Theoretical Studies on Farnesyl Cation Cyclization:  Pathways to Pentalenene

Abstract

In this article, we describe studies, using quantum chemical computations, on possible polycyclization pathways of the farnesyl cation leading to the complex sesquiterpene pentalenene. Two distinct pathways to pentalenene with similar activation barriers are described, each differing from previous mechanistic proposals, and each involving unusual and unexpected intermediates. Direct deprotonation of intermediates on these pathways leads to sesquiterpene byproducts, such as humulene, protoilludene, and asteriscadiene, supporting the notion that a key function of pentalenene synthase, the enzyme that produces pentalenene in Nature, is to regulate the timing and location of proton removal. The implications of the computational results for experimental studies on pentalenene synthase are discussed.

Unearthing the roots of the terpenome

“…For example, structural and enzymological studies of certain terpenoid synthases suggest that a π bond or the diphosphate group of the substrate, and not an enzyme-bound residue, serves as a catalytic base [12,28,54]; generally speaking, such regiospecific and stereospecific deprotonations are not well understood and merit further study. Theoretical studies of terpenoid synthase mechanisms further highlight the role of substrate conformation in governing intramolecular proton transfer steps in catalysis and promise to illuminate new features of isoprenoid coupling and cyclization reactions [55]. Thus, it is remarkable that the exquisite structural and stereochemical diversity of the terpenome may well be a consequence of the fact that terpenoid synthases do not excessively intrude on the complex organic transformations occurring in their active sites.…”

Identification of Sesquiterpene Synthases fromNostoc punctiformePCC 73102 andNostocsp. Strain PCC 7120

“…This would produce the germacren-8-yl tertiary carbenium ion 7, which could, in turn, undergo a second, now-transannular proton transfer to C-2 to provide an alternate entry to cation 5. In this regard, it is intriguing to consider the possible role of proton sandwich structure 8, in light of the interesting observations about such species from the Tantillo laboratories (19,20,40). Finally, it is even possible to consider an analogous delocalized intermediate, namely, structure 9, for the initial 1,6-proton transfer taking structure 3 to structure 7.…”

Nature as organic chemist

“…76,[83][84][85][86] Complementing and enriching these studies, Prof Dean J Tantillo (U. C. Davis) has deepened the understanding of the mechanisms and energetics of terpene cyclization reactions through detailed quantum chemical calculations of the reaction pathways linking carbocationic intermediates and transition state structures for a wide variety of terpene synthase-catalyzed reactions. [87][88][89][90][91] In spite of the substantial progress in cloning terpene synthases, the search for additional terpene synthase genes was seriously hindered by the exceptionally low levels of mutual sequence similarity among known terpene synthases, thus thwarting the routine application of homology-based cloning methods to this class of microbial proteins. It occurred to me that it might be possible to find and then biochemically characterize microbial terpene synthases by using known terpene synthase sequences to query the then newly emerging microbial genome sequences.…”