Rhodium catalyzed stereospecific reductive carbocyclization of 1,6-enynes and synthesis of 4′-methyl-6′-substituted aristeromycins

Abstract

The need of long-term treatment for chronic HBV, emergence of drug-resistant viruses and inefficiency of currently approved therapies to eliminate covalently closed circular DNA (cccDNA), mandates identification of potent and selective inhibitors of HBV replication with novel mechanisms of action. Entecavir, a carbocyclic guanosine nucleoside analog, is the most potent inhibitor of HBV replication on the market. Moreover, the naturally occurring carbocyclic nucleosides aristeromycin are known for their wide range of antiviral activities.

In this research, we have utilized BINAP directed rhodium catalyzed reductive carbocyclization of 1,6-enynes (8a–b) through asymmetric hydrogenation which is an approach, not yet explored in carbocyclic sugar synthesis. Interestingly, we obtained exclusive anti-(9a) and Z-anti (9b) carbocyclic sugars. The new aristeromycin analogs (10a–b) with scaffold combination of entecavir and aristeromycin were then synthesized using the Mitsunobu reaction followed by deprotection.

Keywords:

• Stereospecific reductive carbocyclization
• BINAP
• rhodium
• aristeromycins
• entecavir

Acknowledgements

Authors acknowledge GVK Biosciences Pvt. Ltd, Hyderabad for facilitating academic research activity. We are grateful to the Central Instruments Facility (CIF), BIT, Mesra for analytical support. We acknowledge DST FIST at Department of Chemistry, BIT, Mesra (SR/FST/CSI-242/2012) for NMR and computational chemistry facility.