Taxol semisynthesis: A highly enantio- and diastereoselective synthesis of the side chain and a new method for ester formation at C-13 using thioesters

Article abstract of DOI:10.1021/jo9703212

A very simple, new, and straightforward approach to the Paclitaxel (Taxol) and Docetaxel (Taxotere) side chains has been developed using the imine addition reaction of thioester-derived boron enolates bearing chiral ligands. The addition reaction was studied extensively, using a combination of different thioesters (ROCH₂COSPh, ROCH₂COSt-Bu), oxygen protecting groups (R = Bn, TBDMS, COPh, EE, TMS), chiral boron ligands [derived from both (-) and (+)-menthone], imines (PhCH=NSiMe₃, PhCH=NCOPh), and in the presence or in the absence of additional Lewis acids (BF₃-OEt₂, Et₂AlCl, TiCl₄). The side chain was assembled in a few steps with the correct relative (syn) and absolute stereochemistry (2R,3S). The stereochemical outcome of the boron-mediated reaction was rationalized using chair vs boat transition state structures. A new direct route for attachment of the side chains to the baccatin nucleus using thioester chemistry has also been developed. By treatment of a mixture of a thioester (8, 12, or 17) and protected baccatin III (2b, 2c) with LHMDS, the 13-0 acylated compounds were obtained in high yield (up to 90%). Hydrolysis of 18b gave Paclitaxel (1a) in 80% yield.

Full text of DOI:10.1021/jo9703212

4746
J . Org. Chem. 1997, 62, 4746-4755
Ta xol Sem isyn th esis: A High ly En a n tio- a n d Dia ster eoselective
Syn th esis of th e Sid e Ch a in a n d a New Meth od for Ester
F or m a tion a t C-13 Usin g Th ioester s
Cesare Gennari,*,† Michela Carcano,† Monica Donghi,† Nicola Mongelli,‡ Ermes Vanotti,‡ and
Anna Vulpetti†,§
Dipartimento di Chimica Organica e Industriale, Centro CNR per lo Studio delle Sostanze Organiche
Naturali, Universita` di Milano, via G. Venezian 21, I-20133 Milano, Italy, and Pharmacia&Upjohn,
Nerviano (Milano), Italy
Received February 19, 1997X
A very simple, new, and straightforward approach to the Paclitaxel (Taxol) and Docetaxel (Taxotere)
side chains has been developed using the imine addition reaction of thioester-derived boron enolates
bearing chiral ligands. The addition reaction was studied extensively, using a combination of
different thioesters (ROCH2COSPh, ROCH2COSt-Bu), oxygen protecting groups (R ) Bn, TBDMS,
COPh, EE, TMS), chiral boron ligands [derived from both (-) and (+)-menthone], imines
(PhCHdNSiMe3, PhCHdNCOPh), and in the presence or in the absence of additional Lewis acids
(BF3-OEt2, Et2AlCl, TiCl4). The side chain was assembled in a few steps with the correct relative
(syn) and absolute stereochemistry (2R,3S). The stereochemical outcome of the boron-mediated
reaction was rationalized using chair vs boat transition state structures. A new direct route for
attachment of the side chains to the baccatin nucleus using thioester chemistry has also been
developed. By treatment of a mixture of a thioester (8, 12, or 17) and protected baccatin III (2b,
2c) with LHMDS, the 13-O acylated compounds were obtained in high yield (up to 90%). Hydrolysis
of 18b gave Paclitaxel (1a ) in 80% yield.
In tr od u ction
Paclitaxel (Taxol, 1a ), isolated from the bark of the
Pacific Yew Taxus brevifolia, is considered one of the
most promising cancer chemotherapeutic agents and has
recently been approved for treatment of metastatic
ovarian and breast cancer.1 It is also undergoing clinical
trials in nonsmall cell lung cancer (nsclc), head and neck
cancer, glioblastoma, and oesophageal cancer. The scar-
city of 1a and its highly challenging structure have
stimulated interest in its synthesis. Central to all
synthetic strategies is the attachment of the C-13 side
chain to the baccatin III nucleus, since the presence of
this side chain has proven to be essential for the biological
activity of Paclitaxel.1 Owing to the chemical complexity
of Paclitaxel (1a ), its commercial production by total
synthesis is not likely to be economical. However, the
naturally derived 10-deacetylbaccatin III (2a ) is readily
available in relatively high yield from the needles of the
European Yew T. baccata. Preparation of quantities of
Paclitaxel economically by a semisynthetic approach
which involves the condensation of suitably protected 10-
deacetylbaccatin III (2b,c) with suitably protected N-ben-
zoyl-(2R,3S)-3-phenylisoserine (3) provides an alternative
source of this important natural product and access to
semisynthetic analogs.
Therefore, the development of short and practical
synthetic routes to phenylisoserine derivatives, as well
as procedures for attaching the C-13 side chain to the
baccatin III nucleus, which are adaptable for industrial-
scale production, have become very important.
The numerous papers devoted to the preparation of
enantiomerically enriched (3) include research on semi-
synthesis drawing from the chiral pool,2 enzymatic and/
or microbal processes,3 diastereoselective reactions with
covalently-bound chiral auxiliaries or with chiral sub-
* To whom correspondence should be addressed. Tel.: int + 2-2367-
593. Fax: int + 2-2364-369. E-mail: cesare@iumchx.chimorg.unimi.it.
† Dipartimento di Chimica Organica e Industriale, Centro CNR per
lo Studio delle Sostanze Organiche Naturali, Universita` di Milano.
‡ Pharmacia&Upjohn.
§ New address: Pharmacia&Upjohn.
X Abstract published in Advance ACS Abstracts, J une 15, 1997.
(1) Taxol is the registered trademark of Bristol-Myers Squibb
Company for Paclitaxel. For a review, see: Nicolaou, K. C.; Dai, W.-
M.; Guy, R. K. Angew. Chem. 1994, 106, 38-67; Angew. Chem., Int.
Ed. Engl. 1994, 33, 15-44.
(2) For references after 1993, see: (a) Kearns, J .; Kayser, M. M.
Tetrahedron Lett. 1994, 35, 2845-2848. (b) Dondoni, A.; Perrone, D.;
Semola, T. Synthesis 1995, 181-186.
S0022-3263(97)00321-6 CCC: $14.00 © 1997 American Chemical Society

Taxol Semisynthesis
J . Org. Chem., Vol. 62, No. 14, 1997 4747
strates,4 asymmetric catalysis,5 and chemical resolution
of racemic acids.6
Sch em e 1
In contrast, only a few reactions have been developed
to attach the “side chain” to the free C-13 OH group of
baccatin derivatives. This esterification reaction appears
to be hampered by the steric hindrance around the C-13
OH group.1 Essentially only two general methods have
been developed to solve this problem: the first one relies
on the DCC protocol by Rhone-Poulenc Rorer/Gif/Greno-
ble,7,8 and the second one on the â-lactam protocol by
Holton et al. and Ojima et al. (Scheme 1).9,10
Under forcing conditions (excess of DCC, DMAP, 75
°C in toluene), coupling of (2R,3S)-N-benzoyl-O-(1-
ethoxyethyl)-3-phenylisoserine with suitably protected
baccatin III led to the corresponding ester; unfortunately,
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Bunnage, M. E.; Davies, S. G.; Goodwin, C. J . J . Chem. Soc., Perkin
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M.; Park, Y. H.; Sun, C. M.; Brigaud, T. Tetrahedron 1992, 48, 6985-
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acylation under the above mentioned conditions led also
to the 2′-epimerized compound.7a,b In order to prevent
epimerization at carbon 2′, other esterification procedures
have been developed. In particular the use of cyclic
derivatives (oxazolidines) allow milder conditions and no
epimerization (Scheme 1, DCC approach).4a,7c,e,11 Follow-
ing a similar route, an oxazoline acid intermediate has
been synthesized and used for the DCC coupling reaction
with no epimerization (Scheme 2).8 Recently it has been
shown that even substrates with the wrong stereochem-
istry [2(S)] can be transformed into the esterified com-
pounds with the right stereochemistry [2′(R)], using the
oxazolidine/DCC approach (Scheme 2).7d
(10) For applications after 1993, see: (a) Nicolaou, K. C.; Nantermet,
P. G.; Ueno, H.; Guy, R. K.; Couladouros, E. A.; Soresen, E. J . J . Am.
Chem. Soc. 1995, 117, 624-633. (b) Holton, R. A. et al. J . Am. Chem.
Soc. 1994, 116, 1597-1598. (c) Ojima, I.; Park, Y. H.; Sun, C.-M.;
Fenoglio, I.; Appendino, G.; Pera, P.; Bernacki, R. J . J . Med. Chem.
