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1.
Acc Chem Res ; 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34351757

RESUMO

ConspectusAt the heart of synthetic chemistry is the holy grail of predictable catalyst design. In particular, researchers involved in reaction development in asymmetric catalysis have pursued a variety of strategies toward this goal. This is driven by both the pragmatic need to achieve high selectivities and the inability to readily identify why a certain catalyst is effective for a given reaction. While empiricism and intuition have dominated the field of asymmetric catalysis since its inception, enantioselectivity offers a mechanistically rich platform to interrogate catalyst-structure response patterns that explain the performance of a particular catalyst or substrate.In the early stages of an asymmetric reaction development campaign, the overarching mechanism of the reaction, catalyst speciation, the turnover limiting step, and many other details are unknown or posited based on related reactions. Considering the unclear details leading to a successful reaction, initial enantioselectivity data are often used to intuitively guide the ultimate direction of optimization. However, if the conditions of the Curtin-Hammett principle are satisfied, then measured enantioselectivity can be directly connected to the ensemble of diastereomeric transition states (TSs) that lead to the enantiomeric products, and the associated free energy difference between competing TSs (ΔΔG⧧ = -RT ln[(S)/(R)], where (S) and (R) represent the concentrations of the enantiomeric products). We, and others, speculated that this important piece of information can be leveraged to guide reaction optimization in a quantitative way.Although traditional linear free energy relationships (LFERs), such as Hammett plots, have been used to illuminate important mechanistic features, we sought to develop data science derived tools to expand the power of LFERs in order to describe complex reactions frequently encountered in modern asymmetric catalysis. Specifically, we investigated whether enantioselectivity data from a reaction can be quantitatively connected to the attributes of reaction components, such as catalyst and substrate structural features, to harness data for asymmetric catalyst design.In this context, we developed a workflow to relate computationally derived features of reaction components to enantioselectivity using data science tools. The mathematical representation of molecules can incorporate many aspects of a transformation, such as molecular features from substrate, product, catalyst, and proposed transition states. Statistical models relating these features to reaction outputs can be used for various tasks, such as performance prediction of untested molecules. Perhaps most importantly, statistical models can guide the generation of mechanistic hypotheses that are embedded within complex patterns of reaction responses. Overall, merging traditional physical organic experiments with statistical modeling techniques creates a feedback loop that enables both evaluation of multiple mechanistic hypotheses and future catalyst design. In this Account, we highlight the evolution and application of this approach in the context of a collaborative program based on chiral phosphoric acid catalysts (CPAs) in asymmetric catalysis.

2.
Molecules ; 27(18)2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36144811

RESUMO

Herein, we report the design and synthesis of a series of chiral pyrrolidine-substituted ferrocene-derived ligands. The proficiency of this novel structural motif was demonstrated in the Rh-catalyzed asymmetric hydrogenation of dehydroamino acid esters and α-aryl enamides. The products were obtained with full conversions and excellent levels of enantioselectivities of up to >99.9% ee and 97.7% ee, respectively, using a BINOL-substituted phosphine-phosphoaramidite ligand which possesses planar, central, and axial chirality elements.


Assuntos
Ródio , Alcenos , Catálise , Compostos Ferrosos , Hidrogenação , Ligantes , Metalocenos , Pirrolidinas , Ródio/química , Estereoisomerismo
3.
J Am Chem Soc ; 143(45): 19078-19090, 2021 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-34735129

RESUMO

We report the development of a method to diastereoselectively access tetrasubstituted alkenes via nickel-catalyzed Suzuki-Miyaura cross-couplings of enol tosylates and boronic acid esters. Either diastereomeric product was selectively accessed from a mixture of enol tosylate starting material diastereomers in a convergent reaction by judicious choice of the ligand and reaction conditions. A similar protocol also enabled a divergent synthesis of each product isomer from diastereomerically pure enol tosylates. Notably, high-throughput optimization of the monophosphine ligands was guided by chemical space analysis of the kraken library to ensure a diverse selection of ligands was examined. Stereoelectronic analysis of the results provided insight into the requirements for reactive and selective ligands in this transformation. The synthetic utility of the optimized catalytic system was then probed in the stereoselective synthesis of various tetrasubstituted alkenes, with yields up to 94% and diastereomeric ratios up to 99:1 Z/E and 93:7 E/Z observed. Moreover, a detailed computational analysis and experimental mechanistic studies provided key insights into the nature of the underlying isomerization process impacting selectivity in the cross-coupling.

