Stereoselective Synthesis of 1‘-C-Branched Arabinofuranosyl Nucleosides via Anomeric Radicals Generated by 1,2-Acyloxy Migration

Abstract

Stereoselective C-C bond formation at the anomeric position of uracil and adenine nucleoside has been accomplished through reaction of the anomeric radical, generated by 1,2-acyloxy migration, with a radical acceptor. The present method consists of the following steps: (1) electrophilic addition (bromo-pivaloyloxylation) to 3',5'-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-protected 1',2'-unsaturated nucleoside, (2) tin radical-mediated reaction of the resulting adduct with a radical acceptor. The use of allyl(tributyl)tin gave the 1'-C-allylated uracil nucleoside 14 in 66% yield together with the unrearranged 2'-C-allylated product 15 (6%). Radical acceptors such as styryl(tributyl)tin and 3-bromo-2-methylacrylonitrile can also be used in the reaction of 5, giving 16 (70%) and 17 (76%) without the formation of unrearranged product. The radical-mediated C-C bond formation of the adenine counterpart 12 was also investigated.

From the Chemistry of Epoxy-Sugar Nucleosides to the Discovery of Anti-HIV Agent 4'-ethynylstavudine-Festinavir

“…The first report on the basis of this strategy is shown in Scheme 3 [12]. Thus, when bromo-pivaloyloxy derivative 7 was treated with tributyltin radical, the incipient 2′-carbon radical III was rearranged to anomeric radical IV through 1,2-acyloxy migration and subsequent reaction of IV with allyltributyltin gave 1′-allyl-arabinofuranosyluracil 8 .…”

Ring Opening of Nucleoside 1‘,2‘-Epoxides with Organoaluminum Reagents: Stereoselective Entry to Ribonucleosides Branched at the Anomeric Position

“…Evidence for the depicted stereochemistry of 8 was provided by NOE experiment: H-6/H-4‘ (4.6%), CH 3 -1‘/H-3‘ (1%), and H-2‘/H-4‘ (2.7%). Under similar reaction conditions, the TIPDS (1,1,3,3-tetraisopropyl-disiloxane-1,3-diyl)-protected substrate ( 9 )12b gave the arabinofuranosyl nucleosides 10 α (36%) and 10 β (6%). Apart from the stereochemistry of the introduced 1‘-methyl group, these results suggest that epoxidation of 2 and 9 had proceeded preferentially, if not exclusively, from the β-face of the 1-enofuranosyl structure…”

“…In the case of the DTBS (di- tert -butylsilylene)-protected 1‘,2‘-unsaturated uridine ( 11 ),12b the epoxide 12 obtained after evaporation of the oxidation mixture was found to be fairly stable in CDCl 3 . Its 1 H NMR spectrum combined with NOE studies confirmed that the epoxide 12 was a single isomer with 1‘,2‘-α-epoxy stereochemistry, the observed NOE correlation being 15.4% between H-3‘ and H-6.…”

Synthesis of C-Arylnucleoside Analogues

“…In this regards, Haraguchi and co-workers reported the ring opening of a nucleoside 1',2'-epoxide with an organoaluminium reagent for the preparation of the 1'- C -phenyl uridine analogue 147 [35]. The strategy developed by the authors was to start with the 1',2'-unsaturated nucleoside analogue 145 obtained in three steps from uridine ( 1 ) (Scheme 17) [36].…”

“…Reagents and Conditions : (i) Reference [36]; (ii) dimethyldioxirane, acetone, CH 2 Cl 2 ; (iii) Ph 3 Al, CH 2 Cl 2 , −30 °C, 4.5 h, 55%.…”