1994, 37, 1408-1410. J . Org. Chem. 1994, 59, 515-517. (d) Holton,
R. A.; Somoza, C.; Chai, K.-B. Tetrahedron Lett. 1994, 35, 1665-1668.
(e) Nicolaou, K. C. et al. Nature 1994, 367, 630-634. (f) Kant, J .;
O’Keeffe, W. S.; Chen, S.-H.; Farina, V.; Fairchild, C.; J ohnston, K.;
Kadow, J . F.; Long, B. H.; Vyas, D. Tetrahedron Lett. 1994, 35, 5543-
5546. (g) Chen, S.-H.; Farina, V.; Fairchild, C.; J ohnston, K.; Kadow,
J . F. J . Org. Chem. 1994, 59, 6156-6158. (h) Boge, T. C.; Himes, R.
H.; Vander Velde, D. G.; Georg, G. I. J . Med. Chem. 1994, 37, 3337-
3343. (i) Nicolaou, K. C.; Renaud, J .; Nantermet, P. G.; Couladouros,
E. A.; Guy, R. K.; Wrasidlo, W. J . Am. Chem. Soc. 1995, 117, 2409-
2420. (j) Young, W. B.; Masters, J . J .; Danishefsky, S. J . Am. Chem.
Soc. 1995, 117, 5228-5234. (k) Masters, J . J .; Link, J . T.; Snyder, L.
B.; Young, W. B.; Danishefsky, S. J . Angew. Chem. 1995, 107, 1886-
1888; Angew. Chem., Int. Ed. Engl. 1995, 34, 1723-1726. (l) Georg,
G. I.; Harriman, G. C. B.; Hepperle, M.; Clowers, J . S.; Vander Velde,
D. G.; Himes, R. H. J . Org. Chem. 1996, 61, 2664-2676. (m) Kant, J .;
Schwartz, W. S.; Fairchild, C.; Gao, Q.; Huang, S.; Long, B. H.; Kadow,
J . F.; Langley, D. R.; Farina, V.; Vyas, D. Tetrahedron Lett. 1996, 37,
6495-6498. (n) Park, H.; Hepperle, M.; Boge, T. C.; Himes, R. H.;
Georg, G. I. J . Med. Chem. 1996, 39, 2705-2709.
(11) (a) Neidigh, K. A.; Ghapure, M. M.; Rimoldi, J . M.; Kingston,
D. G. I.; J iang, Y. Q.; Hamel, E. Tetrahedron Lett. 1994, 35, 6839-
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(c) Pulicani, J . P.; Bourzat, J . D.; Bouchard, H.; Vuilhorgne, M.;
Commercon, A. Tetrahedron Lett. 1994, 35, 9713-9716. (d) Pulicani,
J . P.; Bourzat, J . D.; Bouchard, H.; Commercon, A. Tetrahedron Lett.
1994, 35, 9709-9712. (e) Klein, L. L.; Yeung, C. M.; Li, L.; Plattner,
J . J . Tetrahedron Lett. 1994, 35, 4707-4710. (f) J ohnson, R. A.; Nidy,
E. G.; Dobrowolski, P. J .; Gebhard, I.; Qualls, S. J .; Wicnienski, N. A.;
Kelly, R. C. Tetrahedron Lett. 1994, 35, 7893-7896; (Upjohn) WO 94/
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G. I. J . Org. Chem. 1995, 60, 2918-2921. (h) Kelly, R. C.; Wicnienski,
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Tetrahedron Lett. 1996, 37, 1777-1780.

4748 J . Org. Chem., Vol. 62, No. 14, 1997
Gennari et al.
Sch em e 2
Sch em e 3
We have developed a very simple, new, and straight-
forward approach to the Paclitaxel side chain using the
imine addition reaction of thioester-derived boron eno-
lates bearing chiral ligands.12-14 The results are de-
scribed in this paper.
gen to nitrogen4e,8f,16 to give the desired compound 7,
which was isolated practically pure by simple solvent
extraction and without the need of chromatography. The
overall yield is around 60% (starting from 4), and the
stereochemical control is high (syn:anti g 96:4; ee g
96%).17 Treatment of 7 with 2-methoxypropene and
pyridinium p-toluenesulfonate (PPTS) in toluene smoothly
furnished oxazolidine (8) (g90%), and the small amount
of the unwanted anti diastereomer was removed in this
step by chromatography (the anti compound does not
cyclize under these conditions). The absolute configura-
tion was checked by chemical correlation to known
intermediates, and the enantiomeric excess was deter-
mined by 1H-NMR analysis of the Mosher ester derivative
of 7 (see the Supporting Information).
Following a different approach, the easily accessible
phenyl [(tert-butyldimethylsilyl)oxy]thioacetate (9) was
enolized with triethylamine and the chiral boron reagent
derived from (-)-menthone (ent-5)13 and then treated
with N-(trimethylsilyl)benzaldimine15a (6) (Scheme 4).
After quenching and extraction, the crude product was
transformed into the amine hydrochloride to free the
reaction product from the boron ate-complex. The white
solid salt was then treated in dichloromethane with
PhCOCl, Et3N, and a catalytic amount of DMAP, and the
resulting crude product was purified by filtration through
silica gel to give 10 (anti) and traces of the syn diaste-
reomer.17 The overall yield was 71% (starting from 9),
the anti:syn ratio is 97:3, and the major anti compound
(10) is g95% enantiomerically pure (average over several
experiments). The 97:3 mixture was then treated with
aqueous HF in acetonitrile, and the resulting crude
compound 11 (100%, anti:syn 97:3)17 was cyclized by
treatment with thionyl chloride in refluxing 1,2-dichlo-
roethane. Oxazoline formation occurred uneventfully
with complete inversion of stereochemistry at the C-2
stereocenter8e,f to give 12 (65% yield, average over several
experiments), and the traces of the unwanted syn dias-
tereomer were removed in this step by chromatography
(the syn compound does not cyclize under these condi-
Resu lts a n d Discu ssion
P a clita xel Sid e Ch a in . The side chain is assembled
in one step with the correct relative (syn) and absolute
stereochemistry (2R,3S). The easily accessible tert-butyl
(benzoyloxy)thioacetate (4) was enolized with triethyl-
amine and the chiral boron reagent 5 derived from (+)-
menthone13 and then treated with N-(trimethylsilyl)-
benzaldimine15a (6) (Scheme 3). After quenching and
extraction, the crude product was transformed into the
amine hydrochloride. Salt formation freed the reaction
product from the boron ate-complex and allowed easy
removal of all the byproducts simply by washing the
resulting white solid with ether; this workup protocol
represents a major experimental improvement compared
to the usual H2O2 oxidative workup of the boron-mediated
reactions with aldehydes. Treatment of the amine
hydrochloride with buffered MeOH-H2O at pH 8.0
caused clean intramolecular COPh migration from oxy-
(12) For a preliminary account on this work, see: (a) Gennari, C.;
Vulpetti, A.; Donghi, M.; Mongelli, N.; Vanotti, E. Angew. Chem. 1996,
108, 1809-1812; Angew. Chem., Int. Ed. Engl. 1996, 35, 1723-1725.
(b) Gennari, C.; Mongelli, N.; Vanotti, E.; Vulpetti, A. (Pharmacia),
WO 97/00870, 1997; GB Appl. No. 9512471.5, 1995.
(13) (a) Gennari, C.; Hewkin, C. T.; Molinari, F.; Bernardi, A.;
Comotti, A.; Goodman, J . M.; Paterson, I. J . Org. Chem. 1992, 57,
5173-5177. (b) Gennari, C.; Moresca, D.; Vieth, S.; Vulpetti, A. Angew.
Chem. 1993, 105, 1717-1719; Angew. Chem., Int. Ed. Engl. 1993, 32,
1618-1621. (c) Gennari, C.; Vulpetti, A.; Moresca, D. Tetrahedron Lett.
1994, 35, 4857-4860. (d) Bernardi, A.; Gennari, C.; Goodman, J . M.;
Paterson, I. Tetrahedron: Asymmetry 1995, 6, 2613-2636. (e) Gennari,
C.; Pain, G.; Moresca, D. J . Org. Chem. 1995, 60, 6248-6249. (f)
Gennari, C.; Pain, G. Tetrahedron Lett. 1996, 37, 3747-3750. (g)
Gennari, C. Pure Appl. Chem. 1997, 68, 507-512. (h) Gennari, C.;
Moresca, D.; Vulpetti, A.; Pain, G. Tetrahedron 1997, 53, 5593-5608.
(i) Gennari, C.; Vulpetti, A.; Pain, G. Tetrahedron 1997, 53, 5909-
5924.
