19 research outputs found
Biosynthesis of thiocarboxylic acid-containing natural products.
Thiocarboxylic acid-containing natural products are rare and their biosynthesis and biological significance remain unknown. Thioplatensimycin (thioPTM) and thioplatencin (thioPTN), thiocarboxylic acid congeners of the antibacterial natural products platensimycin (PTM) and platencin (PTN), were recently discovered. Here we report the biosynthetic origin of the thiocarboxylic acid moiety in thioPTM and thioPTN. We identify a thioacid cassette encoding two proteins, PtmA3 and PtmU4, responsible for carboxylate activation by coenzyme A and sulfur transfer, respectively. ThioPTM and thioPTN bind tightly to β-ketoacyl-ACP synthase II (FabF) and retain strong antibacterial activities. Density functional theory calculations of binding and solvation free energies suggest thioPTM and thioPTN bind to FabF more favorably than PTM and PTN. Additionally, thioacid cassettes are prevalent in the genomes of bacteria, implicating that thiocarboxylic acid-containing natural products are underappreciated. These results suggest that thiocarboxylic acid, as an alternative pharmacophore, and thiocarboxylic acid-containing natural products may be considered for future drug discovery
Distortion, Tether, and Entropy Effects on Transannular Diels–Alder Cycloaddition Reactions of 10–18-Membered Rings
Distortion, Tether, and Entropy Effects on Transannular Diels-Alder Cycloaddition Reactions of 10-18-Membered Rings.
Quantum Mechanical Elucidations of the Mechanisms, Reactivities, and Selectivities of Organocatalysis and Cycloadditions
Organocatalysis, the use of small organic molecules to accelerate organic reactions, has been of significant interest to synthetic chemists, and publications in this field have increased rapidly since the beginning of this century. In the meanwhile, density functional theory has been extensively applied to explore the origins of catalysis and selectivities observed in these transformations. The first portion of this dissertation reports the theoretical findings of a broad scope of reactions catalyzed by primary and secondary amines, aminoalcohols, and squaramides. The second part focuses on the understanding and the development of cycloadditions including the Diels–Alder and hetero-Diels–Alder reactions, 1,3-dipolar cycloadditions, and higher-order cycloadditions.Two examples of asymmetric catalyses with cinchona-alkaloid-derived primary amines are described in Chapters 1 and 2: (1) an intramolecular alkylation towards the synthesis of a migraine drug candidate, and (2) higher-order cycloadditions between tropone and cyclopentenone. We showed that three key interactions are responsible for enantioselectivity of the first reaction, and they are achieved with less distortion in the preferred transition state (TS). Modeling with the counterion is proved crucial to reproducing experimental stereoselectivities. Our TS model for the second example suggests the hydrogen bond formed between the quinuclidinium and the tropone oxygen determines periselectivity. The reaction between an oxyallyl cation and indoles catalyzed by a novel aminoalcohol developed in the MacMillan group is presented in Chapter 3. The uncatalyzed addition of indole to oxyallyl cation is predicted to have a high (S,S)/(R,R) diastereoselectivity. Two hydrogen bonds and a cation–π interaction facilitate binding of the oxyallyl cation to the catalyst. The cyclohexane moiety, a new addition to the Hayashi–J�rgensen catalyst, controls enantioselectivity. Chapter 4 reports the computational design, synthesis, and applications of a new chiral hydrogen-bond donor catalyst. In addition to the bidentate hydrogen-bond donor motif, the squaramide catalyst features three chiral centers and hydrogen-bond acceptors. DFT calculations indicate that C−H���O hydrogen-bonding is crucial to the enantioselective Friedel–Crafts alkylation catalyzed by the squaramide. Chapter 5 discusses the experimental development of an unnatural amino acid mutagenesis method and the computational investigation of cation–π interactions in methyllysine reader proteins. Our results suggest that the two tyrosines in the binding pocket of a model reader protein interact with the methyllysine cation to a different extent. This work suggests the degree of contacts between reader proteins and cationic substrates may be exploited to enhance selective inhibition. Chapters 6–9 consist of DFT studies of the mechanisms, reactivities, and selectivities of a collection of cycloadditions. The remarkable reactivities of transannular Diels–Alder (TADA) reactions are investigated and discussed in Chapter 6. Among 13 TADA reactions computed, 12-membered macrocycles have the largest rate acceleration. This is due to the lowering of distortion energy from the strained reactant to the TS. TADA reactivities are further improved by fine-tuning the ring size, namely by incorporating heteroatoms such as oxygen and nitrogen and alkyne to the macrocycle. Chapter 7 explores the mechanism and selectivity of [6 + 4] cycloadditions of tropone (T) and dimethylfulvene (F), a classic reaction reported in 1967 by Houk and Woodward. An ambimodal [6T + 4F]/[4T + 6F] TS is located using DFT calculations. Reaction dynamics simulations reveal the initial product distribution and predict high [6 + 4] periselectivity. Chapter 8 focuses on the regioselectivity of 1,3-dipolar cycloadditions of benzo- and mesitylnitrile oxides with alkynyl pinacol and MIDA boronates. The electronic energies of activation are mainly controlled by distortion energies. In Chapter 1, the N,N-diquaternized cinchona-alkaloid-derived amine catalyzes an intramolecular alkylation reaction, and the last chapter is a second example of quaternary ammonium salts as powerful Lewis acidic organocatalysts. The mechanism of the aza-Diels–Alder reaction catalyzed by onium salts is predicted to be concerted asynchronous when modeled with a counter anion
