RESUMEN
Modern retrosynthetic analysis in organic chemistry is based on the principle of polar relationships between functional groups to guide the design of synthetic routes1. This method, termed polar retrosynthetic analysis, assigns partial positive (electrophilic) or negative (nucleophilic) charges to constituent functional groups in complex molecules followed by disconnecting bonds between opposing charges2-4. Although this approach forms the basis of undergraduate curriculum in organic chemistry5 and strategic applications of most synthetic methods6, the implementation often requires a long list of ancillary considerations to mitigate chemoselectivity and oxidation state issues involving protecting groups and precise reaction choreography3,4,7. Here we report a radical-based Ni/Ag-electrocatalytic cross-coupling of substituted carboxylic acids, thereby enabling an intuitive and modular approach to accessing complex molecular architectures. This new method relies on a key silver additive that forms an active Ag nanoparticle-coated electrode surface8,9 in situ along with carefully chosen ligands that modulate the reactivity of Ni. Through judicious choice of conditions and ligands, the cross-couplings can be rendered highly diastereoselective. To demonstrate the simplifying power of these reactions, concise syntheses of 14 natural products and two medicinally relevant molecules were completed.
Asunto(s)
Productos Biológicos , Técnicas de Química Sintética , Descarboxilación , Electroquímica , Electrodos , Preparaciones Farmacéuticas , Ácidos Carboxílicos/química , Nanopartículas del Metal/química , Oxidación-Reducción , Plata/química , Productos Biológicos/síntesis química , Productos Biológicos/química , Níquel/química , Ligandos , Preparaciones Farmacéuticas/síntesis química , Preparaciones Farmacéuticas/química , Electroquímica/métodos , Técnicas de Química Sintética/métodosRESUMEN
α-Branched heteroaryl amines are prevalent motifs in drugs and are typically prepared through C-N bond formation. In contrast, C-C bond-forming approaches to branched amines may dramatically expand available chemical space but are rarely pursued in parallel format due to a lack of established library protocols. Methods for the synthesis of α-branched heteroaryl amines via aldimine addition have been evaluated for compatibility with parallel synthesis. In situ activation of aliphatic carboxylic acids as redox-active esters enables Zn-mediated decarboxylative radical imine addition to access aliphatic-branched heterobenzylic amines. In situ activation of (hetero)aryl bromides via Li-halogen exchange enables heteroaryl-lithium addition to imines to access (hetero)benzhydryl amines. Condensation of heteroaryl amines with heteroaryl aldehydes provides aldimines which may be intercepted with aryl Grignard reagents to provide modular access to (hetero)benzhydryl amines. These protocols minimize synthetic step count and maximize accessible design space, enhancing access to α-branched heteroaryl amines for medicinal chemistry.
Asunto(s)
Aminas , Química Farmacéutica , Aldehídos/química , Aminas/química , Ácidos Carboxílicos , Iminas/químicaRESUMEN
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.
Asunto(s)
Alcoholes/química , Alcoholes/síntesis química , Aminas/química , Aminas/síntesis química , Cetonas/química , Cetonas/síntesis química , Técnicas de Química Sintética , Radicales Libres/químicaRESUMEN
The direct union of primary, secondary, and tertiary carboxylic acids with a chiral glyoxylate-derived sulfinimine provides rapid access into a variety of enantiomerically pure α-amino acids (>85 examples). Characterized by operational simplicity, this radical-based reaction enables the modular assembly of exotic α-amino acids, including both unprecedented structures and those of established industrial value. The described method performs well in high-throughput library synthesis, and has already been implemented in three distinct medicinal chemistry campaigns.
