Enantioselective total synthesis of taxol [13]

Full text of DOI:10.1021/ja9824932

12980
J. Am. Chem. Soc. 1998, 120, 12980-12981
Enantioselective Total Synthesis of Taxol
Koichiro Morihira, Ryoma Hara, Shigeru Kawahara,
Toshiyuki Nishimori, Nobuhito Nakamura,
Hiroyuki Kusama,* and Isao Kuwajima*,†
Department of Chemistry, Tokyo Institute of Technology
O-okayama, Meguro-ku, Tokyo 152-8551, Japan
ReceiVed July 15, 1998
Taxol isolated from pacific yew trees1 continues to be of
extreme interest as a synthetic target2 because of the challenging
and complex molecular structure coupled with important biologi-
cal activities.3 The major problems in taxol synthesis seem to be
focused on the following: (1) construction of a taxane tri-
carbocycle and (2) stereocontrol of nine asymmetric centers. This
paper describes an enantioselective total synthesis of (-)-taxol.
Our strategy for taxol synthesis was based on initial construc-
tion of an endo tricarbocyclic intermediate A with the correct
stereochemistry at the C1 and C2 sites4 followed by an appropriate
functional group elaboration on the B- and C-rings. The structural
feature of A may allow us to introduce the C19-methyl from the
upper site of the C-ring. The use of a C-ring fragment 2 serves as
a clue for installation of C4- and C7-oxygen functionalities from
the convex â-face. We also envisioned that the present approach
would lead to an enantioselective synthesis of taxol by using
aldehyde 1 which has a chiral center at C1 site. Thus, chelation-
controlled coupling of the enantiomerically pure hydroxyaldehyde5
with the C-ring fragment 2 would confirm the stereochemical
outcome at the C1 and C2 sites, and a subsequent B-ring cycli-
zation between the C9 and C10 atoms6 would lead to the en-
antioselective formation of the key intermediate A for taxol.
In the presence of Mg(II) ion, the reaction of 1 with the lithiated
2 gave the corresponding coupling product with complete stereo-
control in the desired fashion (Scheme 1). Protection of vicinal
diol6b as a boronate gave the cyclization precursor 3, and then the
crucial B-ring cyclization was examined. Among several Lewis
acids examined, TiCl2(OiPr)2 proved to be the most efficient one
to induce the cyclization. Subsequent removal of boronate pro-
duced the corresponding C9R,C10â-disubstituted tricarbocycle 4.
For the introduction of C19-methyl, we adopted a similar
strategy to that of taxusin synthesis,7 namely, the cyclopropanation
on the ∆3,8-double bond followed by ring cleavage of cyclopropyl
t
ketone. Thus, 4 was treated successively with BuLi and Bu2Si-
(H)Cl8 at low temperature. On warming up the reaction temper-
ature, hydrogen evolved to give the dioxasilapentane.9 Reduction
of the C13-keto group followed by silylation afforded 5. Singlet
oxygen oxygenation of the diene moiety took place selectively
from the â-face of the C-ring. A subsequent treatment with Bu3-
SnH and AIBN induced both peroxide bond cleavage and removal
of the phenylthio group, giving a diol. Removal of the benzyl
group followed by the C7,C9-diol protection yielded 6 as a mix-
ture of diastereomers (R:â ) ca. 1:4). Of the two diastereomers
of 6, the major â-isomer underwent the expected methylenation
by treating with Et2Zn/ClCH2I,10 whereas the methylene transfer
could not be effected with the R-isomer. Dess-Martin oxidation11
of the C4-hydroxy group afforded the cyclopropyl ketone 7.
During the synthetic studies of taxusin, it was revealed that
the role of C13-OH is critical in converting an enol produced via
the cyclopropane ring cleavage to the desired ketone: Conversion
of the C13-OH-protected enol to the C3R-protonated ketone via
intermolecular protonation was exceedingly difficult because the
protonation to the C3 had to occur from the highly congested
concave face. To overcome this difficulty, we achieved the enol/
keto isomerization by utilizing the closely situated C13-OH to
direct the protonation from the R-face.7 Based on this observation,
we initially removed the C13- as well as the C1,C2-silicon
protecting groups of 7, and the resulting triol was used for ring
cleavage. Under the influence of SmI2, the cyclopropane ring
cleavage took place readily, but the resulting enol was exception-
ally unstable, and in the presence of air, it quickly decomposed
to form a complex mixture of unidentified products. At this stage,
enol/keto isomerization was examined by using the protected C1,-
C2-diol substrate. Replacement of the C7,C9-protecting group of
7 with the carbonate followed by treatment with TBAF/AcOH
gave a diol. Then the vicinal diol was protected with a benzylidene
group and the carbonate was removed to give 8. On exposure to
SmI2-HMPA-methanol,12 8 was smoothly converted to an enol
stable enough to allow further manipulation under various reaction
conditions. After several attempts, it was found that the removal
of the TBS group followed by treatment under basic conditions
† Present address: The Kitasato Institute, 5-9-1 Shirokane, Minato-ku,
Tokyo 108-8642, Japan.
