70 results on '"Houk, Kendall N."'
Search Results
2. Unusual Enantiodivergence in Chiral Brønsted Acid‐Catalyzed Asymmetric Allylation with β‐Alkenyl Allylic Boronates
- Author
-
Gao, Shang, Duan, Meng, Andreola, Laura R, Yu, Peiyuan, Wheeler, Steven E, Houk, Kendall N, and Chen, Ming
- Subjects
Alcohols ,Aldehydes ,Catalysis ,Stereoisomerism ,Boronates ,C-H center dot center dot center dot pi Interactions ,Chiral Phosphoric Acids ,Enantiodivergence ,Organocatalysis ,C−H⋅⋅⋅π Interactions ,Chemical Sciences ,Organic Chemistry - Abstract
We report herein a rare example of enantiodivergent aldehyde addition with β-alkenyl allylic boronates via chiral Brønsted acid catalysis. 2,6-Di-9-anthracenyl-substituted chiral phosphoric acid-catalyzed asymmetric allylation using β-vinyl substituted allylic boronate gave alcohols with R absolute configuration. The sense of asymmetric induction of the catalyst in these reactions is opposite to those in prior reports. Moreover, in the presence of the same acid catalyst, the reactions with β-2-propenyl substituted allylic boronate generated homoallylic alcohol products with S absolute configuration. Unusual substrate-catalyst C-H⋅⋅⋅π interactions in the favoured reaction transition state were identified as the origins of observed enantiodivergence through DFT computational studies.
- Published
- 2022
3. Bioinspired Asymmetric Total Synthesis of Emeriones A–C**
- Author
-
Jänner, Sven, Isak, Daniel, Li, Yuli, Houk, Kendall N, and Miller, Aubry K
- Subjects
Cyclization ,Oxidation-Reduction ,Stereoisomerism ,Biomimetic Synthesis ,Cascade Reactions ,Electrocyclizations ,Polyketides ,Total Synthesis ,Chemical Sciences ,Organic Chemistry - Abstract
We report asymmetric bioinspired total syntheses of the fungal metabolites emeriones A-C via stereoselective oxidations of two bicyclo[4.2.0]octadiene diastereomers. The central bicyclic scaffolds are prepared in an 8π/6π electrocyclization cascade of a stereodefined pentaene, which contains the fully assembled side chains of the emeriones. The anti-aldol side chain is made using a Paterson-aldol addition, and the epoxide of the dioxabicyclo[3.1.0]hexane side chain via ring-closure onto an oxidized acetal. Our work has enabled the structural revision of emerione C, and resulted in the synthesis of a "missing" family member, which we call emerione D. DFT calculations identified two methyl groups that govern torquoselectivity in the 8π/6π cascade.
- Published
- 2022
4. Electrochemical Fluorination of Vinyl Boronates through Donor‐Stabilized Vinyl Carbocation Intermediates**
- Author
-
Wigman, Benjamin, Lee, Woojin, Wei, Wenjing, Houk, Kendall N, and Nelson, Hosea M
- Subjects
Alkenyl Boronates ,Electrochemistry ,Fluorination ,Vinyl Carbocations ,Vinyl Fluorides ,Chemical Sciences ,Organic Chemistry - Abstract
The electrochemical generation of vinyl carbocations from alkenyl boronic esters and boronates is reported. Using easy-to-handle nucleophilic fluoride reagents, these intermediates are trapped to form fully substituted vinyl fluorides. Mechanistic studies support the formation of dicoordinated carbocations through sequential single-electron oxidation events. Notably, this electrochemical fluorination features fast reaction times and Lewis acid-free conditions. This transformation provides a complementary method to access vinyl fluorides with simple fluoride salts such as TBAF.
- Published
- 2022
5. Chiral Phosphoric Acid Catalyzed Conversion of Epoxides into Thiiranes: Mechanism, Stereochemical Model, and New Catalyst Design
- Author
-
Duan, Meng, Díaz‐Oviedo, Christian David, Zhou, Yang, Chen, Xiangyang, Yu, Peiyuan, List, Benjamin, Houk, Kendall N, and Lan, Yu
- Subjects
Catalyst Design ,Chiral Phosphoric Acids ,DFT Calculations ,Organocatalysis ,Stereochemical Model ,Chemical Sciences ,Organic Chemistry - Abstract
Computations and experiments leading to new chiral phosphoric acids (CPAs) for epoxide thionations are reported. Density functional theory calculations reveal the mechanism and origin of the enantioselectivity of such CPA-catalyzed epoxide thionations. The calculated mechanistic information was used to design new efficient CPAs that were tested experimentally and found to be highly effective. Bulky ortho-substituents on the 3,3'-aryl groups of the CPA are important to restrict the position of the epoxide in the key transition states for the enantioselectivity-determining step. Larger para-substituents significantly improve the enantioselectivity of the reaction.
- Published
- 2022
6. Systematic Variation of Both the Aromatic Cage and Dialkyllysine via GCE-SAR Reveal Mechanistic Insights in CBX5 Reader Protein Binding
- Author
-
Kean, Kelsey M, Baril, Stefanie A, Lamb, Kelsey N, Dishman, Sarah N, Treacy, Joseph W, Houk, Kendall N, Brustad, Eric M, James, Lindsey I, and Waters, Marcey L
- Subjects
Medicinal and Biomolecular Chemistry ,Chemical Sciences ,Generic health relevance ,Chromobox Protein Homolog 5 ,Genetic Code ,Humans ,Ligands ,Lysine ,Molecular Structure ,Mutagenesis ,Site-Directed ,Peptidomimetics ,Protein Binding ,Static Electricity ,Structure-Activity Relationship ,Organic Chemistry ,Pharmacology and Pharmaceutical Sciences ,Medicinal & Biomolecular Chemistry ,Pharmacology and pharmaceutical sciences ,Medicinal and biomolecular chemistry ,Organic chemistry - Abstract
Development of inhibitors for histone methyllysine reader proteins is an active area of research due to the importance of reader protein-methyllysine interactions in transcriptional regulation and disease. Optimized peptide-based chemical probes targeting methyllysine readers favor larger alkyllysine residues in place of methyllysine. However, the mechanism by which these larger substituents drive tighter binding is not well understood. This study describes the development of a two-pronged approach combining genetic code expansion (GCE) and structure-activity relationships (SAR) through systematic variation of both the aromatic binding pocket in the protein and the alkyllysine residues in the peptide to probe inhibitor recognition in the CBX5 chromodomain. We demonstrate a novel change in driving force for larger alkyllysines, which weaken cation-π interactions but increases dispersion forces, resulting in tighter binding. This GCE-SAR approach establishes discrete energetic contributions to binding from both ligand and protein, providing a powerful tool to gain mechanistic understanding of SAR trends.
- Published
- 2022
7. Tunable Amine‐Reactive Electrophiles for Selective Profiling of Lysine
- Author
-
Tang, Kuei‐Chien, Cao, Jian, Boatner, Lisa M, Li, Linwei, Farhi, Jonathan, Houk, Kendall N, Spangle, Jennifer, Backus, Keriann M, and Raj, Monika
- Subjects
Cancer ,Lysine ,bioconjugation ,chemoselective ,mass sensitivity boosters ,protein labeling ,traceless ,Chemical Sciences ,Organic Chemistry - Abstract
Proteome profiling by activated esters identified >9000 ligandable lysines but they are limited as covalent inhibitors due to poor hydrolytic stability. Here we report our efforts to design and discover a new series of tunable amine-reactive electrophiles (TAREs) for selective and robust labeling of lysine. The major challenges in developing selective probes for lysine are the high nucleophilicity of cysteines and poor hydrolytic stability. Our work circumvents these challenges by a unique design of the TAREs that form stable adducts with lysine and on reaction with cysteine generate another reactive electrophiles for lysine. We highlight that TAREs exhibit substantially high hydrolytic stability as compared to the activated esters and are non-cytotoxic thus have the potential to act as covalent ligands. We applied these alternative TAREs for the intracellular labeling of proteins in different cell lines, and for the selective identification of lysines in the human proteome on a global scale.
- Published
- 2022
8. A Diazo-Hooker Reaction, Inspired by the Biosynthesis of Azamerone
- Author
-
Yahiaoui, Oussama, Murray, Lauren AM, Zhao, Fengyue, Moore, Bradley S, Houk, Kendall N, Liu, Fang, and George, Jonathan H
- Subjects
Organic Chemistry ,Chemical Sciences ,Terpenes ,Chemical sciences - Abstract
Motivated by the biosynthesis of azamerone, we report the first example of a diazo-Hooker reaction, which involves the formation of a phthalazine ring system by the oxidative rearrangement of a diazoketone. Computational studies indicate that the diazo-Hooker reaction proceeds via an 8π-electrocyclization followed by ring contraction and aromatization. The biosynthetic origin of the diazoketone functional group was also chemically mimicked using a related natural product, naphterpin, as a model system.
