Synthesis of 2-Substituted-5-halo-2,3-dihydro-4(<i>H</i>)-pyrimidin-4-ones and Their Derivatization Utilizing the Sonogashira Coupling Reaction in the Enantioselective Synthesis of α-Substituted β-Amino Acids

A convenient, one-pot procedure for the synthesis of 1-benzoyl-2(S)-substituted-5-iodo-2,3-dihydro-4(H)-pyrimidin-4-ones by tandem decarboxylation/β-iodination of the corresponding 6-carboxy-perhydropyrimidin-4-ones was developed. In addition, several 1-benzoyl-2(S)-substituted-5-bromo-2,3-dihydro-4(H)-pyrimidin-4-ones were readily prepared by bromination of 1-benzoyl-2(S)-substituted-2,3-dihydro-4(H)-pyrimidin-4-ones. Subsequently, Sonogashira coupling of the halogenated heterocyclic enones with various terminal alkynes produced 1-benzoyl-2(S)-isopropyl-5-alkynyl-2,3-dihydro-4(H)-pyrimidin-4-ones in good yields. Hydrogenation of the unsaturated C−C moieties in the Sonogashira products followed by acid hydrolysis afforded highly enantioenriched α-substituted β-amino acids.本研究开发了一种简便的一锅法合成策略，通过对相应的6-羧基全氢嘧啶-4-酮类化合物进行串联脱羧/β-碘代反应，制备得到1-苯甲酰基-2(S)-取代-5-碘代-2,3-二氢-4(H)-嘧啶-4-酮类化合物。此外，通过对1-苯甲酰基-2(S)-取代-2,3-二氢-4(H)-嘧啶-4-酮类化合物进行溴代反应，可便捷制备数种1-苯甲酰基-2(S)-取代-5-溴代-2,3-二氢-4(H)-嘧啶-4-酮类化合物。随后，将上述卤代杂环烯酮与多种末端炔烃进行薗头偶联反应（Sonogashira coupling），可得到收率优异的1-苯甲酰基-2(S)-异丙基-5-炔基-2,3-二氢-4(H)-嘧啶-4-酮类化合物。对该薗头偶联产物中的碳碳不饱和键进行氢化反应，再经酸水解后，即可得到高对映体富集的α-取代β-氨基酸类化合物。