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.