- Published
- 2022
9. Stereodivergent Attached‐Ring Synthesis via Non‐Covalent Interactions: A Short Formal Synthesis of Merrilactone A
- Author
-
Huffman, Benjamin J, Chu, Tiffany, Hanaki, Yusuke, Wong, Jonathan J, Chen, Shuming, Houk, Kendall N, and Shenvi, Ryan A
- Subjects
Cyclization ,Lactones ,Molecular Structure ,Sesquiterpenes ,Stereoisomerism ,attached-ring ,diastereoselectivity ,Michael addition ,natural products ,synthesis design ,Chemical Sciences ,Organic Chemistry - Abstract
A strategy to control the diastereoselectivity of bond formation at a prochiral attached-ring bridgehead is reported. An unusual stereodivergent Michael reaction relies on basic vs. Lewis acidic conditions and non-covalent interactions to control re- vs. si- facial selectivity en route to fully substituted attached-rings. This divergency reflects differential engagement of one rotational isomer of the attached-ring system. The successful synthesis of an erythro subtarget diastereomer ultimately leads to a short formal synthesis of merrilactone A.
- Published
- 2022
10. Selective skeletal editing of polycyclic arenes using organophotoredox dearomative functionalization
- Author
-
Ji, Peng, Davies, Cassondra C, Gao, Feng, Chen, Jing, Meng, Xiang, Houk, Kendall N, Chen, Shuming, and Wang, Wei
- Subjects
Inorganic Chemistry ,Organic Chemistry ,Chemical Sciences ,Anthracenes ,Isoquinolines ,Naphthalenes ,Oxidation-Reduction ,Phenanthrenes - Abstract
Reactions that lead to destruction of aromatic ring systems often require harsh conditions and, thus, take place with poor selectivities. Selective partial dearomatization of fused arenes is even more challenging but can be a strategic approach to creating versatile, complex polycyclic frameworks. Herein we describe a general organophotoredox approach for the chemo- and regioselective dearomatization of structurally diverse polycyclic aromatics, including quinolines, isoquinolines, quinoxalines, naphthalenes, anthracenes and phenanthrenes. The success of the method for chemoselective oxidative rupture of aromatic moieties relies on precise manipulation of the electronic nature of the fused polycyclic arenes. Mechanistic studies show that the addition of a hydrogen atom transfer (HAT) agent helps favor the dearomatization pathway over the more thermodynamically downhill aromatization pathway. We show that this strategy can be applied to rapid synthesis of biologically valued targets and late-stage skeletal remodeling en route to complex structures.
- Published
- 2022
11. Performance-limiting formation dynamics in mixed-halide perovskites
- Author
-
Huang, Tianyi, Tan, Shaun, Nuryyeva, Selbi, Yavuz, Ilhan, Babbe, Finn, Zhao, Yepin, Abdelsamie, Maged, Weber, Marc H, Wang, Rui, Houk, Kendall N, Sutter-Fella, Carolin M, and Yang, Yang
- Subjects
Macromolecular and Materials Chemistry ,Chemical Sciences ,Physical Chemistry - Abstract
Wide-bandgap (WBG) mixed-halide perovskites as the front cell absorber are accomplishing perovskite-based tandem solar cells with over 29% power conversion efficiency. However, their large voltage deficits limit their ultimate performance. Only a handful of studies probe the fundamental mechanisms underlying the voltage deficits, which remain an unsolved challenge in the field. In this study, we investigate the formation dynamics and defect physics of WBG mixed-halide perovskites in contrast with their corresponding triiodide-based perovskites. Our results show that the inclusion of bromide introduced a halide homogenization process that occurs during the perovskite growth stage from an initial bromide-rich phase toward the final target stoichiometry. We further elucidated a physical model that correlates the role of bromide with the formation dynamics, defect physics, and eventual optoelectronic properties of the film. This work provides a fundamental and unique perspective toward understanding the performance-limiting factors affecting WBG mixed-halide perovskites.
- Published
- 2021
12. Cycloaddition Cascades of Strained Alkynes and Oxadiazinones
- Author
-
Ramirez, Melissa, Darzi, Evan R, Donaldson, Joyann S, Houk, Kendall N, and Garg, Neil K
- Subjects
Organic Chemistry ,Chemical Sciences ,Theoretical and Computational Chemistry ,arynes ,cyclic alkynes ,cycloadditions ,density functional theory ,polycyclic aromatic hydrocarbons ,Chemical sciences - Abstract
We report a computational and experimental study of the reaction of oxadiazinones and strained alkynes to give polycyclic aromatic hydrocarbons (PAHs). The reaction proceeds by way of a pericyclic reaction cascade and leads to the formation of four new carbon-carbon bonds. Using M06-2X DFT calculations, we interrogate several mechanistic aspects of the reaction, such as why the use of non-aromatic strained alkynes can be used to access unsymmetrical PAHs, whereas the use of arynes in the methodology leads to symmetrical PAHs. In addition, experimental studies enable the rapid synthesis of new PAHs, including tetracene and pentacene scaffolds. These studies not only provide fundamental insight regarding the aforementioned cycloaddition cascades and synthetic access to PAH scaffolds, but are also expected to enable the synthesis of new materials.
- Published
- 2021
13. Origins of Endo Selectivity in Diels–Alder Reactions of Cyclic Allene Dienophiles
- Author
-
Ramirez, Melissa, Svatunek, Dennis, Liu, Fang, Garg, Neil K, and Houk, Kendall N
- Subjects
Cycloaddition Reaction ,Cyclohexenes ,Molecular Structure ,Stereoisomerism ,cyclic allenes ,cycloadditions ,density functional theory ,diastereoselectivity ,substituent effects ,Chemical Sciences ,Organic Chemistry - Abstract
Strained cyclic allenes, first discovered in 1966 by Wittig and co-workers, have recently emerged as valuable synthetic building blocks. Previous experimental investigations, and computations reported here, demonstrate that the Diels-Alder reactions of furans and pyrroles with 1,2-cyclohexadiene and oxa- and azaheterocyclic analogs proceed with endo selectivity. This endo selectivity gives the adduct with the allylic saturated carbon of the cyclic allene endo to the diene carbons. The selectivity is very general and useful in synthetic applications. Our computational study establishes the origins of this endo selectivity. We analyze the helical frontier molecular orbitals of strained cyclic allenes and show how secondary orbital and electrostatic effects influence stereoselectivity. The LUMO of carbon-3 of the allene (C-3 is not involved in primary orbital interactions) interacts in a stabilizing fashion with the HOMO of the diene in such a way that the carbon of the cyclic allene attached to C-1 favors the endo position in the transition state. The furan LUMO, allene HOMO interaction reinforces this preference. These mechanistic studies are expected to prompt the further use of long-avoided strained cyclic allenes in chemical synthesis.
- Published
- 2021
14. Library construction of stereochemically diverse isomers of spirooliganin: their total synthesis and antiviral activity
- Author
-
Wang, Ru-Bing, Ma, Shuang-Gang, Jamieson, Cooper S, Gao, Rong-Mei, Liu, Yun-Bao, Li, Yong, Wang, Xiao-Jing, Li, Yu-Huan, Houk, Kendall N, Qu, Jing, and Yu, Shi-Shan
- Subjects
Chemical Sciences - Abstract
The construction of libraries of stereoisomers of natural products serves as an important approach to investigating the correlation between the stereostructure and biological activity. However, the total synthesis and isomerzation of polycyclic scaffolds with multiple chrial centers are rare. Spirooliganin (1), a new skeleton natural product isolated from the plant Illicium oligandrum, was structurally characterized by comprehensive analysis of NMR spectroscopic data and ECD which revealed an unprecedented 5-6-6-6-7 polycyclic framework with six chiral centers. Here we report a 17-step total synthesis to prepare a library of stereochemically diverse isomers of spirooliganin, including 16 diastereoisomers and 16 regioisomers. In addition to a regioselective hetero-Diels-Alder cycloaddition, the synthetic strategy involves a photo-induced stereoselective Diels-Alder reaction, which gives only the abnormal trans-fused product as rationalized by density functional theory calculations. Preliminary biological evaluation showed that spirooliganin and regioisomers 39 exhibited potent inhibition of Coxsackievirus B3. It also revealed the pharmacophore effect of the D-ring (16R,18R,24R, and 26R) for their antiviral activities.
- Published
- 2021
15. Biosynthesis of para-Cyclophane-Containing Hirsutellone Family of Fungal Natural Products
- Author
-
Ohashi, Masao, Kakule, Thomas B, Tang, Man-Cheng, Jamieson, Cooper S, Liu, Mengting, Zhao, Yi-Lei, Houk, Kendall N, and Tang, Yi
- Subjects
Acremonium ,Biological Products ,Bridged-Ring Compounds ,Catalysis ,Cycloaddition Reaction ,Fungi ,Heterocyclic Compounds ,4 or More Rings ,Hypocreales ,Molecular Conformation ,Oxidation-Reduction ,Oxidoreductases ,Pyrrolidinones ,Stereoisomerism ,Chemical Sciences ,General Chemistry - Abstract
Hirsutellones are fungal natural products containing a macrocyclic para-cyclophane connected to a decahydrofluorene ring system. We have elucidated the biosynthetic pathway for pyrrocidine B (3) and GKK1032 A2 (4). Two small hypothetical proteins, an oxidoreductase and a lipocalin-like protein, function cooperatively in the oxidative cyclization of the cyclophane, while an additional hypothetical protein in the pyrrocidine pathway catalyzes the exo-specific cycloaddition to form the cis-fused decahydrofluorene.
