Taxol

624
J. Am. Chem. SOC. 1995,117, 624-633
Total Synthesis of Taxol. 1. Retrosynthesis, Degradation, and

Reconstitution
K. C. Nicolaou,* P. G. Nantermet, H. Ueno, R. K. Guy, E. A. Couladouros, and
E. J. Sorensen
Contributionfrom the Department of Chemistry, The Scripps Research Institute, 10666 North
Torrey Pines Road, La Jolla, Califomia 92037, and Department of Chemistry and Biochemistry,
University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093
Received July 7, 1994@
Abstract: A successful strategy for the enantioselective synthesis of the natural stereoisomer of Taxol (1) has been
developed. This strategy utilized the convergent assembly of Taxol's central eight-membered B ring from preformed
synthons for rings A (10) and C (9) followed by late introduction of the D ring and side chain. Degradative studies
c o n f i i e d the viability of certain crucial manipulations including oxidation of the C13 position (35
3) and
regioselective introduction of the C I-hydroxyl, CZbenzoyloxy moiety (29 31). Additionally, a convenient method
for the large-scale production of 29, a derivative useful for C2 analog production, was developed.
Introduction
Taxol (Figure 1, 1),lq2a diterpene produced by several plants

of the genus
was isolated from the cytotoxic methanolic
extract of the bark of T. brevifolia." Taxol interacts with
microtubules, important cellular structural proteins,5in a manner
that catalyzes their formation from tubulin and stabilizes the
resulting structures.6 In cells this phenomenon leads to an
altered morphology with the microtubules forming stable
bundles and the cell being unable to assemble a normal mitotic
spindle.' Cells treated with Taxol normally arrest at the
transition between interphase and mitosis and die. The elucidation of this unique mechanism of action during the late 1970s
and early 1980s sped Taxol's development as an anticancer drug.
Since that time, Taxol has revealed unusual efficacy as a clinical
agent,* experiencing rapid development for the treatment of
b r e a ~ tovarian,'O
,~
skin," lung,12 and head and neck13 cancers.
* Address correspondence to this author at The Scripps Research Institute

or the University of California.
Abstract published in Advance ACS Abstracts, December 15, 1994.
(l)Nicola~u,K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem., In?. Ed.
Engl. 1994,33, 15.
(21 Kingston. D. G. I. Fortschr. Chem. Ora. Narurst. 1993,61,1.
(3) ApGndino, G. Fitoterapia 1993,54, Sippl. NI, 5 .
(4) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggen, P.; McPhail, A.
T. J. Am. Chem. SOC.1971,93,2325.
(5) (a) Mandelkow, E.; Mundelkow, E.-M. Curr. Opin. Struct. Biol. 1994,
4 , 171. (b) Avila, J. Life Sci. 1991,50, 327.
(6) Manfredi, J. J.; Horwitz, S. B. Pharmacal. Ther. 1984,25,83.Schiff,
P. B.; Fant, J.; Horwitz, S. B. NarUre 1979,277, 665.
(7)Schiff, P. B.; Horwitz, S. B. Proc. Natl. Acad. Sci. USA. 1980,77,
1561.
(8) Lavelle, F. Curr. Opin. Invest. Drugs 1993,2, 627. Rowinsky, E.
K.; Onetto, N.; Canetta, R. M.; Arbuck, S. G. Semin. Oncol. 1992, 19,
646.
(9) Holmes, F. A,; Waters, R. J.; Theriault, R. I.; Forman, A. D.; Newton,
L. K.; Raber, M. N.; Buzdar, A. U.; Frye, D. K.; Hortobagyi, G. N. J. Natl.
Cancer Inst. U S A . 1991,83, 1797.
(10) McGuire, W. P.; Rowinsky, E. K.; Rosenshein, N. B.; Grumbine,
F. C.; Ettinger, D. S.; Armstrong, D. K.; Donehower, R. C. Ann. Intern.
Med. 1989,111, 273. Einzig, A. I.; Wiemik, P. H.; Sasloff, J.; Garl, S.;
Runowicz, C.; O'Hanlan, K. A.; Goldberg, G. Proc. Am. Assoc. Cancer
Res. 1990,31, 187 (Abstract 1114). Pazdur, R.; Ho, D. H.; Lassere, Y.;
Bready, B.; Kvakoff, I. H.; Raber, M. N. Proc. Am. SOC. Clin. Oncol. 1992,
11, 1 1 1 (Abstract 265). Caldas, C.; McGuire, W. P., III. Semin. Oncol.
1993,20 (4 Suppl. 3), 50.
(1 1) Einzig, A. I.; Hochster, H.; Wiemik, P. H.; Trump, D. L.; Dutcher,
J. P.; Garowski, E.; Sasloff, J.; Smith.T. J. Invest. New Drum 1991.9.59.
Legha, S. S.; Ring, S.; Papadopoulos, N.; Raber, M. N.{Benjamin, R.
Cancer 1990,65, 2478.
@
1: Taxol
2: 10-deacetylbaccatin111
Figure 1. Structure of Taxol (1)and 10-deacetylbaccatin III (2).
In 1993, Taxol was approved by the FDA for use in the U.S.
for treatment of breast and ovarian cancers.
Taxol's development as a therapeutic agent precipitated a
fundamental problem with its production: the original source
of its isolation, T. brevifolia, was a slowly growing and rare
tree whose content of Taxol could not possibly meet the
demand.14 The public's perception of the ecological disaster
involved in harvesting these trees from the last remaining old
growth forests of the Pacific Northwest caused an ongoing
debate about the ethics of producing Tax01.l~ A wide range of
research was carried out to solve this problem, including
plantation farming, cellular culture, semisynthesis, and total
synthesis.l4 A semisynthetic process utilizing 10-deacetylbaccatin 111 (2, Figure l), derived from the common T. baccata
shrub, as the starting material has, at least temporarily, resolved
this dilemma.14 Over the past two decades some 30 synthetic
(12) Chang, A.; Kim, K.; Glick, J.; Anderson, T.; Karp, D.; Johnson, D.
J. Natl. Cancer Inst. USA. 1993,85,388. Murphey, W. K.; Winn, R. J.;
Fossella, F. V.; Shin,D. M.; Hynes, H. E.; Gross, H. M.; Davila, E.; Leimert,
J. T.; Dhinga, H. M.; Raber, M. N.; Krakoff, I. H.; Hong, W. K. Proc. Am.
SOC.Clin. Oncol. 1993,85,384. Ettinger, D. S. Semin. Oncol. 1993,ZO(4
Suppl. 3), 46.
(13) Forastiere, A. A. Semin. Oncol. 1993,20 (4 Suppl. 3), 56.
(14) Borman, S. Chem. Eng. News 1991,Sept 2, 11.
(15)Hartzell, H. The Yew Tree, A Thousand Whispers; Hulogosi:
Eugene, OR, 1991.
0002-7863/95/15
17-0624$09.00/0 0 1995 American Chemical Society
J. Am. Chem. SOC., Vol. 117,No. 2, 1995 625
Total Synthesis of Taxol. 1

groups, attracted by the molecule's challenging architecture and
importance in medicine, undertook the task of the total synthesis
of Taxo1.l~~
Herein and in the following articles16-18we report
the total synthesis of Taxol (l).l9
Scheme 1. Retrosynthetic Analysis of Taxol (1)"

0
Retrosynthetic Analysis and Strategy
i)H
The retrosynthetic analysis and final synthetic strategy discussed below emerged after considering several options and
examining information gathered during preliminary studies in
this program. Aspects of alternative plans originally considered
will be discussed in the context of the overall story as revealed
in this and the following papers in this series.
In considering a strategy for the total synthesis of Taxol (l),
we set the following postulate as a condition: the route should
be short and flexible to allow for the eventuality of producing
the natural product and a variety of its analogs in a practical
way and to deliver the target molecule in its enantiomerically
pure and correct form. To best fulfill this criteria, a convergent
sequence was chosen in which rings A and C were to be
constructed separately and then brought together to form the
8-membered ring B. Examples already in the literature and
knowledge derived from our own experience led us to conclude
that we could leave for the final stages the attachment of the
side chain,20,21the oxygenation of the C13 position,22and the
formation of the oxetane ring.23-25
Scheme 1 shows the retrosynthetic analysis of Taxol (1)on
which the synthetic strategy was based. Thus, appropriate
protection, removal of the side chain, and deoxygenation
transforms at C13 led, retrosynthetically, to the baccatin
derivative 3. Functional group manipulation at C1 and C2 led
to the 5-membered ring derivative 4 which was envisioned as
a precursor to the 1-hydroxy-2-benzoate system of Taxol.
Retrosynthetic disassembly of the oxetane ring in 4 and
introduction of a double bond in ring C allowed the generation
of intermediate 5 as a possible precursor. The carbocyclic ABC
taxoid core 5 was then retrosynthetically broken by standard
functional group manipulations and disconnection of the C9C10 bond leading to dialdehyde 6. The latter was considered
(16) Nicolaou, K. C.; Liu, J.-J.; Yang, Z.; Ueno, H.; Sorensen, E. J.;
Claiborne, C. F.; Guy, R. K.; Hwang, C.-K.; Nakada, M.; Nantermet, P. G.
J. Am. Chem. SOC. 1995, 117, 634.
(17) Nicolaou, K. C.; Yang, Z.; Liu, J.-J.; Nantermet, P. G.; Claiborne,
C. F.; Renaud, J.; Guy, R. K.; Shibayama, K. J . Am. Chem. SOC. 1995,
I 1 7, xxx.
(18) Nicolaou, K. C.; Ueno, H.; Liu, J.-J.; Nantermet, P. G.; Yang, Z.;
Renaud, J.; Paulvannan, K.; Chadha, R. J . Am. Chem. SOC.1995,117, xxx.
(19) Nicolaou, K. C.; Yang, Z.; Liu, J.-J.; Ueno, H.; Nantermet, P. G.;
Guy, R. K.; Claiborne, C. F.; Renaud, J.; Couladouros, E. A.; Paulvannan,
K.; Sorensen, E. J. Nature 1994, 367, 630. Holton, R. A.; Somoza, C.;
Kim, H.-B.; Liang, F. F.; Biediger, R. J.; Boatman, P. D.; Shindo,M.; Smith,
C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.;Zhang,
P.; Murthi, K. K.; Gentile, L. N.; Liu, J. H. J.Am. Chem. SOC. 1994, 116,
1597. Holton, R. A.; Kim, H. B.; Somoza, C.; Liang, F.; Biediger, R. J.;
Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.; Suzuki,
Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K. K.; Gentile, L. N.;
Liu, J. H. J . Am. Chem. SOC. 1994, 116, 1599.
(20) Holton, R. A. Workshop on Taxol and Taxus, 1991. Holton, R. A.
Eur. Pat. Appl. EP400,971 1990; Chem. Abstr. 1990, 114, 16456817.
(21) Ojima, I.; Habus, I.; Zhao, M.; Georg, G. I.; Jayasinghe, L. R. J .
Org. Chem. 1991, 56, 1681. Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.;
Park, Y. H.; Sun, C. M.; Brigaud, T. Tetrahedron 1992,48, 6985. Ojima,
I.; Sun, C. M.; Zucco, M.; Park, Y. M.; Duclos, 0.;Kuduk, S. Tetrahedron
Lett. 1993, 34, 4149.
(22) Ulman Page, P. C . ; McCarthy, T. J. In Comprehensive Organic

Synthesis; Trost, B. M., Fleming, I., Ley, S. V., FRS, Eds.; Pergamon
Press: New York, 1991; Vol. 7, p 99.
(23) Ettouati, L.; Ahond, A.; Poupat, C.; Potier, P. Tetrahedron 1991,
47, 9823.
(24) Magee, T. V.; Bornmann, W. G.; Isaccs, R. C. A.; Danishefsky, S .
J. J . Org. Chem. 1992, 57, 3274.
(25) Nicolaou, K. C.; Liu, J.-J.; Hwang, C.-K.; Dai, W.-M.; Guy, R. K.
J . Chem. SOC., Chem. Commun. 1992, 1118.
i
\
'0R3
0R3
7
i
NNHS0,Ar
10
+OAC
11
=?
CN
3
HO
12
OH
13
14
Bz = COPh; R, R1,Rz,RJ,%, Rs = protecting groups.
as a good candidate to afford, in the synthetic direction,

compound 5 via a McMurry pinacol coupling.26 Continuing
with the simplification of structure, intermediate 6 was traced
back to diol 7 and then to allylic alcohol 8 as potential
progenitors. Finally, disconnection of 8 via a Shapiro2'
transform led to hydrazone 10 representing ring A and aldehyde
(26) McMurry, J. E. Chem. Rev. 1989,89, 1513. McMurry, J. E. Acc.
Chem. Res. 1983, 16, 405. Lenoir, D. Synthesis 1989, 883.
Nicolaou et al.
626 J. Am. Chem. SOC.,Vol. 117,No. 2, 1995
Scheme 2. Preparation of 7-TES-baccatin III (17)a

0
1 :taxol
Scheme 3. Benzylation of the C7 Position and Oxetane

Ring Opening"
IS: baccatin 111
15: baccatin 111
Ib
I H+
OBn
1 A0
q
2: 10-deacetyl baccatin Ill
16:R=H
d L 17:R=Ac
Reagents and conditions: (a) excess n-B@B&, CHzClz, 25 "C,

7 h, then AcOH, 77%; (b) 30 equiv of EtsSiCl, pyridine, 25 "C, 24 h,
85%; (c) 20 equiv of Et3SiC1, pyridine, 25 "C, 17 h, 91%; (d) 5 equiv
of AcCl, pyridine, 0 "C, 48 h, 82%. TES = SiEt3, Bz = COPh.
9 representing ring C. The cyclohexene derivatives 10 and 9

were then disassembled by Diels- Alder transforms to afford
olefins 11-14 as potential starting materials.
The synthetic strategy derived from the analysis discussed
above included a number of sensitive and rather daring steps
in its final stages. In order to explore these final steps and
establish their viability, we embarked, in parallel with the
forward execution of the scheme, on degradation studies starting
with Taxol (1) and 10-deacetylbaccatin 111 (2).** Included
amongst our goals in this program were the following: deoxygenation of the C13 position and exploration of its allylic
oxidation, establishment of a suitable cyclic protecting group
for the C1 and C2 hydroxyl groups and its regioselective
conversion to the requisite C1 hydroxy, C2 benzoate functionality, and cleavage of the C9-C10 bond in order to obtain
intermediates suitable for exploring the McMurry pinacol
coupling as a means to construct the 8-membered ring of Taxol.
Preparation of 7-TES-baccatin I11
Since 7-benzyl and 7-triethylsilyl (TES) baccatin 111 were
projected as advanced intermediates in our synthesis, one of
our early objectives was to prepare these compounds from the
naturally occumng Taxol (1) and 10-deacetylbaccatin III (2).
While the former natural product is found in the bark of the
Pacific Yew tree (T. Brevifolia) in rather limited amounts, the
latter compound is readily available from the needles of the
European Yew tree (T.baccata). Scheme 2 summarizes the
chemistry that led to the preparation of 17 from 1 and 2. Thus
removal of the side chain from Taxol (1) via reduction of the
C13 ester linkage proceeded according to Kingston's method
( ~ - B U ~ N B Hto~ )afford
* ~ baccatin I11 (15) in 77% yield. Our
synthetic strategy was best served by a 7-benzyl derivative and
we, therefore, first considered the preparation of such an
intermediate. Basic conditions were, however, unacceptable
because of the well-documented epimerization at C7 via a
retroaldoValdo1 s e q u e n ~ e .Acidic
~ ~ ~ conditions
~ ~ ~ ~ (benzyl trichlo(27) Chamberlin, A. R.; Bloom, S. H. Org. React. 1990,39, 1.
(28) Nicolaou, K. C.; Nantermet, P. G.; Ueno, H.; Guy, R. K. J. Chem.
SOC.,
Chem. Commun. 1994,295.
(29) Magri, N. F.; Kingston, D. G. I.; Jitrangsri, C.; Piccariello, T. J .
Org. Chem. 1986,51, 3239.
(30) Kingston, D. G. I. P h a m c o l . Ther. 1991,52, 1.
OBn
H
1s
20
21
Reagents and conditions: (a) 20 equiv of benzyl tsichloroacetimidate, 1.0 equiv of triflic acid, CHzC12.25 "C, 40 h, 50%. Bz = COPh,
Bn = CHZPh.
roacetimidateitriflic acid),32also proved too destructive: giving

opening of the oxetane ring30 and leading to compound 18
(Scheme 3) as a major product (C7 stereochemistry not defined,
acid-catalyzed epimerization at this position has also been
r e p ~ r t e d ) . ~This
~ compound was presumably formed via
intermediates 19-21 as shown in Scheme 3 by a mechanism
similar to that proposed by Kingston in his oxetane opening
reaction induced by Meerwein's reagent.31
Failing to introduce a benzyl group at the C7 hydroxyl, we
then turned to a silyl group. In agreement with Greene,34we
observed that a tert-butyldimethylsilyl (TBS)group could not
be efficiently introduced. Installation of a triethylsilyl (TES)
group at C7, however, was smoothly accomplished with TESCl
in pyridine34(85% yield) to afford 7-TES-baccatin IIX (17).The
same compound was obtained from 10-deacetylbaccatin I11 (2)
following Greene' s procedure34 involving selective silylation
at the C7 hydroxyl group followed by acetylation of the C10
hydroxyl group. The latter step (AcCl, pyridine, 0 "C) proved
rather capricious on a larger scale, presumably due to the oxetane
opening and ring A skeletal rearrangements-although the
byproducts were not isolated.31~33~35-37
As we will see later in
this discussion, however, a more reliable method for this
transformation was discovered and utilized.
Formation of the 1,2-Carbonate Ring and Reconversion

to the 1-Hydroxy, 2-Benzoate System
With 7-TES-baccatin III (17) in hand, we then turned our
attention to the hydrolysis of the C2-benzoate and the C10acetate in order to gain access to further degradation products
(Scheme 4). Early trials using hydrolysis, methanolysis, or
(31) Samaranayake, G.; Magri, N. F.; Jitrangsri, C.; Kingston, D. G. I.
J. Org. Chem. 1991,56, 5114.
(32) Iversen, T.; Bundle, K. R.; J . Chem. Soc., Chem. Commun. 1981,
1240. White, J. D.; Reddy, G. N.; Spessard, G. 0. J. Am. Chem. SOC.1988,
110, 1624. Widmer, U. Synthesis 1987,568.
(33) Wahl, A.; GuBritte-Voegelein, F.; GuBnard, D.; Le Goff, M.-T.;
Potier, P. Tetrahedron 1992,48, 6965.
(34) Denis, J. N.; Greene, A. E.; Gutnard, D.; Gutritte-Voegelein, F.;
Mangatal, L.; Potier, P. J . Am. Chem. SOC. 1988,110, 5917.
(35) Appendino, G.; Ozen, H. C.; Gariboldi, P.;Torregiani, E.; Gabetta,
B.; Nizzola, R.; Bombardelli, E. J. Chem. SOC.Perkin Trans. 11993,1563.
(36) Kingston, D. G. I.; Samaranayake, G.; Ivey, C. A. J. Nat. Prod.
1990,53,1.
(37) Gutritte-Voegelein, F.; Gutnard, D.; Potier, P. J . Nar. Prod. 1987,
50, 9.
J. Am. Chem. SOC., Vol. 117, No. 2, 1995 627
Total Synthesis of Taxol. I
Scheme 4. Early Attempts at C2 and C10 Hydrolysis"
Scheme 5. Preparation of Carbonate 30 from

7-TES-baccatin III (17) and Its Transformation to Enone 25"
17: 7-TES baccatin 111
22
17: 7-TES baccatin Ill
25
lb
23
24
Reagents and conditions: (a) excess LiAlK, THF, -78 "C or -30
"C, 1-5 h; (b) excess K2CO3, MeOH, H20, 0 OC or 25 OC, 1-5 h.
TES = SEt3, BZ = COPh.
metal hydride reductions gave poor yields of tetrol 22, in

agreement with previous observation^.^^^^^^^^ The principal
byproducts seemed to result from deacetylation at C4 and
various intramolecular reactions such as the opening of the
oxetane ring by the newly liberated C2 hydroxyl group to form
compound 23 (Scheme 4). The intramolecular engagement of
the C4 acetate and C13 hydroxyl in a hydrogen-bonding
arrangement (structure 24, Scheme 4) is presumably responsible
for the ease of deacetylation of the C4 oxygen. Similar
structures have previously been invoked to explain deacetylation
of C4 in analogous s i t ~ a t i o n s . ~It, ~was,
~ , ~therefore,
~
decided
to remove any possible interference from the C13 hydroxyl
group by either oxidizing it to the enone or removing it
altogether. Such manipulations would also further our exploration of degradative and synthetic chemistry.
Oxidation of C l p was projected not only as a means to
remove the troublesome hydroxyl group but also as a way to
change the conformation of the molecule to the extent that might
affect the rate of hydrolysis of the C4 acetate and prevent attack
of the C2 alkoxide on the oxetane ring. This 0 p e r a t i o n ~ 9(17
~~
25, Scheme 5) was smoothly carried out in 98% yield using
Ley's TPAPNMO system.42 As hoped, enone 25 was readily
hydrolyzed in basic conditions (K2CO3, MeOH, HzO,0 "C) to
provide triol 26 in 91% yield. Contrary to the previously
accepted order of ester reactivity in taxoids (C9, C10 > C2),2
it was observed that, if so desired, the C10-acetate of compound
26 could be partially retained, as it reacts more slowly than the
C2-benzoate under the above conditions.
Initial attempts to introduce a ben~ylidene,"~a potential
precursor to the C1-hydroxy, C2-benzoate system,44 or an
a ~ e t o n i d eprotecting
~~
group at the Cl-C2 site met with failure,
+
(38) Klein, L. L. Tetrahedron Lett. 1993,34,2047.

(39) Chen, S.-H.; Wei, J.-M.; Farina, V. Tetrahedron Len. 1993,34,3205.
(40)Harrison, J. W.; Scrowsten, R. M.; Lythgoe, B. J . Chem. Soc. C
1966,1932.
(41) Senilh, V.; Gutritte, F.; GuCnard, D.; Colin, M.; Potier, P. C. R.
Acad. Sei. Pans 1984,299,1039.
(42) Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990,23, 13.
(43) Albert, R.; Dax, K.;Pleschko, R.; Stutz, K. Carbohydr. Res. 1985,
137,282. Yamanoi, T.;Akiyama, E.; Inazu, T. Chem. Lett. 1989,335.
Crimmins, M. T.; Hollis, W. G., Jr.; Lever, G. J. Tetrahedron Lett. 1987,
28, 3647.
(44) Binkley, R. W.; Goewey, G. S.; Johnston, J. C. J . Org. Chem. 1984,
49,992.
(45) Evans, M. E.; Parrish, F. W.; Long, L., Jr. Carbohydr. Res. 1967,
3,453. Lipshutz, B. H.; Barton, J. C. J . Org. Chem. 1988,53,4495.
28
29:R=H
30 : R = AC
31
25
Reagents and conditions: (a) 1.5 equiv of 4-methylmorpholine

N-oxide (NMO), 0.05 equiv of tetrapropylammonium permthenate
(TPAP), CH3CN, 25 "C, 1.5 h, 98%; (b) excess KzC03, MeOH, HzO,
0 "C, 4 h, 91%; (c) 0.05 equiv of camphorsulfonic acid (CSA), 1.0
equiv of benzaldehyde dimethyl acetal or excess 2,2-dimethoxypropane,
CHzC12, 25 "C, 20 h; (d) 10 equiv of phosgene, pyridine, 0 "C, 0.5 h,
85% or 6 equiv of carbonyldiimidazole, THF,40 "C, 0.5 h, then 1 N
aqueous HC1, THF, 25 "C, 15 min, 93%; (e) 4.5 equiv of AczO, 9
equiv of 4-(dimethylamino)pyridine (DMAP), CHzClZ, 25 "C, 0.5 h,
95%; (f) 10 equiv of PhLi, THF, -78 "C, 0.5 h, 85%; (g) 10 equiv of
AczO, 5 equiv of DMAP, CH&, 25 "C, 2.5 h, 95%; (h) 5 equiv of
PhLi, THF,-78 "C, 15 min, 70% plus 10% of 31. TES = SiEt3, Bz
= COPh.
a
as the C2-hydroxyl group opened the oxetane ring under the

acidic conditions used. In both instances the resulting product
was the tetrahydrofuran derivative 28 (Scheme 5).33.38,46Attention then focused on constructing a carbonate ring at the C1C2 site, an operation that required basic rather than acidic
conditions. Despite the scarcity of reports of nucleophilic
additions to carbonates to form
we entertained the
possibility of converting such functionality directly to the desired
1,2-hydroxybenzoate of Taxol(1) in the synthetic direction, by
addition of nucleophilic phenyl species (Scheme 5 ) . Even
though the regiospecificity of such an opening was questionable,
(46) Farina, V.; Huang, S . Tetrahedron Lett. 1992,33,3979.
(47) Satyanarayana, G . ; Sivaram, S . Synth. Commun. 1990,20, 3273.
(48) Wender, P. A.; Kogen, H.; Lee, H. Y . ;Munger, J. D.; Wilhelm, R.
S.; Williams, P. D. J . Am. Chem. Soc. 1989,Ill, 8957.
628 J. Am. Chem. SOC., Vol. 117, No. 2, 1995
Nicolaou et al.
we expected the distinctly different steric environment of the

Scheme 6. Selective Oxidation of the C13 Hydroxyl Group
and Preparation of Enone 26"
two positions to favor the less crowded C2 regioisomer.
Treatment of triol 26 with phosgene in pyridine provided the
desired carbonate 29 in 85% yield.49 It was later discovered
that the carbonate 29 could be obtained in 93% yield by using
carb~nyldiimidazole~~
and 4-(dimethy1amino)pyridine (DMAP)
in THF followed by acidic hydrolysis of the imidazole carbamate
at C10.
0
0
With a practical preparation of carbonate 29 secured, we then
32:R = H.Me
29
proceeded to investigate the anhydrous nucleophilic opening
of the carbonate ring with organometallic species-a rather
daring proposition considering the presence of four additional
carbonyl groups within the molecule. To our pleasant surprise,
exposure of 29 to excess phenyllithium in THF at -78 "C for
0.5 h resulted in the regioselectiveformation of the CZbenzoate
31 in 85% yield. This product was readily acetylated (95%
yield) at the C10 hydroxyl position to afford compound 25. The
carbonate ring opening was also performed on the C10-acetate
derivative 30, resulting in the formation of a mixture of 25 (70%)
1s
33
and the corresponding 10-deacetylderivative 31 (10%). Acetylation of the crude reaction mixture under standard conditions
followed by chromatographic purification afforded 25 in 80%
overall yield from 30. The resistance of the other carbonyl
moieties in these substrates to phenyllithium attack is, presumably, due to their steric shielding by the surrounding groups. In
addition to providing a clear path for some of the final steps in
the projected synthesis of Taxol (l), this chemistry was exploited
to deliver a variety of C2 analogs of the natural p r o d u ~ t . ~ ~ , ~ ~
IC
31
Attempts To Cleave the C9-C10 Bond of the Taxol

Skeleton. Preparation of Enone 26
With the Cl-C2 diol system protected and the C9-C10 site
free as a hydroxy ketone, as in compound 29 (Scheme 6), we
attempted the cleavage of the C9-C10 bond under a variety of
oxidative conditions. Unfortunately, however, none of these
methods (including Pb(OAc)4, Na104,53and Baeyer-Villiger/
h y d r ~ l y s i s ~led
~ ) to the expected aldehyde 32 (Scheme 6) or
any other cleavage product. Steric crowding is presumably
again responsible for this inertness. This phenomenon also
manifested itself in the reluctance of 7-TES-10-deacetylbaccatin
III (16) to enter in any cleavage process to afford 33 (Scheme
6) under similar conditions. In the reaction of 16 with
Pb(OAc)4, it was surprising to observe a 20% yield of the C13oxidized product, namely enone 31 (Scheme 6), in addition to
recovered starting material (60%). This selective oxidation (16
31) could be carried out more efficiently with TPAP-NM@*
in methylene chloride (96% yield). Subsequent hydrolysis (K2C03, MeOH, HzO, 0 "C) of the C2-benzoate from 31 provided
triol 26 in 93% yield. This sequence allows the conversion of
naturally occurring 10-deacetylbaccatinIII (2) to compound 26
in three steps and in 81% overall yield, avoiding the problematic
acetylation at C10.
(49) Haworth, W. N.; Porter, C. R. J . Chem. Soc. 1930, 151.

(50) Kutney, J. P.; Ratcliffe, A. H. Synth. Commun. 1975, 5, 47.
(51) Nicolaou, K. C.; Couladouros, E. A.; Nantermet, P. G.; Renaud, J.;
Guy, R. K.; Wrasidlo, Angew. Chem., Int. Ed. Engl. 1994, 33, 1581.
(52) Nicolaou, K. C.; Renaud, J.; Nantermet, P. G.; Guy, R. K.;
Couladouros, E. A.; Wrasidlo, W. Submitted.
(53) Shing, T. K. M. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Ley, S.V., FRS, Eds.; Pergamon Press: New York, 1991;
Vol. 7, p 708. Crimmins, M. T.; Jung, D. K.; Gray, J. L. J . Am. Chem.
Soc. 1993, 115, 3146.
(54) Krow, G. R. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Ley, S. V., FRS, Eds.; Pergamon Press: New York, 1991;
Vol. 7, p 671. Ogata, Y.; Sawaki, Y.; Shiroyama, M. J. Org. Chem. 1977,
42, 4061.
2s
"Reagents and conditions: (a) 15 equiv of Pb(OAc)4, MeOH,

50 OC; or excess of NaI04, MeOH, H20, 25 'C; or 2
benzene, 0
equiv of HzOz,8 equiv of NaOH, MeOH, HzO, 0 "C, 1.25 h; (b) 15
equiv of Pb(OAc)d, MeOH, benzene, 50 "C, 24 h; (c) 1.0 equiv of
4-methylmorpholine N-oxide (NMO), 0.05 equiv of tetrapropylammoCHzClz, 25 "C, 2 h, 96%; (d) 10 equiv of
nium permthenate (TPAP),
KzCO3, MeOH, H20,O OC, 2.5 h, 93% based on 81% conversion. TES
= SiEt3, BZ = COPh.
C13 Deoxygenation, Reoxygenation, and Side-Chain

Attachment
In order to delve further into our planned synthetic strategy,
we focused our efforts on the deoxygenation of the C13 position
and on its subsequent reoxygenation. The fust objective proved
rather problematic as initial attempts of Wolf-Kishner reductionJ5 of enone 25 (Scheme 5) and thioacetal formation/
reduction56of the same compound failed. A Barton deoxygenation5' was then considered. Although a C13 xanthate could
not be produced, strenuous conditions (excess (thiocarbony1)diimidazole and DMAP, 75 "C, 18 h) allowed the conversion
of 7-TES-baccatin 111 (17) to thiocarbamate 34 (Scheme 7) in
86% yield. Treatment of 34 with excess n-Bu3SnH in toluene
at 85 "C in the presence of a catalytic amount of AIBN provided
the desired C13 deoxy derivative 35 in 59% yield, together with
its A12J3regioisomer 36 (17% yield). Increasing the concentration of n-Bu3SnH in an attempt to trap the initially formed C13
radical before it rearranges to its C11 isomer, responsible for
the formation of the byproduct 36, did not change the ratio of
the two products.
The desired oxidation of the C13 allylic position22 to a
carbonyl function was demonstrated on intermediate 35 by
(55) Todd. Org. React. 1962, 12, 356.
(56) Van Tamelen. Org. React. 1948,4, 378. Dailey, 0. D., Jr. J. Org.
Chem. 1987,52, 1984. Corey, E. J.; Shimoji. Tetrahedron Lett. 1983, 24,
169.
(57) Barton, D. H. R.; McCombie, S. W. J . Chem. SOC.,Perkin Trans.
11975, 1574. Barton, D. H. R.; Dorchak, J.; Jaszberenyi Tetrahedron 1992,
48, 7435. Hartwig Tetrahedron 1983, 39, 2609.
Scheme 7. C13 Deoxygenation and Oxygenation"
1 7 7-TES baccatin 111
Scheme 8. Taxol's Side-Chain Attachment"
34
Ib
40: R = TES
41:R=EE
0
36
35
IC
42: R = TES
43: R = EE
0
37
1: Taxd
35
25
Reagents and conditions: (a) 20 equiv of (thiocarbonyl)diimidazole,

30 equiv of 4-(dimethylamino)pyridine (DMAP), THF,75 "C, sealed
tube, 18 h, 86%; (b) 10 equiv of n-BusSnH, 0.1 equiv of azobis(isobutyronitile) (AIBN), toluene, 85 "C, 2 h, 59% of 35 plus 17% of 36;(c)
20 equiv of KzC03, MeOH, THF, H20,O "C, 6 h, then -20 "C, 10 h,
94% based on 62% conversion; (d) 10 equiv of phosgene, pyridine, 25
"C, 15 min, 86%; (e) m-pyridine, THF, 25 "C, 2 h, 88%; (f) 50 equiv
of Et3SiC1, pyridine, 25 "C, 24 h, 85%; (g) 5 equiv of PhLi, THF,-78
OC, 15 min, 80%; (h) 30 equiv of pyridinium chlorochromate (PCC),
30 equiv of NaOAc, Celite, benzene reflux, 1 h, 75%. TES = SiEt3,
Bz = COPh.
exposure to pyridinium chlorochromate (PCC)58in the presence

of NaOAc and Celite in refluxing benzene to afford, in 75%
yield, enone 25 (Scheme 7).
The C13 deoxy intermediate 35 was converted to the
corresponding diol 37 (Scheme 7) via selective benzoate
hydrolysis (K2CO3, MeOH, H20, THF, 0 "C, 94% yield based
on 62% conversion). The carbonate ring was installed at the
Cl-C2 positions of the latter compound by the phosgenepyridine method,49 furnishing intermediate 38 in 86% yield.
Desilylation of the C7 hydroxyl group by exposure to
H F ~ y r i d i n eled
~ ~to 39, in 88% yield, a compound that was
projected as an advanced intermediate in our synthetic scheme.
Using the key intermediate 39 (Scheme 7), obtained from
10-deacetylbaccatin III(2) as described above, a sequence was
(58) Parish, E. J.; Wei, T. Y. Synrh. Commun. 1987.17,1227. Rathore,
R.; Saxena, N.; Chadrasekaran Synfh. Commun. 1986,16, 1493.
(59) Nicolaou, K. C.; Webber, S. E. Synthesis 1986,453.
Reagents and conditions: (a) excess NaBK, MeOH, 25 OC, 3 h,

94% based on 88% conversion; (b) for 42, 3 equiv of NaN(SiMe3)2, 3.5 equiv of B-lactam 40, THF,0 "C, 0.5 h, 86% based on
89% conversion; for 43, 2.5 equiv of NaN(SiMe&, 1.2 equiv of
B-lactam 41, THF, 0 "C, 20 min, 80% based on 54% conversion; (c)
for 42, HF-pyridine, THF, 25 "C, 1.25 h, 80%; for 43, EtOH, 0.5%
aqueous HC1, 0 "C, 72 h, 80%. TES = SiEt3, Bz = COPh, EE =
ethoxyethyl.
established toward Taxol (1) as follows: (a) silylation with

TESCl under standard condition^^^,^ to afford 38 (85% yield);
(b) carbonate ring opening with phenyllithium, as described
above, to convert 38 to 35 (80%yield, Scheme 7); (c) allylic
oxidation (75%); (d) stereoselective reduction of the enone
carbonyl of 25 with N a B b according to Potier's m e t h ~ d ~ ~ v ~ l
to provide 7-TES-baccatin 111 (17, Scheme 8) in 94% yield,
based on 88% conversion; and finally (e) attachment of the side
chain onto 17 using the Ojima-Holton p-lactam method20q21
(Scheme 8). To the latter end, both optically active p-lactams
40 and 41 were prepared according to Ojima's procedure and
coupled to 17 using NaN(SiMe3)z to provide the 2',7-diprotected
Taxol derivatives 42 and 43, respectively. Deprotection of 42
with H F ~ y r i d i n ein~ THF
~
furnished Taxol (1) in 80% yield,
whereas exposure of 43 to dilute HCl in EtOH61 led to the same
target (1) in a similar fashion (80%).
Conclusion
The chemistry described in this article shed light on the
chemical properties of Taxol (1) and its derivatives and opened
(60) Hart,T. W.; Metcalfe, D. A.; Scheinmann,F. J. Chem. SOC.,Chem.
Commun. 1979, 156. Roush, W. R.; Russo-Rodrigez, S. J. Org. Chem.
1987,52, 598.
(61) Ogilvie, K. K.; Thompson, E. A.; Quiliam, M. A,; Westmore, J. B.
Tetrahedron Left. 1974,2865.

