Weinreb Amidation as the Cornerstone of an Improved Synthetic Route to A-Ring-Modified Derivatives of Luotonin A

Abstract

Weinreb amidation of ethyl 4-oxo-3,4-dihydroquinazoline-2-carboxylate with aromatic amines provides a significantly improved route to anilide-type key intermediates for the synthesis of the anticancer alkaloid, luotonin A, and new A-ring-modified derivatives thereof. This method has advantages concerning overall yield, brevity, and versatility with regard to the aromatic amine component, even if the latter has less favourable nucleophilicity, solubility and/or stability properties. This is demonstrated by the concise synthesis of a small library of luotonin A analogues, including a novel thiophene isostere of the alkaloid.

Keywords

• Weinreb amidation
• luotonin A
• [4+2] cycloaddition
• thiophene