
John Wiley & Sons, Inc., New York, 2002, vol 59, 851-860.
[10] (a) Oppolzer, W. Tetrahedron 1987, 43, 1969-2004. (b) Oppolzer, W. Pure & Appl.
Chem. 1990, 62, 1241-1250.
[11] (a) Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre, D. J.; Bartroli, J.
Pure & Appl. Chem. 1981, 53, 1109-1127. (b) Evans, D. A. Aldrichimica Acta 1982, 15, 23-
32. (c) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835-875. (d) Ager, D. J.;
Prakash, I.; Schaad, D. R. Aldrichimica Acta 1997, 30, 3-14.
13
O O O O
S MgBr S
HN MeMgBr N
O O O
1
S
39 R N
O O 41
SOCl2
R1 OH R1 Cl
37 38 O O
R1 N O
O O
HN O MeMgBr MgBr
N O R2 R3
42
R2 R3 R2 R3
40
Scheme 2.3. Attachment of two different chiral auxiliaries to acyl chloride 38.
(1S)-(–)-Camphorsultam 39 (and the enantiomer) and oxazolidinone

derivatives 40 are examples of commercially available chiral auxiliaries, which
have frequently been used in various asymmetric reactions.10,11 A number of
other chiral auxiliaries derived from the chiral pool are also available.12 For the
former auxiliaries, mild and efficient methods are available for their removal
from the product.10,11 Typical reagents for this include LiAlH4, LiOH, alkoxides
and Grignard reagents. This furnishes the corresponding primary alcohol, acid,
ester and tertiary alcohol respectively, along with the recovered chiral auxiliary.
When reacted with cyclic achiral or chiral azomethine ylides, dipolarophiles
attached to camphorsultam give high asymmetric induction.13,14 High
diastereofacial selectivities have also been reported when azomethine ylides
attached to camphorsultam were reacted with various achiral dipolarophiles.15
Camphorsultam has also been used as a chiral auxiliary in other types of 1,3-
dipolar cycloadditions.16
[12] Blaser, H.-U. Chem. Rev. 1992, 92, 935-952.

[13] Pandey, G.; Laha, J. K.; Mohanakrishnan, A. K. Tetrahedron Letters 1999, 40, 6065-
6068.
[14] Garner, P.; Ho, W. B. J. Org. Chem. 1990, 55, 3973-3975.
[15] (a) Garner, P.; Dogan, O. J. Org. Chem. 1994, 59, 4-6. (b) Garner, P.; Dogan, Ö.;
Youngs, W. J.; Kennedy, V. O.; Protasiewics, J.; Zaniewski, R. Tetrahedron 2001, 57, 71-85.
(c) Dogan, Ö.; Öner, I.; Ulku, D.; Arici, C. Tetrahedron: Asymmetry 2002, 13, 2099-2104.
[16] Cycloadditions of nitrones: (a) Tejero, T.; Dondoni, A.; Rojo, I.; Merchán, F. L.; Merino,
P. Tetrahedron 1997, 53, 3301-3318. (b) Gefflaut, T.; Bauer, U.; Airola, K.; Koskinen, A. M. P.
Tetrahedron: Asymmetry 1996, 7, 3099-3102. (c) Murahashi, S.-I.; Imada, Y.; Kohno, M.;
Kawakami, T. Synlett 1993, 395-396. (d) ref. 117. Cycloadditions of nitrile oxides: (a)
Wallace, R. H.; Liu, J.; Zong, K. K.; Eddings, A. Tetrahedron Letters 1997, 38, 6791-6794.
(b) Kim, B. H.; Chung, Y. J.; Keum, G.; Kim, J.; Kim, K. Tetrahedron Letters 1992, 33, 6811-
6814. (c) Curran, D. P.; Heffner, T. A. J. Org. Chem. 1990, 55, 4585-4595. (d) Zhang, J.;
Curran, D. P. J. Chem. Soc. Perkin Trans. 1 1991, 2627-2631. (e) ref. 24. Cycloadditions of
diazoalkanes: (a) Mish, M. R.; Guerra, F. M.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119,
8379-8380. Cycloadditions of silyl nitronates: (a) Kim, B. H.; Lee, J. Y. Tetrahedron:
Asymmetry 1991, 2, 1359-1370. (b) Kim, B. H.; Lee, J. Y.; Kim, K.; Whang, D. Tetrahedron:
Asymmetry 1991, 2, 27-30. Cycloadditions of thiocarbonyl ylides: See section 3.2.
14
Compared with camphorsultam, chiral non-racemic oxazolidinones have not
been as extensively used as chiral auxiliaries in 1,3-dipolar cycloaddition
reactions, but there are some examples in the literature involving achiral
azomethine ylides17,18 and other types of 1,3-dipoles.19
When the work described in paper I was started, no general and efficient 1,3-
dipolar cycloaddition approach for the preparation of enantiopure trans-3,4-
disubstituted pyrrolidines existed.20 Therefore, the potential of using the above
mentioned chiral auxiliaries as well as other auxiliaries in such reactions was
investigated (Scheme 2.4).
O
Ph OEt
Me3Si N OMe
Bn Ti(OiPr)4 N
43 EtOH, ∆X Bn
( )-3S,4R-47
CF3CO2H
cat. O O O
Ph Xc Ph Xc
Ph Xc
4R 3S
44 (a-e) +
N N
N
Bn Bn
Bn
43# 45 (a-e) 46 (a-e)
O O O O
O
H-Xc: HN HN HN S HN H OH O
O O O
H O
O
O
O
a b c d e
Scheme 2.4. 1,3-Dipolar cycloaddition reaction of azomethine ylide 43# with dipolarophile 44
attached to various chiral auxiliaries a-e.
Thus, a number of well known chiral auxiliaries a-e were screened in the
reaction of the azomethine ylide 43# with cinnamoyl derivative 44. Various
oxazolidinones (a, b, d), camphorsultam (c), and a sugarderivative (e) (Scheme
2.4) were used as chiral auxiliaries (H-Xc). Trifluoroacetic acid (TFA) catalysed
azomethine ylide generation21 from compound 43 in the presence of one of the
[17] Ma, Z.; Wang, S.; Cooper, C. S.; Fung, A. K. L.; Lynch, J. K.; Plagge, F.; Chu, D. T. W.
[18] Hale, J. J.; Budhu, R. J.; Mills, S. G.; Maccoss, M.; Malkowitz, L.; Siciliano, S.; Gould, S.
L.; DeMartino, J. A.; Springer, M. S. Bioorg. & Med. Chem. Lett. 2001, 11, 1437-1440.
[19] Cycloadditions of nitrones: refs. 16c, 77a, 77b and 117b. Cycloadditions of nitrile
oxides: (a) Yamamoto, H.; Watanabe, S.; Kadotani, K.; Hasegawa, M.; Noguchi, M.;
Kanemasa, S. Tetrahedron Letters 2000, 41, 3131-3136.
[20] At the time of manuscript preparation, a work similar to this was published where some
oxazolidinone derived dipolarophiles had been screened in the above reaction with similar
results, see ref. 17.
[21] Terao, Y.; Kotaki, H.; Imai, N.; Achiwa, K. Chem. Pharm. Bull. 1985, 33, 2762-2766.
15
dipolarophiles 44 (a-e) gave in general a high yield of the separable
diastereomeric cycloadducts 45 and 46. However, the diastereofacial selectivity
obtained was low to moderate using any of these auxiliaries a-e (Table 2.1). The
best result was obtained when camphorsultam c was used as the auxiliary (dr up
to 74:26, entry 6). The solvent and the temperature had a certain effect on the
diastereofacial selectivity (Table 2.1).
X-ray chrystallography established the absolute configuration of the major
diasteromer 45b as 3S,4R. Transformation of this compound to the correspond-
ing ethyl ester (–)-3S,4R-47 (Scheme 2.4) allowed the assignment of the same
3S,4R absolute configuration of the other major diastereomeric cycloadducts
45a, 45c and 45d after transformation of the latter to the same ester (–)-3S,4R-
47. However, auxiliary e gave a small preference for the 3R,4S diastereomer 46e.
Table 2.1. 1,3-Dipolar cycloaddition of ylide 43# with dipolarophile 44 attached to

various chiral auxiliaries a-e, resulting in the diastereomeric cycloadducts 45 and
46.
O O
Ph Xc Ph Xc
O
N
+ +
Ph Xc Bn N N
Bn Bn
44 (a-e) 43# 45 (a-e) 46 (a-e)
o
Entry HXc Solvent Temp. ( C) Yield (%) Dr 45:46
O
1 CH2Cl2 –78 10 58:42
HN
2 O CH2Cl2 0 quant. 57:43
3 a Toluene +20 quant. 70:30
O
4 CH2Cl2 –20 55 59:41
HN
O
5 CH2Cl2 +20 quant. 64:36
b
O
O
6 HN S CH2Cl2 +40 quant. 74:26
7 Toluene +20 quant. 66:34

c
O
8 CH2Cl2 –20 quant. 54:46
HN
O
H
9 Toluene +20 quant. 63:37

d
H OH O
10 O O CH2Cl2 –20 quant. 48:52
O
O
e
16
Remarkably, reaction of 43# with both dipolarophile 44a and 44b having
opposite absolute configurations at the oxazolidinone moiety, gave diastereomer
45 with the 3S,4R configuration as the major adduct. This means that the reaction
pathways for these reactions probably proceed through different intermediates,
where the two dipolarophiles 44a and 44b adopt two different major
conformations in the reaction with the dipole 43#.
It is known that N-enoyl-oxazolidinones, in the absence of Lewis acids, prefer a
low energy s-cis conformation (conformers A and D, Figure 2.1).22 The s-trans
conformers B and C are both significantly destabilised due to unfavourable
interactions between the alkene- and the oxazolidinone moiety. Among the two
lowest energy conformers A and D, the one having the two carbonyl oxygens
trans-disposed (Z-conformer D, Figure 2.1) is the most stable one. This is due to
an unfavourable dipole alignment in the U-conformer A. Thus, it is possible that
the dipolarophile 44b mainly reacts via the lowest energy s-cis Z-conformer D
whereas 44a mainly reacts via the s-cis U-conformer A with ylide 43#. Attack of
the ylide 43# from the least sterically hindered side of the π-bond of both of
these will furnish the same 3S,4R stereoisomer 45 which also was that sense of
π-facial selectivity experimentally observed.
R1
R1
O O O O O O
1
R N O N O N O N O
O O
1
* R * * *
R2 R2 R2 R2
A B C D
s-cis s-trans s-trans s-cis
= U - conformers = Z -conformers
Figure 2.1.
Molecular modelling (CS Chem3D ProTM 4.0) indicated that the energy
difference between the U- and the Z-conformer of dipolarophiles 44a and 44b
was 3.5 and 5.5 kcal/mol respectively (Figure 2.2, this figure was incorrectly
depicted in paper I). Thus, due to this energy difference for the two
dipolarophiles it is possible that 44a reacts mainly via the high energy U-
conformation, whereas 44b reacts mainly via the low energy Z-conformation
(Figure 2.2). There are also examples in the literature in which N-
enoylderivatives attached to auxiliary b (Scheme 2.5) react, in the absence of
bidentate chelating Lewis acids, with the same sense of π-facial selectivity as
44b with reagents other than 1,3-dipoles.23
[22] Kim, B. H.; Curran, D. P. Tetrahedron 1993, 49, 293-318.

[23] See e.g. Schneider, C.; Reese, O. Synthesis 2000, 1689-1694.
17
Dipole attacks Dipole attacks
from the back from the front
O O O O O
O
N O N O O N O O N
* O
R R
44a = U - conformer = Z -conformer 44b
Energy difference U- Z
45a (major) R = t-Bu: ~ 5,5 Kcal / mol 45b (major)
R = Ph: ~ 3,5 Kcal / mol
∆G*U 3,5 ∆G*Z

∆G*U 5,5 ∆G*Z
U-44a U-44b
Z-44a
45a 46a Z-44b 45b
46b
Figure 2.2. Proposed reaction pathways via two different conformers of 44a and 44b. It is assumed
that ∆G*U and ∆G*Z are approximately equal for both reactions of ylide 43# with 44a and 44b and
that ∆G*U < ∆G*Z for the individual reactions.
The sense of π-facial selectivity observed when reacting ylide 43# with the
camphorsultam derived dipolarophile 44c can be explained by the model
depicted in Figure 2.3. It has been proposed that N-enoyl camphorsultams, in the
absence of Lewis acids, react with 1,3-dipoles such as nitrile oxides in an s-cis
conformation, where the sulfone oxygens of the sultam moiety and the carbonyl
oxygen are trans-located in relation to the C-N amide bond.22,24 Attack of the
dipole then occurs on the opposite side to that occupied by the axially oriented
sulfone oxygen (Oα) due to unfavourable interactions between the incoming
dipole and the axially oriented sulfone oxygen (Oα, Figure 2.3).22,24 Thus, in
accordance with the experimentally observed π-facial selectivity in the reaction
of 44c with ylide 43#, the major pathway is probably the one depicted in Figure
2.3.
Bn
N
O H
N
S Oβ H Ph
Oα
Figure 2.3. Proposed major reaction pathway when reacting ylide 43# with dipolarophile 44c.
[24] (a) Curran, D. P.; Kim, B. H.; Daugherty, J.; Heffner, T. A. Tetrahedron Letters 1988, 29,
3555-3558. (b) Kim, K. S.; Kim, B. H.; Park, W. M.; Cho, S. J.; Mhin, B. J. J. Am. Chem.
Soc. 1993, 115, 7472-7477.
18
2.3 Doubly diastereoselective reactions using chiral
auxiliaries
Although there are successful examples of 1,3-dipolar cycloadditions of chiral
azomethine ylides with achiral dipolarophiles resulting in high π-facial
selectivities,25 those reactions sometimes proceed in low to moderate
diastereofacial selectivities.26 Improvement in the selectivity can often be
achieved if both the azomethine ylide and the dipolarophile are chiral and non-
racemic.27 The singly diastereoselective 1,3-dipolar cycloaddition reactions
described in section 2.2 proceeded in low to moderate diastereofacial
selectivities. Therefore it was tempting to apply a doubly diastereoselective
approach in this reaction.
Paper II describes the efforts to increase the diastereofacial selectivity in the
reaction depicted in Scheme 2.4 by using the phenylethylamine derived chiral
non-racemic azomethine ylides 48# and 49# (Scheme 2.5). Doubly
diastereoselective reactions with a broader set of chiral dipolarophiles are
included in paper III and IV.
[25] See e.g. (a) Deprez, P.; Royer, J.; Husson, H.-P. Tetrahedron: Asymmetry 1991, 2,
1189-1192. (b) Alker, D.; Hamblett, G.; Harwood, L. M.; Robertson, S. M.; Watkin, D. J.;
Williams, C. E. Tetrahedron 1998, 54, 6089-6098. (c) Alker, D.; Harwood, L. M.; Williams, C.
E. Tetrahedron Letters 1998, 39, 475-478. (d) Enders, D.; Meyer, I.; Runsink, J.; Raabe, G.
Tetrahedron 1998, 54, 10733-10752. (e) Felluga, F.; Pitacco, G.; Visintin, C.; Valentin, E.
Helv. Chim. Acta 1997, 80, 1457-1472. (f) Schnell, B.; Bernardinelli, G.; Kündig, E. P. Synlett
1999, 348-350. (g) Jones, R. C. F.; Howard, K. J.; Snaith, J. S. Tetrahedron Letters 1996,
37, 1707-1710. (h) Garner, P.; Sunitha, K.; Ho, W.-B.; Youngs, W. J.; Kennedy, V. O.; Djebli,
A. J. Org. Chem. 1989, 54, 2041-2042.
[26] See e.g. (a) Negron, G.; Roussi, G.; Zhang, J. Heterocycles 1992, 34, 293-301. (b)
Deprez, P.; Rouden, J.; Chiaroni, A.; Riche, C.; Royer, J.; Husson, H.-P. Tetrahedron Letters
1991, 32, 7531-7534. (c) Rouden, J.; Royer, J.; Husson, H.-P. Tetrahedron Letters 1989, 30,
5133-5136. (d) Husinec, S.; Savic, V. J. Serb. Chem. Soc. 1998, 63, 921-930. (e) Wittland,
C.; Risch, N. J. Prakt. Chem. 2000, 342, 311-315. (f) Garner, P.; Sunitha, K.; Shanthilal, T.
Tetrahedron Letters 1988, 29, 3525-3528. (g) Takano, S.; Moriya, M.; Ogasawara, K.
Tetrahedron: Asymmetry 1992, 3, 681-684. (h) Cottrel, I. F.; Hands, D.; Kennedy, D. J.;
Paul, K. J.; Wright, S. H. B.; Hoogsteen, Karst. J. Chem. Soc. Perkin Trans 1 1991, 1091-
1097.
[27] See e.g. (a) Garner, P.; Ho, W. B.; Grandhee, S. K.; Youngs, W. J.; Kennedy, V. O. J.
Org. Chem. 1991, 56, 5893-5903. (b) Fray, A. H.; Meyers, A. I. Tetrahedron Letters 1992,
33, 3575-3578. (c) Fray, A. H.; Meyers, A. I. J. Org. Chem. 1996, 61, 3362-3374. (d) Reed,
A. D.; Hegedus, L. S. J. Org. Chem. 1995, 60, 3787-3794. (e) ref. 14.
19
Me3Si N OMe O O O
O
R1 H-Xc: HN S
HN HN
43: R1 = Bn O O
48: R1 = (R)-1-phenylethyl
49: R1 = (S)-1-phenylethyl
a b c
O
CF3COOH cat O O
Ph Xc Ph Xc Ph Xc
44 (a-c)
N +
N N
R1
R1 R1
Major Minor
43#: R1 = Bn 45 R1= Bn 46
48#: R1 = (R)-1-phenylethyl 50 R1 = (R)-1-phenylethyl 51
49#: R1 = (S)-1-phenylethyl 52 R1 = (S)-1-phenylethyl 53
Scheme 2.5. 1,3-Dipolar cycloadditions of either the achiral ylide 43# or the chiral ones, 48# and
49#, with dipolarophile 44 attached to various chiral auxiliaries a-c.
Table 2.2. Singly and doubly diastereoselective 1,3-Dipolar cycloadditions.
Products
Entry HXc Solvent Ylide Dr
major (minor)
N
1 Toluene 43# 45 (46) 70:30
O Ph
HN
O N
2 Toluene 48# 50 (51) 75:25
Ph Me
a
N
3 Toluene 49# 52 (53) 66:34
Ph Me
N
4 CH2Cl2 43# 45 (46) 64:36
O Ph
HN
O N
5 CH2Cl2 48# 50 (51) 75:25
Ph Me
b
N
6 CH2Cl2 49# 52 (53) 57:43
Ph Me
N
7 CH2Cl2 43# 45 (46) 74:26
O Ph
O
HN S
N
8 CH2Cl2 48# 50 (51) 78:22
Ph Me
c
N
9 CH2Cl2 49# 52 (53) 71:29
Ph Me
20
Table 2.2 shows that the diastereofacial selectivity is mainly controlled by the
chiral dipolarophiles rather than by the chiral azomethine ylides. The
mismatched cases (i.e. reactions with the ylide 49#) gave slightly lower
diastereofacial selectivities compared to the reactions involving the achiral
azomethine ylide 43#. In the matched cases (i.e. reactions with the ylide 48#),
the highest diastereofacial selectivities were obtained.
The doubly diastereoselective reactions of the chiral ylides 48# and 49# with
the dipolarophile 54 were also investigated (Scheme 2.6). Although being a more
electron-rich dipolarophile compared with the cinnamoyl derivatives 44 and
thus, it should be less reactive than the latter ones, I hoped that this vinyl ether
containing dipolarophile (i.e. 54) should be reactive enough in reactions with the
ylides 48# and 49# to provide a pyrrolidine containing an oxygen-functionality
in position 4 of the pyrrolidine ring.
48 or 49
H+ O O O O
O O O
O BnO S BnO
O N N S
BnO N S
+ N +
N N
R1
R1 R1
Major Minor
54 48#: R1 = (R)-1-phenylethyl 1
55 R = (R)-1-phenylethyl 56 (matched)
49#: R1 = (S)-1-phenylethyl 1
57 R = (S)-1-phenylethyl 58 (mismatched)
Scheme 2.6. 1,3-Dipolar cycloaddition of either the chiral ylide 48# or 49# with dipolarophile 54.
Table 2.3. Diastereofacial selectivity as a function of solvent polarity [ET(30)] in