- Published
- 2021
16. Computational Exploration of Ambiphilic Reactivity of Azides and Sustmann’s Paradigmatic Parabola
- Author
-
Chen, Pan-Pan, Ma, Pengchen, He, Xue, Svatunek, Dennis, Liu, Fang, and Houk, Kendall N
- Subjects
Azides ,Cycloaddition Reaction ,Physical Phenomena ,Static Electricity ,Medicinal and Biomolecular Chemistry ,Organic Chemistry - Abstract
We examine the theoretical underpinnings of the seminal discoveries by Reiner Sustmann about the ambiphilic nature of Huisgen's phenyl azide cycloadditions. Density functional calculations with ωB97X-D and B2PLYP-D3 reproduce the experimental data and provide insights into ambiphilic control of reactivity. Distortion/interaction-activation strain and energy decomposition analyses show why Sustmann's use of dipolarophile ionization potential is such a powerful predictor of reactivity. We add to Sustmann's data set several modern distortion-accelerated dipolarophiles used in bioorthogonal chemistry to show how these fit into the orbital energy criteria that are often used to understand cycloaddition reactivity. We show why such a simple indicator of reactivity is a powerful predictor of reaction rates that are actually controlled by a combination of distortion energies, charge transfer, closed-shell repulsion, polarization, and electrostatic effects.
- Published
- 2021
17. Library construction of stereochemically diverse isomers of spirooliganin: their total synthesis and antiviral activity.
- Author
-
Wang, Ru-Bing, Ma, Shuang-Gang, Jamieson, Cooper S, Gao, Rong-Mei, Liu, Yun-Bao, Li, Yong, Wang, Xiao-Jing, Li, Yu-Huan, Houk, Kendall N, Qu, Jing, and Yu, Shi-Shan
- Subjects
Chemical Sciences - Abstract
The construction of libraries of stereoisomers of natural products serves as an important approach to investigating the correlation between the stereostructure and biological activity. However, the total synthesis and isomerzation of polycyclic scaffolds with multiple chrial centers are rare. Spirooliganin (1), a new skeleton natural product isolated from the plant Illicium oligandrum, was structurally characterized by comprehensive analysis of NMR spectroscopic data and ECD which revealed an unprecedented 5-6-6-6-7 polycyclic framework with six chiral centers. Here we report a 17-step total synthesis to prepare a library of stereochemically diverse isomers of spirooliganin, including 16 diastereoisomers and 16 regioisomers. In addition to a regioselective hetero-Diels-Alder cycloaddition, the synthetic strategy involves a photo-induced stereoselective Diels-Alder reaction, which gives only the abnormal trans-fused product as rationalized by density functional theory calculations. Preliminary biological evaluation showed that spirooliganin and regioisomers 39 exhibited potent inhibition of Coxsackievirus B3. It also revealed the pharmacophore effect of the D-ring (16R,18R,24R, and 26R) for their antiviral activities.
- Published
- 2021
18. Fungal Dioxygenase AsqJ Is Promiscuous and Bimodal: Substrate‐Directed Formation of Quinolones versus Quinazolinones
- Author
-
Einsiedler, Manuel, Jamieson, Cooper S, Maskeri, Mark A, Houk, Kendall N, and Gulder, Tobias AM
- Subjects
Organic Chemistry ,Chemical Sciences ,Aspergillus nidulans ,Biocatalysis ,Dioxygenases ,Molecular Structure ,Quinazolinones ,Quinolones ,biocatalysis ,biosynthesis ,enzyme mechanism ,Fe-II/alpha-ketoglutarate dependent dioxygenases ,natural products ,FeII/α-ketoglutarate dependent dioxygenases ,Chemical sciences - Abstract
Previous studies showed that the FeII /α-ketoglutarate dependent dioxygenase AsqJ induces a skeletal rearrangement in viridicatin biosynthesis in Aspergillus nidulans, generating a quinolone scaffold from benzo[1,4]diazepine-2,5-dione substrates. We report that AsqJ catalyzes an additional, entirely different reaction, simply by a change in substituent in the benzodiazepinedione substrate. This new mechanism is established by substrate screening, application of functional probes, and computational analysis. AsqJ excises H2 CO from the heterocyclic ring structure of suitable benzo[1,4]diazepine-2,5-dione substrates to generate quinazolinones. This novel AsqJ catalysis pathway is governed by a single substituent within the complex substrate. This unique substrate-directed reactivity of AsqJ enables the targeted biocatalytic generation of either quinolones or quinazolinones, two alkaloid frameworks of exceptional biomedical relevance.
- Published
- 2021
19. Fungal Dioxygenase AsqJ Is Promiscuous and Bimodal: Substrate-Directed Formation of Quinolones versus Quinazolinones.
- Author
-
Einsiedler, Manuel, Jamieson, Cooper S, Maskeri, Mark A, Houk, Kendall N, and Gulder, Tobias AM
- Subjects
FeII/α-ketoglutarate dependent dioxygenases ,biocatalysis ,biosynthesis ,enzyme mechanism ,natural products ,Fe-II/alpha-ketoglutarate dependent dioxygenases ,Organic Chemistry ,Chemical Sciences - Abstract
Previous studies showed that the FeII /α-ketoglutarate dependent dioxygenase AsqJ induces a skeletal rearrangement in viridicatin biosynthesis in Aspergillus nidulans, generating a quinolone scaffold from benzo[1,4]diazepine-2,5-dione substrates. We report that AsqJ catalyzes an additional, entirely different reaction, simply by a change in substituent in the benzodiazepinedione substrate. This new mechanism is established by substrate screening, application of functional probes, and computational analysis. AsqJ excises H2 CO from the heterocyclic ring structure of suitable benzo[1,4]diazepine-2,5-dione substrates to generate quinazolinones. This novel AsqJ catalysis pathway is governed by a single substituent within the complex substrate. This unique substrate-directed reactivity of AsqJ enables the targeted biocatalytic generation of either quinolones or quinazolinones, two alkaloid frameworks of exceptional biomedical relevance.
- Published
- 2021
20. Computational Exploration of Ambiphilic Reactivity of Azides and Sustmann's Paradigmatic Parabola.
- Author
-
Chen, Pan-Pan, Ma, Pengchen, He, Xue, Svatunek, Dennis, Liu, Fang, and Houk, Kendall N
- Subjects
Medicinal and Biomolecular Chemistry ,Organic Chemistry - Abstract
We examine the theoretical underpinnings of the seminal discoveries by Reiner Sustmann about the ambiphilic nature of Huisgen's phenyl azide cycloadditions. Density functional calculations with ωB97X-D and B2PLYP-D3 reproduce the experimental data and provide insights into ambiphilic control of reactivity. Distortion/interaction-activation strain and energy decomposition analyses show why Sustmann's use of dipolarophile ionization potential is such a powerful predictor of reactivity. We add to Sustmann's data set several modern distortion-accelerated dipolarophiles used in bioorthogonal chemistry to show how these fit into the orbital energy criteria that are often used to understand cycloaddition reactivity. We show why such a simple indicator of reactivity is a powerful predictor of reaction rates that are actually controlled by a combination of distortion energies, charge transfer, closed-shell repulsion, polarization, and electrostatic effects.
- Published
- 2021
21. Photochemical intermolecular dearomative cycloaddition of bicyclic azaarenes with alkenes
- Author
-
Ma, Jiajia, Chen, Shuming, Bellotti, Peter, Guo, Renyu, Schäfer, Felix, Heusler, Arne, Zhang, Xiaolong, Daniliuc, Constantin, Brown, M Kevin, Houk, Kendall N, and Glorius, Frank
- Subjects
Alkenes ,Catalysis ,Cycloaddition Reaction ,Energy Transfer ,Hydrocarbons ,Aromatic ,Molecular Structure ,Quinolines ,Stereoisomerism ,General Science & Technology - Abstract
Dearomative cycloaddition reactions represent an ideal means of converting flat arenes into three-dimensional architectures of increasing interest in medicinal chemistry. Quinolines, isoquinolines, and quinazolines, despite containing latent diene and alkene subunits, are scarcely applied in cycloaddition reactions because of the inherent low reactivity of aromatic systems and selectivity challenges. Here, we disclose an energy transfer-mediated, highly regio- and diastereoselective intermolecular [4 + 2] dearomative cycloaddition reaction of these bicyclic azaarenes with a plethora of electronically diverse alkenes. This approach bypasses the general reactivity and selectivity issues, thereby providing various bridged polycycles that previously have been inaccessible or required elaborate synthetic efforts. Computational studies with density functional theory elucidate the mechanism and origins of the observed regio- and diastereoselectivities.
- Published
- 2021
22. How the Lewis Base F– Catalyzes the 1,3-Dipolar Cycloaddition between Carbon Dioxide and Nitrilimines
- Author
-
Svatunek, Dennis, Hansen, Thomas, Houk, Kendall N, and Hamlin, Trevor A
- Subjects
Chemical Sciences ,Theoretical and Computational Chemistry ,Medicinal and Biomolecular Chemistry ,Organic Chemistry ,Medicinal and biomolecular chemistry ,Organic chemistry - Abstract
The mechanism of the Lewis base F- catalyzed 1,3-dipolar cycloaddition between CO2 and nitrilimines is interrogated using DFT calculations. F- activates the nitrilimine, not CO2 as proposed in the literature, and imparts a significant rate enhancement for the cycloaddition. The origin of this catalysis is in the strength of the primary orbital interactions between the reactants. The Lewis base activated nitrilimine-F- has high-lying filled FMOs. The smaller FMO-LUMO gap promotes a rapid nucleophilic attack and overall cycloaddition with CO2.
