A synthesis of taxanes by lactam-sulfoxide ring contraction and intramolecular pinacol coupling

Article abstract of DOI:10.1055/s-1999-3101

A synthesis of the taxane ring system is described. The A-ring moiety 5, containing the carbons for construction of the Bring, was prepared from Wieland-Miescher ketone via Beckmann fragmentation of the oxime 10. The B- ring was formed by means of 12-membered lactam-sulfoxide ring contraction. The formation of the C-ring was carried out by aldol condensation of the resulting AB-ring moiety 3 followed by intramolecular pinacol coupling to give the tricyclic diol 23.

Full text of DOI:10.1055/s-1999-3101

LETTER
975
A Synthesis of Taxanes by Lactam-sulfoxide Ring Contraction and
Intramolecular Pinacol Coupling
Kazuhiko Takatori,a Yoshinari Takeuchi,a Yuka Shinohara,a Kenji Yamaguchi,a Masayuki Nakamura,a Tatsuya
Hirosawa,a Takeshi Shimizu,a Masae Saito,a Shouich Aizawa,a Osamu Sugiyama,a Yasuo Ohtsukab, Masahiro
Kajiwaraa*
a Department of Medicinal Chemistry, Meiji Pharmaceutical University, 2-252-1 Noshio, Kiyose-shi, Tokyo 204-8588, Japan
b Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-0002, Japan
Fax +81(424)957458; E-mail: kajiwara@my-pharm.ac.jp
Received 29 January 1999
Our synthetic plan is shown in Scheme 1. The B-ring of
ketone 3, a key intermediate in the synthesis, is construct-
ed by means of the lactam-sulfoxide ring contraction.6
The lactam-sulfoxide 4 containing the o-thioaniline moi-
Abstract: A synthesis of the taxane ring system is described. The
A-ring moiety 5, containing the carbons for construction of the B-
ring, was prepared from Wieland-Miescher ketone via Beckmann
fragmentation of the oxime 10. The B-ring was formed by means of
12-membered lactam-sulfoxide ring contraction. The formation of ety as a spacer is formed from carboxylic acid 5, which is
the C-ring was carried out by aldol condensation of the resulting
AB-ring moiety 3 followed by intramolecular pinacol coupling to
give the tricyclic diol 23.
prepared from the Wieland-Miescher ketone (6) by cleav-
age of the bond between the quaternary carbon and the
carbonyl carbon.
Key words: taxane, ring contraction, SmI2, pinacol coupling,
Beckmann fragmentation
Ketone 7 was selected as starting material and prepared
from 6 in 2 steps by known methods (Scheme 2).7 Wittig
reaction of 7 and selective oxidation of the resulting exo-
olefin with OsO4 in the presence of NMO gave the diol 8
Taxol® (paclitaxel, 1), isolated from Taxus brevifolia,1 is
as a 3:2 diastereomeric mixture. Acetonide formation and
a clinically useful antimitotic agent and its total synthesis
has already been achieved.2 The taxane framework is a tri-
cyclic ring system containing a highly strained 8-mem-
bered ring as the B ring, and many approaches to this ring
system have been developed.3 In the biosynthesis of 1, the
initial step is cyclization of geranylgeranyl diphosphate to
taxa-4(5),11(12)-diene (2).4 But the nature of the subse-
quent oxidation process from 2 to 1 has not been report-
ed.4b In preparation for tracer experiments with 13C-
labeled derivatives, we examined the synthesis of 2 and its
oxidation products.5
hydrolysis of the ketal in 8 proceeded in one pot under
acidic conditions in acetone to give ketone 9. Cleavage of
the bond between the quaternary carbon and the carbonyl
carbon in 9 was achieved by Beckmann fragmentation8 of
the oxime 10 with TsCl in pyridine to afford a mixture of
the dienes 11. Hydrolysis of the cyano group of 11 with
KOH, followed by Birch reduction gave carboxylic acid
5, which contains all the carbons of the AB-ring moiety
and the desired tetrasubstituted olefin in the A-ring.9
Scheme 2
Scheme 1
Synlett 1999, S1, 975–977 ISSN 0936-5214 © Thieme Stuttgart · New York