access to a number of valuable taxoid intermediates. Specifically, it allowed the definition of a series of key intermediates
and of a track along which our total synthesis was to follow
(39 38 35 25 17 1). Furthermore, the easy access
to the 5-membered ring carbonate intermediate 29 developed
in this program was crucial to providing a practical entry into
a plethora of C2 analogs of Taxol (1)via nucleophilic opening
of the carbonate ring with a variety of reagents. The following
papers in this series describe the total synthesid6-18 of Taxol
(1)and a variety of its a n a l ~ g s . ~ l * ~ ~
- - - - -
Experimental Section
General Techniques. All reactions were canied out under an argon
atmosphere with dry, freshly distilled solvents under anhydrous
conditions, unless otherwise noted. Tetrahydrofuran (THF) and ethyl
ether (EtZO) were distilled from sodium-benzophenone, and methylene
chloride (CHzClz), benzene (PhH), and toluene from calcium hydride.
Yields refer to chromatographically and spectroscopically ('H NMR)
homogeneous materials, unless otherwise stated. All solutions used
in workup procedures are saturated unless otherwise noted. All reagents
were purchased at highest commercial quality and used without further
purification unless otherwise stated.
All reactions were monitored by thin-layer chromatography canied
out on 0.25 mm E. Merck silica gel plates (6OF-254) using W light
as visualizing agent and 7% ethanolic phosphomolybdic acid or
p-anisaldehyde solution and heat as developing agents. E. Merck silica
gel (60, particle size 0.040-0.063 mm) was used for flash column
chromatography.62 Preparative thin-layer chromatography (F'TLC)
separations were carried out on 0.25 or 0.50 mm E. Merck silica gel
plates (6OF-254).
N M R spectra were recorded on Brucker AMX-500 or AM-300
instruments and calibrated using residual undeuterated solvent as an
intemal reference. The following abbreviations were used to explain
the multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
band, several overlapping signals; b, broad. The carbon numbering of
Taxol (1)was used to assign protons. IR spectra were recorded on a
Perkin-Elmer 1600 series FT-IRspectrometer. Optical rotations were
recorded on a Perkin-Elmer 241 polarimeter. High-resolution mass
spectra (HRMS) were recorded on a VG ZAB-ZSE mass spectrometer
under fast atom bombardment (FAB) conditions. Melting points (mp)
are uncorrected, recorded on a Thomas Hoover capillary melting point
apparatus.
Experimental techniques and data for compounds 15, 16, 18, and
28 may be found in the supplementary material.
7-TES-baccatinIII (17). A. Silylation of 15 to 17. To a solution
of baccatin III (15,165 mg, 0.28 "01)
in pyridine (14 mL) was added
chlorotriethylsilane (1.42 mL, 8.45 m o l ) dropwise. The solution was
stirred at 25 "C for 24 h. After dilution with Et20 (100 mL), the
solution was washed with aqueous CuSO4 (3 x 20 mL) and brine (20
mL). The organic extract was dried (MgSOd), concentrated, and
50% EtOAc in
purified by flash chromatography (silica, 35
petroleum ether) to give 17 (168 mg, 85%) as a white solid.
B. Acetylation of 16 to 17. To a solution of 7-TES-10-deacetylbaccatin ID (16, 0.21 g, 0.318 m o l ) in pyridine (8 mL) at 0 "C was
added acetyl chloride (0.1 13 mL, 1.59 "01)
dropwise. The solution
was stirred at 0 "C for 48 h. After dilution with Et20 (20 mL), the
reaction was quenched with aqueous NaHCO3 (10 mL). The organic
layer was separated, washed with aqueous CuSO4 (2 x 10 mL) and
brine (5 mL), dried (MgSOd), concentrated, and purified by flash
chromatography (silica, 25 50% EtOAc in petroleum ether) to give
7-TES-baccatin LII (17, 183 mg, 82%) as a white solid.
C. Reduction of Enone 25 to 17. A solution of enone 25 (10 mg,
0.014 mmol) in MeOH (2 mL) was treated with an excess of N a B a
for 3 h at 25 "C. The reaction was quenched with aqueous NH&l(l
mL), and the resulting mixture was stirred at 25 "C for 15 min. After
dilution with water (5 mL), the reaction mixture was extracted with
CHzClz (3 x 10 mL). The combined organic layer was dried (Nazsod),concentrated, and purified by flash chromatography (silica, 25
50% EtOAc in petroleum ether) to give starting enone 25 (1.2 mg,
(62) Still, W. C.; Kahn,M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
Nicolaou et al.
12%) and 7-TES-baccatin IJJ (17, 8.3 mg, 94% based on 88%
conversion) as a white powder: Rj = 0.43 (silica, 50% EtOAc in
hexanes); [aIZZ~
-49 (c 0.4, MeOH); IR (thin film) vm 3518, 2914,
1723, 1448, 1237 cm-'; 'H N M R (500 MHz, CDCl3) 6 8.08 (d, J =
7.5 Hz,2 H, Bz), 7.58 (t, J = 7.4 Hz, 1 H, Bz), 7.46 (t, J = 7.4 Hz,
2 H, Bz), 6.44 (s, 1 H, 10-H), 5.61 (d, J = 7.0 Hz, 1 H, 2-H), 4.94 (d,
J = 9.5 Hz, 1 H, 5-H), 4.82 (m, 1 H, 13-H), 4.47 (dd, J = 10.5, 6.8
Hz,lH,7-H),4.28(AofAB,d,J=8.3H~,lH,20-H),4.12(Bof
AB, d, J = 8.3 Hz, 1 H, 20-H), 3.86 (d, J = 7.0 Hz, 1 H, 3-H), 2.51
(m, 1 H, 6-H), 2.27 (s, 3 H, OAc), 2.25 (m, 1 H, 14-H), 2.17 (s, 3 H,
OAc), 2.16 (s, 3 H, 18-CH3), 2.05 (m, 1 H, 14-H), 1.85 (m, 1 H, 6-H),
1.55 (s, 3 H, Ig-CHs), 1.17 (s, 3 H, 16-CH3), 1.02 (s, 3 H, 17-CH3),
0.90 (t, J = 8.0 Hz,9 H, Si(CHzCH3)3). 0.62-0.50 (band, 6 H, Si(CH2CH3)3); I3C N M R (125 MHz, CDCl3) 6 202.2, 171.0, 169.4, 167.1,
143.9, 133.6, 132.6, 130.1, 129.4, 128.6, 84.2, 80.8, 78.7, 76.5, 75.8,
74.7, 72.3, 67.9, 58.6, 47.2, 42.7, 38.2, 37.2, 26.8, 22.7, 21.0, 20.1,
15.0, 9.9, 6.7, 5.2; FAB H R M S (NBNCsI) d e 833.2339, M Csf
calcd for C37HszOllSi 833.2333.
Enone 25. A. Oxidation of Alcohol 17 to 25. To a solution of
7-TES-baccatin III (17,30 mg, 0.043 "01)
and 4-methylmorpholine
N-oxide (NMO, 7.5 mg, 0.064 "01)
in acetonitrile (5 mL) was added
4-A molecular sieves (20 mg), and the suspension was stirred at 25 "C
for 5 min. A catalytic amount of tetrapropylammonium permthenate
(TPAP) was added, and the reaction mixture was stirred at 25 "C for
1.5 h. The reaction mixture was concentrated, suspended in CHzClz
(20 mL), and filtered through silica gel. Elution with CHzClz (20 mL)
and 50% EtOAc in hexanes (20 mL), followed by concentration, gave
enone 25 (29 mg, 98%) as a white solid.
B. Conversion of Carbonate 30 to 25. A solution of carbonate
30 (17.6 mg, 0.028 "01)
in THF (2 mL) at -78 "C was treated with
PhLi (0.070 mL, 2 M in cyclohexane, 0.14 "01)
and stirred at -78
"C for 15 min. The reaction was quenched with aqueous NH&l (1
mL), and the resulting mixture was allowed to warm to 25 "C. After
dilution with Et20 (10 mL), the organic layer was separated, dried
(MgSOd), and concentrated to give hydroxy benzoate 25 containing
ca. 10% of the 10-deacetylated compound ('H NMR). The crude
mixture was dissolved in CHzClz (1.5 mL), treated with 4-(dimethy1amino)pyridine (DMAP, 61.0 mg, 0.50 mmol) and acetic anhydride
(0.024 mL, 0.25 mmol), and stirred at 25 "C for 1 h. The reaction
mixture was diluted with Et20 (10 mL), washed with 10% aqueous
HCl (5 mL), 10% aqueous NaOH (5 mL), and brine (5 mL), dried
(MgS04), concentrated, and purified by flash chromatography (silica,
25
50% EtOAc in petroleum ether) to give hydroxy benzoate 25
(15.9 mg, 80%) as a white solid.
C. Acetylation of Alcohol 31 to 25. To a solution of alcohol 31
(650 mg, 0.989 mmol) in CH2C12 (50 mL) were added 4-(dimethylamino)pyridine (DMAP, 600 mg, 4.9 "01)
and acetic anhydride (0.9
mL, 9.89 "01).
The solution was stirred at 25 "C for 2.5 h, the
reaction was quenched with aqueous NaHC03 (10 mL), and the
resulting mixture was diluted with Et20 (100 mL), washed with 10%
aqueous HCl (50 mL), 10% aqueous NaOH (50 mL), and brine (30
mL), dried (MgSOd), concentrated, and purified by flash chromatography (silica, 35% EtOAc in petroleum ether) to give acetate 25 (657
mg, 95%) as a white solid.
D. Allylic Oxidation of 35 to 25. A solution of 35 (1.3 mg, 0.0019
"01)
in benzene (0.5 mL) was treated with anhydrous NaOAc (4.7
mg, 0.057 mmol), anhydrous Celite (12.0 mg), and pyridinium
chlorochromate (12.0 mg, 0.056 m o l ) and stirred at reflux for 1 h.
The reaction mixture was filtered through silica gel, eluted with Et20
(20 mL), concentrated, and purified by preparative TLC (silica, 30%
Et20 in benzene) to give enone 25 (1.0 mg, 75%) as a film: Rj = 0.5
(silica, 50% EtOAc in hexanes); [aIz2~
- 19.8 (c 0.85, CHC13); IR
(thin film) vmax3499, 2956, 1758, 1732, 1673, 1657, 1604 cm-'; 'H
NMR(~~~MHZ,CDCI~)~~.O~(~,J=~.~H~,~H,B
7.5 Hz, 1 H, Bz), 7.47 (t, J = 7.8 Hz,2 H, Bz), 6.57 (s, 1 H, 10-H),
5.67 (d, J = 6.7 Hz, 1 H, 2-H), 4.90 (d, J = 8.4 Hz, 1 H, 5-H), 4.46
(dd, J = 10.4, 6.8 Hz, 1 H, 7-H), 4.31 (A of AB, d, J = 8.5 Hz, 1 H,
20-H), 4.09 (B of AB, d, J = 8.5 Hz, 1 H, 20-H), 3.89 (d, J = 6.7 Hz,
1 H, 3-H), 2.92 (A' Of A'B', d, J = 19.9 Hz, 1 H, 14-H), 2.63 (B' of
A'B', d, J = 19.9 Hz, 1 H, 14-H), 2.50 (m, 1 H, 6-H), 2.21 (s, 3 H,
OAc), 2.17 (s, 3 H, OAc), 2.16 (s, 3 H, 18-CH3), 1.82 (m, 1 H, 6-H),
1.65 (s, 3 H, 19-CH3), 1.25 (s, 3 H, 16-CH3), 1.17 (s, 3 H, 17-CH3),
J. Am. Chem. Soc., Vol. 117, No. 2, 1995 631
0.90 (t, J = 7.9 Hz,9 H, Si(CHzCH3)3), 0.65-0.45 (band, 6 H, Si(CH2CH3)3); 13C NMR (125 MHz, CDC13) 6 200.2, 198.3, 170.1, 168.9,
166.8, 153.0, 140.2, 133.9, 130.0, 128.8, 128.7, 83.9, 80.5,78.4, 76.1,
76.0, 72.8, 72.2, 59.4, 46.2, 43.4, 42.4, 37.1, 33.0, 21.7, 21.0, 18.2,
13.5, 9.5, 6.7, 5.1; FAB H R M S (NBA) m/e 699.3220, M Hf calcd
for C37H50011Si 699.3201.
Diol 26. A. Hydrolysis of 25 to 26. To a solution of enone 25
(124 mg, 0.034 mmol) in MeOH (29 mL) at 0 "C was added an aqueous
solution of KzC03 (291 mg in 7.3 mL HzO). The solution was stirred
at 0 "C for 4 h. The reaction was quenched with aqueous NH&1(30
mL), and the resulting mixture was extracted with CHC13 (2 x 50 mL).
The organic layer was dried (MgSOd), concentrated, and purified by
flash chromatography (silica, 25 50% EtOAc in petroleum ether) to
give triol 26 (96 mg, 91%) containing a small amount of the
10-acetylated product ('H NMR).
B. Hydrolysis of 31 to 26. To a solution of enone 31 (1.44 g,
2.19 mmol) in MeOH (300 mL) at 0 "C was slowly added an aqueous
solution of KzC03 (3.0 g in 32 mL of HzO). The solution was stirred
at 0 "C for 2.5 h. The reaction was quenched with aqueous NH&l
(150 mL), and the resulting mixture was extracted with CHzClz (2 x
200 mL). The organic layer was dried (NazSOd), concentrated, and
50% EtOAc in
petroleum ether) to give enone 31 (270 mg, 19%) and triol 26 (912
mg, 93% based on 81% conversion): Rj = 0.24 (silica, 50% EtOAc in
hexanes); [a]*%+38 (c 0.15, CHC13); IR (thin film) vmax3414, 2957,
2881, 1727, 1664, 1370 cm-'; IH NMR (500 MHz, CDC13) 6 5.23 (d,
J = 9.5 Hz, 1 H, 10-H), 4.89 (d, J = 9.5 Hz, 1 H, 5-H), 4.63 (A of
AB, d, J = 9.5 Hz, 1 H, 20-H), 4.56 (B of AB, d, J = 9.5 Hz, 1 H,
20-H), 4.32 (dd, J = 11.0, 7.0 Hz, 1 H, 7-H), 4.28 (d, J = 2.5 Hz, 1
H, 10-OH), 3.89 (dd, J = 6.5, 4.0 Hz, 1 H, 2-H), 3.57 (d, J = 6.5 Hz,
1 H, 3-H), 2.78 (A' of A'B', d, J = 19.5 Hz, 1 H, 14-H), 2.58 (d, 4.0
Hz, 1 H, 2-OH), 2.52 (B' of A'B', d, J = 19.5 Hz, 1 H, 14-H), 2.46
(m. 1 H, 6-H), 2.03 (s, 3 H, OAc), 1.88 (m, 1 H, 6-H), 1.68 (s, 3 H,
18-CH3), 1.21 ( s , 3 H, 16-CH3), 1.04 ( s , 3 H, I"-CHs), 0.90 (t, J = 8.0
Hz,9 H, Si(CHzCH&), 0.60-0.40 (band, 6 H, Si(CHzCH&); 13CNMR
(125 MHz, CDC13) 6 208.9, 198.5, 170.1, 156.7, 138.8, 83.8, 81.2,
77.6, 75.7, 72.8, 72.5, 58.8, 45.8, 43.1, 42.8, 37.3, 32.7, 21.6, 17.5,
13.6, 9.7, 6.7, 5.1; FAB H R M S (NBA/NaI) m/e 575.2648, M Na+
calcd for CzgH4409Si 575.2652.
Carbonate 29. Method A. To a solution of diol 26 (96.0 mg,
0.187 mmol) in pyridine (10 mL) at 0 "C was added phosgene (0.97
mL of a 1.93 M solution in toluene, 1.87 mmol). The solution was
stirred at 0 "C for 0.5 h and poured onto ice (10 mL). After dilution
with Et20 (25 mL), the organic layer was separated, washed with
aqueous CuSO4 (2 x 15 mL) and aqueous NaHC03 (20 mL), dried
(MgS04), and concentrated to give carbonate 29 (86 mg, 85%) as an
amorphous solid.
Method B. A solution of diol 26 (60.0 mg, 0.109 mmol) in THF
(2 mL) was treated with carbonyldiimidazole (1 10.0 mg, 0.678 m o l )
and stirred at 40 "C for 0.5 h. The reaction mixture was concentrated
and redissolved in THF (5 mL). TLC analysis confmed total
consumption of starting material. Then 1 N aqueous HCl(5 mL) was
added, and the resulting solution was allowed to stir for 15 min at 25
OC. Et20 (25 mL) was added, and the organic layer was separated,
washed with aqueous NaHCO3 (10 mL) and brine (10 mL), dried
(MgS04), and concentrated to give carbonate 29 (58 mg, 93%) as a
white foam: Rf = 0.50 (silica, 35% EtOAc in hexanes); [alZZ~
+48 (c
0.5, CHCh); IR (thin film) vmax3438, 2957, 2882, 1820, 1731, 1685,
1370, 1236 cm-'; 'H NMR (500 MHz, CDC13) 6 5.27 (d, J = 2.5 Hz,
1 H, 10-H), 4.89 (d, J = 9.0 Hz, 1 H, 5-H), 4.60 (A of AB, d, J = 9.0
Hz, 1 H, 20-H), 4.45 (B of AB, d, J = 9.0 Hz, 1 H, 20-H), 4.43 (d, J
= 6.0 Hz, 1 H, 2-H), 4.33 (dd, J = 10.0, 7.5 Hz, 1 H, 7-H), 4.28 (d,
J = 2.5 Hz, 1 H, lO-OH), 3.54 (d, J = 6.0 Hz, 1 H, 3-H), 2.88 (A' of
AB', d, J = 20.0 Hz, 1 H, 14-H), 2.75 (B' of A'B', d, J = 20.0 Hz, 1
H, 14-H), 2.50 (m, 1 H, 6-H), 2.08 (s, 3 H, OAc), 2.06 (s, 3 H, 18CH,), 1.88 (m, 1 H, 6-H), 1.77 (s, 3 H, 19-C&), 1.31 (s, 3 H, 16CH3), 1.15 (s, 3 H, 17-CH3), 0.88 (t. J = 8.5 Hz,9 H, Si(CHzCH&),
0.55-0.45 (band, 6 H, Si(CHzCH&); 13CNMR (125 MHz, CDC13) 6
208.4, 195.5, 170.5, 154.0, 152.0, 141.2, 88.4, 83.9, 79.8, 79.0, 76.7,
75.7, 71.9, 60.3, 43.0,41.6, 39.8, 37.7, 31.6, 21.5, 17.8, 14.4,9.7, 6.6,
5.0; FAB HRMS (NBA) m/e 579.2652, M H+ calcd for CZ~&ZO~OSi 579.2626.
Acetate 30. To a solution of carbonate 29 (86.0 mg, 0.159 mmol)

in CHzClz (2 mL) were added 4-(dimethy1amino)pyridine (DMAP,
177.0 mg, 1.45 mmol) and acetic anhydride (0.069 mL, 0.723 mmol).
The solution was stirred at 25 "C for 0.5 h, diluted with Et20 (100
mL), washed with 10% aqueous HCl(5 mL), 10% aqueous NaOH (5
mL) and brine (5 mL), dried (MgSOd), concentrated, and purified by
flash chromatography (silica, 10 50% EtOAc in petroleum ether) to
give carbonate 30 (94 mg, 95%) as an amorphous solid Rj = 0.50
(silica, 35% EtOAc in hexanes); [alZz~
+14 (c 0.5, CHC13); IR (thin
film) vmax2926, 1823, 1754, 1731, 1689 cm-'; 'H NMR (500 MHz,
CDCl3) 6 6.52 (s, 1 H, IO-H), 4.89 (d, J = 9.0 Hz, 1 H, 5-H), 4.60 (A
of AB, d, J = 9.0 Hz, 1 H, 20-H), 4.48 (d, J = 5.5 Hz,1 H, 2-H), 4.45
(B of AB, d, J = 9.0 Hz, 1 H, 20-H), 4.42 (dd, J = 9.5, 7.0 Hz, 1 H,
7-H), 3.49 (d, J = 5.5 Hz,1 H, 3-H), 2.90 (A' of AB', d, J = 20.0 Hz,
1 H, 14-H), 2.78 (B' of A'B', d, J = 20.0 Hz, 1 H, 14-H), 2.55 (m, 1
H, 6-H), 2.19 (s, 3 H, OAC), 2.16 (s, 3 H, OAC), 2.07 ( s , 3 H, 18CH3), 1.87 (m, 1 H, 6-H), 1.71 (s, 3 H, 19-CH3), 1.28 (s, 3 H, 16CH3), 1.26 (s, 3 H, 17-CH3), 0.89 (t, J = 8.0 Hz, 9 H, Si(CHzCH&),
0.60-0.50 (band, 6 H, Si(CHzCH3)3); 13C NMR (125 MHz, CDCl,) 6
200.2, 195.7, 170.5, 168.7, 152.0, 150.4, 142.5, 88.2, 83.9, 79.8, 79.2,
76.6, 75.7, 71.5, 61.0, 43.1, 39.8, 37.7, 31.6, 21.5, 20.7, 18.4, 14.4,
9.7, 6.7, 5.1; FAB H R M S (NBA) m/e 621.2745, M Hf calcd for
C~lH44011Si621.273 1.
Enone 31. A. Oxidation of 16 to 31. To a solution of 7-TESdeacetylbaccatin 111 (16,1.5 g, 2.28 mmol) and 4-methylmorpholine
N-oxide (NMO, 240 mg, 2.05 mmol) in CHzClz (5 mL) was added
4-A molecular sieves (200 mg), and the suspension was stirred at 25
"C for 10 min. A catalytic amount of tetrapropylammonium permthenate (TPAP, 40 mg, 0.11 mmol) was added by portions, and the
reaction mixture was stirred at 25 "C for 0.5 h. Small amounts of
4-methylmorpholine N-oxide and TPAP were added altematively at
0.5 h intervals until the starting material was consumed to the extent
of ca. 95% by TLC. The reaction mixture was filtered through silica
gel, eluted with CHzClz (100 mL), and concentrated to give enone 31
(1.44 g, 96%) as a white solid.
29 (1.5 mg, 0.0026 mmol) in THF (0.3 mL) at -78 "C was treated
with PhLi (0.013 mL, 0.026 mmol) and stirred at -78 "C for 0.5 h.
The reaction was quenched with aqueous W C l (10 mL). After
dilution with Et20 (20 mL), the organic layer was separated, washed
with brine (10 mL), dried (NazSOd), and purified by flash chromatography (silica, 25
35% EtOAc in petroleum ether) to give hydroxy
benzoate 31 (1.4 mg, 85%) as a film: Rf = 0.5 (silica, 50% EtOAc in
hexanes); [a]*'D +11 (c 0.56, CHC13); IR (thin film) vm 3446, 2957,
2882, 1726, 1672, 1456, 1367, 1243, 1106 cm-'; IH NMR (500 MHz,
CDC13) 6 8.05 (dd, J = 8.0, 1.0 Hz, 2 H, Bz), 7.61 (t, J = 7.5 Hz, 1
H, Bz), 7.45 (t, J = 7.5 Hz, 2 H, Bz), 5.63 (d, J = 7.5 Hz, 1 H, 2-H),
5.30 (d, J = 2.0 Hz, 1 H, 10-H), 4.90 (d, J = 8.0 Hz, 1 H, 5-H), 4.36
20-H), 4.30 (d, J = 2.0 Hz, 1 H, 10-OH), 4.11 (B of AB, d, J = 8.5
Hz, 1 H, 20-H), 3.93 (d, J = 7.5 Hz, 1 H, 3-H), 2.92 (A' of A'B', d,
J = 19.5 Hz, 1 H, 14-H), 2.62 (B'of A'B', d, J = 19.5 Hz, 1 H, 14-H),
2.46 (m, 1 H, 6-H), 2.17 (s, 3 H, OAc), 2.08 (s, 3 H, 18-CH3), 1.87
(m, 1 H, 6-H), 1.77 (s, 1 H, 1-OH), 1.70 (s, 3 H, 19-CH3), 1.21 (s, 3
H, 16-CH3), 1.14 ( s , 3 H, 17-CH3), 0.90 (t, J = 8.0 Hz, 9 H,
Si(CHzCH3)3), 0.60-0.42 (band, 6 H, Si(CHzCH3)3); 13C NMR (125
MHz, CDC13) 6 208.2, 198.1, 170.2, 166.8, 156.6, 139.1, 134.0, 130.0,
128.8, 128.8, 84.0, 80.4, 78.5, 76.2, 75.7, 72.9, 72.8, 58.8, 45.9, 43.4,
42.5, 37.2, 33.0, 21.7, 17.5, 13.6, 9.6, 6.7, 5.1; FAB HRMS (NBA/
NaI) d e 657.3070, M Na+ calcd for C35&g010Si 657.3095.
Thiocarbamate 34. A solution of 7-TES-baccatin I11 (17,48 mg,
0.069 mmol) in THF (1 mL) was treated with 4-(dimethylamino)pyridine (DMAP, 251 mg, 2.05 mmol) and (thiocarbony1)diimidazole
(244 mg, 1.37 mmol) and stirred at 75 "C in a sealed flask for 18 h.
The reaction mixture was diluted with EtOAc (15 mL), washed with
10% aqueous HC1 (5 mL) and aqueous NaHC03 (10 mL), dried
20
50% EtOAc in petroleum ether) to give thiocarbamate 34 (48
ing, 86%) as a white solid Rf = 0.27 (silica, 25% EtOAc in benzene);
-59 ( C 0.17, CHCls); IR (thin film) v,, 3478,2954,1726, 1465,
1388, 1284, 1238, 1104 cm-'; 'H NMR (500 MHz, CDC13) 6 8.50 (s,
1 H, imid.), 8.01 (d, J = 7.5 Hz, 2 H, Bz), 7.79 (s, 1 H, imid.), 7.56
632 J. Am. Chem. SOC.,Vol. 117, No. 2, 1995

(t, J = 7.5 Hz, 1 H, Bz), 7.42 (t. J = 7.5 Hz, 2 H, Bz), 7.10 (s, 1 H,
imid.), 6.53 (t, J = 9.0 Hz, 1 H, 13-H), 6.46 (s, 1 H, 10-H), 5.66 (d,
J = 7.0 Hz, 1 H, 2-H), 4.89 (d, J = 8.5 Hz, 1 H, 5-H), 4.46 (dd, J =
10.5, 7.0 Hz, 1 H, 7-H), 4.25 (A of AB, d, J = 8.5 Hz, 1 H, 20-H),
4.13 (B of AB, d, J = 8.5 Hz, 1 H, 20-H), 3.85 (d, J = 7.0 Hz, 1 H,
3-H), 2.72 (dd, J = 15.0, 9.0 Hz, 1 H, 14-H), 2.53 (m, 1 H, 6-H), 2.21
(s, 3 H, OAc), 2.17 (s, 3 H, OAc), 2.12 (dd, J = 15.0, 7.5 Hz, 1 H,
14-H), 1.91 (s, 3 H, 18-CH3), 1.88 (m, 1 H, 6-H), 1.65 (s, 3 H, 19CH3), 1.25 (s, 3 H, 16-CH3), 1.17 (s, 3 H, 17-CH3), 0.91 (t, J = 8.0
Hz,9 H, Si(CHzCH3)3), 0.62-0.51 (band, 6 H, Si(CHzCH,)3); 13CN M R
(125 MHz, CDCl3) 6 201.5, 183.5, 170.0, 169.3, 166.9, 138.7, 137.7,
134.8, 133.8, 131.3, 130.0, 128.9, 128.6, 118.3, 84.1, 81.3, 80.1, 78.9,
76.6, 75.0, 74.3, 72.5, 58.9, 46.8, 43.3, 37.4, 35.0, 29.7, 26.9, 21.9,
20.9, 20.3, 15.4, 9.9, 6.7, 5.2; FAB H R M S (NBA/NaI) d e 833.3110,
M Naf calcd for C41H5401lN~SSi833.3115.
Benzoate 35. A. Deoxygenation of 34 to 35. To a solution of
thiocarbamate 34 (960 mg, 1.18 mmol) in degased toluene (250 mL)
stirred at 85 "C were added tributyltin hydride (3.2 mL, 11.8 "01)
and azobis(isobutyronitri1e) (AIBN, 16.4 mg in 1 mL of toluene, 0.1
mmol). The reaction mixture was stirred at 85 "C for 2 h, concentrated,
and purified by flash chromatography (silica, 15
25% EtOAc in
petroleum ether) to give a mixture of alcohol 35 and isomer 36 (620
mg, 76%) as one single fraction containing 77% of 35 (59% yield)
and 23% of 36 (17% yield). Analytical samples of both isomers were
obtained by preparative TLC (silica, 30% EtOAc in benzene).
Isomer 35: Rf= 0.47 (silica, 25% EtOAc in benzene); [alZz~
-50.6
(c 0.5, CHC13); IR (thin film) vmax3517,2922, 1728, 1456, 1371, 1242,
1109 cm-'; 'H NMR (500 MHz, CDC13) 6 8.06 (d, J = 8.0 Hz, 2 H,
Bz), 7.58 (t, J = 7.5 Hz, 1 H, Bz), 7.45 (t, J = 7.5 Hz, 2 H, Bz), 6.45
(s, 1 H, 10-H), 5.59 (d, J = 7.0 Hz, 1 H, 2-H), 4.95 (d, J = 9.0 Hz, 1
H, 5-H), 4.45 (dd, J = 10.5, 7.0 Hz, 1 H, 7-H), 4.30 (A of AB, d, J =
8.5 Hz, 1 H, 20-H), 4.14 (B of AB, d, J = 8.5 Hz, 1 H, 20-H), 3.75 (d,
J = 7.0 Hz, 1 H, 3-H), 2.65 (m, 1 H, 13-H), 2.53 (m, 1 H, 13-H), 2.30
(s, 3 H, OAC),2.30-2.17 (band, 2 H, 6-CH2), 2.16 (s, 3 H, OAc), 2.07
(s, 3 H, 18-CH3), 1.93-1.81 (band, 2 H, 14-CH2), 1.64 (s, 3 H, 19CH3). 1.18 (s, 3 H, 16-CH3), 1.04 (s, 3 H, 17-C&), 0.89 (t, J = 8.0
Hz, 9 H, Si(CHtCH&), 0.65-0.49 (band, 6 H, Si(CHzCH3)3); 13CN M R
(125 MHz, CDCl3) 6 202.5, 169.8, 169.5, 167.0, 141.6, 133.6, 132.3,
130.0, 129.3, 128.6, 84.0, 81.4, 80.6, 76.5,75.9,73.8,72.4,58.8,46.8,
42.2, 37.4, 30.0, 26.7, 25.2, 22.1, 21.1, 20.5, 19.0, 9.6, 6.7, 5.3; FAB
HRMS (NBNCsI) m/e 817.2380, M
Csf calcd for C37H52010Si
817.2384.
Isomer 36: Ry = 0.48 (silica, 25% EtOAc in benzene); 'H NMR
(500 MHz, CDC13) 6 8.04 (d, J = 7.0 Hz, 2 H, Bz), 7.58 (t, J = 7.5
Hz, 1 H, Bz),7.47 (t, J = 7.5 Hz, 2 H, Bz), 5.96 (s, 1 H, 10-H), 5.48
(dd, J = 5.0, 1.5 Hz, 1 H, 2-H), 5.45 (m, 1 H, 13-H), 4.98 (dd, J =
8.3, 1.9Hz, l H , 5 - H ) , 4 . 3 9 ( A o f A B , d , J = 8 . 5 H z , 1H,20-H),4.35
(dd, J = 10.4, 6.5 Hz, 1 H, 7-H), 4.25 (B of AB, d, J = 8.5 Hz, 1 H,
20-H), 4.00 (d, J = 5.0 Hz, 1 H, 3-H), 2.72 (m, 1 H, 14-H), 2.48 (m,
1 H, 6-H), 2.29 (s, 3 H, OAC), 2.16 (s, 3 H, OAC), 2.05-1.93 (band,
2 H, 6-H and 14-H), 1.89 (s, 3 H, 18-CH3), 1.60 (s, 3 H, 19-C&),
1.23 (s, 3 H, 16-CH3),1.07 (s, 3 H, 17-C&), 0.88 (t, J = 8.0 Hz,9 H,
Si(CH2CH3)3), 0.65-0.49 (band, 6 H, Si(CH&H&).
38 (1 mg, 0.0016 "01)
in THF (1 mL) at -78 "C was treated with
PhLi (0.016 mL, 2 M in cyclohexane, 0.008 mmol) and stirred at -78
"C for 15 min. The reaction was quenched with aqueous W C l (2
mL). After dilution with Et20 (10 mL), the organic layer was separated,
dried (MgSOd), concentrated, and purified by preparative TLC (silica,
25% Et20 in benzene) to give benzoate 35 (0.9 mg, 80%) as a colorless
film.
Diol 37. To a mixture of benzoates 35 and 36 (71.8 mg, 0.105 mmol,
ca. 77:23) in MeOH (13.5 mL) and THF (3.6 mL) at 0 "C was added
an aqueous solution of KzCO3 (270 mg in 3.5 mL of H20). The solution
was stirred at 0 "C for 6 h and at -20 OC for 10 h. The reaction was
quenched with aqueous W C l ( 2 0 mL), and the resulting mixture was
extracted with CHC13 (2 x 100 mL). The organic layer was dried
(MgSOd), concentrated, and purified by flash chromatography (silica,
20
40% EtOAc in petroleum ether) to give the benzoate mixture
35/36 (27 mg, 38%) and diol 37 (27 mg, 94% based on 62%
conversion): R f = 0.18 (silica, 50% EtOAc in hexanes);
-43.6
(c 0.28, CHCl3); IR (thin film) vmiu 3479, 2923, 1721, 1461, 1372,
Nicolaou et al.
1237 cm-I; 'H NMR (500 MHz, CDC13) 6 6.38 (s, 1 H, 10-H), 4.95
20-H), 4.55 (B of AB, d, J = 9.0 Hz, 1 H, 20-H), 4.40 (dd, J = 10.5,
7.0 Hz, 1 H, 7-H), 3.83 (dd, J = 6.5, 4.5 Hz, 1 H, 2-H), 3.38 (d, J =
6.5 Hz, 1 H, 3-H), 2.69-2.58 (band, 1 H, 13-H), 2.54 (d, 4.5 Hz,1 H,
2-OH), 2.51 (m, 1 H, 6-H), 2.16 (s, 3 H, OAc), 2.14 (s, 3 H, OAc),
2.13-2.01 (band, 1 H, 13-H), 2.01 (s, 3 H, 18-CH3), 1.92-1.83 (band,
2 H, 14-CH2), 1.78 (m, 1 H, 6-H), 1.62 (s, 3 H, 19-C&), 1.07 (s, 3 H,
16-CH3), 1.05 (s, 3 H, 17-C&), 0.88 (t, J = 7.5 Hz,9 H, Si(CHzCH&),
0.61-0.48 (band, 6 H, Si(CH2CHs)s); FAB HRMS (NBA/NaI) m/e
603.2970, M -t Naf calcd for C3&809Si 603.2965.
Carbonate 38. A. Conversion of Diol 37 to Carbonate 38. To
a solution of diol 37 (16 mg, 0.028 "01)
in pyridine (2 mL) at 25 "C
was added phosgene (0.143 mL of a 1.93 M solution in toluene, 0.28
m o l ) . The solution was stirred at 25 "C for 15 min. After dilution
with Et20 (20 mL), the organic layer was separated, washed with
aqueous CuSO4 (3 x 10 mL) and aqueous NaHC03 (10 mL), dried
(MgSOd), concentrated, and purified by flash chromatography (silica,
10 35% EtOAc in petroleum ether) to give carbonate 38 (14.4 mg,
86%) as a white foam.
B. Silylation of 39 to 38. A solution of alcohol 39 (1.0 mg, 0.002
m o l ) in pyridine (0.5 mL) was treated with chlorotriethylsilane
(TESCl, 0.017 mL, 0.1 m o l ) and stirred at 25 "C for 24 h. After
dilution with Et20 (10 mL), the organic layer was separated, washed
with aqueous CuSO4 (3 x 5 mL), dried (MgSOd), concentrated, and
35% EtOAc in
petroleum ether) to give carbonate 38 (1.0 mg, 85%) as a colorless
film: Rf= 0.82 (silica, 50% EtOAc in hexanes); [ a ] " ~-49.4 (c 0.93,
CHCb); IR (thin film),v 2924, 1814, 1728,1461, 1372,1238 cm-I;
'H NMR (500 MHz, cDc13) 6 6.40 (s, 1 H, 10-H), 4.95 (d, J = 9.0
Hz, 1 H, 5-H), 4.60 (A of AB, d, J = 9.0 Hz, 1 H, 20-H), 4.47 (B of
AB, d, J = 9.0 Hz, 1 H, 20-H), 4.43 (dd, J = 10.0,7.5 Hz, 1 H, 7-H),
4.39 (d, J = 5.5 Hz, 1 H, 2-H), 3.36 (d, J = 5.5 Hz, 1 H, 3-H), 2.71
(m, 1 H, 13-H), 2.56 (m, 1 H, 13-H), 2.17 (s, 3 H, OAc), 2.15 (s, 3 H,
OAc), 2.12 (m. 1 H), 2.07 (s, 3 H, 18-CH3), 1.97 (m, 1 H), 1.88 (m, 2
H), 1.78 (s, 3 ,H, 19-CH3), 1.23 (s, 3 H, 16-CH3), 1.17 (s, 3 H, 17CH,), 0.88 (t, J = 7.5 Hz,9 H, Si(CH2CH3)3), 0.60-0.50 (band, 6 H,
Si(CHzCH&); 13C N M R (125 MHz, CDC13) 6 202.6, 170.3, 169.2,
153.1, 144.0, 130.7, 92.8, 84.0, 80.3, 80.0,76.4,76.1,60.3,43.5,38.0,
29.7,29.4,25.5,23.1,21.9,21.1,19.1,9.8,6.7,5.2;FABHRMS(NBN
CsI) d e 739.1929, M Cs+ calcd for C31&010Si 739.1915.

