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Dive into the research topics where Ashay Patel is active.

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Featured researches published by Ashay Patel.


Organic Letters | 2012

A torquoselective 6π electrocyclization approach to reserpine alkaloids.

Gregg A. Barcan; Ashay Patel; K. N. Houk; Ohyun Kwon

A highly torquoselective thermal triene 6π electrocyclization controls the relative stereochemistry between the C3 and C18 stereocenters of the dodecahydroindolo[2,3-a]benzo[g]quinolizine skeleton of reserpine-type alkaloids. Employing a tandem cross-coupling/electrocyclization protocol allowed us to form the requisite triene and ensure its subsequent cyclization. A novel low-temperature dibromoketene acetal Claisen rearrangement established the requisite exocyclic dienylbromide precursor for the palladium-catalyzed cross-coupling reaction.


Nature Chemical Biology | 2014

A carbonate-forming Baeyer-Villiger monooxygenase

Youcai Hu; David Dietrich; Wei Xu; Ashay Patel; Justin Thuss; Jingjing Wang; Wen-Bing Yin; Kangjian Qiao; K. N. Houk; John C. Vederas; Yi Tang

Despite the remarkable versatility displayed by flavin-dependent monooxygenases (FMOs) in natural product biosynthesis, one notably missing activity is the oxidative generation of carbonate functional groups. We describe a multifunctional Baeyer-Villiger monooxygenase CcsB, which catalyzes the formation of an in-line carbonate in the macrocyclic portion of cytochalasin E. This study expands the repertoire of activities of FMOs and provides a possible synthetic strategy for transformation of ketones into carbonates.


Journal of the American Chemical Society | 2015

Transannular [6 + 4] and Ambimodal Cycloaddition in the Biosynthesis of Heronamide A

Peiyuan Yu; Ashay Patel; K. N. Houk

The transannular [6 + 4] cycloaddition proposed as a step in the biosynthesis of heronamide A has been modeled using density functional theory. The proposed cycloaddition is highly stereoselective, affording a single product. The reaction proceeds through an ambimodal transition state that directly leads to a [4 + 2] adduct in addition to the observed [6 + 4] adduct. Interconversion of these adducts is possible via a facile Cope rearrangement. The [6 + 4] adduct is thermodynamically more stable than the [4 + 2] adduct by 5.2 kcal mol(-1) due to a combination of the ring and steric strain in the [4 + 2] product. The results strongly support the plausibility of the proposed transannular [6 + 4] cycloaddition in the biogenesis of heronamide A and may provide insights to designing substrates that selectively undergo [6 + 4] cycloaddition to form unbridged 10-membered rings.


Organic Letters | 2013

Stereoselective Synthesis of Dienyl-Carboxylate Building Blocks: Formal Synthesis of Inthomycin C

Caroline Souris; Frédéric Frébault; Ashay Patel; Davide Audisio; K. N. Houk; Nuno Maulide

A direct synthesis of stereodefined halodienes is reported. Those key building blocks enable a concise access to polyenic products, as demonstrated in a modular synthesis of Inthomycin C.


ChemBioChem | 2015

Involvement of Lipocalin-like CghA in Decalin-Forming Stereoselective Intramolecular [4+2] Cycloaddition.

Michio Sato; Fumitoshi Yagishita; Takashi Mino; Nahoko Uchiyama; Ashay Patel; Yit-Heng Chooi; Yukihiro Goda; Wei Xu; Hiroshi Noguchi; Tsuyoshi Yamamoto; Kinya Hotta; K. N. Houk; Yi Tang; Kenji Watanabe

Understanding enzymatic Diels–Alder (DA) reactions that can form complex natural product scaffolds is of considerable interest. Sch 210972 1, a potential anti‐HIV fungal natural product, contains a decalin core that is proposed to form through a DA reaction. We identified the gene cluster responsible for the biosynthesis of 1 and heterologously reconstituted the biosynthetic pathway in Aspergillus nidulans to characterize the enzymes involved. Most notably, deletion of cghA resulted in a loss of stereoselective decalin core formation, yielding both an endo (1) and a diastereomeric exo adduct of the proposed DA reaction. Complementation with cghA restored the sole formation of 1. Density functional theory computation of the proposed DA reaction provided a plausible explanation of the observed pattern of product formation. Based on our study, we propose that lipocalin‐like CghA is responsible for the stereoselective intramolecular [4+2] cycloaddition that forms the decalin core of 1.


