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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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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Sesterterpenoids are a relatively rare class of plant terpenes. Sesterterpene synthase (STS)‐mediated cyclization of the linear C25 isoprenoid precursor geranylfarnesyl diphosphate (GFPP) defines ...sesterterpene scaffolds. So far only a very limited number of STSs have been characterized. The discovery of three new plant STSs is reported that produce a suite of sesterterpenes with unprecedented 6/11/5 and 6/6/7/5 fused ring systems when transiently co‐expressed with a GFPP synthase in Nicotiana benthamiana. Structural elucidation, feeding experiments, and quantum chemical calculations suggest that these STSs catalyze an unusual cyclization path involving reprotonation, intramolecular 1,6 proton transfer, and concerted but asynchronous bicyclization events. The cyclization is diverted from those catalyzed by the characterized plant STSs by forming unified 15/5 bicyclic sesterterpene intermediates. Mutagenesis further revealed a conserved amino acid residue implicated in reprotonation.
Cyclizing to uncharted scaffolds: Terpene synthase (TPS)‐mediated cyclization defines the structures of terpene natural product scaffolds. Three diverged plant TPSs reroute carbocation cyclization towards formation of 6/11/5 and 6/6/7/5 scaffolds via de/re‐protonation, intramolecular proton transfer, and concerted but asynchronous double cyclization. A conserved amino acid residue implicated in reprotonation was identified.
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We describe the various escape channels available to dirhodium carbene intermediates from cycloheptatrienyl diazo compounds located with density functional theory. An intramolecular cyclopropanation ...would, in principle, provide a new route to semibullvalenes (SBVs). A detailed exploration of the potential energy surface reveals that methylating carbon-7 suppresses a competing β-hydride migration pathway to heptafulvene products, giving SBV formation a reasonable chance. During our explorations, we additionally discovered unusual spirononatriene, spironorcaradiene, and metal-stabilized 9-barbaralyl cation structures as local minima.
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The eunicellane diterpenoids are a unique family of natural products seen in marine organisms, plants, and bacteria. We used a series of biochemical, bioinformatics, and theoretical experiments to ...investigate the mechanism of the first diterpene synthase known to form the eunicellane skeleton. Deuterium labeling studies and quantum chemical calculations support that Bnd4, from Streptomyces sp. (CL12‐4), forms the 6,10‐bicyclic skeleton through a 1,10‐cyclization, 1,3‐hydride shift, and 1,14‐cyclization cascade. Bnd4 also demonstrated sesquiterpene cyclase activity and the ability to prenylate small molecules. Bnd4 possesses a unique D94NxxxD motif and mutation experiments confirmed an absolute requirement for D94 as well as E169.
Enzymatic and mechanistic characterization of Bnd4, a bacterial diterpene synthase and the first terpene synthase known to form the 6,10‐bicyclic eunicellane skeleton, is reported. Isotope labeling experiments and quantum chemical calculations support the cyclization mechanism for benditerpe‐2,6,15‐triene. An unusual DNxxxD motif was found to be essential for cyclization activity.
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"Soft theories,"
i.e.
, "heuristic models based on reasoning by analogy" largely drove chemistry understanding for 150 years or more. But soft theories have their limitations and with the expansion ...of chemistry in the mid-20
th
century, more and more inexplicable (by soft theory) experimental results were being obtained. In the past 50 years, quantum chemistry, most often in the guise of applied theoretical chemistry including computational chemistry, has provided (a) the underlying "hard evidence" for many soft theories and (b) the explanations for chemical phenomena that were unavailable by soft theories. In this publication, we define "hard theories" as "theories derived from quantum chemistry." Both soft and hard theories can be qualitative and quantitative, and the "Houk quadrant" is proposed as a helpful categorization tool. Furthermore, the language of soft theories is often used appropriately to describe quantum chemical results. A valid and useful way of doing science is the appropriate use and application of both soft and hard theories along with the best nomenclature available for successful communication of results and ideas.