the reaction of either the ylide 48# (matched case) or 49# (mismatched case) with
dipolarophile 54.
-1
Entry Solvent ET(30) [kcal mol ] Dr matched (mismatched)
1 Heptane 31.1 63:37 (65:35)
2 Cyclohexane 30.9 64:36 (62:38)
3 CCl4 32.4 61:39 (50:50)
4 1,4-Dioxane 36.0 79:21 (61:39)
5 Toluene 33.9 70:30 (52:48)
6 Diethyl ether 34.5 70:30 (54:46)
7 CHCl3 39.1 74:26 (69:31)
8 EtOAc 38.1 78:22 (58:42)
9 THF 37.4 75:25 (58:42)
10 CH2Cl2 40.7 83:17 (71:29)
11 Acetone 42.2 85:15 (73:27)
12 CH3CN 45.6 88:12 (75:25)
13 DMF 43.2 87:13 (71:29)
14 DMSO 45.1 86:14 (76:24)
21
Indeed, under optimised conditions, reaction of ylide 48# with dipolarophile
54 (Scheme 2.6) furnished cycloadduct 55 in up to 88:12 dr and in a good yield
in most cases (up to 93% combined isolated yield of 55 and 56). The π-facial
selectivity of this reaction was found to be strongly dependent on the solvent
polarity because, when screening various solvents, selectivities in the matched
cases (i.e. reactions with the ylide 48#) were in the range of 1.6:1 to 7:1 dr (Table
2.3). In general, the mismatched cases (i.e. reactions with the ylide 49#) gave
slightly lower diastereofacial selectivities.
O O N O O O O O O
O S S
S BnO BnO
N N
BnO N Ph Me
48# +
N N
solvent
Ph Me Ph Me
54 55 56
Major Minor
11
0,8
0.8
0,6
0.6
log (dr)
0,4
0.4
0,2
0.2
00
30 35 40 45
30 35 40 ]
ET(30) [kcal mol -1 45
Figure 2.4. Log (dr) as a function of solvent polarity ET (30) in the reaction of the ylide 48# with
dipolarophile 54.
22
A linear relationship between the logarithm of the diastereomeric ratio [log
(dr)] and the solvent polarity as expressed by the ET(30) parameter28 was
observed (Figure 2.4). Such linear relationships have been observed by others in
Diels-Alder reactions with camphorsultam derivatives as chiral auxiliaries.29
When reacted with acyclic dipolarophiles, the influence from the chiral
azomethine ylides on the π-facial selectivity, is obviously small (Table 2.2).
However, these ylides are derived from one of the enantiomers of phenylethyl-
amine which is a cheap, commercially available starting material. Thus, in order
to prepare enantiomerically pure trans-3,4-disubstituted pyrrolidines, the doubly
diastereoselective approach presented above should be useful for obtaining
maximum diastereofacial selectivity.
Based on the results discussed above and with the moderate diastereofacial
selectivities obtained in mind, I hoped that the chiral azomethine ylides 48# and
49# would react with cyclic dipolarophiles in higher diastereofacial selectivities.
Because, there were no examples in the literature of 1,3-dipolar cycloaddition
reactions of azomethine ylides with monocyclic five- and six-membered α,β-
unsaturated acyl derivatives attached to chiral auxiliaries, this was investigated.
The camphorsultam auxiliary, which when attached to acyclic dipolarophiles,
had so far given the highest diastereofacial selectivities, was attached to
cyclopent-1-enecarboxylic acid chloride and 2,5-dihydrothiophene-1-carboxylic
acid chloride. This furnished dipolarophiles 59 and 60, respectively (Scheme
2.7). When these were reacted with either the chiral azomethine ylide 48# or the
enantiomer 49#, a major influence from the chiral ylides was observed (Figure
2.5).
[28] (a) Reichardt, C. Chem. Rev. 1994, 94, 2319-2358. (b) Reichardt, C.; Schäfer, G.
Liebigs Ann. 1995, 1579-1582.
[29] (a) Chapuis, C.; Kucharska, A.; Rzepecki, P.; Jurczak, J. Helv. Chim. Acta. 1998, 81,
2314-2325. (b) Chapuis, C.; Kucharska, A.; Jurczak, J. Tetrahedron: Asymmetry 2000, 11,
4581-4591.
23
Me3Si N OMe
R1
43: R1 = Bn
48: R1 = (R)-1-phenylethyl
49: R1 = (S)-1-phenylethyl
CF3COOH cat R1 R1
N O N O
O O O O O + O O
S S S
N H H N
N
+ N
Y Y
Y R1
59: Y = CH2 43#: R1 = Bn 61 R1= Bn 62

60: Y = S 48#: R1 = (R)-1-phenylethyl Y = CH2 63 R1 = (S)-1-phenylethyl 64
49#: R1 = (S)-1-phenylethyl 65 R1 = (R)-1-phenylethyl 66
Y=S 67 R1 = (S)-1-phenylethyl 68
Scheme 2.7. 1,3-Dipolar cycloaddition of either the achiral azomethine ylide 43# or the chiral ones
48# and 49#, with the cyclic dipolarophiles 59 or 60.
5
Xylene CCl4 toluene dioxane DMF acetone CH3CN THF CH2Cl2
4
2
dipole 1 with 43#
reaction
dr 1 reaction
dipole 2 with 49#
2 dipole 3 with 48#

reaction
0
3
-1
-2
4
-3
Figure 2.5. Diastereomeric ratio (dr) as a function of solvent and ylide used (43#, 48# or 49#) in the
reaction with dipolarophile 59. Bars down mean an excess of the cycloadduct 61 or 65. Bars up mean
an excess of the cycloadduct 62, 64 or 66.
For example, when the ylide 48# was reacted with dipolarophile 59 in CH2Cl2,
cycloadduct 65 was obtained in 82:18 dr (65:66). When the enantiomer 49# was
reacted with the same dipolarophile under the same conditions, the π-facial
selectivity was reversed (dr 32:68, 63:64). The solvent also had a great influence
on the diastereofacial selectivity in all individual reactions involving the chiral
ylides 48# and 49# (Figure 2.5). However, reactions with the achiral ylide 43#
gave a low selectivity in all solvents investigated. The sulphur-containing
dipolarophile 60 reacted with the ylide 49# in approximately the same
diastereofacial selectivity as that observed for dipolarophile 59, to give a mixture
of the major cycloadduct 68 and the minor one 67 in a good yield.
24
The diastereomeric cycloadducts 61/62, 63/64, 65/66 and 67/68 could be
separated, either by column chromatography or by recrystallisation to give the
individual, pure diastereomers. One of these (compound 64) was transformed to
an enantiopure known precursor of an antibacterial compound (section 2.5). This
allowed the assignment of the absolute configurations of the newly created
stereocentres of compound 64 by optical rotation measurements. The
configurations of the other major and minor diastereomeric cycloadducts could
then be established by the optical rotation values of suitable compounds obtained
after some transformations.
In contrast to their reactions with acyclic dipolarophiles, the chirality of the
ylides 48# and 49# obviously had a relatively high effect on the diastereofacial
selectivity when these were reacted with chiral cyclic dipolarophiles 59 and 60.
For comparison, I also wanted to investigate whether such a high influence also
could be obtained when those chiral ylides were reacted with achiral cyclic
dipolarophiles. Thus, when reacted with either compound 69 or 70 in CH2Cl2,
ylide 49# furnished two diastereomeric cycloadducts (71 and 72) or (73 and 74),
respectively, both in a 64:36 diastereomeric ratio (Scheme 2.8). Although only a
moderate selectivity was achieved, the diastereomeric cycloadducts 71/72 and
73/74 were obtained in excellent yields and were readily separated by column
chromatography. Therefore, the singly diastereoselective approach depicted in
Scheme 2.8, should be useful for the preparation of enantiopure bicyclic fused
pyrrolidines.
Me3Si N OMe
Ph Me
49
CF3CO2H cat
CH2Cl2
Y Y
O O
Y
H H
dr 64:36 OR + OR
N
+ N N
OR 94%
Ph Me
O Ph Me Ph Me
major minor
69: R = Et, Y = CH2 49# 71 R = Et, Y = CH2 72
70: R = Me, Y = S 73 R = Me, Y = S 74
Scheme 2.8. Reaction of the chiral azomethine ylide 49# with two different achiral cyclic
dipolarophiles 69 and 70.
25
2.4 Enantioselective reactions using chiral catalysts
Examples of enantioselective metal-catalysed 1,3-dipolar cycloaddition reactions
of azomethine ylides with dipolarophiles are few and all of these employ
azomethine ylides of type 75 (Scheme 2.9) which are stabilised by an adjacent
electron acceptor. The Lewis acid catalysed reactions of such stabilised
azomethine ylides generally proceed via an intermediate in which the ylide
coordinates to the catalyst in a bidentate fashion (Scheme 2.9). Cycloaddition
with an electron-deficient dipolarophile of type 76 furnishes a highly
functionalised pyrrolidine 77.
O
*M
O R2 R3
O
* *
Ar N OR1
OR1 +
R2 R3 Ar * N *
H O
75 76 77
M* = Chiral Lewis acid
Scheme 2.9. Coordination of a chiral Lewis acid to a stabilised azomethine ylide 75 and subsequent
cycloaddition with an electron-deficient dipolarophile 76.
The first reported enantioselective reaction of this type involved chiral non-
racemic ephedrine ligands in conjunction with MnBr2 or CoCl2 as catalysts in the
reaction of α-amino ester derived azomethine ylides with methyl acrylate.30
Thus, up to 96% ee was obtained for the cycloadducts. Other catalysts such as
chiral phosphane ligands in conjunction with Ag(I) salts have also been used in
such types of reactions.31,32 Very recently, Zinc(II)-bisoxazolines were used as
efficient catalysts in the same type of reaction, which furnished highly
substituted proline derivatives in good diastereo- and enantioselectivities.33
It was tempting to investigate whether such an enantioselective approach also
could be employed in reactions with non-stabilised azomethine ylides (Scheme
2.10). Because reactions of most non-stabilised azomethine ylides with electron-
deficient dipolarophiles are HOMO(dipole)-LUMO(dipolarophile) controlled,
coordination of a Lewis acid to the dipolarophile might result in an increased
reaction rate, whereas coordination to the azomethine ylide might result in a
decreased one. Thus, in order to obtain a catalytic process, the Lewis acid should
coordinate to the dipolarophile rather than to the ylide. A bidentate chelation of
the Lewis acid to the dipolarophile is expected to give a stronger complex than a
monodentate binding.34 This can be accomplished by using dipolarophiles
containing two Lewis basic carbonyl oxygens, that is, using dipolarophile 79
instead of 78 (Scheme 2.10). The key issue was, whether a bidentate binding to
[30] Allway, P.; Grigg, R. Tetrahedron Letters 1991, 32, 5817-5820.

[31] Grigg, R. Tetrahedron: Asymmetry 1995, 6, 2475-2486.
[32] Patent application: Zhang, X. WO 01/58588 A1, 2002.
[33] Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem. Int. Ed.
2002, 41, 4236-4238.
[34] Gothelf, K. V.; Jensen, K. B.; Jørgensen, K. A. Science Progress 1999, 82, 327-350.
26
the dipolarophile was enough favoured over binding to the ylide 43#. Chiral non-
racemic bis-oxazolines and bis-oxazolinylpyridines (e.g. 81 and 82) are well
known chiral ligands, which in conjunction with various metals form chiral
Lewis acids suitable for use in enantioselective transformations35 such as Diels-
Alder reactions,36 cyclopropanation reactions,37 1,3-dipolar cycloaddition
reactions of nitrones34 and stabilised azomethine ylides as have been described
above.33
Me3Si N OMe O O
Bn
43 N N
Ph Cu2+ Ph
CF3 COOH cat
O 2 OTf -
Ph R 81
O
81 or 82
Ph R + N
N O
Bn O N
Bn
78: R = OEt 43# 80 N Cu 2+ N
O up to 8% ee 2 OTf -
79: R = N O 82
Scheme 2.10. Attempt to introduce chiral catalysts 81 and 82 in the reaction of the unstabilised
azomethine ylide 43# with either dipolarophile 78 or 79.
With the aim of developing a general method for the enantioselective