Alcohol 39. A solution of silyl ether 38 (3.0 mg,0.0049 "01)
in
THF (1.5 mL) was treated with HF-pyridine (0.5 mL) and stirred for 2
h at 25 "C. The reaction mixture was diluted with EtOAc (10 mL),
and the reaction was quenched with aqueous NaHC03 (10 mL). The
organic layer was separated, washed with 10% aqueous NaOH (10 mL)
and brine (10 mL), dried (MgSOd), and purified by preparative TLC
(silica, 30% EtOAc in petroleum ether) to give alcohol 39 (2.1 mg,
88%) as a colorless film: Rf = 0.22 (silica, 50% EtOAc in petroleum
-23 (c 1.0, CHC13); IR (thin film) vmax2923,2854, 1809,
ether); [a12%
1723, 1460, 1374, 1238, 1018 cm-'; 'H NMR (500 MHz, CDC13) 6
6.25 (s, 1 H, 10-H), 4.94 (d, J = 8.0 Hz, 1 H, 5-H), 4.56 (A of AB, d,
J = 9.0 Hz, 1 H, 20-H), 4.41 (B of AB, dd, J = 9.0, 0.5 Hz, 1 H,
20-H), 4.38 (m, 1 H, 7-H), 4.31 (d, J = 5.5 Hz, 1 H, 2-H), 3.33 (d, J
= 5.5 Hz, 1 H, 3-H), 2.73 (m, 1 H, 13-H), 2.57 (m, 1 H, 6-H), 2.28 (d,
J 4.0 Hz, 1 H, OH), 2.15 (s, 3 H, OAc), 2.13 (s, 3 H, OAc), 2.122.02 (band, 2 H, 14-CH2), 1.94 (d, J = 1.0 Hz,3 H, 18-CH3), 1.951.80 (band, 2 H, 13-H and 6-H), 1.65 (s, 3 H, 19-CH3), 1.18 (s, 3 H,
16-CH3), 1.08 (s, 3 H, 17-CH3); 13CNMR (125 MHz, CDCl3) 6 204.3,
170.9, 170.2, 153.0, 146.4,92.8,84.2, 80.4,76.7,75.9,71.5,60.3,43.0,
36.4, 31.0, 29.7, 29.6, 25.5, 23.2, 21.9, 21.6, 20.9, 19.0, 9.2.
2',7-diTES-Taxol (42). To a solution of 7-TES-baccatin III (17,
20.0 mg, 0.0285 "01)
and B-lactam 40 (38 mg, 0.0998 mmol) in
THF (1.5 mL) at 0 "C was added NaN(SiMe& (0.086 mL of a 1.0 M
solution in THF, 0.086 "01)
dropwise. The reaction mixture was
stirred at 0 "C for 0.5 h, and the reaction was quenched with aqueous
m C 1 (2 mL). After dilution with Et20 (15 mL), the organic layer
was separated, washed with brine (5 mL), dried (MgSOd), concentrated,
50% EtOAc in
petroleum ether) to give starting material 17 (2.2 mg, 11%) and 2',7diTES-Taxol(42) (23.7 mg, 86% based on 89% conversion) as a white
solid: Rf = 0.59 (silica, 50% EtOAc in hexanes); [a]22D-48 (c 0.4,
Total Synthesis of Taxol. I
CHCl3); IR (thin film)Y,, 3440, 2958, 1719, 1664 cm-'; 'H NMR
(500 MHz, CDC13) 6 8.11 (d, J = 7.0 Hz, 2 H, Bz), 7.72 (d, J = 7.5
Hz, 2 H, Bz), 7.60-7.25 (band, 11 H, Ar), 7.11 (d, J = 9.0 Hz,1 H,
NH), 6.43 (s, 1 H, 10-H), 6.22 (b t, J = 8.5 Hz, 1 H, 13-H), 5.69 (m,
2 H, 3'-H and 2-H), 4.93 (b d, J = 8.0 Hz, 1 H, 5-H), 4.69 (d, J = 2.0
lH,7-H),4.31(AOfAB,d,J=8.5H~,lH,20-H),4.19(BofAB,
d, J = 8.5 Hz, 1 H, 20-H), 3.79 (d, J = 7.0 Hz, 1 H, 3-H), 3.61 (d, J
= 5.5 Hz, 1 H, 2'-OH), 2.55 (m, 1 H, 6-H), 2.49 (d, J = 4.0 Hz, 1 H,
7-OH), 2.39 (s, 3 H, OAC), 2.40-2.25 (band, 2 H, 14-CHz), 2.24 ( s , 3
H, OAc), 1.88 (m, 1 H, 6-H), 1.82 (s, 1 H, 1-OH), 1.79 (s, 3 H, 18H~,lH,2'-H),4.45(dd,J=11.0,7.0H~,lH,7-H),4.30(AofAB,
CH3), 1.69 (S, 3 H, 19-CH3), 1.24 (s, 3 H, 16-CH3), 1.14 ( s , 3 H, 17d, J 8.5 Hz, 1 H, 20-H), 4.19 (B of AB, d, J = 8.5 Hz, 1 H, 20-H),
CH3); I3CN M R (125 MHz, CDC13) 6 203.6, 172.7, 171.3, 170.4, 167.0,
3.82 (d, J = 7.0 Hz, 1 H, 3-H), 2.53 ( s , 3 H, OAC), 2.38 (dd, J = 9.5,
167.0, 142.0, 137.9, 133.7, 133.6, 133.1, 132.0, 130.2, 129.1, 129.0,
15.0 Hz, 1 H, 14-H), 2.18 (s, 3 H, OAC), 2.12 (dd, J = 15.0, 8.0 Hz,
128.7, 128.7, 128.4, 127.1, 127.0, 84.4, 81.1, 79.0, 76.5, 75.5, 74.9,
1 H, 14-H), 2.00 (s, 3 H, 18-CH3). 1.89 (m, 2 H, 6-CHz), 1.68 (s, 3 H,
73.2, 72.3, 72.2, 58.6, 55.0, 45.6, 43.1, 35.6, 35.6, 26.8, 22.6, 21.8,
19-CH3), 1.20 (s, 3 H, 16-CH3), 1.16 (s, 3 H, 17-CH3),0.89 (t, J = 8.0
20.9, 14.9, 9.5; FAB HFWS (NBA) mle 854.3360, M H+ calcd for
Hz, 9 H, Si(CHzCH&), 0.80 (t, J = 8.0 Hz, 9 H, Si(CHzCH&), 0.62C47H51014N 854.3388.
0.51 (band, 6 H, Si(CHzCH3)3), 0.51-0.35 (band, 6 H, Si(CHzCH&);
'3CNMR(125MH~,CDcb)6201.7,
170.1, 169.3, 167.2, 167.0, 140.1,
Acknowledgment. We thank Dr. E. Bombardelli for a
138.3, 134.2, 133.7, 133.6, 131.8, 130.2, 130.1, 129.2, 128.7, 128.3,
generous gift of 10-deacetylbaccatin III and Drs. Dee H. Huang
127.9, 127.0, 126.4, 84.2, 81.2, 78.7,76.6, 75.0,74.9, 74.8,72.2, 71.5,
and Gary Siuzdak for NMR and mass spectroscopic assistance,
58.4, 55.7, 46.6, 43.3, 37.2, 35.5, 26.5, 23.1, 21.5, 20.9, 14.1, 10.1,
respectively. This work was financially supported by NIH, The
6.7, 6.5, 5.3, 4.3; FAB HRMS (NBA/CsI) mle 1214.4089, M Cs+
calcd for C59H79014NSi~1214.4093.
Scripps Research Institute, fellowships from Mitsubishi Kasei
Taxol (1). A solution of silyl ether 42 (22 mg, 0.020 m o l ) in
Corporation (H.U.), Rh8ne-Poulenc Rorer (P.G.N.), The Office
THF (1 mL) was treated with HFTyridine (0.2 mL) and stirred for
of Naval Research (R.K.G.), The Agricultural University of
1.25 h at 25 "C. The reaction mixture was diluted with Et20 (15 mL),
Athens (E.A.C.), R.W. Johnson-ACS Division of Organic
and the reaction was quenched with aqueous NaHCO3 (5 mL). The
Chemistry (E.J.S.), and grants from Merck Sharp & Dohme,
organic layer was separated, washed with aqueous CuS04 (2 x 5 mL)
Pfizer, Inc., Schering Plough and the ALSAM Foundation.
and brine (5 mL), dried (Na~S04),and purified by flash chromatography
(silica, 50
75% EtOAc in petroleum ether) to give Taxol (1, 13.9
Supplementary Material Available: Experiment techniques
mg, 80%) as a white solid Rf= 0.125 (silica, 50% EtOAc in hexanes);
-49 (c 0.45, MeOH); IR (thinfilm)vmax3432,2937,1720, 1652,
and data for compounds 15, 16, 18, and 28 (3 pages). This
1520, 1241 cm-I; 'H NMR (500 MHz, CDC13) 6 8.13 (dd, J = 8.5,
material is contained in many libraries on microfiche, im1 . 2 H z , 2 H , B z ) , 7 . 7 4 ( d d , J = 8 . 2 , 1.2Hz,2H,Bz),7.62,(t,J=7.5
mediately follows this article in the microfilm version of the
Hz, 1 H, Bz), 7.52-7.32 (band, 7 H, Ar), 7.02 (d, J = 9.0 Hz, 1 H,
journal, and can be ordered from the ACS: See any current
NH), 6.27 (s, 1 H, 10-H), 6.23 (b t, J = 9.0 Hz, 1 H, 13-H), 5.79 (dd,
masthead page for ordering information.
J = 9.0, 2.5 Hz, 1 H, 3'-H), 5.67 (d, J = 7.0 Hz, 1 H, 2-H), 4.95 (b d,
J = 8.0 Hz, 1 H, 5-H), 4.79 (dd, J = 2.5, 5.5 Hz, 1 H, 2'-H), 4.40 (m,
JA9421922
634
J. Am. Chem. SOC. 1995,117, 634-644
Total Synthesis of Taxol. 2. Construction of A and C Ring

Intermediates and Initial Attempts To Construct the ABC Ring
System
K. C. Nicolaou,* J.-J. Liu, Z. Yang, H. Ueno, E. J. Sorensen, C. F. Claiborne,
R. K. Guy, C.-K. Hwang, M. Nakada, and P. G. Nantermet
Contribution from the Department of Chemistry, The Scripps Research Institute, 10666 North
Torrey Pines Road, La Jolla, California 92037, and Department of Chemistry and Biochemistry,
University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093
Abstract: A method for the formation of Taxol's ABC ring system has been developed. General methods for the
synthesis of versatile synthons for Taxol's A ring (8) and C ring (55) are presented. A model study using a simplified
C ring synthon (17) c o n f i i e d the viability of the sequential Shapiro-McMurry strategy for formation of Taxol's
B ring. Careful exploration of the chemistry of various A-B ring conjugates allowed the development of a successful
method for formation of the B ring in a more functionalized system.
Introduction
The preceding paper' established a convergent strategy toward
Taxol(1, Figure 1) and described a number of chemical studies
that provided direction toward the appropriate intermediatesand
final path. In this article we describe the construction of rings
A and C and discuss the refinements to these methods that were
necessary to arrive at the key building blocks that were utilized
in the synthesis.
1:Taxol
Figure 1. Structure and numbering of Taxol (1).

Scheme 1. Construction of Ring A Key Intermediates 8-1W
Construction of Ring A
COzEt
In keeping with the themes of convergency and of using the

Diels-Alder reaction as a means to construct both rings A and
C of Taxol (l), we embarked on the synthesis of intermediates
9 and 10 as summarized in Scheme 1. The possibility of steric
hindrance ovemding the well-known electronic induction of
regiocontrol in the Diels- Alder reaction2 warranted concem
initially. This worry proved unfounded, however, as the readily
prepared diene S3s4 and 1-chloroacrylonitrile (6) provided,
through a Diels-Alder reaction that proceeded smoothly at 130
"C in a sealed tube, an 80% yield of desired product 7 as a
single regioisomer, whose structure was c o n f i i e d by both
spectroscopic and X-ray crystallographicanalyses. Application
of the protocol of Shine$s6 (KOH, 'BuOH, 70 "C) freed the
latent carbonyl group at C1 with concomitant acetate removal
to give hydroxy ketone 8 (90%, based on 70% conversion).
Reprotection of the primary hydroxyl group of 8 as either a
* Address correspondenceto this author at the Scripps Research Institute

@Abstractpublished in Advance ACS Abstracts, December 15, 1994.
(1) Nicolaou, K. C.; Nantennet, P. G.; Ueno, H.; Guy, R. K.; Couladouros, E. A,; Sorensen, E. J. J . Am. Chem. SOC. 1995, 117, 624.
(2) Carruthers, W. Cycloaddition Reactions in Organic Synthesis in
Tetrahedron Organic Chemistry Series; Baldwin, J. E., FRS, Magnus, P.
D., FRS,Eds.; Pergamon Press: New York 1990; Vol. 8, p 1.
(3) Kazi, M. A.; Khan, I. H.; Khan, M. H. J. Chem. SOC. 1964, 1511.
(4) Alkonyi, I.; Szabo, D. Chem. Ber. 1967, 2773.
(5) Shiner, C. S.; Fisher, A. M.; Yacobi, F. Tetrahedron Lett. 1983.24,
5687.
(6)See also: Madge, N. C.; Holmes, A. B. J. Chem. SOC., Chem.
Commun. 1980, 956. Evans, D. A.; Scott, W. L.; Truesdale, L. K.
Tetrahedron Len. 1972, 121. Monti, S. A.; Chen, S. C.; Yang, Y. L.; Yuan,
S. S.; Bourgeois, 0. P. J. Org. Chem. 1978, 43, 4062.
OR
10
Ac
r O R
9: R = TBS
10: R = MEM
Reagents and conditions: (a) 1.2 equiv of MeMgBr, EtzO, 0
25 "C,
8 h, then 0.2 equiv of p-TsOH, benzene, 65 "C, 3 h, 70%; (b) 2.2 equiv of
i-BuzAIH, CHzClz, -78
25 "C, 12 h, 92%; (c) 1.1 equiv of AczO, 1.2
equiv of Et,N, 0.2 equiv of 4-(dimethy1amino)pyridine (DMAP), CHZC12,

0
25 "C, 1 h, 96%; (d) 1.0 equiv of 5, 1.5 equiv of 6, 130 "C, 72 h,
80%; (e) 6.0 equiv of KOH, t-BuOH, 70 "C, 4 h, 90% based on 70%
conversion; (f)for 9, 1.1 equiv of TBSCl, 1.2 equiv of imidazole, CHZC12,
25 "C, 2 h, 85%; for 10, 1.2 equiv of MEMCl, 1.3 equiv of i-PrzNEt,
CHzClz, 25 "C, 3 h, 95%. TBS = Si-t-BuMez, MEM = (methoxyethoxy)methyl.
tert-butyldimethylsily18 or (methoxyethoxy)methy17 ether afforded compounds 9 (85% yield) and 10 (95% yield), respectively.
(7) Jacobson, R. M.; Clader, J. W. Synth. Commun. 1979, 9, 57.
(8) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. SOC.1972, 94, 6190.
0002-7863/95/1517-0634$09.00/00 1995 American Chemical Society
Scheme 2. Chemistry of A Ring Ketones 8-10 and Construction of

Hydrazones 15 and 16"
of a hydrazone, a precursor to vinyllithium species, was then

attempted. To our surprise and delight, hydrazones 15 and 16
were both easily prepared from the corresponding ketones 9
and 10 via addition of (triisopropylsulfonyl)hydrazine.ll As will
be discussed below, these hydrazones served admirably in
Shapiro c o ~ p l i n g s ' ~with
J ~ appropriately functionalized ring C
partners.
11
A Feasibility Study for the Shapiro-McMurry Strategy
\\
10
12
0Tf
With a suitable ring A vinyllithium precursor in hand, we

were now ready to test the feasibility for the proposed ShapiroMcMurry strategy toward the taxoid skeleton. To this end the
model aldehyde 21,14representing Taxol's ring C, was prepared
from diester 1715via the sequence summarized in Scheme 3 .
Then, reaction of hydrazone 16 with 2.1 equiv of n-BuLi in
THF at -78 "C followed by warming to 0 "C and addition of
aldehyde 21 furnished a mixture of diastereomeric C2 alcohols
(ca. 2:l) in 83% total yield. The major diastereoisomer, isolated
chromatographically, was proven to be of the desired stereochemistry, as indicated in stmcture 22, by X-ray crystallographic
analysis on a subsequent intermediate (vide infra). Vanadiumcatalyzed epoxidation of allylic alcohol 22 according to the
Sharpless procedure16proceeded regio- and stereoselectively to
afford epoxide 23 in 91% yield. Regioselective opening of this
epoxide using lithium aluminum hydride" in Et20 at 0-25 "C
provided diol 24 in 96% yield. Following our tactical intention
to preorganize the substrate prior to McMurry reactions,I8 we
engaged the vicinal 1,Zdiol system in 24 as the acetonide 25.19
Sequential removal of the primary alcohols' protecting groups
and oxidationz0with TPAP-NMO furnished dialdehyde 30 in
50% overall yield from 25 (Scheme 4). An X-ray crystallographic analysis of compound 30 confirmed its structure and
those of its precursors (see ORTEP drawing, Figure 2).
Having secured dialdehyde 30 we were within sight of a
tricyclic taxoid skeleton provided the pending McMurry coupling'* would be successful. Mindful of Kende's precedentz1
which resulted in the formation of an olefin at the C9-C10
site instead of the C9-C10 diol system that we desired, we
proceeded cautiously and systematically to develop proper
conditions for this ring closure. After considerable experimentation it was found that exposure of dialdehyde 30 to Ti(0)
generated from Tic13 and Zn-Cu couple in DME at 50 "C under
high-dilution conditions gave the desired diol 31 in 40% yield
KEM
\
SnMe,
14
13
vNNHS0,Ar
9: R = TBS
10: R = MEM
15: R = TBS
18: R = MEM
Reagents and conditions: (a) 1.1 equiv of KH,1.05equiv of PhCHZBr,

THF, 0 25 "C, 1.5 h, 37%; (b) 1.1 equiv of LiN-i-Pr2, DME, -78 "C,
2 h, then 1.07equiv of N-phenyltrifluoromethanesulfonimide,DME, -78
0 "C, 4 h, 80%; (c) 0.90 equiv of MesSnSnMes, 6.35 equiv of LiCl,
0.02equiv of (PhsP)Pd, THF, 60 "C, 18 h, 90%; (d) 1.0equiv of PhCOCl,
0.05 equiv of PhCHzPd(Cl)(PhsP)z, HMPA, 65 "C, 18 h, 65%; (e) for 15,
1.0equiv of (2,4,6-t1iisopropylbenzenesulfonyl)hydrazine,
THF, 25 "C, 24
h, 88%; for 16, 1 .O equiv of (2,4,6-t1iisopropylbenzenesulfonyl)hydrazine,
MeOH 25 "C, 4 h, 85%. Ar = 2,4,6-triisopropylbenzene,TBS = Si-tBuMe2, MEM = (methoxyethoxy)methyl, HMPA = hexamethylphosphoramide.
Early attempts to engage ketones 9 or 10 in coupling with

nucleophiles revealed their reluctance to enter in such reactions,
probably due to both steric hindrance and ease of enolization.
The reaction of 8 with benzyl bromide under basic conditions
evidenced the latter by giving rise to dibenzyl derivative 11
(37%, Scheme 2), rather than the expected benzyl ether.
Having failed to induce the ring A derivatives 8-10 to
undergo nucleophilic additions at their carbonyl site, it was then
decided to umpolung the system, that is to convert it into a
nucleophilic species. Early attempts utilized the vinyltin
derivative 13 (Scheme 2), prepared from ketone 10 via triflate
U9as summarized in Scheme 2, as a vinyllithium precursor or
a nucleophillic partner in a Stille couplinglo reaction. However,
neither reaction proved fruitful with a functionalized ring C
partner, even though a Stille coupling of 13 with benzoyl
chloride did afford enone 14 (65% yield, Scheme 2). With some
reluctance due to the expected steric hindrance, the formation
(9)McMurry, J. E.; Scott, W. I. Tetrahedron Len. 1983,24,979. Wulff,
W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron, K. L.; Gilbertson,
S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J . Org. Chem. 1986,51,
277.
(10) (a) Milstein, D.; Stille, J. K. J . Am. Chem. SOC.1978, 3636. (b)
Milstein, D.; Stille, J. K. J . Org. Chem. 1979, 44, 1613. (c) For a review,
see: Stille, J. K. Angew. Chem., Znt. Ed. Engl. 1986, 25, 508.
(11)Cusack, N. J.; Reese, C. B.; Risius, A. C.; Roozpeikar, B.

Tetrahedron 1976, 32, 2157.
(12)Shapiro, R. H. Org. React. 1976, 23, 405. Chamberlin, A. R.;
Bloom, S. H. Org. React. 1990, 39, 1-83. Martin, S . F.;Daniel, D.;
Cherney, R. J.; Liras, S. J . Org. Chem. 1992, 57, 2523.
(13)This strategy was later used by others to accomplish similar
couplings: Di Grandi, M. J.; Jung, D. K.; Krol, W. J.; Danishefsky, S . J.
J . Org. Chem. 1993, 58,4989. Masters, J. J.; Jung, D. K.; Bornmann, W.
G.; Danishefsky, S. J. Tetrahedron Lett. 1993, 34, 7253.
(14)Nicolaou, K.C.; Yang, Z.; Sorensen, E.; Nakada, M. J . Chem. Soc.,
Chem. Commun. 1993, 1024.
(15)Mundy, B. P.; Theodore, J. J. J . Am. Chem. SOC. 1980, 102, 2005.
(16)Sharpless, K.B.;Michaelson, R. C. J . Am. Chem. SOC.1973, 95,
6136. Sharpless, K. B.; Verhoeven, T. R. Aldrichimica Acta 1979, 12,63.
Rao, A. S.In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Ley, S. V., FRS, Eds.; Pergamon Press: New York, 1991;Vol. 7,p 376.
(17)Mwai, S.;Mwai, T.; Kato, S. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991;Vol. 8,
p 871.
(18)McMurry, J. E. Chem. Rev. 1989, 89, 1513. McMurry, J. E. Acc.
Chem. Res. 1983, 16, 405. McMurry, J. E.;Lectka, T.; Rico, J. G . J .
Org. Chem. 1989,54, 3748. McMuny, J. E.; Rico, J. G. Tetrahedron Lett.
1989, 30, 1169;Lenoir, D. Synthesis 1989, 883.
(19)Evans, M. E.; Parrish, F. W.; Long, L., Jr. Carbohydr. Res. 1967,
3,453. Lipshutz, B. H.; Barton, J. C. J . Org. Chem. 1988, 53, 4495.
(20)Griffith, W. P.; Ley, S . V. Aldrichimica Acta 1990, 23, 13.
(21)Kende, A.S.;Johnson, S.; Sanfilippo, P.; Hodges, J. C.; Jungheim,
L. N. J . Am. Chem. SOC. 1986, 108,3513.
Nicolaou et al.
Scheme 3. Synthesis of the Acetonide Model System 25 by the Shapiro

Reaction'
'"...
- 'p- P
HO
E t O , C n
EtOzC
Scheme 4. Synthesis of the ABC Taxoid Systems 33 and 35 by the

McMuny Reaction"
HO
HO
HO
17
18
10
BnO
OMEM
30
c
-
HO
21
20
el
23
22
g1
35
33
Reagents and conditions: (a) H2,20% Pd(OH)2 on C, EtOH, 25 OC, 2

h, 100%; (b) 1.2 equiv of Ac20, 1.3 equiv of 4-(dimethylamino)pyridine
(DMAP), CHzClz, 0 25 "C, 2.5 h, 97%; (c) 1.0 equiv of TiCL, CHzC12,
-78 OC, 10 min, then -20 "C, 10 min, 65%; (d) 0.1 equiv of KzC03,
MeOH, 25 "C, 4 h, 91%; (e) 0.05 equiv of tetrapropylammonium
permthenate (TPAP),3.0 equiv of 4-methylmorpholine N-oxide (NMO),
4-A sieves, CH2C12,25 OC, 10 min, 87%; (f)8.0 equiv of TiCls-(DME)1.5,
15 equiv of Zn-Cu, DME, 50 "C, 5 h, 40% of 31,25% of 32;(g) excess
MnOz, CH2C12, 25 "C, 20 min, 90%; (h) excess AczO, excess pyridine,
CHzClz, 25 "C, 0.5 h, 98%; (i) 30 equiv of pyridinium chlorochromate
(PCC), 30 equiv of NaOAc, Celite, benzene reflux, 2 h, 71%. MEM =
(methoxyeth0xy)ethyl.
25
24
Reagents and conditions: (a) 5.0 equiv of i-BuzAlH, CHKlz, -78

25 "C, 10 h, 95%; (b) Hz, 0.2 equiv of PdC, EtOAc, 3 h, 100%; (c) 1.0
equiv of KH, 1.0 equiv of PhCHZBr, THF, 0 25 "C, 1.5 h, 85%; (d) 2.0
equiv of pyridinium dichromate (PDC), molecular sieves, CHzC12,O 25
"C, 4 h, 90%; (e) 16,2.1 equiv of n-BuLi, THF, -78 OC, 0.5 h, then 0 "C,
10 min, 1.3 equiv of 21,THF, 0 25 "C, 5 h, 83% (cu. 2:l diastereomeric
mixture); (f) 1.1 equiv of r-BuOOH, 0.014 equiv of VO(acac)z, PhH, 25
OC, 2 h, 91%; (g) 2.0 equiv of LiAla, EtzO, 0 "C, 20 min, 25 "C, 6 h,
96%; (h) 2 equiv of 2,2-dimethoxypropane, 0.2 equiv of camphorsulfonic
acid (CSA), CHzC12, 25 OC, 12 h, 85%. MEM = (methoxyethoxy)ethyl,
Bn = CHzPh, acac = acetylacetonate.
(I
as a mixture of two diastereoisomers (stereochemistry unassigned). This reaction produced no A C9-C10 olefin, although
the C9-Cl2 coupled byproduct 32 was formed (25% yield) as
also observed by Kende.21 The mechanistic aspects of this
reaction will be discussed in a subsequent paper in this series.
Oxidation of the mixture of diols 3 1 with Mn0222 gave the
dienediol 33 in 90% yield, and acetylation of 31 followed by
PCC oxidation23 led to enone 35 via diacetate 34. The work
presented in Schemes 3 and 4 demonstrated the viability of our
Shapiro-McMuny strategy toward Taxol (1) and placed us in
the position of facing the challenge of Taxol (1) itself.
Construction of C Ring Systems
a. The Diels-Alder Reaction. In contrast to the achiral

ring A system, ring C of Taxol, with its numerous stereocenters
(22) Fatiadi, A. J. Synthesis 1976,65.
(23) Parish,E. J.; Wei, T. Y. Synrh. Commun. 1987,17,1227. Rathore,
R.; Saxena, N.; Chadrasekaran Synth. Commun. 1986,16, 1493.
and high degree of oxygenation, presented a more serious

challenge to the Diels-Alder approach. Early approaches
examined the reaction of dienophile 40 (prepared from l-hydroxy-2-propene (36) according to Scheme 5) and 3-carbomethoxy-2-pyrone (43) (Scheme 6). According to previous
work by CoreyZ4and BrysonZ5with the latter compound, and
considering the substitution pattem of dienophile 40, we
expected this reaction to proceed regio- and stereoselectively
to afford product 45 via intermediate 44. Diene 45 was then
expected to serve as a precursor to a fully functionalized ring
C for coupling with ring A. In the event, however, this DielsAlder reaction (155 "C, 24 h, 81% yield based on 51%
conversion) proceeded with the opposite regiochemistry from
that expected, furnishing product 47, via presumed intermediate
46, the latter undergoing a facile decarboxylation under the
reaction conditions. A series of regio- and stereochemically
controlled reactions, as shown in Scheme 6, converted cyclohexadiene system 47 into crystalline diol 51. X-ray crystallographic analysis of 51 (see ORTEP drawing, Figure 2)
(24) Corey, D. I.; Watt, D. S. J. Am. Chem. SOC. 1973,95, 2303.
(25) Bryson, T. A.; Donelson, D. M. J. Org. Chem. 1977,42, 2930.
Scheme 5. Synthesis of Dienophiles 40-42"
Q:
CI 7
37
4 0 R = TPS
41:R=THP
42: R = H
zd
Reagents and conditions: (a) 1.1 equiv of TPSC1, 1.15 equiv of

imidazole, DMF, 0 "C, 1 h, then 0 3 , CH2C12, -78 "C, 1 h, then 2.2 equiv
of Ph3P. -78 "C 25 "C; (b) 2.1 equiv of dihydropyran, 0.005 equiv of
p-TsOH, CH2C12, 25 "C, 0.5 h, then 0 3 , CH2C12, -78 T, 5 h, then 1.0
25 "C, 98%; (c) for 40, 1.4 equiv of
equiv of Ph3P, -78 "C
Ph3P=C(CH3)C02Et, CH2C12,25 "C, 20 h, 91% from 36; for 41, 1.03 equiv
of Ph3P=CHC02Et, CH2C12, 0 "C, 4 h, then 25 "C, 18 h, 90%; (d) 0.05
equiv of p-TsOH, MeOH, 25 "C, 18 h, 92%. TPS = Si-t-BuPh2, THP =
tetrahydropyranyl.
a
30
HO
OH
Scheme 6. Early Diels-Alder Attemptsa

0
51
C02Me
OTPS
40
HO
43
46
OH
TPSO
-IC021
'"OTBS
TPSO
TPSO
C02Me
C02Me
60
44
45
47
bl
p,p
Po
A0
RO
I""'
OH
TPSO
OH
TPSO
E102C\"" C02Me
HO
HO
a7
50: R = TPS
49
4a
'CSI:R=H
Reagents and conditions: (a) 1.0 equiv of 40, 2.0 equiv of 43, neat,
155 OC, 24 h, 81% based on 51% conversion; (b) 4.0 equiv of m-CPBA,
CH2C12, 25 'C, 4 h, 71% plus 19% of a epoxide; (c) excess i-Bu?AlH,
EtzO, 0 "C, 2 h, 91%; (d) excess 2,2-dimethoxypropane, 0.05 equiv of
camphorsulphonic acid (CSA), CH2C12, 25 "C, 1 h, 90%; (e) 1.0 equiv of
n-BWNF (TBAF), THF, 25 "C, 1 h, 95%. TPS = Si-t-BuPh2.
confirmed its structure and those of its precursors and revealed

the undesired regioselectivity of the Diels- Alder reaction.
Faced with this unfortunate regiochemical outcome, we then
focused our attention on 3-hydroxy-2-pyrone (52, Scheme 7 )
as a diene in the Diels-Alder reaction. Although Corey26has
demonstrated that this system would give the opposite regiochemical pathway from that required for our purposes, the
pioneering work of Narasaka*' afforded us the possibility for
success in this endeavor. Scheme 7 demonstrates Narasaka's
Figure 2. ORTEP drawings for intermediates 7, 30, 51, 60, 87, 103.
(26) Corey, E. J.; Kozikowski, A. P. Tetrahedron Len. 1975, 2389.

