A Rapid Synthetic Route to Conformationally Restricted [5,5]-Bicyclic Nucleoside-Amino Acid Conjugates

Abstract

A concise synthetic route to a novel class of conformationally rigid 3 ′,4 ′-cis-fused bicyclic nucleoside derivatives has been developed. The synthetic strategy and approach involves initial synthesis of a key [5,5]-bicyclic 6-aminofurofuran-2-one scaffold, employing an L-serine derived aminobutenolide as a strategically functionalized chiral template. Subsequent utilization of the carbonyl functionality of the above bicyclic lactone toward nucleobase incorporation, and linking of the resident amine functionality with appropriately protected amino acids completed the syntheses of the target bicyclic nucleoside-amino acid conjugates. Following the above route, and utilizing a combination of easily available nucleobases (4) and amino acids (4) as the two diversity elements, combinatorial synthesis of a 16-member demonstration library of the title amino acid-linked nucleosides has been accomplished.

Keywords:

• Bicyclic nucleoside
• conformational rigidity
• nucleoside-amino acid conjugate
• chiral aminobutenolide
• combinatorial synthesis

Acknowledgments

We thank the National Institute of General Medical Sciences (KU-CMLD, P50 GM-069663) for financial support, and, Tanvi Parikh for assisting with initial experiments. We also thank Dr. David VanderVelde, Nuclear Magnetic Resonance Laboratory, University of Kansas, Lawrence for his assistance with the high resolution NMR experiments.