preparation of trans-3,4-disubstituted pyrrolidines, the chiral non-racemic bis-
oxazoline 81 and bis-oxazolinylpyridine 82 were tested as catalysts in the
reaction of the unstabilised azomethine ylide 43# with two different
dipolarophiles 78 and 79 (Scheme 2.10). Because, in the absence of a Lewis
acid, the azomethine ylide 43# reacts very fast with electron-deficient
dipolarophiles, a stoichiometric amount of chiral Lewis acid was used. Thus, to a
pre-formed complex between one of the dipolarophiles 78 or 79 and one of the
catalysts 81 or 82 was added ylide precursor 43. Acid catalysed (TFA) generation
of the corresponding ylide followed by cycloaddition resulted in the formation of
cycloadduct 80, unfortunately in a very low ee (up to 8% ee using catalyst 82
and dipolarophile 78).
On addition of the ylide precursor 43, the initially formed complex between
the catalyst and the dipolarophile was probably decomposed, which could
explain the disappointing results obtained. Thus the ylide precursor 43 is
probably a stronger Lewis base than the carbonyl oxygens of the dipolarophiles
78 and 79. Support for this idea was also obtained by some 13C NMR studies of
the initially formed complex and its decomposition when the ylide precursor was
added. Therefore, further studies of this catalytic approach were abandoned.
[35] Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahedron: Asymmetry 1998, 9, 1-45.
[36] See e.g. (a) Corey, E. J.; Imai, N.; Zhang, H.-Y. J. Am. Chem. Soc. 1991, 113, 728-729.
(b) Ghosez, L.; Jnoff, E. J. Am. Chem. Soc. 1999, 121, 2617-2618. (c) Evans, D. A.; Murry,
J. A.; von Matt, P.; Norcross, R. D.; Miller, S. J. Angew. Chem. Int. Ed. 1995, 34, 798-800.
(d) Evans, D. A.; Miller, S. J.; Lectka, T. J. Am. Chem. Soc. 1993, 115, 6460-6461.
[37] Østergaard, N.; Jensen, J. F.; Tanner, D. Tetrahedron 2001, 57, 6083-6088 and
references cited therein.
27
2.5 Applications
Many natural alkaloids contain a pyrrolidine ring.38 Examples are numerous of
the successful syntheses of such naturally occurring alkaloids and their
analogues in which an asymmetric 1,3-dipolar cycloaddition of an azomethine
ylide with a dipolarophile has played a key role in the synthetic sequence. Some
recent examples are the total synthesis of the antitumor antibiotic (–)-
quinocarcin,39 a precursor to the alkaloid (+)-conessine (used in the treatment of
dysentery),40 (+)- and (–)-spirotryprostatin B,41 (–)-2α-tropanol,42 (–)-
cucurbitine,43 (–)-horsfiline,44 and the analgesic alkaloid epibatidine45 (Figure
2.6). Asymmetric 1,3-dipolar cycloadditions of azomethine ylides have also been
utilised as key steps in the total syntheses of many unnatural bioactive
substances, for example some cocaine antagonists,46 antibacterial compounds17
and glucosidase inhibitors.26g 3,4-Disubstituted pyrrolidines (section 2.2 and 2.3)
have found applications as receptor antagonists.18
Me H
N Me H O
O N N
Me N Me
N CO2H H O O N
H H
MeO HN HO
H
MeO
Quinocarcin Conessine precursor Spirotryprostatin B 2α-Tropanol
CO2
MeO N Me H Cl
H3N N
O N
N N
H H H
Cucurbitine Horsfiline Epibatidine
Figure 2.6. Examples of alkaloids synthesised via an asymmetric 1,3-dipolar cycloaddition of an
azomethine ylide as a key step. The pyrrolidine unit obtained in this step is marked in red.
[38] (a) Jeger, O.; Prelog, V. In The alkaloids: Chemistry and Physiology; Manske, R. H. F.,
Ed.; Academic press: New York, 1960; Vol. VII, 319-342. (b) Torssell, K. B. G. Natural
Product Chemistry; Swedish Pharmaceutical Press: Stockholm, Sweden, 1997; 348-406.
[39] (a) Garner, P.; Ho, W. B.; Shin, H. J. Am. Chem. Soc. 1992, 114, 2767-2768. (b) Garner,
P.; Ho, W. B.; Shin, H. J. Am. Chem. Soc. 1993, 115, 10742-10753.
[40] Kopach, M. E.; Fray, A. H.; Meyers, A. I. J. Am. Chem. Soc. 1996, 118, 9876-9883.
[41] (a) Sebahar, P. R.; Williams, R. M. J. Am. Chem. Soc. 2000, 122, 5666-5667. (b)
Sebahar, P. R.; Osada, H.; Usui, T.; Williams, R. M. Tetrahedron 2002, 58, 6311-6322.
[42] (a) Takahashi, T.; Kitano, K.; Hagi, T.; Nihonmatsu, H.; Koizumi, T. Chem. Lett. 1989,
597-598. (b) Takahashi, T.; Fujii, A.; Sugita, J.; Hagi, T.; Kitano, K.; Arai, Y.; Koizumi, T.;
Shiro, M. Tetrahedron: Asymmetry 1991, 2, 1379-1390.
[43] Williams, R. M.; Fegley, G. J. Tetrahedron Letters 1992, 33, 6755-6758.
[44] (a) Palmisano, G.; Annunziata, R.; Papeo, G.; Sisti, M. Tetrahedron: Asymmetry 1996,
7, 1-4. (b) Cravotto, G.; Giovenzana, G. B.; Pilati, T.; Sisti, M.; Palmisano, G. J. Org. Chem.
2001, 66, 8447-8453.
[45] (a) Pandey, G.; Bagul, T. D.; Sahoo, A. K. J. Org. Chem. 1998, 63, 760-768. (b) Pandey,
G.; Laha, J. K.; Lakshmaiha, G. Tetrahedron 2002, 58, 3525-3534.
[46] Prakash, K. R. C.; Trzcinska, M.; Johnson, K. M.; Kozikowski, A. P. Bioorg. & Med.
Chem. Lett. 2000, 10, 1443-1446 and references cited therein.
28
Having demonstrated that enantiopure 3,4-disubstituted pyrrolidines could be
obtained via singly and doubly diastereoselective 1,3-dipolar cycloaddition
reactions (section 2.2 and 2.3), I also wanted to find synthetic applications of
such reactions. Hence, these were utilised as key steps in the syntheses of two
bioactive substances containing a pyrrolidine ring. First a short synthesis of a
known47,48 enantiomerically pure glycosidase inhibitor (compound 84, Scheme
2.11) was accomplished. Thus, starting from the chiral ylide precursor 49 and
dipolarophile ent-54, compound ent-55 was obtained via a doubly diastereoselec-
tive 1,3-dipolar cycloaddition (section 2.3) in 75% yield and >99:1 dr, after
removal of the minor diastereomer ent-56 by column chromatography (Scheme
2.11). This compound was treated with LiAlH4 to give alcohol 83 in 88% yield,
along with recovered camphorsultam (90% yield). Reductive removal of the
benzylic groups of 83 using Pd/C under an atmosphere of hydrogen furnished the
enantiomerically pure compound 84 in 99% yield (65% overall yield from ent-
54). The enantiomer ent-84 was also synthesised starting from the antipodes of
the dipole precursor 49 (i.e. 48) and the dipolarophile ent-54 (i.e. 54). The new
synthetic pathway for the synthesis of 84 described here is shorter and more high
yielding compared with the already existing one.47
BnO OH HO OH
LiAlH4,THF H2, Pd/C
Me3Si N OMe
88% 99% N
N
Ph Me H
49 Ph Me
83 84
CF3COOH cat
O O
O BnO BnO
N N
N N S S
BnO + +
S O O O O
Ph Me N N
O O
Ph Me Ph Me
ent-54 49# ent-55 ent-56
75% 18%
Scheme 2.11. Synthesis of a known inhibitor of glycosidase 84.
Enantiomerically pure derivatives of azabicyclo[3.3.0]octanes (i.e. 87 and its

enantiomer, Scheme 2.12) exhibit antibacterial activity against both Gram-
positive and Gram-negative organisms.49 Such compounds can be prepared via a
1,3-dipolar cycloaddition of an achiral azomethine ylide with an achiral
dipolarophile followed by resolution of the racemic cycloadducts in a later
step.49 An alternative route to obtain these compounds is via an asymmetric 1,3-
dipolar cycloaddition with the aid of chiral auxiliaries. This approach has the
advantage that the chirality is introduced in an early step.
[47] Makino, K.; Ichikawa, Y. Tetrahedron Letters 1998, 39, 8245-8248.

[48] Hollis, T.; Ichikawa, Y.; Ellenberger, T. The EMBO journal 2000, 19, 758-766.
[49] Ogata, M.; Matsumoto, H.; Shimizu, S.; Kida, S.; Nakai, H.; Motokawa, K.; Miwa, H.;
Matsuura, S.; Yoshida, T. Eur. J. Med. Chem. 1991, 26, 889-906.
29
Thus, using the doubly diastereoselective approach described in section 2.3
and some other transformations, I prepared the enantiomerically pure known49
azabicyclo[3.3.0]octane 87 according to Scheme 2.12.
O O O O O
H S H H H Br
N a OEt b NH2 c, d, e
NH3
N N N N
H2 Br
Ph Me Ph Me Ph Me
64 85 86 87
Scheme 2.12. Preparation of a precursor to an antibacterial compound. (a) Ti(OEt)4, EtOH, reflux,
90%. (b) NH2Li, THF, reflux, 77%. (c) LiAlH4, THF. (d) H2, Pd/C. (e) HBr, 80% yield from 86.
Hence, compound 64, which was obtained via an asymmetric 1,3-dipolar

cycloaddition in 59% yield and >99:1 dr after removal of the minor diastereomer
(section 2.3), was subjected to Ti(OEt)4 catalysed ethanolysis.50 This afforded
ester 85 in 90% yield, which upon treatment with lithium amide in excess
furnished the primary amide 86 (77%). Reduction of this using LiAlH4 followed
by removal of the phenylethyl group using Pd/C under hydrogen gave the
corresponding diamine which was treated with aqueous HBr to give the
enantiomerically pure target salt 87, in 80% overall yield from amide 86.
Compound 87 was identical in all respects with the one previously prepared.49
Because as will be described in section 4.3, substituted pyrrolidines are
frequently employed as organocatalysts in various enantioselective
transformations, I hoped that the bicyclic compounds 71-74 (Scheme 2.8), due to
their rigid structure, could act as efficient potential organocatalysts after some
transformations. To be able to screen a variety of differently substituted
derivatives of such catalysts, functional group transformations have to be
performed with the cycloadducts 71-74. These contain a carbonyl group, which
can act as an electrophilic site to which various nucleophiles can be added.
Moreover, compounds 73 and 74 both incorporate sulfide moieties, which can be
transformed into other functional groups. Thus, addition of Grignard reagents to
cycloadducts 71-74 will furnish tertiary alcohols. After some additional
transformations, potential catalysts capable of forming hydrogen bonds can be
obtained. The resulting alcohols can be protected as ethers resulting in catalysts
possessing other properties. Furthermore, the sulphur-containing compounds 73
and 74 can be oxidised to the corresponding sulfones. This will lead to the
incorporation of a more polar and sterically restricted moiety which may play an
important role for the efficiency of the catalyst. Thus, various substituted
derivatives of cycloadducts 71-74 have been synthesised and their potential as
catalysts in enantioselective transformations has been evaluated.
[50] Seebach, D.; Hungerbuhler, E.; Naef, R.; Schnurrenberger, P.; Weidmann, B.; Zuger, M.
Synthesis 1982, 138-141.
30
To be able to build up a library of structurally different potential catalysts,
large amounts of the starting fused bicyclic pyrrolidines were needed. These
could be obtained via doubly diastereoselective 1,3-dipolar cycloadditions as
described in section 2.3. However, as already described (section 2.3), the
chirality of the ylide was more important than that of the cyclic dipolarophile for
obtaining a high π-facial selectivity. Therefore, I decided to prepare the desired
bicyclic adducts from the chiral azomethine ylide 48# and achiral cyclic
dipolarophiles via singly diastereoselective reactions. As will be presented in
section 4.3, out of the bicyclic fused pyrrolidines tested, the ones containing a
sulfone moiety were found to be the most efficient catalysts. Therefore, only the
syntheses of these are presented in Scheme 2.13.
O O O O
S S
Ar Ar
H OH c H OH
Ar Ar
N N
Me3Si N OMe H2 Cl
Ph Me
Ph Me 91: Ar = Ph 93: Ar = Ph
48 92: Ar = p-MeOC6H4 94: Ar = p-MeOC6H4
CF3CO2H (cat)
CH2Cl2 a
O O O O
O O S S
S O O
+ H ent-93
+ N dr 60:40 H a, c
OMe OMe OMe and
94% N N
Ph Me ent-94
O
Ph Me Ph Me
88 48# 89 90
major minor
a
O O O O
S S
Ar Ar
b, c
H OMe H OH
Ar Ar
N N
H2 Cl
Ph Me
96: Ar = Ph 95: Ar = Ph
Scheme 2.13. Preparation of some potential organocatalysts: a) PhMgBr or p-MeO(C6H4)MgBr,

THF, 62%. b) NaH, MeI, THF, 88%. c) (i) 1-chloroethylchloroformate, 1,8-
bisdimethylaminonaphtalene, ClCH2CH2Cl, reflux. (ii) MeOH, reflux, 65-96% overall.
31
Thus, a 1,3-dipolar cycloaddition of the chiral azomethine ylide derived from
48 with the achiral dipolarophile 88 gave a 60:40 diastereomeric mixture of
cycloadducts 89 and 90. Column chromatography afforded the individual pure
diastereomers in >99:1 dr. Grignard addition to the major diastereomer 89 using
either PhMgBr or p-MeO(C6H4)MgBr yielded the corresponding tertiary
alcohols 91 and 92, respectively. The phenylethyl groups of these were removed
by treatment with a dealkylation reagent51 to give the pyrrolidinium salts 93 and
94. Attempts to remove the phenylethyl group by using other reagents such as
Pd/C under hydrogen failed. Only desulfurised byproducts along with the
recovered starting material were obtained. The same transformations were made
starting from the minor cycloadduct 90 to give compounds ent-93 and ent-94.
Compound 96 was obtained from the minor cycloadduct 90 via a Grignard
reaction and transformation of the resulting alcohol 95 to the corresponding
methyl ether, followed by removal of the phenylethyl group. It must be noted
that compounds 93, 94 and 96 and the corresponding enantiomers of these could
also be prepared via a 1,3-dipolar cycloaddition reaction of 2,5-
dihydrothiophene-3-carboxylic acid methyl ester 70 with ylide 48# (Scheme
2.8). However, using 70 as the dipolarophile required one extra step in the
synthetic sequence (i.e. oxidation of the sulphur moiety). Therefore, the methyl
sulfolenecarboxylate 88 was chosen as the dipolarophile.
The catalytic efficiency of the metal-free, new, potential organocatalysts
depicted in Scheme 2.13 in 1,3-dipolar cycloaddition reactions of nitrones with
some dipolarophiles are presented in section 4.3.
[51] Olofson, R. A.; Martz, J. T.; Senet, J.-P.; Piteau, M.; Malfroot, T. J. Org. Chem. 1984, 49,
2081-2082.
32
3. 1,3-Dipolar cycloaddition reactions of thiocarbonyl
ylidesV,VI
3.1 General aspects

As depicted in Scheme 3.1, thiocarbonyl ylides have the general structure 100.
They belong to the allyl anion type having four resonance structures as described
in section 1.2 (only one shown in Scheme 3.1). Thiocarbonyl ylides are often
reactive, short lived species and thus have to be prepared in situ from a
precursor. Examples of generation of these are decomposition of 2,5-dihydro-
1,3,4-thiadiazoles 97, CsF catalysed elimination of Me3SiCl from compound 98
and deprotonation of sulfenium salts 99 (Scheme 3.1).52 Other methods also
exist.52 The resulting ylide 100 readily undergoes 1,3-dipolar cycloaddition
reactions, mainly with electron-deficient dipolarophiles (i.e. 101), to give
tetrahydrothiophenes 102.53 Depending on the substitution pattern of the
dipolarophile and the ylide, up to four new stereogenic centres can be created in
one single step.
N N
R1 R3 - N2
2 S 4 O O
R R
97 R6 5
R R6 R5
R1 R3 * R3
Me3Si S Cl
CsF 101 R1 *
- Me3SiCl R2 S R4 4
98 R2 * S * R
R1 R3
H Base 100 102
R2 S R4 - HX
X
99 R1 = R2 = R3 = R4 = H
from 98
Scheme 3.1. Examples of generation of thiocarbonyl ylides 100. In the presence of an electron-
deficient dipolarophile 101, these undergo cycloaddition to give tetrahydrothiophene derivatives 102.

With the exception of a few 1,3-dipolar cycloaddition reactions of a masked
thiocarbonyl ylide (i.e. a thioisomünchnone) with some chiral non-racemic
nitroalkenes resulting in dihydrothiophenes after rearrangement,54 there are,
[52] Mloston, G.; Heimgartner, H. Polish J. Chem. 2000, 74, 1503-1532.

[53] Mloston, G.; Heimgartner, H. In Synthetic Applications of 1,3-Dipolar Cycloaddition
[54] (a) Areces, P.; Avalos, M.; Babiano, R.; González, L.; Jiménez, J. L.; Méndez, M. M.;
Palacios, J. C. Tetrahedron Letters 1993, 34, 2999-3002. (b) Avalos, M.; Babiano, R.;
Cabanillas, A.; Cintas, P.; Diánez, M. J.; Estrada, M. D.; Lopez-Castro, A.; Palacios, J. C.;
Garrido, S. P. J. Chem. Soc. Chem. Commun. 1995, 2213-2214. (c) Avalos, M.; Babiano,
R.; Cabanillas, A.; Cintas, P.; Higes, F. J.; Jiménez, J. L.; Palacios, J. C. J. Org. Chem.
1996, 61, 3738-3748.
33
except for the two works included in this thesis,V,VI to my knowledge no reported
asymmetric 1,3-dipolar cycloaddition reactions of thiocarbonyl ylides with
dipolarophiles.
Having demonstrated that enantiomerically pure trans-3,4-disubstituted
pyrrolidines can be obtained via 1,3-dipolar cycloaddition reactions with the aid
of chiral auxiliaries (section 2.2 and 2.3), it was interesting to investigate if a
similar approach could be used for the syntheses of enantiomerically pure trans-
3,4-disubstituted tetrahydrothiophenes.
Me3Si S Cl
98
CsF O O O O O O O O O
S R S R S
R N N N
CH3CN +
S +
0 oC S S
98# 89-95% Major Minor
dr ~ 90:10
103: R = Bu 104: R = Bu 105: R = Bu
54: R = BnO 106: R = BnO 107: R = BnO
44c: R = Ph 108: R = Ph 109: R = Ph
Scheme 3.2. 1,3-Dipolar cycloaddition of thiocarbonyl ylide 98# with dipolarophile 103, 54 or 44c.
Compound 98 (Scheme 3.2), when treated with CsF in CH3CN, is known to

