A special type of C–H functionalization can be achieved through C–H insertion combined with Cope rearrangement (CHCR) in the presence of dirhodium catalysts. This type of reaction was studied using ...density functional theory and ab initio molecular dynamics simulations, the results of which pointed to the dynamic origins of low yields observed in some experiments. These studies not only reveal intimate details of the complex reaction network underpinning CHCR reactions but also further cement the generality of the importance of nonstatistical dynamic effects in controlling Rh2L4-promoted reactions.
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IJS, KILJ, NUK, PNG, UL, UM
Recent computational studies highlighting the importance of accounting for dynamic effects on organic reactivity are discussed, accompanied by descriptions of the factors that led the author to ...pursue these projects.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Carbocation rearrangement reactions are of great significance to synthetic and biosynthetic chemistry. In pursuit of a scale of inherent migratory aptitude that takes into account dynamic effects, ...both uphill and downhill ab initio molecular dynamics (AIMD) simulations were used to examine competing migration events in a model system designed to remove steric and electronic biases. The results of these simulations were combined with detailed investigations of potential energy surface topography and variational transition state theory calculations to reveal the importance of nonstatistical dynamic effects on migratory aptitude.
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Density functional theory calculations have been used to explore the reaction mechanism of (4 + 2) and (2 + 2) cycloadditions of benzyne with classical dienes. The results indicate the following: (1) ...(4 + 2) products arise via concerted pathways, (2) (2 + 2) products arise via stepwise pathways with diradical intermediates, and (3) these diradical intermediates are formed via isomerization of carbene intermediates. The origins of periselectivity in these reactions are analyzed using distortion/interaction analysis for the key steps, and they indicate that the tiny distortion in the very early 4 + 2 transition structure, coupled with an entropic favorability, controls selective (4 + 2) cycloaddition.
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Heathcock’s classic cyclization/rearrangement cascade for formation of Daphniphyllum alkaloids is subjected to analysis using density functional theory calculations. The results of these calculations ...are consistent with a two-step pathway involving two pericyclic reactions, a Diels–Alder cycloaddition and an ene reaction.
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Noncovalent interactions involving sulfur atoms play essential roles in protein structure and function by significantly contributing to protein stability, folding, and biological activity. Sulfur is ...a highly polarizable atom that can participate in many types of noncovalent interactions including hydrogen bonding, sulfur−π interactions, and S–lone pair interactions, but the impact of these sulfur-based interactions on molecular recognition and drug design is still often underappreciated. Here, we examine, using quantum chemical calculations, the roles of sulfur-based noncovalent interactions in complex naturally occurring molecules representative of thiopeptide antibiotics: glycothiohexide α and its close structural analogue nocathiacin I. While donor–acceptor orbital interactions make only very small contributions, electrostatic and dispersion contributions are predicted to be significant in many cases. In pursuit of understanding the magnitudes and nature of these noncovalent interactions, we made potential structural modifications that could significantly expand the chemical space of effective thiopeptide antibiotics.
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Sesterterpenoids are a rare terpene class harboring untapped chemodiversity and bioactivities. Their structural diversity originates primarily from the scaffold-generating sesterterpene synthases ...(STSs). In fungi, all six known STSs are bifunctional, containing C-terminal trans-prenyltransferase (PT) and N-terminal terpene synthase (TPS) domains. In plants, two colocalized PT and TPS gene pairs from Arabidopsis thaliana were recently reported to synthesize sesterterpenes. However, the landscape of PT and TPS genes in plant genomes is unclear. Here, using a customized algorithm for systematically searching plant genomes, we reveal a suite of physically colocalized pairs of PT and TPS genes for the biosynthesis of a large sesterterpene repertoire in the wider Brassicaceae. Transient expression of seven TPSs from A. thaliana, Capsella rubella, and Brassica oleracea in Nicotiana benthamiana yielded fungal-type sesterterpenes with tri-, tetra-, and pentacyclic scaffolds, and notably (−)-ent-quiannulatene, an enantiomer of the fungal metabolite (+)-quiannulatene. Protein and structural modeling analysis identified an amino acid site implicated in structural diversification. Mutation of this site in one STS (AtTPS19) resulted in premature termination of carbocation intermediates and accumulation of bi-, tri-, and tetracyclic sesterterpenes, revealing the cyclization path for the pentacyclic sesterterpene (−)-retigeranin B. These structural and mechanistic insights, together with phylogenetic analysis, suggest convergent evolution of plant and fungal STSs, and also indicate that the colocalized PT–TPS gene pairs in the Brassicaceae may have originated from a common ancestral gene pair present before speciation. Our findings further provide opportunities for rapid discovery and production of sesterterpenes through metabolic and protein engineering.
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Meroterpenes derived from dimethylorsellinic acid (DMOA) and farnesyl pyrophosphate have attracted much biosynthetic attention, yet only recently have synthetic solutions to any family members ...appeared. A key point of divergence in DMOA‐derived meroterpene biosynthesis is the protoaustinoid A carbocation, which can be diverted to either the berkeleyone, andrastin, or terretonin structural classes by cyclase‐controlled rearrangement pathways. Shown herein is that the protoaustinoid bicyclo3.3.1nonane nucleus can be reverted to either andrastin or terretonin ring systems under abiotic reaction conditions. The first total syntheses of members of these natural product families are reported as their racemates.
All positives: A key point of divergence in dimethylorsellinic‐acid‐derived meroterpene biosynthesis is the protoaustinoid A carbocation, which can be diverted to either the berkeleyone, andrastin, or terretonin structural classes by cyclase‐controlled rearrangements. Shown herein is that the carbocation can be reverted to either andrastin or terretonin ring systems under abiotic reaction conditions. The first total syntheses of members of these natural product families are reported as their racemates.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Quantum chemical methods are useful for probing the energetic viability of chemical mechanisms involved in natural product biosynthesis. Typical computational approaches are described and ...representative examples of mechanistic studies on radical, pericyclic, and carbocation rearrangement reactions that lead to polycyclic skeletons of complex natural products showcase the utility of such methods in providing understanding and shaping future experimental studies. The importance of inherent substrate reactivity is highlighted and cautions for interpreting computational results are discussed.
This article is categorized under:
Structure and Mechanism > Reaction Mechanisms and Catalysis
Theoretical and Physical Chemistry > Reaction Dynamics and Kinetics
Structure and Mechanism > Computational Biochemistry and Biophysics
Atomic‐level details of chemical mechanisms involved in the biosynthesis of complex natural products can be revealed through quantum chemical calculations.
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