期刊
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
卷 2011, 期 25, 页码 4899-4909出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/ejoc.201100614
关键词
Phosphoramidates; Asymmetric synthesis; Diastereoselectivity; Pronucleotides; Antiviral agents; Nucleosides
资金
- Deutsche Forschungsgemeinschaft (DFG) [ME1161/9-1]
- University of Hamburg
- K. U. Leuven [GOA 10/14]
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.
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