J. Am. Chem. Soc. 1997, 119, 9927-9928
9927
acetate.9 This catalytic oxygenation process proceeds with 50:1
position selectivity for the terminal double bond of geranylgera-
nyl acetate to form the (R)-diol with 95% enantiomeric purity
under the influence of the Noe-Lin catalyst.9 Monomesylate
formation and K2CO3-MeOH cyclization9 converted this diol
to the (S)-oxirane 3 in 90% yield. The bromide 4 was produced
from 3 by reaction with methanesulfonyl chloride-triethyl-
amine-lithium bromide in tetrahydrofuran (THF) at -40 to 0
°C over 1 h and treated with the R-lithio derivative of 510
(prepared from 5 and 1 equiv of lithium diisopropylamide, LDA)
at -30 °C for 1 h to afford after mild acidic hydrolysis (biphasic
pentane-H2O-HOAc-NaOAc, 23 °C, 3 h) the acylsilane 6
in 89% yield.10 Reaction of 6 with the R-sulfonyl lithio
derivative of 7 (from 7 and 1 equiv of BuLi in THF-Et2O-
hexamethylphosphoramide (HMPA)) at -78 °C for 20 min and
0 °C for 10 min provided the silylated enol ether 8 (75%), the
product of carbonyl addition of lithio-7 to 6 followed by Brook
rearrangement and â-elimination of benzenesulfinate ion.10
Tetracyclization of 8 was carried out with MeAlCl2 as Lewis
acid catalyst in CH2Cl2 at -94 °C for 30 min to give, after
sequential treatment of the crude product (9) with HF-H2O-
CH3CN (to effect desilylation of the 3-hydroxyl group) and 10%
KOH in MeOH (to effect R f â equilibration of the side chain
alpha to the D-ring carbonyl group) hydroxy ketone 10 in 30%
overall yield (ca. 75% per ring formed).
A Simple Enantioselective Synthesis of the
Biologically Active Tetracyclic Marine Sesterterpene
Scalarenedial
E. J. Corey,* Guanglin Luo, and Linus Shouzhong Lin
Department of Chemistry and Chemical Biology
HarVard UniVersity, Cambridge, Massachusetts 02138
ReceiVed August 4, 1997
The sesterterpenoids of marine origin display impressive
variety with respect to chemical structure and biological activity.
The scalarane subfamily, which contains a characteristic 6/6/
6/6-tetracarbocyclic fused ring system, includes members with
multiple biological effects, for example, scalar-16-ene-19,20-
dial (scalarenedial) (1)1 displays not only potent fish anti-feedant
properties but also antitumor and antiinflammatory effects.1-7
The scalaranes are very ancient natural products as indicated
by their widespread occurrence in petroleum and sea sediments
in the form of the chiral hydrocarbon 2.8 We describe herein
the first enantioselective total synthesis of 1 by a biomimetic
route involving the simultaneous formation of all four carbocy-
clic rings. To the best of our knowledge this is the first example
of a stereo- and enantiospecific tetracyclization reaction starting
from a chiral oxirane (8).
The tetracyclic hydroxy ketone 10 was deoxygenated at C(3)
by the Barton-McCombie process11 to give 11 which was
transformed into the vinyl triflate 12 by McMurry’s method
using potassium hexamethyldisilazane (KHMDS) as base.12
Hydroxy desilylation13 of 12 afforded the homoallylic primary
alcohol which was carbonylated to the γ-lactone 13 using a Pd-
(0) 1,3-(bisdiphenylphosphino)propane (dppp) catalyst and 1 atm
CO at 65 °C (94% overall from 12). Scalarenedial 1 was then
produced from 13 in two steps: (1) reduction with diisobutyl-
aluminum hydride in CH2Cl2 to the corresponding diol (95%
yield) and (2) Swern oxidation (90% yield). The synthetic
scalarenedial 1 was identical with the natural product1,7 by
comparison of mp 203-204 °C (lit. 200-203 °C); rotation,
[R]23D -20.7 (c 0.27, CHCl3) (lit. [R]25D -19 (c 0.7, CHCl3));
1
IR, H NMR, 13C NMR, and mass spectral data.