Angewandte Chemie | 2015

Synthesis of ent‐Ketorfanol via a C–H Alkenylation/Torquoselective 6π Electrocyclization Cascade

Eric M. Phillips; Tehetena Mesganaw; Ashay Patel; Simon Duttwyler; Brandon Q. Mercado; K. N. Houk; Jonathan A. Ellman

The asymmetric synthesis of ent-ketorfanol from simple and commercially available precursors is reported. A Rh(I) -catalyzed intramolecular CH alkenylation/torquoselective 6π electrocyclization cascade provides a fused bicyclic 1,2-dihydropyridine as a key intermediate. Computational studies were performed to understand the high torquoselectivity of the key 6π electrocyclization. The computational results demonstrate that a conformational effect is responsible for the observed selectivity. The ketone functionality and final ring are introduced in a single step by a redox-neutral acid-catalyzed rearrangement of a vicinal diol to give the requisite carbonyl, followed by intramolecular Friedel-Crafts alkylation.


Journal of the American Chemical Society | 2017

Mechanisms and Origins of Periselectivity of the Ambimodal [6 + 4] Cycloadditions of Tropone to Dimethylfulvene

Peiyuan Yu; Tiffany Quantine Chen; Zhongyue Yang; Cyndi Qixin He; Ashay Patel; Yu-hong Lam; Ching-Yang Liu; K. N. Houk

The mechanisms and selectivities of the cycloadditions of tropone to dimethylfulvene have been investigated with M06-2X and B3LYP-D3 density functional theory (DFT) calculations and quasi-classical direct molecular dynamics simulations. The originally proposed reaction mechanism (Houk) involves a highly peri-, regio-, and stereoselective [6F + 4T] cycloaddition of tropone [4π] to dimethylfulvene [6π], followed by a [1,5] hydrogen shift, and, finally, a second [6 + 4] cycloaddition of tropone [6π] to the cyclopentadiene moiety [4π]. Paddon-Row and Warrener proposed an alternative mechanism: the initial cycloaddition involves a different [6T + 4F] cycloaddition in which fulvene acts as the 4π component, and a subsequent Cope rearrangement produces the formal [6F + 4T] adduct. Computations now demonstrate that the initial cycloaddition proceeds via an ambimodal transition state that can lead to both of the proposed [6 + 4] adducts. These adducts can interconvert through a [3,3] sigmatropic shift (Cope rearrangement). Molecular dynamics simulations reveal the initial distribution of products and provide insights into the time-resolved mechanism of this ambimodal cycloaddition. Competing [4 + 2] cycloadditions and various sigmatropic shifts are also explored.


Organic Letters | 2015

Highly torquoselective electrocyclizations and competing 1,7-hydrogen shifts of 1-azatrienes with silyl substitution at the allylic carbon.

Zhi-Xiong Ma; Ashay Patel; K. N. Houk; Richard P. Hsung

Highly torquoselective electrocyclizations of chiral 1-azatrienes are described. These 1-azatrienes contain an allylic stereocenter that is substituted with a silyl group and are derived in situ from condensation of γ-silyl-substituted enals with vinylogous amides. The ensuing stereoselective ring closures are part of a tandem sequence that constitutes an aza-[3 + 3] annulation method for constructing 1,2-dihydropyridines. Several mechanisms for the formal 1,7-hydrogen shift of these 1-azatrienes were evaluated computationally.