decompose to the corresponding thiocarbonyl ylide 98#, which in the presence of
achiral electron-deficient dipolarophiles undergo cycloadditions to give racemic
3,4-disubstituted tetrahydrothiophenes.55
When the same ylide was allowed to react with some chiral dipolarophiles
attached to camphorsultam (103, 54 and 44c, Scheme 3.2), the major
diastereomeric tetrahydrothiophenes 104, 106 and 108 were formed together
with the separable minor diastereomers 105, 107 and 109, respectively, in high
diastereofacial selectivities (dr ~90:10) and good yields (89-95% yield). Thus,
the first asymmetric 1,3-dipolar cycloaddition of a thiocarbonyl ylide with chiral
dipolarophiles resulting in trans-3,4-disubstituted tetrahydrothiophenes had been
developed. It is worth noting, that when some chiral oxazolidinones were
screened as chiral auxiliaries in the same reaction, considerably lower
diastereofacial selectivities were obtained.
In order to secure the absolute configurations of the newly created stereocen-
tres in the tetrahydrothiophene rings, the major cycloadducts 104, 106 and 108
were transformed into enantiomerically pure compounds 112, 113 and 115 of
known absolute configurations (Scheme 3.3). The signs of optical rotation of
these were compared with the ones in the literature.
[55] Hosomi, A.; Matsuyama, Y.; Sakurai, H. J. Chem. Soc. Chem. Commun. 1986, 1073-
1074.
34
O O
LiOH R OH R OH
Ra-Ni
104 or 108
THF/H2O EtOH
S
110: R = Bu 112: R = Bu
111: R = Ph 113: R = Ph
BnO OH BnO OH
LiAlH4 Ra-Ni
106
S EtOH
114 115
Scheme 3.3. Preparation of the enantiomerically pure known compounds 112, 113 and 115.
Thus, hydrolysis of compounds 104 and 108 furnished the acids 110 and 111,
respectively, along with recovered camphorsultam, whereas reduction of 106
using LiAlH4 gave the alcohol 114 (Scheme 3.3). Desulfurisation of these
tetrahydrothiophene derivatives using Ra-Ni in refluxing ethanol gave the
enantiomerically pure compounds 112, [α]D25 = – 38.1 (lit.56 for ent-112 [α]D23 =
+ 40.65), 113 [α]D25 = – 55.9 (lit.57 [α]D20 = – 41.7) and 115 [α]D25 = – 63.1,
(lit.56 for ent-115 [α]D21.5 = + 53.1). Thus, the major cyloadducts 104, 106 and
108 have the absolute configurations as depicted in Scheme 3.2. The sense of π-
facial selectivity is thus the same as that observed when azomethine ylides were
reacted with the same dipolarophiles as above (section 2.2 and 2.3). The reaction
pathway probably proceeds in the same manner as that depicted in Figure 2.3.
3.3 Applications
Because the asymmetric 1,3-dipolar cycloaddition chemistry of thiocarbonyl
ylides is an almost unexplored area, there are only examples of some non-
asymmetric cycloadditions, which have served as key steps for the construction
of racemic tetrahydrothiophenes. One example is the total synthesis of biotin in
racemic form. This vitamin has been obtained via two different approaches, both
involving an intermolecular 1,3-dipolar cycloaddition reaction of a thiocarbonyl
ylide as the key step (Scheme 3.4).58,59 Other 1,3-dipolar cycloadditions of
thiocarbonyl ylides with various dipolarophiles resulting in racemic heterocycles
have been described elsewhere.53 It must be noted that enantiopure biotin has
been obtained via asymmetric intramolecular 1,3-dipolar cycloadditions of a
nitrone and an azide respectively, both derived from L-cysteine.60
[56] Oppolzer, W.; Kingma, A. J.; Poli, G. Tetrahedron 1989, 45, 479-488.
[57] Baker, R.; Boyes, R. H. O.; Broom, D. M. P.; O´Mahony, M. J.; Swain, C. J. J. Chem.
Soc. Perkin Trans. 1 1987, 1613-1621.
[58] Alcázar, V.; Tapia, I.; Morán, J. R. Tetrahedron 1990, 46, 1057-1062.
[59] Yamano, T.; Tanaka, M.; Takanohashi, K. Heterocycles 1993, 36, 2397-2405.
[60] (a) Baggiolini, E. G.; Lee, H. L.; Pizzolato, G.; Uskokovic, M. R. J. Am. Chem. Soc.
1982, 104, 6460-6462. (b) Deroose, F. D.; Clercq, P. J. D. Tetrahedron Letters 1993, 34,
4365-4368.
35
O
O Cl
O O O Cl
O
HN NH +
+ H H SMe
CO2H OMe
S SiMe3 S S
(+/ )-Biotin O O
Scheme 3.4. Two different approaches for the synthesis of (+/–)-biotin via intermolecular 1,3 dipolar
cycloaddition reactions of thiocarbonyl ylides.
Having established an efficient approach for the syntheses of enantiopure

trans-3,4-disubstituted tetrahydrothiophenes, I was especially delighted to find,
that dipolarophile 54, although being relatively electron-rich, was reactive
enough to undergo cycloaddition with ylide 98# (Scheme 3.2). The reason for
my delight was that the resulting major cycloadduct 106 incorporated a 3-
methylalkan-2-ol unit (Figure 3.1), a frequently observed structural motif in
many natural products.61 Although various approaches already existed for the
construction of this moiety,62 the cycloaddition approach described in Scheme
3.2 would furnish, in one single step, an enantiopure derivative of the threo-unit
of this in high yield.
OR2 OR2
R1 * * R1 * *
erythro threo
Figure 3.1. The 3-methylalkan-2-ol unit.
[61] See e.g. (a) Nakamura, Y.; Mori, K. Eur. J. Org. Chem. 1999, 2175-2182. (b) Larsson,
M.; Nguyen, B.-V.; Högberg, H.-E.; Hedenström, E. Eur. J. Org. Chem. 2001, 353-363. (c)
Byström, S.; Högberg, H.-E.; Norin, T. Tetrahedron 1981, 37, 2249-2254. (d) Tai, A.;
Higashiura, Y.; Kakizaki, M.; Naito, T.; Tanaka, K.; Fujita, M.; Sugimura, T.; Hara, H.;
Hayashi, N. Biosci. Biotechnol. Biochem. 1998, 62, 607-608. (e) De Marino, S.; Iorizzi, M.;
Palagiano, E.; Zollo, F.; Roussakis, C. J. Nat. Prod. 1998, 61, 1319-1327. (f) Middleton, R.
F.; Foster, G.; Cannel, R. J. P.; Sidebottom, P. J.; Taylor, N. L.; Noble, D.; Todd, M.; Dawson,
M. J.; Lawrence, G. C. J. Antibiot. 1995, 48, 311-316. (g) Sunazuka, T.; Obata, R.;
Zhuorong, L.; Takamatsu, S.; Komiyama, K.; Omura, S.; Smith, A. B. Tetrahedron Letters
1994, 35, 2635-2636. (h) Yamamoto, K.; Shiinoki, Y.; Furukawa, J.; Nakamura, S. Chem.
Pharm. Bull. 1991, 39, 1436-1439. (i) Takle, A.; Kocienski, P. Tetrahedron 1990, 46, 4503-
4516. (j) Tanner, D.; Somfai, P. Tetrahedron 1987, 43, 4395-4406.
[62] See e.g. (a) Harada, T.; Matsuda, Y.; Imanaka, S.; Oku, A. J. Chem. Soc. Chem.
Commun. 1990, 1641-1643. (b) Larsson, M.; Högberg, H.-E. Tetrahedron 2001, 57, 7541-
7548. (c) Baker, R.; Boyes, R. H. O.; Broom, D. M. P.; Devlin, J. A.; Swain, C. J. J. Chem.
Soc. Chem. Commun. 1983, 829-831. (d) refs. 61a-d and 61i-j.
36
One example of a compound containing a chiral non-racemic threo-3-
methylalkan-2-ol unit is the active sex pheromone component of Macrodiprion
nemoralis 116 (Scheme 3.5). For identification purposes, this compound and
each of its 15 stereoisomers have recently been synthesised by me.63 One key
step employed in the total syntheses of the threo-isomers was the coupling of an
alkyllithium (e.g. 117) with an enantiopure lactone (e.g. 118) followed by a
Huang-Minlon reduction and a Mitsunobo inversion of the secondary alcohol
(Scheme 3.5).63 However, because this sequence was not very efficient, an
alternate pathway to obtain the threo-isomers in an improved overall yield was
desirable.
OAc OAc
H H
C
116 119 120 121

ref. 63
O
X OBn
Li + O X
S S
S
117 118 122 123 124
Scheme 3.5. Retrosynthetic analysis of the active sex pheromone component of Macrodiprion
nemoralis 116, and previous approach to obtain this from the building blocks 117 and 118.
From the retrosynthetic analysis (Scheme 3.5), bond breaking of the

targetmolecule 116 as indicated furnishes three synthons 119-121, one of which
can be referred to as a threo-3-methylalkan-2-ol unit (i.e. 121). This synthon is
equivalent to the building block 124, which can easily be obtained via an
asymmetric 1,3-dipolar cycloaddition followed by further transformations
(section 3.2). Synthon 119 is equivalent to the corresponding alkyl halide 122
and the dianionic synthon 120 corresponds to 1,3-dithiane, 123. Thus, two
sequential alkylations of 1,3-dithiane with the two building blocks 122 and 124
followed by a few synthetic steps would furnish the target molecule 116.
Outlined below is the total synthesis of the active sex pheromone component
of Macrodiprion nemoralis, (2S,3R,7R,9S)-3,7,9-trimethyl-2-tridecyl acetate 116
(Scheme 3.6). As described in section 3.2, an asymmetric 1,3-dipolar
cycloaddition reaction of the thiocarbonyl ylide 98# with dipolarophile 54
furnishes the major diastereomeric tetrahydrothiophene 106 and the minor one
107. After separation of these and reductive removal of the chiral auxiliary of the
major diastereomer 106, one obtains compound 114 (Scheme 3.2 and 3.3). The
building block ent-114 was prepared using the same sequence but starting from
the antipode of 54.
[63] Karlsson, S.; Hedenström, E. Acta. Chem. Scand. 1999, 53, 620-630.
37
This was transformed to the corresponding bromide 126 using PPh3 and Br2
(Scheme 3.6). The same functional group transformation was performed with
enantiomerically pure alcohol 125 which was obtained via two sequential
asymmetric alkylations as previously described.63 The resulting bromide 127 was
coupled with 1,3-dithiane, 123, after deprotonation of the latter using
butyllithium (BuLi). This furnished compound 128 in 95% yield. Deprotonation
of this using BuLi followed by the addition of DMPU as a cosolvent and the
bromide 126 yielded the dialkylated dithiane 129 in 83% yield. In order to obtain
a satisfactory yield in this step it was necessary to perform the reaction using an
excess of compound 128. Unreacted 128 could then be recovered almost
quantitatively in the purification step. Treatment of 129 with Ra-Ni in refluxing
ethanol accomplished the simultaneous reduction of the dithiane and the
tetrahydrothiophene unit as well as the removal of the benzyl group. Thus, after
treatment with AcCl, the target pheromone 116 was obtained in 83% yield.
Unfortunately, according to GC- and 13C NMR analyses performed, a certain
degree of epimerisation at the C-2 and C-3 stereogenic centres had occurred
during the desulfurisation-debenzylation reaction.
OBn OBn
HO Br
S S
ent-114 PPh3, Br2 126
or ~90%
OH Br
125 127
O
S S H
127 126
a S S S S
b S
123 128 129
OAc
c,d 2
3
116
Scheme 3.6. Total synthesis of the active sex pheromone component of Macrodiprion nemoralis 116.
(a) (i) BuLi, THF, –20 oC. (ii) add 127 , –78 oC. (iii) –78 oC à R.T, 95% yield. (b) (i) BuLi, THF, –78
o
C. (ii) –78 oC à –20 oC. (iii) –78 oC, DMPU, add 126. (iv) –78 oC à –30 oC, 83% yield. (c) Ra-Ni,
EtOH, H2, 22 oC, 72% yield. (d) AcCl, CH2Cl2, 100% yield.
38
However, it was found that the undesired epimerisation could be suppressed if
the reaction, at room temperature, was performed in the presence of hydrogen
gas with Ra-Ni as the catalyst. Thus, 116 was now obtained in 72% yield in
>99% stereoisomeric purity after esterification. It is well known that secondary
alcohols often suffer from epimerisation when subjected to Ra-Ni,64 and that this
can be circumvented if a hydrogen source is added to the reaction mixture.65 The
epimerisation is proposed to occur through a reversible oxidation-reduction
mechanism of the secondary alcohol.66 However, in this case epimerisation also
occurred at the C-3 stereogenic centre. When a stereoisomerically pure sample of
the alcohol of 116 was subjected to Ra-Ni in refluxing ethanol, epimerisation
was observed only at the C-2 stereogenic centre. Therefore, the observed C-3
epimerisation for the 129 à 116 transformation probably originates from the
desulfurisation reaction of the tetrahydrothiophene unit.
The new approach shown above, in which a 1,3-dipolar cycloaddition reaction
was used as one key step for the synthesis of the the active sex pheromone
component of Macrodiprion nemoralis, proved to be more efficient than the
approach previously published.63 It could probably also be used for the syntheses
of other natural products containing this threo-3-methylalkan-2-ol unit.
[64] See e.g. (a) Peppiatt, E. G.; Wicker, R. J. J. Chem. Soc. 1955, 3122-3125. (b) Eliel, E.
L.; Schroeter, S. H. J. Am. Chem. Soc. 1965, 87, 5031-5038. (c) Ishibashi, H.; Sato, K.;
Ikeda, M.; Maeda, H.; Akai, S.; Tamura, Y. J. Chem. Soc. Perkin Trans. 1 1985, 605-609. (d)
Ishibashi, H.; So, T. S.; Okochi, K.; Sato, T.; Nakamura, N.; Nakatani, H.; Ikeda, M. J. Org.
Chem. 1991, 56, 95-102. (e) Nishide, K.; Shigeta, Y.; Obata, K.; Inoue, T.; Node, M.
Tetrahedron Letters 1996, 37, 2271-2274. (f) Node, M.; Nishide, K.; Shigeta, Y.; Obata, K.;
Shiraki, H.; Kunishige, H. Tetrahedron 1997, 53, 12883-12894.
[65] See e.g. (a) refs. 64e, 64f, (b) Nakamura, K.; Ushio, K.; Oka, S.; Ohno, A.; Yasui, S.
Tetrahedron Letters 1984, 25, 3979-3982.
[66] Bonner, W. A. J. Am. Chem. Soc. 1952, 74, 1033-1034 and references cited therein.
39
4. 1,3-Dipolar cycloaddition reactions of nitronesVII,VIII
4.1 General aspects

Nitrones have been used in numerous studies of asymmetric 1,3-dipolar
cycloadditions. In general, nitrones are relatively stable species and do not need
to be prepared in situ. The most convenient approach for the generation of these
is condensation between secondary hydroxylamines 130 and an aldehyde or a
ketone, but other methods also exist such as oxidation of tertiary hydroxylamines
131 or alkylation of oximes 132 with alkyl halides (Scheme 4.1).67
R3
HO O
NH R2
O R3
R1
- H2 O N
130
R1 R2 R4 R4 R4 R4 R4
HO R3 133 R4
3
Ox. 134 * * R Red.
* * R3
N O 2 HO 2
R1 R 2
N * R HN * R
131 R1 R 1
R3 O R2 135 136
HO
N R1-X N
R2 R1 R3
132 133
Scheme 4.1. Examples of generation of nitrones 133 and subsequent 1,3-dipolar cycloaddition with
dipolarophile 134. The resulting isoxazolidine 135 can be ring opened to give an amino alcohol 136.
The resulting nitrone 133 exists as an equilibrium mixture of the Z- and the E-
form with the Z-configuration being, in general, the most stable form. 68
Jørgensen et al. have carried out some analyses on C-N-diphenylnitrone and
found that the Z-isomer is the most stable one by 11 kcal/mol.69 The activation
energy for the conversion of the Z- to the E-form is calculated to be 33 kcal/mol
and therefore, the conversion will be very slow at ambient temperature. The
configuration of aliphatic aldonitrones (i.e. R2 or R3 = H in 133) has not been
extensively investigated but there are some examples where they prefer the Z-
configuration.70 However, some nitrones have been isolated in good yields in
their E-forms.71 Depending on which form of the nitrone that reacts with a
[67] (a) Hamer, J.; Macaluso, A. Chem. Rev. 1964, 64, 473-495. (b) Torssell, K. B. G. Nitrile
Oxides, Nitrones, and Nitronates in Organic Synthesis; VCH: Weinheim, 1988, 87-93.
[68] (a) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New
York, 1984, Vol 2, 87-89. (b) Björgo, J.; Boyd, D. R.; Neill, D. C. J. Chem. Soc. Chem.
Commun. 1974, 478-479. (c) Jennings, W. B.; Boyd, D. R.; Waring, L. C. J. Chem. Soc.
Perkin Trans. 2 1976, 610-613. (d) DeShong, P.; Lander, S. W. Jr.; Leginus, J. M.; Dicken,
C. M. In: Advances in Cycloaddition, Curran, D. P.; Ed, JAI Press, London, 1988, 89-93. (e)
Torssell, K. B. G. Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis; VCH:
Weinheim, 1988, p. 85.
[69] Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. Acta Chem. Scand. 1997, 51, 1234-1235.
[70] Aurich, H. G.; Franzke, M.; Kesselheim, H. P. Tetrahedron 1992, 48, 663-668.
[71] Sivasubramanian, S.; Mohan, P.; Thirumalaikumar, M.; Muthusubramanian, S. J. Chem.
Soc. Perkin Trans. 1 1994, 3353-3354.
40
dipolarophile (i.e. 134) and the mode of approach of this (endo/exo), either the
endo- or the exo-diastereomer of an isoxazolidine 135 is formed containing up to
three new stereogenic centres (Scheme 4.1).
Isoxazolidines can easily be ring opened by treatment with various reagents
such as palladium or Raney nickel, both in the presence of hydrogen, Na(Hg) or
Zn/AcOH to give aminoalcohols of the type 136. Such aminoalcohols are
valuable building blocks for the preparation of biologically important
compounds.72,73 The reactions of nitrones with electron-deficient dipolarophiles
are in general dominated by HOMO(dipole)-LUMO(dipolarophile) interactions,
whereas reactions with electron-rich dipolarophiles are dominated by
LUMO(dipole)-HOMO(dipolarophile) interactions.74

Because no diastereoselective 1,3-dipolar cycloadditions of nitrones using chiral
auxiliaries have been investigated by me, such reactions are not discussed in this
thesis. Instead, the readers are referred to the literature describing this topic.8,9
4.3 Enantioselective reactions using chiral catalysts

The enantioselective variant of the 1,3-dipolar cycloaddition chemistry of
nitrones has until recently been an unexplored area. The first enantioselective
reaction was reported in 1994, when some chiral oxazaborolidines were found to
catalyse the reactions of some nitrones with electron-rich dipolarophiles.75 Since
then, numerous other chiral catalysts have been used in this type of reaction.76
The 1,3-dipolar cycloaddition of a nitrone with a dipolarophile is either
referred to as a normal electron-demand reaction or an inverse electron-demand
reaction.76 The former reaction is dominated by a HOMO(dipole)-
LUMO(dipolarophile) interaction, whereas the latter is dominated by a
LUMO(dipole)-HOMO(dipolarophile) interaction. Thus, the activation energy
for a normal electron-demand reaction is lowered when a Lewis acid is
coordinating to the dipolarophile, whereas coordination to the nitrone in an
inverse electron-demanding reaction gives the same effect. In order to favour a
coordination of the catalyst to the dipolarophile rather than to the nitrone, a
dipolarophile containing two Lewis basic sites can be used (see section 1.8 and
2.4). Therefore, in normal electron-demand reactions, dipolarophiles of type 138
(Scheme 4.2) containing two carbonyl oxygens are often used. These can, in
combination with a Lewis acid, chelate in a bidentate fashion to the metal.
[72] Frederickson, M. Tetrahedron 1997, 53, 403-425.

