Enantioselective Total Synthesis of Alkaloids: (+)-Nitramine, (+)-Isonitramine, (-)-Isonitramine, and (-)-Sibirine via Asymmetric Phase-Transfer Catalytic α-Allylations of α-Carboxylactams.

Many optically active 2-azaspirocyclic structures have frequently been found in biologically active natural products. In particular, alkaloids, (+)-nitramine, (+)-isonitramine, (-)-isonitramine, and (-)-sibirine, have stereogenicity on their quaternary carbon of the 2-azaspiro[5,5]undecane-7-ol structure. To synthesize alkaloids, we developed a new enantioselective synthetic method for chiral α-quaternary lactams via the α-alkylation of α--butoxycarbonyl lactams. α-Alkylation of α--butoxycarboxylactams in the circumstances of phase-transfer catalytic (PTC) system (solid KOH, toluene, and -40 °C) by virtue of the catalytic action of (,)-NAS bromide (5 mol %) furnished the corresponding α-alkyl-α--butoxycarbonyl lactams in very high chemical (<99%) and enantioselectivity (<98% ee). Our catalytic methodology was successfully applied for the enantioselective total synthesis of 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 (,)-NAS bromide to (,)-NAS bromide afforded (-)-isonitramine (98% ee, 41% yield). (-)-Sibirine was synthesized by -ethoxycarbonylation of (-)-isonitramine followed by reduction (98% ee, 14 steps, 32% yield). Furthermore, the diastereoselective reduction of ()-2-benzhydryl-2-azaspiro[5.5]undecane-1,7-dione [()-] followed by reductive removal of the diphenylmethyl group successfully gave (+)-nitramine (98% ee, 11 steps, 40% yield).