title: [Synthesis of phosphonic acid and phosphinic acid derivatives for development of 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 alpha-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 alpha-aminoaldehydes afforded threo- and erythro-beta-amino-alpha-hydroxyphosphonates under chelation and nonchelation controlled conditions, respectively. The asymmetric dihydroxylation of alpha, beta-, and beta, gamma-unsaturated phosphonates with AD-mix-alpha and AD-mix-beta reagents gave alpha, beta- and beta, gamma-dihydroxyphosphonates with high enantioselectivity. The method was applied to the kinetic resolution of racemic alpha-oxygetated beta, gamma-unsaturated phosphonates. Treatment of allyloxymethylphosphonates with the base afforded alpha-hydroxyphosphonates via the [2,3]-Wittig reaction. Threo- and erythro-beta-amino-alpha-hydroxyphosphinates were obtained with high diastereoselectivity by phosphinylation of alpha-aminoaldehydes in the presence of (R)- and (S)-ALB, respectively. The phosphinylation of alpha-oxygenated aldehydes afforded the corresponding alpha, beta-dioxygenated phosphinates, but with low diastereoselectivity. Sphingomyelin analogues containing CF(2)PO(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 alpha, alpha-difluorobenzylphosphonates was established based on the cross coupling reaction of an iodobenzene derivative with ZnCuBr(2)CF(2)PO(OEt)(2). The synthetic utility of ZnCuBr(2)CF(2)PO(OEt)(2) was examined to obtain alpha, alpha-difluoromethylenenphosphonates. The method was applied to a synthesis of PNP-inhibitory active compounds by combination of the purine base and alcohols containing difluoromethylenephosphonate. The methodology for the beta-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.
authors.affiliation: School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji 192-0392, Japan. shibuyas@ps.toyaku.ac.jp
authors.forename: Shiroshi
authors.initials: S
authors.lastname: Shibuya
mesh_terms: D002625:Chemistry, Organic; D004002:Clodronic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D003521:Cyclopropanes / Q000138:chemical synthesis; D015195:Drug Design; D006801:Humans; D009711:Nucleotides / Q000138:chemical synthesis; D055601:Organic Chemistry Phenomena; D063065:Organophosphonates / Q000138:chemical synthesis*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors; D013109:Sphingomyelins / Q000138:chemical synthesis
chemical_list: D003521:Cyclopropanes; D009711:Nucleotides; D063065:Organophosphonates; D013109:Sphingomyelins; C465523:difluoromethylenesulfonic acid; D004002:Clodronic Acid; C041121:difluoromethylene diphosphonate; C030797:cyclopropane; D017027:Protein Tyrosine Phosphatases; D013108:Sphingomyelin Phosphodiesterase