Biosynthetic consequences of multiple sequential post-transition-state bifurcations

Abstract

Selectivity in chemical reactions that form complex molecular architectures from simpler precursors is usually rationalized by comparing competing transition-state structures that lead to different possible products. Herein we describe a system for which a single transition-state structure leads to the formation of many isomeric products via pathways that feature multiple sequential bifurcations. The reaction network described connects the pimar-15-en-8-yl cation to miltiradiene, a tricyclic diterpene natural product, and isomers via cyclizations and/or rearrangements. The results suggest that the selectivity of the reaction is controlled by (post-transition-state) dynamic effects, that is, how the carbocation structure changes in response to the distribution of energy in its vibrational modes. The inherent dynamical effects revealed herein (characterized through quasiclassical direct dynamics calculations using density functional theory) have implications not only for the general principles of selectivity prediction in systems with complex potential energy surfaces, but also for the mechanisms of terpene synthase enzymes and their evolution. These findings redefine the challenges faced by nature in controlling the biosynthesis of complex natural products.

Plasticity and Evolution of (+)-3-Carene Synthase and (−)-Sabinene Synthase Functions of a Sitka Spruce Monoterpene Synthase Gene Family Associated with Weevil Resistance

“…As none of these amino acids were found to be positioned in the active site cavity, these substitutions likely influence product specificity by contributing to the overall barrel structure and/or contour of the class I active site as has been demonstrated in other terpene synthases (11). Quantum chemical calculations have shown that changes of the carbocation structure in response to the distribution of energy in its vibrational nodes could play a substantial role in terpene synthase reaction selectivity (28), suggesting that Phe 596 or these synergistic amino acids might play a role in modulating the reaction energy landscape of the intermediate to promote dynamic tendencies that lead to the formation of (Ϫ)-sabinene as opposed to directly stabilizing the intermediate.…”

Cryptic post-transition state bifurcations that reduce the efficiency of lactone-forming Rh-carbenoid C–H insertions

“…While it was suggested previously that the formation of two (or more) products in dynamics simulations initiated from a TSS 1,25 and “shoulders” along IRCs ( i.e. , transitions from a low gradient to a high gradient) can be indicative of PTSBs, 3,55 the results of the current study suggest that changes to the IRC product with (1) relatively minor functional group substitutions on the substrate, (2) the relative stereochemistry of the TSS, (3) the conformation of the TSS, and/or (4) the functional used to locate the TSS and compute its IRC, may also point to PTSBs.…”

“…2,3,25–29 Our hope is that the results of this study will help to shed light on a phenomenon rarely considered in the design of transition metal (and other) catalysts.…”

Feasibility of Intramolecular Proton Transfers in Terpene Biosynthesis – Guiding Principles

“…The potential energy surface connected to these proton-transfer processes is also quite complex (e.g., note that whether or not there is a barrier between the C8−H and C9−H reactants depends on the level of theory; Table 1). 29 The migrating protons in these transition-state structures each interact with three carbons.…”