(27) Narasaka, K.; Shimada, S.; Osoka, K.; Iwasawa, N. Synthesis 1991,
1171.
Nicolaou et al.
Scheme 7. Synthesis of Common C-Ring Intermediate 55

52
+Et
OH
OH
42
Scheme 8. Structural Confirmation of 55"
EtOzC
55: R = H
%:R=Ac
53
57
'I
HO
OH
e
55
54
"Reagents and conditions: 1.4 equiv of 52, 1.4 equiv of PhB(OH)z,

PhH, reflux (Dean-Stark trap), 48 h, then 1.4 equiv of 2,2-dimethyl-1,3propanediol, 25 "C, 1 h, 79% based on 77% conversion of 42.
principle of temporarily tethering the two reaction partners in

order to dictate the regiochemistry of the Diels-Alder reaction.
Thus, reaction of dienophile 42 (prepared from 1,3-dihydroxycis-2- butene (37), Scheme 6) with 2-hydroxy-2-pyrone (52) in
the presence of phenylboronic acid under dehydrating conditions
led, after decomplexation with excess 2,2-dimethyl-1,3-propanediol, to compound 55. Evidently, the initially formed
Diels-Alder product 54 promptly rearranges under the reaction
conditions via intramolecular acyl transfer from the secondary
to the primary hydroxyl group to afford the observed product
in 79% yield based on 77% conversion of 42.28 Relief of strain
in going from the [2.2.2] cycloaddition product 54 to the [3.4.0]
bicyclic system 55 may be the primary reason for this facile
rearrangement.
Scheme 8 demonstrates a number of useful transformations
of compound 55 that led not only to confiiation of its structure
but also to more advanced intermediates as required for our
plans. Exhaustive acetylation of 55 led to diacetate 56 which
exhibited significant downfield shifts in its proton NMR
spectrum (CDC13, 6 Ha, 4.59
5.84 and Hb, 3.10
3.90).
Pyridinium dichromate (PDC) oxidationz9of 55 furnished enone
57 in accord with the assigned structure (55), whereas persilylation of the same compound with TBSOTf3O gave the bis(sily1
ether) 58 isolated as a C20 hydrate. The latter compound
underwent selective reduction with LAH in Et20 at 0 25 "C
to afford primary alcohol 59 (97% yield) which was monodesilylated with camphorsulfonic acid (CSA) in Me0H:CHzClz
to afford the crystalline lactone diol 60 in 94% yield. X-ray
crystallographic analysis of 60 (see ORTEP drawing, Figure 2)
confirmed its structure and those of its progenitors. An NMR
experiment (500 MHz, CDCl3) c o n f i i e d that neither acid
(CSA) nor base (DMAP) causes any skeletal rearrangement of
55, serving as a control for the reactions summarized in Scheme
8.
b. The First Attempt at a CD Ring System. Oxetane Is
Formed but Interferes with Subsequent Chemistry. One of
our early plans was to construct a CD ring system with the
oxetane ring already in place before coupling with a ring A
+
(28) For obvious practical reasons, large-scale reactions are performed

with 1.0 equiv of diene and dienophile each and 0.95 equiv of PhB(0H)z;
diol 55 is typically obtained in ca. 60% yield based on ca. 50% conversion.
The crude starting material mixture is recycled in the same process.
(29) Corey, E. J.; Boger, D. L. Tetrahedron Lett. 1978, 2461.
(30) Corey, E. J.; Cho, H.; Rucker, C.; Hua, D. H. Tetrahedron Lett.
1981, 22, 3455.
OH
50: R E C02Et
L 59: R = CH2OH
'0
60
"Reagents and conditions: (a) 5.0 equiv of AczO, 2.5 equiv of

4-(dimethylamino)pyridine (DMAP), CHZC12, 25 "C, 10 min, 100%; (b)
1.2 equiv of pyridinium dichromate (PDC), 4-A molecular sieves, CHZClz,
25 OC, 1 h, 81%; (c) 4.0 equiv of t-BuMezSiOTf, 4.0 equiv of 2,6-lutidine,
0.1 equiv of DMAP, CHzClz, 0 "C, 4 h, 92%; (d) 1.1 equiv of LiAW,
Etz0,O 25 "C, 0.5 h, 97%; (e) 0.05 equiv of camphorsulfonicacid (CSA),
CHzClz, MeOH, 25 "C, 1 h, 94%. TBS = Si-t-BuMez, Tf = S02CFs.
hydrazone. To this end, diol 55 (Scheme 9) was dibenzylated

using excess KH and benzyl bromide31to afford compound 61
which was then reduced with excess LAH in ether at 0 "C to
give hydroxy lactol 62 as a 1:l mixture of diastereoisomers
(71% yield from 55). Selective monoprotection of the primary
alcohol using fert-butyldiphenylsilyl chloride (TPSCl) and
imidazole in DMF3zfollowed by further reduction of the lactol
with LAH in THF at 25 "C furnished diol 64 in 78% yield.
Reaction of 64 with pivaloyl chloride (1.05 equiv) under basic
conditions led to a 1:3.2 mixture of the two pivaloate esters 65
and 66 which were chromatographically separated.
The next task was the introduction of an alcohol at C5. Even
though a previous
had shown that the primary hydroxyl
group in a similar system could be used to direct the hydroboration of the cyclohexene double bond, the feasibility of using
a mesylate (SOzCH3) as a possible directing group in this
hydr~boration~~
was explored. Such a method would more
efficiently lead to the targeted oxetane system. Indeed hydroboration of 68, prepared from 65 by standard mesylation,
with borane in THF (0-25 "C) followed by oxidative workup,
led to the formation of the C5 alcohol 69 as the major product
and in 53% yield. Treatment of the latter compound with NaH
in THF at 45 "C resulted in the formation of oxetane 70 in
86% yield, confirming the stereochemical orientation of the
newly generated alcohol in 69. Attempts to reach the targeted
C2 aldehyde were, however, thwarted by failure to cleanly
remove the pivaloate group from 70, presumably due to
interference from the oxetane ring under the reductive or basic
conditions employed in these attempts. Nevertheless, this
sequence confirmed the potential feasibility of constructing the
oxetane ring by this method and rendered the aldehyde 67
(31) Evans, M. E.; Parrish, F. W.; Long, L., Jr. Carbohydr. Res. 1967,
3, 453. Lipshutz, B. H.; Barton, J. C. J . Org. Chem. 1988, 53, 4495.
(32) Hanessian, S.; Lavallb, P.Can.J . Chem. 1975,53,2975. Hanessian,
S . ; Lavalike, P. Can. J . Chem. 1977, 55, 562.
(33) Nicolaou, K. C.; Liu, J.-J.; Hwang, C.-K.; Dai, W.-M.; Guy, R. K.
(34) Smith,K.; Pelter, A. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 8, p 703.
Scheme 10. Synthesis of ACD Ring System 81"
Scheme 9. Synthesis of Oxetane-Containing C-ring 70"

0
OR
RO
OBn
TPSO
QBn
bR
TBSO
55: R = H
a 6 6 1 : R = Bn
"1
62:R=H
cC6yR=TPS
71:R=H
c 7 2 : R = MOM
64
55
73:R=H
6 7 4 : R = CHPh
OBn
TPSO
Ph
+
OH
67
66
65
79
gl
TpsQ
'o
@'
OBn
Opiv
OBn
OH
"bBn
OPiv
OMS
70
TPSO
MOM
RO
R = TBS
R=H
'@
OBn
OR
'
75: R = H
K 7 6 : R = Ts
h TPSO
OPiv
69
'bBn
I-Pr
15
Ph
Ph
68
Reagents and conditions: (a) 3.5 equiv of PhCHzBr, 3.5 equiv of KH,
0.05 equiv of n - B N 0 "C 25 "C, 2 h, 75%; (b) 2.0 equiv of LiAlH4,
Et20, 0 "C, 1 h, 94%; (c) 1.4 equiv of TPSC1, 1.5 equiv of imidazole,
DMF, 0 "C, 2 h, 25 "C, 4 h, then excess n-BWF, THF, 10 h, 82% based
on 54% conversion; (d) 1.3 equiv of LiAIh, THF, 0 "C 25 "C, 0.5 h,
96%; (e) 1.05 equiv of PivC1, 1.5 equiv of 4-(dimethylamino)pyndine
(DMAP), CH2C12, 0 "C, 0.5 h, 55% of 66,plus 17% of 65,plus 24% of
C2-C20 dipivalate, based on 84% conversion; (0 0.05 equiv of tetrapropylammonium permthenate (TPAP), 1.5 equiv of 4-methylmorpholine
N-oxide (NMO), CH3CN, 25 'C, 1.5 h, 91%; (g) 1.5 equiv of MsCl, 2.0
equiv of DMAP, CHZClz, 0 "C
25 "C, 1.5 h, 95%; (h) 10 equiv of
BHqTHF, THF, 25 "C, 10 h, then excess H202, aqueous NaHC03, 53%;
(i) 5.0 equiv of NaH, THF, 45 "C, 3 h, 86%. Bn = CHzPh, TPS = Si-tBuPh2, Piv = CO-t-Bu, Ms = S02CH3.
available through oxidation of 66 using the TPAP-NMO

method.*O The latter compound was utilized in a subsequent
attempt to construct the ABC ring skeleton of Taxol (1) as will
be discussed in a later section of this paper.
c. A Second Attempt at the CD Ring System. Success
but the Oxetane Ring Interferes Again after the Shapiro
Coupling. After our first attempt to construct a suitable CD
aldehyde failed, we quickly redesigned our approach, choosing
new protecting groups and targeting aldehyde 79 as a potential
electrophile for the Shapiro coupling. Scheme 10 outlines the
chemistry involved in this second approach. Thus, upon
treatment with KH and TBSCl, intermediate 55 underwent
skeletal rearrangement involving acyl migration from the
primary to the secondary hydroxyl group, presumably driven
by trapping of the primary hydroxyl as a silyl ether, to afford
71. Protection of the tertiary alcohol as a methoxymethyl
(MOM) ether7 led to 72. Reduction of the ester and lactone
functionalities in 72 using excess LAH in THF formed triol
73. Introduction of the benzylidene group35protected the C7C9 diol system in the latter compound, furnishing 74 in 72%
yield from 72. The possibility of generating a C7 benzyl, C9
hydroxy derivative directly from the b e n ~ y l i d e n edictated
~~
the
choice of this protecting group. Directed hydroboration of olefin
(35)Albert, R.; Dax, K.; Pleschko, R.; Stutz, K. Carbohydr. Res. 1985,
137, 282. Yamanoi, T.; Akiyama, E.; Inazu, T. Chem. Lett. 1989, 335.
Crimmins, M. T.; Hollis, W. G., Jr.; Lever, J. G. Tefrahedron Left. 1987,
28, 3647.
80
81
Reagents and conditions: (a) 2.0 equiv of KH, 1.2 equiv of TBSC1,
THF, 25 OC, 0.5h, 61%; (b) 2.0 equiv of MOMC1, 1.5 equiv of KH, CH2C12,
25 "C, 12 h, 92%; (c) 5.0equiv of LiAlb, THF, 25 "C, 1 h; (d) 3.8 equiv
of PhCH(OMe)Z, 0.05 equiv of camphorsulfonic acid (CSA), CH2C12, 25
"C, 72% from 72;(e) 3.0equiv of BHyTHF, THF, 25 "C, 10 h, then excess
Hz02, aqueous NaHCO3, 37%; (f) 1.6 equiv of TsCl, 3.0 equiv of
4-(dimethy1amino)pyridine(DMAP), CHzC12, 25 "C, 5 h; (g) 2.2equiv of
NaH, THF, 45 "C, 10 h, 78% from 75;(h) excess n-BuflF, THF, 25 "C,
2 h, 95%; (i) 3.0 equiv of Dess-Martin periodinane, CH2Cl2, 25 "C, 2 h,
91%; Q) 1.2equiv of 15,2.4 equiv of n-BuLi, THF, -78 'C, 0.5 h, 80%.
then 0 "C; 1.0equiv of 79,THF, 0 "C, 0.5 h, 85% (ca. 5:3 mixture); (k)
excess t-BuOOH, 0.05 equiv of VO(acac)z, PhH, 25 "C, 2 h. MOM =
methoxymethyl, TBS = Si-t-BuMez, Ts = S02-p-Tol. acac = acetylacetonate.
74 resulted in the formation of the C5 ,8-hydroxy compound

75 in 37% yield. Tosylation (80%) of the latter followed by
exposure to NaH in THF at 45 "C led to oxetane 77 (78%) via
tosylate 76. Finally, desilylation of 77 using TBAF,37followed
by Dess-Martin ~ x i d a t i o n furnished
,~~
aldehyde 79 via 78 in
86% overall yield. The Shapiro reaction proceeded well in
combining hydrazone 15 and aldehyde 79 to produce alcohol
80 (85%, mixture of diastereoisomers, Scheme 10). Epoxide
81 could not, however, be cleanly obtained from the major
isomer 80 using the vanadium-catalyzed procedure.
Due to the problems encountered in the two approaches
discussed above, the strategy of having the oxetane installed in
the molecule prior to the coupling reactions was abandoned in
favor of schemes involving oxetane construction at a later stage.
d. Successful Progression to the McMurry Cyclization
Stage. Having just experienced the complications of the highly
(36)Takano, S.;Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983,
1593. Hatakeyama, S.;Sakurai, K.; Saijo, K.; Takano, S. Tetrahedron Lett.
1985,26,1333. Schreiber, S. L.; Wang, Z . ; Schulte, G. Tetrahedron Lett.
1988,29, 4085. Adam, G.;Seebach, D. Synthesis 1988,373.
(37)Corey, E. J.; Venkateswarlu, A. J . Am. Chem. SOC.1972,94, 6190.
(38)Dess, D. B.; Martin, J. C. J . Org. Chem. 1983,48,4155.Dess, D.
B.; Martin, J. C. J . Am. Chem. SOC. 1991,113, 7277. Ireland, R. E.; Liu,
L. J . Org. Chem. 1993,58,2899.
Nicolaou et al.
640 J. Am. Chem. Soc., Vol. I 17, No. 2, 1995

Scheme 11. Synthesis of A-C Ring System 87"
HO oen
(Re face)
Nu'
1%
QB"
OH
82: X = 0
6 8 3 : X = (OMe)*
62
88: Li+chelate derived from aldehyde 86
86
TBSO
Figure 3. Stereoselectivity of the Shapiro reaction. The model was

generated with Chem3d, most hydrogens are omitted for clarity.
i-Pr.
oxygenated intermediates of the previous schemes, we decided

to minimize such problems by targeting aldehyde 86 (Scheme
11). Oxidation of intermediate 62, readily available as described
in Scheme 10, with D e ~ s - M a r t i n ~
reagent
~
afforded aldehyde
lactone 82. Protection of the aldehyde as a methoxy acetal39
produced compound 83 (81% yield from 62) which was then
reduced with LAH in THF at reflux to give diol 84. Treatment
of the latter compound with pivaloyl chloride in the presence
of DMAPOselectively protected the C20 alcohol as a pivaloate
ester, leading to intermediate 85 in 70% yield from 83.
Molecular models revealed the C2 hydroxyl group of 84 to be
more crowded [interference from bis(methoxy) group] than the
C20 hydroxyl group (pseudo axial position) and thus the
selectivity observed. Finally, oxidation with either TPAPNM020 or Dess-Martin reagent38 easily converted compound
85 to aldehyde 86 (83% yield).
With the aldehyde 86 in hand, we then proceeded to the
Shapiro reaction utilizing hydrazone 15 as the precursor to the
vinyllithium reagent. This coupling reaction furnished alcohol
87 as a single diastereoisomer in 74% yield. X-ray crystallographic analysis allowed the assignment of the stereochemistry
of this intermediate (see ORTEP drawing, Figure 2). The
stereoselectivity of this reaction can be explained by invoking
6-membered ring chelate intermediate 88, as shown in Figure
3. In this model, the re face of the aldehyde is more accessible
to nucleophilic attack than the si face due to shielding by the
C8 methyl and C20 pivaloyl groups.
Early attempts to unblock the aldehyde group of 87 under

acidic conditions failed due to formation of a cyclic hemiacetal
with the C2 hydroxyl group. Epoxidation of the allylic system
in 87 proved rather slow and, therefore, the C20 hydroxyl group
was called upon to assist in this reaction. Treatment of 87 with
LAH in ether resulted in the formation of diol 89 (88% yield)
which underwent smooth epoxidation with tBuOOH in the
presence of VO(acac)2 catalyst to afford epoxide 90 in 82%
yield (Scheme 12).
At this point our plan involved engaging the two hydroxyl
groups of our latest intermediate (90) in a cyclic system in order
to both prevent the undesired hemiacetal formation and to
preorganize the substrate prior to the construction of ring B.
To this end, diol 90 was treated with phosgene in the presence
of pyridine41 in an attempt to produce the 7-membered ring
carbonate. These conditions, however, produced exclusively
the tetrahydrofuran derivative 91, presumably via nucleophilic
attack by the C2 hydroxyl group on the activated C20 chloroformyl intermediate. To circumvent this problem, both alcohols
were engaged in a cyclic lactone by exposure of diol 90 to
Dess-Martin reagent,38giving the y-lactone 92 in 61% yield.
Removal of the silyl group from compound 92, followed by
oxidation with Dess-Martin reagent,38 afforded aldehyde 94,
via intermediate alcohol 93, in 71% overall yield. Revealing
the C9 aldehyde by exposure to trifluoroacetic acid42(TFA) at
0 OC,produced, in addition to dialdehyde 95 (51% yield), the
conjugated system 96 (24%) (Scheme 13), presumably arising
from 95 via acid-induced epoxide opening.
Several attempts to cyclize dialdehyde 95 using the McMurry
reaction under a variety of conditions were unsuccessful. The
only detectable product was the diol 97, apparently produced
by reduction of both aldehyde groups. It became clear that this
particular design did not favor the required ring closure and
that we had to design yet another synthetic sequence.
e. First Attempt with the C1-CZCarbonate Approach.
Aiming to enforce a different conformation in the McMuny
substrate, we decided to introduce a C1-C2-carbonate ring.
(39) Wenkert, E.; Goodwin, T. E. Synth. Commun. 1977, 7, 409.

(40) Hofle, G.; Steglich, W.; Vorbriiggen, H. Angew. Chem., Znt. Ed.
Engl. 1978, 17, 569.
(41) Haworth, W. N.; Porter, C. R. J. Chem. SOC. 1930, 151.

(42) Ellison, R. A.; Lukenbach, E. R.; Chiu, C.-W. Tetrahedron Lett.
1975, 499.
15, Ar =*i-pr
07
i-Pr
Reagents and conditions: (a) 3.0 equiv of Dess-Martin periodinane,
CH2C12, 0 "C
25 "C, 12 h; (b) excess of HC(OMe)3, 0.05 equiv of
camphorsulfonic acid (CSA), MeOH, CH2C12, 25 "C, 12 h, 81% from 62;
(c) 1.2 equiv of LiAl&, THF, reflux, 1 h; (d) 1.5 equiv of PivC1,5.0 equiv
of 4-(dimethylamino)pyridine (DMAP), CH2C12, 0 "C, 15 min, 70% from
83; (e) 1.7 equiv of Dess-Martin periodinane, CH2C12, 25 "C, 1.5 h, 83%;
(f) 15, 2.2 equiv of n-BuLi, THF, -78 "C, 0.5 h, then 0 "C; 1.2 equiv of
86, THF, -40 "C, 5 min, 74%. Bn = CH2Ph, Piv = CO-t-Bu, TBS =
Si-t-BuMe2.
a
J. Am. Chem. SOC.,Vol. 117, No. 2, 1995 641
Scheme 13. First Attempt at the McMurry Cyclization"
Scheme 12. Synthesis of Lactone 93a

TBSO
TBSO
8 7 R = PN
a L : R = ti
94
02
01
97
O5
96
Reagents and conditions: (a) trifluoroacetic acid neat, 0 "C, 15 min,

51%; (b) 10 equiv of TiC13*(DME)1,5,15 equiv of Zn-Cu, DME, 60 "C, 4
h, 95 added over 5 h (syringe pump), then 55 "C, 3 h, 34% based on 43%
conversion. Bn = CHZPh.
a
04
03
Reagents and conditions: (a) 2.0 equiv of LiAlb, EtzO, -10 "C, 5
min, 88%; (b) 2.0 equiv of r-BuOOH, 0.25 equiv of VO(acac)z, PhH, 25
"C, 0.5 h, 82%; (c) 5.0 equiv of phosgene, pyridine, 75 "C, 2.5 h, 35%; (d)
10 equiv of Dess-Martin periodinane, CHzC12,50 "C, 1 h, 61%; (e) excess
n-B-,
THF, 25 "C,2 h; (f) 5.0 equiv of Dess-Martin periodinane,
CHzClz, 25 "C, 0.5 h, 71% from 92. TBS = Si-t-BuMez, Bn = CHZPh,
Piv = CO-t-Bu, acac = acetylacetonate.
Molecular modeling (S ybyl) indicated that this functionality

would preorganize the expected intermediate geometry by
bringing the two aldehydes to the same face of the molecule.
Learning from our previous experience with protecting groups,
we decided to utilize aldehyde 67 (prepared as described in
Scheme 9, above) and hydrazone 15 as partners for the Shapiro
reaction. Thus (as shown in Scheme 14) the Shapiro reaction
produced compound 98, as a single isomer (stereochemistry
confirmed by X-ray crystallographic analysis of subsequent
intermediate 103) in 82% yield. Deprotection with LAH
afforded diol 99 (87% yield). Vanadium-catalyzed epoxidation
of 99 with 'BuOOH led stereoselectively to epoxide 100 in 95%
yield. Regioselective epoxide opening with LAH gave triol 101
in 78% yield based on 81% conversion. Selective protection
of the primary alcohol in 101 as a MOM ether proceeded
smoothly under standard conditions to afford compound 102
in almost quantitative yield. Diacetate 103 was prepared using
acetic anhydride and DMAP (83% yield). X-ray crystallographic analysis of the latter compound confirmed the
previously proposed stereochemistry (see ORTEP drawing,
Figure 2).
By this time both our model studies and degradation work'
pointed to a carbonate protecting group at Cl-C2 as the most
suitable device for our synthetic scheme. In order to install
the latter into our intermediate (102), it was necessary to use
rather strong conditions (excess KH, phosgene, ether:HMPA,
1:1, 25 "C, 88% yield based on 57% conversion) as compared
to those used in making the taxoid carbonate II.' The flexibility
of the 1,2-diol 102 as compared to the rigidity of the corresponding taxoid diol employed in the degradation studies is
probably responsible for this relative unreactivity. The carbonate 104 was then desilylated with fluoride ion and oxidized with
TPAP-NMOZo to afford dialdehyde 106 via the corresponding
diol (105) in 80% overall yield.
With the requisite dialdehyde 106 in hand, we proceeded to
investigate its-conversion to a cyclic taxoid system through
McMurry coupling. In traversing the temperature range from
0 to 70 "C, no cyclic coupling products were observed; at 85
"C, however, a 15% yield of the cyclic olefin 107 (Scheme 14)
was isolated, suggesting that the desired cyclic diol might remain
elusive even with these rigid precursors. The conclusion was
that further preorganization was needed in order to lower the
activation energy to avoid deoxygenation of carbons 9 and 10
during the McMurry cyclization.
Conclusion
In this paper we described the evolution of the chemistry that
eventually led to a successful construction of a taxoid system
containing the ABC ring framework of Taxol (1). While the
construction of a suitable ring A fragment proceeded smoothly
via a Diels-Alder approach, that of a suitable ring C fragment
presented more difficulties. Although the highly functionalized
and stereochemically defined ring C intermediate was easily
produced via a boron template controlled reaction, the finetuning
of the functional groups for proper elaboration required considerable experimentation. Through the process of design,
experimentation, and redesign, however, enough knowledge was
gathered that made the final push toward a suitable ABC taxoid
ring system possible. This final and successful approach is
discussed in the following paper.
General Techniques. For a description of general technique, see
the Fist paper in this series.' Experimental techniques and data for
compounds 10-14, 16, 18-35, 47-51, 57, 58, 61-80, 82-87, and
89-107 can be found in the supplementary material.
Diene 3. A solution of ketone 2 (245.0 g, 1.44 mol) in Et20 (1500
mL) at 0 "C was treated with methylmagnesium bromide (576 mL of
a 3.0 M solution in EtzO, 1.73 mol). The reaction mixture was allowed
to warm to 25 OC and stirred for 8 h. After cooling to 0 "C,the reaction
was quenched with aqueous NI&C1(600 mL). The organic layer was
separated and washed with H20 (2 x 400 mL) and brine (400 mL).
Nicolaou et al.
Scheme 14. Formation of the ABC taxoid system 107 by a McMuny

cyclizationa
TBSO
98: R = Piv
bCe0: R = H
TBSO
"1
TBSO
101
vu
107
"'OBn
'OMOM
&
"
H OBn
Y
o
CMOM
0
108
Reagents and conditions: (a) 1.3 equiv of 15, 2.6 equiv of n-BuLi,
THF, -78 "C, 0.5 h, then 0 "C, 1.0 equiv of 67, THF, -78 "C, 20 min,
82%; (b) 2.0 equiv of LiAW, EtzO, 25 "C, 0.5 h, 87%; (c) 2.0 equiv of
t-BuOOH, 0.05 equiv of VO(acac)z, PhH, 25 "C, 0.5 h, 95%; (d) 15 equiv
of LiAl&, EtzO, 25 "C, 3 h, 78% based on 81% conversion; (e) 10 equiv
of MOMCl, 12 equiv of i-PrWt, CHZClZ, 25 "C, 10 h, 99%; ( f ) excess
n-Bu$rTF(TBAF), THF, 25 "C, 2 h, then 4.0 equiv of AczO, 6.0 equiv of
4-(dimethylamino)pyridine(DMAP), CHZC12,25 "C, 2 h, 83%; (g) 5.0 equiv
of phosgene, 5.0 equiv of KH, EtzO, HMPA, 25 "C, 1 h, 88% based on
57% conversion; (h) excess TBAF,THF, 25 "C, 1 h, 88%; (i) 0.05 equiv
of tetrapropylammonium permthenate (TPAP), 3.O equiv of 4-methylmorpholine N-oxide (NMO),
CH~CN-CH~C~Z
(1:l). 25 "C, 0.5 h, 91%; (j) 10
equiv of TiCly(DME)1.5,20 equiv of Zn-Cu, DME, reflux, 3 h, 106 added
over 1 h, then 1.5 h, 15%. Piv = CO-t-Bu, TBS = Si-t-BuMez, Bn =
CHzPh, TPS = Si-t-BuPhz, MOM = methoxymethyl.
a
The combined aqueous layer was extracted with Et20 (2 x 200 mL).
The combined organic layer was dried (MgS04) and concentrated to
give the corresponding alcohol which was taken in the next step without
further purification.
A solution of the previous alcohol in benzene (600 mL) was treated
with p-toluenesulfonic acid (54 g, 276 "01)
and heated to 65 "C for
3 h. After being cooled to 25 "C, the reaction mixture was treated
with Et3N (39 mL, 280 mmol), diluted with Et20 (600 mL), washed
with H20 (400 mL), aqueous NaHC03 (400 mL), and brine (400 mL),
dried (MgS04), concentrated (bath temperature <30 "C), and distilled
(40-45 "C, 0.05 " H g ) to give 3 (169 g, 70%) as a colorless liquid
Rf = 0.35 (silica, 2% Et20 in petroleum ether); 'H NMR (300 MHz,

CDC13) 6 5.05 (d, J = 1.0 Hz, 1H, HC=C), 4.74 (d, J = 1.0 Hz, 1 H,
HC-),
4.14 (q, J = 7.0 Hz, 2 H, C02CH2CH3), 1.97 (s, 3 H,
CH~C-CHZ),1.80 (s, 3 H, CH~CSC), 1.78 (s, 3 H, CH3C%), 1.24
(t, J = 7.0 Hz, 2 H, C02CHzCH3).
Alcohol 4. A solution of ester 3 (169 g, 1.01 mol) in CH2C12 (1000
mL) at -78 "C was treated with diisobutylaluminum hydride (2220
mL of a 1.0 M solution in CHzC12, 2.22 mol) and stirred at -78 "C for
0.5 h. The reaction mixture was allowed to warm to 25 "C and stirred
for 12 h. The reaction mixture was slowly poured into a mixture of
ice (600 mL) and glacial acetic acid (300 mL), and the resulting mixture
was stirred for 3.5 h. The aqueous layer was separated and extracted
with CHzClz (2 x 500 mL). The combined organic layer was washed
with brine (2 x 500 mL), dried (MgSOd), concentrated (bath temperature <25 "C), and purified by flash chromatography (silica, 20% Et20
in petroleum ether) to give 4 (117.4 g, 92%) as a pale yellow oil: Rf
= 0.26 (silica, 20% Et20 in petroleum ether); 'H NMR (300 MHz,
CDCl3) 6 5.08 (b d, J = 1.0 Hz, 2 H, C-CHz), 4.71 (b d, J = 1.0 Hz,
2 H, C=CHz), 4.16 (s, 2 H, CHzOH), 1.82 (t, J = 1.0 Hz, 3 H,
(CH3)C+Hz), 1.76 (s, 3 H, Ce(CH3)z), 1.71 (s, 3 H, C=(CH3)2).
Acetate 5. A solution of alcohol 4 (113.6 g, 0.9 mol) in CHzClz
(lo00 mL) at 0 "C was treated with Et3N (150.5 mL, 1.08 mol),
4-(dimethylamino)pyridine (DMAP, 22 g, 0.18 mol), and Ac20 (94.3
mL, 1.0 mol). The reaction mixture was allowed to warm to 25 "C
and stirred for 1 h. The reaction mixture was washed with HzO (2 x
300 mL) and brine (300 mL), and the combined aqueous layer was
extracted with CH2C12 (2 x 300 mL). The combined organic layer
was dried (Mgsod), concentrated, and purified by flash chromatography
(silica, 5% Et20 in petroleum ether) to give 5 (145.4 g, 96%) as a pale
yellow oil: Rf = 0.66 (silica, 20% Et20 in petroleum ether); 'H NMR
(300 MHz, CDCls) 6 4.96 (s, 1 H, C=CH2), 4.64 (s, 3 H, CsCH2 and
CHZOAC),2.02 (s, 3 H, COCH3), 1.77 (s, 3 H, CH,C=C), 1.75 (s, 3
H, CHsC=C), 1.71 (s, 3 H, CHsC=C).
Chloro Nitrile 7. A mixture of diene 5 (90.3 g, 537 "01)
and
freshly distilled 2-chloroacrylonitrile (65 mL, 806 "01,
purchased
from Tokyo-Kasei) was stirred at 130 "C in a sealed tube for 72 h.
During the course of the reaction, the reaction mixture turned dark
brown. The reaction mixture was allowed to cool to 25 "C and purified
by flash chromatography (silica, 10% Et20 in petroleum ether) to give
7 (110 g, 80%) as clear crystals: mp 86-88 "C, from EtzO; Rf= 0.25
(silica, 10% Et20 in petroleum ether); IR (thin film) v, 2979, 2938,
1730, 1436, 1370, 1240 cm-'; 'H NMR (300 MHz, CDC13) 6 4.63 (s,
2 H, CH~OAC),2.48-2.29 (band, 4 H, 13-CH2 and 14-CH2), 2.07 (s,
3 H, COCHj), 1.75 (s, 3 H, l8-CH3), 1.39 (s, 3 H, 16-CH3), 1.28 (s, 3
H, 17-CH3); FAB HRMS (NBNCsI) d e 388.0080, M
Cs+ calcd
for C13H&102N 388.0080.
Hydroxy Ketone 8. A solution of chloro nitrile 7 (15 g, 58.7 "01)
and KOH (19.8 g, 352 "01)
in t-BuOH (293 mL) was heated to 70
"C and stirred for 4 h. After being cooled to 25 "C, the reaction mixture
was diluted with EtOAc (lo00 mL) and washed with H20 (2 x 300
mL) and brine (300 mL). The combined aqueous layer was extracted
with EtOAc (4 x 200 mL), and the combined organic layer was dried
25
30% EtOAc in benzene) to give 7 (4.5 g, 30%) and 8 (6.2 g,
90% based on 70% conversion) as a pale orange oil: Rj = 0.30 (silica,
30% EtOAc in benzene); IR (thin film) v, 3410, 2980, 2930, 1710,
991 cm-l; IH NMR (500 MHz, CDC13) 6 4.26 (s, 2 H, CHZOH),2.53
(t, J = 8.5 Hz, 2 H, 13-CHz), 2.38 (t, J = 8.5 Hz, 2 H, 14-CHz), 1.84
(s, 3 H, 18-CH3), 1.44 (b S, 1 H, OH), 1.19 (s, 6 H, 16-CH3 and 17CH3); FAB H R M S (NBA/NaI) d e 191.1048, M
Naf calcd for
Cl&IlaOz 191.1050.
TBS Ether 9. A solution of alcohol 8 (4.00 g, 23.8 "01)
and
imidazole (1.95 g, 28.6 m o l ) in CHzClz (40 mL) at 0 "C was treated
with tert-butyldimethylsilyl chloride (TBSCl, 3.96 g, 26.2 mmol),
allowed to warm to 25 "C, and stirred for 2 h. After dilution with
Et20 (300 mL), the reaction mixture was washed with HzO (100 mL)
and brine (100 mL), dried (MgSOd), concentrated, and purified by flash
chromatography (silica, 5
10% Et20 in petroleum ether) to give 9
(5.71 g, 85%) as a pale yellow oil: Rj = 0.48 (silica, 10% Et20 in
petroleum ether); IR (thin film) v, 2929, 2857, 1716, 1462, 1377,
1253 cm-'; 'H NMR (500 MHz, CDC13) 6 4.12 (s, 2 H, lO-CHZ), 2.51
J. Am. Chem. SOC., Vol. 117, No. 2, I995 643

(t, J = 7.0 Hz, 2 H, 13-CHz), 2.36 (t, J = 7.0 Hz,2 H, 14-CHz), 1.74
(s, 3 H, 18-CH3), 1.18 (s, 6 H, 16-CH3 and 17-CH3), 0.87 (s, 9 H,
SiC(CH3)3(CH3)2), 0.05 (s, 6 H, SiC(CH3)3(CH3)2); I3C NMR (125 MHz,
CDC13) 6 215.2, 135.6, 131.8, 59.2, 41.2, 35.7, 30.5, 25.8, 24.6, 22.5,
18.2, -5.5; FAB HRMS (NBNCsI) d e 697.3056, M Cs+ calcd for
C 1&002Si 697.3085.
TBS Hydrazone 15. A solution of ketone 9 (2.79 g, 9.88 "01)
in THF (33 mL) at 25 "C was treated with (2,4,6-triisopropylbenzenesulfony1)hydrazine (2.95 g, 9.88 "01)
and stirred for 24 h. The
reaction mixture was concentrated, and the solid residue was dissolved
in a minimum amount of Et20 (10 mL). The solution was diluted with
petroleum ether (50 mL) and cooled to -20 "C to induce crystallization.
After removal of the mother liquor by filtration, the crystalline material
was washed with petroleum ether (30 mL) and dried in vacuo to give
15 (4.89 g, 88%) as colorless crystals: mp 135-137 "C, from EtzOpetroleum ether; Rf = 0.24 (silica, 20% Et20 in petroleum ether); IR
(thin film) v, 3250,2957, 1600 cm-I; IH NMR (500 MHz, CDC13)
6 7.68 (b s, 1 H, NH),7.21 (s, 2 H, Ar), 4.28 (septet, J = 7.0 Hz, 2 H,
o-CH(CH&), 4.14 (s, 2 H, lO-CH;?), 2.95 (septet, J = 7.0 Hz, 1 H,
p-CH(CH3)2), 2.44 (t, J = 7.0 Hz, 2 H, 13-CH2), 2.21 (t, J = 7.0 Hz,
2 H, 14-CH2), 1.75 (s, 3 H, 18-CH3), 1.33 (d, J = 7.0 Hz, 12 H, O-CH(cH3)2), 1.32 (d, J = 7.0 Hz, 6 H, p-CH(CH3)2), 1.13 (s, 6 H, 16-CH3
and 17-C&), 0.92 (s, 9 H, SiC(CH3)3(CH3)2), 0.10 (s, 6 H, SiC(CH3)3(CH3)2); I3C NMR (125 MHz, CDC13) 6 164.0, 152.9, 151.1, 136.0,
131.5, 131.4, 124.0, 123.4,59.0,42.2, 34.1,30.6,29.8, 26.0,26.0,25.9,
25.9, 25.8, 24.9, 24.8, 24.7, 24.6, 23.5, 21.4, 19.5, 18.3, -5.4; FAB
HRMS (NBA) d e 563.3716, M
H+ calcd for C31H5403N2SSi
563.3703.
Aldehyde 39. A solution of 1,4-dihydroxy-cis-2-butene
(137 g, 1.56
mol) and p-toluenesulfonic acid (1.35 g, 7 "01)
in CH2C12 (2000
mL) at 25 "C was treated with dihydropyran (300 mL, 3.29 mol),
dropwise, over the period of 0.5 h. After being stirred for 10 min, the
mixture was treated with Et3N (2.0 mL, 14 mmol), reduced in volume
to a total of 2 L, treated with decolorizing carbon, filtered through a
pad of silica gel, and concentrated to give a yellow oil that was taken
to the next step without further purification: Rf = 0.30 (silica, 25%
EtOAc in hexanes); IR (thin film) v,, 2950,2800, 1200, 1050 cm-I;
'H NMR (500 MHz, CDC13) 6 5.65 (t, J = 5.0 Hz, 2 H, CH), 4.55 (b
s, 2 H, OCHO), 4.19 (m. 2 H, CH2CH20),4.03 (m, 2 H, CHZCHZO),
3.77 (m, 2 H, CHCHzO), 3.42 (m, 2 H, OCHzCH), 1.75-1.43 (band,
12 H, CH2); I3C NMR (125 Hz, CDC13) 6 129.0,97.7,62.6, 61.9.30.4,
25.3, 19.2; FAB HRMS (NBA/NaI) d e 279.1572, M Na+ calcd for
Cl4H2404 279.1572.
A solution of the previous alkene (200 g, 0.78 mol) in CHZClz (600
mL) was treated with ozone at -78 "C until the solution tumed blue.
The reaction was quenched by the careful addition of triphenylphosphine
(205 g, 0.78 mol) in portions. The mixture was allowed to warm to
25 "C over the period of 8 h, concentrated, washed with Et20 (3 x
500 mL), and filtered. The combined washes were concentrated and
purified by flash chromatography (silica, 25% EtOAc in hexanes) to
give aldehyde 39 (220 g, 98%) as a clear oil: Rf = 0.20 (silica, 25%
EtOAc in hexanes); IR (thin film) vmax2944,2889, 1739, 1136, 1078,
1033; 'H NMR (500 MHz, CDC13) 6 9.72 (s, 1 H, HCO), 4.63 (t, J =
4.0 Hz, 1 H, OCHO), 4.22 (d, J = 18.0 Hz, A of AB, COCHzO), 4.16
(d, J = 18.0 Hz, B of AB, COCHZO),3.83 (m, 2 H, CHZCHZO),3.50
(m, 2 H, CHZCH~O),
2.00 - 1.50 (band, 4 H, CHI); 13C NMR (125
Hz, CDC13) 6 201.2, 99.4, 72.9, 62.5, 30.2, 25.1, 19.6; FAB HRMS
(NBADJaI) d e 167.0684, M Na+ calcd for C7H1203 167.0684.
Silyl Ether 40. Aldehyde 38 from 36. To a solution of allylic
and imidazole (15.7 g, 230.9 m o l )
alcohol 36 (11.6 g, 200.0 "01)
in DMF (200 mL) was added tert-butylchlorodiphenylsilane(58.4 mL,
220.0 mmol) dropwise at 0 OC. The solution was stirred at 0 OC for 1
h. After dilution with Et20 (500 mL), the solution was washed with
aqueous NH4Cl (100 mL), H20 (3 x 50 mL), and brine (100 mL).
The organic layer was dried (MgS04) and concentrated to give the
corresponding crude silyl ether (66.2 g) which was taken to the next
step without further purification.
A fraction of the crude silyl ether (13.0 g) was dissolved in CHZC12
(300 mL) and treated with 03 at -78 "C for 1 h. The reaction was
quenched with Ph3P (25.0 g, 96.0 mmol) at -78 OC, and the resulting
mixture was allowed to warm to 25 "C. After being stirred at 25 "C
for 0.5 h, the reaction mixture was diluted with toluene (100 mL) and
concentrated to give crude aldehyde 38 as a yellowish solid (40.7 g)