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(8) At first, a synthetic route using a benzylidene protecting group for the
(3) (a) Taxol: Science and Applications; Suffness, M., Ed.; CRC, Boca
Raton, FL, 1995. (b) Taxane Anticancer Agents: Basic Science and Current
Status; Georg, G. I., Chen, T. T., Ojima, I., Vyas, D. M., Eds.; ACS
Symposium Series 583; American Chemical Society: Washington, DC, 1995.
(4) The taxane numbering system is used throughout.
(5) Nakamura, T.; Waizumi, N.; Horiguchi, Y.; Kuwajima, I. Tetrahedron
Lett. 1994, 35, 7813.
C1,C2-diol moiety was examined. However, cyclopropanation of the ∆3,8
-
double bond did not proceed at all.
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1998, 63, 2422.
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10.1021/ja9824932 CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/01/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 49, 1998 12981
Scheme 1a
a tBuMgCl, THF, -78 °C; then 2, -78 °C, 68%. (b) (MeBO)3, pyr, benzene, 77%. (c) TiCl2(OiPr)2, CH2Cl2, -78-0 °C. (d) Pinacol, DMAP,
benzene, 59% from 3. (e) BuLi, tBu2Si(H)Cl, THF, -78-0 °C. (f) DIBAL, CH2Cl2, -78 °C. (g) TBSOTf, 2,6-lutidine, CH2Cl2, -23 °C, 62% from 4;
(h) O2, TPP, hv, CH2Cl2. (i) Bu3SnH, AlBN, benzene, reflux, 80% from 5. (j) Pd/C, H2, EtOH. (k) PhCH(OMe)2, CSA, CH2Cl2, -23 °C, 79% in 2 steps
(R:â ) ca. 1:4). (l) Et2Zn, ClCH2I, toluene, 0 °C, 66%. (m) Dess-Martin, CH2Cl2, 77%. (n) Pd(OH)2, H2, EtOH, 84%. (o) Triphosgene, pyr, CH2Cl2,
-45 °C. (p) TBAF, AcOH, THF, 95% in 2 steps. (q) PhCH(OMe)2, PPTS, benzene, reflux, 86%. (r) K2CO3, MeOH-THF, quant. (s) SmI2, THF-
MeOH-HMPA, quant. (t) TBAF, BHT, THF. (u) NaOMe, BHT, degassed MeOH, 45% in 2 steps (ca 50% of 9 was recovered); 65% by repeating this
isomerization procedure twice. (v) PhB(OH)2, CH2Cl2; (w) TBSOTf, 2,6-lutidine, CH2Cl2, -45 °C; (x) H2O2, NaHCO3, AcOEt, 70% from 10. (y)
Dess-Martin, CH2Cl2, 92%. (z) 2-Methoxypropene, PPTS, CH2Cl2, 97%. (aa) KHMDS, PhNTf2, -78 °C, 89%; (bb) Pd(PPh3)4, TMSCH2MgCl, Et2O,
91%; (cc) NCS, MeOH, 88%; (dd) 2-methoxypropene, PPTS, CH2Cl2, 89%. (ee) LDA, MoOPH, THF, -23 °C, 80%. (ff) Ac2O, DMAP, CH2Cl2, 92%.
(gg) DBN, toluene, reflux, 68% at 92% conversion. (hh) OsO4, pyr, Et2O, 86%. (ii) DBU, toluene, reflux, 86%. (jj) PPTS, MeOH. (kk) TESCl, imidazole,
DMF, 97% in 2 steps. (ll) Pd(OH)2, H2, EtOH, 97%. (mm) triphosgene, pyr, CH2Cl2, -78-0 °C, 94%. (nn) Ac2O, DMAP, CH2Cl2, 66%. (oo) PhLi,
THF, -78 °C, 83%. (pp) HF‚pyr, THF, 88%. (qq) trocCl, pyr, CH2Cl2, 94%. (rr) TASF, THF, 80%. (ss) LHMDS, 18, THF, -78-0 °C, 77% at 90%
conversion. (tt) Zn, AcOH-H2O, 84%.
of the resulting enol 9 induced the isomerization to give an almost
1:1 equilibrium mixture of 9 and 10. Finally, the C3R-protonated
ketone 10 was obtained in 65% yield by repeating this enol/keto
isomerization procedure twice.
