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1.
Digit Discov ; 2(5): 1233-1250, 2023 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-38013906

RESUMO

Large-language models (LLMs) such as GPT-4 caught the interest of many scientists. Recent studies suggested that these models could be useful in chemistry and materials science. To explore these possibilities, we organized a hackathon. This article chronicles the projects built as part of this hackathon. Participants employed LLMs for various applications, including predicting properties of molecules and materials, designing novel interfaces for tools, extracting knowledge from unstructured data, and developing new educational applications. The diverse topics and the fact that working prototypes could be generated in less than two days highlight that LLMs will profoundly impact the future of our fields. The rich collection of ideas and projects also indicates that the applications of LLMs are not limited to materials science and chemistry but offer potential benefits to a wide range of scientific disciplines.

2.
J Org Chem ; 88(17): 12668-12676, 2023 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-37603684

RESUMO

The influence of steric effects on the rates of hydrogen atom transfer (HAT) reactions between oxyradicals and alkanes is explored computationally. Quantum chemical density functional theory computations of transition states show that activation barriers and reaction enthalpies are both influenced by bulky substituents on the radical but very little by substituents on the alkane. The activation barriers remain roughly correlated with reaction enthalpies via the Evans-Polanyi relationship even when steric repulsion effects become important, although dispersion effects sometimes stabilize transition states. By making comparisons to previously developed Evans-Polanyi and modified Roberts-Steel relationships, we find that HAT reactions between bulky molecules remain well-described by these relationships.

3.
Angew Chem Int Ed Engl ; 62(40): e202311266, 2023 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-37589717

RESUMO

We uncovered and reconstituted a concise biosynthetic pathway of the strained dipeptide (+)-azonazine A from marine-derived Aspergillus insulicola. Formation of the hexacyclic benzofuranoindoline ring system from cyclo-(l-Trp-N-methyl-l-Tyr) is catalyzed by a P450 enzyme through an oxidative cyclization. Supplementing the producing strain with various indole-substituted tryptophan derivatives resulted in the generation of a series of azonazine A analogs.


Assuntos
Sistema Enzimático do Citocromo P-450 , Dipeptídeos , Dipeptídeos/metabolismo , Oxirredução , Ciclização , Sistema Enzimático do Citocromo P-450/metabolismo
4.
Metab Eng ; 76: 193-203, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36796578

RESUMO

Deciphering the mechanisms of bacterial fatty acid biosynthesis is crucial for both the engineering of bacterial hosts to produce fatty acid-derived molecules and the development of new antibiotics. However, gaps in our understanding of the initiation of fatty acid biosynthesis remain. Here, we demonstrate that the industrially relevant microbe Pseudomonas putida KT2440 contains three distinct pathways to initiate fatty acid biosynthesis. The first two routes employ conventional ß-ketoacyl-ACP synthase III enzymes, FabH1 and FabH2, that accept short- and medium-chain-length acyl-CoAs, respectively. The third route utilizes a malonyl-ACP decarboxylase enzyme, MadB. A combination of exhaustive in vivo alanine-scanning mutagenesis, in vitro biochemical characterization, X-ray crystallography, and computational modeling elucidate the presumptive mechanism of malonyl-ACP decarboxylation via MadB. Given that functional homologs of MadB are widespread throughout domain Bacteria, this ubiquitous alternative fatty acid initiation pathway provides new opportunities to target a range of biotechnology and biomedical applications.


Assuntos
3-Oxoacil-(Proteína de Transporte de Acila) Sintase , Pseudomonas putida , Pseudomonas putida/genética , Pseudomonas putida/metabolismo , 3-Oxoacil-(Proteína de Transporte de Acila) Sintase/genética , Mutagênese , Ácidos Graxos
5.
Nat Chem ; 15(4): 526-534, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36635598

