A simplified route to a key intermediate in the synthesis of the Chinese nootropic agent huperzine A

Abstract

A n efficient one-pot, three-component process for the preparation of 2-pyridones from a carbonyl compound, ammonia, and methyl propiolate has been found which provides ready access t o a key intermediate in the synthesis of huperzine A.

An annulation method for the synthesis of alkyl-substituted 6-carbomethoxy-2-pyridones

“…8 The simplicity of the procedure and the fact that it produces 5,6-disubstituted 2-pyridones were appealing. Unfortunately, its utility is restricted to symmetrical ketones and ketones which can only form a single enamine.…”

The Lyconadins: Enantioselective Total Syntheses of (+)-Lyconadin A and (−)-Lyconadin B

“…From the outset, we had envisioned use of the one-pot protocol developed by Kozikowski,39 employing methyl propiolate and ammonia to access (+)-lyconadin A ( 1 ). Unfortunately this approach was not successful; only unreacted starting materials were obtained.…”

The pharmacology and therapeutic potential of (-)-huperzine A

“…This modified route proceeded in four steps and 48% overall yield from 1,4-cyclohexanedione monoethylene ketal (7) and methyl propiolate (12), via the pyridone 13. 69 Chassaing et al 70 and Haudrechy et al 71 later developed an alternative strategy to access the β-ketoester 8 in six steps and 24% yield from 2-hydroxy-6-methylpyridine 14 ( Figure 6B ).…”