Enantiodivergent Synthesis of Bis-Spiropyrrolidines via Sequential Interrupted and Completed (3 + 2) Cycloadditions

J Org Chem. 2015 Dec 4;80(23):11755-67. doi: 10.1021/acs.joc.5b01418. Epub 2015 Oct 16.

Abstract

Both (5R)- and (5S)-1,7-diazaspiro[4.4]nonan-6-ones are obtained via a sequence of interrupted and completed stepwise (3 + 2) cycloadditions between azomethine ylides and π-deficient alkenes. The only source of chirality along the whole process is an enantiopure ferrocenyl pyrrolidine catalytic ligand. When the starting imine incorporates two aryl groups or one aryl group with one electron-releasing substituent, the reaction between the azomethine ylide and the alkene stops at the first step, leading to the corresponding Michael adduct. When imines derived from p-methoxybenzaldehyde are used, the corresponding syn-α-amino-γ-nitro ester is obtained with almost complete enantiocontrol. In contrast, imines derived from benzophenone lead to the corresponding anti analogue. From this interrupted (3 + 2) cycloaddition, cis- and trans-α-amino-γ-lactams can be obtained via hydrogenation of the nitro group followed by in situ cyclization. Imines derived from these latter compounds are the precursors of N-metalated azomethine ylides from which up to four new chiral centers can be generated via completed (3 + 2) cycloaddition reactions with full regio- and diastereocontrol. Cis- and trans-γ-lactams lead to opposite bis-spiropyrrolidine enantiomers. Therefore, both enantiomeric series of spiro compounds can be obtained by means of the same catalytic system. The potential of these rigid, densely substituted homochiral compounds in medicinal chemistry is briefly described.

Publication types

  • Research Support, Non-U.S. Gov't