Journal of Organic Chemistry | 2014

Terminal Substituent Effects on the Reactivity, Thermodynamics, and Stereoselectivity of the 8π–6π Electrocyclization Cascades of 1,3,5,7-Tetraenes

Ashay Patel; K. N. Houk

M06-2X/6-31+G(d,p) computations are reported for the 8π–6π electrocyclization cascades of 1,3,5,7-tetraenes. The rate-determining step for these cascades is typically the second (6π) ring closure. According to experiment and theory, un- and monosubstituted tetraenes readily undergo 8π electrocyclic ring closure to form 1,3,5-cyclooctatrienes; however, the 6π electrocyclizations of these cyclooctatriene intermediates are slow and reversible, and mixtures of monocyclic and bicyclic products are formed. Computations indicate that di- and trisubstituted tetraenes undergo facile but less exergonic 8π electrocyclization due to a steric clash that destabilizes the 1,3,5-cyclooctatriene intermediates. Relief of this steric clash ensures the subsequent 6π ring closures of these intermediates are both kinetically facile and thermodynamically favorable, and only the bicyclic products are observed for the cascade reactions of naturally occurring tri- and tetrasubstituted tetraenes (in agreement with computations). The 6π electrocyclization step of these cascade electrocyclizations is also potentially diastereoselective, and di- and trisubstituted tetraenes often undergo cascade reactions with high diastereoselectivities. The exo mode of ring closure is favored for these 6π electrocyclizations due to a steric interaction that destabilizes the endo transition state. Thus, theory explains both the recalcitrance of the unsubstituted 1,3,5,7-octatetraene and 1-substituted tetraenes toward formation of the bicyclo[4.2.0]octa-2,4-diene products, as well as the ease and the stereoselectivity with which terminal di- and trisubstituted tetraenes are known to react biosynthetically.


Proceedings of the National Academy of Sciences of the United States of America | 2018

Influence of water and enzyme SpnF on the dynamics and energetics of the ambimodal [6+4]/[4+2] cycloaddition

Zhongyue Yang; Song Yang; Peiyuan Yu; Yanwei Li; Charles Doubleday; Jiyong Park; Ashay Patel; Byung-sun Jeon; William K. Russell; Hung Wen Liu; David H. Russell; K. N. Houk

Significance The investigation of time-resolved mechanisms of enzymatic reaction with accurate quantum-mechanics method is a holy grail of computational chemistry, and we now develop an efficient method, environment-perturbed transition-state sampling, to study single-molecule trajectories in enzymes and calculate activation barriers. In 2011, the Liu group published evidence for the first monofunctional Diels–Alderase, SpnF, in the biosynthetic pathway of Spinosyn A. We discovered later that the reaction bifurcates to the [4+2] and [6+4] adduct through a single ambimodal transition state. We now elucidate in detail the mechanism of the reaction and show how the SpnF enzyme dynamically controls product formation. Our method will find great application in the design of enzymes to control selectivity, particularly for reactions involving ambimodal transition states. SpnF is the first monofunctional Diels–Alder/[6+4]-ase that catalyzes a reaction leading to both Diels–Alder and [6+4] adducts through a single transition state. The environment-perturbed transition-state sampling method has been developed to calculate free energies, kinetic isotope effects, and quasi-classical reaction trajectories of enzyme-catalyzed reactions and the uncatalyzed reaction in water. Energetics calculated in this way reproduce the experiment and show that the normal Diels–Alder transition state is stabilized by H bonds with water molecules, while the ambimodal transition state is favored in the enzyme SpnF by both intramolecular hydrogen bonding and hydrophobic binding. Molecular dynamics simulations show that trajectories passing through the ambimodal transition state bifurcate to the [6+4] adduct and the Diels–Alder adduct with a ratio of 1:1 in the gas phase, 1:1.6 in water, and 1:11 in the enzyme. This example shows how an enzyme acts on a vibrational time scale to steer post-transition state trajectories toward the Diels–Alder adduct.

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K. N. Houk

University of California

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Peiyuan Yu

University of California

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Wei Xu

University of California

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Yi Tang

University of California

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Zhongyue Yang

University of California

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Cyndi Qixin He

University of California

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Hung Wen Liu

University of Texas at Austin

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Ohyun Kwon

University of California

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Richard P. Hsung

University of Wisconsin-Madison

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Zhi-Xiong Ma

University of Wisconsin-Madison

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