Total synthesis of (±)-taxusin

Full text of DOI:10.1021/ja9610949

9186
J. Am. Chem. Soc. 1996, 118, 9186-9187
Total Synthesis of (()-Taxusin
Ryoma Hara, Takashi Furukawa, Yoshiaki Horiguchi, and
Isao Kuwajima*
Department of Chemistry
Tokyo Institute of Technology
O-okayama, Meguro-ku, Tokyo 152, Japan
ReceiVed April 3, 1996
The taxane diterpenes (Figure 1) isolated from various yew
trees continue to be of extreme interest as synthetic targets1
because of the challenging, complex molecular structure coupled
with the important biological activities. Taxol (3) and its
synthetic analogs are well-known to exhibit promising antitumor
activities2 and several other natural taxanes such as taxinine
(2) were recently revealed to be inhibitors against the P-
glycoprotein.3 Remarkable contribution of both of these proper-
ties to development of new fields of cancer chemotherapy is
expected. We now report a concise total synthesis of (()-
taxusin (1).4
Figure 1. Structure of natural taxanes.
Scheme 1a
In the synthetic plan, we envisioned two key transforma-
tions: (1) construction of the tricyclic taxane skeleton via
cyclization of the eight-membered B ring between C9 and C10
and (2) subsequent installation of the C19 methyl group onto
the ring system.5 We have already established a powerful
method for the eight-membered B ring cyclization by means of
intramolecular vinylogous aldol reaction, using aromatic C ring
derivatives as substrates.6 It was essential for success of this
total synthesis that the methodology could be extended to non-
aromatic, allyl ester-type C ring derivatives such as 12. The C
ring allyl ester moiety was incorporated to serve as a flag for
installation of the C19 methyl group.
Our first task was preparation of cyclization precursor 12
(Scheme 1). We chose vinyl bromide 47 as the starting material,
which corresponds to the C ring of taxusin. Successive
(1) There have been reported four total syntheses of natural taxanes. For
taxusin, see: (a) Holton, R. A.; Juo, R. R.; Kim, H.-B.; Williams, A. D.;
Harusawa, S.; Lowenthal, R. E.; Yogai, S. J. Am. Chem. Soc. 1988, 110,
6558. For taxol, see: (b) Holton, R. A.; Somoza, C.; Kim, H.-B.; 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, 1597, 1599.
(c) 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. Nicolaou, K. C.; Nantermet, P. G.;
Ueno, H.; Guy, R. K.; Couladouros, E. A.; Sorensen, E. J. J. Am. Chem.
Soc. 1995, 117, 624 and following papers. (d) Masters, J. J.; Link, J. T.;
Snyder, L. B.; Young, W. B.; Danishefsky, S. J. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1723.
a (a) (1) Et2O, -78 °C, 1.5 h; (2) -45 °C, 1 h; (3) -23 °C, 2 h. (b)
4A-MS, CH2Cl2, rt, 1.5 h, 66% from 4. (c) THF, -78 to 5 °C, 7 h,
quantitative. (d) (1) THF, 0 °C, 1 h; (2) 0 °C, 4 h, 60%. (e) THF, -78
°C, 2.5 h, 86%. (f) (1) CH2Cl2, -45 °C, 1 h, 79%; (2) THF, rt,
overnight, 83%. (g) THF, rt, 1 week, 67%. (h) (1) THF, 0 °C, 1 h; (2)
-78 °C, 1 h, quantitative.
(2) For reviews, see: (a) Georg, G. I.; Chen, T. T.; Ojima, I.; Vyas, D.
M. Taxane Anticancer Agents; American Cancer Society: San Diego, CA,
1995. (b) Kingston, D. G. I.; Molinero, A. A.; Rimoldo, J. M. Prog. Chem.
Org. Nat. Prod. 1993, 61, 1. (c) Rowinsky, E. K.; Onetto, N.; Canetta, R.
M.; Arbuck, S. G. Semin. Oncol. 1992, 19, 646.
(3) Kobayashi, J.; Ogiwara, A.; Hosoyama, H.; Shigemori, H.; Yoshida,
N.; Sasaki, T.; Li, Y.; Iwasaki, S.; Naito, M.; Tsuruo, T. Tetrahedron 1994,
50, 7401.
(4) (a) Miyazaki, M.; Shimizu, K.; Mishima, H.; Kurabayashi, M. Chem.
Pharm. Bull. 1968, 16, 546. (b) Liu, C. L.; Lin, Y. C.; Lin, Y. M.; Chen,
F. C. T’ai-wan K’o Hsueh 1984, 38, 119. (c) Erdtman, H.; Tsuno, K.
Phytochemistry 1969, 8, 931. (d) Lee, C. L.; Hirose, Y. Nakatsuka Mokuzai
Gakkaishi 1975, 21, 249. (e) Chan, W. R.; Halsall, T. G.; Hornby, G. M.;
Oxford, A. W.; Sabel, W.; Bjamer, K.; Ferguson, G.; Robertson, J. M. J.