- Published
- 2021
23. Catalytic mechanism and endo-to-exo selectivity reversion of an octalin-forming natural Diels–Alderase
- Author
-
Sato, Michio, Kishimoto, Shinji, Yokoyama, Mamoru, Jamieson, Cooper S, Narita, Kazuto, Maeda, Naoya, Hara, Kodai, Hashimoto, Hiroshi, Tsunematsu, Yuta, Houk, Kendall N, Tang, Yi, and Watanabe, Kenji
- Subjects
Generic health relevance - Abstract
We have previously reported the identification of CghA, a proposed Diels-Alderase responsible for the formation of the bicyclic octalin core of the fungal secondary metabolite Sch210972. Here we show the crystal structure of the CghA-product complex at a resolution of 2.0 Å. Our result provides the second structural determination of eukaryotic Diels-Alderases and adds yet another fold to the family of proteins reported to catalyse [4 + 2] cycloaddition reactions. Site-directed mutagenesis-coupled kinetic characterization and computational analyses allowed us to identify key catalytic residues and propose a possible catalytic mechanism. Most interestingly, we were able to rationally engineer CghA such that the mutant was able to catalyse preferentially the formation of the energetically disfavoured exo adduct. This work expands our knowledge and understanding of the emerging and potentially widespread class of natural enzymes capable of catalysing stereoselective Diels-Alder reactions and paves the way towards developing enzymes potentially useful in various bio/synthetic applications.
- Published
- 2021
24. How the Lewis Base F- Catalyzes the 1,3-Dipolar Cycloaddition between Carbon Dioxide and Nitrilimines.
- Author
-
Svatunek, Dennis, Hansen, Thomas, Houk, Kendall N, and Hamlin, Trevor A
- Subjects
Medicinal and Biomolecular Chemistry ,Organic Chemistry - Abstract
The mechanism of the Lewis base F- catalyzed 1,3-dipolar cycloaddition between CO2 and nitrilimines is interrogated using DFT calculations. F- activates the nitrilimine, not CO2 as proposed in the literature, and imparts a significant rate enhancement for the cycloaddition. The origin of this catalysis is in the strength of the primary orbital interactions between the reactants. The Lewis base activated nitrilimine-F- has high-lying filled FMOs. The smaller FMO-LUMO gap promotes a rapid nucleophilic attack and overall cycloaddition with CO2.
- Published
- 2021
25. Synthetic, Mechanistic, and Biological Interrogation of Ginkgo biloba Chemical Space En Route to (−)-Bilobalide
- Author
-
Demoret, Robert M, Baker, Meghan A, Ohtawa, Masaki, Chen, Shuming, Lam, Ching Ching, Khom, Sophia, Roberto, Marisa, Forli, Stefano, Houk, Kendall N, and Shenvi, Ryan A
- Subjects
Bromides ,Cyclopentanes ,Furans ,GABA-A Receptor Antagonists ,Ginkgo biloba ,Ginkgolides ,Isotope Labeling ,Lactones ,Molecular Conformation ,Oxidation-Reduction ,Stereoisomerism ,Chemical Sciences ,General Chemistry - Abstract
Here we interrogate the structurally dense (1.64 mcbits/Å3) GABAA receptor antagonist bilobalide, intermediates en route to its synthesis, and related mechanistic questions. 13C isotope labeling identifies an unexpected bromine migration en route to an α-selective, catalytic asymmetric Reformatsky reaction, ruling out an asymmetric allylation pathway. Experiment and computation converge on the driving forces behind two surprising observations. First, an oxetane acetal persists in concentrated mineral acid (1.5 M DCl in THF-d8/D2O); its longevity is correlated to destabilizing steric clash between substituents upon ring-opening. Second, a regioselective oxidation of des-hydroxybilobalide is found to rely on lactone acidification through lone-pair delocalization, which leads to extremely rapid intermolecular enolate equilibration. We also establish equivalent effects of (-)-bilobalide and the nonconvulsive sesquiterpene (-)-jiadifenolide on action potential-independent inhibitory currents at GABAergic synapses, using (+)-bilobalide as a negative control. The high information density of bilobalide distinguishes it from other scaffolds and may characterize natural product (NP) space more generally. Therefore, we also include a Python script to quickly (ca. 132 000 molecules/min) calculate information content (Böttcher scores), which may prove helpful to identify important features of NP space.
- Published
- 2020
26. Computational generation of an annotated gigalibrary of synthesizable, composite peptidic macrocycles
- Author
-
Saha, Ishika, Dang, Eric K, Svatunek, Dennis, Houk, Kendall N, and Harran, Patrick G
- Subjects
Information and Computing Sciences ,Medicinal and Biomolecular Chemistry ,Chemical Sciences ,Bioengineering ,Generic health relevance ,macrocyclic peptides ,reaction product prediction ,conformational analysis - Abstract
Peptidomimetic macrocycles have the potential to regulate challenging therapeutic targets. Structures of this type having precise shapes and drug-like character are particularly coveted, but are relatively difficult to synthesize. Our laboratory has developed robust methods that integrate small-peptide units into designed scaffolds. These methods create macrocycles and embed condensed heterocycles to diversify outcomes and improve pharmacological properties. The hypothetical scope of the methodology is vast and far outpaces the capacity of our experimental format. We now describe a computational rendering of our methodology that creates an in silico three-dimensional library of composite peptidic macrocycles. Our open-source platform, CPMG (Composite Peptide Macrocycle Generator), has algorithmically generated a library of 2,020,794,198 macrocycles that can result from the multistep reaction sequences we have developed. Structures are generated based on predicted site reactivity and filtered on the basis of physical and three-dimensional properties to identify maximally diverse compounds for prioritization. For conformational analyses, we also introduce ConfBuster++, an RDKit port of the open-source software ConfBuster, which allows facile integration with CPMG and ready parallelization for better scalability. Our approach deeply probes ligand space accessible via our synthetic methodology and provides a resource for large-scale virtual screening.
- Published
- 2020
27. Understand the Specific Regio- and Enantioselectivity of Fluostatin Conjugation in the Post-Biosynthesis.
- Author
-
Wang, Yuanqi, Zhang, Changsheng, Zhao, Yi-Lei, Zhao, Rosalinda, and Houk, Kendall N
- Subjects
conjugation ,regioselectivity ,fluostatin ,stereoselectivity ,π–π stacking interaction ,conjugation ,regioselectivity ,pi-pi stacking interaction ,Biochemistry and Cell Biology - Abstract
Fluostatins, benzofluorene-containing aromatic polyketides in the atypical angucycline family, conjugate into dimeric and even trimeric compounds in the post-biosynthesis. The formation of the C-C bond involves a non-enzymatic stereospecific coupling reaction. In this work, the unusual regio- and enantioselectivities were rationalized by density functional theory calculations with the M06-2X (SMD, water)/6-311 + G(d,p)//6-31G(d) method. These DFT calculations reproduce the lowest energy C1-(R)-C10'-(S) coupling pathway observed in a nonenzymatic reaction. Bonding of the reactive carbon atoms (C1 and C10') of the two reactant molecules maximizes the HOMO-LUMO interactions and Fukui function involving the highest occupied molecular orbital (HOMO) of nucleophile p-QM and lowest unoccupied molecular orbital (LUMO) of electrophile FST2- anion. In particular, the significant π-π stacking interactions of the low-energy pre-reaction state are retained in the lowest energy pathway for C-C coupling. The distortion/interaction-activation strain analysis indicates that the transition state (TScp-I) of the lowest energy pathway involves the highest stabilizing interactions and small distortion among all possible C-C coupling reactions. One of the two chiral centers generated in this step is lost upon aromatization of the phenol ring in the final difluostatin products. Thus, the π-π stacking interactions between the fluostatin 6-5-6 aromatic ring system play a critical role in the stereoselectivity of the nonenzymatic fluostatin conjugation.
- Published
- 2020
28. Demystifying the asymmetry-amplifying, autocatalytic behaviour of the Soai reaction through structural, mechanistic and computational studies
- Author
-
Athavale, Soumitra V, Simon, Adam, Houk, Kendall N, and Denmark, Scott E
- Subjects
Organic Chemistry ,Chemical Sciences ,Aldehydes ,Butanols ,Catalysis ,Density Functional Theory ,Kinetics ,Models ,Chemical ,Organometallic Compounds ,Pyridines ,Stereoisomerism ,Zinc ,Chemical sciences - Abstract
The Soai reaction has profoundly impacted chemists' perspective of autocatalysis, chiral symmetry breaking, absolute asymmetric synthesis and its role in the origin of biological homochirality. Here we describe the unprecedented observation of asymmetry-amplifying autocatalysis in the alkylation of 5-(trimethylsilylethynyl)pyridine-3-carbaldehyde using diisopropylzinc. Kinetic studies with a surrogate substrate and spectroscopic analysis of a series of zinc alkoxides that incorporate specific structural mutations reveal a 'pyridine-assisted cube escape'. The new tetrameric cluster functions as a catalyst that activates the substrate through a two-point binding mode and poises a coordinated diisopropylzinc moiety for alkyl group transfer. Transition-state models leading to both the homochiral and heterochiral products were validated by density functional theory calculations. Moreover, experimental and computational analysis of the heterochiral complex provides a definitive explanation for the nonlinear behaviour of this system. Our deconstruction of the Soai system reveals the structural logic for autocatalyst evolution, function and substrate compatibility-a central mechanistic aspect of this iconic transformation.
