Synthesis of phosphonic acids and phosphinic acids derivatives toward to biologically active compounds

Abstract

This paper covers recent publications from our laboratory on the synthesis of a variety of phosphonate and phosphinate derivatives. New methods for the enantioselective synthesis of α-hydroxyphosphonates were established by Lewis acid-mediated cleavage of homochiral 1,3-dioxaneacetals with P(OEt) 3 and chiral metal ligand-mediated hydrophosphonylation of aldehydes. Two diastereomers of HPmp derivatives were prepared by an application of these methods. The HPmp derivatives were convered to FPmp derivatives but with low diastereoselectivity. Hydrophosphonylation of α-aminoaldehydes afforded threo- and erythro-β-amino-α-hydroxyphosphonates under chelation and nonchelation controlled conditions, respectively. The asymmetric dihydroxylation of α, β-, and β, γ-unsaturated phosphonates with AD-mix-α and AD-mix-β reagents gave α, β-, and β, γ-dihydroxyphosphonates with high enantioselectivity. The method was applied to the kinetic resolution of racemic α-oxygetated β, γ-unsaturated phosphonates. Treatment of allyloxymethylphosphonates with the base afforded α-hydroxyphosphonates via the [2,3]-Wittig reaction. Threo- and erythro-β-amino-α-hydroxyphosphinates were obtained with high diastereoselectivity by phosphinylation of α-aminoaldehydes in the presence of (R)- and (S)-ALB, respectively. The phosphinylation of α-oxygenated aldehydes afforded the corresponding α, β-dioxygenated phosphinates, but with low diastereoselectivity. Sphingomyelin analogues containing CF2PO(OH)2 were synthesized starting from (S)- and (R)-Garner aldehyde for the purpose of obtaining potent sphyngomyelinase inhibitors. A useful method for the synthesis of α, α-difluorobenzylphosphonates was established based on the cross-coupling reaction of an iodobenzene derivative with ZnCuBr 2CF2PO (OEt)2. The synthetic utility of ZnCuBr2CF2PO (OEt)2 was examined to obtain α, α-difluoromethylenenphosphonates. The method was applied to the synthesis of PNP-inhibitory active compounds by combination of the purine base and alcohols containing difluoromethylenephosphonate. The methodology for the β-selective N-glycosylation of 2,3-dideoxy glucoside was established by introducing phosphonothioates at the 3-position of glycosyl doners instead of phosphonate. Synthesis of new acylic nucleotide analogues designed based on the structural modification of ARS2267 is also described. Finally, kiral synthesis of some phosphonates was achieved using lipase through kinetic resolution. © 2004 The Pharmaceutical Society of Japan.