which was taken to the next step without further purification.
Aldehyde 38: Rf = 0.60 (silica, 50% Et20 in petroleum ether); 'H
NMR (300 MHz, CDC13) 6 9.72 (s, 1 H, CHO), 7.67-7.37 (band, 10
H, Ar), 4.21 (s, 2 H, CHz), 1.09 (s, 9 H, t-Bu).
Conversion of 38 to 40. To a solution of the crude aldehyde 38
(13.2 g) in CHzClz (200 mL) was added (carbethoxyethy1idene)triphenylphosphorane(22.3 g, 62.0 m o l ) in one portion. The reaction
mixture was stirred at 25 "C for 20 h, concentrated, and purified by
10% Et20 in petroleum ether) to
flash chromatography (silica, 5
give 40 (13.7 g, 91% from 36) as an oil: Rf = 0.80 (silica, 20% Et20
in petroleum ether); 'H NMR (300 MHz, CDC13)6 7.70-7.36 (band,
lOH,Ar),6.87(t,J=5.6H~,CH=),4.36(d,J=5.6H~,2H,CHz),
4.20 (q, J = 7.2 Hz, 2 H, COOCHz), 1.64 (s, 3 H, Me), 1.30 (t, J =
7.2 Hz, 3 H, COOCHZCH~),1.05 (s, 9 H, t-Bu).
Ester 41. A solution of aldehyde 39 (159 g, 1.10 mol) in CHzClz
(600 mL) at 0 "C was treated with a solution of (carbethoxymethy1ene)triphenylphosphorane (408 g, 1.13 mol) in CHZC12 (1200 mL) over
the period of 4 h. The solution was allowed to warm to 25 "C and
stirred for 18 h. The mixture was concentrated, suspended in 30%
Et20 in hexanes, and filtered through a pad of silica gel to give 41
(222 g, 90%) as an oil: Rf = 0.40 (silica, 30% EtOAc in hexanes); 'H
NMR (500 MHz, CDC13) 6 6.78 (m, 1 H, %H), 4.59 (m, 1 H, OCHO),
4.37 (m, 1 H, A of AB, CH~CHZO),
4.13 (band, 3 H, =CCH20 and
CH~CHZO),
3.80 (m, 1 H, B of AB, CHZCH~O),
3.47 (m, 1 H, B of
AB, =CCHzO), 1.79 (s, 3 H, CH3), 1.76-1.47 (band, 6 H, CHz), 1.23,
(t, J = 7.0 Hz, 3 H, CH3CH2).
Alcohol 42. A solution of ether 41 (222 g, 0.97 mol) in MeOH
(2500 mL) at 25 "C was treated with p-toluenesulfonic acid (1 g) and
stirred at 25 "C for 18 h. The mixture was treated with Et3N (2 mL),
concentrated, redissolved in EtOAc (1500 mL), washed with aqueous
NaHC03 (2 x 100 mL), HzO (2 x 100 mL), and brine (2 x 100 mL),
dried (MgS04). filtered, and concentrated to give a clear oil that was
purified by flash chromatography (silica, 40% ethyl acetate in hexanes)
to give 42 (128 g, 92%) as a colorless oil: Rf = 0.20 (silica, 30%
EtOAc in hexanes); IR (thin film) vm, 3434,2983,2934, 1713, 1650,
1446, 1368, 1261, 1132, 1031, 731; 'H NMR (500 MHz, CDC13) 6
6.62 (b S , 1 H, =CH), 4.11 (d, J = 6.0 Hz, 2 H, OCHzCH), 3.98 (q, J
= 7.0 Hz, 2 H, CHZCH~),
3.90 (s, 1 H, OH), 1.61 (s, 3 H, CH3C), 1.09
(t, J = 7.0 Hz, 3 H, CH2CH3); 13C NMR (125 Hz, CDC13) 6 167.5,
140.6, 127.5, 60.4, 58.8, 13.7, 12.0; FAB HRMS (NBNCsI) d e
276.9841, M Cs+ calcd for C7H1203 276.9846.
Diol 55. A. Small-Scale Procedure. A mixture of dienophile 42
(1.44 g, 10 mmol), diene 52 (1.52 g, 13.6 mmol), and PhB(OH)2 (1.7
g, 13.9 "01)
in benzene (30 mL) was stirred at reflux with azeotropic
removal of water (Dean-Stark trap) for 48 h. After the solution was
cooled to 25 "C, the reaction was quenched with 2,2-dimethyl-1,3propanediol(l.45 g, 13.9 m o l ) and the resulting mixture was stirred
at 25 "C for 1 h, concentrated, and purified by flash chromatography
(silica, 10 50% EtOAc in hexanes) to give dienophile 42 (0.33 g,
23%), diene 52 (0.51 g, 34%), and diol 55 (1.56 g, 79% based on 77%
conversion) as a yellow oil.
B. Large-Scale Procedure. A mixture of dienophile 42 (70.0 g,
0.49 mol), diene 52 (54.4 g, 0.49 mol), and PhB(0H)z (56.3 g, 0.45
mol) in benzene (lo00 mL) was stirred at reflux with azeotropic removal
of water (Dean-Stark trap) for 144 h. After the solution was cooled
to 25 "C, the reaction was quenched with 1,3-propanediol (36.8 mL,
0.51 mol) and the resulting mixture was stirred at 25 OC for 2.5 h,
concentrated, and purified by flash chromatography (silica, 10 50%
EtOAc in hexanes) to give dienophile 42 and diene 52 (64.7 g, 52%,
1:l mixture), plus diol 55 (34.88 g, 58% based on 48% conversion) as
a yellow oil: Rf = 0.13 (silica, 50% EtOAc in hexanes); IR (thin film)
vmax3423,2987, 1766, 1715, 1257, 1202, 1021 cm-I; 'H NMR (500
MHz, CDC13) 6 6.06 (dd, J = 10.0, 4.0 Hz, 1 H, 6-H), 5.78 (b d, J =
10.0 Hz, 1 H, 5-H), 4.57 (dd, J = 9.5, 7.5 Hz, 1 H, 2-H), 4.57-4.55
(band, 1 H, 7-H), 4.42 (dd, J = 9.5, 8.5 Hz, 1 H, 2-H), 4.15 (q, J =
7.0 Hz, 2 H, COZCH~CH~),
4.18-4.12 (band, 1 H, 4-OH), 3.07 (b t, J
= 8.5 Hz, 1 H, 3-H), 3.04 (b d, J = 5.0 Hz, 1 H, 7-OH), 1.25 ( s , 3 H,
19-CH3), 1.94 (t, J = 7.0 Hz, 3 H, C02CHzCH3); I3C NMR (125 MHz,
CDC13) 6 176.5, 175.6, 133.0, 124.9,71.6, 66.8, 62.4,47.3,46.6,42.0,
15.4, 13.8; FAB HRMS (NBA/NaI) mle 279.0859, M Na+ calcd for
C&1606 279.0845.
644 J. Am. Chem. SOC.,Vol. 117, No. 2, I995
Nicolaou et al.
Bis(sily1 ether) 58. A solution of diol 55 (28.5 g, 111 mmol), 2,6Diol 60. A solution of alcohol 59 (43.9 g, 99 "01)
in CHzClz
lutidine (102 mL, 445 mmol), and 4-(dimethylamino)pyridine (DMAP,
(250 mL) and MeOH (20 mL) was treated with camphorsulfonic acid
1.50 g, 12.2 "01)
in CHzClz (250 mL) was treated with teri(CSA, 0.52 g, 5 "01)
and stirred at 25 OC for 1 h. After dilution
butyldimethylsilyl trifluoromethanesulfonate (TBSOW, 52.0 mL, 445
with CHzClz (300 mL), the reaction was quenched with aqueous
"01)
and stirred at 0 "C for 4 h. The reaction mixture was added to
(150 mL). The organic layer was separated, and the aqueous
aqueous NaHCo3 (100 mL), extracted with Et20 (2 x 150 mL), washed
layer was extracted with Et20 (2 x 200 mL). The combined organic
with aqueous CuSO4 (2 x 100 mL), dried (NazSOh), concentrated, and
layer was dried (NazS04), concentrated, and purified by flash chro15% Et20 in petroleum
matography (silica, 50% Et20 in petroleum ether) to give diol 60 (32.6
ether) to give 58 (49.6 g, 92%) as a white solid: Rf = 0.62 (silica,
g, 94%) as white crystals: mp 109-1 11 "C, from EtOAc-hexanes; Rf
15% Et20 in petroleum ether); IR (thin film) vmm2960, 2936, 2857,
= 0.38 (silica, EtzO); IR (thinfilm) vmm3433,2932,2859,1766,1469,
1746, 1256 cm-'; 'H NMR (500 MHz, C&) 6 6.19 (dd,J = 8.5, 5.0
1384, 1081, 1023; 'H N M R (500 MHz, CDCl3) 6 5.99 (ddd, J = 18.0,
Hz, 1 H, 6-H), 6.10 (dd, J = 8.5, 1.0 Hz, 1 H, 5-H), 4.12 (dd, J = 8.5,
3.0, 1.5 Hz, 1 H, 5-H),
5.82 (dd, J = 18.0, 1.5 Hz, 1 H, 6-H), 4.38 (A
4.5 Hz, 1 H, 2-H), 4.11 (dd, J = 5.0, 1.0 Hz, 1 H, 7-H), 3.83-3.70
of ABX, dd, J = 9.5, 7.5 Hz, 1 H, 2-H), 4.33 (B of ABX, ddd, J =
(band, 2 H, CO~CHZCH~),
3.40 (d, J = 8.5 Hz, 1 H, 2-H), 2.83 (d, J
9.5, 5.0, 1.0 Hz, 1 H, 2-H), 4.24 (b S, 1 H, 7-H), 3.57 (A' of A'B', d
= 4.5 Hz, 1 H, 3-H), 1.22 (s, 3 H, 19-C&), 1.02 (s, 9 H, Si(C(CH3)3)b, J = 11.0 Hz, 1 H, 9-H), 3.39 (B' of A'B', b d, J = 11.0 Hz, 1 H,
(CH3)Zh 0.97 (s, 9 H, S~(C(CH~)S)(CH~)Z),
0.32 (s, 3 H, Si(C(CH3M9-H), 2.70-2.33 (band, 2 H, 9-OH and 7-OH), 2.55 (X of ABX,dd,
0.21 (s, 3 H, Si(C(CHsh)(cH3)2), 0.30 (s, 3 H, S~(C(CH~M(CH~)Z),
7.5,S.O
Hz, 1 H, 3-H), 0.88 (s, 3 H, 19-c&), 0.83 (s, 9 H, Si(C(CH3)3)(CH3)2), 0.15 (S, 3 H, Si(C(CH&)(CH3)2); 13CNMR (125 MHz, CD.5)
(CH3)2), 0.16 (s, 6 H, Si(C(CH3)3)(CH3)2);13CNMR (125 MHz, CDC13)
6 174.0, 133.5, 132.4, 119.0, 80.0, 70.9, 62.8, 60.6, 53.0, 45.9, 26.0,
6 175.7, 135.1, 124.4, 74.5, 68.7, 67.7, 66.4, 47.5, 41.9, 25.6, 18.1,
25.9, 20.5, 18.4, 14.0; FAB HRMS (NBA/NaI) mle 617.1731, M
12.9, -2.7, -3.1; FAB H R M S ( M A ) d e 329.1772, M H+ calcd
Na+ calcd for C2&06Si2 617.1731.
for C 1 & ~ 0 ~ S329.1784.
i
Alcohol 59. A solution of ester 58 (49.6 g, 102 "01)
in Et20
(500 mL) at 0 "C was treated with LiAEb (1 10 mL of a 1 M solution,
110 mmol), allowed to warm to 25 "C, and stirred at 25 "C for 0.5 h.
Acknowledgment. We thank Drs. Dee H. Huang, Gary
After the solution was cooled to -78 "C, the reaction was quenched
Siuzdak, and Raj Chadha for NMR, mass spectroscopic, and
with EtOAc (25 mL) and aqueous NH&1 (150 mL). The reaction
X-ray crystallographic assistance, respectively. This work was
mixture was allowed to warm to 25 "C and stirred for 1 h. The organic
financially supported by NM, The Scripps Research Institute,
layer was separated, and the aqueous layer was extracted with Et20 (3
fellowships from Mitsubishi Kasei Corporation (H.U.), R.W.
x 200 mL). The combined organic layer was dried (Na2S04),
The
Johnson-ACS Division of Organic Chemistry (E.J.S.),
Office of Naval Research (R. K. G.), Glaxo, Inc. (C.F.C.), Mr.
Et20 in petroleum ether) to give 59 (43.9 g, 97%) as a white solid: Rj
Richard Staley (C.F.C.), RhBne-Poulenc Rorer (P.G.N.), and
= 0.22 (silica, 30% Et20 in petroleum ether); IR (thin film) vman2955,
2931, 2857, 1471, 1280, 1253 cm-'; lH NMR (500 MHz, CDC13) 6
grants from Merck Sharp & Dohme, Pfizer, Inc., Schering
6.43 (dd, J = 8.5, 5.3 Hz, 1 H, 6-H), 6.20 (dd, J = 8.5, 1.7 Hz, 1 H,
Plough, and the ALSAM Foundation.
5-H),
4.10 (dd, J = 8.0, 4.1 Hz,1 H, 2-H), 3.95 (dd, J = 5.3, 1.7 Hz,
1 H, 7-H), 3.58 (d, J = 8.0 Hz, 1 H, 2-H), 3.25 (dd, J = 10.4, 4.3 Hz,
Supplementary Material Available: Experimental tech1 H, 9-H), 3.15 ( d d , J = 10.4,4.3 Hz, 1 H, 9-H), 1.60 (b t, J = 4 . 3 Hz,
niques and data for compounds 10-14,16,18-35,47-51,57,
1 H, 9-OH), 1.47 (d, J = 4.1 Hz, 1 H, 3-H), 1.22 ( s , 3 H, Ig-CH,),
0.92 (s, 9 H, Si(C(CH3)3)(CH3)d70.86 (s, 9 H, S~(C(CH~)~)(CH~)Z), 58, 61-80, 82-87, and 89-107 (44 pages). This material is
0.17 (s, 3 H, Si(C(CH3)3)(CH3)2). 0.15 (s, 3 H, S~(C(CH~)~)(CH~)Z), contained in many libraries on microfiche, immediately follows
this article in the microfilm version of the journal, and can be
0.12 (s, 3 H, Si(C(CHMCH3M, 0.10 (s, 3 H, Si(C(CH3)3)(CH3)2);
I3C NMR (125 MHz, C a s ) 6 132.8, 131.7, 119.0, 80.0, 72.0, 69.6,
ordered from the ACS. See any current masthead page for
63.1, 46.0,44.7, 26.0, 25.7, 18.9, 18.2, 18.0, -2.9, -3.0, -3.1, -3.2;
ordering information.
FAB HRMS (NBA/CsI) mle 575.1636, M Cs+ calcd for CzzH4205JA942 193U
Si2 575.1625.
J. Am. Chem. SOC.1995,117,645-652
645
Total Synthesis of Taxol. 3. Formation of Taxol's ABC Ring

Skeleton
K. C. Nicolaou,* Z. Yang,J.-J. Liu, P. G. Nantermet, C. F. Claiborne, J. Renaud,
R. K. Guy, and K. Shibayama
Contribution from the Department of Chemistry, The Scripps Research Institute,
10666 North Torrey Pines Road, La Jolla, Califomia 92037,and Department of Chemistry
and Biochemistry, University of Califomia, San Diego, 9500 Gilman Drive,
La Jolla, Califomia 92093
Abstract: The synthesis of Taxol's ABC ring system has been achieved. The Shapiro coupling of an aldehydic C
ring synthon (8) with an anionic A ring synthon derived from hydrazone 9 gave, diastereoselectively, A-B conjugate
10. Functional group manipulations and McMuny ring closure produced the highly functionalized ABC ring system
17. Extensive attempts to optimize the McMuny reaction revealed a single predominant side reaction leading to
byproducts 19 and 20. Resolution of the C9,ClO-diol (f)-17 via its camphanyl esters provided the ABC ring system
as its natural isomer (+)17.
Introduction
In the preceding two papers1-*in this series, we described

our degradation and reconstruction studies with Taxol (1, Figure
l), preliminary investigations with rings A and C, and possible
schemes for their elaboration to an appropriately functionalized
ABC taxoid framework. Armed with the knowledge gained in
these studies, we were now ready to attempt the final drive
toward Taxol's ABC ring skeleton. As already discussed, the
starting materials were defined as hydrazone 92 (Scheme 2) and
aldehyde 8 (Scheme l),the synthesis of which is detailed below.
The C4-C20 five-membered acetonide group was chosen as a
means to protect the vicinal diol system of the intermediate and
to introduce additional rigidity in the system prior to cyclization
to form the 8-membered ring.
1: Taxol
Scheme 1. Synthesis of C Ring Aldehyde 8"

HO
OH
OR
TPSO
TPSO
08
)TBS
Construction of Taxol's ABC Ring Skeleton

a. Synthesis of the C Ring Aldehyde 8. Scheme 1
summarizes the preparation of the targeted aldehyde 8 from the
previously described intermediate 2.* Thus, treatment of diol
2 with tert-butyldiphenylsilyl chloride (TPSC1) and imidazole3
resulted in monosilylation of the primary alcohol, providing the
C7 hydroxyl, C9 silyl ether 3 in 92% yield. Benzylation of the
C7 hydroxyl group using KH and benzyl bromide4 afforded
benzyl ether 4 in 88% yield. Exhaustive reduction of the lactone
ring in 4, accompanied by removal of the C4 TBS group,
resulted in the formation of triol 5 (80% yield). The crucial
5-membered ring acetonide was then installed using 2,2dimethoxypropane in the presence of a catalytic amount of CSA5
in methylene chloride:ether (98:2) at ambient temperature.
Under these conditions, the reaction was found to be quite rapid
* Address correspondenceto this author at The Scripps Research Institute

(1) Nicolaou, K. C.; Nantennet, P. G.; Ueno, H.; Guy, R. K.; Couladouros, E. A.; Sorensen, E. J. J . Am. Chem. SOC. 1995, 117, 624.
(2) Nicolaou, K. C.; Liu, J.-J.; Yang, Z.; Ueno, H.; Sorensen, E. J.;
Claibome, C. F.; Guy, R. K.; Hwang, C.-K.;Nakada, M.; Nantermet, P. G.
J . Am. Chem. SOC. 1995, 117, 634.
(3) Hanessian, S.; Lavallk, P. Can. J. Chem. 1975,53,2975. Hanessian,
S.: LavallBe. P. Can. J. Chem. 1977. 55. 562.
(4) Kand;, K.; Sakamoto, I.; Ogawa, S:; Suami,T. Bull. Chem. SOC.Jpn.
1987, 60, 1529.
(5) Lipshutz, B. H.; Barton, J. C. J. Org. Chem. 1988, 53, 4495.
@
Reagents and conditions: (a) 1.3 equiv of TPSCl, 1.35 equiv of

imidazole, DMF, 25 "C, 12 h, 92%; (b) 1.2 equiv of KH, 1.2 equiv of
PhCHZBr, 0.04 equiv of n - B N , EtzO, 25 OC, 1 h, 88%; (c) 3.0 equiv
of LiAlH4, EtzO, 25 OC, 12 h, 80%; (d) 5.0 equiv of 2,2-dimethoxypropane, 0.05 equiv of camphorsulfonicacid (CSA), CHzC1Z:EtzO(98:
2), 25 OC, 7 h, 82%; (e) 0.05 equiv of tetrapropylammonium
permthenate (PAP), 1.5 equiv of 4-methylmorpholineN-oxide W O ) ,
CH3CN, 25 "C, 2 h, 97%. TBS = Si-t-BuMez, Bn = CHZPh, TPS =
Si-t-BuPhz.
with the initially formed 7-membered ring acetonide 6 rearranging slowly and essentially completely to the desired, and
thermodynamically more stable, 5-membered ring isomer 7
(82%). Finally, PAP-NMO oxidation6 of the remaining
hydroxyl group in 7 furnished the targeted aldehyde 8 in 97%
0002-786319511517-0645$09.0010 0 1995 American Chemical Society
Nicolaou et al.

(Re face)
Nu'
12
16: L? chelate derived from aldehyde 8
Figure 3. Stereoselectivity of the Shapiro reaction. The model was
generated with Chem3d. Most hydrogens are omitted for clarity.
qn
k"
0
0
%
20
wo,
0
Scheme 2 to afford allylic alcohol 10 as a single diastereoisomer

and in 82% yield. X-ray crystallographic analysis of a
subsequent intermediate confirmed the stereochemical structure
of 10 (vide infra). The stereoselectivity of this reaction can be
explained by invoking the chelated intermediate 16, depicted
in Figure 3, in which the acetonide plays a crucial role. As
seen in this model, the aldehyde group is fixed by the lithium
template in a conformation in which nucleophilic attack can
freely proceed from only one side, the re face, with the si face
being blocked by the C8 methyl group.
Directed epoxidation9 of the C1-C14 double bond in 10,
although slow, proceeded smoothly to afford the single epoxide
11 in 87% yield. Regioselective openingloof the epoxide group
in 11 with LiAl& resulted in the formation of diol 12 in 76%
yield. The crystalline diol 12 was subjected to X-ray crystallographic analysis (see ORTEP drawing, Figure 2) confirming
the assigned stereochemistry of all intermediates in Scheme 2.
Exposure of 12 to excess KH and phosgene in ether:HMPA
(3: 1) resulted in the formation of carbonate 13 (86%yield, 58%
conversion). Desilylation of 13 with fluoride ion3 furnished
diol 14 (80%yield), which was oxidized smoothly with TPAPNM06 to afford the dialdehyde 15 (92% yield)preorganized in a conformation favorable for the upcoming
McMurry cyclization.
c. The McMurry Cyclization and Synthesis of the ABC

Ring Skeleton 17. The search for the conditions required to
yield the requisite cyclized product using the McMurry pinacol
Po
30
Figure 2. ORTEP drawings for compounds 12, 19, 20, and 30.
Yield. Thus a rapid and efficient Pathway to key i n t e r m d a t e

8 was established.
The
Reaction and Synthesis Of
reacti0n7'8 Of
Dialdehyde 15* The Shapiro
9 with aldehyde 8 proceeded under the conditions specified in
(6) Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23, 13.

(7) Shapiro, R. H. Org. React. 1976,23,405. Chamberlin, A. R.; Bloom,
S. H. Org. React. 1990, 39, 1. Martin, S. F.; Daniel, D.; Cherney, R. J.;
Liras, S. J. Org. Chem. 1992, 57, 2523.
(8) This strategy was later used by others to accomplish similar
couplings: Di Grandi, M. J.; Jung, D. K.; Krol, W. J.; Danishefsky, S. J.
J. Org. Chem. 1993, 58, 4989. Masters, J. J.; Jung, D. K.; Bornmann, W.
G.; Danishefsky, S. J. Tetrahedron Lett. 1993, 34, 7253.
(9) Sharpless, K. E.; Michaelson, R. C. J. Am. Chem. SOC. 1973, 95,
6136. Sharpless, K. B.; Verhoeven, T. R. Aldrichimica Acta 1979, 12, 63.
Rao, A. S . In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Ley, S. V., FRS, Eds.; Pergamon Press: New York, 1991; Vol. 7, p 376.
(10) Murai, S.; Murai, T.; Kato, S. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 8,
p
871.
(11) McMuny, J. E. Chem. Rev. 1989, 89, 1513. McMurry J. E. Acc.

Chem. Res. 1983,16,405. McMurry, J. E.; Lectka, T.; Rico, J. G. J . Org.
Chem. 1989,54,3748. McMurry, J. E.; Rico, J. G. Tetrahedron Lett. 1989,
30, 1169. Lenoir, D. Synthesis 1989, 883.
Scheme 3. McMurry Cyclization and Synthesis of Diol 17"
Scheme 2. Shapiro Coupling of 8 with 9 and Synthesis of

Dialdehyde 15"
TBSO
OBn
TPSO
&OTBS+
NNHS02Ar
OHC
i-Pr.
9, Ar = e i - P r
10
i-Pr
TBSO
TBSO
17 (23-25%)
18 (10%)
11
12
20 (15%)
19 (40%)
15
Reagents and conditions: 11 equiv of TiCl3*(DME)1.5,26equiv of

Zn-Cu, DME, reflux, 3.5 h, then 70 "C, then 15 added over 1 h, then
70 "C, 0.5 h. Bn = CH2Ph.
a
a Reagents and conditions: (a) 1.1 equiv of 9,2.3 equiv of n-BuLi,

0 "C, 1.0 equiv of 8, THF,-78 "C, 0.5 h, 82%; (b) 0.03
THF, -78
equiv of VO(acac)z, 3.0 equiv of t-BuOOH, PhH, 4 8,molecular sieves,
25 "C, 14 h, 87%; (c) 5.0 equiv of LiAlh, 25 "C, Et20,7 h, 76%; (d)
3.0 equiv of KH, Et20:HMPA (3:1), 1.6 equiv of phosgene (20% in
toluene), 25 "C, 0.5 h, 86% based on 58% conversion; (e) 3.8 equiv of
n - B u m (TBAF), THF, 25 O C , 14 h, 80%; (f) 0.05 equiv of
tetrapropylammonium permthenate (TPAF'), 3.O equiv of 4-methylmorpholine N-oxide (NMO), CH3CN, CH2Cl2, (2:1), 25 "C, 2 h, 92%.
TBS = Si-t-BuMez, TPS = Si-t-BuPh2, Bn = CHzPh.
coupling methodology included varying the temperature (0

100 "C), solvent (e.g. THF, DME, ether) and stoichiometry, as
well as the use of various bases as additives. It was finally
determined that 11 equiv of TiC13*(DME)1.5 and 26 equiv of
Zn-Cu couple in DME at 70 "C provided the optimum yield
of diol 17 (25%, Scheme 3). In addition to diol 17, whose
stereochemistry was assigned on the basis of a subsequent
intermediate (vide infia), a number of other products were
obtained including olefin 18 (10% yield), lactoll9 (40% yield),
and formate ester 20 (15% yield). The structures of 17 and 18
were based solely upon spectroscopic evidence (except for the
stereochemistry of 17 at C9 and C10 which was later confirmed,
vide infra), whereas those of 19 and 20 were secured from both
spectroscopic and X-ray crystallographic data (see ORTEP
drawings, Figure 2).
Analysis of molecular models for dialdehyde 15 indicated a
possible ground state conformation in which the two aldehyde
moieties of 15 are in close proximity (Figure 4), thus requiring
only small conformational changes to reach the geometry
necessary for cyclization. Rotation around the C2-C3 carboncarbon bond would either bring the two aldehyde groups in very
close proximity, as desired, or induce strong steric interactions
between ring A and the acetonide group. In contrast, dialdehyde
21 (see Figure 5 and previous paper2 in this series, Scheme 13,
6
'
O
0x
o
0 3 O
15
Figure 4. Possible ground state conformation of 15. The model was

generated with Chem3d. The C7 benzyl protecting group and all
hydrogens are omitted for clarity. Bn = CH9h.
structure 95) offers much higher conformational freedom via
rotation around the Cl-C2 carbon-carbon bond. Analysis of
molecular models indicated a possible ground state conformation
(21) (Figure 5) for this compound in which the two aldehyde
functionalities are far apart. Failure to cyclize to such a system
Nicolaou et al.
Scheme 4. Postulated Mechanism of the McMurry

Cyclization and Formation of Products 17 and 18
Ph
Tio
21
Figure 5. Possible ground state conformation of 21. The model was

generated with Chem3d. All hydrogens are omitted for clarity.
in the McMurry reaction may reflect the large entropic and

enthalpic cost for the conformational change necessary for
reaction to take place.
Mechanistic rationales for the formation of products 17-28
are shown in Schemes 4 and 5. The pathways leading to 1719 are in accord with previous proposals by McMurryl' and
Kende.12 The formation of the keto formate 20, however,
requires an additional oxygen atom which may, presumably,
come from molecular oxygen introduced during workup. A
speculative mechanism for its formation is proposed in Schemes
4 (15
22 24) and 5 (24 25 27 28 20).
Attempts at masking the C11-Cl2 double bond in order to
avoid the formation of byproducts 19 and 20 were abandoned
after unsuccessful early trials. Further studies along this line,
however, may prove useful in controlling product formation in
this reaction.
d. Resolution of ABC Ring System Diol 17. To secure
enantiomerically pure intermediates for the synthesis of Taxol
(l),we decided to attempt a resolution of the racemic diol 17
obtained from the McMurry cyclization as described above.
Encouraged by a successful resolution of a similar taxoid13 via
camphanate esters,14 we applied the sequence shown in Scheme
6 to our system. Treatment of diol (f)-17 with an excess of
(18-(-)-camphanic chloride in methylene chloride in the
presence of Et3N resulted in the formation of two diastereomeric
monoesters 29 and 30 in 36% total yield (1:l ratio). Chromatographic separation of the mixture allowed the more polar
isomer (30, Rf= 0.21, silica, 15% EtOAc in PhH; [ a ] 2-133
2~
(c 0.49, CHC13)) to crystallize. X-ray crystallographic analysis
(see ORTEP drawing, Figure 2) revealed the absolute stereochemistry of the latter diastereoisomer and thus allowed
identification of the requisite isomer for the synthesis of Taxol
as the less polar diastereoisomer (29; Rf = 0.26, silica, 15%
EtOAc in PhH;
+117 (c 0.54, CHC13)). Hydrolysis of
this isomer (29) under basic conditions (K2CO3, MeOH)
regenerated diol (+)-17 (90% yield; [o!]22D +187 (c 0.5,
CHC13)), now in its enantiomerically pure form.
- -
- - - -
(12) Kende, A. S.; Johnson, S.; Sanfilippo,P.; Hodges, J. C.; Jungheim,

L. N. J. Am. Chem. SOC. 1986, 108, 3513.
(13) Nicolaou, K. C.; Claiborne, C. F.; Nantermet, P. G.; Couladouros,
E. A.; Sorensen, E. J. J . Am. Chem. SOC. 1994, 116, 1591.
(14) Gerlach, H. Helv. Chim. Acta 1978, 61, 2773.
23
17
24
18
The appearance of the chiral auxiliary on the C9 hydroxyl

group of these esters (29 and 30) was at first surprising,
particularly in view of the fact that monoacetylation of diol 17
leads selectively to the C10 acetate (see following paper).15
Inspection of molecular models revealed rather similar steric
environments for these two positions, and therefore, predictions
or rationalizations were not easy to make. Apparently, the more
reactive allylic C10 hydroxyl group attracts the smaller acetate
group, whereas only the C9 hydroxyl can accommodate the
bulkier camphanate ester functionality.
Conclusion
In this paper we describe the successful construction of a
suitable ring C aldehyde (8) and its stereoselective coupling
with the ring A hydrazone (9) through a Shapiro reaction.
Elaboration of the A-C-coupled product (10) led to a dialdehyde (15) which entered into a successful McMurry cyclization
to afford ring B with retention of the C9 and C10 oxygens.
Resolution of the resulting racemic ABC taxoid diol 17 through
its diastereomeric camphanate esters (29 and 30) set the stage
for an enantioselective synthesis of Taxol(1). The final stages
of the total synthesis of this target molecule are described in
the following paper.15
the first paper in this series.l
Silyl Ether 3. A solution of diol 2 (9.20 g, 28.0 m o l ) in DMF
(50 mL) was treated with imidazole (2.58 g, 37.9 m o l ) and
(15) Nicolaou, K. C.; Ueno, H.; Liu, J.-J.; Nantermet, P. G.; Yang, Z.;
Renaud, J.; Paulvannan, K.; Chadha, R. J. Am. Chem. Soc. 1995,117,653.
Total Synthesis of Tmol. 3
J. Am. Chem. SOC., Vol. I 17, No. 2, 1995 649
Scheme 5. Postulated Mechanism for the Formation of

Products 19 and 20
- /
Scheme 6. Resolution of Diol 17"
O%
Ti0
Tio
02
(f)-l7
25
"I
27
H+ 1
Ti
/I
It
26
28
29
[a]"~
+117 (c 0.54, CHC13)
&p
OReagents and conditions: (a) 5.0 equiv of (18-(-)-camphanic

chloride, 20 equiv of EtsN, 0.05 equiv of 4-(dimethy1amino)pyridine
(DMAP), CHzC12, 25 "C, 1 h, 86%; (b) 7.0 equiv of K2C03, MeOH,
25 "C, 0.5 h, 90%. Bn = CHgh.
li "0
o
19
20
tea-butylchlorodiphenylsilane(9.46 mL, 36.0 m o l ) and stirred at 25