- Published
- 2020
29. Differentiation and functionalization of remote C–H bonds in adjacent positions
- Author
-
Shi, Hang, Lu, Yi, Weng, Jiang, Bay, Katherine L, Chen, Xiangyang, Tanaka, Keita, Verma, Pritha, Houk, Kendall N, and Yu, Jin-Quan
- Subjects
Generic health relevance ,Carbon ,Catalysis ,Coordination Complexes ,Hydrogen ,Isoquinolines ,Molecular Structure ,Norbornanes ,Palladium ,Quinolines ,Chemical Sciences ,Organic Chemistry - Abstract
Site-selective functionalization of C-H bonds will ultimately afford chemists transformative tools for editing and constructing complex molecular architectures. Towards this goal, it is essential to develop strategies to activate C-H bonds that are distal from a functional group. In this context, distinguishing remote C-H bonds on adjacent carbon atoms is an extraordinary challenge due to the lack of electronic or steric bias between the two positions. Herein, we report the design of a catalytic system leveraging a remote directing template and a transient norbornene mediator to selectively activate a previously inaccessible remote C-H bond that is one bond further away. The generality of this approach has been demonstrated with a range of heterocycles, including a complex anti-leukaemia agent and hydrocinnamic acid substrates.
- Published
- 2020
30. Demystifying the asymmetry-amplifying, autocatalytic behaviour of the Soai reaction through structural, mechanistic and computational studies.
- Author
-
Athavale, Soumitra V, Simon, Adam, Houk, Kendall N, and Denmark, Scott E
- Subjects
Organic Chemistry ,Chemical Sciences - Abstract
The Soai reaction has profoundly impacted chemists' perspective of autocatalysis, chiral symmetry breaking, absolute asymmetric synthesis and its role in the origin of biological homochirality. Here we describe the unprecedented observation of asymmetry-amplifying autocatalysis in the alkylation of 5-(trimethylsilylethynyl)pyridine-3-carbaldehyde using diisopropylzinc. Kinetic studies with a surrogate substrate and spectroscopic analysis of a series of zinc alkoxides that incorporate specific structural mutations reveal a 'pyridine-assisted cube escape'. The new tetrameric cluster functions as a catalyst that activates the substrate through a two-point binding mode and poises a coordinated diisopropylzinc moiety for alkyl group transfer. Transition-state models leading to both the homochiral and heterochiral products were validated by density functional theory calculations. Moreover, experimental and computational analysis of the heterochiral complex provides a definitive explanation for the nonlinear behaviour of this system. Our deconstruction of the Soai system reveals the structural logic for autocatalyst evolution, function and substrate compatibility-a central mechanistic aspect of this iconic transformation.
- Published
- 2020
31. Differentiation and functionalization of remote C-H bonds in adjacent positions.
- Author
-
Shi, Hang, Lu, Yi, Weng, Jiang, Bay, Katherine L, Chen, Xiangyang, Tanaka, Keita, Verma, Pritha, Houk, Kendall N, and Yu, Jin-Quan
- Subjects
Organic Chemistry ,Chemical Sciences - Abstract
Site-selective functionalization of C-H bonds will ultimately afford chemists transformative tools for editing and constructing complex molecular architectures. Towards this goal, it is essential to develop strategies to activate C-H bonds that are distal from a functional group. In this context, distinguishing remote C-H bonds on adjacent carbon atoms is an extraordinary challenge due to the lack of electronic or steric bias between the two positions. Herein, we report the design of a catalytic system leveraging a remote directing template and a transient norbornene mediator to selectively activate a previously inaccessible remote C-H bond that is one bond further away. The generality of this approach has been demonstrated with a range of heterocycles, including a complex anti-leukaemia agent and hydrocinnamic acid substrates.
- Published
- 2020
32. Isoquinoline thiosemicarbazone displays potent anticancer activity with in vivo efficacy against aggressive leukemias
- Author
-
Sun, Daniel L, Poddar, Soumya, Pan, Roy D, Rosser, Ethan W, Abt, Evan R, Van Valkenburgh, Juno, Le, Thuc M, Lok, Vincent, Hernandez, Selena P, Song, Janet, Li, Joanna, Turlik, Aneta, Chen, Xiaohong, Cheng, Chi-An, Chen, Wei, Mona, Christine E, Stuparu, Andreea D, Vergnes, Laurent, Reue, Karen, Damoiseaux, Robert, Zink, Jeffrey I, Czernin, Johannes, Donahue, Timothy R, Houk, Kendall N, Jung, Michael E, and Radu, Caius G
- Subjects
Medicinal and Biomolecular Chemistry ,Organic Chemistry ,Chemical Sciences ,Rare Diseases ,Hematology ,Cancer ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Pharmacology and Pharmaceutical Sciences ,Medicinal and biomolecular chemistry ,Organic chemistry - Abstract
A potent class of isoquinoline-based α-N-heterocyclic carboxaldehyde thiosemicarbazone (HCT) compounds has been rediscovered; based upon this scaffold, three series of antiproliferative agents were synthesized through iterative rounds of methylation and fluorination modifications, with anticancer activities being potentiated by physiologically relevant levels of copper. The lead compound, HCT-13, was highly potent against a panel of pancreatic, small cell lung carcinoma, prostate cancer, and leukemia models, with IC50 values in the low-to-mid nanomolar range. Density functional theory (DFT) calculations showed that fluorination at the 6-position of HCT-13 was beneficial for ligand-copper complex formation, stability, and ease of metal-center reduction. Through a chemical genomics screen, we identify DNA damage response/replication stress response (DDR/RSR) pathways, specifically those mediated by ataxia-telangiectasia and Rad3-related protein kinase (ATR), as potential compensatory mechanism(s) of action following HCT-13 treatment. We further show that the cytotoxicity of HCT-13 is copper-dependent, that it promotes mitochondrial electron transport chain (mtETC) dysfunction, induces production of reactive oxygen species (ROS), and selectively depletes guanosine nucleotide pools. Lastly, we identify metabolic hallmarks for therapeutic target stratification and demonstrate the in vivo efficacy of HCT-13 against aggressive models of acute leukemias in mice.
- Published
- 2020
33. Understand the Specific Regio- and Enantioselectivity of Fluostatin Conjugation in the Post-Biosynthesis
- Author
-
Wang, Yuanqi, Zhang, Changsheng, Zhao, Yi-Lei, Zhao, Rosalinda, and Houk, Kendall N
- Subjects
Biochemistry and Cell Biology ,Bioinformatics and Computational Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Medical Biotechnology ,Density Functional Theory ,Fluorenes ,Molecular Structure ,Polyketides ,Stereoisomerism ,fluostatin ,conjugation ,regioselectivity ,stereoselectivity ,pi-pi stacking interaction ,conjugation ,regioselectivity ,π–π stacking interaction ,Biochemistry and cell biology ,Bioinformatics and computational biology ,Medical biotechnology - Abstract
Fluostatins, benzofluorene-containing aromatic polyketides in the atypical angucycline family, conjugate into dimeric and even trimeric compounds in the post-biosynthesis. The formation of the C-C bond involves a non-enzymatic stereospecific coupling reaction. In this work, the unusual regio- and enantioselectivities were rationalized by density functional theory calculations with the M06-2X (SMD, water)/6-311 + G(d,p)//6-31G(d) method. These DFT calculations reproduce the lowest energy C1-(R)-C10'-(S) coupling pathway observed in a nonenzymatic reaction. Bonding of the reactive carbon atoms (C1 and C10') of the two reactant molecules maximizes the HOMO-LUMO interactions and Fukui function involving the highest occupied molecular orbital (HOMO) of nucleophile p-QM and lowest unoccupied molecular orbital (LUMO) of electrophile FST2- anion. In particular, the significant π-π stacking interactions of the low-energy pre-reaction state are retained in the lowest energy pathway for C-C coupling. The distortion/interaction-activation strain analysis indicates that the transition state (TScp-I) of the lowest energy pathway involves the highest stabilizing interactions and small distortion among all possible C-C coupling reactions. One of the two chiral centers generated in this step is lost upon aromatization of the phenol ring in the final difluostatin products. Thus, the π-π stacking interactions between the fluostatin 6-5-6 aromatic ring system play a critical role in the stereoselectivity of the nonenzymatic fluostatin conjugation.
