tetrahydrofuran and 2,6-disubstituted tetrahydropyran sys-
tems12 based on the reductive cyclization of the correspond-
ing enantiopure hydroxysulfinyl ketones using the Et3SiH/
TMSOTf system.13 In this paper, we extend this methodology
to the enantioselective synthesis of 2,7-cis-disubstituted
oxepanes illustrating its usefulness with the short formal
synthesis of (+)-isolaurepan (3).
Scheme 1
The synthesis began with the condensation of the lithium
anion derived from (SR)-methyl-p-tolylsulfoxide14 and di-
methyl (4) or diethyl adipate (5) to give enantiopure â-keto
sulfoxides (SR)-6 and (SR)-7 in 70% and 79% yield,
respectively (Scheme 1). Reduction of derivative 4 with
DIBAL-H in the presence of ZnBr2 afforded â-hydroxysulf-
oxide (6R,SR)-8 in 73% yield with an excellent diastereo-
selectivity (de >98%). When DIBAL-H alone was used to
reduce the ketosulfinyl ester 5, compound (6S,SR)-9 was
exclusively formed in 88% yield. The synthesis of Weinreb’s
amides (6R,SR)-10 and (6S,SR)-11 was, respectively, achieved
by treatment of esters 8 (76% yield) and 9 (86% yield based
on 23% recovered starting material) with N-methyl meth-
ylhydroxylamine in the presence of an excess of AlMe3.15
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Without protection of the OH group, amide 10 reacted
with an excess of phenylmagnesium bromide in THF
affording enantiopure aryl ketone (6R,SR)-12 in 83% yield,
whereas alkyl derivative (6S,SR)-13 was obtained from 11
by treatment with n-hexylmagnesium bromide in THF/Et2O
in 78% isolated yield.
With hydroxysulfinyl ketones in hand, we tried the
reductive cyclization conditions to access the cis-2,7-
disubstituted oxepane ring. Thus, when phenyl ketone 12
was treated with 10 equiv of triethylsilane followed by 1.5
equiv of trimethylsilyl triflate in CH2Cl2 at 0 °C, oxepane
(2S,7R,SR)-14 was formed in only 30 min as the exclusive
diastereoisomer and isolated in 83% yield (Scheme 2). The
relative cis configuration of this derivative was initially
assigned from the NOESY enhancements observed between
H2 and H7 protons in 14 and later by the chemical correlation
with racemic known compound 15.
Finally, the treatment of sulfoxide 14 with Raney nickel
in EtOH at room temperature gave rise to (2S,7S)-7-methyl-
2-phenyloxepane (15) [[R]20D ) -53 (c 1, CHCl3)], in 90%
yield. This compound was shown to be identical, except in
the R value, to the racemic derivative described by Nico-
laou,13 allowing us to confirm the cis stereochemistry of
compound 14.
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