Using state-of-the-art density functional theory, we have determined whether these reactions are feasible biosynthetic transformations, elucidated the mechanistic subtleties of these reactions, and proposed how enzymes may catalyze such transformations. Chapter 1 describes a computational study of a strained biosynthetic transannular 1,3-dipolar cycloaddition. Computations reveal that substrate preorganization overrides distortion in the transitions, resulting in a reaction is feasible. Strategic hydrogen bonding, according to theory, can accelerate the reaction by fold.
Chapter 2 summarizes a computational investigation of the Diels-Alder reaction involved in the biosynthesis of spinosyn A. Chapter 3 discusses an ongoing collaboration with the Tang laboratory at UCLA and involves an effort to understand the intramolecular Diels-Alder reaction involved in the biosynthesis of cholesterol-reducing agent, lovastatin.
We have modeled the reaction of a related cycloaddition performed experimentally, and computations recapitulate the selectivity observed experimentally for this nonenzymatic process.
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The stereochemical outcome of the enzymatic reaction diverges from the outcome of its synthetic analogue. Computation of the reactive conformer of the model substrate suggests that substrate preorganization could accelerate the intramolecular Diels-Alder reaction by approximately a fold. Theoretical studies of stereoselective electrocyclic reactions are described in Chapters 4, 5, 6, 7, and 8.
These reactions have been examined by experimentally by chemists in the laboratory and, subsequently, have been modeled using quantum mechanical computations.
From this computational work, we have determined the stereoselectivity of several synthetically relevant electrocyclic reactions, the effect of substituents of the reactivity of the electrocyclization precursors. In Chapter 4, we summarize our work with Dr.
Gregg Barcan and Prof. Ohyun Kwon to elucidate the origins of 1,6-stereoinduction of a triene electrocyclization employed in their total synthesis of reserpine. Allylic strain destabilizes the disfavored mode of ring closure. According to both theory and experiment, stereoselectivity is shown to be sensitive to the size of the substituent involved in the A1,3 strain. Van De Water, R. Tetrahedron 58 , — Snider, B. Li, L. Biochemical characterization of a eukaryotic decalin-forming Diels—Alderase.
Halo, L. Late stage oxidations during the biosynthesis of the 2-pyridone tenellin in the entomopathogenic fungus Beauveria bassiana. Jansson, A. Aclacinomycin hydroxylase is a novel substrate-assisted hydroxylase requiring S -adenosyl-L-methionine as cofactor. Jiang, C. Iwig, D.
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Insight into the polar reactivity of the onium chalcogen analogues of S -adenosyl-L-methionine. Biochemistry 43 , — Coward, J. Analogs of S -adenosylhomocysteine as potential inhibitors of biological transmethylation. Specificity of the S -adenosylhomocysteine binding site. Bauer, N. Purification, characterization, and kinetic mechanism of S -adenosyl-L-methionine:macrocin O -methyltransferase from Streptomyces fradiae.
Patel, A. Ess, D. Bifurcations on potential energy surfaces of organic reactions. Hong, Y.
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Biosynthetic consequences of multiple sequential post-transition-state bifurcations. Xu, W. Analysis of intact and dissected fungal polyketide synthase-nonribosomal peptide synthetase in vitro and in Saccharomyces cerevisiae. Frisch, M. Gaussian 09 Rev. Download references. All authors analysed and discussed the results.
SAM-dependent enzyme-catalysed pericyclic reactions in natural product biosynthesis | Nature
Correspondence to Kenji Watanabe or K. Houk or Yi Tang. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. To obtain permission to re-use content from this article visit RightsLink. Marine Drugs Natural Product Reports Sensors and Actuators B: Chemical Nature Chemistry The cyclobutene-1,3-butadiene interconversion proceeds much less readily, even in the thermodynamically favorable direction of ring opening.
However, substituted dienes and cyclobutenes often react more rapidly. A striking feature of thermal electrocyclic reactions that proceed by concerted mechanisms is their high degree of stereospecificity. Thus when cis -3,4-dimethylcyclobutene is heated, it affords only one of the three possible cis-trans isomers of 2,4-hexadiene, namely, cis , trans -2,4-hexadiene:. You will notice that with this particular case, if conrotation occurs to the left, rather than the right, the same final product results:.
When a cyclobutene is so constituted that conrotation cannot occur for steric reasons, then the concerted reaction cannot occur easily. Substances that otherwise might be predicted to be highly unstable often turn out to be relatively stable. An example is bicyclo[2.
This rearrangement does occur, but not so fast as to preclude isolation of the substance:. How can we explain the fact that this substance can be isolated? The explanation is that, if the reaction has to be conrotatory, then the product will not be ordinary 1,3-cyclopentadiene, but cis , trans -1,3-cyclopentadiene - surely a very highly strained substance. Try to make a ball-and-stick model of it! This means that the concerted mechanism is not favorable:.
For example,. In this case, the disrotation of the groups toward one another would lead to the cis,cis,cis product. Because this product is not formed, it seems likely that rotation of the methyl groups toward each other must be sterically unfavorable:. How can we account for the stereoselectivity of thermal electrocyclic reactions? Let us see why this is so. Consider the electrocyclic interconversion of a 1,3-diene and a cyclobutene. The three principal types of pericyclic reactions are cycloaddition , electrocyclic rearrangement , and sigmatropic rearrangement :.
The factors that control if and how these cyclization and rearrangement reactions occur in a concerted manner can be understood from the aromaticity or lack of aromaticity achieved in their cyclic transition states. We summarize here a procedure to predict the feasibility and the stereochemistry of thermally concerted reactions involving cyclic transition states.
The 1,2 rearrangement of carbocations will be used to illustrate the approach. This is a very important reaction of carbocations which we have discussed in other chapters.