Conversion of Meso to dl Form and Vice Versa in Bisphosphonates: Synthesis and Structures of New Meso, dl and (Meso + dl) Bisphosphonates Derived from Cyclic Phosphites and Dialkyl Acetylenedicarboxylates

Abstract

The bisphosphonates [(OCH₂CR₂­CH₂O)P(O)CHC(O)OR′]₂ [R = R′ = Me (5), R = Me, R′ = Et (6), R = Et, R′ = Me (7), R = R′ = Et (8)], [CH₂(6-t-Bu-4-Me-C₆H₄O)₂P(O)CHC(O)OR]₂ [R = Me (9), Et (10)] and [(OCH₂CMe₂­CH₂O)P(S)CHC(O)OR]₂ [R = Me (11), Et (12)] have been prepared by the reaction of the corresponding cyclic phosphites with dimethyl acetylenedicarboxylate or diethyl acetylenedicarboxylate in the presence of a base [Et₃N or n-BuLi]. The structures of dl-, meso- and (dl + meso) forms [6a, 6b and 6ab] of 6 as well as the meso form of 8 are determined from X-ray crystallography. By means of combined X-ray structural and ³¹P NMR spectroscopic investigations, it is shown that the meso form can be converted to the dl form and vice versa. A possible rationale invoking the intermediacy of an enolic form is proposed for this observation.

Key words

bisphosphonates - epimerization - diastereomers - X-ray structures - ³¹P NMR

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12

It can be noted that the proton attached to the carbon α to the phosphorus can be removed in the presence of a base (Horner-Wadsworth-Emmons reaction); in the present case it is suggested that the proton migrates due to thermal rearrangement.