Kenji Suemune

Facile synthesis of aryl(difluoromethyl)phosphonates through CuBr-mediated cross coupling reactions of [(diethoxyphosphinyl)difluoromethyl]zinc bromide with aryl iodides

Abstract The CuBr-promoted coupling reaction of [(diethoxyphosphinyl)difluoromethyl]zinc bromide 6 with aryl iodides in either DMF or DMA was examined to give a series of aryl(difluoromethyl)phosphonates. The coupling reaction was applicable to the selective synthesis of α,α-difluoro-4- iodobenzylphosphonale 11e, a useful intermediate for the preparation of F2Pmp. 1-[(Diethylphosphono)difluoromethyl] naphthalene 15 and the regioisomer 16 were obtained in high yields from 1- and 2-iodonaphthalene, respectively. The phosphonate 16 was transformed to the free acid 4a, a low molecular-mass inhibitor of protein phosphatases.

Enantioselective synthesis of α-hydroxyphosphinic acid derivatives through hydrophosphinylation of aldehydes catalyzed by Al-Li-BINOL complex

Abstract The first catalytic asymmetric synthesis of (S)-α-hydroxy-H-phosphinates and (S,S)-α,α′-dihydroxyphosphinates were achieved by the reaction of methyl phosphinate with aldehydes in the presence of Al-Li-BINOL complex.

Synthesis of 1,1-difluoro-5-(1H-9-purinyl)-2-pentenylphosphonic acids and the related methano analogues. Remarkable effect of the nucleobases and the cyclopropane rings on inhibitory activity toward purine nucleoside phosphorylase.

A series of 1,1-difluoro-5-(1H-9-purinyl)-2-pentenylphosphonic acids, (E)-2a,b and (Z)-2a,b, as well as the related methano analogues (+/-)-3a,b and (+/-)-4a,b were prepared for evaluation of their PNP inhibitory activities. The cyclopopane ring and the hypoxanthine residue were found to increase the profile of inhibitory activity. The IC50 and Ki values of difluoro¿(1R*,2S*)-2-[2-(6-oxo-6,9-dihydro-1H-9-purinyl)ethyl]cycl opropyl¿methylphosphonic acid (+/-)-3b toward PNP purified from Cellulomonas sp. were determined to be 70 nM and 8.8 nM, respectively.

Enantioselective synthesis of threo-α,β-dihydroxyphosphonates by asymmetric dihydroxylation of 1(E)-alkenylphosphonates with AD-mix reagents

Abstract Asymmetric dihydroxylation (AD) of 1(E)-alkenylphosphonates with an AD-mix-α or -β reagent was examined to give a series of optically active threo-α,β-dihydroxyphosphonates. Good enantioselectivity (>88% ee) was observed in the AD reaction of 1(E)-alkenylphosphonates with conjugated aromatic substituents. The steric effects of the ester functionality in the course of the dihydroxylation were also evaluated. Enantioselectivity and yield were significantly improved when the AD reaction was carried out with dimethyl phosphonate instead of diethyl phosphonate.

Enantioselective synthesis of threo-α,β-dihydroxyphosphonates by asymmetric dihydroxylation of vinylphosphonates. An application to the stereocontrolled synthesis of (4S,5S)-4-diethylphosphono-5-hydroxymethyl-2,2-dimethyl-1,3-dioxolane

Abstract The asymmetric dihydroxylation (AD) reaction of vinylphosphonates with AD-mix-α and -β reagents was successfully applied to the enantioselective synthesis of threo - α , β-dihydroxyphosphonates. β-Aryl substituents on the vinyl phosphonates were found to be good directors for the reaction with respect to the yield and enantioselectivity. The utility of chiral α, β-dihydroxyphosphonate 2c was illustrated by the stereocontrolled synthesis of (4 S ,5 S )-4-diethylphosphono-2,2-dimethyl-5-hydroxymethyl-1,3-dioxolane 6 , a potentially useful chiron for asymmetric synthesis of α-heteroatom-substituted phosphonates.