(14) For related chemistry, involving silyl ketene acetal additions
to chiral imines mediated by a chiral boron Lewis acid, see: (a) Hattori,
K.; Miyata, M.; Yamamoto, H. J . Am. Chem. Soc. 1993, 115, 1151-
1152. (b) Hattori, K.; Yamamoto, H. Tetrahedron 1994, 50, 2785-2792.
(15) (a) Hart, D. J .; Kanai, K.; Thomas, D. G.; Yang, T. K. J . Org.
Chem. 1983, 48, 289-294. (b) Kupfer, R.; Meier, S.; Wuerthwein, E.-
U. Synthesis 1984, 688-690.
(16) Denis, J .-N.; Greene, A. E.; Serra, A. A.; Luche, M.-J . J . Org.
Chem. 1986, 51, 46-50.
(17) The syn:anti mixture was used in the next synthetic step. Pure
syn and anti compounds were separated and isolated only for analytical
purposes.

Taxol Semisynthesis
J . Org. Chem., Vol. 62, No. 14, 1997 4749
Sch em e 4
several experiments), the anti:syn ratio is >99:1 (the syn
diastereomer is not detected by 1H-NMR), and the major
anti compound (11) is ca. 85-88% enantiomerically pure
(85% from R1 ) EE, 88% from R1 ) TMS). This
procedure has several advantages compared to the one
shown in Scheme 4 (TBDMS protecting group): EE- and
TMS-protection is less expensive than TBDMS-protec-
tion, EE and TMS are immediately removed on quench-
ing the aldol reaction mixture, and the anti:syn ratio is
excellent (>99:1). The disadvantage is that both the
enantiomeric excess (ca. 85-88%) and the yield (ca. 40%)
of the aldol product 11 are lower.
The boron enolate-imine reaction was carried out with
a combination of different thioesters (COSPh, COSBut),
oxygen protecting groups (Bn, TBDMS, COPh), chiral
boron ligands [derived from both (-)- and (+)-menthone],
imines (PhCHdNSiMe3,15a PhCHdNCOPh4a,15b), and in
the presence or in the absence of additional Lewis acids
(BF3-OEt2, Et2AlCl, TiCl4). The results can be sum-
marized as follows (Table 1):18
(1) In the reaction of the above described chiral boron
enolates with N-(trimethylsilyl)benzaldimine PhCHd
NSiMe3 (6) a preponderance of the syn diastereoisomer
is obtained with the COSBut thioesters (Table 1, entries
1-3), while a preponderance of the anti isomer is
obtained with the COSPh thioesters (entries 4-6).
(2) With the COSBut thioesters and N-(trimethylsilyl)-
benzaldimine (6), the syn:anti ratios vary from 70:30
(entry 1, TBDMS oxygen protecting group, see below
Scheme 7) to 75:25 (entry 2, Bn oxygen protecting group)
to g96:4 (entry 3, PhCO oxygen protecting group, see
Scheme 3). The desired imine re-face attack, leading to
the 3(S) stereocenter in the major syn isomer, was
obtained in all cases with high selectivity (re:si g 98:2;
ee g 96%) using the chiral boron reagent 5 derived from
(+)-menthone (Scheme 6i).
Sch em e 5
(3) With the COSPh thioesters and N-(trimethylsilyl)-
benzaldimine (6), the anti:syn ratios vary from g90:10
(entry 6, PhCO oxygen protecting group) to 97:3 (entry
4, TBDMS oxygen protecting group, see Scheme 4) to
g98:2 (entry 5, Bn oxygen protecting group). The desired
imine re-face attack, leading to the 3(S) stereocenter in
the major anti isomer, was obtained in all cases with high
selectivity (re:si g 97.5:2.5; ee g 95%) using the chiral
boron reagent ent-5 derived from (-)-menthone. The
minor syn isomer had the opposite and undesired con-
figuration at C-3 (R) (Scheme 6ii).
The practical use of the aldol product with PhCO
oxygen protecting group was hampered by failure to give
clean intramolecular COPh migration from oxygen to
nitrogen by treatment of the amine hydrochloride with
buffered MeOH-H2O (pH 7.0-8.0) because of competi-
tive thiophenyl ester hydrolysis.
tions). The absolute configuration was checked by chemi-
cal correlation with known intermediates, and the enan-
tiomeric excess was determined by H-NMR analysis of
the Mosher ester derivative of anti (11) (see the Sup-
porting Information). The synthesis of 12 has an overall
yield of 46% (starting from 9) and requires only two
chromatographic purifications, the first one (purification
of 10) being a silica gel filtration rather than a real
chromatography.
A simple variant of the above procedure makes use of
more acid labile oxygen-protecting groups. Thus, glyco-
late thioester R1OCH2COSPh (13, R1 ) EE ) 1-ethoxy-
ethyl or R1 ) TMS ) trimethylsilyl) was enolized with
triethylamine and the chiral boron reagent derived from
(-)-menthone (ent-5)13 and then treated with
N-(trimethylsilyl)benzaldimine15a (6) (Scheme 5). After
quenching with pH 7 phosphate buffer and extraction,
the organic phase was treated with HCl-MeOH-H2O,
with consequent removal of the protecting groups. The
resulting crude â-amino alcohol [PhCH(NH3+)CH(OH)-
COSPh Cl-] was washed several times with ethyl ether
and then N-benzoylated in dichloromethane/water (1:1
v:v) with PhCOCl and NaHCO3 under Schotten-Bau-
mann conditions. The resulting crude mixture was
purified by flash cromatography to give the anti com-
pound 11. The overall yield is about 40% (average over
1
(4) The reaction of the above described chiral boron
enolates with imine PhCHdNCOPh needs the presence
of additional Lewis acid in order to give high yields. With
the COSBut thioesters, the syn:anti ratios vary from 87:
13 [(a) entry 9, Bn oxygen protecting group, BF3-OEt2
Lewis acid] to 57:43 [for both (b) entry 8, Bn oxygen
(18) Syn-anti ratios were determined by observing the 1H-NMR
C(2)H-C(3)H coupling constant values of the N-benzoyl compounds
(J syn ) 2.1-2.5 Hz; J anti ) 5.0-5.7 Hz). Enantiomeric excesses were
determined via Eu(hfc)3 1H-NMR analysis of the N-benzoyl compounds
and/or 1H-NMR analysis of the Mosher derivatives (esters with the
C-2 OH group). The absolute configurations were determined via
chemical correlation with known compounds (see the Supporting
Information, and Mukai, C.; Kim, I. J .; Hanaoka, M. Tetrahedron:
Asymmetry 1992, 3, 1007-1010).

4750 J . Org. Chem., Vol. 62, No. 14, 1997
Gennari et al.
a
Ta ble 1.
Bor on En ola te-Im in e Rea ction s w ith a Com bin a tion of Differ en t Th ioester s, Oxygen P r otectin g Gr ou p s (R),
Ch ir a l Bor on Liga n d s, Im in es, Ad d ition a l Lew is Acid s (Sch em e 6)
additional
Lewis acid
absolute config
(major isomer)
entry
R
thioester
L2BBr
imine
syn:anti ratio
% ee
1
2
3
4
5
6
7
8
9
TBDMS
Bn
PhCO
TBDMS
Bn
PhCO
TBDMS
Bn
St-Bu
St-Bu
St-Bu
SPh
SPh
SPh
St-Bu
St-Bu
St-Bu
SPh
SPh
SPh
5
5
5
6
6
6
6
6
6
-
70:30
75:25
g96:4
3:97
e2:98
e10:90
57:43
57:43
87:13
15:85
20:80
48:52
2(R),3(S)
2(R),3(S)
2(R),3(S)
2(S),3(S)
2(S),3(S)
2(S),3(S)
2(R),3(S)
2(R),3(S)
2(R),3(S)
2(S),3(S)
2(S),3(S)
2(S),3(S)
g96
g96
g96
g95
g95
g95
62
46
82
40
60
-
-
ent-5
ent-5
ent-5
ent-5
ent-5
ent-5
5
-
-
-
PhCHdNCOPh
PhCHdNCOPh
PhCHdNCOPh
PhCHdNCOPh
PhCHdNCOPh
PhCHdNCOPh
BF3-OEt2
TiCl4
Bn
TBDMS
Bn
BF3-OEt2
Et2AlCl
BF3-OEt2
BF3-OEt2
10
11
12
5
5
TBDMS
20
a
For determination of the syn:anti ratios, of the enantiomeric excesses (ee), and of the absolute configurations, see footnote 18, the
Experimental Section, and the Supporting Information.
Sch em e 6
protecting group, TiCl4 Lewis acid and (c) entry 7,
TBDMS oxygen protecting group, BF3-OEt2 Lewis acid].
