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1.
Nature ; 618(7965): 513-518, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37015289

RESUMO

The replacement of benzene rings with sp3-hybridized bioisosteres in drug candidates generally improves pharmacokinetic properties while retaining biological activity1-5. Rigid, strained frameworks such as bicyclo[1.1.1]pentane and cubane are particularly well suited as the ring strain imparts high bond strength and thus metabolic stability on their C-H bonds. Cubane is the ideal bioisostere as it provides the closest geometric match to benzene6,7. At present, however, all cubanes in drug design, like almost all benzene bioisosteres, act solely as substitutes for mono- or para-substituted benzene rings1-7. This is owing to the difficulty of accessing 1,3- and 1,2-disubstituted cubane precursors. The adoption of cubane in drug design has been further hindered by the poor compatibility of cross-coupling reactions with the cubane scaffold, owing to a competing metal-catalysed valence isomerization8-11. Here we report expedient routes to 1,3- and 1,2-disubstituted cubane building blocks using a convenient cyclobutadiene precursor and a photolytic C-H carboxylation reaction, respectively. Moreover, we leverage the slow oxidative addition and rapid reductive elimination of copper to develop C-N, C-C(sp3), C-C(sp2) and C-CF3 cross-coupling protocols12,13. Our research enables facile elaboration of all cubane isomers into drug candidates, thus enabling ideal bioisosteric replacement of ortho-, meta- and para-substituted benzenes.

2.
J Org Chem ; 89(7): 5010-5018, 2024 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-38532573

RESUMO

Recent years have seen novel modalities emerge for the treatment of human diseases resulting in an increase in beyond rule of 5 (bRo5) chemical matter. As a result, synthetic innovations aiming to enable rapid access to complex bRo5 molecular entities have become increasingly valuable for medicinal chemists' toolkits. Herein, we report the general synthesis of a new class of noncanonical amino acids (ncAA) with a cyclopropyl backbone to achieve conformational constraint and bearing C(sp3)-rich benzene bioisosteres. We also demonstrate preliminary studies toward utilities of these ncAA as building blocks for medicinal chemistry research.


Assuntos
Aminoácidos , Benzeno , Humanos , Aminoácidos/química , Aminas , Conformação Molecular
3.
J Am Chem Soc ; 145(5): 3092-3100, 2023 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-36696089

RESUMO

The replacement of aryl rings with saturated carbocyclic structures has garnered significant interest in drug discovery due to the potential for improved pharmacokinetic properties upon substitution. In particular, 1,3-difunctionalized bicyclo[1.1.1]pentanes (BCPs) have been widely adopted as bioisosteres for parasubstituted arene rings, appearing in a number of lead pharmaceutical candidates. However, despite the pharmaceutical value of 2-substituted BCPs as replacements for ortho- or meta-substituted arene rings, general and rapid syntheses of these scaffolds remain elusive. Current approaches to 2-substituted BCPs rely on installation of the bridge substituent prior to BCP core construction, leading to lengthy step counts and often nonmodular sequences. While challenging, direct functionalization of the strong bridge BCP C-H bonds would offer a more streamlined pathway to diverse 2-substituted BCPs. Here, we report a generalizable synthetic linchpin strategy for bridge functionalization via radical C-H abstraction of the BCP core. Through mild generation of a strong hydrogen atom abstractor, we rapidly synthesize novel 2-substituted BCP synthetic linchpins in one pot. These synthetic linchpins then serve as common precursors to complex 2-substituted BCPs, allowing one-step access to a number of previously inaccessible electrophile and nucleophile fragments at the 2-position via two new metallaphotoredox protocols. Altogether, this platform enables the expedient synthesis of four pharmaceutical analogues, all of which show similar or improved properties compared to their aryl-containing equivalents, demonstrating the potential of these 2-substituted BCPs in drug development.

4.
J Org Chem ; 88(3): 1665-1694, 2023 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-36695785

RESUMO

We describe the first general transition-metal-free synthesis of gem-diboromethyl-substituted bicyclo[1.1.1]pentane (BCP) and other related C(sp3)-rich carbocyclic benzene bioisosteres from their corresponding p-tosylhydrazones. These novel functionalized benzene bioisosteres demonstrated unique reactivities toward palladium-catalyzed C(sp2)-C(sp3) cross couplings. The overall transformation can be applied to relatively complex substrates with potential utility in drug discovery.

