Synthesis of the CD ring in taxol from (S)-(+)-carvone

Article abstract of DOI:10.1016/S0040-4039(01)01802-0

The tricycle 16 containing a functionalized CD ring is constructed from (S)-(+)-carvone in 21 steps involving a Baeyer-Villiger oxidation, an Oppenaurer oxidation and Meerwein-Ponndorf-Verley reduction, a stereospecific Grignard addition, and an intramole

Full text of DOI:10.1016/S0040-4039(01)01802-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8361–8363
Synthesis of the CD ring in taxol from (S)-(+)-carvone
Tony K. M. Shing,* Chi M. Lee and Ho Y. Lo
Department of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong, China
Received 6 July 2001; accepted 21 September 2001
Abstract—The tricycle 16 containing a functionalized CD ring is constructed from (S)-(+)-carvone in 21 steps involving a
Baeyer–Villiger oxidation, an Oppenaurer oxidation and Meerwein–Ponndorf–Verley reduction, a stereospecific Grignard addi-
tion, and an intramolecular SN2 reaction as the key steps. © 2001 Elsevier Science Ltd. All rights reserved.
Paclitaxel (Taxol)1 (1) is a tetracyclic diterpenoid anti-
cancer drug routinely used for the treatment of breast,
lung, and ovarian carcinomas.2 The outstanding cyto-
toxic activity of taxol is believed to arise from its
unique propensity to hinder cell replication by prevent-
ing microtubules from depolymerization.3 To date, six
total syntheses of taxol have been published.4 The
shortest route was reported by Wender et al.,4d starting
from (1R)-(+)-verbenone and involving 37 steps in an
overall yield of about 0.37%.
O
O
EtAlCl2, rt, 48 h
100%
+
H
R-(--)-Carvone
2
Isoprene
These experiments have also indicated that in order to
obtain the correct absolute configuration at the angular
methyl group in taxol, (S)-(+)-carvone has to be
employed in our synthesis. Thus, the intermolecular
Diels–Alder reaction of (S)-(+)-carvone with isoprene
using EtAlCl2 as the catalyst followed by protection6 of
the carbonyl group with ethylene glycol gave acetal 3 in
an overall yield of 82%. Dihydroxylation of the two
double bonds in acetal 3 with a catalytic amount of
osmium tetroxide and N-methylmorpholine-N-oxide
(NMO)7 furnished the corresponding tetraol which was
subjected to a selective glycol cleavage oxidation8 at the
terminal diol unit, giving ketone 4, mp 171.5–172°C;
[h]2D0+3.0 (c 0.3, CHCl3), in a 74% overall yield. Baeyer–
Villiger oxidation9 of ketone 4 using m-chloroperben-
zoic acid (mCPBA) afforded acetate 5, mp
175.5–176°C; [h]2D0−15.1 (c 0.37, CHCl3), in 90% yield.
Protection of the vicinal diol unit in 5 with 2,2-
dimethoxypropane (DMP) followed by deacetylation
and pyridinium chlorochromate (PCC) oxidation of the
resultant hydroxy group afforded ketone 6, mp 89.5–
90.5°C; [h]2D0+40.6 (c 0.4, CHCl3). After considerable
experimentation, direct introduction of a 1-carbon unit
to C-4 (taxol numbering) was unsuccessful and an
alternative route was adopted. Thus, selective
enolisation10 of ketone 6 with Et3N occurred at C-4 and
subsequent treatment with tert-butyldimethylsilyltriflate
(TBSOTf) at −78°C gave the corresponding silyl enol
ether which was oxidized with Oxone11 to give the
h-hydroxy ketone 7 in 65% overall yield. The inter-
In our quest for the discovery of a structurally sim-
plified, synthetically accessible taxol analogue which
possesses a comparable biological profile, we started a
project to investigate a facile and flexible construction
of the CD rings of the taxol carbon skeleton. Our
preliminary experiments have shown that the Diels–
Alder reaction between (R)-(−)-carvone and isoprene
occurred preponderantly in an anti orientation with
respect to the isopropylene group in (R)-(−)-carvone to
give the decalin 2.5 Such a decalin system 2, containing
a stereo-defined angular methyl group, could be a
valuable synthetic precursor for the taxol C ring
system.
Keywords: taxoids; hydroxylation; Baeyer–Villiger reactions; Grig-
nard reactions.
* Corresponding author. E-mail: tonyshing@cuhk.edu.hk
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01802-0

