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
Db. Berkowitz et al., 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, Journal of organic chemistry, 61(14), 1996, pp. 4666-4675
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.