Chem. Soc., Chem. Commun. 1966, 923.
(5) The taxane numbering system, as illustrated in 1, is used throughout.
(6) (a) Horiguchi, Y.; Furukawa, T.; Kuwajima, I. J. Am. Chem. Soc.
1989, 111, 8277. (b) Furukawa, T.; Morihira, K.; Horiguchi, Y.; Kuwajima,
I. Tetrahedron 1992, 48, 6975. (c) Seto, M.; Morihira, K.; Katagiri, S.;
Furukawa, T.; Horiguchi, Y.; Kuwajima, I. Chem. Lett. 1993, 133. (d)
Morihira, K.; Seto, M.; Furukawa, T.; Horiguchi, Y.; Kuwajima, I.
Tetrahedron Lett. 1993, 34, 345. (f) Nakamura, T.; Waizumi, N.; Tsuruta,
K.; Horiguchi, Y.; Kuwajima, I. Synlett 1994, 584. (g) Seto, M.; Morihira,
K.; Horiguchi, Y.; Kuwajima, I. J. Org. Chem. 1994, 59, 3165.
treatment of 4 with t-BuLi and CuCN produced the correspond-
ing cyanocuprate, and its reaction with 3,4-epoxy-1-hexene8
gave rise to the SN2′ coupling product 5. Pyridinium dichromate
(PDC) oxidation9 of the resulting allyl alcohol 5 afforded enone
6 in 66% yield (2 steps). Conjugate addition of the lithium
enolate of ethyl isobutyrate to 6 proceeded with fairly high 1,4-
asymmetric induction (4:1) to yield 7 as the major isomer.10
(7) The starting material can be prepared in large scale from 3-isobutoxy-
2-cyclohexen-1-one in 5 steps (58% overall yield) by means of the method
developed in our laboratory16 via (1) bromination with NBS, (2) 1,2-addition
of (benzyloxy)(phenylthio)methyllithium and acidic workup, (3) acetal
exchange with CuCl2, CuO, and BnOH, (4) DIBAL reduction, and (5)
protection with TBS group.
(8) Sauleau, J.; Bouget, H.; Huet, J. C. R. Acad. Sci., Ser. C 1971, 273,
829.
(9) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 399.
(10) The relative stereochemistry was inferred on the analogy of a closely
related compound of which stereochemistry was confirmed by the X-ray
analysis of its derivative, see: Takenaka, Y.; Sakai, Y.; Ohashi, Y.;
Furukawa, T.; Horiguchi, Y.; Kuwajima, I. Anal. Sci. 1993, 883. The origin
of the 1,4-asymmetric induction will be discussed in detail in the full paper.
S0002-7863(96)01094-3 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 38, 1996 9187
Scheme 2
Scheme 3a
The Dieckmann-type cyclization of 7 upon treatment with
t-BuOK and in situ silylation with triisopropylsilyl chloride
(TIPSCl) afforded â-siloxyenone 8 in 60% yield (2 steps). Then,
1,2-addition of (benzyloxy)methyllithium11 to 8, followed by
successive treatment with Montmorillonite K 10 (K10) and
BnOH in the presence of molecular sieves 4 Å (4A-MS) and
then with TBAF, furnished 10 in 56% yield (3 steps). Because
the opposite relative 1,4-stereochemistry was supposed to be
advantageous at the later stages (cyclopropanation, Vide infra),
the stereochemistry of C4 was inverted at this stage by the
Mitsunobu reaction (DEAD, Ph3P, PivOH) to give 11.12
Enolization of 11 under thermodynamic control and subsequent
silylation with TIPSCl afforded 12, the cyclization precursor
with allyl ester-type C ring in 67% yield (2 steps).
a (a) (1) THF, rt, overnight; (2) CH2Cl2, -23 °C, 1 h; (3) CH2Cl2,
-78 °C, 1 h, 87% from 13. (b) Et2O, rt, 6 h, quantitative. (c) 4A-MS,
CH2Cl2, rt, 1.5 h, 85%. (d) (1) NH3(l), THF, -78 °C, 1 h; (2) rt, 1 h,
91%. (e) THF, -78 °C, 10 min, then 0 °C, 30 min. (f) CH2Cl2, 0 °C,
10 min. (g) CH2Cl2, rt, 1.5 h, 80% from 19. (h) Ph3PdCH2, benzene,
hexane, 0 °C, 1.5 h, 53% based on 32% conversion.
