CHIROSPECIFIC SYNTHESES OF PRECURSORS OF CYCLOPENTANE AND CYCLOPENTENE CARBOCYCLIC NUCLEOSIDES BY [3-COUPLING AND TRANSANNULAR ALKYLATION(3])

A new method is reported for the preparation of enantiomerically pure )-1-amino-2-hydroxy-4-(hydroxymethyl)cyclopentane, S)-1-amino-2-fluoro -4-(hydroxymethyl)cyclopentane, and (1R,4S)-1-amino-4-(hydroxymethyl)- 2-cyclopentene, advanced precursors to carbocyclic nucleosides. The me thod involves initial conversion of D-serine into an aldehyde with 9-p henylfluorenyl protection at nitrogen and O-benzyl protection at oxyge n. A [3 + 3]-coupling of this aldehyde with a titanium homoenolate der ived from tert-butyl 3-iodopropionate gave the corresponding anti-lact one in high yield. Regioselective hydrogenolysis of the amine protecti ng group, accompanied by intramolecular O- to N-cyclization formed a l actam. After suitable nitrogen protection and functional group manipul ation, transannular alkylation afforded the corresponding 2-benzyl- or enzyl)-6-hydroxy-2-azabicycclo[2.2.1]-3-heptanone. Functional group m odification of the 2-benzyl analogue gave the resulting 6(S)-hydroxy a nd 6(R)-fluoro N-BOC imides; alternatively, the 2-(p-methoxybenzyl) an alogue was converted to an N-BOC imide containing an olefinic Linkage at C-5 and C-6 of the bicycle. Subjecting each of the N-BOC imides to a reduction-deprotection sequence then afforded the desired carbocycli c analogues. The [3 + 3]-coupling method also allowed improved and exp edient access to an advanced tribenzylated lactam previously used in t he racemic syntheses of the hydroxylated alkaloids D-mannonolactam, de oxymannojirimycin, and prosopinone, providing a formal asymmetric synt hesis of these alkaloids.