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3.
Chimia (Aarau) ; 77(3): 159-160, 2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38047821

RESUMO

Industrial representatives from the Swiss chemistry ecosystem met to formulate unmet needs in the field of sustainability and share the content of the exchange. The aim is to spark inspiration and trigger ambitious and pre-competitive projects collectively at the interface of the academic and industrial worlds, with the hope to profoundly change the current practices and provide an answer to some of the most urgent environmental challenges.


Assuntos
Indústria Química , Universidades , Suíça , Humanos
4.
J Med Chem ; 65(1): 838-856, 2022 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-34967623

RESUMO

The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder whose current therapies are limited in scope and efficacy. In this report, we describe a rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated in the discovery of brain-penetrant, candidate-quality molecules as represented by compounds 22 and 24. These compounds exhibit remarkable selectivity against the kinome and offer good oral bioavailability and low projected human doses. Furthermore, they showcase the implementation of stereochemical design elements that serve to enable a potency- and selectivity-enhancing increase in polarity and hydrogen bond donor (HBD) count while maintaining a central nervous system-friendly profile typified by low levels of transporter-mediated efflux and encouraging brain penetration in preclinical models.


Assuntos
Antiparkinsonianos/síntese química , Antiparkinsonianos/farmacologia , Encéfalo/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/antagonistas & inibidores , Quinazolinas/síntese química , Quinazolinas/farmacologia , Antiparkinsonianos/farmacocinética , Disponibilidade Biológica , Desenho de Fármacos , Humanos , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacocinética , Relação Estrutura-Atividade
5.
J Am Chem Soc ; 141(12): 5034-5044, 2019 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-30827090

RESUMO

The synthesis and spectroscopic characterization of a family of Ni-X (X = Cl, Br, I, H) complexes supported by the bulky α-diimine chelate N, N'-bis(1 R,2 R,3 R,5 S)-(-)-isopinocampheyl-2,3-butanediimine (ipcADI) are described. Diimine-supported, three-coordinate nickel(I)-X complexes have been proposed as key intermediates in a host of catalytic transformations such as C-C and C-heteroatom cross-coupling and C-H functionalization but have until now remained synthetically elusive. A combination of structural, spectroscopic, electrochemical, and computational studies were used to establish the electronic structure of each monomeric [(ipcADI)NiX] (X = Cl, Br, I) complex as a nickel(I) derivative supported by a redox-neutral α-diimine chelate. The dimeric nickel hydride, [(ipcADI)Ni(µ2-H)]2, was prepared and characterized by X-ray diffraction; however, magnetic measurements and 1H NMR spectroscopy support monomer formation at ambient temperature in THF solution. This nickel hydride was used as a precatalyst for the hydrogen isotope exchange (HIE) of C-H bonds in arenes and pharmaceuticals. By virtue of the multisite reactivity and high efficiency, the new nickel precatalyst provided unprecedented high specific activities (50-99 Ci/mmol) in radiolabeling, meeting the threshold required for radioligand binding assays. Use of air-stable and readily synthesized nickel precursor, [(ipcADI)NiBr2], broad functional group tolerance, and compatibility with polar protic solvents are additional assets of the nickel-catalyzed HIE method.


Assuntos
Halogênios/química , Hidrogênio/química , Iminas/química , Níquel/química , Preparações Farmacêuticas/química , Catálise , Técnicas de Química Sintética , Isótopos/química , Ligantes , Modelos Moleculares , Conformação Molecular
6.
J Am Chem Soc ; 141(1): 127-132, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30562018

RESUMO

A base-mediated protocol that allows for the site-selective sp2 C-H silylation of azines is described. This method is distinguished by its mild conditions, simplicity and excellent site-selective modulation for a diverse set of azines, even in the context of late-stage functionalization, while exhibiting orthogonal reactivity with classical silylation reactions.

7.
Angew Chem Int Ed Engl ; 58(7): 2064-2068, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30575235

RESUMO

The ability to selectively forge C-heteroatom bonds by C-F scission is typically accomplished by metal catalysts, specialized ligands and/or harsh reaction conditions. Described herein is a base-mediated defluorosilylation of unactivated C(sp2 )-F and C(sp3 )-F bonds that obviates the need for metal catalysts. This protocol is characterized by its simplicity, mild reaction conditions, and wide scope, even within the context of late-stage functionalization, constituting a complementary approach to existing C-Si bond-forming protocols.