The desired imine re-face attack, leading to the 3(S)
stereocenter in the major syn isomer, was obtained in all
cases with modest selectivity [re:si 91:9 (a), 73:27 (b), 81:
19 (c)] using the chiral boron reagent ent-5 derived from
(-)-menthone (Scheme 6iii).
The stereochemical results with imine PhCHdNCOPh
and N-(trimethylsilyl)benzaldimine are quite different,
in particular the absolute configuration is opposite: cf.
Scheme 6i with 6iii. This can be rationalized by a change
in the reaction mechanism, i.e. the usual cyclic transition
structures involving N-(trimethylsilyl) benzaldimine (see
the stereochemical analysis in the relevant paragraph
below and Scheme 8) are replaced in the case of imine
PhCHdNCOPh by open transition structures, due to the
presence of the additional Lewis acid.
(5) With the COSPh thioesters and imine PhCHd
NCOPh, the anti:syn ratios vary from 85:15 [(a) entry
10, TBDMS oxygen protecting group, Et2AlCl Lewis acid]
to 80:20 [(b) entry 11, Bn oxygen protecting group, BF3-
OEt2 Lewis acid] to 52:48 [(c) entry 12, TBDMS oxygen
protecting group, BF3-OEt2 Lewis acid]. The desired
imine re-face attack, leading to the 3(S) stereocenter in
the major anti isomer, was obtained in all cases with low
selectivity (re:si 60:40-80:20) using the chiral boron
reagent 5 derived from (+)-menthone. The minor syn
isomer had the opposite and undesired configuration at
C-3 (R) (Scheme 6iv).

Taxol Semisynthesis
J . Org. Chem., Vol. 62, No. 14, 1997 4751
Sch em e 7
explanation why this strong stereocontrol is operating
as a function of R2 (tBu vs Ph), while the role of the
oxygen protecting group R1 is relatively minor (see results
above).
Sem isyn t h esis of P a clit a xel a n d Docet a xel.
Thioester oxazoline 12 and oxazolidine 8 were attached
directly to the baccatin nucleus. By treatment of a
mixture of protected baccatin III (7-TES, 2b)7a or pro-
tected 10-deacetylbaccatin III (7,10-di-Troc, 2c)21 and
oxazoline (12) or oxazolidine (8) in THF at 0 °C with
lithium bis(trimethylsilyl)amide (LHMDS), the 13-O acy-
lated compounds 18 and 19 were obtained with high
conversion and yield (89-90% for 18 and 74-75% for 19,
Scheme 9).12
The enantiomeric excess of oxazoline 12 was also
confirmed in the reaction with 7-TES-protected baccatin
III (2b) by isolating, besides the desired compound 18b
(89%), trace amounts (about 2%) of the “wrong” Taxol
derivative 7-(triethylsilyl)-13-O-[[(4R,5S)-2,4-diphenyl-
4,5-dihydrooxazol-5-yl]carbonyl]baccatin (see the Experi-
mental Section).
Doceta xel Sid e Ch a in . Docetaxel (Taxotere, 1b)19
side chain was assembled using an approach similar to
the ones discussed for Paclitaxel (see above). The easily
accessible tert-butyl [(tert-butyldimethylsilyl)oxy]thioace-
tate (14) was enolized with triethylamine and the chiral
boron reagent 5 derived from (+)-menthone13 and then
treated with N-(trimethylsilyl)benzaldimine15a (6) (Scheme
7). After quenching and extraction, the crude product
was transformed into the amine hydrochloride to free the
reaction product from the boron ate-complex. The white
solid salt was then treated in dichloromethane with Et3N
and di-tert-butyl dicarbonate, and the resulting crude
product was purified by silica gel filtration to give 15 (syn:
anti 70:30)17 with an overall yield of 66% (starting from
14). Compound 15 was then treated with HF-pyridine
(7:3) in pyridine-acetonitrile (2:1) at 50 °C,19d and the
resulting compound was purified by flash chromatogra-
phy to give the major syn alcohol (16) (49%; re:si g 98:2;
ee g 96%) together with the minor anti diastereomer
(21%). Oxazolidine formation occurred using 2-methoxy-
propene and PPTS in toluene to give (17) (66%).7c,19c The
absolute configuration was checked by chemical correla-
tion to known intermediates, and the enantiomeric excess
was determined by 1H-NMR analysis of the Mosher esters
derived from 16 (see the Supporting Information).
The use of lithium amides for C-13 OH metalation of
protected baccatin III is well described in the literature.9a,c,d
The most surprising yet gratifying aspect of this new
coupling reaction is the high reactivity of the thioester
derivatives, given the scarcity of methods for this impor-
tant transformation and its difficulty. Thioesters have
attracted the interest of organic chemists since the
discovery that they are used by Nature in enzymatic
acylation processes.22 The resonance overlap of the lone-
pair electrons with the carbonyl group is much weaker
for the sulfur atom than for the oxygen atom; thus a
thioester carbonyl group is much less stabilized by
resonance than the carbonyl group of an ester and is
therefore much more reactive.22 In addition, thioesters
8 and 12 are particularly electrophilic due to the presence
of electron-withdrawing substituents in both the R and
â position. Replacement of the amide group in the â
position (PhCON in 8) with a carbamate group (BocN in
17) makes the thioester carbonyl group less reactive
toward C-13 OH nucleophilic addition. In fact, the yield
of the Docetaxel precursor 20c under the above conditions
is somewhat lower (ca. 60%) (Scheme 9).
Various attempts were made to promote the coupling
reaction between 10-deacetylbaccatin III (7,10-di-Troc,
2c)21 and thioester oxazolidine 8 or oxazoline 12 without
the use of lithium amides. The ester formation was
attempted using different Lewis acids as promoters [Ag-
(OCOCF3), Ag(OSO2CF3), Cu(OSO2CF3)2, Cu(OSO2CF3)-
PhH, Hg(OCOCF3)2] in different solvents (CH2Cl2, CH3-
CN, THF).23 In most cases no formation of the desired
compound was observed, while the use of Ag(OCOCF3)
in dichloromethane or benzene at room temperature
promoted the coupling reaction between 2c and thioester
oxazoline (12) to give 18c only in poor yields (30%).
Both 188 and 19-type7c,d,e compounds have been depro-
Ster eoch em ica l An a lysis of th e En ola te Ad d i-
tion s. From a mechanistic standpoint, the stereochem-
ical divergence of the reactions of E(OB) boron enolates
with aldehydes (anti products)13c and imines (syn
products)13f was reasonably expected based on the dif-
ferent coordination of aldehydes and trans imines to the
boron atom in the chairlike cyclic transition states (cf.
the two chair transition state structures in Scheme 8).13i
On the contrary, the stereodivergence caused by the
different type of thioester in the addition to imines
(COStBu: syn products vs COSPh :anti products) is quite
surprising. The stereochemical outcome can be rational-
ized by using chair vs boat transition structures, as
shown in Scheme 8.20 However, there is no obvious
(20) Ab initio MO calculations (3-21G basis set) featuring the
addition of the BH2 enol borinate derived from acetaldehyde to
formaldehyde-imine have recently shown that two competing cyclic
transition structures are important: the chair and the boat. Bernardi,
A.; Gennari, C.; Raimondi, L.; Villa, M. B. Tetrahedron 1997, 53, 7705-
7714.
(21) Gue´ritte-Voegelein, F.; Se´nilh, V.; David, B.; Gue´nard, D.;
Potier, P. Tetrahedron 1986, 42, 4451-4460.
(22) Bruice, T. C.; Benkovic, S. J . Bioorganic Mechanisms; W. A.
Benjamin Inc.: New York, 1966; Vol. 1, Chapter 3.
(19) Taxotere is the registered trademark of Rhone-Poulenc Rorer
Company for Docetaxel. For recent references on Docetaxel semisyn-
thesis, see: (a) Didier, E.; Fouque, E.; Commercon, A. Tetrahedron Lett.
1994, 35, 3063-3064. (b) Didier, E.; Fouque, E.; Taillepied, I.;
Commercon, A. Tetrahedron Lett. 1994, 35, 2349-2352. (c) Bourzat,
J . D.; Commercon, A. Tetrahedron Lett. 1993, 34, 6049-6052. (d)
Ojima, I.; Kuduk, S. D.; Slater, J . C.; Gimi, R. H.; Sun, C. M.
Tetrahedron 1996, 52, 209-224.
(23) (a) Masamune, S.; Hayase, Y.; Schilling, W.; Chan, W. K.; Bates,
G. S. J . Am. Chem. Soc. 1977, 99, 6756-6758. (b) Booth, P. M.; Fox,
C. M. J .; Ley, S. V. J . Chem., Soc. Perkin Trans. 1 1987, 121-129.

4752 J . Org. Chem., Vol. 62, No. 14, 1997
Gennari et al.