RESUMO

The Diels-Alder cycloaddition is one of the most powerful approaches in organic synthesis and is often used in the synthesis of important pharmaceuticals. Yet, strictly controlling the stereoselectivity of the Diels-Alder reactions is challenging, and great efforts are needed to construct complex molecules with desired chirality via organocatalysis or transition-metal strategies. Nature has evolved different types of enzymes to exquisitely control cyclization stereochemistry; however, most of the reported Diels-Alderases have been shown to only facilitate the energetically favourable diastereoselective cycloadditions. Here we report the discovery and characterization of CtdP, a member of a new class of bifunctional oxidoreductase/Diels-Alderase, which was previously annotated as an NmrA-like transcriptional regulator. We demonstrate that CtdP catalyses the inherently disfavoured cycloaddition to form the bicyclo[2.2.2]diazaoctane scaffold with a strict α-anti-selectivity. Guided by computational studies, we reveal a NADP+/NADPH-dependent redox mechanism for the CtdP-catalysed inverse electron demand Diels-Alder cycloaddition, which serves as the first example of a bifunctional Diels-Alderase that utilizes this mechanism.


Assuntos
Oxirredutases , Reação de Cicloadição , Catálise , Oxirredutases/metabolismo , Técnicas de Química Sintética , Oxirredução
6.
Angew Chem Int Ed Engl ; 62(20): e202210254, 2023 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-36610039

RESUMO

In the biosynthesis of the tryptophan-linked dimeric diketopiperazines (DKPs), cytochromes P450 selectively couple DKP monomers to generate a variety of intricate and isomeric frameworks. To determine the molecular basis for selectivity of these biocatalysts we obtained a high-resolution crystal structure of selective Csp2 -N bond forming dimerase, AspB. Overlay of the AspB structure onto C-C and C-N bond forming homolog NzeB revealed no significant structural variance to explain their divergent chemoselectivities. Molecular dynamics (MD) simulations identified a region of NzeB with increased conformational flexibility relative to AspB, and interchange of this region along with a single active site mutation led to a variant that catalyzes exclusive C-N bond formation. MD simulations also suggest that intermolecular C-C or C-N bond formation results from a change in mechanism, supported experimentally through use of a substrate mimic.


Assuntos
Dicetopiperazinas , Simulação de Dinâmica Molecular , Dicetopiperazinas/química , Conformação Molecular , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Isomerismo
7.
ACS Catal ; 11(8): 4670-4681, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-34354850

RESUMO

Hapalindoles and related compounds (ambiguines, fischerindoles, welwitindolinones) are a diverse class of indole alkaloid natural products. They are typically isolated from the Stigonemataceae order of cyanobacteria and possess a broad scope of biological activities. Recently the biosynthetic pathway for assembly of these metabolites has been elucidated. In order to generate the core ring system, L-tryptophan is converted into the cis-indole isonitrile subunit before being prenylated with geranyl pyrophosphate at the C-3 position. A class of cyclases (Stig) catalyzes a three-step process including a Cope rearrangement, 6-exo-trig cyclization and electrophilic aromatic substitution to create a polycyclic core. Formation of the initial alkaloid is followed by diverse late-stage tailoring reactions mediated by additional biosynthetic enzymes to give rise to the wide array of structural variations observed in this compound class. Herein, we demonstrate the versatility and utility of the Fam prenyltransferase and Stig cyclases toward core structural diversification of this family of indole alkaloids. Through synthesis of cis-indole isonitrile subunit derivatives, and aided by protein engineering and computational analysis, we have employed cascade biocatalysis to generate a range of derivatives, and gained insights into the basis for substrate flexibility in this system.

8.
J Org Chem ; 86(3): 2632-2643, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33476142

RESUMO

Systematic evaluation of 1,5-dienes bearing 3,3-electron-withdrawing groups and 4-methylation results in the discovery of a Cope rearrangement for Meldrum's acid-containing substrates that have unexpectedly favorable kinetic and thermodynamic profiles. The protocol is quite general due to a concise and convergent synthesis from abundant starting materials. Furthermore, products with an embedded Meldrum's acid moiety are prepared, which, in turn, can yield complex amides under neutral conditions. We have now expanded the scope of the reductive Cope rearrangement, which, via chemoselective reduction, can promote thermodynamically unfavorable [3,3] sigmatropic rearrangements of 3,3-dicyano-1,5-dienes to form reduced Cope rearrangement products. The Cope rearrangement is found to be stereospecific and can yield enantioenriched building blocks when chiral, nonracemic 1,3-disubstituted allylic electrophiles are utilized. We expand further the use of Cope rearrangements for the synthesis of highly valuable building blocks for complex- and drug-like molecular synthesis.