"C for 12 h. After dilution with Et20 (400 mL), the reaction was
quenched with aqueous NaHCO3 (100 mL). The organic layer was
separated, and the aqueous layer was extracted with Et20 (2 x 50 mL).
The combined organic layer was washed with brine (50 mL), dried
(Na2S04),concentrated, and purified by flash chromatography (silica,
30% Et20 in petroleum ether) to give 3 (14.6 g, 92%) as a pale yellow
oil: Rj = 0.41 (silica, 50% Et20 in petroleum ether); IR (thin film)
vmax3460,2954,2931,2857, 1770, 1471, 1110, 1086 cm-'; 'HNMR
(500 MHz, CDCl3) 6 7.65-7.55 (band, 4 H, Ar), 7.48-7.35 (band, 6
H, Ar), 5.91 (dd, J = 10.5, 2.0 Hz, 1 H, 6-H), 5.84 (dd, J = 10.5, 2.5
Hz, 1 H, 5-H), 4.58 (m, 1 H, 7-H), 4.19 (dd, J = 10.0, 6.5 Hz, 1 H,
2-H), 3.95 (dd, J = 10.0, 2.0 Hz, 1 H, 2-H), 3.61 (d, J = 10.6 Hz, 1
H, 9-H), 3.41 (d, J = 10.6 Hz, 1 H, 9-H), 2.59 (dd, J = 6.5, 2 Hz, 1
H, 3-H), 2.05 (d, J = 5.5 Hz, 1 H, 7-OH), 1.07 (s, 9 H, SiC(CH3)sPhz), 0.80 (s, 9 H, SiC(CH3)3(CH&), 0.69 (s, 3 H, 19-C&), 0.11 (s, 6
H, SiC(CH&(CH&); 13C NMR (125 MHz, CDC13) 6 175.3, 136.1,
135.6, 135.5, 132.6, 132.5, 130.1, 127.9, 124.6, 74.5, 68.7, 66.6, 65.6,
47.2,44.1,26.9,25.4, 19.2, 18.0, 11.0, -2.8, -3.1; FAB H R M S (NBN
NaI) mle 589.2795, M Na+ calcd for C3zH4605Si~589.2782.
Benzyl Ether 4. A solution of alcohol 3 (21.5 g, 37.9 mmol), benzyl
bromide (5.4 mL, 45.4 mmol), and n - B W (0.5 g, 1.35 mmol) in Et20
(300 mL) was treated with KH (6 g of a 30% suspension in mineral
oil, 44.8 mmol, prewashed with dry EtzO) and stirred at 25 "C for 1 h.
After the reaction was quenched with MeOH (5 mL), the reaction
mixture was stirred at 25 "C for 15 min. After dilution with Et20
(200 mL), the resulting solution was washed with brine (100 mL), dried
(Na2S04), concentrated, and purified by flash chromatography (silica,
30% Et20 in petroleum ether) to give 4 (21.9 g, 88%) as a
10
yellowish oil: Rj = 0.57 (silica, 25% Et20 in petroleum ether); IR
(thin film) vmax2956, 2925,2849, 1773, 1467, 1101 cm-I; 'H NMR
(500 MHz, CDC13) 6 7.65-7.55 (band, 4 H, Ar), 7.45-7.25 (band, 11
H, Ar), 6.04 (dd, J = 10.0, 2.5 Hz, 1 H, 6-H), 5.82 (dd, J = 10.0, 2.5
(+)-17
Hz, 1 H, 5-H), 4.72 (d, J = 11.5 Hz, 1 H, OCHzPh), 4.58 (d, J = 11.5
Hz, 1 H, OCH2Ph). 4.36 (dd, J = 2.5, 2.0 Hz, 1 H, 7-H), 4.08 (dd, J
= 9.5, 7.0 Hz, 1 H, 2-H), 3.96 (dd, J = 9.5, 3.5 Hz, 1 H, 2-H), 3.69
(d, J = 10.6 Hz, 1 H, 9-H), 3.39 (d, J = 10.6 Hz, 1 H, 9-H), 2.66 (dd,
J = 7.0, 3.5 Hz, 1 H, 3-H), 1.08 (s, 9 H, SiC(CH3)3Ph2), 0.78 (s, 9 H,
SiC(CH3)3(CH3)2), 0.77 (s, 3 H, 19-C&), 0.12 (s, 3 H, SiC(CH3)3(cH3)2), 0.11 (s, 3 H, SiC(CHs)s(CH3)2); 13CNMR (125 MHz, CDCl3)
6 175.6, 138.3, 135.6, 132.9, 132.9, 132.8, 130.0, 129.8, 128.4, 127.8,
127.7, 127.6, 127.4, 124.7,74.5,74.4,72.6,65.7,65.6,47.5,43.9,27.0,
25.5, 19.3, 18.0, 12.8, -2.8, -3.1; FAB H R M S (NBNCsI) mle
789.2395, M Cs+ calcd for C39H5205Si~789.2408.
Triol 5. A solution of lactone 4 (14.7 g, 22.4 m o l ) in Et20 (150
mL) was treated with LiAlH4 (66 mL of a 1 M solution in EtzO, 66.0
mmol) and stirred at 25 "C for 12 h. After dilution with Et20 (200
mL), the reaction mixture was cooled to -78 "C, and the reaction was
quenched with aqueous W C 1 (100 mL). After the solution was
w m e d to 25 OC, the organic layer was separated, washed with brine
(100 mL), dried (NazSOd), concentrated, and purified by flash
chromatography (silica, 60% EtOAc in petroleum ether) to give 5 (9.8
g, 80%) as a colorless oil: Rj = 0.23 (silica, 50% EtOAc in hexanes);
IR (thin film) vmar3374, 2927, 2851, 1463, 1422, 1387, 1105 cm-';
'H NMR (500 MHz, CDC13) 6 7.65-7.55 (band, 4 H, Ar),7.45-7.15
(band, 11 H, Ar),5.85 (dd, J = 10.0,2.5 Hz, 1 H, 6-H), 5.69 (dd, J =
10.0, 1.5 Hz, 1 H, 5-H), 4.55 (d, J = 11.5 Hz, 1 H, OCHzPh), 4.27 (d,
J = 11.5 Hz, 1 H, OCHzPh), 4.01 (b S, 1 H, 7-H), 3.96-3.89 (band, 3
H, 20-CH2 and 2-H), 3.72 (d, J = 10.5 Hz, 1 H, 9-H), 3.70 (s, 1 H,
4-OH), 3.58 (m, 1 H, 2-H), 3.51 (d, J = 10.5 Hz, 1 H, 9-H), 3.453.35 (band, 2 H, 2-OH and 20-OH), 2.15 (dd, J = 6.5, 3.5 Hz, 1 H,
3-H), 1.09 (s, 9 H, SiC(CH3)3Phz), 0.89 (s, 3 H, 19-CI-h); 13C NMR
(125 MHz, CDC13) 6 138.1, 135.8, 135.7, 132.9, 131.2, 129.9, 129.8,
128.3, 128.2, 127.7, 127.5, 127.3, 76.2, 73.1, 71.6, 67.1, 66.7, 59.4,
48.0, 43.4, 27.0, 25.8, 19.3, 15.3; FAB H R M S (NBNCsI) mle
679.1871, M Cs+ calcd for C33H4205Si 679.1856.
Acetonide 7. A solution of triol 5 (16.2 g, 29.6 mmol) and 2,2dimethoxypropane (18.2 mL, 148 mmol) in CH2Cl2 (98 mL) and Et20
(2 mL) was treated with camphorsulfonic acid (350 mg, 1.5 m o l )
and stirred at 25 "C for 7 h. After the reaction was quenched with

aqueous NaHC03 (50 mL), the organic layer was separated, dried (Nazconcentrated, and purified by flash chromatography (silica, 50%
Et20 in petroleum ether) to give 7 (14.25 g, 82%) as a colorless oil:
Rf = 0.51 (silica, 50% Et20 in petroleum ether); IR (thin film) vmax
3467,2932,2858, 1462, 1373, 1210, 1106, 1054 cm-'; 'H NMR (500
MHz, CDC13) 6 7.66-7.60 (band, 4 H, Ar), 7.45-7.20 (band, 9 H,
Ar), 7.15-7.05 (band, 2 H, Ar), 5.79 (dd, J = 10.0, 1.5 Hz, 1 H, 6-H),
5.72 (dd, J = 10.0, 2.5 Hz, 1 H, 5-H), 4.45 (d, J = 11.5 Hz, 1 H,
OCHZPh), 4.16 (d, 9.0 Hz, 1 H, 20-H), 4.11 (d, J = 11.5 Hz, 1 H,
OCHzPh), 3.99 (b S, 1 H, 7-H), 3.97-3.89 (band, 2 H, 2-CH2), 3.81
(d, 9.0 Hz, 1 H, 20-H), 3.76 (A of AB, d, J = 10.5 Hz, 1 H, 9-H), 3.73
(B of AB, d, J = 10.5 Hz, 1 H, 9-H), 3.42 (b t, J = 6.0 Hz, 1 H,
2-OH), 2.14 (t, J = 4.0 Hz, 1 H, 3-H), 1.44 (s, 3 H, C(CH3)2), 1.42 (s,
3 H, C(CH&), 1.09 (s, 9 H, SiC(CH&Phz), 0.87 (s, 3 H, 19-CH3); 13C
NMR (125 MHz, CDCl3) 6 138.1, 135.9, 135.8, 132.9, 132.7, 132.5,
129.9, 129.8, 128.2, 127.7, 127.4, 127.2, 126.6, 107.9, 81.9,75.9,71.3,
70.0, 67.1, 58.8, 48.1, 44.2, 27.3, 27.0, 26.4, 19.3, 14.1; FAB HRMS
(NBA/NaI) m/e 609.3028, M Na+ calcd for C36H4605si 609.3012.
Aldehyde 8. A solution of alcohol 7 (9.7 g, 16.5 m o l ) in CH3CN
(100 mL) was treated with tetrapropylammoniumpenuthenate (TPAP,
290 mg, 0.83 "01)
and 4-methylmorpholine N-oxide (NMO, 2.91 g,
24.8 "01)
and stirred at 25 "C for 2 h. After dilution with CHzCl2
(400 mL), the reaction mixture was filtered through silica gel. The
resulting solution was concentrated and purified by flash chromatography (silica, 30% Et20 in petroleum ether) to give 8 (9.37 g, 97%) as
a white foam: Rf = 0.45 (silica, 30% Et20 in petroleum ether); IR
(thin film) vmax2931, 2857, 1720, 1472, 1428, 1371, 1111 cm-'; 'H
NMR (500 MHz, CDCls) 6 9.98 (d, J = 3.5 Hz, 1 H, 2-H), 7.65-7.55
(band, 4 H, Ar), 7.47-7.22 (band, 9 H, Ar), 7.17-7.10 (band, 2 H,
Ar), 5.84 (dd, J = 10.5, 1.5 Hz, 1 H, 6-H), 5.71 (dd, J = 10.5, 2.0 Hz,
Nicolaou et al.
28.6, 26.9, 26.7, 26.1, 26.0, 24.6, 19.4, 19.3, 19.2, 18.3, -5.3; FAB
Cs+ calcd for C52H7406Si~
HRMS (NBNCsI) d e 983.4050 M
983.4078.
Epoxide 11. A solution of allylic alcohol 10 (18.7 g, 22.0 "01)
in benzene (500 mL) was treated with 4-A molecular sieves (2 g), VO(acac)~(175 mg, 0.66 mmol), and t-BuOOH (22 mL of a 3 M solution
in decane, 66.0 "01)
and stirred at 25 "C for 14 h. After the reaction
was quenched with MezS (5 mL) and aqueous N&Cl (300 mL), the
reaction mixture was extracted with Et20(200 mL). The organic layer
was dried (Na~S04),concentrated, and purified by flash chromatography
(silica, 15% Et20 in petroleum ether) to give 11 (16.6 g, 87%) as a
colorless oil: Rf= 0.47 (silica, 15% EtzO in petroleum ether); IR (thin
film) Y- 3490, 2935, 2852, 1471, 1257, 1049 cm-'; 'H NMR (500
MHz, CDC13) 6 7.65-7.55 (band, 4 H, Ar), 7.50-7.28 (band, 11 H,
Ar), 5.82 (d, J = 10.0 Hz, 1 H, 5-H), 5.74 (dd, J = 10.0, 5.0 Hz, 1 H,
6-H), 4.82 (d, J = 4.5 Hz, 1 H, 2-H), 4.70 (d, J = 11.5 Hz, 1 H,
OCHzPh), 4.56 (d, J = 10.0 Hz, 1 H, 20-H), 4.54 (d, J = 11.5 Hz, 1
H, OCHzPh), 4.14 (A of AB, d, J = 11.5 Hz, 1 H, 10-H), 4.1 1 (B of
AB, d, J = 11.5 Hz, 1 H, 10-H), 4.06 (d, J = 10.0 Hz, 1 H, 20-H),
3.85 (d, J = 10.0 Hz, 1 H, 9-H), 3.71 (d, J = 5.0 Hz, 1 H, 7-H), 3.54
(d, J = 10.0 Hz, 1 H, 9-H), 3.35 (d, J = 4.5 Hz, 1 H, 2-OH), 2.93 (s,
1 H, 14-H), 2.49 (b S, 2 H, 13-CH2), 1.80 (s, 1 H, 3-H), 1.70 (s, 3 H,
18-CH3), 1.41 (s, 3 H, Ig-CHs), 1.30 (s, 3 H, C(CH3)2), 1.29 (s, 3 H,
C(CH3)2), 1.25 (s, 3 H, C(CH3)2), 1.24 (s, 3 H, C(CH3)2), 1.06 (s, 9 H,
SiC(CH3)3Ph2),0.90 (s, 9 H, SiC(CH3)3(CH3)2),0.08 (s, 3 H, SiC(CH3)3(cH3)2), 0.07 (s, 3 H, SiC(CH3)3(CH3)2); 13CNMR (125 MHz, CDCl3)
6 137.8, 135.9, 135.6, 135.6, 135.4, 134.1, 133.7, 129.4, 129.3, 128.3,
127.7, 127.4, 127.2, 123.9, 122.0, 107.1, 79.6, 74.3, 72.3, 70.8, 69.2,
64.1, 58.8, 53.4, 44.9, 42.3, 39.6, 31.7, 28.3, 26.9, 26.1, 25.9, 25.9,
25.8, 23.2, 21.9, 19.4, 19.3, 16.8, -5.5, -5.6; FAB HRMS (NBN
CsI) d e 999.4050, M Cs' calcd for C52H7407Si2 999.4027.
1H,5-H),4.50(d,J~11.5H~,1H,OCH~Ph),4.22(d,J~11.5H~,
Diol 12. A solution of epoxide 11 (20.06 g, 23.1 "01)
in Et20
1 H, OCHzPh), 4.20 (d, 9.5 Hz, 1 H, 20-H), 4.10 (dd, J = 2.0, 1.5 Hz,
(100 mL) was treated with LiA1I-b (115 mL of a 1 M solution in EtzO,
1 H, 7-H), 3.84 (d, 9.5 Hz, 1 H, 20-H), 3.72 (A of AB, d, J = 10.0 Hz,
115 "01)
and stirred at 25 OC for 7 h. After dilution with Et20 (200
1 H, 9-H), 3.70 (B of AB, d, J = 10.0 Hz, 1 H, 9-H), 3.18 (d, J = 3.5
mL), the reaction mixture was cooled to -78 "C, and the reaction was
Hz, 1 H, 3-H), 1.42 (s, 3 H, C(CH3)z). 1.39 (s, 3 H, C(CH3)z). 1.09 (s,
quenched with EtOAc (25 mL) followed by aqueous NI&Cl(100 mL).
9 H, SiC(CH&Phz), 1.04 (s, 3 H, 19-CH3); 13C NMR (125 MHz,
After warming to 25 "C, the organic layer was separated and the
CDC13)G 202.3, 138.1, 135.8, 135.8, 135.7, 135.6, 133.0, 132.9, 131.1,
aqueous layer was extracted with Et20 (2 x 100 mL). The combined
129.7, 129.7, 129.5, 128.8, 128.2, 128.2, 127.6, 127.4, 127.4, 127.2,
organic layers were dried (NazSOd),concentrated, and purified by flash
127.2, 127.1, 108.6, 80.7.75.4, 71.8,70.0,65.7, 57.6,44.9, 26.9, 26.5,
chromatography (silica, 30% Et20 in petroleum ether) to give 12 (15.3
g, 76%) as colorless crystals: mp 115-1 17 "C, from CHzCl2-hexanes;
19.3, 13.6; FAB HRMS (NBA/NaI) mle 607.2865, M Na+ calcd for
Rf = 0.58 (silica, 30% Et20 in petroleum ether); IR (thin film) Y,,
C36Hu05Si 607.2856.
3468,2955,2857, 1471, 1367, 1254, 1052 cm-'; IH NMR (500 MHz,
Alcohol 10. To a solution of hydrazone 9 (28.2 g, 50.1 "01)
in
CDC13) 6 7.65-7.61 (band, 4 H, Ar), 7.42-7.28 (band, 11 H, Ar),
THF (400 mL) at -78 OC was added dropwise n-BuLi (65.5 mL of a
5.85(d,J=10.5H~,lH,5-H),5.67(dd,J=10.5,5.0Hz, 1H,6-H),
1.6 M solution in hexanes, 105 "01).
After the reaction mixture was
4.63 (d, J = 11.0 Hz, 1 H, OCHZPh), 4.55 (d, J = 10.0 Hz, 1 H, 20stirred at -78 "C for 20 min, it was allowed to warm to 0 OC, resulting
H), 4.54 (d, J = 11.0 Hz, 1 H, OCHZPh), 4.18 (d, J = 4.5 Hz, 2-H),
in Nz gas evolution. The resulting bright orange solution was cooled
4.16
(d, J = 11.0 Hz, 1 H, 10-H), 4.07 (d, J = 10.0 Hz, 1 H, 10-H),
to -78 "C, and a solution of the aldehyde 8 (26.4 g, 45.1 mmol) in
3.97
(d, J = 4.5 Hz, 1 H, 2-OH), 3.87 (d, J = 11.0 Hz, 1 H, 20-H),
THF (100 mL) was slowly added via canula. The reaction mixture
3.79
(d,
J = 10.0 Hz, 1 H, 9-H), 3.64 (d, J = 5.0 Hz, 1 H, 7-H), 3.57
was stirred at -78 "C for 0.5 h, and then the reaction was quenched
(d, J = 10.0 Hz, 1 H, 9-H), 3.22 (b S, 1 H, 1-OH), 2.23-2.04 (band,
with aqueous N&Cl (50 mL). After being warmed to 25 "C, the
2 H, 13-CHz), 2.15 (s, 1 H, 3-H), 1.77-1.59 (band, 2 H, 14-CH2),
reaction mixture was extracted with Et20 (2 x 200 mL). The organic
1.67 (s, 3 H, 18-CH3), 1.23 (s, 6 H, C(CH3)2), 1.19 (s, 3 H, 19-CH3),
layer was dried (Na2S04), concentrated, and purified by flash chro1.07 (s, 3 H, C(CH&), 1.06 (s, 9 H, SiC(CH&Phz), 0.98 (s, 3 H,
matography (silica, 15% Et20 in petroleum ether) to give 10 (31.7 g,
C(CH&), 0.92 (s, 9 H, SiC(CH3)3(CH3)2),0.09 (s, 3 H, SiC(CH3)382%) as a colorless oil: Rf= 0.25 (silica, 10% Et20 in petroleum ether);
(CH3)2), 0.08 (s, 3 H, SiC(CH3)3(CH3)2); I3CNMR (125 MHz, CDC13)
IR (thin film) v, 3445, 2935, 2852, 1251, 1464, 1429, 1370, 1049
6 137.5, 136.3, 135.7, 135.6, 135.0, 133.9, 133.7, 129.9, 129.4, 129.3,
cm-'; 'H NMR (500 MHz, CDC13)6 7.73-7.65 (band, 4 H, Ar), 7.48128.3, 127.9, 127.7, 127.3, 122.6, 107.2, 79.5, 74.5, 74.3, 72.7, 72.6,
7.25 (band, 11 H, Ar), 5.98 (b s, 1 H, 14-H), 5.97 (d, J = 10.0 Hz, 1
71.1, 68.8, 59.5, 47.2, 44.3, 43.6, 29.9, 28.5, 27.8, 26.9, 26.7, 25.9,
H, 5-H), 5.79 (dd, J = 10.0, 5.0 Hz, 1 H, 6-H), 4.88 (b S, 1 H, 2-H),
20.9, 19.3, 19.1, 19.0, 18.3, -5.4, -5.5; FAB HRMS (NBNCsI) m/e
4.73 (d, J = 11.5 Hz, 1 H, OCHzPh), 4.59 (d, J = 11.5 Hz, 1 H, OCH21001.4170, M cs+ calcd for C52H7607Si~1001.4184.
Ph), 4.45 (d, 9.5 Hz, 1 H, 20-H), 4.33 (d, J = 10.5 Hz, 1 H, 10-H),
Carbonate 13. A solution of diol 12 (9.67 g, 11.1 "01)
in Et20
4.29 (d, J = 3.5 Hz, 1 H, 2-OH), 4.24 (d, J = 10.5 Hz, 1 H, 10-H),
(150 mL) and hexamethylphosphoramide(HMPA, 50 mL) was treated
3.96 (d, 9.5 Hz, 1 H, 20-H), 3.79 (d, J = 10.0 Hz, 1 H, 9-H), 3.72 (d,
with KH (4.41 g of a 30% suspension in mineral oil, 33.0 "01,
J = 10.0 Hz, 1 H, 9-H), 3.70 (d, J = 5.0 Hz, 1 H, 7-H), 2.80-2.65
prewashed with dry Et20) and stirred at 25 OC for 20 min, after which
(band, 3 H, 3-H and 13-CH2), 1.81 (s, 3 H, 18-CH3), 1.43 (s, 3 H,
was added.
phosgene (10 mL of a 20% solution in toluene, 17.5 "01)
C(CH3)2), 1.41 (s, 3 H, C(CH3)z). 1.35 (s, 3 H, 16-CH3), 1.32 (s, 3 H,
The reaction mixture was stirred at 25 OC for 0.5 h. After dilution
17-CH3), 1.25 (s, 3 H, 19-C&), 1.11 (s, 9 H, SiC(CH&Ph2), 0.98 (s,
with Et20 (300 mL), the reaction mixture was added to a half saturated
9 H, SiC(CH&(CH3)2), 0.15 (s, 6 H, SiC(CH3)3(CH3)2); 13CN M R (125
solution of tartaric acid. The organic layer was separated, washed with
MHz, CDC13) 6 145.1, 137.5, 137.0, 135.7, 135.7, 135.1, 133.9, 133.7,
brine (150 mL), dried (NazSOd), concentrated, and purified by flash
129.4, 129.4, 129.0, 128.4, 127.8, 127.7, 127.4, 127.4, 122.6, 120.7,
chromatography (silica, 2% MeOH in CH2C12) to give diol 12 (4.06 g,
106.7, 80.2, 74.1, 72.4, 71.4, 70.9, 68.4, 59.1, 46.9, 43.3, 39.2, 33.6,
42%) and carbonate 13 (4.72 g, 86% based on 58% conversion) as a
Total Synthesis of Tarol. 3
yellow solid Rf = 0.64 (silica, 2% MeOH in CHZC12); IR (thin film)

v, 2932, 2857, 1800, 1472, 1254, lo00 cm-'; 'H N M R (500 MHz,
cDc13) 6 7.63-7.58 (band, 5 H, Ar), 7.42-7.28 (band, 10 H, Ar),
0.5 h. After cooling to 25 "C, the reaction mixture was added to a

saturated solution of NaHC03 (100 mL), and the resulting mixture was
stirred at 25 "C for 2 h. The organic layer was separated, and the
5.85(dd,J~10.0,5.0Hz,1H,6-H),5.79(d,J~10.0Hz,1H,5-H),
aqueous phase was extracted with EtOAc (3 x 75 mL). The combined
5.32 (s, 1 H, 2-H), 4.66 (d, J = 11.5 Hz, 1 H, OCHZPh), 4.36 (d, J =
organic layer was dried (NaZSOd), concentrated, and purified by flash
11.5 Hz, 1 H, OCHzPh), 4.09 (A of AB, d, J = 11.5 Hz, 1 H, 20-H),
4.06(BofAB,d,J=11.5Hz,lH,20-H),4.04(d,J=9.0Hz,lH, products 17 (65.3 mg, 25%), 18 (24.6 mg, lo%), 19 (104.4 mg, 40%),
lO-H), 3.97 (d, J = 9.0 Hz, 1 H, 10-H), 3.73 (d, J = 10.5 Hz, 1 H,
and 20 (40.5 mg, 15%).
9-H), 3.62 (d, J = 5.0 Hz, 1 H, 7-H), 3.60 (d, J = 10.5 Hz,1 H, 9-H),
Diol 17: Rf = 0.41 (silica, 50% EtOAc in hexanes); IR (thin film)
2.42-2.02 (band, 4 H, 13-CHz and 14-CH2), 2.26 (s, 1 H, 3-H), 1.65
Y3490,2970,1789,1456,1100 cm-1; 'H NMR (500 MHz, CDc13)
(s, 3 H, 18-CH3), 1.25 (s, 3 H, C(CH3)2), 1.24 (s, 3 H, C(CH&), 1.14
6 7.42-7.31 (band, 5 H, Ar), 5.97 (dd, J = 10.0, 1.5 Hz, 1 H, 5-H),
(s, 3 H, 19-CH3), 1.09 (s, 3 H, C(CH&), 1.07 (s, 9 H, SiC(CH3)3Ph2),
5.63 (dd, J = 10.0, 1.5 Hz, 1 H, 6-H), 5.46 (d, J = 5.0 Hz, 1 H, 2-H),
1.03 (s, 3 H, C(CH3)2), 0.88 (s, 9 H, SiC(CH3)3(CH3)2),0.05 (s, 3 H,
4.77 (d, J = 12.0 Hz, 1 H, OCHZPh), 4.49 (d, J = 8.5 Hz, 1 H, 20-H),
S~C(CH~)~(CH~)Z),
0.03 (s, 3 H, SiC(CH3)3(CH&); NMR (125 MHz,
4.39 (d, J = 12.0 Hz, 1 H, OCHZPh), 4.29 (b t, J = 6.0 Hz, 1 H,
CDC13) 6 154.7, 138.7, 135.7, 135.6, 134.0, 133.7, 133.5, 132.5, 130.5,
lO-H), 4.24 (dd, J = 6.0, 3.0 Hz,1 H, 9-H), 3.80 (d, J = 8.5 Hz, 1 H,
129.5, 129.4, 128.0, 127.6, 127.4, 127.3, 125.2, 107.3, 88.2,79.7,78.9,
20-H), 3.58 (b S, 1 H, 7-H), 2.87 (d, J = 3.0 Hz, 1 H, 9-OH), 2.70
73.1, 71.2, 71.2, 70.4, 59.4, 46.5, 44.2, 43.4, 29.3, 27.9, 27.0, 26.6,
(ddd, J = 15.0, 10.5, 3.0 Hz,1 H, 14-H), 2.54 (ddd, J = 20, 12.0, 3.0
25.8, 25.2, 19.3, 19.1, -5.6; FAB H R M S (NBNCsI) mle 1027.3950,
Hz, 1 H, 13-H), 2.31 (d, J = 5.0 Hz, 1 H, 3-H), 2.18 (d, J = 6.0 Hz,
M 4-cs+ calcd for C53H7408Si~1027.3977.
1 H, lO-OH), 1.93 (ddd, J = 20.0, 10.5, 3.0 Hz, 1 H, 13-H), 1.78
Diol 14. A solution of carbonate 13 (4.72 g, 5.27 m o l ) in THF
(ddd, J = 15.0, 12.0, 3.0 Hz,1 H, 14-H), 1.56 (s, 3 H, 18-CH3),1.42
(20 mL) was treated with n - B W (TBAF,20 mL of a 1.0 M solution
(S, 3 H, 19-CH3), 1.39 (s, 3 H, 16-CH3), 1.38 (s, 3 H, 17-CH3), 1.16 (s,
in THF,20.0 m o l ) and stirred at 25 "C for 14 h. After dilution with
3 H, C(CHJ)Z),1.05 (s, 3 H, C(CH3)z); 13CNMR (125 MHz, CDC13)
EtzO (50 mL), HzO (50 mL) was added. The organic layer was
6 153.9, 139.4, 137.3, 136.1, 135.6, 128.7, 128.5, 128.3, 122.0, 108.2,
separated, washed with brine (30 mL), dried (NaZSOd), concentrated,
93.5, 82.4, 77.9, 75.7, 74.2, 71.2, 70.4, 69.3, 46.3, 44.3, 40.0, 31.2,
and purified by flash chromatography (silica, 80% Et20 in petroleum
28.9, 27.9, 26.8, 23.6, 21.7, 21.3, 16.0; FAB H R M S (NBNCsI) d e
ether) to give 14 (2.29 g, 80%) as a white solid: Rf = 0.49 (silica,
673.1782, M -I- Cs+ calcd for c31bo8 673.1778.
EtzO); IR (thin film) v, 3438,2980,2879, 1778, 1371, 1061 cm-';
Alkene 18: Rf = 0.95 (silica, 50% EtOAc in hexanes); IR (thin
'H NMR (500 MHz, CDCl3) 6 7.33-7.27 (band, 5 H, Ar), 5.99 (dd,
film) Vmax 2971,1726 cm-'; 'H NMR (500 MHz, CDC13) 6 7.35-7.27
J = 10.0, 3.5 Hz, 1 H, 6-H), 5.89 (d, J = 10.0 Hz, 1 H, 5-H), 5.23 (s,
(band, 5 H, Ar), 5.93 (dd, J = 10.5, 2.5 Hz, 1 H, 6-H), 5.86 (b d, J =
l H , 2 - H ) , 4 . 7 2 ( d , J = l l . O H z , IH,OCHzPh),4.42(d,J=ll.OHz,
12.0 Hz, 1 H, lO-H), 5.56 (dd, J = 10.5, 1.5 Hz, 1 H, 5-H), 5.48 (d,
1 H, OCHzPh), 4.27 (b d, J = 9.0 Hz, 1 H, 10-H), 4.11 (b S, 2 H,
J
= 12.0 Hz, 1 H, 9-H), 4.67 (d, J = 7.0 Hz, 1 H, 2-H), 4.65 (d, J =
20-CHz), 4.02 (d, J = 9.0 Hz, 1 H, 10-H), 3.69 (dd, J = 9.5, 5.0 Hz,
10.5 Hz, 1 H, OCHZPh), 4.49 (d, J = 8.0 Hz, 1 H, 20-H), 4.44 (d, J =
1 H, 9-H), 3.49 (d, J = 3.5 Hz, 1 H, 7-H), 3.25 (dd, J = 9.5, 9.0 Hz,
10.5 Hz, 1 H, OCHzPh), 3.80 (d, J = 8.0 Hz, 1 H, 20-H), 3.68 (b S, 1
1 H, 9-H), 2.77 (dd, J = 9.0, 5.0 Hz, 1 H, 9-OH), 2.40-2.18 (band, 4
H, 7-H), 2.86 (d, J = 7.0 Hz, 1 H, 3-H), 2.35-2.22 (band, 3 H, 13H, 13-CHz and 14-CHz), 2.37 (s, 1 H, 349, 1.72 (s, 3 H, 18-CH3),
CHZand 14-H), 1.96 (m, 1 H, 14-H), 1.54 (s, 6 H, 18-CH3and 191.47 (s, 3 H, C(CH3)2), 1.44 (s, 3 H, C(CH3)2), 1.08 (s, 3 H, 19-C&),
CH3), 1.45 (s, 3 H, C(CH&), 1.39 (s, 3 H, C(CH&), 1.37 (s, 3 H,
1.05 (s, 3 H, C(CH&), 1.03 (s, 3 H, C(CH3)z); 13CNMR (125 MHz,
C(CH&), 1.07 (s, 3 H, C(CH3)z); I3CNMR (125 M H z , cW13) 6 149.4,
CDCls) 6 154.6, 136.8, 133.9, 133.5, 132.8, 128.2, 127.8, 127.6, 126.2,
143.2, 137.6, 137.3, 133.4, 128.7, 128.2, 128.1, 127.7, 125.3, 122.0,
106.7, 88.4, 80.5, 78.8, 74.5, 71.6, 71.2, 67.9, 58.6, 44.3, 44.2, 43.5,
108.4, 90.6, 81.7, 75.7, 72.0, 71.0, 62.3, 47.5, 43.7, 36.3, 29.7, 29.1,
29.2, 27.2, 26.2, 24.5, 23.7, 20.2, 19.1, 18.5; FAB HRMS (NBNCsI)
26.8, 26.6, 26.4, 24.4, 16.1, 14.4; FAB H R M S (NBNCsI) mle
mle 675.1942, M Cs+ calcd for C31b208 675.1934.
639.1736, M Cs+ calcd for C31H3806 639.1723.
Dialdehyde 15. A solution of diol 14 (0.66 g, 1.22 "01)
and
Hemiacetal 19: mp 170-174 "C, 195-200 "C (corresponding
4-methylmorpholine N-oxide (NMO, 0.43 g, 3.67 "01)
in CH3CN
aldehyde), from CHzClz-hexanes; Rf = 0.51 (silica, 50% EtOAc in
(40 mL) and CHzClz (20 mL) was treated with 4-A molecular sieves
hexanes ); IR (thin film) vm, 3422, 2924, 1797, 1454, 1381, 1216,
(50 mg) and stirred at 25 "C for 10 min. Tetrapropylammonium
1052 cm-l; 'H NMR (500 MHz, CDCl3) 6 7.35-7.30 (band, 5 H, Ar),
permthenate ("PAP,
22 mg, 0.062 "01)
was added, and the reaction
6.05 (dd, J = 10.5, 1.0 Hz, 1 H, 5-H), 5.71 (dd, J = 10.5, 1.0 Hz, 1 H,
mixture was stirred at 25 "C for 2 h. After dilution with CHzClz (100
6-H), 5.57 (d, J = 2.0 Hz, 1 H, 10-H), 5.20 (d, J = 8.5 Hz, 1 H, 2-H),
mL), the reaction mixture was filtered through silica gel. The resulting
4.67 (d, J = 11.5 Hz,1 H, OCHzPh). 4.45 (d, J = 11.5 Hz, 1 H, OCHzsolution was concentrated to give dialdehyde 15 (0.611 g, 92%) as a
Ph), 4.27 (d, J = 8.5 Hz, 1 H, 20-H), 4.26 (s, 1 H, 9-H), 3.97 (b S, 1
white solid: Rf = 0.70 (silica, 50% EtOAc in hexanes); IR (thin film)
H, 7-H), 3.90 (d, J = 8.5 Hz, 1 H, 20-H), 3.19 (d, J = 8.5 Hz, 1 H,
vmax2919,1793, 1724, 1669,1063 cm-'; 'H NMR (500 MHz, (CD3)23-H), 2.42 (d, J = 2.0 Hz, 1 H, 11-H), 2.30-1.85 (band, 4 H, 13-CHz
CO) 6 10.98 (S, 1 H, 10-H), 9.40 (s, 1 H, 9-H), 7.39-7.29 (band, 5 H,
and 14-CHz), 1.51 (s, 3 H, 16-CH3), 1.49 (s, 3 H, I7-CH3), 1.32 (s, 3
Ar), 6.25 (dd, J = 10.0, 4.5 Hz, 1 H, 6-H), 5.84 (d, J = 10.0 Hz, 1 H,
H, C(CH~)Z),
1.24 (s, 3 H, C(CH3)2), 1.11 (s, 3 H, 18-CH3), 1.07 (s, 3
5-H), 5.35 (d, J = 2.5 Hz, 1 H, 2-H), 4.81 (d, J = 11.0 Hz, 1 H,
OCHzPh), 4.56 (d, J = 11.0 Hz, 1 H, OCHzPh), 4.28 (d, J = 4.5 Hz,
H,
N M R (125 MHz, CDC13) 6 153.2, 137.2, 134.0, 128.4,
1 H, 7-H), 3.97 (s, 2 H, 20-CHz). 2.91 (d, J = 2.5 Hz, 1 H, 3-H), 2.65
128.0, 127.9, 124.0, 108.0,98.4,89.6,82.5,77.9,74.8,71.6,69.6,62.6,
45.3, 43.9, 42.2, 38.5, 38.1, 30.2, 29.0, 27.1, 26.4, 25.9, 20.3, 15.7;
(m, 1 H, 13-H), 2.52-2.46 (band, 2 H, 13-H and 14-H), 2.23 (m, 1 H,
FAB H R M S (NBNCsI) d e 673.1760, M Cs+ calcd for c31bo8
14-H), 2.16 (s, 3 H, 18-CH3), 1.41 (s, 3 H, Ig-CHs), 1.29 (s, 3 H,
673.1778.
C(CH3)z), 1.25 (s, 3 H, C(CH3)2), 1.21 (s, 3 H, C(CH3)z), 1.15 (s, 3 H,
C(CH3)z); 13C NMR (125 MHz, (CD3)zCO)) 6 198.9, 192.2, 155.2,
Formate Ester 20: mp 222-224 "C, from CHzClz-hexanes; Rf =
154.2, 139.5, 137.5, 133.3, 129.0, 128.4, 128.4, 109.3, 89.9,80.4,77.0,
0.59 (silica, 50% EtOAc in hexanes); IR (thin f i ) vmax2986, 1799,
72.6, 72.5, 72.2, 53.8, 46.4, 43.4, 32.4, 27.3, 26.8, 25.2, 24.1, 18.8,
1728, 1383, 1139, 1058, cm-l; *HNMR (500 MHz, CDCl3) 6 7.89 (s,
18.6, 17.7; FAB HRMS (NBNCsI) mle 671.1630, M Cs+ calcd for
1 H, 9-CHO), 7.41-7.32 (band, 5 H, Ar), 6.11 (dd, J = 10.0, 1.5 Hz,
C31H3808 671.1621.
1 H, 5-H), 5.71 (dd, J = 10.0, 1.0 Hz, 1 H, 6-H), 5.54 (s, 1 H, 9-H),
8-Membered Ring Intermediates 17-20. TiC13.(DME)l.5 (1.53 g,
5.16(d,J=9.0Hz,lH,2-H),4.73(d,J=11.5H~,lH,OCH2Ph),
and ZdCu couple (1.66 g, 12.7 m o l ) were transferred to
5.3 "01)
4.52 (d, J = 11.5 Hz, 1 H, OCHzPh), 4.30 (d, J = 8.5 Hz, 1 H, 20-H),
a dry flask under argon (glovebag). The mixture was further dried at
4.09 (b S, 1 H, 7-H), 3.89 (d, J = 8.5 Hz, 1 H, 20-H), 3.42 (d, J = 9.0
140 "C, under vacuum for 10 min. Freshly distilled DME (70 mL)
Hz, 1 H, 3-H), 2.42-2.22 (band, 4 H, 13-CHz and 14-CHz), 1.52 (s, 3
was then added, and the suspension was stirred at reflux for 3.5 h.
H, C(CH3)2), 1.50 (s, 3 H, C(CH3)2), 1.37 (s, 3 H, 16-CH3), 1.28 (s, 3
After the mixture was cooled to 70 "C, a solution of dialdehyde 15
H, 17-CH3), 0.99 (s, 3 H, 18-CH3), 0.89 (s, 3 H, 19-CH3);
NMR
(260 mg, 0.48 "01)
in DME (25 mL) was added via syringe pump
(125 MHz, CDCl3) 6 211.4, 158.4, 152.3, 136.6, 134.3, 128.6, 128.5,
over 1 h. The reaction mixture was stirred at 70 "C for an additional
128.2, 123.6, 108.4, 98.5, 88.1, 82.2,77.6,77.5, 75.5, 71.5,69.5, 52.0,
-.
652 J. Am. Chem. SOC., Vol. 117,No. 2, 1995
Nicolaou et al.
50.6, 47.0, 43.6, 29.5, 28.9, 27.1, 25.4, 24.6, 24.6, 18.9, 15.4; FAB
H R M S (NBNCsI) mle 687.1570, M
Cs+ calcd for C31H3809
687.1570.
Camphanate Esters 29 and 30. A solution of diol 17 (42 mg,
0.077 mmol) and Et3N (0.217 mL, 1.5 "01)
in CHzClz (3.5 mL) was
treated with a catalytic amount of 4-(dimethylamino)pyridhe (DMAP,
0.5 mg, 0.004 mmol) and (19-(-)-camphanic chloride (84 mg, 0.388
mmol) at 25 "C for 1 h. After dilution with Et20 (10 mL), the reaction
was quenched with aqueous NaHC03 (5 mL), and the resulting mixture
was stirred at 25 "C for 15 min. The organic layer was separated, and
the aqueous layer was extracted with CHzClz (3 x 10 mL). The
combined organic layer was washed with brine (10 mL), dried (MgSOd),
concentrated, and purified by preparative TLC (silica, 20% EtOAc in
benzene) to give camphanic esters 29 and 30 (23 and 25 mg,
respectively, 86% combined yield) as white solids.
Ester 29: Rf = 0.26 (silica, 15% EtOAc in benzene);
+117
(c 0.54, CHC13); IR (thin film) vmax3500, 2970, 2930, 1792, 1744,
1458, 1103, 1058, 914 cm-'; IH NMR (500 MHz, CDC13) 6 7.337.24 (band, 5 H, Ar), 5.94 (dd, J
10.5, 1.5 Hz, 1 H, 6-H), 5.74 (d,
J = 5.0 Hz, 1 H, 9-H), 5.63 (dd, J = 10.5, 1.0 Hz, 1 H, 5-H), 5.51 (d,
J = 4.5 Hz, 1 H, 2-H), 4.70 (d, J = 12.0 Hz, 1 H, OCHzPh), 4.64 (d,
J = 8.5 Hz, 1 H, 20-H), 4.45 (d, J = 12.0 Hz, 1 H, OCHzPh), 4.36
(dd, J = 5.0,3.0 Hz, 1 H, 10-H), 3.78 (d, J = 8.5 Hz, 1 H, 20-H), 3.70
(b S, 1 H, 7-H), 2.72 (ddd, J = 14.0, 10.0, 3.5 Hz, 1 H, 13-H), 2.632.53 (band, 1 H, 14-H), 2.56 (d, J = 3.0 Hz, 10-OH), 2.38 (ddd, J =
14.0, 11.0,4.0 Hz, 1 H, CH(H)CHz camph.), 2.33 (d, J = 4.5 Hz, 1 H,
3-H), 2.12-1.88 (band, 3 H, 13-H and CH(H)CH(H) Camph.), 1.81
(ddd, J = 14.5, 12.0, 2.5 Hz, 1 H, 14-H), 1.71 (ddd, J = 13.5,9.0, 4.0
Hz, 1 H, CH(H)CH2 camph.), 1.62 ( s , 3 H, 18-CH3), 1.57 (s, 3 H,
OC(O)C(CHd), 1.41 ( s , 3 H, (O)zC(CH3)z), 1.40 (s, 3 H, (0)zC(CH3Mr
1.12 (s, 6 H, C(CH& camph.), 1.10 (s, 3 H, 16-CH3), 1.06 (s, 3 H,
17-CH3). 1.00 (s, 3 H, 19-CH3); NMR (125 MHz, CDC13) 6 178.0,
166.2, 153.8, 143.6, 137.1, 135.5, 132.7, 128.7, 128.5, 128.3, 122.1,
108.4, 93.4, 90.8, 82.5, 78.0, 74.9, 74.0, 74.0, 71.2, 70.9, 54.8, 54.3,
47.2, 44.8, 39.8, 31.5, 30.9, 29.0, 28.8, 28.0, 26.9, 23.6, 21.7, 21.7,
16.8, 16.8, 16.2,9.6; FAB H R M S (NBNCsI) mle 853.2545, M Cs+
calcd for C~IHSZOII
853.2564.
Ester 30. colorless crystals, mp 240 "C, dec, from CH2Cl~-hexanes;
Rj = 0.21 (silica, 15% EtOAc in benzene); [aIz2~
133 (c 0.49,
CHC13); IR (thin film) vmax3498,2976,1793,1742,1457,1378,1265,
1059 cm-'; 'H NMR (500 MHz, CDC13)6 7.35-7.30 (band, 5 H, Ar),
5.96 (dd, J = 10.0, 1.5 Hz, 1 H, 6-H), 5.85 (d, J = 5.5 Hz, 1 H, 9-H),
5.63 (dd, J = 10.0, 1.0 Hz, 1 H, 5-H), 5.53 (d, J = 4.5 Hz, 1 H, 2-H),
4.71 (d, J = 12.0 Hz, 1 H, OCHZPh), 4.48 (d, J = 8.0 Hz, 1 H, 20-H),
4.46 (d, J = 12.0 Hz, 1 H, OCH2Ph). 4.33 (dd, J = 5.5, 3.0 Hz, 1 H,
lO-H), 3.79 (d, J = 8.0 Hz, 1 H, 20-H), 3.74 (b S, 1 H, 7-H), 2.77
(ddd, J = 14.0, 10.5, 3.0 Hz, 1 H, 13-H), 2.68-2.55 (band, 1 H, 14H), 2.58 (d, J = 3.0 Hz, 10-OH), 2.48 (ddd, J = 13.5, 10.5, 4.0 Hz, 1
H, CH(H)CHz camph.), 2.36 (d, J = 4.5 Hz, 1 H, 3-H), 2.15-1.92
(band, 3 H, 13-H and CH(H)CH(H) camph.), 1.90-1.65 (band, 2 H,
14-H and CH(H)CHz camph.), 1.72 (s, 3 H, 18-CH3), 1.57 (s, 3 H,
OC(O)C(CH3)),1.44 (s, 3 H, (O)ZC(CH~)Z),
1.42 (s, 3 H, (O)zC(CH3)z),
1.14 (s, 6 H, C(CH3)z cmph.), 1.11 (s, 3 H, 16-CH3), 1.08 (s, 3 H,
17-CHs), 0.98 (s, 3 H, 19-CH3); 13CNMR (125 MHz, CDCl3) 6 177.8,
166.2, 153.8, 143.6, 137.1, 135.4, 132.8, 128.6, 128.3, 128.2, 122.3,
108.3, 93.4, 91.5, 82.4, 77.9, 75.2, 74.1, 73.6, 71.2, 71.1, 54.8, 54.4,
47.1, 44.7, 39.7, 31.4, 31.1, 29.0, 28.8, 27.8, 26.9, 23.5, 21.7, 21.5,
17.1, 16.8, 16.1, 9.6; FAB HRMS (NBNCsI) mle 853.2543, M Cs+
calcd for C41HSZOll 853.2564.
Diol (+)-17. A solution of ester 29 (23 mg, 0.032 "01)
in MeOH
(3.5 mL) was treated with KzCO3 (3.0 mg, 0.22 mmol) and stirred at
25 "C for 0.5 h. After dilution with CHzClz (15 mL), the reaction was
quenched with aqueous m C 1 (10 mL). The organic layer was
separated, and the aqueous layer was extracted with CHzCl2 (3 x 10
mL). The combined organic layer was dried (MgSOd), concentrated,
50% EtOAc in
petroleum ether) to give diol (+)-17(15.5 mg, 90%) as a white solid:
[alzZ~
+187 (c 0.5, CHC13).
Acknowledgment. We thank Drs. Dee H. Huang, Raj

