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1.
Org Lett ; 21(24): 10159-10163, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31820654

RESUMO

Generation of a ketyl radical from unactivated aliphatic carbonyl compounds is an important strategy in organic synthesis. Herein, catalytic generation and use of a ketyl radical for the reductive coupling of aliphatic carbonyl compounds and styrenes by organic photoredox catalysis is described. The method is applicable to both aliphatic ketones and aldehydes to afford the corresponding tertiary and secondary alcohols in continuous flow and batch. Preliminary mechanistic investigation suggests the catalytic formation of a ketyl radical intermediate.

2.
J Org Chem ; 84(22): 15001-15007, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31657562

RESUMO

We report the preparation of enantiomerically enriched ß-thio-α-hydroxy and α-chloro carboxylic acid and ester building blocks by diazotization of S-sulfonyl-cysteines. The thiosulfonate protecting group demonstrated resistance to oxidation and attenuation of sulfur's nucleophilicity by the anomeric effect. The key transformation was optimized by a 22 factorial design of experiment, highlighting the unique reactivity of cysteine derivatives in comparison with aliphatic amino acids.

3.
Chemistry ; 25(64): 14527-14531, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31625640

RESUMO

A strategy for the continuous flow synthesis of angiotensin converting enzyme (ACE) inhibitors is described. An optimization effort guided by in situ IR analysis resulted in a general amide coupling approach facilitated by N-carboxyanhydride (NCA) activation that was further characterized by reaction kinetics analysis in batch. The three-step continuous process was demonstrated by synthesizing 8 different ACE inhibitors in up to 88 % yield with throughputs in the range of ≈0.5 g h-1 , all while avoiding both isolation of reactive intermediates and process intensive reaction conditions. The process was further developed by preparing enalapril, a World Health Organization (WHO) essential medicine, in an industrially relevant flow platform that scaled throughput to ≈1 g h-1 .


Assuntos
Alanina/química , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/síntese química , Enalapril/química , Cinética , Espectrofotometria Infravermelho
4.
Org Lett ; 21(19): 8027-8030, 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31523969

RESUMO

Synthesis of the fused polycyclic ether motif comprising the EFG rings of the marine ladder polyethers tamulamides A and B has been achieved via two different etherification strategies. Ultimately, a reductive etherification approach proved most successful due to tolerance of the G ring substitution and provided the EFG 6,7,6 ring system in 58% yield.

5.
Science ; 365(6453)2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31395756

RESUMO

The synthesis of complex organic molecules requires several stages, from ideation to execution, that require time and effort investment from expert chemists. Here, we report a step toward a paradigm of chemical synthesis that relieves chemists from routine tasks, combining artificial intelligence-driven synthesis planning and a robotically controlled experimental platform. Synthetic routes are proposed through generalization of millions of published chemical reactions and validated in silico to maximize their likelihood of success. Additional implementation details are determined by expert chemists and recorded in reusable recipe files, which are executed by a modular continuous-flow platform that is automatically reconfigured by a robotic arm to set up the required unit operations and carry out the reaction. This strategy for computer-augmented chemical synthesis is demonstrated for 15 drug or drug-like substances.

6.
J Am Chem Soc ; 141(28): 11239-11244, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31283211

RESUMO

Herein, we report the first total synthesis of marine ladder polyether gymnocin B (1) based on a two-phase strategy. In Phase I, inspired by the proposed biosynthesis, epoxide-opening cascades assemble 10 out of 15 cyclic ether rings making up the molecular core. In the subsequent Phase II, coalescence elevates the molecular complexity further by coupling of these subunits. Our two-phase synthetic approach significantly improved the step efficiency of the synthesis of this class of natural products.

7.
Org Lett ; 21(15): 6112-6116, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31314541

RESUMO

A modular continuous flow synthesis of imatinib and analogues is reported. Structurally diverse imatinib analogues are rapidly generated using three readily available building blocks via a flow hydration/chemoselective C-N coupling sequence. The newly developed continuous flow hydration and amidation modules each exhibit a broad scope with good to excellent yields. Overall, the method described does not require solvent switches, in-line purifications, or packed-bed apparatuses due to the judicious manipulation of flow setups and solvent mixtures.

