The highly enantioselective aza-Michael
reaction of tert-butyl β-naphthylmethoxycarbamate
to cyclic enones
has been accomplished by using a new cinchona alkaloid
derived C(9)-urea ammonium catalyst under phase-transfer catalysis
conditions with up to 98% ee at 0 °C. The resulting aza-Michael
adducts can be converted to versatile intermediates by selective deprotection
and the cyclic 1,3-aminoalcohols by diastereoselective reduction with
up to 32:1, which have been widely used as important pharmacophores
in pharmaceutical development.
Many
optically active 2-azaspirocyclic structures have frequently
been found in biologically active natural products. In particular, Nitraria alkaloids, (+)-nitramine, (+)-isonitramine, (−)-isonitramine,
and (−)-sibirine, have stereogenicity on their quaternary carbon
of the 2-azaspiro[5,5]undecane-7-ol structure. To synthesize Nitraria alkaloids, we developed a new enantioselective
synthetic method for chiral α-quaternary lactams via the α-alkylation
of α-tert-butoxycarbonyl lactams. α-Alkylation
of α-tert-butoxycarboxylactams in the circumstances
of phase-transfer catalytic (PTC) system (solid KOH, toluene, and
−40 °C) by virtue of the catalytic action of (S,S)-NAS bromide (5 mol %) furnished the
corresponding α-alkyl-α-tert-butoxycarbonyl
lactams in very high chemical (<99%) and enantioselectivity (<98%
ee). Our catalytic methodology was successfully applied for the enantioselective
total synthesis of Nitraria alkaloids. (+)-Isonitramine
was obtained in 12 steps (98% ee, 43% yield) from δ-valerolactam
through enantioselective phase-transfer catalytic allylation, Dieckmann
condensation, and diastereoselective reduction as the key reactions.
(−)-Sibirine and (+)-nitramine were prepared from (−)-isonitramine
or its intermediate. Switching the phase-transfer catalyst from (S,S)-NAS bromide to (R,R)-NAS bromide afforded (−)-isonitramine
(98% ee, 41% yield). (−)-Sibirine was synthesized by N-ethoxycarbonylation of (−)-isonitramine followed
by reduction (98% ee, 14 steps, 32% yield). Furthermore, the diastereoselective
reduction of (R)-2-benzhydryl-2-azaspiro[5.5]undecane-1,7-dione
[(R)-15] followed by reductive removal
of the diphenylmethyl group successfully gave (+)-nitramine (98% ee,
11 steps, 40% yield).
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