The importance of inherent substrate reactivity for terpene synthase enzymes is discussed, with a focus on recent experimental tests of predictions derived from computations on gas‐phase reactivity ...of carbocations.
I know what I like: The importance of inherent substrate reactivity for terpene synthase enzymes is discussed in this Minireview. Experimental studies are highlighted that support predictions from quantum chemistry that inherent carbocation reactivity is expressed in the presence of terpene synthase enzymes.
This review describes applications of quantum chemical calculations in the field of terpene biosynthesis, with a focus on insights into the mechanisms of terpene-forming carbocation rearrangements ...arising from theoretical studies.
Conspectus Rh2L4 catalysts have risen in popularity in the world of organic synthesis, being used to accomplish a variety of reactions, including C–H insertion and cyclopropanation, and often doing ...so with high levels of stereocontrol. While the mechanisms and origins of selectivity for such reactions have been examined with computational quantum chemistry for decades, only recently have detailed pictures of the dynamic behavior of reacting Rh2L4-complexed molecules become accessible. Our computational studies on Rh2L4 catalyzed reactions are described here, with a focus on C–H insertion reactions of Rh2L4-carbenes. Several issues complicate the modeling of these reactions, each providing an opportunity for greater understanding and each revealing issues that should be incorporated into future rational design efforts. First, the fundamental mechanism of C–H insertion is discussed. While early quantum chemical studies pointed to transition structures with 3-center C–H–C substructures and asynchronous hydride transfer/C–C bond formation, recent examples of reactions with particularly flat potential energy surfaces and even discrete zwitterionic intermediates have been found. These reactions are associated with systems bearing π-donating groups at the site of hydride transfer, allowing for an intermediate with a carbocation substructure at that site to be selectively stabilized. Second, the possible importance of solvent coordination at the Rh atom distal to the carbene is discussed. While effects on reactivity and selectivity were found to be small, they turn out not to be negligible in some cases. Third, it is shown that, in contrast to many other transition metal promoted reactions, many Rh2L4 catalyzed reactions likely involve dissociation of the Rh2L4 catalyst before key chemical steps leading to products. When to expect dissociation is associated with specific features of substrates and the product-forming reactions in question. Often, dissociation precedes transition structures for pericyclic reactions that involve electrons that would otherwise bind to Rh2L4. Finally, the importance of nonstatistical dynamic effects, characterized through ab initio molecular dynamics studies, in some Rh2L4 catalyzed reactions is discussed. These are reactions where transition structures are shown to be followed by flat regions, very shallow minima, and/or pathways that bifurcate, all allowing for trajectories from a single transition state to form multiple different products. The likelihood of encountering such a situation is shown to be associated again with the likelihood of formation of zwitterionic structures along reaction paths, but ones for which pathways to multiple products are expected to be associated with very low or no barriers. The connection between these features and reduced yields of desired products are highlighted, as are the means by which some Rh2L4 catalysts modulate dynamic behavior to produce particular products in high yield.
The existence of post-transition state bifurcations on potential energy surfaces for organic and biological reaction mechanisms has been known for decades, but recently, new reports of bifurcations ...have been occurring at a much higher rate. Beyond simply discovering bifurcations, computational chemists are developing techniques to understand what aspects of molecular structure and vibrations control the product selectivity in systems containing bifurcations. For example, the distribution of products seen in simulations has been found to be extremely sensitive to the local environment of the reacting system (i.e. the presence of a catalyst, enzyme, or explicit solvent molecules). The outlook for the future of this field is discussed, with an eye towards the application of the principles discussed here by experimental chemists to design a reaction setup to efficiently generate desired products.
Differences in entropies of competing transition states can direct kinetic selectivity. Understanding and modeling such entropy differences at the molecular level is complicated by the fact that ...entropy is statistical in nature; i.e., it depends on multiple vibrational states of transition structures, the existence of multiple dynamically accessible pathways past these transition structures, and contributions from multiple transition structures differing in conformation/configuration. The difficulties associated with modeling each of these contributors are discussed here, along with possible solutions, all with an eye toward the development of portable qualitative models of use to experimentalists aiming to design reactions that make use of entropy to control kinetic selectivity.
This Highlight describes applications of quantum chemical calculations to problems in natural products chemistry, including the elucidation of natural product structures (distinguishing between ...constitutional isomers, distinguishing between diastereomers, and assigning absolute configuration) and determination of reasonable mechanisms for their formation.
In this tutorial review, structures encountered in carbocation cascade polycyclization reactions leading to terpene natural products are surveyed. The nature of delocalization in these carbocations ...is discussed in detail. For select cases, the ability of functional groups in enzyme active sites to modulate this delocalization is discussed. In addition to carbocation intermediates, cationic transition state structures are also described.
This review discusses the various types of noncovalent interactions in which sulfur atoms participate and their effects on protein stability, structure, folding and bioactivity. Current approaches ...and recommendations for modelling these noncovalent interactions (in terms of both geometries and interaction energies) are highlighted.
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