Assuntos
Polienos , Cinética , Termodinâmica
9.
Proc Natl Acad Sci U S A ; 117(52): 32910-32918, 2020 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-33376214

RESUMO

Redox biochemistry plays a key role in the transduction of chemical energy in living systems. However, the compounds observed in metabolic redox reactions are a minuscule fraction of chemical space. It is not clear whether compounds that ended up being selected as metabolites display specific properties that distinguish them from nonbiological compounds. Here, we introduce a systematic approach for comparing the chemical space of all possible redox states of linear-chain carbon molecules to the corresponding metabolites that appear in biology. Using cheminformatics and quantum chemistry, we analyze the physicochemical and thermodynamic properties of the biological and nonbiological compounds. We find that, among all compounds, aldose sugars have the highest possible number of redox connections to other molecules. Metabolites are enriched in carboxylic acid functional groups and depleted of ketones and aldehydes and have higher solubility than nonbiological compounds. Upon constructing the energy landscape for the full chemical space as a function of pH and electron-donor potential, we find that metabolites tend to have lower Gibbs energies than nonbiological molecules. Finally, we generate Pourbaix phase diagrams that serve as a thermodynamic atlas to indicate which compounds are energy minima in redox chemical space across a set of pH values and electron-donor potentials. While escape from thermodynamic equilibrium toward kinetically driven states is a hallmark of life and its origin, we envision that a deeper quantitative understanding of the environment-dependent thermodynamic landscape of putative prebiotic molecules will provide a crucial reference for future origins-of-life models.


Assuntos
Quimioinformática/métodos , Simulação de Dinâmica Molecular , Açúcares/química , Aldeídos/química , Configuração de Carboidratos , Ácidos Carboxílicos/química , Cetonas/química , Oxirredução
10.
J Am Chem Soc ; 142(47): 20232-20239, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33190496

RESUMO

We studied the mechanisms of activation and stereoselectivity of a monofunctional Diels-Alderase (PyrI4)-catalyzed intramolecular Diels-Alder reaction that leads to formation of the key spiro-tetramate moiety in the biosynthesis of the pyrroindomycin family of natural products. Key activation effects of PyrI4 include acid catalysis and an induced-fit mechanism that cooperate with the unique "lid" feature of PyrI4 to stabilize the Diels-Alder transition state. PyrI4 enhances the intrinsic Diels-Alder stereoselectivity of the substrate and leads to stereospecific formation of the product.


Assuntos
Proteínas de Bactérias/metabolismo , Produtos Biológicos/metabolismo , Ligases/metabolismo , Sítios de Ligação , Biocatálise , Produtos Biológicos/química , Cristalografia por Raios X , Reação de Cicloadição , Teoria da Densidade Funcional , Macrolídeos/química , Macrolídeos/metabolismo , Simulação de Acoplamento Molecular , Estereoisomerismo , Streptomyces/enzimologia
11.
J Am Chem Soc ; 142(39): 16877-16886, 2020 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-32865415

RESUMO

The mechanism of the organocatalytic Cope rearrangement is elucidated through a combined computational and experimental approach. As reported previously, hydrazides catalyze the Cope rearrangement of 1,5-hexadiene-2-carboxaldehydes via iminium ion formation, and seven- and eight-membered ring catalysts are more active than smaller ring sizes. In the present work, quantum mechanical computations and kinetic isotope effect experiments demonstrate that the Cope rearrangement step, rather than iminium formation, is rate-limiting. The computations further explain how the hydrazide catalyst lowers the free-energy barrier of the Cope rearrangement via an associative transition state that is stabilized by enehydrazine character. The computations also explain the catalyst ring size effect, as larger hydrazide rings are able to accommodate optimal transition-state geometries that minimize the unfavorable lone-pair repulsion between neighboring nitrogen atoms and maximize the favorable hyperconjugative donation from each nitrogen atom into neighboring electron-poor sigma bonds, with the seven-membered catalyst achieving a nearly ideal transition-state geometry that is comparable to that of an unconstrained acyclic catalyst. Experimental kinetics studies support the computations, showing that the seven-membered and acyclic hydrazide catalysts react 10 times faster than the six-membered catalyst. Unraveling the mechanism of this reaction is an important step in understanding other reactions catalyzed by hydrazides, and explaining the ring size effect is critical because cyclic catalysts provide a constrained scaffold, enabling the development of asymmetric variants of these reactions.