[73] Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New
York, 1984, Vol 2, 135-153.
[74] Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New
York, 1984, Vol 2, 95-106.
[75] Seerden, J.-P. G.; Scholte op Reimer, A. W. A.; Scheeren, H. W. Tetrahedron Letters
1994, 35, 4419-4422.
[76] Gothelf, K. V.; Jørgensen, K. A. Chem. Commun. 2000, 1449-1458.
41
Chiral non-racemic ligands of type 140 in combination with Mg(II)- or Zn(II)
salts have been found to catalyse reactions of such dipolarophiles with various
nitrones 137 to give either the exo- or the endo-isomer of 139 as the predominant
cycloadduct in better than 80% ee.77 Depending on the R-groups of ligand 141
and the inorganic salt used, that is, Yb(OTf)3 or Ni(ClO4)2, good to excellent
enantioselectivity of the endo-adduct 139 is obtained.78 Jørgensen et al. found
that catalysts derived from chiral non-racemic diols, that is, ligands of type 142,
and Ti(IV) salts catalysed the reactions of nitrones 137 with dipolarophiles 138
in good enantioselectivities (up to 62% ee).79 Since then numerous variants of
this type of reaction resulting in improvement in enantioselectivity as well as
diastereoselectivity have been reported.80 Some catalysts of this type anchored to
a solid support have also been used in the above reaction with similar results as
for the related catalysts in solution.81 Pd(II) complexes have also been employed
as catalysts in reactions of electron-deficient dipolarophiles with nitrones. The
BINAP ligand 143 in combination with various Pd(II) salts catalyse the reaction
depicted in Scheme 4.2 (upper half) and give high enantiomeric excesses for
both the exo- and the endo-adduct 139.82 Depending on which salt and which
additive that are used, the analogous BINOL ligand 144 (R1 = H) in combination
with either Sc(OTf)3 or Yb(OTf)3 give either the (+)- or the (–)-enantiomer of
endo-139 in excellent diastereoselectivity and enantioselectivity.83 Good results
have also been obtained when R1 in 144 is exchanged for various chiral non-
racemic bis-oxazolines.84 Recently, very promising results have been obtained in
[77] (a) Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 1996, 61, 346-355. (b)
Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 1998, 63, 5483-5488. (c)
Desimoni, G.; Faita, G.; Mortoni, A., Righetti, P. Tetrahedron Letters 1999, 40, 2001-2004.
(d) Crosignani, S.; Desimoni, G.; Faita, G.; Filippone, S.; Mortoni, A.; Righetti, P.; Zema, M.
[78] (a) S.-Blanco, A. I.; Gothelf, K. V.; Jørgensen, K. A. Tetrahedron Letters 1997, 38, 7923-
7926. (b) Iwasa, S.; Tsushima, S.; Shimada, T.; Nishiyama, H. Tetrahedron Letters 2001, 42,
6715-6717. (c) Iwasa, S.; Tsushima, S.; Shimada, T., Nishiyama, H. Tetrahedron 2002, 58,
227-232. (d) Iwasa, S.; Maeda, H.; Nishiyama, K.; Tsushima, S.; Tsukamoto, Y.; Nishiyama,
H. Tetrahedron 2002, 58, 8281-8287.
[79] Gothelf, K. V.; Jørgensen, K. A. J. Org. Chem. 1994, 59, 5687-5691.
[80] (a) Gothelf, K. V.; Thomsen, I.; Jørgensen, K. A. J. Am. Chem. Soc. 1996, 118, 59-64.
(b) Jensen, K. B.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 1997, 62,
2471-2477. (c) Gothelf, K. V.; Jørgensen, K. A. J. Chem. Soc. Perkin Trans. 2 1997, 111-
115. (d) Jensen, K. B.; Gothelf, K. V.; Jørgensen, K. A. Helv. Chim. Acta. 1997, 80, 2039-
2046.
[81] (a) Sellner, H.; Rheiner, P. B.; Seebach, D. Helv. Chim. Acta 2002, 85, 352-387. (b)
Heckel, A.; Seebach, D. Chem. Eur. J. 2002, 8, 560-572. (c) Heckel, A.; Seebach, D.
Angew. Chem. Int. Ed. 2000, 39, 163-165. (d) Seebach, D.; Marti, R. E.; Hintermann, T.
Helv. Chim. Acta. 1996, 79, 1710-1740.
[82] (a) Hori, K.; Kodama, H.; Ohta, T.; Furukawa, I. J. Org. Chem. 1999, 64, 5017-5023. (b)
Hori, K.; Kodama, H.; Ohta, T.; Furukawa, I. Tetrahedron Letters 1996, 37, 5947-5950.
[83] (a) Kobayashi, S. Pure & Appl. Chem. 1998, 70, 1019-1026. (b) Kobayashi, S.;
Kawamura, M. J. Am. Chem. Soc. 1998, 120, 5840-5841. (c) Kawamura, M.; Kobayashi, S.
Tetrahedron Letters 1999, 40, 3213-3216. (d) Kobayashi, S.; Akiyma, R.; Kawamura, M.;
Ishitani, H. Chem. Lett. 1997, 1039-1040.
[84] Kodama, H.; Ito, J.; Hori, K.; Ohta, T.; Furukawa, I. J. Organomet. Chem. 2000, 603, 6-
12.
42
Ni(II) catalysed reactions using chiral ligand 145. In the presence of this, the
reactions of various nitrones 137 with dipolarophiles of type 138 give endo-139
in excellent diastereo- and enantioselectivity.85
The reactions presented so far have involved electron-deficient dipolarophiles
of type 138 in which the catalyst coordinates to the dipolarophile in a bidentate
fashion. A monodentate binding of the catalyst to the dipolarophile will enable
one to perform reactions using dipolarophiles containing only one Lewis basic
site. Thus, the two extra steps involving the attachment of the oxazolidinone
auxiliary to 138 and its removal from the product will not be needed. Indeed, this
can be accomplished by careful choice of Lewis acid and chiral ligand. Kündig et
al. reported that ruthenium and iron salts in combination with chiral non-racemic
diols are efficient catalysts for the enantioselective 1,3-dipolar cycloadditions of
various nitrones with α,β-unsaturated aldehydes furnishing isoxazolidines in
excellent enantioselectivities.86 Chiral non-racemic cobalt(III) complexes have
also proven to be efficient catalysts in this type of reaction.87
O O O O
R3 R3
O O N O N O
O R1 catalyst
N + R3 N O O 1 + O 1
N R N R
R2 H
R2 R2
137 138 endo-139 exo-139
R3 R2
O O O O O O
N
N R1
N
N N R1
R1
R R R R R1 OH HO
140 141 142
R1
R1 O
PAr2 OH O
N O
PAr2 OH O O R2 B
N N
R3
R1 Ph Ph
143 144 145 146
4 4
O R1 R3O R R5 R3O R R5
R4 R5 catalyst
N +
O 1 + O 1
R2 H 3
R O N R N R
R2 R2
137 147 endo-148 exo-148
Scheme 4.2. Various ligands140-146 used in conjunction with Lewis acids in enantioselective 1,3-
dipolar cycloaddition reactions of nitrones with either electron-deficient dipolarophiles (upper half)
or electron-rich dipolarophiles (lower half).
[85] Kanemasa, S.; Oderaotoshi, Y.; Tanaka, J.; Wada, E. J. Am. Chem. Soc. 1998, 120,
12355-12356.
[86] Viton, F.; Bernardinelli, G.; Kündig, E. P. J. Am. Chem. Soc. 2002, 124, 4968-4969.
[87] Mita, T.; Ohtsuki, N.; Ikeno, T.; Yamada, T. Org. Lett. 2002, 4, 2457-2460.
43
When instead electron-rich dipolarophiles such as vinylethers are employed in
the reactions with nitrones (i.e. inverse electron-demand reactions), coordination
of the catalyst to the nitrone is in general responsible for the rate acceleration.
Ligands 140 and 141 in combination with either Cu(II) or Zn(II) salts form
catalysts, which have been used in reactions of various nitrones 137 with
vinylethers 147 to give isoxazolidines endo-148 and exo-148, both in high
enantiomeric purities (Scheme 4.2).88 When aluminium complexes of BINOL
ligands of type 144 are used in the same reaction, exo-148 is obtained in high
diastereo- and enantioselectivity (up to 97% ee).89 Reactions with cyclic nitrones
also give good results using the same catalysts.90 When vinylethers of type 147
react with nitrones 137 and when immobilised or polymerised aluminium
complexes of ligands of type 144 are used as catalysts, the results are
comparable to those obtained for similar experiments in homogenous solutions.91
C2-symmetrical ligands of type 142 as well as other C2 symmetrical diols and
amines in the presence of Ti(IV) salts have been used with moderate success in
the same type of reaction.92 As mentioned in the beginning of this section,
oxazaborolidines (i.e. 146) catalyse the reactions of nitrones with electron-rich
dipolarophiles. By varying the R-substituents of catalyst 146 and using it in
reactions of some nitrones with electron-rich dipolarophiles, good enantiomeric
purity is obtained for exo-148.75,93 Various other B(III) catalysts derived from
C2-symmetric diols and amines have also been used but with moderate success.94
Low enantioselectivities are obtained if Pd(II) complexes of ligand 143 or a
Ti(IV) complex of chiral non-racemic cyclacene are used as catalysts in reactions
of nitrones 137 with electronrich dipolarophiles 147.95,96
As demonstrated by Ukaji and Inomata et al, enantioselective 1,3-dipolar
cycloaddition reactions of nitrones can also be conducted with allylic alcohols as
dipolarophiles.97 By employing enantiomerically pure diisopropyl tartrate in the
presence of Zn(II), reactions of nitrones with allyl alcohols proceed to give the
corresponding cycloadducts in high diastereo- and enantioselectivities.97
[88] Jensen, K. B.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 1999, 64, 2353-2360.
[89] Simonsen, K. B.; Bayón, P.; Hazell, R. G.; Gothelf, K. V.; Jørgensen, K. A. J. Am. Chem.
soc. 1999, 121, 3845-3853.
[90] Jensen, K. B.; Roberson, M.; Jørgensen, K. A. J. Org. Chem. 2000, 65, 9080-9084.
[91] (a) Sellner, H.; Faber, C.; Rheiner, P. B.; Seebach, D. Chem. Eur. J. 2000, 6, 3692-
3705. (b) Pu, L. Chem. Eur. J. 1999, 5, 2227-2232. (c) Simonsen, K. B.; Jørgensen, K. A.;
Hu, Q.-S.; Pu, L. Chem. Commun. 1999, 811-812.
[92] Bayón, P.; March, P. d.; Espinosa, M.; Figueredo, M.; Font, J. Tetrahedron: Asymmetry
2000, 11, 1757-1765.
[93] (a) Seerden, J.-P. G.; Kuypers, M. M. M.; Scheeren, H. W. Tetrahedron Asymmetry
1995, 6, 1441-1450. (b) Seerden, J.-P. G.; Boeren, M. M. M..; Scheeren, H. W. Tetrahedron
1997, 53, 11843-11852. (c) Meske, M. J. Prakt. Chem. 1997, 339, 426-433.
[94] Bayón, P.; March, P. d.; Figueredo, M.; Font, J.; Medrano, J. Tetrahedron: Asymmetry
2000, 11, 4269-4278.
[95] Hori, K.; Ito, J.; Ohta, T.; Furukawa, I. Tetrahedron 1998, 54, 12737-12744.
[96] Ellis, W. W.; Gavrilova, A.; L.-Sands, L.; Rheingold, A. L.; Bosnich, B. Organometallics
1999, 18, 332-338.
[97] (a) Ukaji, Y.; Taniguchi, K.; Sada, K.; Inomata, K. Chem. Lett. 1997, 547-548. (b) Ding,
X.; Taniguchi, K.; Ukaji, Y.; Inomata, K.; Chem. Lett. 2001, 468-469. (c) Ding, X.; Ukaji, Y.;
Fujinami, S.; Inomata, K. Chem. Lett. 2002, 302-303.
44
All of the enantioselective reactions described so far have involved catalysts
composed of enantiomerically pure ligands coordinated to various metal-salts.
Those catalysts often have to be used under dry conditions under an inert
atmosphere. A more easily managed, metal-free catalyst gives operational and
economical advantages over the ones containing metals. Therefore,
organocatalysis has become a very active research field at present. Organocata-
lysts are often low molecular weight compounds readily available from
inexpensive starting materials. They can in general be reused in a convenient
manner. Because organocatalysts do not contain any heavy metals, they are, in
general, more environmentally friendly than most chiral Lewis acid catalysts.
Moreover, organocatalysed reactions can often be conducted under air and even
in wet solvents.
A milestone in the field of organocatalysis is the development of the
enantioselective Robinson annulation of triketones of type 149 catalysed by
proline (Scheme 4.3).98 Thus, in the presence of this naturally occurring amino
acid (i.e. 150), such triketones undergo Robinson annulation to give chiral non-
racemic bicycles 151, which, after dehydration, furnish compounds of type 152.
CO2H
O
O O N
R2 O R2 O
R2 H N
R1 150 H O - H 2O
O
n n
n R2 O O
O OH
R1 R1 R1
149 n 151 152
O
n = 1 or 2
Scheme 4.3. Asymmetric Robinson annulation of triketone 149 mediated by proline catalyst 150.
This approach has opened a new route for enantioselective syntheses of steroids
and other natural products such as taxol.99 The mechanism of this reaction has
been a subject of debate100 and has recently been proposed to occur through the
transition state depicted in Scheme 4.3.101 Support for this proposal has been
gained from kinetic studies. Thus enamine formation from proline and the
carbonyl moiety of the triketone is followed by an intramolecular cyclisation.
The reaction is facilitated by the simultaneous mediated proton transfer from the
carboxylic acid moiety of the proline to the carbonyl oxygen of the ketone.
[98] (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615-1621. (b) Eder, U.; Sauer,
G.; Wiechert, R. Angew. Chem. Int. Ed. 1971, 10, 496-497; Eder, U.; Sauer, G.; Wiechert, R.
Angew. Chem. 1971, 83, 492-493.
[99] Danishefsky, S. J.; Masters, J. J.; Young, W. B.; Link, J. T.; Snyder, L. B.; Magee, T. V.;
Jung, D. K.; Isaacs, R. C. A.; Bornmann, W. G.; Alaimo, C. A.; Coburn, C. A.; Di Grandi, M.
J. J. Am. Chem. Soc. 1996, 118, 2843-2859.
[100] (a) List, B. Tetrahedron 2002, 58, 5573-5590. (b) Jarvo, E. R.; Miller, S. J. Tetrahedron
2002, 58, 2481-2495.
[101] Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16-17
and references cited therein.
45
Since the discovery of the proline catalysed Robinson annulation reaction
discussed above, organocatalysis has become a rapidly growing research area in
organic chemistry.102 In the field of 1,3-dipolar cycloaddition reactions,
MacMillan et al. have been the first to explore organocatalysis.103 They have
developed a general protocol for the enantioselective syntheses of isoxazolidines
from nitrones of type 137 and α,β-unsaturated aldehydes 153 catalysed by the
phenylalanine derived organocatalyst 154 (Scheme 4.4).103
O Me
N
Me
O O
Bn N Me
H R3 H R3 H
O R1 O HX
N 154 O 1 + O 1
+ R3 H N R N R
R2 H CH3NO2-H2O 2 2
R R
HX = organic or
137 153 endo-155 exo-155
inorganic acid
up to 99% ee
Scheme 4.4. The first reported organocatalytic 1,3-dipolar cycloaddition reaction.
Thus, various nitrones of type 137 react with α,β-unsaturated aldehydes 153 in
the presence of this catalyst to give endo-155 in high diastereo- and
enantioselectivity. The rate acceleration caused by catalyst 154 is due to iminium
ion formation from a condensation reaction between the catalyst and the
aldehyde (Figure 4.1).103 Compared with the uncatalysed reaction, the formation
of the iminium salt results in a lowering of the LUMO energy of the π-moiety of
the dipolarophile. The major attack of the nitrones occurs on the least sterically
hindered side of the π-bond as indicated in Figure 4.1. Hydrolysis in situ of the
iminium species furnishes the aldehyde product and the catalyst 154, which then
is ready for another catalytic cycle.
O Me
N
Me
Bn N Me
H
3
R
Attack from the back