Sch em e 8
Sch em e 9a
involves the hydrolysis of 18b to give Paclitaxel (1a ) in
80% yield (Scheme 9). This represents the third original
approach (after the two described in the introduction)4a,7-11
for the attachment of the Paclitaxel side chain.
Exp er im en ta l Section
Gen er a l. Chromatographic purification of products was
carried out by “flash chromatography”24 using Merck silica gel
60 (230-400 mesh). Thin layer chromatography was carried
out on Merck silica gel 60F plates. Organic solutions were
dried over sodium sulfate (Na2SO4). 1H NMR spectra were
obtained at 200 MHz and 13C NMR at 50.28 MHz at 25 °C
(unless otherwise stated). Chemical shifts are reported in
parts per million (ppm), δ, from TMS ) 0.00 ppm. J values
are given in Hz.
ter t-Bu tyl (Ben zoyloxy)th ioa ceta te (4). A solution of
AlMe3 (2.0 M in hexanes, 30.4 mL, 60.8 mmol) in CH2Cl2 (65
mL) was treated at 0 °C with t-BuSH (6.85 mL, 60.8 mmol).
After 20 min at 0 °C, a solution of methyl glycolate (HOCH2-
COOMe, 0.786 mL, 10.1 mmol) in CH2Cl2 (15.2 mL) was added
at -10 °C. The mixture was stirred at 0 °C for 48 h, quenched
with NH4Cl saturated aqueous solution (30 mL), and filtered
through Celite, washing the Celite cake with CH2Cl2. The
organic phase was dried and evaporated to give a crude
mixture which was purified by flash chromatography (hex-
anes-Et2O 7:3) to afford pure tert-butyl (hydroxy)thioacetate
(t-BuSCOCH2OH, 0.795 g, 53%). A solution of the latter
compound (0.72 g, 4.88 mmol) in CH2Cl2 (32.5 mL) was treated
with DMAP (0.06 g, 0.488 mmol), Et3N (1.0 mL, 7.318 mmol),
and PhCOCl (0.736 mL, 6.342 mmol) at 0 °C, under stirring.
After 30 min at 0 °C, a saturated aqueous NH4Cl solution (10
mL) was added, and the organic phase was separated, dried,
and evaporated to give a crude compound, which was purified
by flash chromatography (hexanes-Et2O 94:6) to afford pure
4 (1.09 g, 89%): 1H NMR (CDCl3): δ ) 1.52 (9H, s), 4.89 (2H,
s), 7.45-7.65 (4H, m), 8.10-8.18 (2H, m). Anal. Calcd for
C13H16O3S (252.3): C 61.88, H 6.39, S 12.71. Found: C 61.76;
H 6.40; S 12.68.
tected to give Paclitaxel in high yields. Docetaxel precur-
sor 20c has been transformed into both Docetaxel and
Paclitaxel via known routes.7c,19b Our preferred route
(24) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.

Taxol Semisynthesis
J . Org. Chem., Vol. 62, No. 14, 1997 4753
Ald ol Rea ction To Give ter t-Bu tyl (2R,3S)-3-(Ben zoyl-
am in o)-2-h ydr oxy-3-ph en ylth iopr opion ate (7). To a stirred
solution of 4 (0.184 g, 0.730 mmol) in Et2O (3.2 mL) at -25
°C, under argon atmosphere, were added a solution of reagent
5 in CH2Cl2 (0.4 M; 3.2 mL, 1.28 mmol) and then Et3N (0.188
mL, 1.350 mmol) dropwise. Enol borinate was generated with
concurrent formation and precipitation of Et3N-HBr. After
7.0 h at -25 °C, the mixture was cooled to -78 °C, and imine
6 (1.460 mmol, preparation of the imine in ref 15a) was added
dropwise. The resulting mixture was stirred at -78 °C for
0.5 h and then slowly warmed to -5 °C during 2 h and stirred
at -5 °C overnight. The mixture was then quenched with pH
6 phosphate buffer and extracted several times with CH2Cl2.
The organic phase was evaporated to give a residue which was
dissolved in MeOH:1 N aqueous HCl (1:1 v:v, 24.0 mL) and
stirred at rt for 1 h. The resulting solution was evaporated to
dryness and pumped (0.1 mmHg). The white solid residue was
washed with dry Et2O (3 × 10 mL), removing the ether phase
by centrifugation and decantation. The white solid residue
was then dissolved in MeOH (10.0 mL) and pH 8 phosphate
buffer (10.0 mL) and stirred at rt for 1 h. The pH was adjusted
to 7 with dil (0.1 M) aqueous HCl, the mixture was concen-
trated in order to remove most of the MeOH, and the aqueous
phase was extracted with CH2Cl2 (3 × 10 mL). The organic
phase was dried and evaporated to give practically pure 7
(0.139 g, 53%). In addition, 19.7 mg (7.5%) of 7 was obtained
via flash chromatography (hexanes-acetone 70:30) of the
crude mixture contained in the Et2O phase, used to wash the
white solid residue (see above). Total yield ) 60.5%. The
product was flash chromatographed (pentanes-Et2O 50:50) to
5% aqueous NaOH and saturated brine, dried, and evaporated
to give a crude mixture which was purified by flash chroma-
tography (hexanes-Et2O 95:5) to afford pure 9 (2.74 g, 79%):
1H NMR (CDCl3): δ ) 0.20 (6H, s), 1.01 (9H, s), 4.38 (2H, s),
7.43 (5H, m). Anal. Calcd for C14H22O2SSi (282.5): C 59.53,
H 7.85, S 11.35. Found: C 59.65; H 7.83; S 11.37.
Ald ol Rea ction To Give P h en yl (2S,3S)-3-(Ben zoyl-
a m in o)-2-[(ter t-bu tyld im eth ylsilyl)oxy]-3-p h en ylth iop r o-
p ion a te (10). To a stirred solution of 9 (1.572 g, 5.56 mmol)
in Et2O (25 mL) at 0 °C, under argon atmosphere, were added
a solution of reagent ent-5 in CH2Cl2 (0.4 M; 25 mL, 10.0 mmol)
and then Et3N (1.47 mL, 10.56 mmol) dropwise. Enol borinate
was generated with concurrent formation and precipitation of
Et3N-HBr. After stirring for 0.5 h at 0 °C and 5 h at +15 °C,
the mixture was cooled to -78 °C, and a solution of imine 6
(1.36 g, 7.67 mmol) (for the preparation, see ref 15a) in a
minimum volume of CH2Cl2 (1 mL), cooled to -78 °C, was
added dropwise via cannula. The resulting mixture was
stirred at -78 °C for 0.5 h and then slowly warmed to -5 °C
during 2 h and stirred at -5 °C overnight. The mixture was
then quenched with pH 7 phosphate buffer (23 mL), and
extracted with CH2Cl2 (3 × 25 mL). The combined organic
extracts were dried and evaporated. The crude product was
dissolved in MeOH:0.5 N aqueous HCl (1:1 v:v, 40.0 mL). The
mixture was diluted with CH2Cl2 (3.0 mL), and the resulting
solution was stirred at rt for 3 h and then evaporated to
dryness under reduced pressure. The resulting crude product
was pumped in vacuo (0.1 mmHg) in a desiccator overnight
over P2O5. The white solid residue (2.35 g, 5.56 mmol) was
then dissolved in CH2Cl2 (9.26 mL) and treated at 0 °C with
DMAP (0.068 g, 0.556 mmol), Et3N (5.57 mL, 40.0 mmol), and,
after further 10 min, with PhCOCl (freshly distilled) (2.26 mL,
19.44 mmol). The mixture was stirred at 0 °C for 30 min and
then diluted with EtOAc (72 mL) and quenched at 0 °C with
water and ice. The organic phase was washed with saturated
NaHCO3 aqueous solution and saturated brine, dried, and
evaporated. The crude reaction product was flash chromato-
graphed (hexanes-Et2O 65:35) to give pure compound 10 (anti)
+ traces of syn (71% yield). Chromatography can be used in
this case with a low silica gel product ratio (filtration), just to
remove the major byproducts [the subsequent reaction can be
performed even if the product is not entirely pure (purity
g80%)]. The anti-syn ratio of the product was determined
give analytically pure 7: [R]25 ) -12.2° (c ) 1.69 in CHCl3);
D
1H NMR (CDCl3): δ ) 1.45 (9H, s), 3.85 (1H, br, OH), 4.57
(1H, br d), 5.70 (1H, dd, J ) 2.5, 8.7), 7.14 (1H, d, J ) 8.7),
7.20-7.60 (8H, m), 7.70-7.90 (2H, m); 13C NMR (CDCl3): δ )
29.60, 38.79, 56.42, 79.62, 126.87, 127.02, 127.77, 128.57,
131.61, 138.27, 166.94, 202.16; MS (70 eV, EI): m/ z 358 (M
+ 1), 268, 250, 240, 222, 210, 193, 122, 105, 91, 77. Anal. Calcd
for C20H23NO3S (357.5): C 67.20, H 6.49, N 3.92, S 8.97.
