Asymmetric Synthesis of Substituted Pyrans by Enantioselective Intramolecular [2+2+2] Cyclization of Yne-enones

Abstract

Substituted pyrans are prevalent structural motifs in natural products and bioactive molecules, and their enantioselective synthesis remains an important objective in organic chemistry. Herein, we report a rhodium(I)-catalyzed enantioselective intramolecular [2+2+2] cyclization of yne-enones for the efficient construction of chiral substituted pyrans. Using a commercially available SDP ligand, this transformation proceeds under mild conditions and exhibits good substrate scope, delivering bicyclic pyran derivatives in moderate to good yields with excellent enantioselectivities (up to 98% ee). The transformation proceeds via Rh(I)-mediated oxidative cyclization to form a chiral rhodacycle, followed by carbonyl insertion and reductive elimination to deliver the pyran scaffold. The synthetic utility of this methodology is further demonstrated by a one-pot cyclization/hydrolysis sequence. Treatment of the in situ generated pyran intermediates with Sc(OTf)₃ enables efficient conversion to optically enriched 1,5-diketones bearing two contiguous stereocenters, with high enantioselectivity and moderate diastereoselectivity. Control experiments support a stepwise process involving pyran formation followed by Lewis acid-promoted ring opening. Overall, this work provides an efficient and versatile strategy for the asymmetric synthesis of substituted pyrans and related chiral 1,5-dicarbonyl compounds. The combination of high enantioselectivity, operational simplicity, and broad applicability highlights the potential of this methodology for applications in complex molecule synthesis and asymmetric catalysis.

Keywords

Cyclization / Pyrans / Diketones / Rhodium / Asymmetric synthesis / Yne-enones / Enantioselectivity / Diastereoselectivity

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