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Quantum Mechanical Elucidations of the Mechanisms, Reactivities, and Selectivities of Organocatalysis and Cycloadditions
Organocatalysis, the use of small organic molecules to accelerate organic reactions, has been of significant interest to synthetic chemists, and publications in this field have increased rapidly since the beginning of this century. In the meanwhile, density functional theory has been extensively applied to explore the origins of catalysis and selectivities observed in these transformations. The first portion of this dissertation reports the theoretical findings of a broad scope of reactions catalyzed by primary and secondary amines, aminoalcohols, and squaramides. The second part focuses on the understanding and the development of cycloadditions including the Diels–Alder and hetero-Diels–Alder reactions, 1,3-dipolar cycloadditions, and higher-order cycloadditions.Two examples of asymmetric catalyses with cinchona-alkaloid-derived primary amines are described in Chapters 1 and 2: (1) an intramolecular alkylation towards the synthesis of a migraine drug candidate, and (2) higher-order cycloadditions between tropone and cyclopentenone. We showed that three key interactions are responsible for enantioselectivity of the first reaction, and they are achieved with less distortion in the preferred transition state (TS). Modeling with the counterion is proved crucial to reproducing experimental stereoselectivities. Our TS model for the second example suggests the hydrogen bond formed between the quinuclidinium and the tropone oxygen determines periselectivity. The reaction between an oxyallyl cation and indoles catalyzed by a novel aminoalcohol developed in the MacMillan group is presented in Chapter 3. The uncatalyzed addition of indole to oxyallyl cation is predicted to have a high (S,S)/(R,R) diastereoselectivity. Two hydrogen bonds and a cation–π interaction facilitate binding of the oxyallyl cation to the catalyst. The cyclohexane moiety, a new addition to the Hayashi–J�rgensen catalyst, controls enantioselectivity. Chapter 4 reports the computational design, synthesis, and applications of a new chiral hydrogen-bond donor catalyst. In addition to the bidentate hydrogen-bond donor motif, the squaramide catalyst features three chiral centers and hydrogen-bond acceptors. DFT calculations indicate that C−H���O hydrogen-bonding is crucial to the enantioselective Friedel–Crafts alkylation catalyzed by the squaramide. Chapter 5 discusses the experimental development of an unnatural amino acid mutagenesis method and the computational investigation of cation–π interactions in methyllysine reader proteins. Our results suggest that the two tyrosines in the binding pocket of a model reader protein interact with the methyllysine cation to a different extent. This work suggests the degree of contacts between reader proteins and cationic substrates may be exploited to enhance selective inhibition. Chapters 6–9 consist of DFT studies of the mechanisms, reactivities, and selectivities of a collection of cycloadditions. The remarkable reactivities of transannular Diels–Alder (TADA) reactions are investigated and discussed in Chapter 6. Among 13 TADA reactions computed, 12-membered macrocycles have the largest rate acceleration. This is due to the lowering of distortion energy from the strained reactant to the TS. TADA reactivities are further improved by fine-tuning the ring size, namely by incorporating heteroatoms such as oxygen and nitrogen and alkyne to the macrocycle. Chapter 7 explores the mechanism and selectivity of [6 + 4] cycloadditions of tropone (T) and dimethylfulvene (F), a classic reaction reported in 1967 by Houk and Woodward. An ambimodal [6T + 4F]/[4T + 6F] TS is located using DFT calculations. Reaction dynamics simulations reveal the initial product distribution and predict high [6 + 4] periselectivity. Chapter 8 focuses on the regioselectivity of 1,3-dipolar cycloadditions of benzo- and mesitylnitrile oxides with alkynyl pinacol and MIDA boronates. The electronic energies of activation are mainly controlled by distortion energies. In Chapter 1, the N,N-diquaternized cinchona-alkaloid-derived amine catalyzes an intramolecular alkylation reaction, and the last chapter is a second example of quaternary ammonium salts as powerful Lewis acidic organocatalysts. The mechanism of the aza-Diels–Alder reaction catalyzed by onium salts is predicted to be concerted asynchronous when modeled with a counter anion
Origins of Reactivity and Selectivity of a Series of Proximity-Induced Transannular Diels-Alder Reactions
Transannular Diels-Alder (TADA) reactions are a powerful tool for the construction of polycyclic structures with four stereogenic centers. A series of remarkably facile and stereoselective TADA reactions was observed experimentally by Merlic and coworkers. In this thesis, the mechanism was modeled quantum mechanically and the controlling factors of the high stereoselectivity and reactivity of TADA were determined for these reactions and the analogous bimolecular and intramolecular Diels-Alder reactions
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Distortion, Tether, and Entropy Effects on Transannular Diels-Alder Cycloaddition Reactions of 10-18-Membered Rings.