Chadha, and Gary Siuzdak for the NMR,X-ray crystallographic
analyses, and mass spectroscopy, respectively. This work was
supported by the NIH, The Scripps Research Institute, fellowships from RhBne-Poulenc Rorer (P.G.N.), The Office of Naval
Research (R.K.G.), Glaxo, Inc. (C.F.C.), Mr. Richard Staley
(C.F.C.), NSERC (J.R.), and grants from Merck Sharp and
Dohme, Pfizer, Inc., Schering Plough, and the ALSAM
Foundation.
JA942194M
J. Am. Chem. SOC.1995,117, 653-659
653
Total Synthesis of Taxol. 4. The Final Stages and Completion

of the Synthesis
K. C. Nicolaou,* H. Ueno, J.-J. Liu, P. G. Nantermet, Z. Yang, J. Renaud,
K. Paulvannan, and R. Chadha
Contribution from the Department of Chemistry, The Scripps Research Institute, 10666 North
Torrey Pines Road, La Jolla, Califomia 92037, and Department of Chemistry and Biochemistry,
University of Califomia, San Diego, 9500 Gilman Drive, La Jolla, Califomia 92093
Received July 7, I994@
Abstract: The total synthesis of (-)-Tax01 has been achieved. Functional group manipulation of diol 2 provided
the ABC ring system with the correct C9-keto, C10-acetyloxy functionality. Careful optimization allowed the oxidation
of the C5-C6 alkene in 4 at C5 via a hydroboration reaction. Functional group manipulation of this product, 29,
provided, through two routes, the oxetane D ring as 36. Following the method developed by degradative studies
provided the natural enantiomer of Taxol (1).
Introduction
With a route to optically active diol 2 secured,' a total
synthesis of Taxol (1, Figure 1) looked quite feasible. However,
several issues still remained to be addressed before the final
goal could be reached. Amongst them were the functional group
adjustments at C9 and C10, the installment of an oxygen at the
C5 position, oxetane construction, oxygenation at C13, and sidechain attachment. Below we describe solutions to these
problems and, thus, the total synthesis of Taxol (1).
Final Stages of the Total Synthesis

a. Selective Functionalization at C9 and C10. Continuing
the sequence from diol 2l (Scheme l), our strategy toward Taxol
(1) next called for the adjustment of the functional groups at
C9 and C10 to their final form. Arriving at the desired C9keto, C10-acetate functionality required differentiating between
the two hydroxyl groups of diol 2. Fortunately, the higher
reactivity of the allylic C10 hydroxyl group provided high
selectivity in the desired direction when compound 2 was
exposed to 1.5 equiv of AczO and DMAP in methylene chloride.
The resulting monoacetate 3 (Scheme 1, 95% yield) was
oxidized cleanly with TPAP-NM02 to afford, in 93% yield,
the desired 9-keto, 10-acetate 4. The absence of a conjugated
enone in 4 (as observed in the 13C NMR) and the detection of
long-range coupling (J < 1.5 Hz) between the C10 proton (6
5.65, CDCl3, 500 MHz) and the C12 methyl group (6 1.68) of
monoacetate 3 ('H NMR decoupling experiments) suggested
the indicated regiochemistry of these intermediates. This
assignment was c o n f i i e d by X-ray crystallographic analysis
of benzoate 5, obtained by PCC oxidation3 of compound 4 (see
Scheme 1, and ORTEP drawing in Figure 2). This regioselectivity is in contrast to that observed in the exclusive formation
of the 9-camphonate ester described in the preceding paper,' in
which a speculative explanation for this discrepancy is proposed.
It was now time to address the introduction of an alcohol at
c5.
* Address correspondence to this author at The Scripps Research Institute

(1) Nicolaou, K. C.; Yang, Z.; Liu, J.-J.; Nantermet, P. G.; Claibome,
C. F.; Renaud, J.; Guy, R. K.; Shibayama, K. J. Am. Chem. SOC. 1995,
117, 645.
( 2 ) Griffith, W. P.; Ley, S. V. Aldrichimica Acta 1990, 23 (l), 13.
(3) Angyal, S. J.; James, K. Carbohydr. Res. 1970, 12, 147.
@
1: Taxol
Scheme 1. Functionalization of the C9 and C10 Positions of

the Taxoid Frameworka
OI
"Reagents and conditions: (a) 1.5 equiv of AczO, 1.5 equiv of

4-(dimethylamino)pyridine (DMAP),
CH*C12,25 "C, 2 h, 95%; (b) 0.1
equiv of tetrapropylammonium perruthenate (TPAP),3.0 equiv of
4-methylmorpholine N-oxide (NMO),CH3CN, 25 "C, 2 h, 93%; (c)
30 equiv of pyridinium chlorochromate (PCC), 50 equiv of NaOAc,
Celite, benzene, reflux, 1 h, 50%. Bn = CH2Ph.
b. Early Attempts to Hydroborate the C5-C6 Double

Bond. Our experience with the hydroboration of ring C
systems4s5 led us to adopt similar tactics for the real system.
Potential differentiation of the two faces of the double bond in
(4)Nicolaou, K. C.; Liu, J.-J.; Yang, Z.; Ueno, H.; Sorensen, E. J.;
Claibome, C. F.; Guy, R. K.; Hwang, C.-K.; Nakada, M.; Nantermet, P.G.
J . Am. Chem. SOC. 1995, 117, 634.
0002-786319511517-0653$09.00/0 0 1995 American Chemical Society
Nicolaou et al.
654 J. Am. Chem. Soc., Vol. 117, No. 2, 1995
Scheme 2. Hydroboration Studies 1"
&I(-p
0
5
.i
&
Figure 2. ORTEP diagram for benzoate 5.
ring C of intermediate 4 by an incoming reagent was not obvious

by inspection of molecular models. It was, therefore, decided
to initially explore the utilization of the C20 hydroxyl group as
a handle to direct hydroboration from the p face of the molecule
and at the C5 position as in the simple C ring case. To this
end the acetonide group was removed from 4 under acid
conditions to afford diol 6 (Scheme 2, 88% yield based on 53%
conversion). Attempts to hydroborate6 6 under a variety of
conditions failed, presumably due to the formation of a stable
5-membered ring borane complex involving the two hydroxyl
groups that is both unable to reach the internal alkene and
prohibitively bulky for external hydroboration.
We next considered using the 4-acetoxy, 20-hydroxy compound 7 (Scheme 2) as a possible substrate for the desired
hydroboration reaction, but unfortunately, all attempts to prepare
this intermediate met with failure. Under the various conditions
used, the acetate group migrated facilely from the C-4 to the
C20 a l ~ o h o l ,leading
~
to either the primary acetate 8 or the
starting diol 6 rather than the desired tertiary acetate 7. It
became clear that the acetate at C4 would have to be installed
after oxetane formation or in an intermediate in which the C20
hydroxy group would remain blocked until oxetane ring closure.
We, therefore, turned to the C4 acetate, C20 mesylate 10,
prepared from diol 6 by sequential mesylation (94% yield) and
acetylation (90% yield) as detailed in Scheme 2. Hydroboration
of this compound (10) with borane in THF, however, resulted
not only in hydroxylation at C5 but also in concomitant reductive
cleavage of the C4 acetate to afford compound 11 as the major
product (67% yield) whose stereochemistry at both the C4 and
C5 centers was left unassigned. Similar observations have
previously been reported with simple allylic derivatives8
In order to lower the propensity of the C4 substituent toward
reductive elimination, the 4-benzyloxy compounds 17 and 19
(Scheme 3) were chosen as the next potential candidates for
hydroboration. Exposure to KH and benzyl bromideg failed to
convert mesylate 9 to the desired benzyl ether 19, leading instead
to the formation of epoxide 12 (Scheme 3). The same
( 5 ) Nicolaou, K. C.; Liu, J. J.; Hwang, C.-K.; Dai,W.-M.; Guy, R. K.
( 6 )Smith, K.; Pelter, A. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 8, p 703.
(7) Samaranavake. G.: M a- h.. N. F.: Jitranesri.
- . C.:
. Kineston.. D. G. I. J .
Org.'Chem. 1991, 56, 5114.
(8)Brown, H. C.; Knights, E. F. J . Am. Chem. SOC.1968, 90, 4439.
Pasto. D. J.: Hickman. J. 7. Am. Chem. SOC.1968. 90, 4445.
(9) Kanai, K.; Sakamoto, I.; Ogawa, S.; Suami, T. Bull. Chem. SOC.Jpn.
1987, 60, 1529.
0
11
a Reagents and conditions: (a) 3.0 equiv of p-toluenesulfonic acid,

MeOH, 25 "C, 48 h, 88% based on 53% conversion; (b) 5.0 equiv of
Dess-Martin periodinane, CHZC12,25 "C, 3 h, then 20 equiv of AczO,
25 equiv of 4-(dimethylamino)pyridine (DMAP), CH2C12, 25 "C, 3 h,
then 2.0 equiv of n - B W & , THF, 25 "C, 1 h, 66% from 6; (c) 1.2
equiv of MsCl, 3.0 equiv of DMAP, CH2C12, 25 "C, 1 h, 94%; (d) 10
equiv of AczO, 15 equiv of DMAP, CH2C12, 25 "C, 5 h, 90%; (e) 10
equiv of BHs-THF, THF, 25 "C, 2 h, then excess H202, saturated
aqueous NaHC03, 0.5 h, 67%. Bn = CH2Ph, Ms = S02CH3.
conditions, however, smoothly converted the corresponding

acetate 8 (obtained conveniently by monoacetylation of diol 6)
to the C4 benzyloxy derivative 13 (76% yield). Preparation of
17 from 13 required complete deacetylation under basic
hydrolysis conditions, followed by selective silylation at C20
(triethylsilyl group), acetylation at C10, and desilylation of the
C20 hydroxyl group (52% overall yield). Again, hydroboration
of 17 was disappointing: the major product was the C4 deoxy
compound 18. Hydroboration of the C4-benzyloxy, C20mesylate 19, obtained through mesylation of 17, also failed:
exhibiting sluggish reactivity and undesirable products.
The unwillingness of the C4-benzyloxy mesylate 19 to enter
facilely into hydroboration reactions prompted us to attempt this
reaction on the sterically less demanding C4-hydroxy, C20mesylate 9 (Scheme 4). Thus, exposure of 9 to excess borane
in THF followed by oxidative workup resulted in the formation
of diol 20 as the major product and in 23% yield. The indicated
a stereochemistry of the newly introduced C5 hydroxyl group
was based on 'H NMR data and was confirmed by chemical
correlation as outlined in Scheme 4. Thus, treatment of 20 with
Et3N, DMAP, and AczO resulted in acetylation and intramolecular displacement of the mesylate group to give epoxide 21
(75% yield), which was debenzylated by hydrogenolysis, leading
to compound 22 (95% yield). The latter compound was
identical with a sample prepared from 10-deacetylbaccatin 111
(23) through intermediate 2 4 l 0 by the following short sequence:
(a) exposure of 24 to Meerwein's reagent7 leading to 25 (59%)
and 26 (19%); (b) mesylation of the minor product (26) to give
J. Am. Chem. SOC., Vol. 11 7, No. 2, 1995 655
Scheme 3. Hydroboration Studies 2a
Scheme 4. Chemical Corrolation Studiesu
0
8
12
OMS
S:R=H
b C8 : R = A c
0
20
24
0
0
21
ci
18
If
18
Reagents and conditions: (a) 1.3 equiv of KH, 5.0 equiv of

PhCHZBr, 0.05 equiv of n-BWI, EtzO, HMPA, 25 "C, 15 min, 79%;
(b) 1.2 equiv of Ac20, 1.5 equiv of 4-(dimethylamino)pyridine (DMAP),
CHzC12, 25 "C, 20 min, 95%; (c) 5.0 equiv of KH, 15 equiv of
PhCHzBr, 0.05 equiv of n-BWI, EtzO, HMPA, 25 "C, 4 h, 76%; (d)
10 equiv of DBU, MeOH, CH2Cl2, 25 "C, 3 h, 98%; (e) 1.2 equiv of
Et3SiC1, 1.5 equiv of DMAP, DMF, 25 "C, 1 h; (f) 6.0 equiv of AczO,
6.0 equiv of DMAP, CH2C12, 25 "C, 0.5 h; (g) HF-pyridine, THF, 25
"C, 1 h, 52% from 14; (h) 5.0 equiv of BH3*THF,THF, 0 "C, 0.5 h, 25
"C, 4 h, then excess H202, aqueous NaHCO3, 0.5 h; (i) 3.0 equiv of
MsCl, 5.0 equiv of DMAP, CHzC11, 25 "C, 1 h, 94%. DBU = 1,sdiazabicyclo[5.4.0]undec-7-ene,Bn = CHZPh, Ms = S02CH3, TES =
SiEt3.
27; (c) treatment with KH in THF to form the epoxide ring;

