The importance of saturated nitrogen containing heterocycles cannot be overstated, as they are frequent members of biologically active compounds. Further, various members (especially pyrrolidines, piperidines, morpholines, and piperazines) are considered privileged structures for their ability to (1) confer broad ranges of biological activity while also (2) being selective for specific targets when appropriately decorated with chiral substitution. Another important, yet understudied, member is the 4-membered azetidine. Despite their biological significance and increasing use in medicinal chemistry, synthetic preparations of optically active azetidines are notably scarce. We present various strategies toward the preparation of enantiomerically enriched 2-substituted and 2,3-disubstitued azetidines. Toward 2-substituted azetidines, we employ an organocatalyzed aza-Michael addition through iminium catalysis of α,β-unsaturated aldehydes with phthalimide. After phthalimide deprotection and amine cyclization, this intermediate may provide access to enantioenriched 2-substituted chiral azetidines. A precursor to 2,3-disubstituted azetidines is synthesized using an organocatalyzed Michael addition via enamine catalysis between protected 2-amino-1-nitroethenes and unsaturated aldehydes. After further manipulation of this intermediate, this reaction pathway may provide access to 2,3-disusbstituted azetidines in high enantio- and diastereoselectivity.

Studies toward a general and enantioselective synthesis of 2-substituted and 2,3-disubstituted azetidines using organocatalysis

2019 Spring National Meeting

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