- Published
- 2020
34. Understanding the R882H mutation effects of DNA methyltransferase DNMT3A: a combination of molecular dynamics simulations and QM/MM calculations
- Author
-
Liu, Lanxuan, Shi, Ting, Houk, Kendall N, and Zhao, Yi-Lei
- Subjects
Chemical Sciences ,Theoretical and Computational Chemistry ,Genetics ,Hematology ,Rare Diseases ,Chemical sciences - Abstract
DNA (cytosine-5)-methyltransferase 3A (DNMT3A), a key enzyme for de novo epigenetic methylation in human beings, was reported to undergo an R882H mutation in approximately 25% of M4/M5 subtype acute myeloid leukemia (AML) patients. In this work, a combination of classical molecular dynamics (MD) simulations and QM/MM calculation methods was utilized to reveal the molecular mechanism behind the activity attenuation caused by R882H mutation. We found that R882H mutation induces a "folded" conformation in the methyl donor S-adenosylmethionine (SAM) through different types of hydrogen bond formation at the terminal carbonyl oxygen atom and the hydroxyl O3' atom of the ribose ring on SAM, with Arg891 as a mediator. Energetically, both the pre-reaction state (PRS) and transition state (TS) were stabilized in the R882H mutant. However, the energy barrier of the rate-determining step from the PRS to the TS was calculated to be roughly 1.0 kcal mol-1 larger in the R882H mutant than the WT. Also, a dynamic transformation occurred along the helix where R882H was located, tending to manifest in a quasi-"Newton's cradle" manner from the mutational site to the active site residues of DNMT3A. Our computational results provided molecular insights into the pathogenic R882H mutation and advanced the understanding of its mechanism.
- Published
- 2019
35. Enabling microbial syringol conversion through structure-guided protein engineering
- Author
-
Machovina, Melodie M, Mallinson, Sam JB, Knott, Brandon C, Meyers, Alexander W, Garcia-Borràs, Marc, Bu, Lintao, Gado, Japheth E, Oliver, April, Schmidt, Graham P, Hinchen, Daniel J, Crowley, Michael F, Johnson, Christopher W, Neidle, Ellen L, Payne, Christina M, Houk, Kendall N, Beckham, Gregg T, McGeehan, John E, and DuBois, Jennifer L
- Subjects
Substance Misuse ,Alcoholism ,Alcohol Use and Health ,Cytochrome P-450 Enzyme System ,Lignin ,Methylation ,Oxidation-Reduction ,Oxidoreductases ,O-Demethylating ,Protein Engineering ,Pseudomonas putida ,Pyrogallol ,demethylase ,P450 ,lignin ,biorefinery - Abstract
Microbial conversion of aromatic compounds is an emerging and promising strategy for valorization of the plant biopolymer lignin. A critical and often rate-limiting reaction in aromatic catabolism is O-aryl-demethylation of the abundant aromatic methoxy groups in lignin to form diols, which enables subsequent oxidative aromatic ring-opening. Recently, a cytochrome P450 system, GcoAB, was discovered to demethylate guaiacol (2-methoxyphenol), which can be produced from coniferyl alcohol-derived lignin, to form catechol. However, native GcoAB has minimal ability to demethylate syringol (2,6-dimethoxyphenol), the analogous compound that can be produced from sinapyl alcohol-derived lignin. Despite the abundance of sinapyl alcohol-based lignin in plants, no pathway for syringol catabolism has been reported to date. Here we used structure-guided protein engineering to enable microbial syringol utilization with GcoAB. Specifically, a phenylalanine residue (GcoA-F169) interferes with the binding of syringol in the active site, and on mutation to smaller amino acids, efficient syringol O-demethylation is achieved. Crystallography indicates that syringol adopts a productive binding pose in the variant, which molecular dynamics simulations trace to the elimination of steric clash between the highly flexible side chain of GcoA-F169 and the additional methoxy group of syringol. Finally, we demonstrate in vivo syringol turnover in Pseudomonas putida KT2440 with the GcoA-F169A variant. Taken together, our findings highlight the significant potential and plasticity of cytochrome P450 aromatic O-demethylases in the biological conversion of lignin-derived aromatic compounds.
- Published
- 2019
36. Stable, Reactive, and Orthogonal Tetrazines: Dispersion Forces Promote the Cycloaddition with Isonitriles
- Author
-
Tu, Julian, Svatunek, Dennis, Parvez, Saba, Liu, Albert C, Levandowski, Brian J, Eckvahl, Hannah J, Peterson, Randall T, Houk, Kendall N, and Franzini, Raphael M
- Subjects
Organic Chemistry ,Chemical Sciences ,Alkenes ,Alkynes ,Animals ,Cattle ,Cycloaddition Reaction ,Fluorescent Dyes ,Nitriles ,Optical Imaging ,Serum Albumin ,Bovine ,Structure-Activity Relationship ,Tetrazoles ,Zebrafish ,bioconjugation ,bioorthogonal chemistry ,chemoselectivity ,cycloadditions ,dispersion forces ,Chemical sciences - Abstract
The isocyano group is a structurally compact bioorthogonal functional group that reacts with tetrazines under physiological conditions. Now it is shown that bulky tetrazine substituents accelerate this cycloaddition. Computational studies suggest that dispersion forces between the isocyano group and the tetrazine substituents in the transition state contribute to the atypical structure-activity relationship. Stable asymmetric tetrazines that react with isonitriles at rate constants as high as 57 L mol-1 s-1 were accessible by combining bulky and electron-withdrawing substituents. Sterically encumbered tetrazines react selectively with isonitriles in the presence of strained alkenes/alkynes, which allows for the orthogonal labeling of three proteins. The established principles will open new opportunities for developing tetrazine reactants with improved characteristics for diverse labeling and release applications with isonitriles.
- Published
- 2019
37. Enabling microbial syringol conversion through structure-guided protein engineering.
- Author
-
Machovina, Melodie M, Mallinson, Sam JB, Knott, Brandon C, Meyers, Alexander W, Garcia-Borràs, Marc, Bu, Lintao, Gado, Japheth E, Oliver, April, Schmidt, Graham P, Hinchen, Daniel J, Crowley, Michael F, Johnson, Christopher W, Neidle, Ellen L, Payne, Christina M, Houk, Kendall N, Beckham, Gregg T, McGeehan, John E, and DuBois, Jennifer L
- Subjects
Pseudomonas putida ,Pyrogallol ,Lignin ,Cytochrome P-450 Enzyme System ,Oxidoreductases ,O-Demethylating ,Protein Engineering ,Methylation ,Oxidation-Reduction ,P450 ,biorefinery ,demethylase ,lignin ,Oxidoreductases ,O-Demethylating - Abstract
Microbial conversion of aromatic compounds is an emerging and promising strategy for valorization of the plant biopolymer lignin. A critical and often rate-limiting reaction in aromatic catabolism is O-aryl-demethylation of the abundant aromatic methoxy groups in lignin to form diols, which enables subsequent oxidative aromatic ring-opening. Recently, a cytochrome P450 system, GcoAB, was discovered to demethylate guaiacol (2-methoxyphenol), which can be produced from coniferyl alcohol-derived lignin, to form catechol. However, native GcoAB has minimal ability to demethylate syringol (2,6-dimethoxyphenol), the analogous compound that can be produced from sinapyl alcohol-derived lignin. Despite the abundance of sinapyl alcohol-based lignin in plants, no pathway for syringol catabolism has been reported to date. Here we used structure-guided protein engineering to enable microbial syringol utilization with GcoAB. Specifically, a phenylalanine residue (GcoA-F169) interferes with the binding of syringol in the active site, and on mutation to smaller amino acids, efficient syringol O-demethylation is achieved. Crystallography indicates that syringol adopts a productive binding pose in the variant, which molecular dynamics simulations trace to the elimination of steric clash between the highly flexible side chain of GcoA-F169 and the additional methoxy group of syringol. Finally, we demonstrate in vivo syringol turnover in Pseudomonas putida KT2440 with the GcoA-F169A variant. Taken together, our findings highlight the significant potential and plasticity of cytochrome P450 aromatic O-demethylases in the biological conversion of lignin-derived aromatic compounds.
- Published
- 2019
38. Structural Distortion of Cycloalkynes Influences Cycloaddition Rates both by Strain and Interaction Energies
- Author
-
Hamlin, Trevor A, Levandowski, Brian J, Narsaria, Ayush K, Houk, Kendall N, and Bickelhaupt, F Matthias
- Subjects
alkynes ,azides ,cycloaddition ,density functional calculations ,reaction mechanisms ,Chemical Sciences ,General Chemistry - Abstract
The reactivities of 2-butyne, cycloheptyne, cyclooctyne, and cyclononyne in the 1,3-dipolar cycloaddition reaction with methyl azide were evaluated through DFT calculations at the M06-2X/6-311++G(d)//M06-2X/6-31+G(d) level of theory. Computed activation free energies for the cycloadditions of cycloalkynes are 16.5-22.0 kcal mol-1 lower in energy than that of the acyclic 2-butyne. The strained or predistorted nature of cycloalkynes is often solely used to rationalize this significant rate enhancement. Our distortion/interaction-activation strain analysis has been revealed that the degree of geometrical predistortion of the cycloalkyne ground-state geometries acts to enhance reactivity compared with that of acyclic alkynes through three distinct mechanisms, not only due to (i) a reduced strain or distortion energy, but also to (ii) a smaller HOMO-LUMO gap, and (iii) an enhanced orbital overlap, which both contribute to more stabilizing orbital interactions.