On applying OsO4 oxidation to 14, dihydroxylation took place
selectively on the ∆4,20-site to afford the desired diol in good yield.
By heating with DBU in toluene, oxetane formation2a proceeded
to give the tetracyclic intermediate. Then, we examined acetylation
of the C4R-OH, but the reaction did not take place under the
usual conditions. Considering that the phenyl group might prevent
the C4R-OH from undergoing acetylation, replacement of the
benzylidene group with a carbonate group was examined. Since
the MOP group on C7-OH was also eliminated under the
conditions to remove the benzylidene group, it was initially
replaced by a TES group and then the 1,2-diol protecting group
was converted from the benzylidene to the carbonate. Acetylation
of the C4R-OH took place smoothly, and then the carbonate group
was converted to the C2-benzoyl group2 to afford 16. The TES
group on C7-OH was replaced by a Troc group, and the TBS
group was removed by treatment with TASF.2a,15 Finally, attach-
ment of the side chain using the â-lactam 182a,16 followed by
removal of the protecting groups gave (-)-taxol.
With the crucial synthetic intermediate 10 in hand, the C7,-
C9-diol of 10 was initially protected as a boronate, and then the
C13-OH was silylated with TBSOTf. After removal of the boron
protecting group, selective oxidation of the C9-OH was achieved
by Dess-Martin oxidation11 and the remaining C7-OH was
protected as a 2-methoxy-2-propyl ether (MOP),13 giving 11. Our
next task was to introduce an exomethylene moiety on the C4
site. For such purpose, we explored an original methodology
which may also serve as an introduction of the C5 functionality
to construct the D-ring at a later stage. Regioselective generation
of the ∆4,5-enolate by treating with KHMDS and quenching with
PhNTf2 gave the enol triflate in good yield. Cross-coupling
reaction with TMSCH2MgCl in the presence of Pd(Ph3P)4 gave
the corresponding allylsilane 12, and chlorination of 12 with NCS
in MeOH gave the corresponding C5R-chloride 13 in good yield.
For construction of the D-ring, introduction of a diol moiety
on the ∆4,20-double bond of 13 was examined.2 However, OsO4
oxidation unexpectedly took place at the ∆11,12-double bond on
the A-ring, yielding the C11,12-diol exclusively. At this stage,
we decided to functionalize the C10 site to render the environment
around the ∆11,12-double bond much more crowded. Functional-
In conclusion, we have achieved an enantioselective total
synthesis of taxol. The synthetic route is highlighted by (1)
originally developed B-ring cyclization, (2) introduction of the
C19-methyl via reductive cleavage of the cyclopropyl ketone, and
(3) isomerization of the resulting enol to the ketone.
Acknowledgment. This work was financially supported by Grant-
in-Aids from the Ministry of Education, Science, Sports, and Culture of
the Japanese Government.
ization of the C10 site was performed by generation of a ∆9,10
-
enolate with LDA followed by oxidation with MoO5‚pyr‚HMPA
(MoOPH),14 giving the C10R-alcohol exclusively. Although the
stereochemical result was the opposite, inversion of the C10R-
oxygen functionality to the thermodynamically more favored
C10â configuration was achieved as follows. Acetylation of the
C10-hydroxy group (Ac2O/DMAP) followed by treatment with
DBN afforded the desired C10â-acetate 14 in good yield.
Supporting Information Available: Spectroscopic data and experi-
mental procedures for the reported compounds and the fully detailed
synthetic scheme (35 pages, print/PDF). See any current masthead page
for ordering information and Web access instructions.
JA9824932
(13) We initially chose a TES group as a protecting group on the C7-OH.
However, in the case of the introduction of a C10 functionality, migration of
the TES group to a ∆9,10-enolate oxygen occurred to give an enol silyl ether.
(14) Vedejs, E.; Engler, D. A.; Telschow, J. E. J. Org. Chem. 1978, 43, 188.
(15) Removal of the two silyl groups on 16 with TASF caused partial
epimerization at the C7 stereocenter.
(16) Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.; Sun, C. M.;
Brigaud, T. Tetrahedron 1992, 48, 6985.