4.
J Am Chem Soc ; 143(20): 7859-7867, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-33983721

RESUMO

The site-specific oxidation of strong C(sp3)-H bonds is of uncontested utility in organic synthesis. From simplifying access to metabolites and late-stage diversification of lead compounds to truncating retrosynthetic plans, there is a growing need for new reagents and methods for achieving such a transformation in both academic and industrial circles. One main drawback of current chemical reagents is the lack of diversity with regard to structure and reactivity that prevents a combinatorial approach for rapid screening to be employed. In that regard, directed evolution still holds the greatest promise for achieving complex C-H oxidations in a variety of complex settings. Herein we present a rationally designed platform that provides a step toward this challenge using N-ammonium ylides as electrochemically driven oxidants for site-specific, chemoselective C(sp3)-H oxidation. By taking a first-principles approach guided by computation, these new mediators were identified and rapidly expanded into a library using ubiquitous building blocks and trivial synthesis techniques. The ylide-based approach to C-H oxidation exhibits tunable selectivity that is often exclusive to this class of oxidants and can be applied to real-world problems in the agricultural and pharmaceutical sectors.


Assuntos
Compostos de Amônio/química , Técnicas Eletroquímicas , Estrutura Molecular , Oxirredução
5.
Acc Chem Res ; 53(1): 72-83, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31823612

RESUMO

The appeal and promise of synthetic organic electrochemistry have been appreciated over the past century. In terms of redox chemistry, which is frequently encountered when forging new bonds, it is difficult to conceive of a more economical way to add or remove electrons than electrochemistry. Indeed, many of the largest industrial synthetic chemical processes are achieved in a practical way using electrons as a reagent. Why then, after so many years of the documented benefits of electrochemistry, is it not more widely embraced by mainstream practitioners? Erroneous perceptions that electrochemistry is a "black box" combined with a lack of intuitive and inexpensive standardized equipment likely contributed to this stagnation in interest within the synthetic organic community. This barrier to entry is magnified by the fact that many redox processes can already be accomplished using simple chemical reagents even if they are less atom-economic. Time has proven that sustainability and economics are not strong enough driving forces for the adoption of electrochemical techniques within the broader community. Indeed, like many synthetic organic chemists that have dabbled in this age-old technique, our first foray into this area was not by choice but rather through sheer necessity. The unique reactivity benefits of this old redox-modulating technique must therefore be highlighted and leveraged in order to draw organic chemists into the field. Enabling new bonds to be forged with higher levels of chemo- and regioselectivity will likely accomplish this goal. In doing so, it is envisioned that widespread adoption of electrochemistry will go beyond supplanting unsustainable reagents in mundane redox reactions to the development of exciting reactivity paradigms that enable heretofore unimagined retrosynthetic pathways. Whereas the rigorous physical organic chemical principles of electroorganic synthesis have been reviewed elsewhere, it is often the case that such summaries leave out the pragmatic aspects of designing, optimizing, and scaling up preparative electrochemical reactions. Taken together, the task of setting up an electrochemical reaction, much less inventing a new one, can be vexing for even seasoned organic chemists. This Account therefore features a unique format that focuses on addressing this exact issue within the context of our own studies. The graphically rich presentation style pinpoints basic concepts, typical challenges, and key insights for those "electro-curious" chemists who seek to rapidly explore the power of electrochemistry in their research.


Assuntos
Técnicas Eletroquímicas , Compostos Orgânicos/química , Estrutura Molecular , Compostos Orgânicos/síntese química , Oxirredução
6.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203787

RESUMO

Herein, we report antibacterial and antifungal evaluation of a series of previously prepared (+)-tanikolide analogues. One analogue, (4S,6S)-4-methyltanikolide, displayed promising anti-methicillin-resistant Staphylococcus aureus activity with a MIC of 12.5 µg/mL. Based on the antimicrobial properties of the structurally related (-)-malyngolide, two further analogues (4S,6S)-4-methylmalyngolide and (4R,6S)-4-methylmalyngolide bearing a shortened n-nonyl alkyl side chain were prepared in the present study using a ZrCl4-catalysed deprotection/cyclisation as the key step in their asymmetric synthesis. When these were tested for activity against anti-methicillin-resistant Staphylococcus aureus, the MIC increased to 50 µg/mL.


Assuntos
Lactonas/síntese química , Lactonas/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Antibacterianos/farmacologia , Escherichia coli/efeitos dos fármacos , Lactonas/química , Testes de Sensibilidade Microbiana , Pironas/síntese química , Pironas/química , Pironas/farmacologia
7.
J Am Chem Soc ; 141(2): 774-779, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30605319

RESUMO

A two-step degradation-reconstruction approach to the carbon-14 radiolabeling of alkyl carboxylic acids is presented. Simple activation via redox-active ester formation was followed by nickel-mediated decarboxylative carboxylation to afford a range of complex compounds with ample isotopic incorporations for drug metabolism and pharmacokinetic studies. The practicality and operational simplicity of the protocol were demonstrated by its use in an industrial carbon-14 radiolabeling setting.


