Synthesis and characterization of macrocyclic bisphosphonate dimers

Abstract

Abstract Background: Attempts to optimize the synthetic yield of known macrocyclic phosphonates resulted in the discovery of two new macrocyclic bisphosphonate dimers. Methods: An attempt was carried out to optimize the yield of a known macrocyclic bisphosphonate dimer, 6, over the yield of monomers 2 and 3, using the Mitsunobu protocol in the macrocyclization step. Cyclization reactions were carried out at 0.003 M, 0.004 M, 0.005 M, 0.008 M and 0.02 M, compared to 0.002 M in our initial report of the synthesis of monomers. Results: In this attempt to optimize the production of dimer 6, two new macrocyclic diastereomers of 6, namely 28-membered bisphosphonates 9 and 10, were isolated in yields of 3% and 2%, respectively, and characterized by FTIR, LC-MS, 1 H , 1 3 C and 3 1 P NMR as well as by X-ray crystallography. Conclusions: The results described herein further illustrate the utility of the Mitsunobu macrocyclization (ring-closing) reaction toward the synthesis of macrocyclic phosphonates. The X-ray crystallographic characterization of the three bisphosphonate dimers, together with correlations to specific 1 H and 3 1 P NMR resonances allowed for the assignments of relative stereochemistries between the various dimers.