Figure 4.1. Iminium ion formation from catalyst 154 and aldehyde 153.
[102] Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2001, 40, 3726-3748.
[103] Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874-
9875.
46
Although, the general organocatalytic approach for the construction of
enantiomerically pure isoxazolidines described above is available, cyclic
dipolarophiles such as cyclopent-1-enecarbaldehyde, have not been used in this
type of reaction.104 Therefore, I wanted to investigate the organocatalysed
reactions of such types of dipolarophiles (i.e. 161 and 162, Scheme 4.5) with
various nitrones 163a-g derived from both aliphatic and aromatic aldehydes
(Scheme 4.5). The aim was to find efficient organocatalysts for this type of
reaction in terms of yield, diastereo-, and enantioselectivity.
First, the reaction of aldehyde 161 with nitrone 163a was investigated. When
these were mixed in CH3NO2 at ambient temperature, no reaction occurred. At
elevated temperatures, a mixture of two diastereomeric racemic cycloadducts
was obtained, which after treatment with NaBH4, furnished the more readily
separable reduced major cycloadduct 164a and the minor one 165a (Scheme
4.5). However, these were formed in low exo/endo selectivity along with two
additional regioisomers, albeit in a good yield. Thus, because no reaction
occurred at ambient temperature, this was a good starting point for the
introduction of a catalyst in this reaction. Hence, in the presence of the HCl salt
of the MacMillan catalyst 154 (Scheme 4.5) either in wet CH3NO2 or DMF at
ambient temperature, reaction took place. The reduced cycloadduct 164a was
obtained in a good diastereoselectivity but was nearly racemic (~ 5% ee) and the
yield was low. This disappointing result was in sharp contrast to the results
obtained when acyclic dipolarophiles were used in the same reaction.103 This
encouraged me to investigate other types of organocatalysts for this reaction.
The bicyclic fused pyrrolidines ent-93, ent-94, and 96, prepared via an
asymmetric 1,3-dipolar cycloaddition as described in section 2.5, have very rigid
structures and are substituted with bulky aromatic rings. I reasoned that such
ammonium salts might be suitable as catalysts in the reaction depicted in Scheme
4.5. The main point was whether or not the presence of such catalysts with
increased bulk and rigidity would result in a higher reactivity and selectivity of
the reaction.
[104] After paper VII was published a work describing the use of chiral cobalt(III) complexes
as catalysts in reactions of nitrones with cyclopent-1-enecarbaldehyde appeared: See ref.
87.
47
R2
R1
O O N R1
S H R2
O Me (HX)n
N R1O H
Me 156: R1 = Me, R2 = OH
Bn N Me N 157: R1 = Ph, R2 = OH
H H
HX HCl 158: R1 = Me, R2 = OMe
R2
154 ent-93: R1 = H, R2 = H 159: R1 = H, R2 = N
96: R1= Me, R2= H
ent-94: R1= H, R2= MeO 160: R1 = H, R2 = N
R1 R1 R1 R1 R1 R1
1) One of the catalysts above
O R3 OH OH
wet DMF
+ N H + H
H
R2 H 2) NaBH4, MeOH O O R3
N R3 N
O
R2 R2
major minor
161: R1 = H 163a-g 164a-g R1 = H 165a-g
162: R1 = Me R1 = Me 167d
a: R2 = Me, R3 = Ph 166d
b: R2 = Me, R3 = 1-cyclopentenyl
a-g: same as for 163
c: R2 = Me, R3 = n-propyl
d: R2 = Me, R3 = cyclopropyl
e: R2 = Me, R3 = 2-furyl
f: R2 = Bn, R3 = Me
g: R2 = Ph, R3 = Ph
Scheme 4.5. 1,3-Dipolar cycloadditions of various nitrones 163a-g with either aldehyde 161 or 162
catalysed by some organocatalysts.
Gratifyingly, when compound ent-93, ent-94, or 96, was used as catalyst in the
reaction depicted in Scheme 4.5, a reasonable overall yield of the reduced
diastereomeric cycloadducts 164a and 165a was obtained in a moderate
diastereoselectivity (Table 4.1, entries 1-4). Separation of the enantiomers of the
major diastereomer 164a using chiral stationary phase capillary GC revealed that
when either catalyst ent-93 or ent-94 was used, a good enantioselectivity had
been obtained (up to 76% ee, entry 4). Other catalysts of this type, lacking the
sulfone- and/or the tertiary alcohol functional group(s), were also investigated in
the same reaction. However, when such catalysts were used, considerably lower
enantioselectivities were obtained. Correct choice of solvent also turned out to be
crucial for obtaining good enantioselectivity and for sufficient solubility of the
catalysts. Among the solvents investigated, DMF was the solvent of choice.
48
Table 4.1. 1,3-Dipolar cycloaddition of nitrone 163a with aldehyde 161 catalysed
a
by ammonium salt ent-93, ent-94 or 96.
OH OH
O Ph 1) Catalyst 13 mol% H H
H +
+
N O Ph O Ph
O Me H N N
2) NaBH4, MeOH
Me Me
161 163a 164a 165a
Entry Catalyst Time Temp. Yield Dr %ee

o
( C) (%) (164a:165a) 164a
O O
S
HO H
1 72 h +10 59 83:17 67
N
H
HCl
ent-93
O O
S
MeO H
2 48 h +10 39 89:11 23
N
H
HCl
96
MeO
3 O O 120 h +10 61 80:20 70
S
HO H
4 N 96 h –10 45 72:28 76
H
HCl
MeO
ent-94
a
The nitrone 163a (3.7 mmol) and the catalyst (0.48 mmol) were added to a solution of the aldehyde
161 (4.8 mmol) in DMF (15 ml) and water (86 µl). Work-up using EtOAc/H2O followed by
chromatography furnished two diastereomeric cycloadducts which immediately were subjected to
NaBH4 reduction. This furnished the two individual diastereomers 164a and 165a after a standard
work-up procedure and separation by column chromatography. The yields are based on the overall
isolated yield of 164a and 165a. The enantiomeric excess of 164a was determined of the
corresponding trifluoroacetate of the former using a chiral β-Dex-325 GC capillary column.
When the pyrrolidinium salt ent-94 was applied as the catalyst, the
enantioselectivity obtained in the reaction of aldehyde 161 with nitrone 163a was
good and the yield and diastereoselectivity were reasonable. However, it was
tempting to investigate if the selectivity could be further improved by using other
types of organocatalysts.
49
Proline and derivatives thereof have been used as organocatalysts in various
types of enantioselective reactions100 such as Michael reactions of aliphatic
aldehydes and ketones with nitroolefins105 and of nitroalkanes with α,β-
unsaturated enones,106 in Diels-Alder reactions of α,β-unsaturated aldehydes
with dienes,107 and in the newly discovered nucleophilic addition reaction of
nitrones to ketones.108
Hence, for use in 1,3-dipolar cycloadditions of nitrones, proline seemed to be
a suitable starting material for the preparation of potential organocatalysts. Thus,
pyrrolidinium salts 156-158109 containing a tertiary alcohol or ether moiety and
bicyclic compounds 159-160110 (Scheme 4.5) were prepared according to
literature procedures and explored as catalysts in the reaction of aldehyde 161
with nitrone 163a (Table 4.2).
Reactions of aldehyde 161 with nitrone 163a in the presence of each of the
salts 156-158 proceeded in appreciable conversion only when catalyst 158 was
used (Table 4.2, entries 1-3). At first these results seem puzzling. However,
because catalysts 156 and 157 are amino alcohols they can probably form
catalytically inactive species (i.e. protonated N,O-acetals) with aldehyde 161 as
outlined in Scheme 4.6. The fairly efficient catalysts ent-93 and ent-94 (as HCl-
salts) are also aminoalcohols. However, due to their rigid bicyclic structures,
they are probably unable to form such inactive species. This explains why the
latter catalysts work in this reaction whereas the catalysts 156 and 157 are
inactive. The ether derivative 158 cannot form such an inactive protonated N,O-
acetal with aldehyde 161. Despite this, a very low yield of 164a was obtained
when this was used as catalyst, albeit in a good enantioselectivity (Table 4.2,
entry 3).
O R1
H R1 - H2O Cl
N R1
H
+ N R1 O
H2 OH H2O H
Cl
156
161 or unreactive
157
Scheme 4.6. Formation of an unreactive protonated N,O-acetal from aldehyde 161 and either catalyst
156 or 157.
[105] Reactions of aldehydes: Betancort, J. M.; Barbas, C. F. III Org. Lett. 2001, 3, 3737-
3740. Reactions of ketones: (a) List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423-
2425. (b) Enders, D.; Seki, A. Synlett 2002, 26-28.
[106] Halland, N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67, 8331-8338.
[107] Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243-
4244.
[108] Bøgevig, A.; Gothelf, K. V.; Jørgensen, K. A. Chem. Eur. J. 2002, 8, 5652-5661.
[109] (a) Guoqiang, L.; Hjalmarsson, M.; Högberg, H.-E.; Jernstedt, K.; Norin, T. Acta Chem.
Scand. 1984, 38, 795-801. (b) Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem. 1988,
53, 2861-2863. (c) Bucher, C. B.; Linden, A.; Heimgartner, H. Helv. Chim. Acta. 1995, 78,
935-946.
[110] Hendrie, S. K.; Leonard, J. Tetrahedron 1987, 43, 3289-3294.
50
Table 4.2. 1,3-Dipolar cycloaddition of aldehyde 161 with nitrone 163a catalysed
a
by various ammonium salts 156-160 derived from proline.
R1
1) N R1 OH OH
O Ph
H R2 H H
H (HX)n 13 mol% +
+ N O O
N Ph N Ph
O Me H 2) NaBH4, MeOH
Me Me
161 163a 164a 165a
Entry Catalyst (HX)n Time Temp. Yield Dr %ee

o
( C) (%) (164a:165a) 164a
Me
N OH
1 H Me HCl 72 h +25 0 – –
(HX)n
156
Ph
N OH
2 H Ph HCl 48 h +25 0 – –
(HX)n
157
Me
N OMe
3 H Me HCl 96 h +25 12 80:20 68
(HX)n
158
4 HCl 144 h +10 26 95:5 85
N
N
H
5 (HX)n 2 HCl 72 h +10 50 93:7 89
159
6 HCl 144 h +10 44 95:5 91
7 2 HCl 72 h +10 49 97:3 92
8 2 HClO4 120 h +10 44 80:20 78
9 N 2 TFA 72 h +10 31 84:16 85
10 N 2 HCl 120 h –10 23 93:7 93
b H
11 (HX)n 2 HCl 120 h +10 21 97:3 91
c 160
12 2 HCl 144 h +10 70 95:5 91
d
13 2 HCl 120 h +10 63 89:11 83
d
14 2 HCl 120 h –25 17 28:72 91
a
The reactions were performed as described under Table 4.1. b 1:1 ratio 161:163a, 1 mol% catalyst. c
1:2 ratio 161:163a. d No water added.
Promising results were however obtained when either the ammonium salt 159
or 160 was used as catalysts. With catalyst 160 being the most efficient one, both
a high diastereo- and enantioselectivity were obtained (Table 4.2, entries 4 and
6). Compared with the monohydrochloride salts, the dihydrochloride salts of 159
and 160 were more efficient catalysts in terms of both yield and enantioselectiv-
ity (compare entry 4 vs 5 and 6 vs 7). Because catalyst 160 was slightly more
efficient compared to 159, further investigations were performed using the
former.
51
First, the influence of the counterions of the diammonium salt 160 was
investigated. Thus, whereas the dihydrochloride salt of 160 furnished
isoxazolidine 164a in 92% ee, the corresponding TFA and HClO4 salts gave
much lower enantio- and diastereoselectivities (compare entry 7 with entries 8
and 9, Table 4.2). A low temperature or a low catalyst loading had no significant
influence on the diastereo- and enantioselectivity (entries 10 and 11). However,
the yields dropped significantly. When running the reaction under standard
conditions, but using an excess of nitrone 163a, a good yield with preserved high
enantioselectivity was obtained (Table 4.2, entry 12).
The effect of water in the reaction mixture was also investigated. Thus, when
no water was added to the reaction mixture and depending on the reaction
temperature, either the enantioselectivity or the diastereoselectivity changed
significantly (entries 13-14).
Having established compound 160 (as the 2HCl-salt) as an efficient
organocatalyst in the reaction of nitrone 163a with aldehyde 161 in terms of both
diastereo- and enantioselectivity, the yields are still moderate. This is partly due
to the formation of two diastereomeric byproducts, which have been identified as
adducts 164b and 165b after reduction with NaBH4 (Scheme 4.7). For example,
in one experiment (Table 4.2, entry 10) 164b has been isolated as a major
byproduct in 92% ee. This byproduct is formed through hydrolysis of the
original added nitrone to the corresponding aldehyde and hydroxyl amine. This
hydroxyl amine (i.e. N-methylhydroxylamine) then reacts with aldehyde 161 to
give a new nitrone 163b, which in the presence of the catalyst (e.g. 160) and
aldehyde 161, furnishes, after reduction, the cycloadduct 164b and its
diastereomer 165b (Scheme 4.7).
H
O
O Ph H2O Ph 161 O
HO
N NH + O N
H - H2O - H2O
Me Me H Me H
163a 163b
OH OH
1) 161, catalyst H H
+
O O
2) NaBH4 N N
Me Me
major minor
164b 165b
up to 92% ee
Scheme 4.7. Hydrolysis of the original added nitrone 163a followed by the formation of nitrone 163b
in situ which subsequently undergo cycloaddition with aldehyde 161.
With catalyst 160 in hand, I also wanted to investigate its catalytic perform-
ance in reactions of other types of nitrones with two different cyclic
dipolarophiles 161 and 162. The results are summarised in Table 4.3.
52
Table 4.3. 1,3-Dipolar cycloadditions of various nitrones 163b-g (100 mol%) with
either aldehyde 161 or 162 (100 mol%) in wet DMF in the presence of catalyst
160 (2HCl-salt, 10 mol%) resulting in cycloadducts (164 and 165) or (166d and
a
167d) after reduction with NaBH4.
R1 R1 R1 R1 R1 R1
N
1) N OH OH
H H H
O 3
H R 2 HCl +
+ 160 O R3 O R3
N N N
O
R2 H
2) NaBH4, MeOH R2 R 2
161: R1 = H 163 b-g major minor

162: R1 = Me 164a-g R1 = H 165a-g
166d R1 = Me 167d
Entry Aldehyde Nitrone Time Temp. Yield Dr (164:165) %ee 164

o
( C) (%) or or
(166d:167d) 166d
b
1 120 h +10 68 98:2 76 (>99)
c O b
2 H N 120 h +10 63 99:1 84 (>99)
O Me H b
3 161 163b 120 h –10 50 97:3 90 (>99)
O
4 H N 144 h –25 76 >99:1 57
Me H
161 O 163c
5 O 24 h +20 58 >99:1 41
H N
Me H
6 161 O 163d 24 h –20 48 >99:1 41
O
O
H
7 N 144 h +20 51 98:2 53
O Me H
161 163e
O Me
8 H N 96 h –20 56 >99:1 70
Bn H
161 O 163f
O Ph
9 H N 72 h +5 – 56:44 –
Ph H
161 O 163g
Me Me
10 O 24 h +20 19 >99:1 48
N
H Me H
11 120 h +20 38 >99:1 37
162 O 163d
a
The reactions were performed following the same procedure as described under Table 4.1 but using
a stoichiometric amount of nitrone and aldehyde and 10 mol% catalyst.b >99% ee after one
recrystallisation from EtOAc/heptane. c The nitrone dissolved in DMF was slowly added (36 h) to a
solution containing the aldehyde and the catalyst in wet DMF.
53
Table 4.3 shows that, when other nitrones than 163a were reacted with
aldehyde 161, higher diastereoselectivities and lower enantioselectivities were in
general obtained. One exception was the nitrone 163b, which upon reaction with
161 and after reduction, furnished cycloadduct 164b in both a high diastereo-
and enantioselectivity (entries 1-3). Fortunately, recrystallisation of 164b
improved the enantiomeric excess to >99%. Reaction of nitrone 163g with
aldehyde 161 furnished, after reduction, an inseparable diastereomeric mixture of
the known87 cycloadducts 164g and 165g in low diastereoselectivity (Table 4.3,
entry 9, yield and ee not determined). Initial attempts to react the more sterically
demanding aldehyde 162 with nitrone 163a failed and only traces of the
corresponding diastereomeric cycloadducts were obtained. However, reaction
with the more reactive nitrone 163d furnished the reduced cycloadduct 166d in
excellent diastereoselectivity, albeit in a moderate enantioselectivity and yield
(entries 10 and 11, Table 4.3)
Among the results presented in Table 4.3 were some remarkable ones. First,
comparing the reactions, where 164b was obtained as a byproduct as described
in Scheme 4.7, with reactions under the same conditions between nitrone 163b
and 161, the enantioselectivity obtained of 164b was significantly lower
(compare entry 1, Table 4.3, 76% ee with entry 10, Table 4.2, where 164b was
obtained as a byproduct in 92% ee). Moreover, a higher enantioselectivity was
obtained if the concentration of the nitrone 163b was kept low (compare entries
1 and 2, Table 4.3). In some instances the reaction time also had a certain
influence on the enantioselectivity (compare entries 10 and 11, Table 4.3).
These observations indicated that a competing reaction existed, which
produced racemic cycloadducts. One would suspect that this reaction could be
the uncatalysed reaction of one of the nitrones 163a-g with either aldehyde 161
or 162. However, as mentioned above, in the absence of a catalyst in the reaction
of 163a with aldehyde 161 at ambient temperature, no reaction occurred.
Moreover, the presence of a catalyst in the reaction described in entry 4 (Table
4.3) is a prerequisite to obtain any conversion. Therefore, another competing
reaction is probably taking place. In Scheme 4.7, I described the mechanism for
the formation of non-racemic byproduct 164b obtained in a sequence via
hydrolysis of the original added nitrone 163a followed by the formation of
nitrone 163b. In addition to this competing non-racemic pathway described in
Scheme 4.7, I suspected that a racemic one, involving the same nitrone 163b,
existed. The nitrone 163b is detected in various amounts in the reactions studied
in Scheme 4.5, with the highest amounts in the reactions performed at ambient
temperature. Would it be possible that this nitrone 163b also could act as a
reactive dipolarophile in reactions with the other nitrones? Such a possible
competing reaction is depicted in Scheme 4.8.
54
O
O O 3 N Me 1) Hydrolysis OH
R HO
N + N H H NH
2) NaBH4 +
Me H Me H O R 3 O 3
R Me
N N
Me Me
163b 163 168 rac-164
Scheme 4.8. Possible competing reaction furnishing racemic cycloadducts.
Thus, if the π-bond of the cyclopentenyl moiety of this nitrone 163b is