8.
Org Lett ; 21(10): 3606-3609, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31046296

RESUMO

Skipped polyenes featuring high ( E)-selectivity and varying methyl substitution patterns are synthesized using a nickel-catalyzed cross-coupling reaction between allyl trifluoroacetates and vinyl bromides. The utility of this cross-electrophile coupling is showcased in part by the synthesis of the RST fragment of the marine ladder polyether, maitotoxin. Construction of this fragment is particularly challenging due to the alternating methyl substitution pattern.


Assuntos
Níquel/química , Polienos/síntese química , Compostos de Vinila/química , Catálise , Estrutura Molecular , Polienos/química
9.
Angew Chem Int Ed Engl ; 58(23): 7678-7681, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-30964955

RESUMO

Herein, the blockbuster antibacterial drug linezolid is synthesized from simple starting blocks by a convergent continuous flow sequence involving seven (7) chemical transformations. This is the highest total number of distinct reaction steps ever performed in continuous flow without conducting solvent exchanges or intermediate purification. Linezolid was obtained in 73 % isolated yield in a total residence time of 27 minutes, corresponding to a throughput of 816 mg h-1 .

10.
Chem Sci ; 10(2): 370-377, 2019 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-30746086

RESUMO

We present a supervised learning approach to predict the products of organic reactions given their reactants, reagents, and solvent(s). The prediction task is factored into two stages comparable to manual expert approaches: considering possible sites of reactivity and evaluating their relative likelihoods. By training on hundreds of thousands of reaction precedents covering a broad range of reaction types from the patent literature, the neural model makes informed predictions of chemical reactivity. The model predicts the major product correctly over 85% of the time requiring around 100 ms per example, a significantly higher accuracy than achieved by previous machine learning approaches, and performs on par with expert chemists with years of formal training. We gain additional insight into predictions via the design of the neural model, revealing an understanding of chemistry qualitatively consistent with manual approaches.

12.
Science ; 361(6408): 1220-1225, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-30237351

RESUMO

Chemical synthesis generally requires labor-intensive, sometimes tedious trial-and-error optimization of reaction conditions. Here, we describe a plug-and-play, continuous-flow chemical synthesis system that mitigates this challenge with an integrated combination of hardware, software, and analytics. The system software controls the user-selected reagents and unit operations (reactors and separators), processes reaction analytics (high-performance liquid chromatography, mass spectrometry, vibrational spectroscopy), and conducts automated optimizations. The capabilities of this system are demonstrated in high-yielding implementations of C-C and C-N cross-coupling, olefination, reductive amination, nucleophilic aromatic substitution (SNAr), photoredox catalysis, and a multistep sequence. The graphical user interface enables users to initiate optimizations, monitor progress remotely, and analyze results. Subsequent users of an optimized procedure need only download an electronic file, comparable to a smartphone application, to implement the protocol on their own apparatus.

13.
Organometallics ; 37(16): 2716-2722, 2018 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-30174368

RESUMO

Herein, we report the synthesis and characterization of a new class of air- and moisture-stable phosphine-containing nickel(II) precatalysts, which activate through a Heck-type mechanism. The activities of the precatalysts are demonstrated with a carbonyl-ene coupling reaction.

14.
ChemCatChem ; 10(13): 2873-2877, 2018 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-30147804

RESUMO

Herein, we introduce a new class of bench-stable N-heterocyclic carbene (NHC) nickel-precatalysts for homogeneous nickel-catalysis. The nickel(II) complexes are readily activated to Ni0 in situ under mild conditions, via a proposed Heck-type mechanism. The precatalysts are shown to facilitate carbonyl-ene, hydroalkenylation, and amination reactions.

15.
Bioorg Med Chem ; 26(19): 5327-5335, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-29729986

RESUMO

Synthesis of the fused tetrahydrofuran motif comprising the ABC rings of the marine ladder polyethers tamulamides A and B has been achieved via two different polyepoxide cascade strategies. Investigations into a triepoxide cascade under aqueous conditions revealed the importance of the electronic nature of the cascade end-group with this initial approach. Ultimately, a diepoxide cascade under basic conditions proved most successful, providing the ABC tetrahydropyran triad in 41% yield.