Asunto(s)
Aminoácidos/síntesis química , Radicales Libres/química , EstereoisomerismoRESUMEN
Despite the longstanding importance of polyketide natural products in human medicine, nearly all commercial polyketide-based drugs are prepared through fermentation or semi-synthesis. The paucity of manufacturing routes involving de novo chemical synthesis reflects the inability of current methods to concisely address the preparation of these complex structures. Direct alcohol C-H bond functionalization via"C-C bond forming transfer hydrogenation" provides a powerful, new means of constructing type I polyketides that bypasses stoichiometric use of chiral auxiliaries, premetallated C-nucleophiles, and discrete alcohol-to-aldehyde redox reactions. Using this emergent technology, total syntheses of 6-deoxyerythronolide B, bryostatin 7, trienomycins A and F, cyanolide A, roxaticin, and formal syntheses of rifamycin S and scytophycin C, were accomplished. These syntheses represent the most concise routes reported to any member of the respective natural product families.
Asunto(s)
Productos Biológicos/síntesis química , Policétidos/síntesis química , Productos Biológicos/química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Brioestatinas/síntesis química , Brioestatinas/química , Catálisis , Eritromicina/análogos & derivados , Eritromicina/síntesis química , Eritromicina/química , Humanos , Hidrogenación , Macrólidos/síntesis química , Macrólidos/química , Estructura Molecular , Policétidos/química , Rifamicinas/síntesis química , Rifamicinas/química , EstereoisomerismoRESUMEN
Highly substituted aminotetrahydropyrans were synthesized via sequential C-H functionalizations. The process was initiated with a Pd(II)-catalyzed stereoselective γ-methylene C-H arylation of aminotetrahydropyran, followed by α-alkylation or arylation of the corresponding primary amine. The initial γ-C-H (hetero)arylation was compatible with a range of aryl iodides containing various substituents and provided the corresponding products in moderate to good yields. The subsequent α-alkylation or arylation of the isolated arylated products proceeded with high diastereoselectivity to afford value-added disubstituted aminotetrahydropyrans.
RESUMEN
Silyl glyoxylates react with enolates and enones to afford either glycolate aldol or Michael adducts. Product identity is controlled by the countercation associated with the enolate. Reformatsky nucleophiles in the presence of additional Zn(OTf)(2) result in aldol coupling (A), while lithium enolates provide the Michael coupling (B). Deprotonation of the aldol product A with LDA induces equilibration to form the minor diastereomer of Michael product B. This observation suggests that formation of the major diastereomer of Michael product B does not occur via an aldol/retro-aldol/Michael sequence.
Asunto(s)
Glioxilatos/química , Glioxilatos/síntesis química , Compuestos de Litio/química , Compuestos de Litio/síntesis química , Compuestos de Trimetilsililo/química , Compuestos de Trimetilsililo/síntesis química , Catálisis , Ciclización , Estructura Molecular , EstereoisomerismoRESUMEN
This Perspective describes the discovery and development of silyl glyoxylates, a new family of conjunctive reagents for use in multicomponent coupling reactions. The selection of the nucleophilic and electrophilic components determines whether the silyl glyoxylate reagent will function as a synthetic equivalent to the dipolar glycolic acid synthon, the glyoxylate anion synthon, or the α-keto ester homoenolate synthon. The ability to select for any of these reaction modes has translated to excellent structural diversity in the derived three- and four-component coupling adducts. Preliminary findings on the development of catalytic reactions using these reagents are detailed, as are the design and discovery of new reactions directed toward particular functional group arrays embedded within bioactive natural products.
Asunto(s)
Glioxilatos/química , Indicadores y Reactivos/química , Compuestos de Organosilicio/química , Catálisis , Estructura Molecular , EstereoisomerismoRESUMEN
Bioisosteres provide valuable design elements that medicinal chemists can use to adjust the structural and pharmacokinetic characteristics of bioactive compounds towards viable drug candidates. Aryl oxetane amines offer exciting potential as bioisosteres for benzamides-extremely common pharmacophores-but are rarely examined due to the lack of available synthetic methods. Here we describe a class of reactions for sulfonyl fluorides to form amino-oxetanes by an alternative pathway to the established SuFEx (sulfonyl-fluoride exchange) click reactivity. A defluorosulfonylation forms planar oxetane carbocations simply on warming. This disconnection, comparable to a typical amidation, will allow the application of vast existing amine libraries. The reaction is tolerant to a wide range of polar functionalities and is suitable for array formats. Ten oxetane analogues of bioactive benzamides and marketed drugs are prepared. Kinetic and computational studies support the formation of an oxetane carbocation as the rate-determining step, followed by a chemoselective nucleophile coupling step.
