Diastereoselective Synthesis of (Aryloxy)phosphoramidate Prodrugs

作者：Roman Cristina Arbelo; Wasserthal Philip; Balzarini Jan; Meier Chris^*

来源：European Journal of Organic Chemistry, 2011, (25): 4899-4909.

DOI：10.1002/ejoc.201100614

• Phosphoramidates
• Asymmetric synthesis
• Diastereoselectivity
• Pronucleotides
• Antiviral agents
• Nucleosides

The first diastereoselective synthesis of aryloxyphosphoramidate prodrugs of 3'-deoxy-2',3'-didehydrothymidine monophosphate (d4TMP) was recently reported. The synthetic approach utilized the chiral auxiliary (S)-4-isopropylthiazolidine-2-thione (2). For this strategy, a stereochemically pure phosphorodiamidate intermediate was needed. The diastereoselective formation of this key compound was investigated by using different phenols and L-alanine methyl or benzyl ester. Generally, the reaction with 3- or 4-substituted phenols led to significantly better diastereoselectivities compared to their 2-substituted counterparts. Moreover, variation of the ester group in the amino acid residue resulted in no significant differences with regard to the obtained diastereoselectivity. From the reported results, a model for the transition state was elaborated. Finally, eight new (S(P))-aryl-phosphoramidates were synthesized with very high diastereoselectivities (up to >= 95% de) and tested for their anti-HIV potency, showing a tendency for higher antiviral activity from the (S(P)) diastereomers.

• 出版日期2011-9
• 单位河北医科大学