Catalytic Asymmetric exo-Selective 1,3-Dipolar Cycloaddition of Azomethine Ylides and Ethyl Cyclopropylidene Acetate for Construction of 5-aza-Spiro[2,4]heptane Motif

doi:10.6023/A14040249

Abstract

A direct and facile access to highly functionalized 5-aza-spiro[2,4]heptane derivatives is developed via Cu(CH₃CN)₄BF₄/DTBM-BIPHEP-catalyzed asymmetric exo-selective 1,3-dipolar cycloaddition of azomethine ylides with ethyl cyclopropylidene acetate for the first time. The Cu(CH₃CN)₄BF₄/DTBM-BIPHEP complex was identified as the optimal catalyst for the exo-selectivity. The reaction was carried out smoothly with wide substrate scope, and electron-deficient, electron-neutral and electron-rich aryl substituted imino esters were all compatible with the reaction, affording the 5-aza-spiro[2,4]heptane adducts containing three tertiary stereogenic centers and one spiro quaternary center in moderate to good yield (53%～83%) with excellent diastereoselectivity (>98:2, dr) and high enantioselectivity (up to 99% ee). The less reactive alkyl substituted imino ester derived from butyraldehyde was also tolerated in this annulation. The absolute configuration of the cycloadduct was unequivocally determined to be (4R,6S,7S) by X-ray analysis of N-tosylated derivative of exo-3a. Based on the relative and absolute configuration of the exo-cycloadducts, we proposed that an exo approach of ethyl 2-cyclopropylidene acetate to the copper(I) complex occurred predominantly because of the disfavored steric repulsion generated in the endo approach between the substituents of ethyl 2-cyclopropylidene acetate and the large bulky aryl group on the phosphorus atom of the chiral ligand. The produced 5-aza-spiro[2,4]heptanes fragment is widely present in many bioactive carbapenems derivatives, HSR-903 and substituted oxazolidinones. The optically active compounds with different stereoselectivities show different biological activities, therefore, it is important to develop the atom economical method for the asymmetric synthesis ofbiologically active exo-selective 5-aza-spiro[2,4]heptane derivatives.

Key words: asymmetric catalysis, 1,3-dipolar cycloaddition, azomethine ylide, ethyl cyclopropylidene acetate, 5-aza-spiro[2,4]heptane

Cite this article

Li Qinghua, Huang Rong, Wang Chunjiang. Catalytic Asymmetric exo-Selective 1,3-Dipolar Cycloaddition of Azomethine Ylides and Ethyl Cyclopropylidene Acetate for Construction of 5-aza-Spiro[2,4]heptane Motif[J]. Acta Chimica Sinica, 2014, 72(7): 830-835.

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亚甲胺叶立德与环丙基亚甲基乙酸乙酯参与的催化不对称exo-1,3-偶极环加成反应构建5-氮杂-螺[2,4]庚烷片段