Synthesis of (2′S,3′S)-9-(4′-phosphono-4′,4′-difluoro-2′,3′-methanobutyl)guanine and its enantiomer. Evaluation of the inhibitory activity for purine nucleoside phosphorylase

Abstract Conformationally constrained analogues 2a and ent - 2a of 9-(difluorophosphonopentyl)guanines 1 , a multi-substrate analogue inhibitor of PNP, were prepared from optically active trans -1-(diethoxyphosphinyl)difluromethy-2-hydroxymethylcyclopropanes (+)− 6 and (−)− 6 . Enzymatic double resolution was applied to obtain (+)- 6 and (−)- 6 with high enantiomeric purity. Inhibitory activity of 2a and ent - 2a were found to be 2400-fold less potent than 1 .

Asymmetric dihydroxylation of 1-acyloxy-2(E)-alkenylphosphonates with AD-mix reagents. Effects of 1-acyloxy functional groups on the asymmetric dihydroxylation

Abstract Asymmetric dihydroxylation (AD) of a racemic mixture of 1-acyloxy-2(E)-alkenylphosphonates with AD-mix-α or -β reagents was examined. The kinetic rate of dihydroxylation was highly dependent upon the configuration of the 1-acyloxy functional group as well as the nature of substituents at the 3-position. The reaction of a racemic mixture of diethyl (E)-3-phenyl-1-acetyloxy-2-propenylphosphonate with an AD-mix-β reagent preferentially dihydroxylated the R-enantiomer to leave an unreacted S-enantiomer of high enantiomeric purity. Double diastereoselection of the resolved diethyl 3-phenyl-1-acetyloxy-2(E)-propenylphosphonate in dihydroxylation was also examined.

Diastereoselective synthesis of chiral β-amino-α-hydroxy-H-phosphinates through hydrophosphinylation of α-amino aldehydes

Abstract A stereodivergent synthesis of β-amino-α-hydroxy- H -phosphinates was achieved by ALB-catalyzed hydrophosphinylation of N , N -dibenzyl-α-amino aldehydes tuning the chirality of the catalyst.

Stereoselective Reduction of Cyclopropylalkaones Possessing a Difluoromethylenephosphonate Group at the Ring: Application to Stereoselective Synthesis of Novel Cyclopropane Nucleotide Analogues

Abstract Difluoro{(1S∗,2S∗)-2-[(1S∗)-1-(6-oxo-1,6-dihydro-9H-purin-9-yl)ethyl]cyclopropyl}methylphosphonic acid 12a and the related analogues were prepared as ‘multi-substrate analogue’ inhibitors for purine nucleoside phosphorylase. Reduction of diethyl [(1S∗,2S∗)-2-acethylcyclopropyl](difluoro)methylphosphonate 8a with K-Selectride at a low temperature proceeded from the less-hindered face of the carbonyl in the bisected s-cis conformation to give the corresponding cyclopropylalkanol 9a in high diastereoselectivity (94% de). In an analogous manner, several cyclopropylalkanols 8b–g possessing a difluoromethylene phosphonate functional group at the ring were stereoselectively synthesized. The cyclopropylalkanol 9a was manipulated to the nucleotide analogue 12a through a conventional method. The diastereomeric nucleotide analogue 15 was prepared from 9a via the Mitsunobu inversion. Preliminary results on an assay of PNP inhibitory activity of 9a and 15 are presented.

Asymmetric synthesis of β-amino-α-hydroxyphosphinic acid derivatives through hydrophosphinylation of α-amino aldehydes

Abstract The diastereoselective synthesis of β-amino-α-hydroxyphosphinates was achieved by hydrophosphinylation of N,N-dibenzyl-α-amino aldehydes with ethyl ethylphosphinate catalyzed by (S)-ALB. The hydrophosphinylation using ethyl phosphinate afforded both syn- and anti-β-amino-α-hydroxy-H-phosphinates with high diastereoselectivities by tuning the chirality of ALB.