Nucleic Acid Related Compounds. 94. Remarkably High Stereoselective Reductions of 2′- and 3′-Ketonucleoside Derivatives To Give Arabino, Ribo, and Xylofuranosyl Nucleosides with Hydrogen Isotopes at C2′ and C3′

Abstract

Oxidation of 2′,5′- and 3′,5′- O-( tert-butyldimethylsilyl)-protected ribonucleosides gave the corresponding 3′-keto and 2′-keto derivatives, whose complete oxidation was assayed by total release of the heterocyclic base upon treatment with tetrabutylammonium fluoride/THF. Treatment of the protected ketones with sodium triacetoxyborohydride (generated in situ from sodium borohydride and acetic acid) in acetic acid resulted in hydride delivery at the α face with high stereoselectivity. The xylo/ribo (∼49:1) and arabino/ribo (∼49:1) diastereomers, respectively, were obtained in good to high overall yields upon deprotection. Selective removal of the TBDMS group from O5′ (trifluoroacetic acid/water, 9:1, 0 °C) and treatment of these 5′-hydroxy-(3′- and 2′)-ketones with sodium triacetoxyborohydride effected remarkably selective delivery of hydride at the β face. Deprotection gave the ribo/xylo (∼99:1) and ribo/arabino (∼99:1) nucleosides in high yields. Comparable results were obtained with sodium borodeuteride in acetic acid to give the four 2′[ 2H] and 3′[ 2H] arabino, ribo, and xylo isotopomers with > 95% incorporation of deuterium. Development of efficient procedures and comparison with previous methods are discussed.