Found: C 67.07; H 6.50; N 3.93, S 8.95.
Syn th esis of ter t-Bu tyl (4S,5R)-N-Ben zoyl-2,2-dim eth yl-
4-p h en yl-1,3-oxa zolid in e-5-th ioca r boxyla te (8). A solu-
tion of compound 7 (not chromatographed, containing e4% of
the anti isomer) (186 mg, 0.5203 mmol) in toluene (5.2 mL)
was treated with PPTS (13 mg) and freshly distilled 2-meth-
oxypropene (0.98 mL). The mixture was stirred at rt for 5 min
and at 80 °C for 75 min. After dilution with EtOAc (15 mL),
the organic phase was washed with aqueous NaHCO3 satu-
rated solution (5 mL) and brine (2 × 5 mL), dried, and
evaporated to give a crude mixture. Purification via flash
1
by H NMR analysis, by integration of the relevant peaks of
the anti and syn isomers (97:3). The 97:3 mixture was flash
chromatographed (hexanes-i-Pr2O 50:50) to give pure 10 (anti)
and syn compounds only for analytical purposes.
10 (anti): [R]25 ) -166.6° (c ) 1.29 in CHCl3); 1H NMR
D
(CDCl3): δ ) -0.05 (3H, s), 0.20 (3H, s), 1.02 (9H, s), 4.78 (1H,
d, J ) 5.5), 5.52 (1H, dd, J ) 5.5, 7.8), 6.89 (1H, d, J ) 7.8),
7.10-7.60 (13H, m), 7.70-7.90 (2H, m); 13C NMR (CDCl3):
selected peaks δ ) 25.74, 38.69, 57.53, 80.17, 126.92, 128.18,
128.28, 128.43, 128.53, 129.03, 129.29, 131.62, 134.65, 137.23,
chromatography (hexanes-acetone 90:10) gave pure oxazoli-
1
dine 8 (186 mg, 90%): [R]25 ) +39.4° (c ) 1.0 in CHCl3); H
D
NMR (CDCl3): δ ) 1.52 (9H, s), 1.91 (3H, s), 1.96 (3H, s), 4.50
(1H, d, J ) 5.65), 5.20 (1H, d, J ) 5.65), 6.90-7.30 (10H, m);
13C NMR (CDCl3): δ ) 25.73, 26.27, 29.59, 48.13, 56.37, 87.35,
126.10, 126.66, 127.58, 127.98, 128.23, 128.38, 129.25, 131.57,
137.47, 138.89, 168.00, 198.72; MS (70 eV, EI): m/ z 398 (M
+ 1, 44%), 382, 340, 292, 280 (100%), 250, 210, 162, 146, 105,
91, 77. Anal. Calcd for C23H27NO3S (397.5): C 69.49, H 6.85,
N 3.52, S 8.06. Found: C 69.35; H 6.86; N 3.51, S 8.04.
P h en yl [(ter t-Bu tyld im eth ylsilyl)oxy]th ioa ceta te (9).
Methyl glycolate (1.90 mL, 2.20 g, 24.5 mmol) was added to a
suspension of TBDMS-Cl (4.43 g, 29.4 mmol) and imidazole
(4.17 g, 61.25 mmol) in dry DMF (4.9 mL) at 0 °C, under
stirring. After 90 min stirring at rt, water (60 mL) was added,
and the resulting mixture was extracted with Et2O (3 × 35
mL). The organic phases were combined, washed with water
(3 × 35 mL), dried, and evaporated to give TBDMS-OCH2CO2-
Me (5.0 g, 100%): 1H NMR (CDCl3): δ ) 0.12 (6H, s), 0.93
(9H, s), 3.75 (3H, s), 4.26 (2H, s). A solution of AlMe3 (2.0 M
in hexanes, 12.25 mL, 24.5 mmol) in CH2Cl2 (49 mL) was
treated at 0 °C with PhSH (2.5 mL, 24.5 mmol). After 20 min
at 0 °C, a solution of TBDMS-OCH2COOMe (2.5 g, 12.25 mmol)
in CH2Cl2 (6.125 ml) was added at 0 °C. The mixture was
stirred at rt for 0.5 h, quenched with NH4Cl saturated aqueous
solution (12 mL), and filtered through Celite, washing the
Celite cake with CH2Cl2. The organic phase was washed with
166.53, 200.83. Anal. Calcd for C28H33NO3SSi (491.7):
C
68.39, H 6.76, N 2.85, S 6.00. Found: C 68.53; H 6.75; N 2.86,
S 5.99.
Phenyl (2S,3R)-3-(benzoylamino)-2-[(tert-butyldimethylsi-
lyl)oxy]-3-phenylthiopropionate (syn): [R]25D ) -29.4° (c ) 1.98
1
in CHCl3); H NMR (CDCl3): δ ) -0.21 (3H, s), 0.14 (3H, s),
1.00 (9H, s), 4.60 (1H, d, J ) 2.4), 5.62 (1H, dd, J ) 2.4, 8.8),
7.20-7.60 (13H, m), 7.80-8.00 (2H, m); 13C NMR (CDCl3):
selected peaks δ ) 56.52, 81.03, 166.23.
Syn th esis of P h en yl (2S,3S)-3-(Ben zoyla m in o)-2-h y-
d r oxy-3-p h en ylth iop r op ion a te (11). In a round bottom
Pyrex-glass flask the mixture containing 10 (anti) + traces of
syn (97:3) (1.92 g, 3.91 mmol) was treated with a 0.5 M solution
of HF in CH3CN-H2O (66:1) (62.51 mL), at 0 °C, under
stirring. The mixture was stirred at rt for 24 h. The solvent
was removed under reduced pressure, and the resulting crude
product was pumped in vacuo (0.1 mmHg) in a desiccator
overnight over P2O5. The crude product 11 (anti) + traces of
syn (97:3) was washed with Et2O to give a white amorphous
solid (1.52 g, 103.4%; the crude compound contains impurities
from the glass-HF: yields are typically >100%) and used
without purification for the subsequent reaction. The 97:3

4754 J . Org. Chem., Vol. 62, No. 14, 1997
Gennari et al.
mixture was flash chromatographed (i-Pr2O-EtOAc 95:5) to
give pure 11 (anti) and syn compounds only for analytical
stirred at -5 °C overnight. The mixture was then quenched
with pH 7 phosphate buffer (12 mL) and extracted with CH2-
Cl2 (3 × 10 mL). The combined organic extracts were dried
and evaporated. The crude product was dissolved in MeOH:
0.5 N aqueous HCl (1:1 v:v, 24.0 mL) and stirred at rt for 3 h.
The resulting solution was evaporated to dryness and pumped
in vacuo (0.1 mmHg) in a desiccator overnight over P2O5. The
solid residue (1.074 g, 2.66 mmol) was then dissolved in CH2-
Cl2 (4.44 mL) and treated at 0 °C with Et3N (1.48 mL, 10.64
mmol) and, after further 10 min, with Boc2O (1.32 g, 6.03
mmol). The mixture was stirred at rt for 4 h and then
quenched with NH4Cl and extracted with CH2Cl2 (3 × 20 mL).
The organic phase was washed with saturated brine, dried,
and evaporated. The crude reaction product was flash chro-
matographed (hexanes-Et2O 8:2) to give tert-butyl 3-[(tert-
butoxycarbonyl)amino]-2-[(tert-butyldimethylsilyl)oxy]-3-phen-
ylthiopropionate (0.818 mg, 66% yield). The syn-anti ratio
of the mixture was determined by 1H NMR analysis, by
integration of the relevant peaks of the syn and anti isomers
(70:30).
15 (syn, 70% of the mixture): 1H NMR (CDCl3): δ ) -0.47
(3H, s), -0.1 (3H, s), 0.85 (9H, s), 1.43 (9H, s), 1.54 (9H, s),
4.22 (1H, br s), 5.14 (1H, d, J ) 9.0), 5.59 (1H, d, J ) 9.0),
7.19-7.33 (5H, m).
tert-Butyl (2R,3R)-3-[(tert-Butoxycarbonyl)amino]-2-[(tert-
butyldimethylsilyl)oxy]-3-phenylthiopropionate (anti, 30% of
the mixture): 1H NMR (CDCl3): selected peaks δ ) -0.03 (3H,
s), 0.06 (3H, s), 0.94 (9H, s), 4.35 (1H, d, J ) 4.6), 4.95 (1H,
m).
purposes.
