A post-transition state bifurcation (PTSB) involved in a Pummerer-type rearrangement is characterized using density functional theory (DFT) calculations on potential energy stationary points and ...direct dynamics simulations. A sensitivity of the ratio of products produced
this PTSB to solvent dielectric constant is revealed and implications of such a dependence for selectivity control of organic reactions are discussed.
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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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A variety of (5 + 2) cycloaddition reactions involving oxidopyridinium and oxidopyrylium zwitterions are compared to investigate the effects of nitrogen-for-oxygen substitution on reactivity. ...Activation barriers for nitrogen-containing systems are predicted to be larger than those for analogous oxygen-containing systems. Correlations between barrier heights and synchronicity of C–C bond formation, changes to aromaticity, reactant distortion, and interaction energies between zwitterions and alkenes were assessed, leading to the conclusion that reactivity depends more on distortion effects (including aromaticity loss) than on interaction effects (such as those associated with highest occupied molecular orbital–lowest unoccupied molecular orbital (HOMO–LUMO) interactions).
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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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BFBNIB, FZAB, GIS, IJS, KILJ, OILJ, SBCE, SBMB, UPUK
Biosynthetic production of cyclobutanes leads to many complex natural products. Recently, theoretical work employing quantum chemical calculations has shed light on many of the details of ...cyclobutane-formation, in particular, for terpene natural products. Specific insights and general principles derived from these theoretical studies are described herein.
Theoretical work on the biosynthetic production of complex, cyclobutane-containing natural products is described.
This review describes unexpected dynamical behaviors of rearranging carbocations and the modern computational methods used to elucidate these aspects of reaction mechanisms. Unique potential energy ...surface topologies associated with these rearrangements have been discovered in recent years that are not only of fundamental interest, but also provide insight into the way Nature manipulates chemical space to accomplish specific chemical transformations. Cautions for analyzing both experimental and theoretical data on carbocation rearrangements are included throughout.
Tunnel Vision Tantillo, Dean
American scientist,
09/2021, Volume:
109, Issue:
5
Journal Article
Tunneling reactions are forbidden by classical reactivity rules, but by studying reaction rates, chemists can discover instances in which these prohibited reactions occur. That insight allows us to ...understand the nature of some biochemical reactions, the complex chemistry in interstellar clouds, and the practical chemistry of molecule synthesis. Here, Tantillo discusses the reactions that occur through tunneling and determines how frequently molecules use this reaction path compared with over-the-barrier processes.
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Hydrogen sulfide (H2S) is an endogenously generated and putative signaling/effector molecule. Despite its numerous reported functions, the chemistry by which it elicits its functions is not ...understood. Moreover, recent studies allude to the existence of other sulfur species besides H2S that may play critical physiological roles. Herein, the basic chemical biology of H2S as well as other related or derived species is discussed and reviewed. This review particularly focuses on the per- and polysulfides which are likely in equilibrium with free H2S and which may be important biological effectors themselves.
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•Hydrogen sulfide (H2S) is proposed to be an endogenously synthesized small-molecule signaling agent involved in a variety of physiological functions.•Many of the biological actions proposed for H2S may be due to the presence of other sulfur species such as per- and/or polysulfides.•Persulfides (RSSH) and related species have unique chemistry distinct from other biologically relevant sulfur species.•The biological utility of persulfides may be a result of their enhanced ability (compared to thiols) to serve as nucleophiles and reductants.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Nitrogen heterocycles play a vital role in pharmaceuticals and natural products, with the six‐membered aromatic and aliphatic architectures being commonly used. While synthetic methods for aromatic ...N‐heterocycles are well‐established, the synthesis of their aliphatic functionalized analogues, particularly piperidine derivatives, poses a significant challenge. In that regard, we propose a stepwise dearomative functionalization reaction for the construction of highly decorated piperidine derivatives with diverse functional handles. We also discuss challenges related to site‐selectivity, regio‐ and diastereoselectivity, and provide insights into the reaction mechanism through mechanistic studies and density functional theory computations.
The stepwise dearomative functionalization reaction of pyridines generates highly substituted piperidines, featuring diverse functional handles, with excellent site‐, regio‐, and diastereoselectivity. The origin of the unprecedented selectivities and additional insights into the reaction mechanism are discussed based on combined experimental mechanistic studies and density functional theory computations.
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Byproducts of chemical reactions are generally thought to result from the competition between two reaction pathways, each with its own rate-determining transition state structure. We show here, ...however, that pathways with a single transition state structure followed by a post-transition state bifurcation may also be a source of undesired products, especially those whose appearance is unexpected. The viability of this scenario for intramolecular C-H insertion reactions affording β-lactones
Rh-carbenoid intermediates is assessed through quantum chemical calculations on potential energy surfaces and quasi-classical molecular dynamics simulations. It appears that, in these cases, the rhodium catalyst is to blame for the accessibility of a second, unintended, pathway following the transition state structure for β-lactone formation that leads to fragmentation to a ketene and carbonyl compound. If an unexpected product is formed
a post-transition state bifurcation, conventional strategies for suppressing its formation are unlikely to succeed. Guidelines for recognizing the presence of a post-transition state bifurcation are described here, along with hints at means for controlling product distributions.
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