2056
J . Org. Chem. 1998, 63, 2056-2057
Sch em e 1a
Tota l Syn th esis of (+)-Qu a ssin fr om
(+)-Ca r von e†
Tony K. M. Shing,* Qin J iang, and Thomas C. W. Mak‡
Department of Chemistry, The Chinese University of Hong
Kong, Shatin, Hong Kong
Received December 10, 1997
Quassin (1) belongs to a large and constantly expanding
family of terpenoid bitter principles,1 extracted from the
plant species Simaroubaceae2 and named collectively as
quassinoids. The quassinoids have been demonstrated to
exhibit a wide spectrum of biological properties.1a,3 Their
highly oxygenated tetracyclic/pentacyclic carbon frame-
works, comprising a number of contiguous stereocenters,
pose a formidable synthetic challenge and have attracted
immense interest from synthetic chemists.4
The constitution of quassin (1) was established by Valenta
and co-workers in the early 1960s,5 and the same group
subsequently reported its racemic total synthesis in 1991.6
However, the first total synthesis of (()-quassin was only
realized in 1980 by the impressive Grieco group.7 To date,
there is only one report on the synthesis of optically active
(+)-quassin, which was addressed by the Watt group using
the (-)-enantiomer of the Wieland-Miescher ketone as the
starting material.8 In our own quest for an enantiospecific
avenue toward tetracyclic quassinoids such as (+)-quassin
(1), we already disclosed the construction of a partial
quassinoid skeleton 3 that has the general ABC ring system
with five stereogenic centers common to numerous quassi-
a
Key: (a) TBSOTf, 2-6-lutidine, rt, 5 days (98% yield based on 75%
* To whom correspondence should be addressed. Fax: (852)-2603 5057.
E-mail: tonyshing@cuhk.edu.hk.
conversion); (b) Cr(CO)6, t-BuOOH, CH3CN, reflux (78% yield based
on 84% conversion); (c) Mn(OAc)3, C6H6, reflux (84%); (d) K2CO3,
MeOH, rt (87%); (e) H2, 10% Pd/C, EtOH, rt (99%); (f) NaH, BnBr,
THF, TBAI (cat.), 0 °C to rt (85%); (g) Et2O‚BF3, CH2Cl2, 0 °C to 10 °C
(92%); (h) Ac2O, DMAP, CH2Cl2, rt (94%); (i) LDA, THF, -78 °C (90%);
(j) SOCl2, pyridine, 0 °C (94%); (k) H2, 10% Pd/C, EtOH, rt (92%); (l)
DIBAL-H, THF, -78 °C then concd HCl (cat.), MeOH, 0 °C; (m) DMSO,
TFAA, CH2Cl2, -78 °C then Et3N, -78 °C to rt; (n) NaH, CH3I, DMF,
-20 °C (65% for steps l to n); (o) LDA, THF, -78 °C then MoOPH,
-78 to 0 °C; (p) DMSO, TFAA, CH2Cl2, -78 °C then Et3N, -78 °C to
rt; (q) NaH, CH3I, DMF, -20 °C (53% for steps o to q); (r) HOAc/H2O
(3:2 v/v), reflux; (s) Fetizon’s reagent, C6H6, reflux (79% for steps r
and s).
† Dedicated to the establishment of the HKSAR government.
‡ To whom inquiries concerning X-ray analysis should be directed.
(1) (a) Polonsky, J . Fortschr. Chem. Org. Naturst. 1985, 47, 221; 1973,
30, 101. (b) London, E.; Robertson, A.; Worthington, H. J . Chem. Soc. 1950,
3431. (c) Beer, R. J . S.; J aquiss, D. B. G.; Robertson, A.; Savige, W. E. J .
Chem. Soc. 1954, 3672. (d) Hanson, K. R.; J aquiss, D. B.; Lamberton, J . A.;
Robertson, A.; Savige, W. E. J . Chem. Soc. 1954, 4238. (e) Beer, R. J . S.;
Hanson, K. R.; Robertson, A. J . Chem. Soc. 1956, 3280. (f) Beer, R. J . S.;
Dutton, B. G.; J aquiss, D. B.; Robertson, A.; Savige, W. E. J . Chem. Soc.
1956, 4850. (g) Carman, R. M.; Ward, A. D. Aust. J . Chem. 1962, 15, 807.
(2) For examples of some recently isolated quassinoids, see: Koike, K.;
Yokoh, M.; Furukawa, M.; Ishii, S.; Ohmoto, T. Phytochemistry 1995, 40,
233. Grieco, P. A.; VanderRoest, J . M.; Pineironunez, M. M.; Campaigne,
E. E.; Carmack, M. Phytochemistry 1995, 38, 1463. Ouyang, Y.; Mitsunaga,
K.; Koike, K.; Ohmoto, T. Phytochemistry 1995, 39, 911.
noids, based on a C f ABC f ABCD ring annulation
strategy.9 As an extension of this approach, we now report
our successful elaboration of 3 into the target molecule (+)-
quassin (1).
