TiCl4-n-Bu3N-mediated cascade annulation of ketones with α-ketoesters: a facile synthesis of highly substituted fused γ-alkylidene-butenolides?

Organic & Biomolecular Chemistry Pub Date: 2019-05-17 DOI: 10.1039/C9OB00649D

Abstract

A facile protocol for the synthesis of highly substituted fused γ-alkylidene butenolides using direct annulation of ketones with α-ketoesters, which proceeds through TiCl4-n-Bu3N mediated aldol addition followed by an intramolecular enol-lactonization/cyclization cascade, is reported. Diverse 6-5, 7-5 and 8-5 fused bicyclic γ-ylidene butenolides and highly substituted monocyclic analogs related to biologically relevant natural products were prepared from readily accessible ketone and α-ketoester building blocks. The highly step-economic cascade nature, good substrate scope, easy access to complex products with good to excellent yields, gram-scalability, demonstration of synthetic utility, and unambiguous structural confirmation through X-ray crystallography analyses and analogy are the salient features of this work.

Graphical abstract: TiCl4-n-Bu3N-mediated cascade annulation of ketones with α-ketoesters: a facile synthesis of highly substituted fused γ-alkylidene-butenolides
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