1
11 (anti): [R]25 ) -140.23° (c ) 0.8 in acetone); H NMR
D
(CD3COCD3): δ ) 4.90 (1H, dd, J ) 5.6, 6.3), 5.65 (1H, dd, J
) 5.6, 8.6), 5.94 (1H, d, J ) 6.3), 7.10-7.70 (13H, m), 7.80-
7.90 (2H, m), 8.05 (1H, d, J ) 8.6); 13C NMR (CD3COCD3):
selected peaks δ ) 56.53, 79.10, 127.41, 127.61, 128.00, 128.28,
128.90, 129.32, 131.30, 134.69, 138.15, 139.89, 166.24, 200.39;
MS (70 eV, EI): m/ z 378 (M + 1, 57%), 360, 268, 240, 222,
210, 193, 105 (100%), 91, 77. Anal. Calcd for C22H19NO3S
(377.5): C 70.01, H 5.07, N 3.71, S 8.49. Found: C 69.87; H
5.06; N 3.72, S 8.47.
Phenyl (2S,3R)-3-(benzoylamino)-2-hydroxy-3-phenylthio-
propionate (syn): [R]25 ) -67.0° (c ) 1.04 in acetone); 1H
D
NMR (CD3COCD3): δ ) 4.80 (1H, d, J ) 3.4), 5.70 (1H, dd, J
) 3.4, 8.2), 7.120-7.60 (13H, m), 7.90-8.01 (2H, m); 13C NMR
(CD3COCD3): selected peaks δ ) 56.28, 79.92.
Syn t h esis of P h en yl (4S,5R)-2,4-Dip h en yl-4,5-d ih y-
d r ooxa zole-5-th ioca r boxyla te (12). A solution of 11 (anti)
+ traces of syn (97:3, crude, without chromatography) (1.520
g, 3.89 mmol) in CHCl3 (40.20 mL) was treated with SOCl2
(1.47 mL, 20.13 mmol) and stirred at 45 °C for 3-4 h. The
solvent was removed in vacuo, and the crude product was
pumped (0.1 mmHg) and then dissolved in 1,2-dichloroethane
(20 mL) in the presence of 3 Å molecular sieves. The resulting
mixture was refluxed (100 °C) for 5 h. The solution was then
filtered, dried, and evaporated to give a crude product, which
was purified by flash chromatography (CH2Cl2:hexanes 88:12).
The compound tends to trap CH2Cl2, giving rise to a viscous
oil. Pure 12 was obtained as a white/pale-yellow amorphous
solid by treating the oil with hexane:Et2O (99:1 v:v) and
Syn th esis of ter t-Bu tyl (2R,3S)-3-[(ter t-Bu toxyca r bo-
n yl)a m in o]-2-h yd r oxy-3-p h en ylth iop r op ion a te (16).
A
solution of tert-butyl 3-[(tert-butoxycarbonyl)amino]-2-[(tert-
butyldimethylsilyl)oxy]-3-phenylthiopropionate (syn:anti 70:
30) (0.460 g, 0.985 mmol) in pyridine (49.8 mL) and CH3CN
(24.9 mL), under argon atmosphere, was treated with a
solution of Py (30%)-HF (70%) (Aldrich reagent) (11.7 mL) at
rt. The mixture was warmed at 50 °C and stirred for 5 h. The
solution was diluted with H2O and extracted with EtOAc (3 ×
50 mL). The combined organic extracts were washed with
NaHCO3 (3 × 25 mL) to reach pH 7, dried, and evaporated.
The mixture (syn:anti 70:30) was flash chromatographed
(hexanes:Et2O 65:35) to give the analytically pure 16 (syn)
(0.170 mg) and anti (0.073 mg) diastereoisomers (yield 70%).
collecting the product by filtration (0.909 g, 65% yield): [R]25
D
) +91.28° (c ) 0.8 in CHCl3); 1H NMR (CDCl3): δ ) 5.06 (1H,
d, J ) 5.61), 5.55 (1H, d, J ) 5.61), 7.20-7.60 (13H, m), 8.10-
8.30 (2H, m); 13C NMR (CDCl3): selected peaks δ ) 75.48,
89.10, 126.41, 128.01, 128.60, 128.86, 129.31, 129.72, 132.15,
134.65; MS (70 eV, EI): m/ z 360 (M + 1, 57%), 250, 222, 193,
119, 109, 91 (100%), 77, 65. Anal. Calcd for C22H17NO2S
(359.4): C 73.51, H 4.77, N 3.90, S 8.92. Found: C 73.36; H
4.76; N 3.91, S 8.90.
ter t-Bu tyl [(ter t-Bu tyldim eth ylsilyl)oxy]th ioacetate (14).
Methyl glycolate (0.776 mL, 0.905 g, 10.0 mmol) was added to
a suspension of TBDMS-Cl (1.81 g, 12.0 mmol) and imidazole
(1.7 g, 25.0 mmol) in dry DMF (2.0 mL) at 0 °C, under stirring.
After 90 min stirring at rt, water (25 mL) was added, and the
resulting mixture was extracted with Et2O (3 × 15 mL). The
organic phases were combined, washed with water (3 × 15
mL), dried, and evaporated to give methyl [(tert-butyldimeth-
ylsilyl)oxy]acetate (TBDMSOCH2CO2Me, 2.0 g, 100%): 1H
NMR (CDCl3): δ ) 0.12 (6H, s), 0.93 (9H, s), 3.75 (3H, s), 4.26
(2H, s). A solution of AlMe3 (2.0 M in hexanes, 8.82 mL, 17.64
mmol) in CH2Cl2 (35.28 mL) was treated at 0 °C with t-BuSH
(1.99 mL, 17.64 mmol). After 20 min at 0 °C, a solution of
methyl [(tert-butyldimethylsilyl)oxy]acetate (1.8 g, 8.82 mmol)
in CH2Cl2 (4.41 mL) was added at -20 °C. The mixture was
stirred at -20 °C for 2 h and then diluted with Et2O and
quenched with 1.0 N aqueous HCl (10 mL). The organic phase
was washed with 5% aqueous NaOH and saturated brine,
dried, and evaporated to give a crude mixture which was
purified by flash chromatography (hexanes-CH2Cl2 80:20) to
afford pure 14 (1.81 g, 78%): 1H NMR (CDCl3): δ ) 0.10 (6H,
s), 0.94 (9H, s), 1.47 (9H, s), 4.16 (2H, s). Anal. Calcd for
16 (syn): [R]25 ) -8.7° (c ) 1.0 in CHCl3); 1H NMR
D
(CDCl3): δ ) 1.44 (9H, s), 1.56 (9H, s), 3.56 (1H, br s), 4.43
(1H, br s), 5.21 (1H, d, J ) 8.33), 5.43 (1H, d, J ) 8.33), 7.25-
7.46 (5H, m); 13C NMR (CDCl3): selected peaks δ ) 28.20,
29.66, 57.18, 79.88, 126.704, 127.440, 128.390, 139.154, 155.23,
201.97. Anal. Calcd for C18H27NO4S (353.5): C 61.16, H 7.70,
N 3.96, S 9.07. Found: C 61.28; H 7.68; N 3.95, S 9.09.
tert-Butyl (2R,3R)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-
3-phenylthiopropionate (anti): 1H NMR (CDCl3): δ ) 1.42 (9H,
s), 1.44 (9H, s), 3.26 (1H, d, J ) 7.55), 4.57 (1H, dd, J ) 3.2,
7.55), 5.15 (1H, dd, J ) 3.2, 8.0), 5.55 (1H, d, J ) 8.0), 7.20-
7.40 (5H, m); 13C NMR (CDCl3): selected peaks δ ) 28.23, 29.6,
48.7, 79.29, 79.89, 155.07, 200.48.
Syn th esis of ter t-Bu tyl (4S,5R)-N-(ter t-Bu toxyca r bo-
n yl)-2,2-d im eth yl-4-p h en yl-1,3-oxa zolid in e-5-th ioca r box-
yla te (17). A solution of 16 (0.060 g, 0.17 mmol) in toluene
(8.0 mL) was treated with PPTS (2.14 mg) and freshly distilled
2-methoxypropene (0.384 mL). The mixture was stirred at rt
for 5 min, and at 80 °C for 4 h. After dilution with EtOAc (8
mL), the organic phase was washed with aqueous NaHCO3
saturated solution (3 mL) and brine (2 × 3 mL), dried, and
evaporated to give a crude mixture. Purification via flash
C12H26O2SSi (262.5): C 54.91, H 9.98, S 12.21. Found:
55.02; H 9.96; S 12.19.