976
K. Takatori et al.
LETTER
Construction of the strained B-ring was achieved stepwise BuOK gave 4 with complete stereoselectivity. The stere-
by cyclization of 5 to a 12-membered ring lactam-sulfox- ochemistry of 4 was determined by X-ray crystallographic
ide including the spacer moiety and ring contraction to an analysis.12 Ring contraction of 4 was achieved by treat-
8-membered ring (Scheme 3). Condensation of 5 and the ment with LDA to give the desired 8-membered ketone
o-thioaniline 12, prepared by hydrolysis of 3-methylben- 18. The synthesis of the AB-ring moiety 3 was finished by
zothiazole-2-thione with KOH and conjugate addition of reductive removal of the spacer moiety of 18 with Na-
the resulting thiol to acrylonitrile,6b via the acid chloride Hg.13 The stereochemistry of 3 was determined from dif-
of 5, followed by hydrolysis of the acetonide and tosyla- ference NOE spectra.
tion of the resulting primary alcohol, gave the amide 13.
Cyclization of 13 was accomplished by slow dropwise ad-
dition of 13 to a mixture of K2CO3 and NaBH4 in N,N-
Construction of the C-ring was performed by the introduc-
tion of a four-carbon side chain corresponding to C4-7
into the AB-ring moiety 3 at C8 and cyclization between
dimethylacetamide (DMA) and ethylene glycol at 130 °C
C3 and C4, by means of aldol condensation and SmI2-in-
under high dilution conditions6 to afford the 12-mem-
duced intramolecular pinacol coupling (Scheme 4). Aldol
bered lactam-sulfide 14. In this reaction, the 2-cyanoethyl
condensation of 3 at C8, the more substituted a-carbon,
S-protective group was eliminated, and the resulting thiol-
with LDA and aldehyde 19 afforded a 2:1 mixture of b-
tosylate was cyclized to 14. The presence of NaBH4 pre-
hydroxyketones in excellent yield. The mixture of b-hy-
vented the formation of disulfide from the thiol, and the
droxyketones was converted without separation to the
produced acrylonitrile was reduced to propionitrile to
MOM ethers 20 and 21. The relative stereochemistry of
C19 and the proton adjacent to C1 in 20 and 21 was syn,
as determined by difference NOE experiments, and the
anti isomers were not observed. Removal of the TBS
avoid the reverse reaction to 13. After protection of the
tertiary hydroxyl group in 14 with a MOM group, intro-
duction of the methyl group corresponding to C1910 at the
a-position of the amide carbonyl with LDA and MeI pro-
group of the major isomer 20 with TBAF and Dess-Martin
ceeded with high diastereoselectivity, and oxidation of the
oxidation14 of the resulting primary alcohol gave aldehyde
sulfur with NaIO4 afforded the sulfoxide 15 as a single
22. Cyclization of the C-ring was achieved by treatment of
isomer. Treatment of 15 with LDA caused b-elimination
of the MOMO group and afforded the vinylsulfoxide 16.
The chemical structure of 16 was confirmed by X-ray
crystallographic analysis.11 Selective reduction of the ole-
fin adjacent to sulfur in 16 with LiBHEt3 proceeded
through peripheral attack of hydride at C1 to give the lac-
tam-sulfoxide 17. Since ring contraction of 17 did not pro-
ceed, ring contraction of 4, a diastereomer of 17 with
respect to the methyl group at the a-position of the amide
carbonyl, was examined. Isomerization of 17 with t-
22 with SmI2 in THF15 under reflux conditions to afford
the tricyclic diol 23.16 The stereochemistry of the two hy-
droxyl groups of 23 was syn and the BC ring junction was
trans, as in natural taxanes, as judged from an X-ray crys-
tallographic analysis.17
Thus, the synthesis of the tricyclic ring system of taxanes
was accomplished by means of lactam-sulfoxide ring con-
traction to form the B-ring and SmI2-induced intra-
molecular pinacol coupling to form the C-ring. The result-
Scheme 3
Synlett 1999, S1, 975–977 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Synthesis of Taxanes
977
(9) 5: mp. 69.1–71.3 °C; 1H NMR (CDCl3, 400 MHz) d: 0.99 (3H,
s), 1.09 (3H, s), 1.40 (3H, s), 1.44 (3H, s), 1.63 (3H, s), 1.65–
1.77 (3H, m), 1.85–2.08 (4H, m), 2.21 (1H, m), 2.38 (2H, t, J
= 7.2 Hz), 3.67 (1H, d, J = 8.8 Hz), 3.94 (1H, d, J = 8.8 Hz);
IR (neat) cm-1: 3590–2350 (br), 1709, 1457, 1381, 1371, 1261,
1216, 1159, 1046, 870; EI-MS m/z (%): 296 (M+, 6), 221 (12),
182 (100), 167 (20), 122 (18), 107 (17).