Assuntos
Toxinas Marinhas/síntese química , Oxocinas/síntese química , Ciclização , Compostos de Epóxi/química , Furanos/química
16.
Proc Natl Acad Sci U S A ; 115(23): E5298-E5306, 2018 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-29784819

RESUMO

Chemical methods have enabled the total synthesis of protein molecules of ever-increasing size and complexity. However, methods to engineer synthetic proteins comprising noncanonical amino acids have not kept pace, even though this capability would be a distinct advantage of the total synthesis approach to protein science. In this work, we report a platform for protein engineering based on the screening of synthetic one-bead one-compound protein libraries. Screening throughput approaching that of cell surface display was achieved by a combination of magnetic bead enrichment, flow cytometry analysis of on-bead screens, and high-throughput MS/MS-based sequencing of identified active compounds. Direct screening of a synthetic protein library by these methods resulted in the de novo discovery of mirror-image miniprotein-based binders to a ∼150-kDa protein target, a task that would be difficult or impossible by other means.


Assuntos
Técnicas de Química Combinatória/métodos , Biblioteca de Peptídeos , Engenharia de Proteínas/métodos , Proteínas/síntese química , Aminoácidos , Citometria de Fluxo/métodos , Humanos , Microesferas , Ligação Proteica , Proteínas/genética , Espectrometria de Massas em Tandem/métodos
17.
Org Lett ; 20(11): 3263-3267, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29761699

RESUMO

Highly functionalized 2-arylindoles were synthesized from 2-alkenylarylisocyanides and arylboronic acids using a simple, inexpensive copper catalyst. The reaction exhibits excellent functional group tolerance for both the arylisocyanide and boronic acid coupling partners. To avoid the direct handling of the pungent arylisocyanide starting materials, continuous flow chemistry is further demonstrated to provide safe and effective access to 2-arylindoles through in situ dehydration and cyclization of easy-to-handle 2-alkenyl- N-formylanilines.

18.
Angew Chem Int Ed Engl ; 57(24): 7181-7185, 2018 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-29756689

RESUMO

Dolutegravir (DTG), an important active pharmaceutical ingredient (API) used in combination therapy for the treatment of HIV, has been synthesized in continuous flow. By adapting the reported GlaxoSmithKline process chemistry batch route for Cabotegravir, DTG was produced in 4.5 h in sequential flow operations from commercially available materials. Key features of the synthesis include rapid manufacturing time for pyridone formation, one-step direct amidation of a functionalized pyridone, and telescoping of multiple steps to avoid isolation of intermediates and enable for greater throughput.


Assuntos
Inibidores de Integrase de HIV/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Amidas/síntese química , Amidas/química , Técnicas de Química Combinatória/economia , Técnicas de Química Combinatória/métodos , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/química , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Piridonas/síntese química , Piridonas/química , Fatores de Tempo
19.
Org Lett ; 20(5): 1338-1341, 2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-29431449

RESUMO

An electrochemically driven, nickel-catalyzed reductive coupling of N-hydroxyphthalimide esters with aryl halides is reported. The reaction proceeds under mild conditions in a divided electrochemical cell and employs a tertiary amine as the reductant. This decarboxylative C(sp3)-C(sp2) bond-forming transformation exhibits excellent substrate generality and functional group compatibility. An operationally simple continuous-flow version of this transformation using a commercial electrochemical flow reactor represents a robust and scalable synthesis of value added coupling process.

20.
Chemistry ; 24(11): 2776-2784, 2018 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-29385292

RESUMO

As a demonstration of an alternative to the challenges faced with batch pharmaceutical manufacturing including the large production footprint and lengthy time-scale, we previously reported a refrigerator-sized continuous flow system for the on-demand production of essential medicines. Building on this technology, herein we report a second-generation, reconfigurable and 25 % smaller (by volume) continuous flow pharmaceutical manufacturing platform featuring advances in reaction and purification equipment. Consisting of two compact [0.7 (L)×0.5 (D)×1.3 m (H)] stand-alone units for synthesis and purification/formulation processes, the capabilities of this automated system are demonstrated with the synthesis of nicardipine hydrochloride and the production of concentrated liquid doses of ciprofloxacin hydrochloride, neostigmine methylsulfate and rufinamide that meet US Pharmacopeia standards.


Assuntos
Preparações Farmacêuticas/síntese química , Automação , Ciprofloxacino/síntese química , Ciprofloxacino/isolamento & purificação , Neostigmina/síntese química , Neostigmina/isolamento & purificação , Nicardipino/síntese química , Nicardipino/isolamento & purificação , Preparações Farmacêuticas/isolamento & purificação , Triazóis/síntese química , Triazóis/isolamento & purificação
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