RESUMEN
Enantioselective C(sp3)-H activation has gained considerable attention from the synthetic chemistry community. Despite the intense interest in these reactions, the mechanisms responsible for enantioselection are still vague. In the course of the development of aryl thioether-directed C(sp3)-H arylation, we noticed extreme variation in sensitivity of two substrate classes to substituent effects of ligands and directing groups: whereas 3-pentyl sulfides (prochiral α-center) responded positively to substitution on ligands and directing groups, isobutyl sulfides (prochiral ß-center) were entirely insensitive. Quantitative structure selectivity relationship (QSSR) analyses of directing group and ligand substitution and the development of a new class of mono-N-acetyl protected amino anilamide (MPAAn) ligands led to high enantiomeric ratios (up to 99:1) for thioether-directed C(sp3)-H arylation. Key to the realization of this method was the exploitation of transient chirality at sulfur, which relays stereochemical information from the ligand backbone to enantiotopic carbons of the substrate in a rate- and enantio-determining cyclometallation deprotonation. The absolute stereochemistry of the products for these two substrates were revealed to be opposite. DFT evaluation of all possible diastereomeric transition states confirmed initial premises that guided rational ligand and directing group design. The implications of this study will assist in the further development of enantioselective C(sp3)-H activation, namely by highlighting the non-innocence of directing groups, distal steric influences, and the delicate interplay between steric Pauli repulsion and London dispersion in enantioinduction.
RESUMEN
An efficient approach to the parallel synthesis of benzimidazoles from anilines is described. Library approaches to vary the N1 and C2 vectors of benzimidazoles are well established; however, C4-C7 variation has traditionally relied on 1,2-dianiline building blocks, providing limited chemical space coverage. We have developed an amidine formation/oxidative cyclization sequence that enables anilines as a diversity set for benzimidazole C4-C7 SAR generation in parallel format. The amidine annulation was achieved using PIDA or Cu-mediated oxidation to access both N-H and N-alkyl benzimidazoles. This library protocol has now been utilized for analog production in four medicinal chemistry projects. Additionally, the synthesis of aza-benzimidazoles from aminopyridines was achieved via an analogous sequence.
Asunto(s)
Bencimidazoles/síntesis química , Compuestos de Anilina/química , Bencimidazoles/química , Química Farmacéutica/métodos , Ciclización , Oxidación-Reducción , Bibliotecas de Moléculas Pequeñas/síntesis química , Relación Estructura-ActividadRESUMEN
Despite the prevalence of repeating subunits in chiral natural products, stereocontrolled oligomerization is a largely unexplored strategy for construction of carbon skeletal frameworks. This report describes the use of silyl glyoxylates as dipolar glycolic acid synthons in a controlled oligomerization reaction for the efficient construction of the squalene synthase inhibitor zaragozic acid C. This new methodology allows rapid, stereocontrolled formation of the carbon skeleton with a desirable protecting group scheme while minimizing functional group repair and oxidation state manipulations.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Farnesil Difosfato Farnesil Transferasa/antagonistas & inhibidores , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Carbono/química , Química Orgánica/métodos , Glicolatos/química , Glioxilatos/química , Cinética , Modelos Químicos , Estructura Molecular , EstereoisomerismoRESUMEN
A modular, two-pot assembly of 7-arylpyrazolo[1,5- a]pyrimidones from aryl/heteroaryl halides and aminopyrazoles in library format was developed. Sonogashira coupling of aryl bromides with triethyl orthopropiolate, followed by in situ orthoester hydrolysis, provides access to ß-aryl ynoates, which undergo regioselective cyclocondensation with aminopyrazoles. The ability to vary the C7 vector of 7-arylpyrazolo[1,5- a]pyrimidones in two steps using readily available (hetero)aryl halides significantly enhances synthetic access to this challenging vector.