(3) Grosvenor, P. W.; Gothard, P. K.; Mcwilliam, N. C.; Supriono, A.;
Gray, D. O. J . Ethnopharmacol. 1995, 45, 75. Lidert, Z.; Wing, K.; Polonsky,
J .; Imakurra, Y.; Okano, M.; Tani, S.; Lin, Y.-M.; Kiyokawa, H.; Lee, K.-H.
J . Nat. Prod. 1987, 50, 442. Polonsky, J . In The Chemistry and Chemical
Taxonomy of the Rutales; Waterman, P. G., Grandon, M. F., Eds.; Academic
Press: New York, 1983; p 247.
(4) For examples of some recent synthetic work, see: Chiu, C. K.-F.;
Govindan, S. V.; Fuchs, P. L. J . Org. Chem. 1994, 59, 311. Spino, C.; Liu,
G.; Tu, N.; Girard, S. J . Org. Chem. 1994, 59, 5596. Spino, C.; Tu, N.
Tetrahedron Lett. 1994, 35, 3683. Grieco, P. A.; Pin˜eiro-Nun˜ez, M. M. J .
Am. Chem. Soc. 1994, 116, 7606. Grieco, P. A.; Collins, J . L.; Moher, E. D.;
Fleck, T. J .; Gross, R. S. J . Am. Chem. Soc. 1993, 115, 6078. Grieco, P. A.;
VanderRoest, J . M. J . Am. Chem. Soc. 1993, 115, 5841. Spino, C.; Liu, G.
J . Org. Chem. 1993, 58, 817. Fleck, T. J .; Grieco, P. A. Tetrahedron Lett.
1992, 33, 1813. Sasaki, M.; Murae, T.; Takahashi, T. J . Org. Chem. 1990,
55, 528. Kim, M.; Applegate, L. A.; Kawada, K.; Watt, D. S. Synth. Commun.
1990, 20, 989. Kawada, K.; Kim, M.; Watt, D. S. Tetrahedron Lett. 1989,
30, 5985. Earlier synthetic efforts are described in Professor Watt’s excellent
review; see: Kawada, K.; Kim, M.; Watt, D. S. Org. Prep. Proc. Int. 1989,
21, 521.
Our recent endeavor9d has shown that (+)-carvone (2)
could be readily converted into tricycle 3, involving an aldol
reaction and an intramolecular Diels-Alder reaction to
create the quaternary centers in 1 (Scheme 1).
After considerable experimentation, we realized that the
sensitive ring D could not survive the conditions for the
functionalization of ring A. Consequently, oxygenation of
ring A had to be executed first before assembly of the D ring.
Toward this end, silylation of 39d afforded alkene 4, which
was subjected to a regioselective allylic oxidation10 with
(5) (a) Valenta, Z.; Papadopoulos, S.; Podesva, C. Tetrahedron 1961, 15,
100. (b) Valenta, Z.; Gray, A. H.; Orr, D. E.; Papadopoulos, S.; Podesva, C.
Tetrahedron 1962, 18, 1433.
(9) (a) Shing, T. K. M.; Tang, Y.; Malone, J . F. J . Chem. Soc., Chem.
Commun. 1989, 1294. (b) Shing, T. K. M.; Tang, Y. Tetrahedron 1990, 46,
2187. (c) Shing, T. K. M.; Tang, Y. J . Chem. Soc., Chem. Commun. 1992,
341. (d) Shing, T. K. M.; Tang, Y. J . Chem. Soc., Perkin Trans. 1 1994,
1625.
(10) (a) Pearson, A. J .; Chen, Y.-S.; Hsu, S.-Y.; Ray, T. Tetrahedron Lett.
1984, 25, 1235. (b) Pearson, A. J .; Han, G. R. J . Org. Chem. 1985, 50, 2791.
(c) Pearson, A. J .; Chen, Y.-S.; Han, G. R.; Hsu, S.-Y.; Ray, T. J . Chem.
Soc., Perkin Trans. 1 1985, 267.
(6) Stojanac, H.; Valenta, Z. Can. J . Chem. 1991, 69, 853.
(7) Grieco, P. A.; Ferrin˜o, S.; Vidari, G. J . Am. Chem. Soc. 1980, 102,
7587. Vidari, G.; Ferrin˜o, S.; Grieco, P. A. J . Am. Chem. Soc. 1984, 106,
3539.
(8) Kim, M.; Kawada, K.; Gross, R. S.; Watt, D. S. J . Org. Chem. 1990,
55, 504.
S0022-3263(97)01896-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/06/1998