5.
J Org Chem ; 86(15): 10672-10698, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34314187

RESUMO

We report our efforts toward achieving C(sp2)-C(sp3) coupling reactions with 2,2-difluorobicyclo[1.1.1]pentane (BCP-F2) building blocks. By comparing the reactivities of matching pairs of bicyclo[1.1.1]pentane (BCP) and BCP-F2 analogues, we discovered that the Barluenga coupling reaction was the only cross-coupling protocol that translated well between the two structural motifs in contrast to other reported protocols. In this chemistry, a BCP-F2 bearing a tosylhydrazone functional group is cross-coupled with an arylboronic acid. These results further expanded the scope of BCP-F2 building blocks for potential applications in organic chemistry as well as medicinal chemistry.


Assuntos
Química Orgânica , Química Farmacêutica
6.
Nat Prod Rep ; 36(1): 220-247, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29979463

RESUMO

Covering: up to 2018Pleuromutilins are a clinically validated class of antibiotics derived from the fungal diterpene (+)-pleuromutilin (1). Pleuromutilins inhibit bacterial protein synthesis by binding to the peptidyl transferase center (PTC) of the ribosome. In this review we summarize the biosynthesis and recent total syntheses of (+)-pleuromutilin (1). We review the mode of interaction of pleuromutilins with the bacterial ribosome, which involves binding of the C14 extension and the tricyclic core to the P and A sites of the PTC, respectively. We provide an overview of existing clinical agents, and discuss the three primary modes of bacterial resistance (mutations in ribosomal protein L3, Cfr methylation, and efflux). Finally we collect structure-activity relationships from publicly available reports, and close with some forward looking statements regarding future development.


Assuntos
Antibacterianos/farmacologia , Diterpenos/farmacologia , Diterpenos/síntese química , Diterpenos/química , Humanos , Compostos Policíclicos , Proteína Ribossômica L3 , Relação Estrutura-Atividade , Pleuromutilinas
7.
J Org Chem ; 83(13): 6843-6892, 2018 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-29664634

RESUMO

Antibiotics derived from the diterpene fungal metabolite (+)-pleuromutilin (1) are useful agents for the treatment Gram-positive infections in humans and farm animals. Pleuromutilins elicit slow rates of resistance development and minimal cross-resistance with existing antibiotics. Despite efforts aimed at producing new derivatives by semisynthesis, modification of the tricyclic core is underexplored, in part due to a limited number of functional group handles. Herein, we report methods to selectively functionalize the methyl groups of (+)-pleuromutilin (1) by hydroxyl-directed iridium-catalyzed C-H silylation, followed by Tamao-Fleming oxidation. These reactions provided access to C16, C17, and C18 monooxidized products, as well as C15/C16 and C17/C18 dioxidized products. Four new functionalized derivatives were prepared from the protected C17 oxidation product. C6 carboxylic acid, aldehyde, and normethyl derivatives were prepared from the C16 oxidation product. Many of these sequences were executed on gram scales. The efficiency and practicality of these routes provides an easy method to rapidly interrogate structure-activity relationships that were previously beyond reach. This study will inform the design of fully synthetic approaches to novel pleuromutilins and underscores the power of the hydroxyl-directed iridium-catalyzed C-H silylation reaction.

8.
Beilstein J Org Chem ; 14: 2259-2265, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30202480

RESUMO

We show that cobalt bis(acetylacetonate) [Co(acac)2], tert-butyl hydroperoxide (TBHP), and triethylsilane (Et3SiH) constitute an inexpensive, general, and practical reagent combination to initiate a broad range of Markovnikov-selective alkene hydrofunctionalization reactions. These transformations are believed to proceed by cobalt-mediated hydrogen atom transfer (HAT) to the alkene substrate, followed by interception of the resulting alkyl radical intermediate with a SOMOphile. In addition, we report the first reductive couplings of unactivated alkenes and aryldiazonium salts by an HAT pathway. The simplicity and generality of the Co(acac)2-TBHP-Et3SiH reagent combination suggests it as a useful starting point to develop HAT reactions in complex settings.