- Published
- 2019
39. Structural Distortion of Cycloalkynes Influences Cycloaddition Rates both by Strain and Interaction Energies.
- Author
-
Hamlin, Trevor A, Levandowski, Brian J, Narsaria, Ayush K, Houk, Kendall N, and Bickelhaupt, F Matthias
- Subjects
alkynes ,azides ,cycloaddition ,density functional calculations ,reaction mechanisms ,Chemical Sciences ,General Chemistry - Abstract
The reactivities of 2-butyne, cycloheptyne, cyclooctyne, and cyclononyne in the 1,3-dipolar cycloaddition reaction with methyl azide were evaluated through DFT calculations at the M06-2X/6-311++G(d)//M06-2X/6-31+G(d) level of theory. Computed activation free energies for the cycloadditions of cycloalkynes are 16.5-22.0 kcal mol-1 lower in energy than that of the acyclic 2-butyne. The strained or predistorted nature of cycloalkynes is often solely used to rationalize this significant rate enhancement. Our distortion/interaction-activation strain analysis has been revealed that the degree of geometrical predistortion of the cycloalkyne ground-state geometries acts to enhance reactivity compared with that of acyclic alkynes through three distinct mechanisms, not only due to (i) a reduced strain or distortion energy, but also to (ii) a smaller HOMO-LUMO gap, and (iii) an enhanced orbital overlap, which both contribute to more stabilizing orbital interactions.
- Published
- 2019
40. Cycloadditions of Oxacyclic Allenes and a Catalytic Asymmetric Entryway to Enantioenriched Cyclic Allenes
- Author
-
Yamano, Michael M, Knapp, Rachel R, Ngamnithiporn, Aurapat, Ramirez, Melissa, Houk, Kendall N, Stoltz, Brian M, and Garg, Neil K
- Subjects
Alkadienes ,Catalysis ,Cycloaddition Reaction ,Humans ,Stereoisomerism ,asymmetric catalysis ,catalysis ,cyclic allenes ,cycloadditions ,heterocycles ,Chemical Sciences ,Organic Chemistry - Abstract
The chemistry of strained cyclic alkynes has undergone a renaissance over the past two decades. However, a related species, strained cyclic allenes, especially heterocyclic derivatives, have only recently resurfaced and represent another class of valuable intermediates. We report a mild and facile means to generate the parent 3,4-oxacyclic allene from a readily accessible silyl triflate precursor, and then trap it in (4+2), (3+2), and (2+2) reactions to provide a variety of cycloadducts. In addition, we describe a catalytic, decarboxylative asymmetric allylic alkylation performed on an α-silylated substrate, to ultimately permit access to an enantioenriched allene. Generation and trapping of the enantioenriched cyclic allene occurs with complete transfer of stereochemical information in a Diels-Alder cycloaddition through a point-chirality, axial-chirality, point-chirality transfer process.
- Published
- 2019
41. Enzyme-catalysed [6+4] cycloadditions in the biosynthesis of natural products
- Author
-
Zhang, Bo, Wang, Kai Biao, Wang, Wen, Wang, Xin, Liu, Fang, Zhu, Jiapeng, Shi, Jing, Li, Ling Yu, Han, Hao, Xu, Kuang, Qiao, Hong Yun, Zhang, Xiao, Jiao, Rui Hua, Houk, Kendall N, Liang, Yong, Tan, Ren Xiang, and Ge, Hui Ming
- Subjects
Biocatalysis ,Biological Products ,Crystallography ,X-Ray ,Cycloaddition Reaction ,Density Functional Theory ,Enzymes ,Lactones ,Molecular Dynamics Simulation ,Protein Conformation ,Thermodynamics ,General Science & Technology - Abstract
Pericyclic reactions are powerful transformations for the construction of carbon-carbon and carbon-heteroatom bonds in organic synthesis. Their role in biosynthesis is increasingly apparent, and mechanisms by which pericyclases can catalyse reactions are of major interest1. [4+2] cycloadditions (Diels-Alder reactions) have been widely used in organic synthesis2 for the formation of six-membered rings and are now well-established in biosynthesis3-6. [6+4] and other 'higher-order' cycloadditions were predicted7 in 1965, and are now increasingly common in the laboratory despite challenges arising from the generation of a highly strained ten-membered ring system8,9. However, although enzyme-catalysed [6+4] cycloadditions have been proposed10-12, they have not been proven to occur. Here we demonstrate a group of enzymes that catalyse a pericyclic [6+4] cycloaddition, which is a crucial step in the biosynthesis of streptoseomycin-type natural products. This type of pericyclase catalyses [6+4] and [4+2] cycloadditions through a single ambimodal transition state, which is consistent with previous proposals11,12. The [6+4] product is transformed to a less stable [4+2] adduct via a facile Cope rearrangement, and the [4+2] adduct is converted into the natural product enzymatically. Crystal structures of three pericyclases, computational simulations of potential energies and molecular dynamics, and site-directed mutagenesis establish the mechanism of this transformation. This work shows how enzymes are able to catalyse concerted pericyclic reactions involving ambimodal transition states.
- Published
- 2019
42. Computational Protocol to Understand P450 Mechanisms and Design of Efficient and Selective Biocatalysts
- Author
-
Haatveit, Kersti Caddell, Garcia-Borràs, Marc, and Houk, Kendall N
- Subjects
Medicinal and Biomolecular Chemistry ,Organic Chemistry ,Chemical Sciences ,Generic health relevance ,density functional theory ,theozymes ,MD simulations ,biocatalysis ,cytochrome P450s ,oxidations ,Chemical sciences - Abstract
Cytochrome P450 enzymes have gained significant interest as selective oxidants in late-stage chemical synthesis. Their broad substrate scope enables them to be good candidates for their use in non-natural reactivity. Directed evolution evolves new enzyme biocatalysts that promote alternative reactivity for chemical synthesis. While directed evolution has proven useful in developing biocatalysts for specific purposes, this process is very time and labor intensive, and therefore not easily repurposed. Computational analysis of these P450 enzymes provides great insights into the broad substrate scope, the variety of reactions catalyzed, the binding specificity and the study of novel biosynthetic reaction mechanisms. By discovering new P450s and studying their reactivities, we uncover new insights into how this reactivity can be harnessed. We discuss a standard protocol using both DFT calculations and MD simulations to study a variety of cytochrome P450 enzymes. The approach entails theozyme models to study the mechanism and transition states via DFT calculations and subsequent MD simulations to understand the conformational poses and binding mechanisms within the enzyme. We discuss a few examples done in collaboration with the Tang and Sherman/Montgomery groups toward elucidating enzyme mechanisms and rationally designing new enzyme mutants as tools for selective C-H functionalization methods.
- Published
- 2019
43. Enzymatic one-step ring contraction for quinolone biosynthesis.
- Author
-
Kishimoto, Shinji, Hara, Kodai, Hashimoto, Hiroshi, Hirayama, Yuichiro, Champagne, Pier Alexandre, Houk, Kendall N, Tang, Yi, and Watanabe, Kenji
- Subjects
Escherichia coli ,Aspergillus nidulans ,Carbon Dioxide ,Zinc ,Methylamines ,Isocyanates ,Alkaloids ,Hydroxyquinolines ,Quinolones ,Fungal Proteins ,Recombinant Proteins ,Crystallography ,X-Ray ,Cloning ,Molecular ,Gene Expression ,Binding Sites ,Protein Binding ,Substrate Specificity ,Cyclization ,Kinetics ,Genetic Vectors ,Models ,Molecular ,Biosynthetic Pathways ,Protein Interaction Domains and Motifs ,Protein Conformation ,alpha-Helical ,Hemocyanins ,Cloning ,Molecular ,Crystallography ,X-Ray ,Models ,Protein Conformation ,alpha-Helical - Abstract
The 6,6-quinolone scaffolds on which viridicatin-type fungal alkaloids are built are frequently found in metabolites that display useful biological activities. Here we report in vitro and computational analyses leading to the discovery of a hemocyanin-like protein AsqI from the Aspergillus nidulans aspoquinolone biosynthetic pathway that forms viridicatins via a conversion of the cyclopenin-type 6,7-bicyclic system into the viridicatin-type 6,6-bicyclic core through elimination of carbon dioxide and methylamine through methyl isocyanate.
- Published
- 2018
44. A promiscuous cytochrome P450 aromatic O-demethylase for lignin bioconversion.
- Author
-
Mallinson, Sam JB, Machovina, Melodie M, Silveira, Rodrigo L, Garcia-Borràs, Marc, Gallup, Nathan, Johnson, Christopher W, Allen, Mark D, Skaf, Munir S, Crowley, Michael F, Neidle, Ellen L, Houk, Kendall N, Beckham, Gregg T, DuBois, Jennifer L, and McGeehan, John E
- Subjects
Actinobacteria ,Lignin ,Cytochrome P-450 Enzyme System ,Oxidoreductases ,O-Demethylating ,Bacterial Proteins ,Substrate Specificity ,Oxidation-Reduction ,Protein Multimerization ,Oxidoreductases ,O-Demethylating - Abstract
Microbial aromatic catabolism offers a promising approach to convert lignin, a vast source of renewable carbon, into useful products. Aryl-O-demethylation is an essential biochemical reaction to ultimately catabolize coniferyl and sinapyl lignin-derived aromatic compounds, and is often a key bottleneck for both native and engineered bioconversion pathways. Here, we report the comprehensive characterization of a promiscuous P450 aryl-O-demethylase, consisting of a cytochrome P450 protein from the family CYP255A (GcoA) and a three-domain reductase (GcoB) that together represent a new two-component P450 class. Though originally described as converting guaiacol to catechol, we show that this system efficiently demethylates both guaiacol and an unexpectedly wide variety of lignin-relevant monomers. Structural, biochemical, and computational studies of this novel two-component system elucidate the mechanism of its broad substrate specificity, presenting it as a new tool for a critical step in biological lignin conversion.
