ChemInform Abstract: PLE‐Catalyzed Resolution of α‐Substituted β‐Ketoesters Application to the Synthesis of (+)‐Nitramine and (‐)‐Isonitramine.

Westermann, Bernhard; Scharmann, H. Grosse; Kortmann, I.

doi:10.1002/chin.199404051

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“…4 As part of our research programs for the development of new anticancer therapeutics, we were interested in Nitraria alkaloids and aimed to develop an efficient enantioselective synthetic process of the 2-azaspirocyclic system as a platform skeleton. Most of the enantioselective synthetic approaches for Nitraria alkaloids have employed chiral auxiliaries, 5 chiral substrates, 6 or enzymatic resolution, 7 which are not optimal for largescale processes. However, there are only two reported catalytic allylation methods using organopalladium catalysts.…”

Section: ■ Introductionmentioning

confidence: 99%

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

et al. 2021

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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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Section: ■ Introductionmentioning

confidence: 99%