9.
J Am Chem Soc ; 139(16): 5998-6007, 2017 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-28359149

RESUMO

We report the first reductive coupling of unactivated alkenes with N-methoxy pyridazinium, imidazolium, quinolinium, and isoquinolinium salts under hydrogen atom transfer (HAT) conditions, and an expanded scope for the coupling of alkenes with N-methoxy pyridinium salts. N-Methoxy pyridazinium, imidazolium, quinolinium, and isoquinolinium salts are accessible in 1-2 steps from the commercial arenes or arene N-oxides (25-99%). N-Methoxy imidazolium salts are accessible in three steps from commercial amines (50-85%). In total 36 discrete methoxyheteroarenium salts bearing electron-donating, electron-withdrawing, alkyl, aryl, halogen, and haloalkyl substituents were prepared (several in multigram quantities) and coupled with 38 different alkenes. The transformations proceed under neutral conditions at ambient temperature, provide monoalkylation products exclusively, and form a single alkene addition regioisomer. Preparatively useful and complementary site selectivities in the addition of secondary and tertiary radicals to pyidinium salts are documented: harder secondary radicals favor C-2 addition (2->10:1), while softer tertiary radicals favor bond formation to C-4 (4.7->29:1). A diene possessing a 1,2-disubstituted and 2,2-disubstituted alkene undergoes hydropyridylation at the latter exclusively (61%) suggesting useful site selectivities can be obtained in polyene substrates. The methoxypyridinium salts can also be employed in dehydrogenative arylation, borono-Minisci, and tandem arylation processes. Mechanistic studies support the involvement of a radical process.

10.
J Am Chem Soc ; 138(28): 8718-21, 2016 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-27384921

RESUMO

A general method for the hydropyridylation of unactivated alkenes is described. The transformation connects metal-mediated hydrogen atom transfer to alkenes and Minisci addition reactions. The reaction proceeds under mild conditions with high site-selectivities and allows for the construction of tertiary and quaternary centers from simple alkene starting materials.

11.
J Org Chem ; 81(19): 8673-8695, 2016 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-27598718

RESUMO

Cobalt bis(acetylacetonate) is shown to mediate hydrogen atom transfer to a broad range of functionalized alkenes; in situ oxidation of the resulting alkylradical intermediates, followed by hydrolysis, provides expedient access to ketones and esters. By modification of the alcohol solvent, different alkyl ester products may be obtained. The method is compatible with a number of functional groups including alkenyl halides, sulfides, triflates, and phosphonates and provides a mild and practical alternative to the Tamao-Fleming oxidation of vinylsilanes and the Arndt-Eistert homologation.

12.
J Org Chem ; 80(1): 647-52, 2015 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-25469937

RESUMO

Ethyne is employed as coupling partner in copper-mediated cross-coupling reactions with N-tosylhydrazones and α-diazoacetate, leading to the development of a new synthetic method for terminal allenes. With this novel coupling method, the terminal allenes were obtained in good yields and with excellent functional group tolerance. Copper carbene migratory insertion is proposed as the key step in these transformations.

13.
J Am Chem Soc ; 136(19): 6884-7, 2014 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-24824195

RESUMO

A general method for the selective hydrogenation of alkenyl halides to alkyl halides is described. Fluoro, chloro, bromo, iodo, and gem-dihaloalkenes are viable substrates for the transformation. The selectivity of the hydrogenation is consistent with reduction by a hydrogen atom transfer pathway.

14.
Org Lett ; 26(9): 1947-1951, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38386927

RESUMO

Described herein is our effort toward achieving the decarboxylative functionalization of 2,2-difluorobicyclo[1.1.1]pentane (BCP-F2) building blocks. When compared with the nonfluorinated bicyclo[1.1.1]pentane (BCP) analogues, we discovered divergent reactivities. This is the first successful decarboxylative coupling of BCP-F2 building blocks reported via the photoredox mechanism.