The unusual brevity of the synthesis of 1 which is described
herein is a tribute to the power of several recently developed
methods of synthesis including (1) the position- and enantiose-
lective oxidation of geranylgeranyl acetate, (2) the rapid
assembly and coupling reactions involving the acylsilane 6,10
(3) the tetracyclization 8 f 9, and (4) the hydroxy desilylation
and catalytic carbonylation which are perfectly suited to the
introduction of the ene dial functionality in the D-ring of 1.14
Clearly, a substantial improvement in the efficiency of the
A key to the synthesis is the availability of the mechanistically
designed Noe-Lin catalyst for the catalytic enantio- and position-
selective OsO4-mediated dihydroxylation of geranylgeranyl
(9) (a) Corey, E. J.; Noe, M. C.; Lin, S. Tetrahedron Lett. 1995, 36,
8741. (b) For a review of the Sharpless asymmetric dihydroxylation with
bis-cinchona alkaloid ligands, see: Kolb, H. C.; Van Niuwenhze, M. S.;
Sharpless, K. B. Chem. ReV. 1994, 94, 2483.
(10) (a) Corey, E. J.; Lin, S. J. Am. Chem. Soc. 1996, 118, 8765. (b)
Reich, H. J.; Holtan, R. C.; Bolm, C. J. Am. Chem. Soc. 1990, 112, 5609.
(11) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans I
1975, 1574.
(1) Rueda, A.; Zub´ıa, E.; Ortega, M.; Carballo, J. L.; Salva´, J. J. Org.
Chem. 1997, 62, 1481.
(2) de Carvalho, M. S.; Jacobs, R. S. Biochem. Pharmacol. 1991, 42,
1621.
(12) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979.
(13) (a) Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc., Chem.
Commun. 1984, 29. (b) Fleming, I. Chemtracts-Org. Chem. 1996, 9, 1.
(14) The 1,2-bisformyl-2-cyclohexenyl subunit also occurs in the bicyclic
sesquiterpene derivative polygodial which has previously been synthesized
in racemic form by several groups. See: (a) Kato, T.; Suzuki, T.; Tanemura,
M.; Kumanireng, A. S.; Ototani, N.; Kitahara, Y. Tetrahedron Lett. 1971,
1961. (b) Jallali-Naini, M.; Boussac, G.; Lemaitre, P.; Larcheveque, M.;
Guillerm, D.; Lallemand, J.-Y. Tetrahedron Lett. 1981, 22, 2995. (c) Howell,
S. C.; Ley, S. V.; Mahon, M. J. Chem. Soc., Chem. Commun. 1981, 507.
(d) Jansen, B. J. M.; Sengers, H. H. W. J. M.; Bos, H. J. T.; de Groot, A.
J. Org. Chem. 1988, 53, 855.
(3) Potts, B. C. M.; Faulkner, D. J.; de Carvalho, M. S.; Jacobs, R. S. J.
Am. Chem. Soc. 1992, 14, 5093.
(4) Faulkner, D. J. Nat. Prod. Rep. 1996, 13, 75.
(5) Walker, R. P.; Thompson, J. E.; Faulkner, D. J. J. Org. Chem. 1980,
45, 4976.
(6) Terem, B.; Scheuer, P. J. Tetrahedron 1986, 42, 4409.
(7) De Rosa, S.; Puliti, R.; Crispino, A.; De Giulio, A.; Mattia, C. A.;
Mazzarella, L. J. Nat. Prod. 1994, 57, 256.
(8) Schaeffer, P.; Poinsot, J.; Hauke, V.; Adam, P.; Wehrung, P.; Trendel,
J.-M.; Albrecht, P.; Dessort, D.; Connan, J. Angew. Chem., Int. Ed. Engl.
1994, 33, 1166.
S0002-7863(97)02690-5 CCC: $14.00 © 1997 American Chemical Society
Corey
