Do Anti-Bredt Natural Products Exist? Olefin Strain Energy as a Predictor of Isolability

Abstract

Bredts rule holds a special place in the realm of physical organic chemistry, but its application to natural products chemistry - the field in which the rule was originally formulated - is not well defined. Herein, the use of olefin strain (OS) energy as a readily calculated predictor of the stability of natural products containing a bridgehead alkene is introduced. Schleyer first used OS energies to classify parent bridgehead alkenes into "isolable", "observable", and "unstable" classes. OS calculations on natural products, using contemporary forcefield methods, unequivocally predict all structurally verified bridgehead alkene natural products to be "isolable". Thus, when one assigns the structure of a putative bridgehead alkene natural product, an OS in the "observable" or "unstable" ranges is a red flag for error.