linked to endosome disruptive peptides12 can deliver mol-
ecules into the cytosol and nucleus of mammalian cells.
Windaus13 was the first to report that reaction of choles-
teryl chloride with ammonia, or reduction of cholestenone
oxime, provides 3-substituted cholesterylamines in modest
yields. More recently, stereoselective syntheses of 3ꢀ-azido-
5-cholestene, an important precursor to 3ꢀ-amino-5-choles-
tene, have involved conversion of cholesterol to epicholes-
terol followed by a Mitsunobu reaction with hydrazoic
acid5,14 or treatment of 6ꢀ-methoxy-3R,5-cyclo-5R-choles-
tane and related compounds with hydrazoic acid.6,15,16
However, because of participation of the homoallylic double
bond at the C5 position of the steroid, substitution reactions
of cholesterol and derivatives can suffer from poor stereo-
selectivity, elimination, and rearrangement.17-21 These com-
plications limit existing synthetic methods to small-scale
preparation of 3ꢀ-azido-5-cholestene. To overcome this
limitation, we report here a practical and efficient two-step
method for the synthesis of 3ꢀ-azido-5-cholestene from
cholesterol. As shown in Scheme 1, this new approach,
boron trifluoride etherate (BF3·OEt2) in dichloromethane,
allows preparation of multigram quantities of pure 3ꢀ-azido-
5-cholestene (3) in high yield. Subsequent reduction of 3ꢀ-
14
azido-5-cholestene (3) with LiAlH4 provided 3ꢀ-amino-
5-cholestene (7) in 96% yield (1 mmol scale). Alternatively,
7 could be obtained in 89% yield by hydrogenation of 3 in
THF over 10% palladium on carbon. The high efficiency of
each step of this synthesis allowed the preparation of 3 on a
100 g scale (see the Supporting Information for details).
We additionally examined the utility of other TMS
derivatives for preparation of 3ꢀ-substituted cholestenes.
Correspondingly, as shown in Scheme 1, 3ꢀ-chloro-5-
cholestene (4), 3ꢀ-bromo-5-cholestene (5), and 3ꢀ-iodo-5-
cholestene (6) were synthesized in high yield from Lewis
acids and cognate TMS compounds. This approach is
particularly useful for preparation of compounds 5 and 6 due
to their high susceptibility to elimination reactions.
Our rationale for investigating this approach was inspired
in part by reports22,23 of the use of TMSN3 and Lewis acids
in neighboring group-assisted glycosylation reactions that
proceed with overall retention of configuration. Moreover,
as elucidated by Shoppee21 and Winstein,24,25 cholesterol
and reactive derivatives have been shown to undergo
solvolysis with retention of 3ꢀ-configuration via the involve-
ment of a nonclassical carbocation that is formed by
neighboring participation of the homoallylic alkene. This
homoallylic carbocation reacts rapidly at the C6 position of
the steroid to afford 6ꢀ-substituted-3R,5-cyclosteroids through
a process termed the i-steroid rearrangement. Slower reaction
of this cation at the C3 position yields cholesteryl 3ꢀ-
derivatives.26,27 On the basis of these precedents, we
hypothesized that TMSN3 and Lewis acids might efficiently
convert 2 into 3 with retention of configuration.
Scheme 1. Optimized Synthesis of 3ꢀ-Amino-5-cholestene (7)
and Related 3ꢀ-Derivatives (2-6) from Cholesterol (1)a
Table 1 lists our investigation of the effects of different
Lewis acids and TMSN3 on the conversion of 2 to 3. Among
the Lewis acids investigated, the addition of 2 equiv of
BF3·OEt2 at ambient temperature (22 °C) for 2 h proved
optimal, providing 3 in 93% yield. In addition to azide 3,
SnCl4, TiCl4, and AlCl3 generated 3ꢀ-chloro-cholest-5-ene
(4) as a major byproduct. Reaction of fluoride derived from
BF3·OEt2 with TMSN3 is presumably involved in the
production of the nucleophilic azide, and the high stability
of TMSF likely prevents formation of byproducts compared
to the chlorinated Lewis acids. In control experiments, studies
of the corresponding 3R-mesylate (8) and the dihydro
analogue (9) revealed that both the 3ꢀ-configuration of 2
and the C5 alkene were required for reaction of 2 with
BF3·OEt2/TMSN3. These results are consistent with previous
studies of solvolytic rate enhancements of cholesterol deriva-
a Yields represent reactions on a 1 mmol scale.
involving conversion of cholesterol (1) to the mesylate (2),
followed by treatment with trimethylsilyl azide (TMSN3) and
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