8.
J Am Chem Soc ; 139(7): 2589-2592, 2017 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-28156108

RESUMO

A highly diastereoselective carbon-carbon bond-forming reaction involving the tandem coupling of benzyltriboronates, enoates, and alkyl halides is described. This method was enabled by the discovery of α-diimine nickel catalysts that promote the chemoselective triborylation of benzylic C(sp3)-H bonds using B2Pin2 (Pin = pinacolate). The C-H functionalization method is effective with methylarenes and for the diborylation of secondary benzylic C-H bonds, providing direct access to polyboron building blocks from readily available hydrocarbons. Combination of the benzylic perborylation with a new deborylative conjugate addition-alkylation method enables a one-pot procedure in which multiple simple precursors are combined to generate diastereopure products containing quaternary stereocenters.

9.
J Am Chem Soc ; 139(3): 1191-1197, 2017 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-28030761

RESUMO

Metal-catalyzed transformations that forge carbon-heteroatom bonds are of central importance in organic synthesis. Despite the formidable potential of aryl methyl ethers as coupling partners, the scarcity of metal-catalyzed C-heteroatom bond formations via C-OMe cleavage is striking, with isolated precedents requiring specialized, yet expensive, ligands, high temperatures, and π-extended backbones. We report an unprecedented catalytic ipso-silylation of aryl methyl ethers under mild conditions and without recourse to external ligands. The method is distinguished by its wide scope, which includes the use of benzyl methyl ethers, vinyl methyl ethers, and unbiased anisole derivatives, thus representing a significant step forward for designing new C-heteroatom bond formations via C-OMe scission. Applications of this transformation in orthogonal silylation techniques as well as in further derivatizations are also described. Preliminary mechanistic experiments suggest the intermediacy of Ni(0)-ate complexes, leaving some doubt that a canonical catalytic cycle consisting of an initial oxidative addition of the C-OMe bond to Ni(0) species comes into play.

10.
J Am Chem Soc ; 137(39): 12470-3, 2015 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-26397717

RESUMO

A Ni-catalyzed borylation via C-F activation is described. This protocol is distinguished by a wide scope, including unactivated fluoroarenes, without compromising its efficiency and scalability, thus representing a significant step-forward toward the implementation of C-F activation protocols.

11.
J Am Chem Soc ; 137(21): 6754-7, 2015 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-25978094

RESUMO

A Ni-catalyzed ipso-borylation of aryl ethers via C(sp(2))-OMe and C(sp(3))-OMe cleavage is described. The transformation is characterized by its wide substrate scope under mild conditions and an exquisite divergence in site selectivity that can be easily switched by selecting the appropriate boron reagent.

12.
Chem Soc Rev ; 43(23): 8081-97, 2014 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-25157613

RESUMO

In 1979, the seminal work of Wenkert set the standards for the utilization of aryl and vinyl ethers as coupling partners via C-O bond-cleavage. Although the topic remained dormant for almost three decades, the last few years have witnessed a renaissance in this area of expertise, experiencing an exponential growth and becoming a significant discipline within the cross-coupling arena. The means to utilize readily accessible aryl or vinyl ethers as counterparts does not only represent a practical, powerful and straightforward alternative to organic halides, but also constitutes an excellent opportunity to improve our chemical knowledge about a relatively unexplored area of expertise. This review summarizes the most significant developments in the area of C-O bond-cleavage when employing aryl or vinyl ethers, providing a detailed overview of the current state of the art and including future aspects, when applicable.

13.
J Am Chem Soc ; 136(6): 2236-9, 2014 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-24476124

RESUMO

A Ni/Cu-catalyzed silylation of unactivated C-O electrophiles derived from phenols or benzyl alcohols is described. This transformation is characterized by its wide scope and mild conditions, providing a direct access to synthetically versatile silylated compounds. The protocol allows for the coupling of C(sp(2))-O and even C(sp(3))-O bonds with similar efficiency.

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