A short enantioselective total synthesis of dammarenediol II

Full text of DOI:10.1021/ja9620806

J. Am. Chem. Soc. 1996, 118, 8765-8766
8765
2 h) and isolation. This reaction represents a very practical route
to acylsilanes.9 Although imino silanes have previously been
obtained by sequential reaction of isocyanides with alkyllithium
reagents and trimethylchlorosilane, their selective hydrolysis to
acylsilanes had not been accomplished.10,11 Acylsilane 6 was
treated with 2-lithiopropene in ether at -78 °C for 30 min and
then with iodo thioketal 712 in THF-ether at -78 °C for 2 h to
give stereospecifically the Z-tetrasubstituted enol silyl ether 8
in 60% isolated yield after purification by column chromatog-
raphy. 1H NMR and 13C NMR analysis of both crude and
chromatographed product demonstrated the absence of the
isomeric E-tetrasubstituted enol ether. The use of the trimeth-
ylsilyl analog of 6 in this process afforded a 1:1 mixture of E-
and Z-tetrasubstituted enol ethers, paralleling the results noted
by Reich for a tetrasubstituted case.13 The stereoselectivity of
formation of 8 may be due to a chelated structure (A) for the
intermediate lithio species analogous to chelated magnesium
structures proposed by Kuwajima.14
A Short Enantioselective Total Synthesis of
Dammarenediol II
E. J. Corey* and Shouzhong Lin
Department of Chemistry, HarVard UniVersity
Cambridge, Massachusetts, 02138
ReceiVed June 19, 1996
We report herein an enantioselective and unusually short
synthesis of dammarenediol II (1), the primary product of the
tetracyclization of (S)-2,3-oxidosqualene in plants,1,2 and the
plant analog of the mammalian sterol precursor protosterol,3
hitherto a classical unsolved synthetic problem. Dammarenediol
II is of considerable biosynthetic interest because of recent
progress in the cloning of various (S)-2,3-oxidosqualene cyclase
genes and related bioorganic studies.4 In addition, dammarene-
diol has been found to have antiviral activity against herpes
simplex.5 The sequence which we have developed for the first
total synthesis6 of 1 is summarized in Scheme 1.
The element of enantiocontrol in the synthesis was based on
the recent development of a mechanistically designed bis-
cinchona alkaloid catalyst for the terminal dihydroxylation of
E,E-farnesyl acetate with >120:1 position selectivity and 98:2
enantioselectivity to form diol 2 in 80% yield.7 This key chiral
intermediate was converted in 95% yield to (10S)-10,11-
oxidofarnesol (3)7 by selective mesylation of the 10-hydroxyl
(1.5 equiv of methanesulfonyl chloride and 10 equiv of pyridine
in CH2Cl2 at 23 °C for 12 h) and treatment with potassium
carbonate in methanol at 23 °C for 6 h. Epoxy bromide 4 was
prepared from 3 in a one-flask process consisting of primary
mesylate formation (CH3SO2Cl, Et3N, THF, -45 °C for 30 min)
and further reaction with LiBr in THF solution at 0 °C for 2 h.