Density functional theory calculations were performed on a set of 13 transannular Diels-Alder (TADA) reactions with 10-18-membered rings. The results were compared with those for bimolecular and intramolecular Diels-Alder reactions in order to investigate the controlling factors of the high TADA reactivities. The effects of tether length, heteroatoms, and alkynyl dienophiles on reactivity were analyzed. We found a correlation between tether length and reactivity, specifically with 12-membered macrocycles undergoing cycloaddition most readily. Furthermore, modifying 12-membered macrocycles by heteroatom substitution and utilizing alkynyl dienophiles enhances the reaction rates up to 10(5)-fold
Origins of Stereoselectivity in Chiral Aminoalcohol Catalysis of Oxyallyl Cation–Indole Reactions
The
enantioselective coupling of indoles with racemic α-tosyloxy
ketones mediated by a chiral amino alcohol catalyst is studied with
density functional theory (DFT) calculations. The addition of indole
to an oxyallyl cation intrinsically favors the (<i>S</i>,<i>S</i>) and (<i>R</i>,<i>R</i>)
stereoisomeric products through electrostatic interactions in the
transition state. Our model shows that the enantioselectivity is controlled
by the cyclohexane moiety of the catalyst; selectivity diminishes
upon removal of the cyclohexane ring. Substitution to enhance the
enantioselectivity of this reaction is proposed
Accessing Diverse Azole Carboxylic Acid Building Blocks via Mild C–H Carboxylation: Parallel, One-Pot Amide Couplings and Machine-Learning-Guided Substrate Scope Design
This
manuscript describes a mild, functional group tolerant, and
metal-free C–H carboxylation that enables direct access to
azole-2-carboxylic acids, followed by amide coupling in one pot. This
demonstrates a significant expansion of the accessible chemical space
of azole-2-amides, compared to previously known methodologies. Key
to the described reactivity is the use of silyl triflate reagents,
which serve as reaction mediators in C–H deprotonation and
stabilizers of (otherwise unstable) azole carboxylic acid intermediates.
A diverse azole substrate scope designed via machine-learning-guided
analysis demonstrates the broad utility of the sequence. Density functional
theory calculations provide detailed insights into the role of silyl
triflates in the reaction mechanism. Transferrable applications of
the protocol are successfully established: (i) A low pressure (CO2 balloon) option for synthesizing azole-2-carboxylic acids
without the need for high-pressure equipment; (ii) the use of 13CO2 for the synthesis of labeled compounds; (iii)
isocyanates as alternative electrophiles for direct C–H amidation;
(iv) and the use of the developed chemistry in a 24 × 12 parallel
synthesis workflow with a 90% library success rate. Fundamentally,
the reported protocol expands the use of heterocycle C–H functionalization
from late-stage functionalization applications toward its use in library
synthesis. It provides general access to densely functionalized azole-2-carboxylic
acid building blocks and demonstrates their one-pot diversification
Accessing 3D molecular diversity via benzylic C–H cross coupling
Pharmaceutical and agrochemical discovery efforts rely on robust methods for chemical synthesis that rapidly access diverse molecules. Cross-coupling reactions are the most widely used synthetic methods, but these methods typically form bonds to C(sp2)-hybridized carbon atoms (e.g., amide coupling, biaryl coupling) and lead to a prevalence of "flat" molecular structures with suboptimal physicochemical and topological properties. Benzylic C(sp3)–H cross-coupling methods offer an appealing strategy to address this limitation by directly forming bonds to C(sp3)-hybridized carbon atoms, and emerging methods exhibit synthetic versatility that rivals conventional cross-coupling methods to access products with drug-like properties. Here, we use a virtual library of >350,000 benzylic ethers and ureas derived from benzylic C–H cross-coupling to test the widely held view that coupling at C(sp3)-hybridized carbon atoms affords products with improved three-dimensionality. The results show that the conformational rigidity of the benzylic scaffold strongly influences the product dimensionality. Products derived from flexible scaffolds often exhibit little or no improvement in three-dimensionality, unless they adopt higher energy conformations. This outcome introduces an important consideration when designing routes to topologically diverse molecular libraries. The concepts elaborated herein are validated experimentally through an informatics-guided synthesis of selected targets and the use of high-throughput experimentation to prepare a library of three-dimensional products that are broadly distributed across drug-like chemical space