Assuntos
Hidrazinas/química , Iminas/síntese química , Catálise , Teoria da Densidade Funcional , Iminas/química , Cinética , Estrutura Molecular
12.
J Am Chem Soc ; 142(41): 17413-17424, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-32786740

RESUMO

The dimeric diketopiperazine (DKPs) alkaloids are a diverse family of natural products (NPs) whose unique structural architectures and biological activities have inspired the development of new synthetic methodologies to access these molecules. However, catalyst-controlled methods that enable the selective formation of constitutional and stereoisomeric dimers from a single monomer are lacking. To resolve this long-standing synthetic challenge, we sought to characterize the biosynthetic enzymes that assemble these NPs for application in biocatalytic syntheses. Genome mining enabled identification of the cytochrome P450, NzeB (Streptomyces sp. NRRL F-5053), which catalyzes both intermolecular carbon-carbon (C-C) and carbon-nitrogen (C-N) bond formation. To identify the molecular basis for the flexible site-selectivity, stereoselectivity, and chemoselectivity of NzeB, we obtained high-resolution crystal structures (1.5 Å) of the protein in complex with native and non-native substrates. This, to our knowledge, represents the first crystal structure of an oxidase catalyzing direct, intermolecular C-H amination. Site-directed mutagenesis was utilized to assess the role individual active-site residues play in guiding selective DKP dimerization. Finally, computational approaches were employed to evaluate plausible mechanisms regarding NzeB function and its ability to catalyze both C-C and C-N bond formation. These results provide a structural and computational rationale for the catalytic versatility of NzeB, as well as new insights into variables that control selectivity of CYP450 diketopiperazine dimerases.


Assuntos
Alcaloides/química , Produtos Biológicos/química , Sistema Enzimático do Citocromo P-450/metabolismo , Dicetopiperazinas/química , Aminação , Biocatálise , Carbono/química , Dimerização , Modelos Moleculares , Conformação Molecular , Mutagênese Sítio-Dirigida , Nitrogênio/química , Streptomyces/enzimologia , Especificidade por Substrato
13.
J Org Chem ; 85(13): 8695-8701, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32478513

RESUMO

The rotational dynamics of dirhodium supramolecular gears, formed with four 9-triptycene carboxylates cyclically arranged around a dirhodium core with variable axial ligands as originally designed by Shionoya et al., provide an excellent opportunity to evaluate the potential of computational methods and expand our understanding of the factors determining geared dynamics. Rotational dynamic rates in these structures depend on the nature of the axial ligand as shown by simulations over timescales that are not accessible experimentally. Molecular dynamics simulations gave information on the gearing mechanism, and the activation barriers to gearing were calculated using density functional theory. Steric demands imposed by the axial ligand were quantified using buried volume analysis. We found that gearing takes place in all six dirhodium-gear complexes with different axial ligands and that rotational barriers depend on their steric size.

14.
Nat Chem Biol ; 16(5): 556-563, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32066967

RESUMO

One of the hallmark reactions catalyzed by flavin-dependent enzymes is the incorporation of an oxygen atom derived from dioxygen into organic substrates. For many decades, these flavin monooxygenases were assumed to use exclusively the flavin-C4a-(hydro)peroxide as their oxygen-transferring intermediate. We demonstrate that flavoenzymes may instead employ a flavin-N5-peroxide as a soft α-nucleophile for catalysis, which enables chemistry not accessible to canonical monooxygenases. This includes, for example, the redox-neutral cleavage of carbon-hetero bonds or the dehalogenation of inert environmental pollutants via atypical oxygenations. We furthermore identify a shared structural motif for dioxygen activation and N5-functionalization, suggesting a conserved pathway that may be operative in numerous characterized and uncharacterized flavoenzymes from diverse organisms. Our findings show that overlooked flavin-N5-oxygen adducts are more widespread and may facilitate versatile chemistry, thus upending the notion that flavin monooxygenases exclusively function as nature's equivalents to organic peroxides in synthetic chemistry.


