Over the past few decades, considerable attention has been devoted to the development of asymmetric methodologies for the synthesis of cyclopropane derivatives. However, the examples of enantioselective cyclopropanation reactions via Michael-initiated ring closure between α,β-unsaturated aldehyde and diazo compounds are uncommon. Recently, we developed chiral oxazaborolidinium ion (COBI) catalyzed enantioselective cyclopropanation of α- or α,β-substituted acroleins with various α-alkyl diazo compounds providing highly functionalized cyclopropane compounds with excellent trans/cis ratio (&gt;20:1) and stereoselectivity (up to &gt;99% ee). The synthetic utility of this methodology was demonstrated in the first total synthesis and absolute structure determination of Hamavellone B exhibiting antimalarial activity. We envisaged that this approach could be extended to enantioselective synthesis of 2,5-dihydrooxepine. While 2,5-dihydrooxepine has been synthesized by retro-Claisen rearrangement of the corresponding vinylcyclopropylcarboxaldehyde, examples of asymmetric synthesis of 2,5-dihydrooxepines using this approach are rare due to the multiple steps required for the preparation of the chiral vinylcyclopropylcarboxaldehyde. We developed COBI-catalyzed enantioselective synthesis of 2,5-dihydrooxepine through tandem-cyclopropanation-retro-Claisen rearrangement with α-vinyl diazo compounds. A range of 2,5-dihydrooxepines with aliphatic and aromatic group were obtained in high yield (up to 86%) and excellent enantioselectivity (up to &gt;99% ee).

Chiral Lewis acid catalyzed enantioselective synthesis of cyclopropane and its retro-Claisen rearrangement to 2,5-dihydrooxepine

254th National Meeting (2017)

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