Cyclopropanecarboxylic acid esters as potential prodrugs with enhanced hydrolytic stability

Organic Letters
David M BenderK N Houk

Abstract

Esters of cyclopropanecarboxylic acid demonstrate a substantial increase in stability under both acid- and base-catalyzed hydrolytic conditions. Comparison of the stability of valacyclovir 13 with the cyclopropane analogue 14 shows that at 40 degrees C and pH 6 the half-life of 14 is >300 h while the value for 13 is 69.7 h. CBS-QB3 calculations on isodesmic reactions for transfer of groups from an alkane to an ester show that a cyclopropyl group provides hyperconjugative stabilization.

Citations

Mar 14, 2012·Proceedings of the National Academy of Sciences of the United States of America·Lin TianLuke D Lavis
Jan 20, 2011·Acta Crystallographica. Section B, Structural Science·Aurora J Cruz-Cabeza, Frank H Allen
Mar 23, 2012·Acta Crystallographica. Section B, Structural Science·Aurora J Cruz-Cabeza, Frank H Allen
Mar 28, 2017·The Journal of Organic Chemistry·Wen ChyanRonald T Raines
Jul 4, 2017·Journal of Medicinal Chemistry·Anushka C Galasiti KankanamalageKyeong-Ok Chang
Apr 22, 2008·ACS Chemical Biology·Luke D Lavis
Sep 18, 2009·The Journal of Organic Chemistry·John E BaldwinAlexey P Kostikov
Aug 29, 2009·Organic Letters·Timothy M GreggJohn R Frost

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