Assuntos
Proteínas de Escherichia coli/química , Oxigenases/química , Biocatálise , Cristalografia por Raios X , Dinitrocresóis/química , Proteínas de Escherichia coli/metabolismo , Nitrogênio/química , Oxigênio/química , Oxigenases/metabolismo , Peróxidos/química , Filogenia
15.
J Am Chem Soc ; 142(8): 3873-3879, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-32027134

RESUMO

The evolution of homochirality via attrition-enhanced deracemization (AED) of enantiomorphic solids is carried out using molecules that differ only in the isotopic composition of a phenyl group positioned remote from the chiral center. Enantioenrichment consistently favors the enantiomorph containing a deuterated phenyl group over the protio or 13C version, and the protio version is consistently favored over the 13C version. While these isotopic compounds exhibit identical crystal structures and solubilities, the trend in deracemization correlates with melting points. Understanding the origin of this isotope bias provides fundamental clues about overcoming stochastic behavior to direct the stereochemical outcome in attrition-enhanced deracemization processes. The energy required for breaking symmetry with chiral bias is compared for this near-equilibrium AED process and the far-from-equilibrium Soai autocatalytic reaction. Implications for the origin of biological homochirality are discussed.


Assuntos
Isótopos/química , Estrutura Molecular , Solubilidade , Estereoisomerismo
16.
Nat Chem ; 11(11): 972-980, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31548667

RESUMO

Prenylated indole alkaloids such as the calmodulin-inhibitory malbrancheamides and anthelmintic paraherquamides possess great structural diversity and pharmaceutical utility. Here, we report complete elucidation of the malbrancheamide biosynthetic pathway accomplished through complementary approaches. These include a biomimetic total synthesis to access the natural alkaloid and biosynthetic intermediates in racemic form and in vitro enzymatic reconstitution to provide access to the natural antipode (+)-malbrancheamide. Reductive cleavage of an L-Pro-L-Trp dipeptide from the MalG non-ribosomal peptide synthetase (NRPS) followed by reverse prenylation and a cascade of post-NRPS reactions culminates in an intramolecular [4+2] hetero-Diels-Alder (IMDA) cyclization to furnish the bicyclo[2.2.2]diazaoctane scaffold. Enzymatic assembly of optically pure (+)-premalbrancheamide involves an unexpected zwitterionic intermediate where MalC catalyses enantioselective cycloaddition as a bifunctional NADPH-dependent reductase/Diels-Alderase. The crystal structures of substrate and product complexes together with site-directed mutagenesis and molecular dynamics simulations demonstrate how MalC and PhqE (its homologue from the paraherquamide pathway) catalyse diastereo- and enantioselective cyclization in the construction of this important class of secondary metabolites.


Assuntos
Ascomicetos/química , Alcaloides Indólicos/metabolismo , Oxirredutases/metabolismo , Biocatálise , Reação de Cicloadição , Alcaloides Indólicos/química , Modelos Moleculares , Estrutura Molecular
17.
J Biol Chem ; 294(44): 15947-15961, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31488542