C
Ald ol Rea ction To Give ter t-Bu tyl (2R,3S)-3-[(ter t-
Bu toxyca r bon yl)a m in o]-2-[(ter t-bu tyld im eth ylsilyl)oxy]-
3-p h en ylth iop r op ion a te (15). To a stirred solution of 14
(0.701 g, 2.67 mmol) in Et2O (12.0 mL) at 0 °C, under argon
atmosphere, were added a solution of boron reagent 5 in CH2-
Cl2 (0.4 M; 12.0 ml, 4.8 mmol) and then Et3N (0.706 mL, 5.07
mmol) dropwise. Enol borinate was generated with concurrent
formation and precipitation of Et3N-HBr. After 5 h at rt, the
mixture was cooled to -78 °C, and imine 6 (0.710 g, 4.0 mmol)
was added dropwise. The resulting mixture was stirred at -78
°C for 0.5 h and then slowly warmed to -5 °C during 2 h and
chromatography (hexanes-Et2O 95:5) gave pure 17 (42.5 mg,
1
65.6%): [R]25 ) -7.8° (c ) 1.0 in CHCl3); H NMR (CDCl3,
D
50 °C): δ ) 1.19 (9H, s), 1.51 (9H, s), 1.73 (3H, s), 1.79 (3H,
s), 4.37 (1H, d, J ) 5.0), 5.0 (1H, d, J ) 5.0), 7.2-7.4 (5H, m);
13C NMR (CDCl3): selected peaks δ ) 26.147, 26.601, 27.918,
29.600, 47.764, 63.934, 87.156, 126.137, 127.361, 128.393,
151.472, 199.685; IR (CHCl3): selected peaks ν ) 1702.84 cm-1
(CdO, t-BuSCO), 1672.00 cm-1 [CdO, t-BuO(CO)N]. Anal.
Calcd for C21H31NO4S (393.5): C 64.09, H 7.94, N 3.56, S 8.15.
Found: C 63.96; H 7.96; N 3.57, S 8.17.

Taxol Semisynthesis
J . Org. Chem., Vol. 62, No. 14, 1997 4755
Syn t h esis of 7-(Tr iet h ylsilyl)-13-O-[[(4S,5R)-2,4-d i-
p h en yl-4,5-d ih yd r ooxa zol-5-yl]ca r bon yl]ba cca tin (18b).
A solution of 7-TES-baccatin III (2b, for preparation see ref
7a) (199 mg, 0.284 mmol) and compound 12 (357 mg, 0.994
mmol) in THF (5.68 mL) at 0 °C under argon, with stirring,
was treated with a freshly prepared 0.6 M solution of LHMDS
in THF-hexanes 62:38 (2.13 mL, 1.28 mmol). After 15 min
stirring at 0 °C, the mixture was quenched with a saturated
NH4Cl aqueous solution (14 mL). The aqueous phase was
extracted with Et2O (3 × 20 mL), and the combined organic
extracts were dried and evaporated. The crude product was
purified by flash chromatography (pentanes-Et2O 44:56) to
P a clita xel (1a ). A solution of 18b (360 mg, 0.378 mmol)
in 0.04 N HCl in MeOH:water [1.5:1 (v:v)] (40 mL) was stirred
at 60 °C for 1 h and at 80 °C for 2.5 h. The mixture was cooled
to rt, and a saturated NaHCO3 aqueous solution (8 mL) was
added (final pH ) 7.5). The resulting mixture was stirred at
rt for 16 h. MeOH (ca. 24 mL) was evaporated under vacuum
(0.1 mmHg) at rt; the resulting aqueous mixture was then
extracted with CH2Cl2 (3 × 10 mL). The organic extracts were
dried and evaporated. The crude product was flash chromato-
graphed (hexanes:EtOAc 1:1) to give pure Paclitaxel (1a ) (259
mg, 80%). 1H NMR (CDCl3): δ ) 1.14 (3H, s), 1.25 (3H, s),
1.68 (3H, s), 1.79 (3H, s), 2.23 (3H, s), 2.38 (3H, se), 2.35-
2.40 (2H, m), 2.40-2.60 (2H, m), 3.67 (1H, br s), 3.79 (1H, d,
J ) 6.96), 4.26 (1H, A part of an AB system, J ) 8.42), 4.34
(1H, B part of an AB system, J ) 8.42), 4.13-4.40 (1H, m),
4.79 (1H, br s), 4.94 (1H, dd, J ) 7.98, 1.5), 5.67 (1H, d, J )
6.96), 5.78 (1H, dd, J ) 8.89, 2.45), 6.23 (1H, br t, J ) 9.0),
6.27 (1H, s), 7.03 (1H, d, J ) 8.89), 7.30-7.60 (11H, m), 7.74
give pure 18b (Rf ) 0.275) (241 mg, 89%): [R]25 ) -54.8° (c
D
) 1.0 in CHCl3); 1H NMR (CDCl3): δ ) 0.60 (6H, q, J ) 7.29),
0.94 (9H, t, J ) 7.29), 1.21 (3H, s), 1.25 (3H, s), 1.71 (3H, s),
2.01 (3H, s), 2.08 (3H, s), 2.18 (3H, s), 1.95-2.2 (1H, m), 2.22-
2.45 (2H, m), 2.55 (1H, m), 3.85 (1H, d, J ) 6.99), 4.15 (1H, d,
J ) 8.34), 4.31 (1H, d, J ) 8.34), 4.51 (1H, dd, J ) 6.59, 10.29),
4.96 (1H, d, J ) 6.51), 4.96 (1H, d), 5.62 (1H, d, J ) 6.51),
5.70 (1H, d, J ) 6.99), 6.21 (1H, br t, J ) 8.80), 6.44 (1H, s),
7.30-7.70 (11H, m), 8.09 (2H, d, J ) 7.24), 8.25 (2H, d, J )
7.79); 13C NMR (CDCl3): selected peaks δ ) 5.17, 6.66, 9.93,
14.43, 20.74, 21.60, 26.45, 29.58, 35.48, 37.05, 43.07, 46.90,
58.34, 71.79, 72.19, 74.67, 74.87, 78.90, 80.77, 83.24, 84.10,
126.31, 126.60, 128.17, 128.51, 128.88, 129.97, 132.05, 133.64,
133.93, 139.75, 140.68, 166.91, 169.05, 169.77, 170.09, 201.60;
MS (FAB+): m/ z 950 (M + H+, 71%), 951 (M + 2, 43%), 952
(M + 3, 21%), 972 (M + Na+, 100%), 973 (M + 24, 64%), 974
(M + 25, 28%). Anal. Calcd for C53H63NO13Si (949.4): C 66.99,
H 6.69, N 1.47. Found: C 67.12; H 6.68; N 1.47.
(2H, d, J ) 7.0), 8.13 (2H, d, J ) 7.0). Anal. Calcd for C47H51
-
NO14 (853.3): C 66.09, H 6.02, N 1.64. Found: C 65.96; H
6.03; N 1.64.
Ack n ow led gm en t. Pharmacia&Upjohn Postdoctor-
al Fellowship to A.V. and Postgraduate Fellowship to
M.D. are gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedure and spectroscopic characterization for boron reagents
5 and ent-5; determination of the syn-anti ratios, absolute
configurations, and enantiomeric excesses for compounds 7,
11, and 16; experimental procedures and spectroscopic char-
acterization for compounds 13 and the aldol reactions de-
scribed in Scheme 5; experimental procedures and spectro-
scopic characterization for compounds 18c, 19b, 19c, 20c (14
pages). This material is contained in 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.
The enantiomeric excess of 12 (g95%) was also confirmed
by isolating the “wrong” Taxol derivative 7-(tr ieth ylsilyl)-
13-O-[[(4R,5S)-2,4-d ip h en yl-4,5-d ih yd r ooxa zol-5-yl]ca r -
bon yl]baccatin (5.4 mg, 2%) via flash cromatography (pentane:
Et2O 44:56) (Rf ) 0.35): 1H NMR (CDCl3): δ ) 0.60 (6H, q, J
) 8.0), 0.94 (9H, t, J ) 8.0), 1.25 (3H, s), 1.27 (3H, s), 1.70
(3H, s), 1.97 (3H, s), 2.17 (3H, s), 2.22 (3H, s), 1.75-1.95 (1H,
m), 2.24-2.40 (2H, m), 2.55 (1H, m), 3.85 (1H, d, J ) 7.03),
4.16 (1H, d, J ) 8.21), 4.30 (1H, d, J ) 8.21), 4.51 (1H, dd, J
) 6.46, 10.41), 4.91 (1H, d, J ) 8.5), 4.98 (1H, d, J ) 6.4), 5.57
(1H, d, J ) 6.4), 5.70 (1H, d, J ) 7.03), 6.27 (1H, m), 6.47 (1H,
s), 7.30-7.70 (11H, m), 8.16 (4H, m).
J O9703212