Direct Approach to α-Hydroxyphosphonic and α,ω-Dihydroxyalkane-α,ω-bisphosphonic Acids by the Reduction of (Bis)acylphosphonic Acids

Abstract

Acylphosphonic and bisacylphosphonic acid sodium salts were directly reduced by sodium borohydride to the corresponding hydroxyphosphonates and dihydroxyalkanebisphosphonates. The solution conformation of the (bis)hydroxyphosphonic acid sodium salts, elucidated from the homonuclear and heteronuclear coupling constants of the proton adjacent to the hydroxy and the phosphonic groups, was identical with the solid-state conformation as determined for 1-hydroxy-2-phenylethylphosphonic acid, a representative compound, by X-ray crystallography.In previous papers it was reported from our laboratory that R,R′-difunctionalized long-chain bisphosphonates such as bisacylphosphonates 1 1 and R,R′-bishydroxyiminophosphonates 2 2 are biologically active in calciumrelated disorders such as hydroxyapatite formation and dissolution. This is in contrast to alkane-R,ω-bisphosphonates which are devoid of any activity. 3 To elucidate the roles of the functional groups in R positions for biological activity, we have undertaken a systematic study of synthesizing variously difunctionalized longchain bisphosphonates. This paper describes the development of a practical method for the synthesis of R,ωdihydroxyalkane-R,ω-bisphosphonic acids 3 which are also suitable for the synthesis of simple R-hydroxyphosphonic acids 5.R-Hydroxyphosphonate esters have been obtained previously by the Abramov and Pudovik reactions which consist of adding phosphites to carbonyl compounds 4 or by the reduction of acylphosphonate diesters using various reducing agents. Thus dialkyl acylphosphonates have been reduced to R-hydroxyphosphonates by sodium borohydride, 5,6 aluminum isopropoxide, 7 activated zinc in acetic acid, 7a diborane in tetrahydrofuran, 8 and by lithium triethylborodeuteride. 9 Attempted synthesis of R,ω-dihydroxyalkane-R,ω-bisphosphonic acids 3 by reduction of tetramethyl bisacylphosphonates to the corresponding dihydroxyalkanebisphosphonate tetramethyl esters, followed by bromotrimethylsilane-induced demethylation to the corresponding bisphosphonic acids, gave rise in our hands to impure products which were difficult to purify because of their highly polar nature.We considered that since both acylphosphonic and R-hydroxyphosphonic acids, as well as their salts, are far more stable than the esters 10 (R-hydroxyphosphonate diesters fragment easily to the corresponding carbonyl compound by eliminating dialkyl hydrogen phosphonate 7 ), direct reduction of bisacylphosphonic acids might lead to the desired R-hydroxy and R,R′-dihydroxyalkane-R,ω-bisphosphonic acids more efficiently.

Solid-state NMR of bisphosphonates adsorbed on hydroxyapatite

“…12 The MAS spectrum of 5 [see Fig. 3(c)] shows two sideband systems with an integral intensity ratio of 1 : 1.4.…”

Asymmetric synthesis of α-hydroxymethylphosphonates and phosphonic acids via hydrophosphonylation of aldehydes with chiral H-phosphonate

“…HRMS: calcd for C 7 H 10 O 4 P 189.0317 (M+H) + . Found 189.0320.The spectroscopic data were in agreement with the values described in the literature 24. The free acid was then reacted with cyclohexylamine in EtOH, following the literature procedure, to afford the dicyclohexylammonium salt as a white solid 22.…”

Long-chain functional bisphosphonates: synthesis, anticalcification, and antiresorption activity

“…We have recently described this reaction, along with the structures of the resulting dihydroxybisphosphonates [24]. …”

“…Therefore, we synthesized a series of ␣,xdihydroxypolymethylene-␣,x-bisphosphonic acids (12, 13, 14) [24]. It was found that compounds 12 and 13, corresponding in lengths to AdBP and PiBP, respectively, are inactive at low concentrations (0.1 mM) in vitro.…”