ing tricyclic diol 23 may be further manipulated to extend
the synthesis to taxadienes, and should be useful for stud-
ies on Taxol® (1) biosynthesis.
(10) The taxane numbering system is used throughout.
(11) Crystal system of 16: orthorhombic; unit-cell dimensions: a =
14.877 (3) Å, b = 43.434 (7) Å, c = 11.897 (2) Å; volume of
unit cell: 7688 (2) Å3; Z value: 16; space group: Fdd2;
residuals: R = 2.4%, wR = 3.7%.
(12) Crystal system of 4: orthorhombic; unit-cell dimensions: a =
10.028 (2) Å, b = 21.865 (5) Å, c = 9.294 (2) Å; volume of unit
cell: 2038.0 (6) Å3; Z value: 4; space group: P21cn; residuals:
R = 3.0%, wR = 4.8%.
(13) A synthesis of a diastereomeric mixture of 3 has been
reported, see: Martin S. F.; Assercq, J.-M.; Austin R. E.;
Dantanarayana, A. P.; Fishpaugh, J. R.; Gluchowski, C.;
Guinn, D. E.; Hartmann, M.; Tanaka, T.; Wagner, R.: White,
J. B. Tetrahedron 1995, 51, 3455. 3: mp. 29.0–31.0 °C;
1H NMR (CDCl3, 400 MHz) d: 0.90 (3H, d, J = 6.6 Hz), 1.05
(3H, s), 1.43 (3H, s), 1.44 (3H, s), 1.59 (1H, m), 1.70–2.15
(7H, m), 2.22 (1H, ddd, J = 5.0, 11.5, 14.0 Hz), 2.34 (1H, m),
2.83 (1H, m), 2.90 (1H, dd, J = 5.5, 11.0 Hz); 13C NMR
(CDCl3, 100 MHz) d: 18.7, 20.3, 24.0, 25.1, 27.4, 28.2, 29.8,
37.0, 37.8, 46.1, 49.7, 50.6, 134.2, 136.6, 218.6; IR (neat) cm-
1: 2938, 1688, 1458, 1370, 1202, 1184, 1113, 1066, 1037; HR-
MS m/z : Calcd for C15H24O: 220.1827. Found: 220.1825
(M+); EI-MS m/z (%): 220 (M+, 27), 205 (20), 202 (60), 187
(39), 163 (27), 150 (100), 147 (37), 145 (24), 121 (38), 119
(22), 109 (24), 107 (29), 105 (21).
Scheme 4
(14) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277;
Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
(15) Namy, J. L.; Souppe, J.; Kagan, H. B. Tetrahedron Lett. 1983,
24, 765; Molander, G. A.; Kenny, C. J. Am. Chem. Soc. 1988,
53, 2134.
Acknowledgement
We are grateful to Dr. Keita Matsumoto, Taisho Pharmaceutical
Co., Ltd. for the X-ray crystallographic analyses.
