New stereocontrolled synthesis of isomeric C-branched-[beta]-D-nucleosides by intramolecular free-radical cyclization-opening reactions based on temporary silicon … (original) (raw)
Silicon-bearing ally1 group tethered to a 2' or 3'hydro~l grotqt onto the raakal generated at the vi&al 2' or 3' center in thefke-rat&al precursors II. 15.19 and23 were used to promote intromolectdm stereocontrolled free-radical-cyclisation to give 1% + 12). lb. 20 and 24 in 60-705 yields. The confZguration at the 2' or the 3' center of the allylsihxane group dictated the stereochemical outcome #the radical cyclisation reaction to give cisfused seven-membered rings in conqrounds 16.20 and 24 (from 15.19 and 23, respectively) due to relatively long Si-0 bond and huge C&-O bond angle leadbg to exclurive 7.endo cyclisation. The only exception to this was found in the radical-cyclisation of II in which both &fused and transfused seven-membered rings 120 and 12b were formed as inseparable mixture almost in equal amounts. The seven-membered siloxane ring in the radical-cyclised products 120 + 12b, lb, 20 and 24 were then opened up by a simple oxidation reaction to give different I J-dials 13a + 13). 17,21 and 25 in high yields. The SO -(4methoxytrityl) group from 13a + 139,17.21 and 25 was then removed to give pure and isomeric C-branched nucleosides Ilo. 14b. 18.22 and 26, respectively. The acid catalysed isomerixation of the petttqtitranose ring in 17 to a pyrwwse system in 18 has been concluded on the basis of conqntrative structural analysis sf 17 and 18 by 500 MHz IH-NMR spectroscopy. The confisurations of trio1 18 are C-Z'(S), W'(R). C-S(R). C-6(S). C-7(S) which are also the configurations of the corresponding chiral centers in the precursors 16 and 17. Note that the acid catalyzed isowwization @fhnose in 17 to pyranose ring in 18 has been achieved with full retmtiorn of anomeric co~guration. The conftgtuation Of C-3' in compounds 140, 14b. 22, and C-2' in 26 has been eluci&ted by ID di erential nOe experiments by IH-NMR spectroscopy at 500 MHz in D20 solution at 293K. The estimation of the P JRR coupling constants led us to calculate dihedral angles of 14a, lib, 17.18.22 and 26 using the Karplus-Altona algorithm which have allowed us to define the coaformational parameters of their constituent sugar moieties. Molecular mechanics calculations have been subsequently performed on the initial NMR structures of 17 and 18 to give their energy minimized conformations. The structure of18 Iurs been f&ly co@med by esthnadng proton-proton distances derivedfrom their nOe build-up rates by 20 NOEST experiments at 293K at werent mixing times. Stereocontrolled intramolecular free-radical cyclization has emerged as a powerful tool for carbon-carbon bond formation in organic synthesis owing to our increasing understanding of the mechanistic behaviour of such reaction over the last decade. 12 We have deemed it important for some time now9s1u that such stereocontrolled intramolecular free-radical cyclization reactions are powerful means for introduction of Cbranching at 2', 3' or at 5' centers of B-D-nucleoside& lo. Development of stereoselective synthesis of Cbranched nucleosides have drawn much attention because of the fact that some of these C-branched nucleosides have been found to produce remarkable antibacterial, antitumor, antiviral activities.3 + Dedicated to the memory ofProfcs.wr Tohy Ve&a
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