With the cyclization precursor in hand, the crucial eight-
membered B ring cyclization was examined (Scheme 2). Initial
attempts using Lewis acids such as TiCl4, SnCl4, BF3‚OEt2, and
TMSOTf were fruitless. Thus, aldehyde 14 and spirocyclization
product 15 were obtained in considerable amounts. After
investigating various Lewis acids and reaction conditions, Me2-
AlOTf was found to induce the desired eight-membered ring
cyclization to give 13 in 62% yield. The stereochemistry of
13, namely conformation of the B ring and configuration of C9
taxusin paralleled that previously reported by Holton.1a Treat-
ment of 19 with excess LDA and TMSCl resulted in regiose-
lective enol silyl ether formation at C5, accompanied with
silylation of hydroxyl groups. Oxidation of the resulting
tetrasilyl ether 20 with m-CPBA, followed by acidic workup
produced tetrol 21, of which acetylation gave rise to tetraacetate
22 (80%, 3 steps from 19). Finally, methylenation of C4
carbonyl (Ph3PdCH2, toluene, hexane, room temperature (rt))
furnished (()-taxusin15 identical to natural taxusin in respects
1
and C10, was determined by H NMR.
Then, reduction of the C13 keto group of 13 (Li(t-BuO)3-
AlH), followed by silylation of the resultant hydroxyl group
(TESOTf) and reductive removal of pivalate group (DIBAL),
gave allyl alcohol 16 in 87% yield (3 steps, Scheme 3).
Exclusive formation of the C13R alcohol could be attributed to
the concave nature of the R face.1c,6a,6c The stage was set for
investigation of the C19 methyl group installation according to
the Dauben protocol,13 utilizing the C ring allyl alcohol moiety.
Introduction of the C19 carbon as a methylene group by the
hydroxyl-group-directed cyclopropanation (Et2Zn, CH2I2)14
proceeded to give 17 quantitatively. Subsequent PDC oxida-
tion,9 then, afforded cyclopropyl ketone 18 in 85% yield (2
steps). The Birch reduction13 of 18 induced cleavage of
cyclopropane ring with the correct stereochemistry at C3 and
concomitant removal of two benzyl groups and TES group in
one operation to afford exclusively the desired product 19 (91%).
Formation of the desired C3R protonation product should be a
result of equilibration catalyzed by MeOLi presumably during
evaporation of ammonia. We believe that the C13 hydroxyl
group liberated in situ would play an important role to direct
the protonation from the highly congested concave face.
After the C19 methyl group was successfully installed,
sequential operations for completion of the total synthesis of
1
of H NMR, 13C NMR and IR spectra and TLC mobility.
In conclusion, we have achieved a concise total synthesis of
(()-taxusin (2% overall yield through 25 steps from readily
available 3-isobutoxy-2-cyclohexen-1-one). The synthetic route
is highlighted by (1) remarkably effective eight-membered B
ring cyclization leading to the C ring allyl ester-type tricyclic
taxane skeleton with the desired B ring conformation and C9,
C10 stereochemistry and (2) subsequent installation of the C19
methyl group via the Birch reduction of the cyclopropyl ketone.
Because of failure to introduce C19 methyl group via conjugate
addition,16 this approach is one of the most reasonable solutions
for such purpose.
Acknowledgment. We thank Professor Fa-Ching Chen, National
Taiwan University, for providing a sample and spectral data of natural
taxusin and the Ministry of Education, Science, Sports, and Culture of
Japan for the Grant-in-Aid (nos. 07214211 and 07680624).
Supporting Information Available: Experimental details and
characterization (1H, 13C, IR, and elemental analyses) for 4, 6, 8, 10-
13, 16, 18, 19, 22, and 1 (15 pages). See any current masthead page
for ordering and Internet access instructions.
JA9610949
(15) Although Holton reported 70% yield for the olefination, we faced
rather lower yield (53% yield on 32% conversion) as long as we examined
the reaction a few times in small scale. As Holton stated, 22 is susceptible
to deacetylation during the olefination reaction, see: Holton, R. B. In
Strategies and Tactics in Organic Synthesis; Lindberg, T., Ed.; Academic
Press, Inc.: San Diego, CA, 1991; Vol. 3, pp 165-197.
(11) Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481.
(12) Mitsunobu, O. Synthesis 1981, 1.
(13) For angular methyl group introduction via reductive cleavage of
cyclopropyl ketones, see: Dauben, W. G.; Deviny, E. J. J. Org. Chem.
1966, 31, 3794.
(14) Nishimura, J.; Kawabata, N.; Furukawa, J. Tetrahedron 1969, 25,
3353.
(16) Furukawa, T. Ph.D. Thesis, Tokyo Institute of Technology, Tokyo,
1993.