addition to a methyl ketone (3) and subsequent 5-exo cycli-
zation of bishomoallylic alcohol 2. The C(4)/C(5) functional-
ity would derive from a trans diaxial opening of an epoxide
with a nucleophilic nitrogen source. The equatorial nitrogen
at C(10) would be installed by aziridination of exo-methylene
3. An intramolecular Diels-Alder cycloaddition was ex-
pected to deliver the decalin core, and triene 4 could be
derived from the coupling of â-hydroxy ester 5 and alkyl
bromide 6.
Scheme 2
To set the relative stereochemistry between C(7) and
C(11), â-hydroxy ester (()-5 was treated with lithium
diisopropylamide followed by alkyl bromide 6 (Scheme 1).8,9
Scheme 1
by oxidation with pyridinium chlorochromate afforded cis-
decalin 10 in 65% overall yield from 9 with 5:1 diastereo-
selectivity.12 In the course of screening oxidants, a clear
correlation was observed between the Lewis acidity of the
reagent and diastereoselectivity of the reaction.13
Epoxidation of cis-decalin 10 with dimethyl dioxirane
proceeded with 94:6 diastereoselectivity. Subsequent epimer-
ization afforded a 3:2 mixture of decalins favoring the trans-
decalin, which, upon Wittig methylenation, gave almost
exclusively trans-decalin 11.14 Benzyl deprotection of 11
with sodium metal afforded alcohol 12, which was oxidized
using Dess-Martin periodinane to provide the corresponding
methyl ketone 3.15
Alcohol mixture 7 was obtained in 79% yield, diastereomeric
only at the silyl ether (vide infra). The free alcohol was
protected as its benzyl ether 8, and the substrate was
subjected to diisobutylaluminum hydride reduction and
Swern oxidation to provide aldehyde 9.
Homologation of 9 under Horner-Wadsworth-Emmons
conditions produced the desired triene (4) as a single olefin
isomer (Scheme 2). With the intramolecular Diels-Alder
precursor in hand, initial efforts were focused upon a one-
step deprotection-oxidation-cyclization sequence to obtain
cis-decalin 10 via the anticipated endo-boat transition state.10
Indeed, treatment of 4 with Jones reagent gave 10 as the
major stereoisomer. However, due to the delicate nature of
4, the optimized yield of this reaction was only 30%. Less
acidic conditions were explored, and it was found that
deprotection of 4 with catalytic fluorosilicic acid11 followed
With the ketone at C(11) serving as a handle for in-
corporation of the tetrahydrofuran, selectivity of nucleophilic
addition to ketone 3 was examined (Scheme 3). Reduction
of 3 with sodium borohydride provided a mixture of alcohols
with 91:9 diastereoselectivity. The stereochemistry of the
1
major product differed from that of 12, as observed by H
NMR (see Scheme 2), and thus was assigned as its C(11)
epimer (13). If a homoprenyl carbon nucleophile added with
the same facial selectivity as hydride, the desired C(11)
epimer would be obtained. Interestingly, the desired stere-
oisomer corresponds to the anti-Felkin product.16,17
In an effort to obtain alcohol 14, methyl ketone 3 was
exposed to homoprenylmagnesium bromide (15) under a
(6) For antimalarial activity of other isonitrile-containing compounds,
see: (a) Wright, A. D.; Konig, G. M.; Angerhofer, C. K.; Greenidge, P.;
Linden, A.; Desqueyroux-Faundez, R. J. Nat. Prod. 1996, 59, 710. (b)
Wright, A. D.; Wang, H. Q.; Gurrath, M.; Konig, G. M.; Kocak, G.;
Neumann, G.; Loria, P.; Foley, M.; Tilley, L. J. Med. Chem. 2001, 44,
873. (c) Schwartz, O.; Brun, R.; Bats, J. W.; Schmalz, H. Tetrahedron Lett.
2002, 43, 1009.
(12) Minor component in this ratio represents the combined yield of the
three undesired decalin stereoisomers as determined by GC.
(13) See Supporting Information.
(14) Direct methylenation of the pure cis-decalin led to a variable ratio
of trans- to cis-decalin olefinated product.
(7) White, R. D.; Wood, J. L. Org. Lett. 2001, 3, 1825.
(15) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(16) (a) Fieser, L. F.; Huang, W. Y.; Goto, T. J. Am. Chem. Soc. 1960,
82, 1688. (b) Anh, N. T.; Eisenstein, O. NouV. J. Chim. 1977, 1, 61. (c)
Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 2199. (d) Eliel,
E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds;
Wiley & Sons: New York, 1994.
(8) ()-5 was prepared from reduction of tert-butyl acetoacetate with
sodium borohydride; see: Mohrig, J. R.; Rosenberg, R. E.; Apostol, J. W.
et al. J. Am. Chem. Soc. 1997, 119, 479. Alternatively, (-)-5 can be accessed
by Noyori hydrogenation of tert-butyl acetoacetate. For preparation of alkyl
bromide 6, see Supporting Information.
(9) Frater, G.; Wulf, G.; Mueller, U. HelV. Chim. Acta 1989, 72, 1846.
(10) Taber, D. F.; Gunn, B. P. J. Am. Chem. Soc. 1979, 101, 3992.
(11) Pilcher, A. S.; Hill, D. K.; Shimshock, S. J.; Waltermire, R. E.;
DeShong, P. J. Org. Chem. 1992, 57, 2492.
(17) Methine is the “large” group, the methylene is the “medium” group,
and the hydrogen is the “small” group, as defined by ref 16a. The anti-
Felkin selectivity of hydride addition was also observed in related substrates
with varying functionality at C(4) and C(5).
1124
Org. Lett., Vol. 6, No. 7, 2004