The next phase of the synthetic plan required the stereose-
lective elaboration of the chiral epoxy bromide 4 to Z-
tetrasubstituted silyl enol ether 8. Although there was no strong
precedent for this task, the problem was solved in the following
way. Acetyl-tert-butyldimethylsilane8 and 2-amino-1-methoxy-
propane (Aldrich) were heated at reflux in benzene with
continuous removal of water to give the corresponding imine
5, bp 60-65 °C at 1.5 Torr (85%). Deprotonation of 5 with
1.05 equiv of lithium diisopropylamide (LDA) in THF at -30
°C initially and then at 0 °C for 30 min afforded the
corresponding lithium azaenolate (as a yellow solution) which
was cooled to -30 °C and treated with epoxy bromide 4 (at
-30 °C initially and then at -30° to -10 °C over 1 h) to
produce the acylsilane 6 after imine hydrolysis (biphasic mixture
of pentane and aqueous HOAc-NaOAc buffer, stirring, 23 °C,
The next phase of the total synthesis of 1 was the construction
of the tetracyclic ketone 10. Although the formation of this
intermediate is possible, in principle, through the use of a cation-
olefin tetracyclization of an acyclic epoxy triene precursor
(biomimetic type route), in practice efficient tetracyclizations
of the required type have not been realized to date.15 Conse-
quently, we utilized a strategy involving a favorably arranged
cation-olefin tricyclization which leads to an intermediate that
allows aldol cyclization to form the fourth ring.16 Lewis acid
induced cyclization of the epoxy triene 8 in CH2Cl2 at -95 °C
with 1.5 equiv of a 1 M solution of methylaluminum dichloride
in hexane for 10 min followed by desilylation with a catalytic
amount of 48% aqueous HF in CH3CN at 23 °C for 45 min
and thioketal cleavage with iodobenzene-bis(trifluoroacetate) in
9:1:1 MeOH-H2O-i-PrOH at 0 °C for 45 min produced, after
chromatographic purification on silica gel, the tetracyclic
hydroxy diketone 9, mp 164-165 °C, [R]23D +8.0 (c ) 0.2 in
CH2Cl2) in 42% overall yield (probably not optimal). This
alcohol was converted to the corresponding phenylcarbamate
(92% yield by reaction with phenyl isocyanate in pyridine)
which was cyclized by heating at reflux in C6H6 with a catalytic
amount of p-toluenesulfonic acid to provide the tetracyclic R,â-
enone 10 in 84% yield.17
(9) For reviews on the synthesis of acylsilanes, see: (a) Ricci, A.;
Degl’Innocenti, A. Synthesis 1989, 647. (b) Page, P. C. B.; Klair, S. S.;
Rosenthal, S. Chem. Soc. ReV. 1990, 19, 147.
(10) Niznik, G. E.; Morrison, W. H., III; Walborsky, H. M. J. Org. Chem.
1974, 39, 600.
(11) It should also be mentioned that the alkylation of the metal enolates
of acylsilanes with alkyl halides is generally complicated by the formation
of both mono- and dialkylation products.
(12) Iodo thioketal 7 was prepared from 2-hydroxyethyl-2-methyldithi-
olane (Rama Rao, A. V.; Venkatswamy, G.; Javeed, S. M.; Deshpande, V.
H.; Rao, B. R. J. Org. Chem. 1983, 48, 1552) by reaction with tri-
phenylphosphine, iodine, and imidazole in CH2Cl2 at 23 °C for 17 h.
(13) Reich, H. J.; Olson, R. E.; Clark, M. C. J. Am. Chem. Soc. 1980,
102, 1423.
(14) Enda, J.; Kuwajima, I. J. Am. Chem. Soc. 1985, 107, 5495.
(15) For background, see: (a) Taylor, S. K. Org. Prep. Proced. Intl.
1992, 24, 245. (b) Johnson, W. S. Tetrahedron 1991, 47 (41), xi. (c) Corey,
E. J.; Lee. J.; Liu, D. R. Tetrahedron Lett. 1994, 35, 9149. (d) Corey, E. J.;
Lee. J. J. Am. Chem. Soc. 1993, 115, 8873. (e) Johnson, W. S.; Plummer,
M. S.; Reddy, S. P.; Bartlett, W. R. J. Am. Chem. Soc. 1993, 115, 515. (f)
Tanis, S. P.; Chuang, Y.-H.; Head, D. B. J. Org. Chem. 1988, 53, 4929.
(16) To the best of our knowledge, this approach has not previously been
demonstrated despite the vast amount of effort which has been directed at
the synthesis of steroid-like ring systems.
(1) (a) Mills, J. S. Chem. Ind. (London) 1956, 189. (b) Mills, J. S. J.
Chem. Soc. 1956, 2196. (c) Lehn, J.-M.; Ourisson, G. Bull. Soc. Chim. Fr.
1962, 1137. (d) Biftu, T.; Stevenson, R. J. Chem. Soc., Perkin Trans. 1
1978, 360. (e) Biellmann, J.-F. Bull. Soc. Chim. Fr. 1967, 3459.
(2) Dammarenediol I, the (20R)-diastereomer of dammarenediol, also
occurs naturally.1
(3) (a) Corey, E. J.; Virgil, S. C. J. Am. Chem. Soc. 1990, 112, 6429.