15.
J Med Chem ; 67(13): 11024-11052, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38924388

RESUMO

Oncogenic mutations in the RAS gene account for 30% of all human tumors; more than 60% of which present as KRAS mutations at the hotspot codon 12. After decades of intense pursuit, a covalent inhibition strategy has enabled selective targeting of this previously "undruggable" target. Herein, we disclose our journey toward the discovery of MK-1084, an orally bioavailable and low-dose KRASG12C covalent inhibitor currently in phase I clinical trials (NCT05067283). We leveraged structure-based drug design to identify a macrocyclic core structure, and hypothesis-driven optimization of biopharmaceutical properties to further improve metabolic stability and tolerability.


Assuntos
Descoberta de Drogas , Proteínas Proto-Oncogênicas p21(ras) , Animais , Cães , Humanos , Camundongos , Ratos , Administração Oral , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/química , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Relação Estrutura-Atividade
16.
J Am Chem Soc ; 134(13): 5742-5, 2012 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-22424212

RESUMO

Copper-catalyzed cross-coupling of N-tosylhydrazones with trialkylsilylethynes leads to the formation of C(sp)-C(sp(3)) bonds. Cu carbene migratory insertion is proposed to play the key role in this transformation.

17.
Org Lett ; 22(22): 9133-9138, 2020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-33170018

RESUMO

Compared to the abundance of methodologies accessing 1-substituted and 1,3-disubstuted bicyclo[1.1.1] pentanes (BCPs), the synthetic accessibility of BCPs with substitutions at the methylene position has been limited. Herein, we report a selective synthesis of 1-dialkylamino-2-alkylbicyclo[1.1.1]pentanes from prefunctionalized starting materials. We also achieved further functionalizations of these 1,2-disubstituted BCPs and developed a synthesis of these compounds with minimum necessity of chromatographic purifications starting from 1,3-dichloroacetone. Finally, we also detailed the synthesis of a 1,2,3-trisubstituted BCP analogue.

18.
Org Lett ; 21(18): 7199-7203, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31294572

RESUMO

The bicyclo[1.1.1]pentane (BCP) motif has been utilized as bioisosteres in drug candidates to replace phenyl, tert-butyl, and alkynyl fragments in order to improve physicochemical properties. However, bceause of the difficulty of synthesis, most BCP analogues prepared only bear 1,3-"para"-substituents. We report the first selective synthesis of 2,2-difluorobicyclo[1.1.1]pentanes via difluorocarbene insertion into bicyclo[1.1.0]butanes. Moreover, this methodology should inspire future studies on synthesis of other "ortho/meta-substituted" BCPs via similar mechanisms.

19.
Artigo em Inglês | MEDLINE | ID: mdl-31849839

RESUMO

Context: Primary aldosteronism represents an important and common cause of hypertension and is characterized by autonomous aldosterone secretion that results in severe hypertension and hypokalemia. Nonetheless, its manifestations are atypical in some cases, which renders its diagnosis difficult. Case Description: Presented in this report is a Chinese female patient with blood pressure in the high-normal range, and her parathyroid hormone was significantly elevated. Elevated plasma aldosterone concentration plus suppressed plasma rennin activity was suggestive of primary aldosteronism. 68Ga-pentixafor positron emission tomography/computed tomography revealed an aldosterone-producing adenoma, which was globally the second of its kind ever reported so far. Moreover, the tumor was located in an extremely rare area. Conclusions: Patients with primary aldosteronism may present with normal or high-normal blood pressure and a significantly elevated parathyroid hormone. 68Ga-pentixafor PET/CT is potentially a helpful tool for the non-invasive characterization of patients with primary aldosteronism.

20.
Chem Sci ; 6(11): 6250-6255, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30090243

RESUMO

Classical methods for alkene hydrogenation typically reduce less-substituted or more-strained alkenes, or those in proximity to a directing group, most rapidly. Here we describe a cobalt-mediated hydrogenation protocol that provides complementary selectivities in the reduction of several classes of olefins and alkynes. The selectivity of this reduction derives from a hydrogen atom transfer mechanism, which favors the generation of the more stable alkylradical intermediate. We also report the first alkene hydrobromination, hydroiodination, and hydroselenylation by a hydrogen atom transfer process.

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