and (d) exposure to HFpyridine to remove the silyl group
(81% overall yield from 26) to afford 22. This chemical
correlation firmly established the regio- and stereoselectivity
of the hydroboration reaction of 9. A better candidate was,
however, needed to serve as a precursor to the desired oxetane
system.
c. Final Hydroboration Route to a C5a-Hydroxy Intermediate. Having realized that the C5a-hydroxy compounds
might be a more accessible series of precursors to the oxetane
system, we decided at this point to examine the hydroboration
of acetonide 4 (Scheme 5). Inspection of molecular models
~~~
(10) Nicolaou, K. C.; Nantermet, P. G.; Ueno, H.; Guy, R. K.;

Couladouros, E. A.; Sorensen, R. J. J . Am. Chem. SOC. 1995,11 7, 624.
22
28
Reagents and conditions: (a) 10 equiv of BH3*THF,THF, 25 "C,

1.5 h, then excess H202, aqueous NaHCOs, 0.5 h, 23%; (b) 30 equiv
of Ac20, excess EtsN, 0.05 equiv of 4-(dimethylamino)pyridine
(DMAP), CHzC12,25 "C, 12 h, 75%; (c) H2, Pd(OH)dC, EtOH, 25 "C,
1 h, 95%; (d) 2.1 equiv of EtsOBF4, CH2C12,O "C, 1 h, 59% of 25 plus
19% of 2 6 (e) 10 equiv of MsC1,20 equiv of Et3N, 2.0 equiv of DMAP,
CH2C12, 25 "C, 0.5 h, 90%; (f) excess KH, THF, 25 "C, 0.5 h, 92%;
(g) HFTyridine, THF, 25 "C, 1 h, 98%. Bn = CHZPh, Ms = S02CH3,
TES = SiEt3.
indicated that the a face was somewhat less hindered than the
although the absence of a free hydroxy handle in the
vicinity of the C5 position raised questions regarding the
regiochemical outcome of the intended hydroboration. In the
event, exposure of 4 to excess borane in THF followed by the
usual oxidative workup furnished a mixture of the C5a-alcohol
29 (42% yield based on 83% conversion) and its C6 regioisomer
(22% yield based on 83% conversion) (Scheme 5 ) . While the
stereochemistry of the C6 regioisomer remains unassigned, that
of the C5 a-isomer was confirmed by conversion to intermediate
32,previously obtained from 10-deacetylbaccatin 111 (23)via
desilylation of intermediate 25 (Schemes 4 and 5 ) . Thus, acidcatalyzed removal of the acetonide group from 29 afforded triol
30 (80% yield based on 88% conversion). Under carefully
controlled conditions, acetylation of the primary hydroxyl group
p face,
656 J. Am. Chem. SOC., Vol. 117, No. 2, I995
Scheme 5. Hydroboration Studies 3. Successful

Hydroboration of the C5-C6 Double Bond"
Nicolaou et al.
Scheme 6. Construction of the Oxetane Ring"
,632:ReH
25: R = TES
20
bl
w
O '"OH
M
'Vo
0
0
32:R=H
e r 25 : R = TES
hl
30:R=H
'L31:R=Ac
Reagents and conditions: (a) 10.0 equiv of BH3*THF,THF, 0 "C,

3 h, then excess HzOz, saturated aqueous NaHC03, 25 "C, 1 h, 42%
plus 22% of C6-OH regioisomer, based on 83% conversion; (b) MeOH:
concd HC1 (2:l) 25 "C, 5 h, 80% based on 88% conversion; (c) 1.25
equiv of AczO, 5.0 equiv of pyridine, 0.05 equiv of 4-(dimethylamino)pyridine (DMAP), CHzC12,25 "C, 0.5 h, 95%; (d) Hz, 10% Pd(OH)2/
C, EtOAc, 25 OC, 0.5 h, 97%; (e) HFpyridine, THF, 25 "C, 2 h, 96%.
Bn = CHZPh, TES = SiEt3.
a
in 30 proceeded selectively to afford monoacetate 31 (95%

yield). Finally, hydrogenolysis of the benzyl group from 31
furnished alcohol 32, identical to material obtained from
desilylation (HFpyridine, THF, 96% yield) of 25 in all respects
including absolute stereochemistry (synthetic: [aIz2~
-85.2 (c
0.115, CHC13); degradative:
-85.6 (c 0.43, CHCl3). With
the synthesis of 32, the road to Taxol (1) was now open.
d. Installation of the Oxetane Ring and Completion of

the Total Synthesis. The last remaining challenge in the total
synthesis of Taxol (l),namely the construction of the oxetane
ring, was accomplished following two routes which were based
on work previously performed by Potier's group" on a taxoid
skeleton and by Danishefsky's group12 on a C ring model
system. Both sequences utilized intermediate 25 (available from
total synthesis by silylation of 32 with TESC1-pyridine (85%
yield) or from degradation of 10-deacetylbaccatin 1II)'O and
proceeded as outlined below.
In the first approach, which was modeled after Danishefsky's
work,12 the C20-acetate group was selectively removed from
25 under mildly basic conditions (KzC03-MeOH) to afford triol
33 in 97% yield (Scheme 6). The newly generated primary
alcohol was then selectively silylated with TMSCl in the
presence of base and exposed to triflic anhydride and base to
afford the triflate silyl ether 35 via intermediate 34. The latter
compound converted to oxetane 36 when exposed to mildly
acidic conditions (silica gel, CH2C12) through sequential desilylation of the C20-hydroxyl group followed by internal S N ~
displacement of the triflate. The resulting hydroxy oxetane 36
was acetylated to afford the targeted oxetane system 24 in 40%
overall yield from triol 33.
The second route (Scheme 6), modeled after Potier's studies,"
featured selective mesylation of diol 25 (73% yield) to furnish
hydroxy mesylate 37 which was selectively deacetylated at C20
(11) Ettouati, L.; Ahond, A,; Poupat, C.; Potier, P. Tetrahedron 1991,
47, 9823.
(12) Magee, T. V.; Bornmann, W. G.;Isaccs, R. C. A.; Danishefsky, S .
J. J . Org. Chem. 1992,57, 3274.
'k6
O "'OH
R
OTMS
0
37
OAC
33
34:R=H
dG 35 : R = Tf
0
38
36:RrH
f L24 : R = AC
Reagents and conditions: (a) 25 equiv of EtsSiCl, pyridine, 25 "C,

12 h, 85%; (b) 10 equiv of KzC03, MeOH-HZ0,O "C, 15 min, 97%;
(c) 10 equiv of Me3SiC1, 30 equiv of pyridine, CHZClz, 0 "C, 15 min;
(d) 15 equiv of TfzO, 30 equiv of i-PrzNEt, CHzClz, 0 "C, 0.5 h; (e)
0.05 equiv of camphorsulfonic acid (CSA), MeOH, 25 "C, 15 min,
then silica gel, CHZClz, 25 "C, 1 h, 40% from 33; (f) 8.0 equiv of
AczO, 15 equiv of 4-(dimethylamino)pyridine (DMAP), CHzC12, 25
"C, 4 h, 94%; (g) 10 equiv of MsCl, 20 equiv of DMAP, CHZCL, 25
"C, 1 h, 73%; (h) 10 equiv of KzCO3, MeOH, HzO, 0 "C, 15 min; (i)
12 equiv of n-BWOAc, butanone, reflux, 5 h, 72% from 37. TES =
SiEt3, TMS = SiMe3, Tf = SOzCF3, Ms = SOzCH3.
as before, leading to diol 38 in quantitative yield. The latter
compound was heated in refluxing butanone to afford hydroxy
oxetane 36 (72% yield), which was converted to acetate 24 as
described above.
The final drive toward Taxol (1) from intermediate 24 was
carried out as outlined in Scheme 7 and proceeded along the
lines already described in paper 1 of this series.1 Synthetic
Taxol (1) was identical with an authentic sample by all usual
criteria, including Rf (TLC), fR (HPLC), [a]% IR,'H and 13C
NMR,HFMS, and biological assay (microtubule stabilization
and cytotoxicity against a panel of eight cell lines).
Conclusion
This and the accompanying paper^',^,'^ in this series describe
the studies in these laboratories which eventually culminated
in the total synthesis of Taxol (1). This synthetically challenging
molecule with its 11 stereocenters, four skeletal rings, and
unusual steric congestion, particularly around its 8-membered
ring, provided several serious obstacles and opportunities to
create new strategies and to expand the scope and generality of
known synthetic methods. New knowledge was gained on
issues of regio-, stereo-, and chemoselectivity. Of particular
interest were the applications of the Diels-Alder reaction to
form rings A and C, the Shapiro and McMuny couplings to
J. Am. Chem. SOC., Val. 117, No. 2, 1995 657
Scheme 7. Completion of the Total Synthesis"
24
30
bl
41
40
dl
43:R=TES
1 : R = H, Taxol
42
Reagents and conditions: (a) 5.0 equiv of PhLi, THF, -78 "C, 10
min, then 10 equiv of AczO, 5.0 equiv of 4-(dimethylamino)pyridine
(DMAP), CH2C12, 2.5 h, 80%; (b) 30 equiv of pyridinium chlorochromate (PCC), 30 equiv of NaOAc, Celite, benzene reflux, 1 h, 75%; (c)
excess N&&, MeOH, 25 "C, 3 h, 94% based on 88% conversion; (d)
3.0 equiv of NaN(SiMes)z, 3.5 equiv of B-lactam 42, THF, 0 "C, 0.5 h,
86% based on 89% conversion; (e) HF-pyridine, THF, 25 "C, 1.25 h,
80%. TES = SiEt3, BZ = COPh.
construct ring B, and the regioselective opening of carbonates
with organometallic reagents to form hydroxy esters.
The resulting convergent route to Taxol (1) was utilized for
the construction of several new designed taxoids. A number
of these compounds obtained by total synthesis13 or semisynt h e ~ i s ' ~have
J ~ demonstrated interesting properties and shed light
on the structural requirements for Taxol's biological activity.
Furthermore, water-soluble taxoids that arose from these studies
are providing useful information regarding the conformation of
Taxol in waterI6 and the design of prod rug^^^*^^ of this newly
established chemotherapeutic agent.
the first paper in this series.1 Experimental techniques and data for
compounds 5,6,8-22,27, and 28 may be found in the supplementary
material.
Acetate 3. A solution of diol 2 (138 mg, 0.0256 mmol) and
4-(dimethy1amino)pyridine (DMAP, 47.0 mg, 0.0383 mmol) in CHzClz (10 mL) was treated with AczO (0.04 mL, 0.0383 m o l ) and stirred
at 25 "C for 2 h. After dilution with Et20 (50 mL), the reaction was
quenched with aqueous NH&1(50 mL), and the resulting mixture was
stirred at 25 "C for 15 min. The organic layer was separated, and the
aqueous layer was extracted with Et20 (3 x 20 mL). The combined
(13) Nicolaou, K. C.; Claibome, C. F.; Nantermet, P. G.; Couladouros,

E. A.; Sorensen, E. J. J. Am. Chem. Soc. 1994,116, 1591.
(14) Nicolaou, K. C.; Couladouros, E. A.; Nantermet, P. G.; Renaud, J.;
Guy, R. K.; Wrasidlo, Angew. Chem., Znt. Ed. Engl. 1994,33,1581.
(15) Nicolaou, K. C.; Renaud, J.; Guy, R. K.; Nantermet, P. G.;
Couladouros, E. A.; Wrasidlo, W. Submitted.
(16) Gomez Paloma, L.; Guy, R. K.; Nicolaou, K. C. Chem. B i d 1994,
I, 107.
(17) Nicolaou, K. C.; Guy, R. K.; Pitsinos, E. N.; Wrasidlo, W. Angew.
Chem., Znt. Ed. Engl. 1994,33, 1583.
organic layer was dried (NazSOd), concentrated, and purified by flash

chromatography (silica, 30% Et20 in petroleum ether) to give 3 (141
mg, 95%) as a white foam: Rf = 0.55 (silica, 60% Et20 in petroleum ether); [ a I Z Z D +181 (c 0.48, CHC13); IR (thin film) vmPx3406,
2385, 1792, 1733, 1654, 1457, 1234, 1018 cm-I; IH N M R (500 MHz,
CDC13) 6 7.35-7.27 (band, 5 H, Ar), 5.92 (dd, J = 10.0, 2.0 Hz, 1 H,
6-H), 5.62 (d, J = 5.0 Hz, 1 H, 10-H), 5.57 (dd, J = 10.0, 1.5 Hz, 1
H, 5-H), 5.49 (d, J = 4.5 Hz, 1 H, 2-H), 4.69 (d, J = 12.0 Hz, 1 H,
OCH~h),4.46(d,J=8.0H~,1H,20-H),4.44(d,J=12.0Hz,lH,
OCHzPh), 4.28 (b d, J = 5.0Hz, 1 H, 9-H), 3.77 (d, J = 8.0 Hz, 1 H,
20-H), 3.71 (b S, 1 H, 7-H), 2.72 (ddd, J = 14.5, 10.0, 3.5 Hz, 1 H,
13-H), 2.58 (ddd, J = 20.0, 11.5, 3.0 Hz, 1 H, 14-H), 2.42 (b S, 1 H,
9-OH), 2.36 (d, J = 4.5 Hz, 1 H, 3-H), 2.09 (s, 3 H, OAC),2.01 (ddd,
J = 20.0, 10.0, 3.5 Hz, 1 H, 14-H), 1.80 (ddd, J = 14.5, 11.5, 3.0 Hz,
1 H, 13-H), 1.68 (s, 3 H, 18-CH3), 1.53 (s, 3 H, 19-CH3), 1.42 (s, 3 H,
C(CH3)2), 1.40 (s, 3 H, C(CH3)z). 1.13 (s, 3 H, 16-CH3), 1.05 (s, 3 H,
17-CH3); 13C NMR (125 MHz, C m h ) 6 169.2, 153.9, 142.5, 137.4,
135.4, 133.1, 128.5, 128.2, 122.5, 108.2, 93.3, 82.5, 78.1, 75.3, 74.1,
72.5, 71.2, 47.0, 44.7, 39.9, 31.3, 28.9, 27.8, 26.8, 23.6, 21.7, 21.2,
16.2; FAB H R M S (NBA/NaI) d e 605.2720, M
Na+ calcd for
c33&zog 605.2727.
Ketone 4. A solution of alcohol 3 (141 mg, 0.242 m o l ) in CH3CN (10 mL) was treated with tetrapropylammonium perruthenate
(PAP,85.0 mg, 0.0242 mmol) and 4-methylmorpholine N-oxide
(NMO, 85.0 mg, 0.726 mmol) and stirred at 25 "C for 2 h. After
dilution with CHzClz (30 mL), the reaction mixture was filtered through
silica gel. The resulting solution was concentrated to give 4 (131 mg,
93%) as a white solid: Rf = 0.62 (silica, 30% EtOAc in petroleum
ether); [aIz2D +14 (c 0.52, CHC13); IR (thin film) vmax2925, 1807,
1746, 1717, 1458, 1374, 1230 cm-'; lH NMR (500 MHz, CDC13) 6
7.35-7.27 (band, 5 H, Ar), 6.47 (s, 1 H, 10-H), 5.90 (dd, J = 10.5,
2.0 Hz, 1 H, 6-H), 5.67 (dd, J = 10.5, 1.5 Hz, 1 H, 5-H), 4.66 (d, J =
11.5 Hz, 1 H, OCHSh), 4.57 (d, J = 11.5 Hz, 1 H, OCHZPh), 4.40 (d,
J=8.5Hz,lH,20-H),4.32(m,lH,7-H),4.18(d,J=5.5Hz,lH,
2-H), 3.78 (d, J = 8.5 Hz, 1 H, 20-H), 2.78 (d, J = 5.5 Hz, 1 H, 3-H),
2.78-2.70 (band, 2 H, 13-H and 14-H), 2.23 (m, 1 H, 14-H), 2.22 (s,
3 H, OAc), 1.93 (m, 1 H, 13-H), 1.90 (s, 3 H, 18-CH3), 1.44 (s, 3 H,
C(CH3)2), 1.43 (s, 3 H, C(CH3)z), 1.26 (s, 3 H, 19-CH3), 1.27 (s, 3 H,
16-CH3), 1.15 (s, 3 H, 17-CH3); 13CN M R (125 MHz, CDC13) 6 203.2,
169.3, 152.6, 143.3, 137.1, 134.8, 128.9, 128.4, 128.3, 127.9, 123.9,
108.9, 96.5, 81.8, 80.2, 76.5, 76.2, 71.7, 71.1, 58.9, 47.5, 40.5, 29.9,
28.7, 26.8, 26.1, 23.2, 21.8, 20.8, 18.9, 12.8; FAB H R M S (NBMCsI)
d e 713.1720, M Cs+ calcd for C33&09 713.1727.
Acetate 25. Conversion of Oxetane 24 to Acetates 25 and 26.
A solution of oxetane 24 (14.0 mg, 0.023 mmol) in CHzClz (2.5 mL)
at 0 "C was treated with Et30BF4 (Meerwein's reagent, 1.O M in CHIClz, 0.048 mL, 0.048 mmol) and stirred at 0 "C for 1 h. The reaction
mixture was diluted with Et20 (IO mL), washed with aqueous m C 1
(5 mL) and brine (5 mL), dried (MgSOd), concentrated, and purified
by preparative TLC (silica, 50% EtOAc in petroleum ether) to give
acetate 25 (8.5 mg, 59%) and acetate 26 (2.8 mg, 19%), both as
colorless fiis.
Acetate 25: Rj = 0.28 (silica, 50% EtOAc in petroleum ether); [ a I Z Z D
-74 (C 0.75, CHC13); IR (thin film)vman3483,2943,2884,1802,1743,
1461, 1373, 1232, 1120, 1014 cm-l; 'H N M R (500 MHz, CDC13) 6
6.53 (s, 1 H, lO-H), 4.46 (d, J = 12.0 Hz, 1 H, 20-H), 4.40 (d, J =
12.0 Hz, 1 H, 20-H), 4.39 (dd, J = 11.0, 3.5 Hz, 1 H, 7-H), 4.23 (d,
J=5.0Hz,lH,2-H),3.71(t,J=3.5H~,lH,5-H),3.39(d,J=5.0
Hz, 1 H, 3-H), 3.16 (s, 1 H, 4-OH), 2.82 (ddd, J = 14.0, 10.0, 3.0 Hz,
1 H, 13-H), 2.79 (s, 1 H, SOH), 2.71 (m, 1 H, 14-H), 2.25-2.05 (band,
2 H, 6-H and 14-H), 2.14 (s, 3 H, OAC),2.10 (s, 3 H, 18-CH3), 1.88
(m, 1 H, 14-H), 1.75 (m, 1 H, 6-H), 1.20 (s, 3 H, 16-CH3), 1.18 (s, 3
H, 17-CH3), 1.14 (s, 3 H,
0.63 (t, J = 7.5 Hz, 9 H,
Si(CHzCH&), 0.58-0.45 (band, 6 H, Si(CHzCH3)3); I3C N M R (125
MHz, CDC13) 6 202.8, 170.6, 169.2, 153.2, 144.7, 130.1, 93.4, 81.5,
76.0, 74.8, 70.4, 68.5, 64.8, 61.3, 43.0, 40.4, 33.8, 30.2, 26.5, 23.0,
21.1, 20.9, 20.8, 18.9, 11.9, 6.7, 5.1; FAB HRMS (NBA/NaI) d e
647.2845, M Na+ calcd for C31&8011Si 647.2864.
Acetate 26: Rf = 0.36 (silica, 50% EtOAc in petroleum ether); IH
NMR (500 MHz, CDC13) 6 6.51 (s, 1 H, 10-H), 5.21 (t, J = 3.0 Hz,
l H , 5 - H ) , 4 . 3 0 ( d d , J = l 1 . 0 , 4 . 5 H ~lH,7-H),4.20(d,J=4.5Hz,
,
(18) Nicolaou, K.C.; Riemer, C.; Ken, M. A.; Rideout, D.; Wrasidlo,
W. Nature 1993,364,464.
Nicolaou et al.
1H,2-H),4.03(d,J=11.0H~,1H,20-H),3.58(d,J=11.0Hz,1(0.003 mL, 0.040 mmol), and 4-(dimethylamino)pyridine (DMAP,

H, 20-H), 3.34 (s, 1 H, 4-OH), 3.20 (d, J = 4.5 Hz, 1 H, 3-H), 2.94
catalytic) and stirred at 25 "C for 0.5 h. The reaction was quenched
(ddd, J = 14.0, 10.0, 3.5 Hz, 1 H, 13-H), 2.75 (m, 1 H, 14-H), 2.20 (s,
with aqueous NaHC03 (1 mL), and the resulting mixture was extracted
3 H, 18-CH3), 2.18 (s, 3 H, OAc), 2.16 (s, 3 H, OAc), 2.12 (m, 1 H,
with Et20 (3 x 20 mL). The combined organic layer was washed
14-H), 1.96 (ddd, J = 15.0, 4.5, 4.5 Hz, 1 H, 6-H), 1.90-1.84 (band,
with HzO (5 mL) and brine (5 mL), dried (MgSOd), concentrated, and
2 H, 6-H and 13-H), 1.19 (s, 3 H, 16-CH3), 1.14 (s, 3 H, 17-CH3),
purified by flash chromatography (silica, 50% EtOAc in petroleum
1.04 (s, 3 H, 19-C&), 0.86 (t, J = 8.0 Hz, 9 H, Si(CH2CH,),), 0.55ether) to give diol 8 (4.6 mg, 95%) as an amorphous solid Rr = 0.40
0.49 (band, 6 H, S~(CHZCH~)~).
(silica, 50% EtOAc in petroleum ether); [alZ2~
-51 (c 0.08, CHCb);
'H NMR (500 MHz, CDC13) 6 7.40-7.20 (band, 5 H, Ar),6.51 (s, 1
Silylation of Triol 32 to 25. A solution of triol 32 (2.0 mg, 0.0039
H, lO-H), 4.55 (d, J = 11.5 Hz, 1 H, OCHzPh), 4.48 (d, J = 12.0 Hz,
"01)
in pyridine (0.5 mL) was treated with chlorotriethylsilane
1 H, 20-H), 4.44 (d, J = 11.5 Hz, 1 H, OCHZPh), 4.41 (d, J = 12.0
(TESC1, 0.017 mL, 0.098 "01)
and stirred at 25 "C for 12 h. The
Hz, 1 H, 20-H), 4.22 (d, J = 4.5 Hz,1 H, 2-H), 4.06 (dd, J = 11.O, 4.5
reaction mixture was diluted with Et20 (10 mL), washed with aqueous
Hz, 1 H, 7-H), 3.74 (m, 1 H, 5-H), 3.41 (d, J = 4.5 Hz, 1 H, 3-H),
CuSO4 (3 x 5 mL) and brine (5 mL), dried (MgSOd), concentrated,
3.14 (S, 1 H, 4-OH), 2.83 (ddd, J = 14.5, 10.5, 4.0 Hz, 1 H, 13-H),
and purified by preparative TLC (silica, 50% EtOAc in petroleum ether)
2.75 (b s, 1 H, 5-OH), 2.72 (m, 1 H, 14-H), 2.29 (ddd, J = 14.5, 4.0,
to give silyl ether 25 (2.0 mg, 85%) as a colorless film.
4.0 Hz, 1 H, 6-H), 2.18 (m, 1 H, 14-H), 2.17 (s, 3 H, OAc), 2.10 (s, 3
Alcohol 29. To a solution of acetate 4 (18.7 mg, 0.032 "01)
in
H, OAc), 2.03 (s, 3 H, 18-CH3). 1.90 (m, 1 H, 13-H), 1.69 (m, 1 H,
THF (2 mL) at 0 "C was added BHyTHF (1.0 M, 0.32 mL, 0.32 mmol),
6-H), 1.28 (s, 3 H, Ig-CHs), 1.20 (s, 3 H, 16-CH3), 1.15 (s, 3 H, 17and the reaction mixture was stirred at 0 "C for 3 h. The reaction was
CH3); FAB HRMS (NBNCsI) d e 733.1633, M
Cs+ calcd for
quenched with aqueous NaHCO3 (0.5 mL) and HZOZ(0.5 mL), and
c32&011
733.1625.
the resulting solution was allowed to warm to 25 "C, stirred at 25 OC
for 1 h, and extracted with Et20 (3 x 30 mL). The combined organic
Triol 32. Hydrogenation of 31. A solution of diol 31 (4.6 mg,
0.0077 m o l ) in EtOAc (1 mL) was treated with Pd(0H)JC (1.0 mg)
layer was washed with HzO (5 mL) and brine (5 mL), dried (MgSOd),
under an atmospheric pressure of hydrogen and stirred at 25 OC for
concentrated, and purified by preparative TLC (silica, 10% Et20 in
CHzCl2) to give acetate 4 (3.1 mg, 17%), the monoalcohol 29 (6.8 mg,
0.5 h. The reaction mixture was filtered, concentrated, and purified
by preparative TLC (silica, EtOAc) to give triol 32 (3.8 mg, 97%) as
42% based on 83% conversion) as an amorphous solid, and the
corresponding 6-OH regioisomer (3.3 mg, 22% based on 83% converan amorphous solid Rf = 0.20 (silica, EtZO); [alz2~
-85.2 (c 0.115,
sion) as an amorphous solid.
CHC13); IR (thin film) Y,, 3492,2941,1795,1737, 1714, 1457, 1370,
1230, 1032 cm-'; 'H NMR (500 MHz, CDC13) 6 6.45 (s, 1 H, 10-H),
Alcohol 29: Rf = 0.80 (silica, 10% Et20 in CH2C12); ta1220
-58 (c
4.42 (m, 1 H, 7-H), 4.20 (d, J = 5.0 Hz, 1 H,
4.43 (s, 2 H, ~O-CHZ),
0.45, CHC13); IR (thin film) v, 3523,2924, 1803, 1746,1716, 1459,
2-H), 3.77 (t, J = 3.0 Hz, 1 H, 5-H), 3.39 (d, J = 5.0 Hz, 1 H, 3-H),
1372, 1230, 1064 cm-I; 'H NMR (500 MHz, CDCl3) 6 7.38-7.22
3.21 (S, 1 H, 4-OH), 2.83 (s, 1 H, 5-OH), 2.86-2.71 (band, 2 H, 13-H
(band, 5 H, Ar),6.50 (s, 1 H, 10-H), 5.58 (d, J = 11.5 Hz, 1 H, OCH2and 14-H), 2.27-2.12 (band, 2 H, 6-H and 14-H), 2.18 (s, 3 H, OAC),
Ph), 4.48 (d, J = 11.5 Hz, 1 H, OCHZPh), 4.23 (d, J = 8.5 Hz, 1 H,
20-H),4.16(d,J=4.0H~,1H,2-H),4.06(dd,J=11.0,4.5Hz,12.11 (s, 3 H, OAc), 2.08 (s, 3 H, 18-CH3), 1.91 (m, 1 H, 13-H), 1.80
(m, 1 H, 6-H), 1.23 (s, 6 H, 16-CH3 and 17-CH3), 1.10 (s, 3 H, 19H, 7-H), 3.87 (t, J = 3.0 Hz, 1 H, 5-H), 3.77 (d, J = 8.5 Hz, 1 H,
CH3); 13CNMR (125 MHz, cDcl3) 6 204.3, 170.8, 170.7, 153.1, 146.7,
20-H), 3.46 (d, J = 4.0 Hz, 1 H, 3-H), 2.81-2.68 (band, 2 H, 13-H
129.2, 93.3, 81.6, 76.2, 74.8, 70.2, 68.4, 64.8, 61.1, 42.8, 40.4, 32.4,
and 14-H), 2.61 (b s, 1 H, 5-OH), 2.36 (m, 1 H, 14-H), 2.20 (m, 1 H,
30.4, 26.4, 22.9, 21.7, 20.9, 20.8, 18.8, 11.4; FAB HRMS (NBNCsI)
13-H), 2.19 (s, 3 H, OAc), 2.03 (s, 3 H, 18-CH3), 1.92 (m, 1 H, 6-H),
d e 643.1175, M Cs' calcd for C25H34011 643.1155.
1.61 (m, 1 H, 6-H), 1.45 (s, 6 H, C(CH3)2), 1.22 (s, 3 H, 16-CH3), 1.18
Desilylation of 25. A solution of diol 25 (6.5 mg, 0.010 mmol) in
(s, 3 H, 17-CH3), 1.13 (s, 3 H, 19-CH3);
NMR (125 MHz, CDCl3)
6 203.0, 169.2, 153.0, 144.6, 137.5, 129.8, 128.2, 127.9, 127.5, 108.8,
THF (2.0 mL) at 25 "C was treated with HFTyridine (0.4 mL) and
92.7, 84.6, 80.7, 76.1, 73.8, 71.2, 70.5, 68.8, 60.3, 40.6, 30.2, 29.7,
stirred for 2 h. The reaction mixture was diluted with EtOAc (10 mL),
29.7, 29.6,26.4,26.2,23.0,21.3,20.9,18.8, 11.5; FAB HRMS ( N E W
washed with 10% aqueous NaOH (5 mL) and brine (5 mL), dried
NaI) d e 621.2658, M Na+ calcd for C33b2010 647.2676.
(MgS04), concentrated, and purified by preparative TLC (silica, EtOAc)
to give triol 32 (5.1 mg, 96%) as a colorless film.
Triol 30. A solution of alcohol 29 (6.8 mg, 0.0114 "01)
in MeOH
(2 mL) was treated with concentrated HCl(1 mL) and stirred at 25 "C
Triol 33. A solution of acetate 25 (96.0 mg, 0.154 mmol) in MeOH
for 5 h. The reaction was quenched with aqueous NaHC03 (1 mL),
(16 mL) at 0 'C was treated with a solution of K2C03 (212 mg, 1.54
and the resulting mixture was extracted with EtOAc (3 x 30 mL). The
"01)
in HzO (4 mL). The reaction mixture was stirred at 0 "C for
combined organic layer was washed with H20 (2 mL) and brine (2
15 min, and the reaction was quenched with aqueous N&C1(5 mL).
mL), dried (MgSOd), concentrated, and purified by preparative TLC
The reaction mixture was extracted with CHZClz (3 x 10 mL), and the
(silica, 75% EtOAc in petroleum ether) to give monoalcohol 29 (0.8
combined organic layer was washed with brine (10 mL), dried (MgSOd),
mg, 12%) and triol 30 (6.8 mg, 80% based on 88% conversion) as an
amorphous solid: Rf = 0.30 (silica, 75% EtOAc in petroleum ether);
EtOAc in petroleum ether) to give triol 33 (87.0 mg, 97%) as a white
foam: Rr = 0.42 (silica, 50% EtOAc in petroleum ether); [alZzD
-71 ( c 0.16, CHCls); IR (thin film) v, 3453,2906, 1795, 1743,
-78
1714, 1458, 1372, 1233, 1038 cm-'; 'H NMR (500 MHz, CDC13) 6
(C 0.25, CHC13); IR (thin film) vm,
3458, 2955, 1796, 1751, 1714,
7.28-7.26 (band, 5 H, Ar), 6.49 (s, 1 H, 10-H), 4.55 (d, J = 11.0 Hz,
1461, 1373, 1234 cm-l; IH NMR (500 MHz, CDC13)6 6.51 (s, 1 H,
1 H, OCHzPh), 4.45 (d, J = 11.0 Hz, 1 H, OCHZPh), 4.20 (d, J = 4.5
10-H), 4.39 (dd, J = 11.0, 4.5 Hz, 1 H, 7-H), 4.22 (d, J = 5.0 Hz, 1
Hz, 1 H, 2-H), 4.05 (dd, J 11.0, 4.5 Hz, 1 H, 7-H), 4.03 (b dd, J =
H, 2-H), 4.01 (b d, J = 9.5 Hz, 1 H, 20-H), 3.81 (s, 1 H, 4-OH), 3.70
11.0, 4.5 Hz, 1 H, 20-H), 3.87 (s, 1 H, 4-OH), 3.73 (b t, J = 2.5 Hz,
(b S, 1 H, 5-H), 3.52 (d, J = 9.5 Hz, 1 H, 20-H), 3.33 (d, J = 5.0 Hz,
1 H, 5-H), 3.52 (b dd, J = 11.0, 3.0 Hz, 1 H, 20-H), 3.35 (d, J = 4.5
1 H, 3-H), 3.06 (s, 1 H, 20-OH), 2.95-2.85 (band, 2 H, 13-H and
Hz, 1 H, 3-H), 3.01 (b S, 1 H, 5-OH), 2.92 (ddd, J = 14.5, 10.5, 4.0
5-0H), 2.71 (m, 1 H, 14-H), 2.23 (ddd, J = 19.5, 9.0, 3.0 Hz, 1 H,
Hz, 1 H, 13-H), 2.72 (ddd, J = 20.0, 12.0, 4.0 Hz, 1 H, 14-H), 2.59
14-H), 2.14 (s, 6 H, OAc and 18-CH3), 2.12 (m, 1 H, 6-H), 1.86 (ddd,
(m, 1 H, 20-OH), 2.30 (ddd, J = 14.5, 3.5, 3.0 Hz, 1 H, 6-H), 2.21
J = 14.0, 12.0, 3.0 Hz, 1 H, 6-H), 1.69 (m, 1 H, 13-H), 1.18 (s, 3 H,
(ddd, J = 20.0, 10.5, 3.0 Hz, 1 H, 14-H), 2.17 (s, 3 H, OAC),2.03 (s,
16-CH3), 1.14 (s, 3 H, 17-CH3), 1.09 (s, 3 H, 19-CH3), 0.87 (t, J = 8.0
3 H, 18-CH3), 1.87 (ddd, J = 14.5, 12.0, 2.5 Hz, 1 H, 13-H), 1.61 (m,
Hz,9 H, Si(CHzCH&), 0.60-0.45 (band, 6 H, Si(CHzCH&); I3CNMR
1 H, 6-H), 1.20 (s, 3 H, 19-cH3), 1.16 (s, 3 H, 16-CH3), 1.15 (s, 3 H,
(125 MHz, CDCls) 6 203.3, 169.2, 153.9, 144.8, 130.2, 93.7, 81.9,
17-CH3); 13CNMR (125 MHz, CDCls) 6 203.1, 169.2, 153.4, 144.7,
76.1, 73.6, 11.7, 68.5, 62.6, 61.4, 42.7, 40.5, 33.7, 30.3, 26.4, 22.9,
137.7, 129.8, 128.2, 127.8, 127.5, 97.9, 93.4, 81.5, 76.1, 74.5, 73.7,
21.2,20.9, 18.9, 11.9,6.7,5.1;FABHRMS(NBA/NaI)de605.2735,
72.5, 62.5, 60.0, 42.8, 30.2, 29.6, 29.4, 26.3, 22.8, 21.3, 20.9, 18.8,
M Na+ calcd for C29&010Si 605.2758.
12.4; FAB H R M S (NBA/NaI) d e 581.2341, M
Na+ calcd for
Oxetane 36. Conversion of Triol 33 to 36. A solution of triol 33
C30H38010581.2363.
(10.0 mg, 0.017 "01)
and pyridine (0.142 mL, 0.51 "01)
in CH2Acetate 31. A solution of triol 30 (4.5 mg, 0.008 "01)
in CHzClz
Clz (2.0 mL) at 0 "C was treated with chlorotrimethylsilane (TMSC1,
(1 mL) was treated with Ac2O (0.0009 mL, 0.010 mmol), pyridine
0.022 mL, 0.17 m o l ) and stirred at 0 "C for 15 min. The reaction
Total Synthesis of Tanol. 4
was quenched with aqueous NaHC03 (2.0 mL). The resulting mixture
was allowed to warm to 25 "C and extracted with Et20 (3 x 5 mL).
(MgSOd), and concentrated to give the crude silyl ether 34,which was
taken to the next step without further purification.
A solution of silyl ether 34 and i-PratN (0.090 mL, 0.51 "01)
in
CHzClz (2.0 mL) at 0 "C was treated with triflic anhydride (TfzO, 0.044
mL, 0.26 mmol) and stirred at 0 "C for 0.5 h. The reaction was then
quenched with aqueous NaHCO3 (1.5 mL), and the resulting mixture
was allowed to warm to 25 "C and extracted with Et20 (3 x 5 mL).
(MgSOd), and concentrated to give the crude triflate 35, which was
taken to the next step without further purification.
A solution of triflate 35 in MeOH (2.0 mL) was treated with
camphorsulfonic acid (CSA, 0.5 mg, 0.002 "01)
and stirred at 25 "C
for 15 min. The reaction was quenched with aqueous NaHC03 (1.5
mL), and the mixture was extracted with CHzClz (3 x 5 mL). The
combined organic layer was washed with brine (10 mL), dried (MgS04),
and concentrated. The resulting residue was dissolved in CH2Clz(2.0
mL) and treated with silica gel (E. Merck, 0.1 g) at 25 "C for 1 h. The
reaction mixture was filtered, concentrated, and purified by preparative
TLC (silica, 50% EtOAc in petroleum ether) to give oxetane 36 (3.9
mg, 40% from 33) as a colorless film: Rj = 0.35 (silica, 33% EtOAc
in petroleum ether); [ a ] 2 2-47
~ (c 0.42, CHC13); IR (thin film) vmax
3462,2927, 1805,1747, 1716,1595,1460,1372,1237 cm-l; 'H N M R
(500 MHz, CDC13) 6 6.39 (s, 1 H, 10-H), 4.82 (dd, J = 9.5, 2.0 Hz, 1
H, 5-H), 4.66 (d, J = 9.0 Hz, 1 H, 20-H), 4.42 (d, J = 9.0 Hz, 1 H,
20-H), 4.37 (d, J = 5.5 Hz, 1 H, 2-H), 4.12 (dd, J = 10.5, 7.0 Hz, 1
H, 7-H), 2.71 (m, 1 H, 14-H), 2.63 (d, J = 5.5 Hz, 1 H, 3-H), 2.62 (m,
1 H, 13-H), 2.48 (ddd, J = 15.0, 9.5, 7.0 Hz, 1 H, 6-H), 2.43 (s, 1 H,
4-OH), 2.19 (m, 1 H, 14-H), 2.15 (s, 3 H, OAc), 2.06 (s, 3 H, 18CH3), 1.93 (ddd, J = 15.0, 10.5, 2.0 Hz, 1 H, 6-H), 1.89 (ddd, J =
14.5, 12.0, 2.5 Hz, 1 H, 13-H), 1.62 (s, 3 H, 19-C&), 1.19 (s, 3 H,
16-CH3), 1.18 (s, 3 H, 17-CH3), 0.87 (t, J = 8.0 Hz,9 H, Si(CHzCH3)3),
0.54 (q, J = 8.0 Hz, 6 H, Si(CHzCH&); 13CNMR (125 MHz, CDC13)
6 203.0, 169.3, 153.4, 143.9, 131.1, 93.2, 87.5, 80.7, 80.5, 76.5, 73.8,
71.9, 59.7, 51.6, 47.1, 37.8, 30.0, 26.2, 22.9, 21.7, 20.9, 19.0, 9.8, 6.7,
5.1; FAB H R M S (NBNCsI) d e 697.1790, M
Cs+ calcd for
C29hOgSi 697.1809.
Conversion of Mesylate 38 to Oxetane 36. A solution of crude
diol 38 (11.0 mg, 0.017 mmol) in butanone (1.0 mL) was treated with
n-Bu4NOAc (60.0 mg, 0.20 "01)
and stirred at reflux for 5 h. The
reaction mixture was allowed to cool to 25 "C and partitioned between
Et20 (10 mL) and H2O (5 mL). The organic layer was washed with
brine ( 5 mL), dried (MgS04). concentrated, and purified by flash
oxetane 36 (6.8 mg, 72% from 37) as a colorless film.
Acetate 24. A solution of oxetane 36 (4.0 mg, 0.0091 "01)
and
4-(dimethy1amino)pyridine (DMAP, 17.0 mg, 0.14 "01)
in CHzCl2
(2.0 mL) was treated with acetic anhydride (0.0067 mL, 0.071 "01)
and stirred at 25 OC for 4 h. The reaction mixture was diluted with
Et20 (10 mL), washed with 1 N aqueous HCl (5 mL) and aqueous
NaHC03 ( 5 mL), dried (MgSOb), concentrated, and purified by
preparative TLC (silica, 33% EtOAc in petroleum ether) to give acetate
24 (4.0 mg, 94%) as a colorless film: Rf = 0.82 (silica, 50% EtOAc in
hexanes); [ a l " ~-49.4 (c 0.93, CHCl,); IR (thin film) v, 2924, 1814,
1728, 1461, 1372, 1238 cm-l; lH NMR (500 MHz, CDC13) 6 6.40 (s,
1 H, 10-H), 4.95 (d, J = 9.0 Hz, 1 H, 5-H), 4.60 (A of AB,d, J = 9.0
Hz, 1 H, 20-H), 4.47 (B of AB,d, J = 9.0 Hz, 1 H, 20-H), 4.43 (dd,
J = 10.0. 7.5 Hz, 1 H, 7-H), 4.39 (d, J = 5.5 Hz, 1 H, 2-H), 3.36 (d,
J = 5.5 Hz, 1 H, 3-H), 2.71 (m, 1 H, 13-H), 2.56 (m, 1 H, 13-H), 2.17
(s, 3 H, OAc), 2.15 (s, 3 H, OAc), 2.12 (m, 1 H), 2.07 (s, 3 H, 18CHd, 1.97 (m, 1 H), 1.88 (m, 2 H), 1.78 (s, 3 H, 19-CH3), 1.23 (s, 3
H, 16-CH3), 1.17 (s, 3 H, 17-CH3), 0.88 (t, J = 7.5 Hz, 9 H,
Si(CHzCH&), 0.60-0.50 (band, 6 H, Si(CHzCH3)s); I3C NMR (125
MHz, CDC13) 6 202.6, 170.3, 169.2, 153.1, 144.0, 130.7, 92.8, 84.0,
80.3, 80.0, 76.4, 76.1, 60.3, 43.5, 38.0, 29.7, 29.4, 25.5, 23.1, 21.9,
21.1, 19.1, 9.8, 6.7, 5.2; FAB HRMS (NBNCs1)de 739.1929, M
Cs+ calcd for C31II46010Si 739.1915.
Mesylate 37. A solution of alcohol 25 (46.0 mg, 0.074 mmol) and
4-(dimethylamino)pyridine (DMAP, 180 mg, 1.48 "01)
in CHzClz
(6.0 mL) was treated with mesyl chloride (MsC1.0.056 mL, 0.72 m o l )
and stirred at 25 "C for 1 h. The reaction mixture was diluted with
Et20 (20 mL), washed with 1 N aqueous HCl (10 mL), aqueous
NaHC03 (5 mL), and brine (5 mL), dried (MgS04), concentrated, and
20% EtOAc in
petroleum ether) to give mesylate 37 (37.0 mg, 73%) as a white solid:
Rf = 0.38 (silica, 33% EtOAc in petroleum ether); [ a l z 2-40
~ (c 0.50,
CHC13); R (thin film) Y- 3495,2925, 1804, 1746, 1461, 1365, 1232
cm-I; 'H N M R (500 MHz, CDC13) 6 6.57 (s, 1 H, 10-H), 4.71 (t, J =
2.5 Hz, 1 H, 5-H), 4.53 (d, J = 12.0 Hz, 1 H, 20-H), 4.50 (d, J = 12.0
Hz, lH,20-H),4.37(dd,J=11.0,4.5H~,lH,7-H),4.26(d,J=4.5
Hz, 1 H, 2-H), 3.37 (d, J = 4.5 Hz, 1 H, 3-H), 3.15 (s, 1 H, 4-OH),
3.08 (s, 3 H, OMS), 2.87 (ddd, J = 14.5, 10.0, 3.5 Hz, 1 H, 13-H),
2.74 (ddd, J = 19.5, 12.0, 3.5 Hz, 1 H, 14-H), 2.38 (ddd, J = 19.5,
10.0, 3.0 Hz, 1 H, 14-H), 2.23 (ddd, J = 15.0, 4.5, 2.5 Hz, 1 H, 6-H),
2.19 (s, 3 H, 18-CH3), 2.18 (s, 3 H, OAC), 2.15 (s, 3 H, OAC), 2.02
(ddd,J= 15.0, 11.0, 2.5 Hz, 1 H, 6-H), 1.92 (ddd, J = 14.5, 12.0, 3.0
Hz, 1 H, 13-H), 1.27 (s, 3 H, 19-CH3), 1.22 (s, 3 H, 16-CH3), 1.17 (s,
3 H, 17-C&), 0.91 (t, J = 8.0 Hz,9 H, Si(CHzCH&), 0.59-0.54 (band,
6 H, Si(CH2CH3)d; N M R (125 MHz, CDC13) 6 202.0, 170.9, 169.2,
152.9, 145.4, 130.0, 81.1, 80.9,75.9,73.5,68.5,64.4, 61.1,44.4,40.4,
38.9, 34.7, 30.0, 29.7, 26.5, 23.1, 21.0, 20.9, 20.7, 18.9, 12.3, 6.7, 5.0;
FAB H R M S (NBNCsI) d e 835.1811, M Csf calcd for C32H50013SiS 835.1796.
Diol 38. A solution of acetate 37 (24.0 mg, 0.034 mmol) in MeOH
(3.0 mL) at 0 "C was treated with a solution of K2CO3 (60.0 mg, 0.34
"01
in 0.5 mL of HzO) and stirred at 0 "C for 15 min. The reaction
was quenched with aqueous W C l (2 mL), and the resulting mixture was extracted with CHzClz (3 x 5 mL). The organic layer was
washed with brine (5 mL), dried (MgS04), and concentrated to give
crude diol 38, which was taken to the next step without further
purification.
Diol 38:Rf = 0.51 (silica, 50% EtOAc in petroleum ether); [a]zzD
-35 (c 0.63, CHC13); IR (thin film) vmax3742, 2925, 1800, 1749,
1716, 1461, 1363, 1234 cm-l; 'H NMR (500 MHz, CDC13) 6 6.56 (s,
l H , lO-H),4.74(t,J=3.0Hz, l H , 5 - H ) , 4 . 3 8 ( d d , J = 1 1 . 0 , 4 . O H ~ ,
1 H, 7-H), 4.24 (d, J = 4.5 Hz, 1 H, 2-H), 4.01 (b d, J = 11.0 Hz, 1
H, 20-H), 3.83 (s, 1 H, 4-OH), 3.61 (b d, J = 11.0 Hz, 1 H, 20H), 3.35 (d, J = 4.5 Hz, 1 H, 3-H), 3.11 (s, 3 H, OMS), 2.96 (ddd, J
= 14.5, 10.0, 4.0 Hz, 1 H, 13-H), 2.74 (m, 1 H, 14-H), 2.36 (ddd, J =
19.5, 10.0, 3.0 Hz, 1 H, 14-H), 2.26 (ddd, J = 15.0, 4.0, 3.0 Hz, 1 H,
6-H), 2.20 (s, 3 H, 18-CH3), 2.18 (s, 3 H, OAC), 1.98-1.90 (band, 2
H, 6-H and 13-H), 1.22 (s, 3 H, 1%CH3), 1.17 (s, 3 H, 16-CH3), 1.16
(s, 3 H, 17-CHs), 0.90 (t, J = 8.0 Hz, 9 H, Si(CHzCH&), 0.59-0.53
(band, 6 H, Si(CHzCH3)3);
NMR (125 MHz, CDC13) 6 202.4,
169.1, 153.6, 145.4, 130.0,82.3,81.3,76.0,72.7,68.4,62.4,53.2,43.8,
40.4, 38.5, 34.6, 30.1, 29.6, 26.4, 22.9, 21.0, 20.8, 18.8, 12.1, 6.6,4.9;
FAB MS (NBA/NaI) d e 683, M
Na+ calcd for C3&8012SiS
683.
For the conversion of carbonate 24 to Tax01 (1) and physical data for compounds 1, 39-41, and 43, see the fust paper in this
series.'O
Acknowledgment. We thank Drs. Dee H. Huang, Gary

Siuzdak, Raj Chadha, and Wolfgang Wrasidlo for NMR, mass
spectroscopic, X-ray crystallographic, and biological assays
assistance, respectively. We also thank Dr. Luigi GomezPaloma for helpful discussions regarding NMR and stereochemical issues. This work was financially supported by NIH, The
Scripps Research Institute, fellowships from Mitsubishi Kasei
Corporation (H.U.), Rh6ne-Poulenc Rorer (P.G.N.), NSERC
(J.R.), and grants from Merck Sharp & Dohme, Pfizer, Inc.,
Schering Plough, and the ALSAM Foundation.
Supplementary Material Available: Experimental techniques and data for compounds 5, 6, 8-22, 27, and 28 (12
pages). This material is contained in many libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS. See
any current masthead page for ordering information.
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624

J. Am. Chem. SOC. 1995,117, 624-633

Total Synthesis of Taxol. 1. Retrosynthesis, Degradation, and

Taxol (Figure 1, 1),lq2a diterpene produced by several plants

* Address correspondence to this author at The Scripps Research Institute

Figure 1. Structure of Taxol (1)and 10-deacetylbaccatin III (2).

J. Am. Chem. SOC., Vol. 117,No. 2, 1995 625

Total Synthesis of Taxol. 1

Scheme 1. Retrosynthetic Analysis of Taxol (1)"

Retrosynthetic Analysis and Strategy

(22) Ulman Page, P. C . ; McCarthy, T. J. In Comprehensive Organic

Bz = COPh; R, R1,Rz,RJ,%, Rs = protecting groups.

as a good candidate to afford, in the synthetic direction,

626 J. Am. Chem. SOC.,Vol. 117,No. 2, 1995

Scheme 2. Preparation of 7-TES-baccatin III (17)a

Scheme 3. Benzylation of the C7 Position and Oxetane

IS: baccatin 111

15: baccatin 111

2: 10-deacetyl baccatin Ill

Reagents and conditions: (a) excess n-B@B&, CHzClz, 25 "C,

9 representing ring C. The cyclohexene derivatives 10 and 9

roacetimidateitriflic acid),32also proved too destructive: giving

Formation of the 1,2-Carbonate Ring and Reconversion

J. Am. Chem. SOC., Vol. 117, No. 2, 1995 627

Total Synthesis of Taxol. I

Scheme 4. Early Attempts at C2 and C10 Hydrolysis"

Scheme 5. Preparation of Carbonate 30 from

17: 7-TES baccatin 111

metal hydride reductions gave poor yields of tetrol 22, in

(38) Klein, L. L. Tetrahedron Lett. 1993,34,2047.

Reagents and conditions: (a) 1.5 equiv of 4-methylmorpholine

as the C2-hydroxyl group opened the oxetane ring under the

628 J. Am. Chem. SOC., Vol. 117, No. 2, 1995

we expected the distinctly different steric environment of the

Attempts To Cleave the C9-C10 Bond of the Taxol

(49) Haworth, W. N.; Porter, C. R. J . Chem. Soc. 1930, 151.

"Reagents and conditions: (a) 15 equiv of Pb(OAc)4, MeOH,

C13 Deoxygenation, Reoxygenation, and Side-Chain

J. Am. Chem. SOC., Vol. 117, No. 2, 1995 629

Total Synthesis of Taxol. 1

Scheme 7. C13 Deoxygenation and Oxygenation"

1 7 7-TES baccatin 111

Scheme 8. Taxol's Side-Chain Attachment"

Reagents and conditions: (a) 20 equiv of (thiocarbonyl)diimidazole,

exposure to pyridinium chlorochromate (PCC)58in the presence

Reagents and conditions: (a) excess NaBK, MeOH, 25 OC, 3 h,

established toward Taxol (1) as follows: (a) silylation with

630 J. Am. Chem. SOC., Vol. 117, No. 2, 1995

Total Synthesis of Taxol. 1

J. Am. Chem. Soc., Vol. 117, No. 2, 1995 631

Acetate 30. To a solution of carbonate 29 (86.0 mg, 0.159 mmol)

632 J. Am. Chem. SOC.,Vol. 117, No. 2, 1995

CsI) d e 739.1929, M Cs+ calcd for C31&010Si 739.1915.

Total Synthesis of Taxol. I

J. Am. Chem. Soc., Vol. 117, No. 2, 1995 633

J. Am. Chem. SOC. 1995,117, 634-644

Total Synthesis of Taxol. 2. Construction of A and C Ring

Figure 1. Structure and numbering of Taxol (1).

In keeping with the themes of convergency and of using the

* Address correspondenceto this author at the Scripps Research Institute

Reagents and conditions: (a) 1.2 equiv of MeMgBr, EtzO, 0

equiv of Et,N, 0.2 equiv of 4-(dimethy1amino)pyridine (DMAP), CHZC12,

0002-7863/95/1517-0634$09.00/00 1995 American Chemical Society

Total Synthesis of Taxol. 2