8362
T. K. M. Shing et al. / Tetrahedron Letters 42 (2001) 8361–8363
O
O
O
O
HO
HO
O
OsO4 (cat), NMO
then NaIO4, 74%
1) EtAlCl2, Toluene, 92%
2) HO(CH)2OH, H+, 89%
+
H
H
O
Isoprene S-(+)-Carvone
4
3
1) DMP, H+, 92%
O
O
O
1) TBSOTf, Et3N,
-78 °C, 89%
2) K2CO3, MeOH,
100%
HO
O
O
O
mCPBA
o
3) PCC, 4A MS,
CH2Cl2, 90%
4
CH2Cl2, 90%
HO
2) Oxone, acetone
73%
O
OAc
H
H
6
5
O
O
O
1) TMSCl, Et3N,
96%
O
O
O
O
O
Al(OiPr)3,
O
O
O
5
4
Toluene, 79%
2) VinylMgBr, -78 °C,
100%
O
OH
OH
OH
O
H
H
H
O
OH
3) TBAF, THF, 90%
8
9
7
O
O
O
1) OsO4 (cat), NMO
85%
O
NaH, BnBr,
O
NaBH4
O
2) NaIO4, 89%
80 °C, 86%
MeOH, 94%
O
O
OR
OBn
OBn
OBn
H
H
O
10
11 R = Bn
12 R = H
H2, Pd/C,
70%
O
O
O
1) H2, 10% Pd/C,
EtOH, 91%
O
O
O
NaH, THF,
reflux, 84%
O
O
O
2) Ac2O, Pyr
58%
O
O
O
O
O
OH
H
H
H
OBn
OAc
OBn
OR
15
16
13 R = H
14 R = Ms
MsCl, Collidine,
0 °C, 98%
molecular redox reaction i.e. Oppenaurer oxidation and
Meerwein–Ponndorf–Verley reduction,12 of a-hydroxy
ketone 7 using Al(OiPr)3 as the catalyst gave the ther-
modynamically more stable 5-hydroxy-4-one 8 in 79%
yield. Transient protection of the free alcohol in 8 as a
trimethylsilyl (TMS) ether was followed by the addition
of vinyl magnesium bromide and subsequent deprotec-
tion with tetrabutylammonium fluoride (TBAF),
affording the diol 9, mp 150–151°C; [h]2D0+24.1 (c 0.3,
CHCl3), in 86% overall yield. It is noteworthy that the
Grignard addition was stereoselective and only one
stereoisomer was isolated in a quantitative yield. The
constitution and especially the stereochemistry of the
tertiary alcohol in 9 was confirmed by X-ray crystallo-
graphic analysis.13 Benzylation of the diol 9 gave the
dibenzyl ether 10 without incident, [h]2D0+6.5 (c 1.0,
CHCl3). The double bond in 10 was dihydroxylated7
and then oxidatively cleaved8 to form a rather stable
aldehyde 11, [h]2D0+11.4 (c 0.4, CHCl3), in an overall
yield of 76%. Selective hydrogenolysis of the secondary
benzyl ether in 11 gave the hydroxy aldehyde 12 which
was reduced with sodium borohydride to give diol 13,
[h]2D0+10.6 (c 0.5, CHCl3). Selective mesylation14 of the
less hindered primary alcohol in 13 gave the mesylate
14 that was treated with sodium hydride to cause an
intramolecular SN2 reaction,15 furnishing the oxetane
15, [h]2D0+16.4. (c 0.7, CHCl3), in 82% overall yield. The
benzyl ether protecting group in 15 was transformed
into the desired acetyl group of 16, mp 131–131.5°C;
[h]2D0+26.1 (c 0.25, CHCl3), by hydrogenolysis and

T. K. M. Shing et al. / Tetrahedron Letters 42 (2001) 8361–8363
8363
acetylation. Thus, the tricycle 16 was constructed from
(S)-(+)-carvone in 21 steps with an overall yield of 4%.
V.; Jung, D. K.; Isaacs, R. C. A.; Bornmann, W. G.;
Alaimo, C. A.; Coburn, C. A.; DiGrandi, M. J. J. Am.
Chem. Soc. 1996, 118, 2843; (d) Wender, P. A.; Badham,
N. F.; Comway, S. P.; Floreancig, P. E.; Glass, T. E.;
Houze, J. B.; Krauss, N. E.; Lee, D.; Marquess, D. G.;
McGrane, P. L.; Meng, W.; Natchus, M. G.; Shuker, A.
J.; Sutton, J. C.; Taylor, R. E. J. Am. Chem. Soc. 1997,
119, 2757 and references cited therein; (e) Mukaiyama,
T.; Shiina, I.; Iwadare, H.; Saitoh, M.; Nishimura, T.;
Ohkawa, N.; Sakoh, H.; Nishimura, K.; Tani, Y.;
Hasegawa, M.; Yamada, K.; Saitoh, K. Chem. Eur. J.
1999, 5, 121; (f) Kusama, H.; Hara, R.; Kawahara, S.;
Nishimori, T.; Kashima, H.; Nakamura, N.; Morihara,
K.; Kuwajima, I. J. Am. Chem. Soc. 2000, 122, 3811.
5. Shing, T. K. M.; Lo, H. Y.; Mak, T. C. W. Tetrahedron
1999, 55, 4643.
In summary, we have presented a facile, efficient, and
stereocontrolled synthetic route for the construction of
the functionalized CD ring in taxol. The transformation
of tricycles 15 and 16 into taxol analogues is under
active investigation.
Acknowledgements
Financial support from CUHK Direct Grant (account
no. 2060181) is gratefully acknowledged.
6. Babler, J. H.; Malek, N. C.; Coghlan, M. J. J. Org.
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