sufficiently activated for attack by the original nitrone, cycloaddition will furnish
a new nitrone 168, which upon hydrolysis in situ followed by reduction with
NaBH4 gives racemic cycloadduct 164 along with the corresponding
hydroxylamine (Scheme 4.8). The existence of the proposed competing reaction
depicted in Scheme 4.8 explains why a low concentration of the original added
nitrone results in a higher enantioselectivity and why longer reaction times lead
to a decrease in enantioselectivity.
To test the hypothesis, that such a competing reaction existed, nitrone 163b
was dissolved in dry DMF and stirred for five weeks. This resulted, after
hydrolysis and reduction, in the formation of a considerable amount of the
racemic product 164b (~30% yield). Furthermore, when a diammoniumsalt (i.e.
TMEDA 2HCl-salt) not able to form a catalytic active iminiumspecies was
added, the reaction rate for this reaction increased slightly. Thus, these
observations strongly support the existence of the competing reaction depicted in
Scheme 4.8. Thus, the low enantioselectivity obtained in some of the reactions of
the nitrones 163 with the aldehydes 161 and 162 can be partly due to this
competing reaction. However, the enantioselectivity is evidently dependent also
on the nature of the nitrone and aldehyde used.
In addition to the undesired competing reaction involving nitrone 163b as a
spontaneously reactive dipolarophile, its formation from the original nitrone via
hydrolysis, also led to the production of various amounts of non-racemic
byproducts 164b and 165b (as exemplified in the reaction of nitrone 163a with
aldehyde 161 in Scheme 4.7). Thus, the formation of such adducts provides one
explanation for the moderate yields obtained in most instances involving the
various nitrones 163a-g and the aldehydes 161 and 162 (Table 4.2 and 4.3).
The formation of the nitrone 163b from the original nitrone can be prevented
by lowering the water concentration in the reaction mixture. However, as
mentioned previously, in order to achieve high enantio- and diastereoselectivity,
it is necessary to perform the reactions in wet solvents, and an alternative way to
suppress the formation of nitrone 163b is needed. If the aldehyde from which the
nitrone is derived is present as an additive in the reaction mixture, this aldehyde
might trap any hydroxylamine liberated and thus, less amount of nitrone 163b
will be formed.
This hypothesis was tested in a separate experiment. Thus, the reaction of
nitrone 163c with aldehyde 161 was performed using the conditions in entry 4,
Table 4.3, but in the presence of 10 equiv. of butyraldehyde as an additive.
55
However, while the enantioselectivity remained the same, the yield dropped
significantly. Therefore, another method, which would reduce the amounts of
hydrolysis products from the original added nitrone would be desirable. It must
be noted that the yields were strongly dependent on the reaction time. The
reactions in Scheme 4.5 were quenched after a satisfying conversion had been
obtained but with a maximum reaction time of 144 hours. Thus, slightly better
yields than those presented in Table 4.1, 4.2 and 4.3 could in most cases be
achieved by using prolonged reaction times.
The reactions presented so far have been performed on a 4 mmol scale using
10–13 mol% of the catalyst. To constitute a useful method for the syntheses of
fused non-racemic isoxazolidines, the reactions depicted in Scheme 4.5 ought
also to be possible to perform on a larger scale and with a lower catalyst loading.
The aldehyde 161 and nitrone 163b were chosen as dipolarophile and dipole,
respectively, in such a large scale reaction. Thus, using a stoichiometric amount
of these on a 0.1 molar scale in the presence of 5 mol% of catalyst 160 (2HCl-
salt) and allowing the reaction to go to completion at –8 oC, resulted in a 80%
overall isolated yield of a mixture of the reduced cycloadducts 164b (85% ee, dr
94:6) and 165b after 11 days. One single recrystallisation of the crude mixture of
these from EtOAc/heptane improved the ee and dr of 164b to over 99% and
>99:1, respectively (56% overall yield). Thus, this result was comparable to that
obtained when the reaction was performed on a smaller scale using a higher
catalyst loading (Table 4.3, entry 3). However, the yield was improved.
In summary, when reacting the nitrones 163a-g with aldehyde 161 or 162 in
the presence of catalyst 160 (2HCl-salt), the enantioselectivity is variable and
depends on the nature of the nitrone and aldehyde used. When nitrone 163a is
reacted with aldehyde 161, an enantiomeric excess of up to 93% is obtained. No
matter which nitrone or aldehyde that is used, the diastereoselectivity is, in
general, excellent. However, the yields are often moderate. It must be noted that
the reactions were performed with a low loading of both the catalyst and the
substrate. A high yield, diastereoselectivity, and enantioselectivity, were obtained
when one reaction (i.e. reaction between 163b and 161) was scaled-up and
performed using a prolonged reaction time and a low catalyst loading.
OH OH
8% NOE
H CH2 H 2% NOE
O H O H
N N
H Ph
Me Me
164a 165a
Major Minor
Figure 4.2. NOE observed in the major and the minor cycloadducts 164a and 165a respectively.
The relative configuration of the major and the minor cycloadducts 164a and
165a, respectively, was determined using NOE experiments. Thus, the minor
diastereomer displayed a 2% NOE between the two methine protons as shown in
Figure 4.2. This NOE was absent in the major diastereomer. Instead, a strong
NOE was observed between the phenyl protons and the CH2-OH protons. This
assignment of relative configuration was also supported by the strong shielding
56
effect of the phenyl group resulting in a upfield shift of the CH2-OH signals
(3.27–3.42 ppm) of the major diastereomer relative to those of the minor
diastereomer (3.56–3.75 ppm).
The same assignment of relative configuration of the major cycloadduct 164b
and the minor one 165b was also supported by treatment of a mixture of these
adducts with I2 in the presence of NaHCO3. Thus only the major adduct 164b,
which has the hydroxyl group and the alkene moiety in close proximity,
underwent an intramolecular iodoetherification, leaving the minor diastereomer
unaffected (scheme 4.9). Thus, a single spirocyclic adduct, either with the
structure 169 or 170 (position of the iodine not determined), was obtained.
OH
H H O I H O
O O or O
N N N I
Me Me Me
I2, NaHCO3
164b 169 170
CH3CN
OH OH
H H
O O
N N
Me Me
165b 165b
unreacted
Scheme 4.9. Iodoetherification of a mixture of the two diastereomers 164b and 165b. Only the major
diastereomer 164b reacts and forms a tricyclic spiroadduct.
Although in low diastereoselectivity, the same relative exo-configuration of

the major cycloadduct 164g was secured through comparision of the 1H NMR
data of an inseparable mixture of 164g and 165g (obtained from 161 and 163g,
Table 4.3, entry 9) with those in the literature of 165g.87
It is reasonable to believe that all other major cycloadducts possess the same
relative exo-configuration. Surprisingly, the exo-selectivity obtained in this work
is opposite to that obtained when aldehyde 161 was reacted with C-N-
diarylnitrones in the presence of chiral Lewis acid catalysts.87
In reactions of the nitrones 163a-g with the activated iminiumspecies from
aldehyde 161 and catalyst 160 (2HCl-salt), the origin of diastereoselectivity can
be explained by the models depicted in Figure 4.3.
CH=X CH=X CH=X Cl

3
R H
R3 endo-attack H
exo-attack X= N
H R3
2 O N 2
N R R N
O R2 O
HCl N
exo-product
E-nitrone (refers to R3) Z-nitrone
Figure 4.3. Origin of diastereoselectivity when reacting nitrones 163a-g with the iminiumspecies
from aldehyde 161 and catalyst 160 (2HCl-salt).
57
Thus, either an exo-approach of the Z-forms of the nitrones or an endo-
approach of the E-forms of those explains the observed diastereoselectivity
(Figure 4.3). However, as mentioned in section 4.1, aldonitrones exist almost
exclusively in their Z-forms with a large barrier of interconversion. Moreover, it
has recently been reported that aldonitrones react with α,β-unsaturated aldehydes
in their Z-forms under conditions similar to those used in this work.103 Thus, the
most probable major reaction pathway is the one where the nitrones in their Z-
forms react with the activated iminium species via an exo-approach.
In order to determine the absolute configurations of the major cycloadducts
obtained in Scheme 4.5, one of those, 164a, was transformed via a few synthetic
steps into the diol 172 (Scheme 4.10). The sign of optical rotation of this diol
was compared with that of the enantiomer, ent-172, prepared from compound
173111 with known absolute configuration. The latter compound was generously
supplied by Dr. Kei Manabe. These two compounds, 172 and ent-172, displayed
opposite signs of optical rotation and should therefore be enantiomers. It is
reasonable to assume that the nitrones 163b-g react in the same fashion as
nitrone 163a with aldehyde 161, and thus, the corresponding reduced
cycloadducts should have the absolute configurations as depicted in Scheme 4.5.
OH OAc OH
H H H
a,b c,d
O Ph AcO Ph HO Bn
N AcN
Me Me
164a 171 172
91% ee [α]D25 = - 20.5
O OH
c H
O Bn O dr 8:1 HO Bn
173 ent-172
38% ee [α]D25 = + 6.4
Scheme 4.10. Preparation of diols 172 and ent-172. a) Pd(OH)2, HCl, MeOH, H2. b) AcCl, pyridine,
CH2Cl2, 90% overall yield. c) (i) LiAlH4, THF. (ii) H3O+, ~ 90% yield. d) Pd/C, H2, MeOH, 79% over
two steps.
With the knowledge of the absolute configurations of the reduced major

cycloadducts 164, the origin of π-facial selectivity can be explained as outlined
in Figure 4.4. Reaction between the catalyst 160 (2HCl-salt) and the aldehyde
161 gives a reactive iminium species, which either can adopt a Z- or an E-
conformation. Moreover, the cyclopentenyl moiety of the aldehyde can either
adopt an s-trans or an s-cis conformation, resulting in four possible reactive
intermediates A-D (Figure 4.4). If only steric factors are considered, the major
attack of the nitrones should occur on the least sterically hindered side of the π-
bond of the cyclopentenyl moiety. Thus, intermediates A and D are unlikely to be
[111] Manabe, K. Tetrahedron Letters 1998, 39, 5807-5810.
58
the major reactive intermediates because in order to explain the experimentally
observed sense of π-facial selectivity, attack of the nitrones has to occur on the
sterically hindered side of the π-bond. The two remaining possible intermediates
B and C both fulfill the criterion of having the α-Si–β-Re face more exposed
than the α-Re–β-Si face. Molecular mechanics calculations (CS Chem3D ProTM
4.0) performed on simplified models of B and C (i.e. exchanging the
piperidinium moiety for a trimethylammonium one), indicated that their low
energy conformations had approximately the same energy. Due to the long
distance between the piperidinium ring of the catalyst and the reacting π-bond, in
intermediate B a low degree of discrimination between the two π-faces is
expected. However, in C one of the π-faces is efficiently shielded by the
piperidinium moiety. Thus, attack of the nitrones onto this intermediate will
preferentially occur on the α-Si–β-Re face with a higher degree of discrimination
than that expected for intermediate B. When only steric factors are considered,
reaction involving the intermediate C best explains the observed sense of π-
facial selectivity. However, electronic effects may also play a major role here.
Therefore, B cannot be ruled out as the major reactive intermediate.
A B C D
s-cis s-trans s-cis s-trans
2Cl 2Cl 2Cl 2Cl

H H H H
N N N N N N N N
H H H H
Nitrone Nitrone Nitrone Nitrone
(E)-iminium isomers (Z)-iminium isomers
Figure 4.4. Reactive intermediates from aldehyde 161 and catalyst 160 (2HCl-salt). Attack on the α-
Si–β-Re face by the nitrones 163a-g as indicated by arrows will furnish the major enantiomers of
cycloadducts 164a-g.
59
4.4 Applications
Isoxazolidines are structural key moieties in many bioactive substances and
herbicides.112 Because they are also easily ring opened to the corresponding
aminoalcohols as described in section 4.1, they can serve as attractive building
blocks for the construction of other natural products and bioactive substances.72
Isoxazolidines are also building blocks for the preparation of chiral ligands for
use in enantioselective transformations.113 Because the total syntheses of various
natural products and other bioactive substances via asymmetric 1,3-dipolar
cycloaddition reactions of nitrones are numerous,114 only a few examples will be
presented here (Figure 4.5).
OH N HO
O
N
HO2C(CH2)5 N Me N N
H H H
O
HO
(+)-Azimic acid (+)-Febrifugine (-)-Histrionicotoxin
H
Cl
N OH O
Me N O
N O
H NH
R1 3
(+)-Monomorine I R1 = Me, n = 1: (-)-Hygroline (+)-Acivicin

R1 = H, n = 2: (+)-Sedridine
O
O
O
O
OH NH2 O
Me
H2N N CO2H
N MeO N
H H CHO
(+)-Negamycin Precursor to (-)-haemanthidine,
(+)-pretazettine and (+)-tazettine
Figure 4.5. Examples of alkaloids synthesised via an asymmetric 1,3-dipolar cycloaddition as a key
step. The remaining original atoms, which formed the isoxazolidine ring are marked in red.
[112] Takeuchi, Y.; Furusaki, F. Adv. Heterocycl. Chem. 1977, 21, 207-252.
[113] See e.g. (a) Aurich, H. G.; Biesemeier, F.; Geiger, M.; Harms, K. Liebigs Ann./Recueil
1997, 423-434. (b) Aurich, H. G.; Geiger, M.; Gentes, C.; Harms, K.; Köster, H. Tetrahedron
1998, 54, 3181-3196. (c) Baskaran, S.; Aurich, H. G.; Biesemeier, F.; Harms, K. J. Chem.
Soc. Perkin Trans. 1 1998, 3717-3724. (d) Aurich, H. G.; Soeberdt, M.; Harms, K.
Tetrahedron 1999, 55, 1249-1270. (e) Aurich, H. G.; Gentes, C.; Harms, K. Tetrahedron
1995, 51, 10497-10512. (f) Cicchi, S.; Crea, S.; Goti, A.; Brandi, A. Tetrahedron: Asymmetry
1997, 8, 293-301.
[114] Raymond, C. F. J.; Martin, J. N. In Synthetic Applications of 1,3-Dipolar Cycloaddition
60
Substituted piperidines are naturally occurring compounds, which display
various biological activities. An efficient approach for the syntheses of such
compounds in enantiomerically pure forms is via 1,3-dipolar cycloaddition
reactions of nitrones with dipolarophiles in which one or both of the reacting
partners are chiral and non-racemic. Using this approach, (+)-azimic acid and the
related alkaloid (+)-julifloridine (not shown) were recently obtained (Figure
4.5).115 Other examples include the total synthesis of the antimalarial 2-
substituted piperidine (+)-febrifugine, the related alkaloid (+)-isofebrifugine (not
shown),116 the spirocyclic piperidine derivative (–)-histrionicotoxin isolated from
a “dart-poison” frog,117 and (+)-monomorine I.118
Other types of alkaloids have also been successfully obtained via an
asymmetric 1,3-dipolar cycloaddition reaction as a key step. For example (+)-
sedridine and (–)-hygroline were synthesised starting from cyclic nitrones and
chiral non-racemic vinyl sulfoxides119 and other chiral dipolarophiles (Figure
4.5).16c A doubly diastereoselective reaction of a chiral carbohydrate derived
nitrone with vinylglycine derivatives furnished, after some additional
transformations, (+)-acivicin, which has antitumor activity.120 A carbohydrate
derived nitrone was also used in the synthesis of the antibacterial compound (+)-
negamycin.121 Finally, the pharmacologically active alkaloids (–)-haemanthidine,
(+)-pretazettine and (+)-tazettine were synthesised from the precursor depicted in
Figure 4.5, obtained via an asymmetric intramolecular 1,3-dipolar cycloaddition
reaction followed by some additional synthetic steps.122
[115] Kiguchi, T.; Shirakawa, M.; Honda, R.; Ninomiya, I.; Naito, T. Tetrahedron 1998, 54,
15589-15606.
[116] Ooi, H.; Urushibara, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org. Lett. 2001, 3,
953-955.
[117] (a) Williams, G. M.; Roughley, S. D.; Davies, J. E.; Holmes, A. B.; Adams, J. P. J. Am.
Chem. Soc. 1999, 121, 4900-4901. (b) Davison, E. C.; Fox, M. E.; Holmes, A. B.; Roughley,
S. D.; Smith, C. J.; Williams, G. M.; Davies, J. E.; Raithby, P. R.; Adams, J. P.; Forbes, I. T.;
Press, N. J.; Thompson, M. J. J. Chem. Soc. Perkin Trans. 1 2002, 1494-1514.
[118] (a) Ito, M.; Kibayashi, C. Tetrahedron 1991, 47, 9329-9350. (b) Ito, M.; Kibayashi, C.
[119] (a) Louis, C.; Hootelé, C. Tetrahedron: Asymmetry 1997, 8, 109-131. (b) Louis, C.;
Hootelé, C. Tetrahedron: Asymmetry 1995, 6, 2149-2152.
[120] (a) Mzengeza, S.; Whitney, R. A. J. Org. Chem. 1988, 53, 4074-4081. (b) Mzengeza,
S.; Yang, C. M.; Whitney, R. A. J. Am. Chem. Soc. 1987, 109, 276-277.
[121] (a) Kasahara, K.; Iida, H.; Kibayashi, C. J. Org. Chem. 1989, 54, 2225-2233. (b) Iida,
H.; Kasahara, K.; Kibayashi, C. J. Am. Chem. Soc. 1986, 108, 4647-4648.
[122] (a) Baldwin, S. W.; Debenham, J. S. Org. Lett. 2000, 2, 99-102. (b) Baldwin, S. W.;
Aubé, J.; McPhail, A. T. J. Org. Chem. 1991, 56, 6546-6550.
61
A literature survey reveals that the various bicyclic fused isoxazolidines 164,
obtained via the enantioselective 1,3-dipolar cycloadditions depicted in Scheme
4.5, are structurally similar to known bioactive substances and chiral ligands
used in asymmetric synthesis. Hence, the amino acid moiety 175 (Figure 4.6) has
been found to be an important structural feature in antiviral compounds effective
against herpes simplex virus both in vitro and in vivo.123 This moiety is
structurally related to the isoxazolidines 164 and therefore, such isoxazolidines
could serve as potentially attractive building blocks for the syntheses of such
types of amino acids.
NH2 OH
H H H CO2H
HO O R3
N N O
H
R2
174 164 175
Figure 4.6. Structural similarities between amino alcohol 174, amino acid derivative 175 and
compound 164.
Moreover, compound 164 is a possible building block for the syntheses of

