Enantioselective Synthesis of Saddle-Shaped Eight-Membered Lactones with Inherent Chirality via Organocatalytic High-Order Annulation

Shao-Qing Shi¹, Chen-Chang Cui¹, Lin-Lin Xu, Jin-Peng Zhang, Wen-Juan Hao,* Jianyi Wang,* Bo Jiang*

Inherently chiral medium-ring derivatives have important applications in many research fields, such as materials science, molecular recognition, and asymmetric catalysis. However, the enantioselective assembly of these molecules, especially by organocatalytic strategies, remains a formidable challenge, and few methods are available. Here, we report the enantioselective NHC-catalyzed (NHC: N-heterocyclic carbenes) formal high-order (5+3) annulation of 1-(2-indolyl)naphthalen-2-ols with ynals. In the presence of an NHC pre-catalyst, base, Lewis acid and oxidant, this protocol enables the catalytic formation of C–C and C-O bonds, providing practical and facile access to an array of inherently chiral saddle-shaped eight-membered lactones featuring an oxocin-2-one scaffold with structural diversity in good efficiency and excellent enantiocontrol. Moreover, the scale-up preparation and representative late-stage transformations of the eight-membered lactones further demonstrate the application potential of this synthetic technology.

Nat. Commun. 2024, 15, 8474; DOI:10.1038/s41467-024-52823-3

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