READY ACCESS TO FLUORINATED PHOSPHONATE MIMICS OF SECONDARY PHOSPHATES - SYNTHESIS OF THE (ALPHA,ALPHA-DIFLUOROALKYL) PHOSPHONATE ANALOGS OF L-PHOSPHOSERINE, L-PHOSPHOALLOTHREONINE, AND L-PHOSPHOTHREONINE

In addition to the previously recorded reactions of diethyl lithio(dif luoromethyl)phosphonate (8) with primary triflates and aldehydes, we r eport here that 8 reacts with functionalized, but unactivated, methyl esters to give efficient acyl substitution. Thus, 8 reacts cleanly (-7 8 degrees C, THF) with the following methyl esters (product, yield): m ethyl (S)-isopropylideneglycerate (14, 99%), methyl butyldimethylsilyl )-2-O-tetrahydropyranylglycerate (16, 85%), and the Garner ester deriv ed from D-serine (15, 77%). Expeditious treatment of the resultant alp ha,alpha-difluoro-beta-keto phosphonates with hydride or Grignard reag ents followed by alcohol deoxygenation provides a general method for t he synthesis of (alpha,alpha-difluoroalkyl)phosphonate analogues of se condary phosphates. For tertiary alcohols, Dolan-MacMillan deoxygenati on conditions are employed, The requisite methyl oxalate esters are ob tained by an improved procedure a herein the Lithium alkoxide of the h indered tertiary alcohol is irreversibly generated at low temperature and then condensed with methyl oxalyl chloride. Relative stereochemist ry is assigned via conversion of the Garner ester derived Boc-amino al cohols to the corresponding cyclic, six-membered phosphonate esters an d examination of their H-1 NMR spectra. The relevant vicinal coupling constants are extracted hom these spectra by performing double quantum -filtered phase-sensitive COSY experiments. This new (difluoromethylen e)phosphonate anion-methyl ester condensation, Grignard (hydride) addi tion, deoxygenation sequence has been applied to the synthesis of (alp ha, alpha-difluoroalkyl)phosphonate analogues of L-phosphoserine (grea ter than or equal to 96% ee) and L-phosphoallothreonine (93% ee) from D-serine and of L-phosphothreonine (91% ee) from L-glycerate, respecti vely.