Amino Acids, XI: (±)Pipecolic Acid Derivatives ‐ Part 1: The [4+2] Cycloaddition Pathway

Abstract

[4+2] Cycloadditions of various dienes 1 with the acceptor-substituted imine.'Z furnished the 4-0~0-piperidine-2,2-dic~xyl~ derivatives 3, 5, 11, 12. All efforts to get the regio-isomeric 5-oxoderivatives (Scheme 2) by of the reaction conditions and substitution panem of and res,,,ted Over the last several years we have been concerned with the development of 5-hydroxy-2-piperidone derivatives in enantiomerically pure form'b' or as racemic compounds'c) for the synthesis of pharmacologically active substances. These compounds serve as starting materials for the synthesis of GABA active DAVA-derivative~'~''~), and might serve as sub strates for 5-hydroxy-pipecolic acid2' derivatives (Scheme 1). investigations we have recently initiatedz0.In this paper we detail our investigations in the [4+2] cycloaddition of highly electrophilic N-acyl-imines and N-sulfonyl-imines, resp., with various I ,3-dienes3) to 4-0x0-piperidine-2,2-dicarboxylates. In the following paper we report on the synthesis and stereochemistry of amino acids derived from these cycloaddition products. Recent work by Jung et al!a) raised our interest in this cycloaddition, especially in the claimed product, the regioisomeric 5-0x0-piperidine-2,2dicarboxylate (Scheme 2). ducted under N2. The known dienes 1A-D were generated according to lit. methods*). 'H-and I3C-NMR data of 5d and iso-5d provided by the described procedure (entry 7, table l), revealed, however, that besides 5d the open chain product 6d (Scheme 3) was produced in 17% yield, instead of the 5-oxo-piperidine-2,2-dicarboxylate derivative. An open chain product was found as the sole product by Obrechf et al.4b) in a similar Diefs-Alder reaction, catalyzed by Ti Clz( 0Et)2. The N-acyl(or sulfonyl)-imines5) 2 were prepared as isolable oils (2a-c) by ma-Wiffig reaction6) or in sifu (2d-e) by Stegfich's method7). All these compounds are sensitive to moisture and all cycloaddition reactions should be con-