RESUMO

Cytochromes P450 (P450s) are nature's catalysts of choice for performing demanding and physiologically vital oxidation reactions. Biochemical characterization of these enzymes over the past decades has provided detailed mechanistic insight and highlighted the diversity of substrates P450s accommodate and the spectrum of oxidative transformations they catalyze. Previously, we discovered that the bacterial P450 MycCI from the mycinamicin biosynthetic pathway in Micromonospora griseorubida possesses an unusually broad substrate scope, whereas the homologous P450 from tylosin-producing Streptomyces fradiae (TylHI) exhibits a high degree of specificity for its native substrate. Here, using biochemical, structural, and computational approaches, we aimed to understand the molecular basis for the disparate reactivity profiles of these two P450s. Turnover and equilibrium binding experiments with substrate analogs revealed that TylHI strictly prefers 16-membered ring macrolides bearing the deoxyamino sugar mycaminose. To help rationalize these results, we solved the X-ray crystal structure of TylHI in complex with its native substrate at 1.99-Å resolution and assayed several site-directed mutants. We also conducted molecular dynamics simulations of TylHI and MycCI and biochemically characterized a third P450 homolog from the chalcomycin biosynthetic pathway in Streptomyces bikiniensis These studies provided a basis for constructing P450 chimeras to gain further insight into the features dictating the differences in reaction profile among these structurally and functionally related enzymes, ultimately unveiling the central roles of key loop regions in influencing substrate binding and turnover. Our work highlights the complex nature of P450/substrate interactions and raises interesting questions regarding the evolution of functional diversity among biosynthetic enzymes.


Assuntos
Proteínas de Bactérias/química , Sistema Enzimático do Citocromo P-450/química , Tilosina/metabolismo , Substituição de Aminoácidos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Simulação de Dinâmica Molecular , Ligação Proteica , Streptomyces/enzimologia , Especificidade por Substrato
18.
Biochemistry ; 58(24): 2715-2719, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31181899

RESUMO

Despite its power in identifying highly potent ligands for select protein targets, conventional medicinal chemistry is limited by its low throughput and lack of proteomic selectivity information. We seek to develop a chemoproteomic approach for discovering covalent ligands for protein targets in an unbiased, high-throughput manner. Tripartite probe compounds composed of a heterocyclic core, an electrophilic "warhead", and an alkyne tag have been designed and synthesized for covalently labeling and identifying targets in cells. We have developed a novel condensation reaction to prepare 2-chloromethylquinoline (2-CMQ), an electrophilic heterocycle. These chloromethylquinolines potently and covalently bind to a number of cellular protein targets, including prostaglandin E synthase 2 (PTGES2), a critical regulator of cell proliferation, apoptosis, angiogenesis, inflammation, and immune surveillance. The 2-CMQs that we have developed here are novel PTGES2 binders that have the potential to serve as therapies for the treatment of human diseases such as inflammation.


Assuntos
Sondas Moleculares/farmacologia , Prostaglandina-E Sintases/efeitos dos fármacos , Quinolinas/farmacologia , Glutationa Transferase/química , Glutationa Transferase/efeitos dos fármacos , Células HEK293 , Heme Oxigenase (Desciclizante)/química , Heme Oxigenase (Desciclizante)/efeitos dos fármacos , Humanos , Sondas Moleculares/síntese química , Sondas Moleculares/química , Prostaglandina-E Sintases/química , Proteoma/química , Proteômica/métodos , Quinolinas/síntese química , Quinolinas/química
19.
J Am Chem Soc ; 140(47): 16134-16139, 2018 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-30379070

RESUMO

The thermal [3,3] rearrangement of 3,3-dicyano-1,5-enynes to γ-allenyl alkylidenemalononitriles (the "enyne Cope rearrangement") has largely eluded synthetic value as the desired products, too, are thermally reactive and ultimately yield 6π electrocyclization products. Herein, we describe experimental and computational studies related to the thermal rearrangement of 1,5-enynes, structural features to halt the thermal rearrangement at the allene stage, and a reductive variant for preparing bifunctional allenyl malononitriles. We also describe various ways that the bifunctional building blocks can be manipulated and converted to cyclic and acyclic architectures.

20.
Nat Chem ; 10(10): 1048-1055, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30082883

RESUMO

C-H functionalization represents a promising approach for the synthesis of complex molecules. Instead of relying on modifying the functional groups present in a molecule, the synthetic sequence is achieved by carrying out selective reactions on the C-H bonds, which traditionally would have been considered to be the unreactive components of a molecule. A major challenge is to design catalysts to control both the site- and stereoselectivity of the C-H functionalization. We have been developing dirhodium catalysts with different selectivity profiles in C-H functionalization reactions with donor/acceptor carbenes as reactive intermediates. Here we describe a new dirhodium catalyst capable of the functionalization of non-activated primary C-H bonds with high levels of site selectivity and enantioselectivity.

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