Assuntos
Ácidos Carboxílicos/química , Compostos Radiofarmacêuticos/química , Isótopos de Carbono/química , Radioisótopos de Carbono/química , Ácidos Carboxílicos/síntese química , Catálise , Descarboxilação , Marcação por Isótopo/métodos , Níquel/química , Compostos Radiofarmacêuticos/síntese química
8.
J Am Chem Soc ; 141(16): 6726-6739, 2019 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-30943023

RESUMO

Historically accessed through two-electron, anionic chemistry, ketones, alcohols, and amines are of foundational importance to the practice of organic synthesis. After placing this work in proper historical context, this Article reports the development, full scope, and a mechanistic picture for a strikingly different way of forging such functional groups. Thus, carboxylic acids, once converted to redox-active esters (RAEs), can be utilized as formally nucleophilic coupling partners with other carboxylic derivatives (to produce ketones), imines (to produce benzylic amines), or aldehydes (to produce alcohols). The reactions are uniformly mild, operationally simple, and, in the case of ketone synthesis, broad in scope (including several applications to the simplification of synthetic problems and to parallel synthesis). Finally, an extensive mechanistic study of the ketone synthesis is performed to trace the elementary steps of the catalytic cycle and provide the end-user with a clear and understandable rationale for the selectivity, role of additives, and underlying driving forces involved.


Assuntos
Álcoois/química , Álcoois/síntese química , Aminas/química , Aminas/síntese química , Cetonas/química , Cetonas/síntese química , Técnicas de Química Sintética , Radicais Livres/química
9.
J Org Chem ; 84(2): 473-485, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30376624

RESUMO

Decarboxylative asymmetric protonation (DAP) is a mild and efficient synthetic tool for the catalytic asymmetric formation of tertiary stereocenters adjacent to a carbonyl group. The development of the methodology from the initial racemic report to recent asymmetric examples is summarized. The discovery of an enantiodivergent Pd-catalyzed DAP, in which the choice of the achiral proton source determines the stereochemical outcome, is highlighted. Furthermore, the mechanism of Pd-catalyzed DAP, investigated since the initial report, is also discussed.

10.
J Org Chem ; 82(7): 3806-3819, 2017 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-28345917

RESUMO

Herein, we describe a study into the scope and origin of an enantiodivergent effect in the palladium-catalyzed decarboxylative asymmetric protonation. By switching the achiral proton source, both enantiomers of a series of tertiary α-aryl-1-indanones are readily accessed from the corresponding α-aryl-ß-keto allyl esters. In this example of dual stereocontrol, enantioselectivities up to 94% (S) and 92% (R) were achieved using Meldrum's acid and formic acid, respectively. In an attempt to rationalize this switch in absolute configuration an investigation of the ambiguous mechanism of the decarboxylative asymmetric protonation was conducted. A novel catalytic cycle for the reaction with formic acid is proposed and subjected to a variety of experimental studies.

11.
Science ; 361(6408): 1234-1238, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-30072577

RESUMO

Phosphorothioate nucleotides have emerged as powerful pharmacological substitutes of their native phosphodiester analogs with important translational applications in antisense oligonucleotide (ASO) therapeutics and cyclic dinucleotide (CDN) synthesis. Stereocontrolled installation of this chiral motif has long been hampered by the systemic use of phosphorus(III) [P(III)]-based reagent systems as the sole practical means of oligonucleotide assembly. A fundamentally different approach is described herein: the invention of a P(V)-based reagent platform for programmable, traceless, diastereoselective phosphorus-sulfur incorporation. The power of this reagent system is demonstrated through the robust and stereocontrolled synthesis of various nucleotidic architectures, including ASOs and CDNs, via an efficient, inexpensive, and operationally simple protocol.


Assuntos
Nucleotídeos/química , Oligonucleotídeos Fosforotioatos/síntese química , Terapia Genética , Isomerismo , Oligonucleotídeos Fosforotioatos/química , Oligonucleotídeos Fosforotioatos/uso terapêutico , Enxofre/química
12.
Nat Chem ; 9(4): 361-368, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28338687

RESUMO

The direct and selective functionalization of C-H bonds of arenes is one of the most challenging yet valuable aims in organic synthesis. Despite notable recent achievements, a pre-installed directing group proved to be essential in most of the methodologies reported so far. In this context, the use of a transient directing group that can be generated in situ has attracted attention and demonstrated the great potential of this strategy. Here we report the use of an in situ generated palladacycle to accomplish remote-selective C-H alkylation reactions of arenes. Following the C-H functionalization event, the alkylated aryl ring undergoes a formal migration to provide diversely substituted benzofuran and indole scaffolds. Computational studies revealed that a palladium(IV) intermediate is not involved in the alkylation step. The aryl migration was found to proceed through a sequential C-C bond cleavage, insertion and ß-hydride-elimination process. The increasing steric bulk that builds up during the C-H functionalization step drives the unusual C-C bond cleavage in a non-strained system.

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