(b) Corey, E. J.; Virgil, S. C. J. Am. Chem. Soc. 1991, 113, 4025. (c) Corey,
E. J.; Virgil, S. C.; Sarshar, S. J. Am. Chem. Soc. 1991, 113, 8171.
(4) Baker, C. H.; Matsuda, S. P. T.; Liu, D. R.; Corey, E. J. Biochem.
Biophys. Res. Commun. 1995, 213, 154 and references cited therein.
(5) Poehland, B. L.; Carte, B. K.; Francis, T. A.; Hyland, L. J.; Allaudeen,
H. S.; Troupe, N. J. Nat. Prod. 1987, 50, 706.
(6) A partial synthesis of the dammarenediol II from the naturally
occurring pentacyclic triterpene hydroxyhopanone has been reported. See:
Fujimoto, H.; Tanaka, O. Chem. Pharm. Bull. 1974, 22, 1213; 1970, 18,
1440.
(7) Corey, E. J.; Noe, M. C.; Lin, S. Tetrahedron Lett. 1995, 36, 8741.
(8) For the method of preparation, see: Nowick, J. S.; Danheiser, R. L.
Tetrahedron 1988, 44, 4113.
S0002-7863(96)02080-X CCC: $12.00 © 1996 American Chemical Society

8766 J. Am. Chem. Soc., Vol. 118, No. 36, 1996
Communications to the Editor
Scheme 1. Enantioselective Synthesis of Dammarenediol II
The transformation of enone 10 into dammarenediol II was
accomplished using standard procedures. Reduction of enone
10 with lithium in liquid ammonia at -78 °C for 1 h gave a
crude reduction product which was stirred briefly with pyri-
dinium chlorochromate on alumina (to oxidize a small amount
of secondary alcohol), treated with 1% KOH in 1:1:1 CH3OH-
H2O-THF (to effect equilibration of diastereomers at C(17) to
the more stable 17â-acetyl arrangement) and chromatographed
on silica gel which provided the saturated tetracyclic ketone 11
in 60% yield. Reaction of 11 with 4-methyl-3-hexenylmagne-
sium bromide in dimethoxyethane-ether at 0 °C for 24 h
produced a mixture of C(20)-diastereomeric alcohols (ratio 20S:
20R, 4:1) which was deprotected by heating at reflux with a
THF solution of LiAlH4 and separated chromatographically on
silica gel (50:1 C6H6-acetone for elution) to give dammarene-
diol II (1) in 60% overall yield.18 Totally synthetic 1 was
recrystallized from EtOH-H2O to give long colorless needles,
mp 75-76 °C (mixture mp with an authentic sample 75-76
NMR (at 500 MHz) and 13C NMR (at 125 MHz) spectra, IR
spectrum, and TLC chromatographic behavior on silica gel;
[R]23 +40 (c ) 0.04 in CHCl3).
D
There are a number of noteworthy features of the synthesis
of dammarenediol II which is described herein, apart from its
brevity and stereochemical control. It demonstrates the use of
the now readily available chiral epoxide 27 to fix the absolute
and relative stereochemistry of the final product 1. It illustrates
the power and stereoselectivity of the three-component coupling
which converts acylsilane 6 to silyl enol ether 8 and also a very
useful synthesis of 6. The combined use of cation-olefin
polyannulation with the aldol cyclization clearly represents an
effective synthetic tactic for tetraannulation.
Acknowledgment. We are grateful to the National Institutes of
Health for a Postdoctoral Fellowship and a research grant in support
of this work. Special thanks are due to Dr. John S. Mills for a generous
gift of dammarenediols I and II and to Prof. Jean-Francois Biellmann
for a supply of dipterocarpol (both gifts were made in 1968).
1
°C), identical with naturally derived dammarenediol II by H
Supporting Information Available: Experimental procedures and
characterization data (9 pages). See any current masthead page for
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(17) The phenylcarbamate moiety survived the vigorous acid treatment
required for the acid-catalyzed aldol conversion to 10 in contrast to other
derivatives such as silyl ethers or carboxylic esters.
(18) Dammarenediol I was obtained from the later chromatographic
fractions.
JA9620806