(16) 23: mp. 146.5–147.1 °C; 1H NMR (500 MHz, CDCl3) d: 1.03
(3H, s), 1.04 (3H, s), 1.32 (3H, s), 1.46 (2H, m), 1.72-2.13
(10H, m), 1.81 (3H, s), 2.19 (1H, d, J = 8.6 Hz), 2.28 (1H, ddd,
J = 3.4, 15.3, 16.8 Hz), 2.41 (1H, dd, J = 6.0, 16.8 Hz), 2.43
(2H, m), 3.09 (1H, m), 3.26 (1H, dd, J = 4.3, 11.6 Hz), 3.36
(3H, s), 4.57 (1H, d, J = 6.7 Hz), 4.65 (1H, d, J = 6.7 Hz);
13C NMR (126 MHz, CDCl3) d: 147.7, 126.8, 96.9, 83.1, 80.4,
73.4, 55.8, 48.7, 47.9, 38.4, 35.7, 34.5, 29.3, 29.1, 28.3, 27.0,
26.0, 23.0, 22.9, 21.6, 13.9; IR (neat) cm-1: 3505, 3463, 2951,
2880, 1100, 1034, 911; HR-MS m/z: Calcd for C21H36O4:
352.2613. Found: 352.2619 (M+); EI-MS m/z (%): 352 (M+,
26), 219 (22), 203 (60), 201 (27),187 (24), 173 (27), 171 (22),
159 (46), 145 (49), 143 (24), 136 (24), 135 (63), 134 (34), 133
(67), 131 (39), 123 (42), 122 (32), 121 (100), 120 (31), 119
(93), 117 (26), 111 (29), 109 (63), 107 (94), 105 (93); Anal.
Calcd for C21H36O4: C, 71.55; H, 10.29. Found: C, 71.30; H,
10.07.
References and Notes
(1) Wani, M. C.; Taylor, M. E.; Coggan, P.; McPhail, A. T. J. Am.
Chem. Soc. 1971, 93, 2325.
(2) For the total synthesis of Taxol® (1) by the groups of Holton,
Nicolaou, Danishefsky, Wender, Mukaiyama and Kuwajima,
see ref. 2 in the following paper: Morihira, K.; Hara, R.;
Kawahara, S.; Nishimori, T.; Nakamura, N.; Kusama, H.;
Kuwajima, I. J. Am. Chem. Soc. 1998, 120, 12980.
(3) For reviews see: Nicolaou, K. C.; Dai, W. M.; Guy, R. K.
Angew. Chem., Int. Ed. Engl. 1994, 33, 15; Boa, A. N.;
Jenkins, P. R.; Lawrence, N. J. Contemporary Organic Syn-
thesis 1994, 1, 47.
(4) (a) Lin, X.; Hezari, M.; Koepp, A. E.; Floss, H. G.; Croteau,
R. Biochem. 1996, 35, 2968; Koepp, A. E.; Hezari, M.; Za-
jicek, J.; Vogel, B. S.; LaFever, R. E.; Lewis, N. G.; Croteau,
R. J. Biol. Chem. 1995, 270, 8686. (b) Eisenreich, W.; Men-
hard, B.; Lee, M. S.; Zenk, M. H.; Bacher, A. J. Am. Chem.
Soc. 1998, 120, 9694.
(17) Crystal system of 23: monoclinic; unit-cell dimensions: a =
12.979 (2) Å, b = 19.573 (3) Å, c = 7.770 (2) Å, b = 101.35 (1)
degree; volume of unit cell: 1935.3 (6) Å3; Z value: 4; space
group: P21/n; residuals: R = 3.4%, wR = 3.4%.
(5) For a synthesis of 2 see: Rubenstein, S. M.; Williams, R. M. J.
Org. Chem. 1995, 60, 7215.
(6) (a) Ohtsuka, Y.; Oishi, T. Chem. Pharm. Bull. 1988, 36, 4711,
4722. (b) Ohtsuka, Y.; Niitsuma, S.; Tadokoro, H.; Hayashi,
T.; Oishi, T. J. Org. Chem. 1984, 49, 2326. (c) Ohtsuka, Y.;
Oishi, T. Chem. Pharm. Bull. 1983, 31, 454.
Article Identifier:
1437-2096,E;1999,0,S1,0975,0977,ftx,en;W04599ST.pdf
(7) Bauduin, G.; Pietrasanta, Y., Tetrahedron 1973, 29, 4225;
Kalvoda, J.; Loeffel, H. Helv. Chim. Acta 1957, 40, 2340.
(8) For a review see: Gawley, R. E. In Organic Reactions, Vol.
35; Kende, A. S., Chief Ed.; John Wiley & Sons, Inc.: New
York, 1988; p 1.
Synlett 1999, S1, 975–977 ISSN 0936-5214 © Thieme Stuttgart · New York