- Published
- 2018
45. Direct single-molecule dynamic detection of chemical reactions.
- Author
-
Guan, Jianxin, Jia, Chuancheng, Li, Yanwei, Liu, Zitong, Wang, Jinying, Yang, Zhongyue, Gu, Chunhui, Su, Dingkai, Houk, Kendall N, Zhang, Deqing, and Guo, Xuefeng
- Abstract
Single-molecule detection can reveal time trajectories and reaction pathways of individual intermediates/transition states in chemical reactions and biological processes, which is of fundamental importance to elucidate their intrinsic mechanisms. We present a reliable, label-free single-molecule approach that allows us to directly explore the dynamic process of basic chemical reactions at the single-event level by using stable graphene-molecule single-molecule junctions. These junctions are constructed by covalently connecting a single molecule with a 9-fluorenone center to nanogapped graphene electrodes. For the first time, real-time single-molecule electrical measurements unambiguously show reproducible large-amplitude two-level fluctuations that are highly dependent on solvent environments in a nucleophilic addition reaction of hydroxylamine to a carbonyl group. Both theoretical simulations and ensemble experiments prove that this observation originates from the reversible transition between the reactant and a new intermediate state within a time scale of a few microseconds. These investigations open up a new route that is able to be immediately applied to probe fast single-molecule physics or biophysics with high time resolution, making an important contribution to broad fields beyond reaction chemistry.
- Published
- 2018
46. Direct single-molecule dynamic detection of chemical reactions
- Author
-
Guan, Jianxin, Jia, Chuancheng, Li, Yanwei, Liu, Zitong, Wang, Jinying, Yang, Zhongyue, Gu, Chunhui, Su, Dingkai, Houk, Kendall N, Zhang, Deqing, and Guo, Xuefeng
- Abstract
Single-molecule detection can reveal time trajectories and reaction pathways of individual intermediates/transition states in chemical reactions and biological processes, which is of fundamental importance to elucidate their intrinsic mechanisms. We present a reliable, label-free single-molecule approach that allows us to directly explore the dynamic process of basic chemical reactions at the single-event level by using stable graphene-molecule single-molecule junctions. These junctions are constructed by covalently connecting a single molecule with a 9-fluorenone center to nanogapped graphene electrodes. For the first time, real-time single-molecule electrical measurements unambiguously show reproducible large-amplitude two-level fluctuations that are highly dependent on solvent environments in a nucleophilic addition reaction of hydroxylamine to a carbonyl group. Both theoretical simulations and ensemble experiments prove that this observation originates from the reversible transition between the reactant and a new intermediate state within a time scale of a few microseconds. These investigations open up a new route that is able to be immediately applied to probe fast single-molecule physics or biophysics with high time resolution, making an important contribution to broad fields beyond reaction chemistry.
- Published
- 2018
47. Influence of water and enzyme SpnF on the dynamics and energetics of the ambimodal [6+4]/[4+2] cycloaddition
- Author
-
Yang, Zhongyue, Yang, Song, Yu, Peiyuan, Li, Yanwei, Doubleday, Charles, Park, Jiyong, Patel, Ashay, Jeon, Byung-sun, Russell, William K, Liu, Hung-wen, Russell, David H, and Houk, Kendall N
- Subjects
Bacterial Proteins ,Catalysis ,Cycloaddition Reaction ,Hydrogen Bonding ,Hydrophobic and Hydrophilic Interactions ,Kinetics ,Macrolides ,Models ,Chemical ,Molecular Conformation ,Molecular Dynamics Simulation ,Quantum Theory ,Saccharopolyspora ,Software ,Water ,SpnF enzyme ,time-resolved mechanism ,environment-perturbed transition-state sampling ,potential energy surface bifurcation - Abstract
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.
- Published
- 2018
48. Computational Protocol to Understand P450 Mechanisms and Design of Efficient and Selective Biocatalysts.
- Author
-
Caddell Haatveit, Kersti, Garcia-Borràs, Marc, and Houk, Kendall N
- Subjects
MD simulations ,biocatalysis ,cytochrome P450s ,density functional theory ,oxidations ,theozymes - Abstract
Cytochrome P450 enzymes have gained significant interest as selective oxidants in late-stage chemical synthesis. Their broad substrate scope enables them to be good candidates for their use in non-natural reactivity. Directed evolution evolves new enzyme biocatalysts that promote alternative reactivity for chemical synthesis. While directed evolution has proven useful in developing biocatalysts for specific purposes, this process is very time and labor intensive, and therefore not easily repurposed. Computational analysis of these P450 enzymes provides great insights into the broad substrate scope, the variety of reactions catalyzed, the binding specificity and the study of novel biosynthetic reaction mechanisms. By discovering new P450s and studying their reactivities, we uncover new insights into how this reactivity can be harnessed. We discuss a standard protocol using both DFT calculations and MD simulations to study a variety of cytochrome P450 enzymes. The approach entails theozyme models to study the mechanism and transition states via DFT calculations and subsequent MD simulations to understand the conformational poses and binding mechanisms within the enzyme. We discuss a few examples done in collaboration with the Tang and Sherman/Montgomery groups toward elucidating enzyme mechanisms and rationally designing new enzyme mutants as tools for selective C-H functionalization methods.
- Published
- 2018
49. A promiscuous cytochrome P450 aromatic O-demethylase for lignin bioconversion
- Author
-
Mallinson, Sam JB, Machovina, Melodie M, Silveira, Rodrigo L, Garcia-Borràs, Marc, Gallup, Nathan, Johnson, Christopher W, Allen, Mark D, Skaf, Munir S, Crowley, Michael F, Neidle, Ellen L, Houk, Kendall N, Beckham, Gregg T, DuBois, Jennifer L, and McGeehan, John E
- Subjects
Biological Sciences ,Chemical Sciences ,Industrial Biotechnology ,Actinobacteria ,Bacterial Proteins ,Cytochrome P-450 Enzyme System ,Lignin ,Oxidation-Reduction ,Oxidoreductases ,O-Demethylating ,Protein Multimerization ,Substrate Specificity - Abstract
Microbial aromatic catabolism offers a promising approach to convert lignin, a vast source of renewable carbon, into useful products. Aryl-O-demethylation is an essential biochemical reaction to ultimately catabolize coniferyl and sinapyl lignin-derived aromatic compounds, and is often a key bottleneck for both native and engineered bioconversion pathways. Here, we report the comprehensive characterization of a promiscuous P450 aryl-O-demethylase, consisting of a cytochrome P450 protein from the family CYP255A (GcoA) and a three-domain reductase (GcoB) that together represent a new two-component P450 class. Though originally described as converting guaiacol to catechol, we show that this system efficiently demethylates both guaiacol and an unexpectedly wide variety of lignin-relevant monomers. Structural, biochemical, and computational studies of this novel two-component system elucidate the mechanism of its broad substrate specificity, presenting it as a new tool for a critical step in biological lignin conversion.
- Published
- 2018
50. Enzymatic one-step ring contraction for quinolone biosynthesis
- Author
-
Kishimoto, Shinji, Hara, Kodai, Hashimoto, Hiroshi, Hirayama, Yuichiro, Champagne, Pier Alexandre, Houk, Kendall N, Tang, Yi, and Watanabe, Kenji
- Subjects
Microbiology ,Biological Sciences ,Alkaloids ,Aspergillus nidulans ,Binding Sites ,Biosynthetic Pathways ,Carbon Dioxide ,Cloning ,Molecular ,Crystallography ,X-Ray ,Cyclization ,Escherichia coli ,Fungal Proteins ,Gene Expression ,Genetic Vectors ,Hemocyanins ,Hydroxyquinolines ,Isocyanates ,Kinetics ,Methylamines ,Models ,Molecular ,Protein Binding ,Protein Conformation ,alpha-Helical ,Protein Interaction Domains and Motifs ,Quinolones ,Recombinant Proteins ,Substrate Specificity ,Zinc - Abstract
The 6,6-quinolone scaffolds on which viridicatin-type fungal alkaloids are built are frequently found in metabolites that display useful biological activities. Here we report in vitro and computational analyses leading to the discovery of a hemocyanin-like protein AsqI from the Aspergillus nidulans aspoquinolone biosynthetic pathway that forms viridicatins via a conversion of the cyclopenin-type 6,7-bicyclic system into the viridicatin-type 6,6-bicyclic core through elimination of carbon dioxide and methylamine through methyl isocyanate.
- Published
- 2018
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.