spirocyclic derivatives. Some spirocyclic compounds have found application as
chiral ligands in asymmetric synthesis.124 For example amino alcohol 174 and
derivatives of this have been used with success as chiral auxiliaries in
asymmetric Diels-Alder reactions.125
Encouraged by the good results reported with spirocyclic derivatives as chiral
ligands in asymmetric synthesis, I wanted to synthesise an enantiopure
spirocyclic aminoalcohol from cycloadduct 164 and explore its utility as a chiral
ligand in various asymmetric transformations.126
[123] (a) Moss, N.; Ferland, J.-M.; Goulet, S.; Guse, I.; Malenfant, E.; Plamondon, L.;
Plante, R.; Déziel, R. Synthesis 1997, 32-34. (b) Moss, N.; Beaulieu, P.; Duceppe, J.-S.;
Ferland, J.-M.; Garneau, M.; Gauthier, J.; Ghiro, E.; Goulet, S.; Guse, I.; Jaramillo, J.; L.-
Brunet, M.; Malenfant, É.; Plante, R.; Poirier, M.; Soucy, F.; Wernic, D.; Yoakim, C.; Déziel,
R. J. Med. Chem. 1996, 39, 4173-4180. (c) Moss, N.; Beaulieu, P.; Duceppe, J.-S.; Ferland,
J.-M.; Gauthier, J.; Ghiro, E.; Goulet, S.; Grenier, L.; L.-Brunet, M.; Plante, R.; Wernic, D.;
Déziel, R. J. Med. Chem. 1995, 38, 3617-3623. (d) Moss, N.; Déziel, R.; Ferland, J.-M.;
Goulet, S.; Jones, P. -J.; Leonard, S. F.; Pitner, T. P.; Plante, R. Bioorg. & Med. Chem. 1994,
2, 959-970.
[124] See e.g. (a) Arai, M. A.; Arai, T.; Sasai, H. Org. Lett. 1999, 1, 1795-1797. (b) Chan, A.
S. C.; Hu, W.; Pai, C.-C.; Lau, C.-P. J. Am. Chem. Soc. 1997, 119, 9570-9571. (c)
Srivastava, N.; Mital, A.; Kumar, A. J. Chem. Soc. Chem. Commun. 1992, 493-494. (d)
Dinesh, C. U.; Kumar, P.; Reddy, R. S.; Pandey, B.; Puranik, V. G. Tetrahedron: Asymmetry
1995, 6, 2961-2970. (e) Hu, W.; Yan, M.; Lau, C.-P.; Yang, S. M.; Chan, A. S. C.; Jiang, Y.;
Mi, A. Tetrahedron Letters 1999, 40, 973-976. (f) Banks, M. R.; Cadogan, J. I. G.; Gosney, I.;
Grant, K. J.; Hodgson, P. K. G.; Thorburn, P. Heterocycles 1994, 37, 199-206. (g) Seebach,
D.; Beck, A. K.; Dahinden, R.; Hoffmann, M.; Kühnle, F. N. M. Croat. Chem. Acta 1996, 69,
459-484.
[125] Burke, M. J.; Allan, M. M.; Parvez, M.; Keay, B. A. Tetrahedron: Asymmetry 2000, 11,
2733-2739 and references cited therein.
[126] Unpublished results.
62
In order to synthesise a spirocyclic ring system from isoxazolidines of type
164 (Figure 4.6) the exocyclic sidechains in the former must be connected (i.e.
R3 and the hydroxymethyl substituent). As was mentioned above, cycloadduct
164b, which could be obtained in a good yield on a large scale, and
enantiomerically pure by recrystallisation, underwent iodoetherification in the
presence of iodine and a base to give a single unidentified spirocyclic adduct (i.e.
169 or 170, the position of the iodine not determined, Schemes 4.9 and 4.11). I
thought that further transformation of this could furnish the enantiopure
spirocyclic amino alcohol 178 (Scheme 4.11).
H O I H O
O O
N N
Me Me
OH
169 176
H I2, NaHCO3 1) H2, Pd/C H O
DBU
O or or HO
N CH3CN 2) Zn, AcOH
HN
Me Me
164b H O H O 178
> 99% ee O O ~90% overall
N I N
yield from 164b
Me Me
170 177
Scheme 4.11. Preparation of dispirocyclic compound 178.
Hence, dehydrohalogenation of this iodoetherification product 169/170 by

treatment with a base (DBU) furnished a single compound, which should have
the structure as shown in 176 or 177 (position of double bond not determined).
Catalytic hydrogenation of the π-bond of this followed by ring opening of the
isoxazolidine ring using Zn (dust) in diluted AcOH gave the target dispirocyclic
molecule 178 in ~90% overall yield from compound 164b. It must be noted that
no purification procedure other than extraction was involved in the synthetic
sequence from 164b to the target molecule 178. The direct transformation of
compound 169/170 to 178 in one step was attempted by treatment with various
reagents such as Zn/AcOH and super-hydride. However, all attempts failed and
either hydrodehalogenation only or N-O cleavage only was observed.
Surprisingly, when other reagents than Zn/AcOH were used, the reduction of the
N-O bond proved to be very difficult.
63
Having established an efficient, short and high yielding synthesis of
enantiopure dispirocyclic aminoalcohol 178, this compound was employed as a
chiral ligand in enantioselective transformations.127 Because amino alcohols have
been widely used as chiral ligands in reactions of organozinc with aromatic
aldehydes,128 the efficiency of compound 178 as a ligand in this type of reaction
was first investigated.
Thus, in the presence of 5 mol% of this at –8 oC, the reaction of diethylzinc
with benzaldehyde furnished 1-phenyl-1-propanol in nearly full conversion after
2 days (Scheme 4.12). However, the ee of the product was disappointingly low
(22% ee). Although this result does not encourage further investigation of ligand
178 as catalyst in this type of reaction, amino alcohol 178 is a possible potential
efficient ligand in other types of asymmetric transformations. This is currently
being investigated.
OH
CHO 178 (5 mol%) *
+ Et2Zn
Toluene
22% ee
Scheme 4.12. Diethylzinc addition to benzaldehyde in the presence of chiral ligand 178.
[127] Unpuplished results.

[128] Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833-856.
64
5. Conclusions and outlook
This thesis describes the use of either chiral auxiliaries or chiral catalysts in the
syntheses of chiral non-racemic pyrrolidines, tetrahydrothiophenes, and
isoxazolidines via 1,3-dipolar cycloadditions. With camphorsultam being the
most efficient auxiliary, good asymmetric inductions have been achieved in the
reactions of azomethine ylides and thiocarbonyl ylides. When a chiral non-
racemic azomethine ylide was applied, significant improvement in π-facial
selectivity was observed only when this ylide was reacted with cyclic
dipolarophiles. Because the major and the minor diastereomeric pyrrolidine- and
tetrahydrothiophene cycloadducts were separable either by column
chromatography or by recrystallisation, diastereomerically pure 3,4-disubstituted
pyrrolidines and tetrahydrothiophenes were obtained. Cleavage of the chiral
auxiliaries furnished valuable enantiomerically pure building blocks.
The relatively new field of 1,3-dipolar cycloaddition reactions catalysed by
metal-free chiral non-racemic organocatalysts, has also been investigated. Thus,
various pyrrolidinium salts have been applied as catalysts in the reactions of
some nitrones with 1-cycloalkene-1-carboxaldehydes. In some cases, these
reactions furnish fused bicyclic isoxazolidines in high diastereoselectivities and
enantioselectivities. One can forecast that this area of organocatalysis will be a
fast growing one in the future.
When comparing the two approaches of asymmetric 1,3-dipolar cycloaddition
reactions discussed in this thesis, that is, either by using chiral auxiliaries or
chiral catalysts, one has to consider both the advantages and drawbacks of each
of them. Whereas the former approach demands two extra synthetic steps, that is,
attachment and removal of the auxiliary, the latter approach does not. Moreover,
for the latter one, only a catalytic amount of a chiral material is, in most cases,
needed to achieve an enantioselective process. The advantage of the first
approach involving chiral auxiliaries is, that diastereomeric cycloadducts are
obtained, which are, in general, easy to separate, furnishing, after auxiliary
removal, an enantiopure product. However, when using the chiral catalyst
approach, the cycloadducts are frequently obtained as mixtures of enantiomers,
which are notoriously difficult to resolve. Normally complicated crystallisation
schemes or multistep chromatography on chiral stationary phases are needed to
affect resolution on a preparative scale. Thus, there is a demand to find catalysts
that can furnish practically only the desired enantiomer. Although such catalysts
exist for some types of cycloaddition reactions, they are often limited to certain
kind of dipolarophiles and dipoles. Therefore, the development of more efficient
catalysts can be expected to be a major area of research in the future.
Finally, this thesis has also included the synthetic applications of the
asymmetric 1,3-dipolar cycloaddition reactions towards natural products and
other bioactive substances. Also, potential catalysts have been obtained by using
this approach. From simple starting materials and in one single step, it has been
shown that 1,3-dipolar cycloadditions can furnish very complex cycloadducts
containing several new stereogenic centres. Therefore, it comes as no surprise
that such reactions often are key steps in the total syntheses of natural products.
65
6. Acknowledgements
Jag vill uttrycka min tacksamhet till följande personer som på ett eller annat sätt
bidragit till att denna doktorsavhandling blivit verklighet:
* Prof. Hans-Erik Högberg, min handledare, för stöd och värdefulla

diskussioner under min tid som doktorand.
* Doc. Erik Hedenström, min bihandledare under min första tid som
doktorand. Tack för att du tog så väl hand om mig och introducerade mig in
i ”forskningsvärlden”.
* Dr. Patrizia Caldirola, min handledare under examensarbetet på
Pharamacia & Upjohn. Tack för din otroliga initiativförmåga, ditt engage-
mang och för att du stödde mig att börja doktorera i Sundsvall även om du
helst ville ha mig kvar i Uppsala.
* Prof. Torbjörn Norin, min huvudhandledare på KTH.
* Prof. Kurt B. G. Torssell, Dr. Olof Smitt och Fil. Lic. Fredrik Andersson för
att ni omsorgsfullt tagit er tid att granska manuskriptet till denna avhandling
samt kommit med värdefulla kommentarer.
* Alla nuvarande doktorander i organgruppen, Linda, Marica, Micke, Dan,
Mona, Carina, Jessica, Jimmy, Palle, Jonas och Anna men även de forna
medlemmarna under min tid som doktorand, Ove, Fredrik, Olle, Helen och
Ba-Vu.
* Forna och nuvarande utbytesstudenter i organgruppen. Roligt att ni,
Susan och Per, ville åka hela vägen från Danmark och hit till Sundsvall med
anledning av min disputation.
* Alla doktorander i FSCN huset och de forna och nuvarande doktoranderna
i fysikalisk kemi.
* Håkan N. (för att du är så bra på att hitta kemikalier till mig i kemikalie-
förrådet som egentligen inte finns) och Torborg J. (för att du alltid ställer
upp för mig och hjälper till med både ett och annat och alltid skiner som en
sol).
* Karin! Det finns troligen inte en mer noggrann och roligare städerska.
* All administrativ personal på Mitthögskolan, speciellt Siw, Viktoria, Ingrid
och Hasse för understöd med allt mellan himmel och jord.
* Ingvor Larsson (KTH) för hjälp med det administrativa kring forskarut-
bildningen och Doc. Ulla Jacobsson för hjälp med diverse frågor kring
tryckningen av avhandlingen.
* Min familj: Linda, vi har haft en tuff men rolig tid som doktorander. Nu
väntar nya äventyr. Johanna, min lilla busunge, vad skulle jag göra utan dig.
Du får mig att slappna av och tänka på andra saker än bara kemi.
* Tack på förhand till alla som kommer till disputationsfesten. Hoppas det
blir en toppenkväll för oss alla.
* Slutligen vill jag tacka Mitthögskolan och vetenskapsrådet (VR) för
finansiellt stöd.
66

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Asymmetric 1,3-Dipolar Cycloaddition

Reactions of Azomethine Ylides,

Akademisk avhandling som med tillstånd av Kungliga Tekniska Högskolan i

Publikationen kan beställas från:

Chemistry, Department of Natural and Environmental Sciences,

Organic Chemistry, Department of Chemistry,

Printed by Ekonomi-Print AB, 2003

1.1 The 1,3-dipolar cycloaddition reaction

The asymmetric variants of this reaction using either chiral auxiliaries or

1.2 The 1,3-dipole/ylide

Allyl anion type

propargyl/allenyl anion type

Figure 1.2. Examples of 1,3-dipoles.

1.3 The dipolarophile

1.4 Mechanistic aspects

In addition to the issues concerning diastereoselectivity discussed above,

1) Resolution of a racemic mixture, that is, separation of two enantiomers

2) Diastereoselective synthesis using chiral auxiliaries derived from

3) Enantioselective synthesis from achiral starting materials mediated by a chiral

The two latter approaches will be considered in this thesis.

1.6 Diastereoselective 1,3-dipolar cycloaddition reactions using

When an achiral compound, for example acrylic acid 16 (Scheme 1.6), is

Because diastereomers often have different properties such as polarity and

1.7 Doubly diastereoselective 1,3-dipolar cycloaddition reactions

Matched case Mismatched case

Figure 1.6. Example of a general doubly diastereoselective 1,3-dipolar cycloaddition reaction

1.8 Enantioselective 1,3-dipolar cycloaddition reactions using chiral

no catalyst added catalyst added

dipole dipolarophile dipole dipolarophile

Figure 1.8. Examples of different modes of attachment of a chiral catalyst to a dipolarophile. A:

2.1 General aspects

In the presence of a dipolarophile such as an α,β-unsaturated acyl derivative (i.e.

2.2 Diastereoselective reactions using chiral auxiliaries

A number of asymmetric 1,3-dipolar cycloaddition reactions of azomethine

(1S)-(–)-Camphorsultam 39 (and the enantiomer) and oxazolidinone

[12] Blaser, H.-U. Chem. Rev. 1992, 92, 935-952.

Table 2.1. 1,3-Dipolar cycloaddition of ylide 43# with dipolarophile 44 attached to

7 Toluene +20 quant. 66:34

9 Toluene +20 quant. 63:37

[22] Kim, B. H.; Curran, D. P. Tetrahedron 1993, 49, 293-318.

44a = U - conformer = Z -conformer 44b

∆G*U 3,5 ∆G*Z

Table 2.2. Singly and doubly diastereoselective 1,3-Dipolar cycloadditions.

Table 2.3. Diastereofacial selectivity as a function of solvent polarity [ET(30)] in

59: Y = CH2 43#: R1 = Bn 61 R1= Bn 62

2 dipole 3 with 48#

[30] Allway, P.; Grigg, R. Tetrahedron Letters 1991, 32, 5817-5820.

With the aim of developing a general method for the enantioselective

Quinocarcin Conessine precursor Spirotryprostatin B 2α-Tropanol

Enantiomerically pure derivatives of azabicyclo[3.3.0]octanes (i.e. 87 and its

[47] Makino, K.; Ichikawa, Y. Tetrahedron Letters 1998, 39, 8245-8248.

Hence, compound 64, which was obtained via an asymmetric 1,3-dipolar

Scheme 2.13. Preparation of some potential organocatalysts: a) PhMgBr or p-MeO(C6H4)MgBr,

3.1 General aspects

3.2 Diastereoselective reactions using chiral auxiliaries

[52] Mloston, G.; Heimgartner, H. Polish J. Chem. 2000, 74, 1503-1532.

Compound 98 (Scheme 3.2), when treated with CsF in CH3CN, is known to

Having established an efficient approach for the syntheses of enantiopure

Figure 3.1. The 3-methylalkan-2-ol unit.

116 119 120 121

From the retrosynthetic analysis (Scheme 3.5), bond breaking of the

4.1 General aspects

4.2 Diastereoselective reactions using chiral auxiliaries

∆GU 3,5 ∆GZ