Asunto(s)
Pirazoles/química , Pirimidinonas/química , Catálisis , Complejos de Coordinación/química , Hidrólisis , Oxidación-Reducción , Paladio/química , EstereoisomerismoRESUMEN
Cyclic GMP-AMP synthase (cGAS) is activated by ds-DNA binding to produce the secondary messenger 2',3'-cGAMP. cGAS is an important control point in the innate immune response; dysregulation of the cGAS pathway is linked to autoimmune diseases while targeted stimulation may be of benefit in immunoncology. We report here the structure of cGAS with dinucleotides and small molecule inhibitors, and kinetic studies of the cGAS mechanism. Our structural work supports the understanding of how ds-DNA activates cGAS, suggesting a site for small molecule binders that may cause cGAS activation at physiological ATP concentrations, and an apparent hotspot for inhibitor binding. Mechanistic studies of cGAS provide the first kinetic constants for 2',3'-cGAMP formation, and interestingly, describe a catalytic mechanism where 2',3'-cGAMP may be a minor product of cGAS compared with linear nucleotides.
Asunto(s)
Nucleótidos Cíclicos/química , Nucleótidos Cíclicos/metabolismo , Nucleotidiltransferasas/química , Nucleotidiltransferasas/metabolismo , Asparagina/química , Sitios de Unión , ADN/química , ADN/metabolismo , Humanos , Inmunidad Innata , Cinética , Modelos Moleculares , Nucleotidiltransferasas/genética , Conformación Proteica en Hélice alfaRESUMEN
Synthesis of the spiroisoxazoline natural product (+)-calafianin is reported using asymmetric nucleophilic epoxidation and nitrile oxide cycloaddition as key steps. Synthesis and spectral analysis of all calafianin stereoisomers led to unambiguous assignment of relative and absolute stereochemistry.
Asunto(s)
Productos Biológicos/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/síntesis química , Tirosina/análogos & derivados , Productos Biológicos/química , Dicroismo Circular , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , Tirosina/síntesis química , Tirosina/químicaRESUMEN
1,3-Diols engage in ruthenium-catalyzed hydrogen transfer in the presence of alkyl hydrazines to provide 1,4-disubstituted pyrazoles. Regioselective synthesis of unsymmetrical pyrazoles from ß-hydroxy ketones is also described.
RESUMEN
The ruthenium catalyst derived from Ru3(CO)12 and triphos [Ph2P(CH2CH2PPh2)2] promotes the direct C-C coupling of isoprene with aryl substituted hydantoins 1a1f at the diene C4-position to furnish products of n-prenylation 2a2f. A mechanism involving hydantoin dehydrogenation followed by diene-imine oxidative coupling to furnish a transient aza-ruthencyclopentene is proposed.
Asunto(s)
Butadienos/química , Hemiterpenos/química , Hidantoínas/química , Pentanos/química , Rutenio/química , Alquilación , Catálisis , Complejos de Coordinación/química , Hidrogenación , PrenilaciónRESUMEN
The cyclometalated π-allyliridium 3,4-dinitro-C,O-benzoate complex modified by (R)- or (S)-Cl,MeO-BIPHEP promotes the transfer hydrogenative coupling of allyl acetate to ß-stereogenic alcohols with good to excellent levels of catalyst-directed diastereoselectivity to furnish homoallylic alcohols. Remote electronic effects of the C,O-benzoate of the catalyst play a critical role in suppressing epimerization of the transient α-stereogenic aldehyde.
Asunto(s)
Alcoholes/química , Aldehídos/química , Iridio/química , Alcoholes/síntesis química , Catálisis , Estructura Molecular , EstereoisomerismoRESUMEN
Three-component coupling of the lithium enolate of t-BuOAc, silyl glyoxylate, and an α,ß-unsaturated ketone enables the rapid construction of the trachyspic acid carbon skeleton. A 3,4-disubstituted isoxazole is utilized to mask the C7/C9 dicarbonyl. New enolsilane/nitrile-oxide cycloadditions enable the preparation of various 3,4-disubstituted isoxazoles that are challenging to access by other means.