"Soft theories" largely drove chemical understanding for 150 years or more. In the past 50 years, quantum chemistry has provided (a) the underlying "hard evidence" for many soft theories and (b) the explanations for chemical phenomena that are unavailable by soft theories.
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The 3s,5s‐sigmatropic shift is an example of an orbital‐symmetry forbidden pericyclic reaction that is outcompeted by the allowed 3s,3s‐sigmatropic shift. Density functional theory calculations are ...used to show that PdII‐complexed systems with strategically placed substituents engaging in key stereoelectronic effects can select for the 3s,5s process, thereby outcompeting both orbital‐symmetry‐allowed 3s,3s‐ and 3s,5a‐shifts.
The 3s,5s‐sigmatropic shift is a pericyclic reaction that is forbidden according to the Woodward–Hoffmann rules. Density functional theory calculations are used to show that systems utilizing transition‐state complexation to a metal catalyst and strategically placed substituents engaging in key stereoelectronic effects can select for the 3s,5s process and outcompete both allowed 3s,3s‐ and 3s,5a‐shifts.
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The template‐directed C−H insertion of α,β‐unsaturated esters into quinoline was interrogated by using computational quantum chemistry. An energetically viable mechanism for this complex multistep ...transformation was elucidated, with attention paid throughout to conformational flexibility and alternative ligand binding modes. The selectivity was found to correlate with distortion from a tetrahedral geometry for the carbon atom involved in C−H insertion, a parameter that can be applied to future template design.
Not so simple: Modern computational chemistry (DFT on reaction coordinates, extensive conformational searches, multiple means of treating entropy) has been used to probe the mechanism of a complex organometallic reaction – template‐directed C−H insertion of α,β‐unsaturated esters into quinoline – providing a deep dive into the origins of site selectivity and demonstrating that previous simple models are not sufficient.
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Herein, we report the first enantioselective synthesis of dichrocephones A and B, which are cytotoxic triquinane sesquiterpenes with a dense array of stereogenic centers within a strained polycyclic ...environment. Key features include the application of a catalytic asymmetric Wittig reaction, followed by stereoselective functionalization of the propellane core into a pentacyclic intermediate. Double reductive ring cleavage yielded the proposed structure of dichrocephone A. Mismatched spectroscopic data for our synthetic material compared to the natural isolate led us to revise the previously proposed configuration based on biosynthetic considerations and NMR calculations. Implementation of these findings culminated in the synthesis of dichrocephones A and B.
Cyclize and revise: Total synthesis of the densely functionalized dichrocephones A and B is described. Key features include a catalytic asymmetric Wittig reaction, followed by stereoselective functionalization of the propellane core into a pentacyclic intermediate. Mismatched spectroscopic data for the initial synthetic product compared to the natural isolate led to a revision of the previously proposed configuration.
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Fungal meroterpenoids are a diverse group of hybrid natural products with impressive structural complexity and high potential as drug candidates. In this work, we evaluate the promiscuity of the ...early structure diversity‐generating step in fungal meroterpenoid biosynthetic pathways: the multibond‐forming polyene cyclizations catalyzed by the yet poorly understood family of fungal meroterpenoid cyclases. In total, 12 unnatural meroterpenoids were accessed chemoenzymatically using synthetic substrates. Their complex structures were determined by 2D NMR studies as well as crystalline‐sponge‐based X‐ray diffraction analyses. The results obtained revealed a high degree of enzyme promiscuity and experimental results which together with quantum chemical calculations provided a deeper insight into the catalytic activity of this new family of non‐canonical, terpene cyclases. The knowledge obtained paves the way to design and engineer artificial pathways towards second generation meroterpenoids with valuable bioactivities based on combinatorial biosynthetic strategies.
Fungal meroterpenoid cyclases, a recently discovered family of membrane‐integrated terpene cyclases, have been exploited as tools for the synthesis of second generation meroterpenoid natural products. The results demonstrate a broad substrate tolerance leading to several new meroterpenoid scaffolds. DFT calculations provided insights into the mechanism of enzyme‐mediated polyene cyclizations.
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