RESUMO
A Rh-catalyzed enantioselective hydroamination of allylamines using a chiral BIPHEP-type ligand is reported. Enantioenriched 1,2-diamines are formed in good yields and with excellent enantioselectivities. A diverse array of nucleophiles and amine directing groups are demonstrated, including deprotectable motifs. Finally, the methodology was demonstrated toward the rapid synthesis of 2-methyl-moclobemide.
Assuntos
Compostos Alílicos/síntese química , Aminas/síntese química , Ródio/química , Aminação , Catálise , Complexos de Coordenação/química , Ligantes , Moclobemida/síntese química , EstereoisomerismoRESUMO
The combination of nickel metallaphotoredox catalysis, hydrogen atom transfer catalysis, and a Lewis acid activation mode, has led to the development of an arylation method for the selective functionalization of alcohol α-hydroxy C-H bonds. This approach employs zinc-mediated alcohol deprotonation to activate α-hydroxy C-H bonds while simultaneously suppressing C-O bond formation by inhibiting the formation of nickel alkoxide species. The use of Zn-based Lewis acids also deactivates other hydridic bonds such as α-amino and α-oxy C-H bonds. This approach facilitates rapid access to benzylic alcohols, an important motif in drug discovery. A 3-step synthesis of the drug Prozac exemplifies the utility of this new method.
RESUMO
A weak Brønsted acid-catalyzed asymmetric guanidine aza-conjugate addition reaction has been developed. C2-symmetric, dual hydrogen-bond donating bistriflamides are shown to be highly effective in activating α,ß-unsaturated esters toward the intramolecular addition of a pendant guanidinyl nucleophile. Preliminary mechanistic investigation, including density functional theory calculations and kinetics studies, support a conjugate addition pathway as more favorable energetically than an alternative electrocyclization pathway. This methodology has been successfully applied to the synthesis of the 3,4-dihydroquinazoline-containing antiviral, Letermovir, and a series of analogues.
Assuntos
Acetatos/síntese química , Antivirais/síntese química , Teoria Quântica , Quinazolinas/química , Acetatos/química , Acetatos/farmacologia , Antivirais/química , Antivirais/farmacologia , Catálise , Ciclização , Ligação de Hidrogênio , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/farmacologiaRESUMO
α- and ß-substitution of dihydrocinnamates has been shown to increase the biological activity of various drug candidates. Recently, we identified enantio- and diastereopure α-methyl-ß-cyclopropyldihydrocinnamates to be important pharmacophores in one of our drug discovery programs and endeavored to devise an asymmetric hydrogenation strategy to improve access to this valuable framework. We used high throughput experimentation to define stereoconvergent Suzuki-Miyaura cross-coupling conditions affording (Z)-α-methyl-ß-cyclopropylcinnamates and subsequent ruthenium-catalyzed asymmetric hydrogenation conditions affording the desired products in excellent enantio- and diastereoselectivities. These conditions were executed on multigram to kilogram scale to provide three key enantiopure α-methyl-ß-cyclopropyldihydrocinnamates with high selectivity.
RESUMO
We describe the impact of proline modifications, in our tetracyclic-indole based series of nonstructural protein 5A (NS5A) inhibitors, to their replicon profiles. This work identified NS5A inhibitors with an improved and flattened resistance profiles.
Assuntos
Antivirais/farmacologia , Benzofuranos/farmacologia , Imidazóis/farmacologia , Indóis/química , Prolina/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Benzofuranos/química , Imidazóis/química , Relação Estrutura-AtividadeRESUMO
A microscale chemistry improvement engine: a pre-dosed microscale high-throughput experimentation additives platform enables rapid, serendipitous reaction improvement. This platform allowed one chemist to set up 475 experiments and analyze the results using MISER chromatography in a single day, thus resulting in two high-quality catalytic systems for the construction of the title compound 1. Support for a single-electron transfer mechanism was obtained.
Assuntos
Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/química , Ensaios de Triagem em Larga Escala/métodos , Pirimidinonas/metabolismo , Catálise , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl3/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides.
RESUMO
Identifying catalyst activation modes that exploit one-electron chemistry and overcome associated deactivation pathways will be transformative for developing first-row transition metal catalysts with performance equal or, ideally, superior to precious metals. Here we describe a zinc-activation method compatible with high-throughput reaction discovery that identified scores of cobalt-phosphine combinations for the asymmetric hydrogenation of functionalized alkenes. An optimized catalyst prepared from (R,R)-Ph-BPE {Ph-BPE, 1,2-bis[(2R,5R)-2,5-diphenylphospholano]ethane} and cobalt chloride [CoCl2·6H2O] exhibited high activity and enantioselectivity in protic media and enabled the asymmetric synthesis of the epilepsy medication levetiracetam at 200-gram scale with 0.08 mole % catalyst loading. Stoichiometric studies established that the cobalt (II) catalyst precursor (R,R)-Ph-BPECoCl2 underwent ligand displacement by methanol, and zinc promoted facile one-electron reduction to cobalt (I), which more stably bound the phosphine.
RESUMO
Quantitative structure-activity relationships have an extensive history for optimizing drug candidates, yet they have only recently been applied in reaction development. In this report, the predictive power of multivariate parameterization has been explored toward the optimization of a catalyst promoting an aza-Michael conjugate addition for the asymmetric synthesis of letermovir. A hybrid approach combining 2D QSAR and modern 3D physical organic parameters performed better than either approach in isolation. Using these predictive models, a series of new catalysts were identified, which catalyzed the reaction to provide the desired product in improved enantioselectivity relative to the parent catalyst.
RESUMO
We describe the discovery of MK-6169, a potent and pan-genotype hepatitis C virus NS5A inhibitor with optimized activity against common resistance-associated substitutions. SAR studies around the combination of changes to both the valine and aminal carbon region of elbasvir led to the discovery of a series of compounds with substantially improved potency against common resistance-associated substitutions in the major genotypes, as well as good pharmacokinetics in both rat and dog. Through further optimization of key leads from this effort, MK-6169 (21) was discovered as a preclinical candidate for further development.
Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Farmacorresistência Viral/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacocinética , Cães , Genótipo , Hepacivirus/genética , Hepacivirus/metabolismo , Masculino , Ratos , Distribuição TecidualRESUMO
A practical and asymmetric synthesis of a functionalized trans-cyclopropoxy building block for the preparation of the HCV NS3/4a protease inhibitor grazoprevir is reported. Intramolecular SN2 displacement-ring closure, followed by a Baeyer-Villiger oxidation, yields the desired trans-cyclopropanol with full control of diastereoselectivity. A terminal alkyne is then effectively installed using LiNH(CH2)2NEt2. Starting from (S)-epichlorohydrin, the cyclopropoxy building block is prepared in 51% overall yield with >99.8% optical purity without isolation of any intermediates.
RESUMO
The direct and chemoselective 3'-phosphoramidation, phosphorylation and acylation of nucleosides are described. Upon the discovery of a novel 3'-phosphorylamidation of therapeutic nucleoside analogues with DBU, we explored the mechanism of this rare selectivity through a combination of NMR spectroscopy and computational studies. The NMR and computational findings allowed us to develop a predictive computational model that accurately assesses the potential for 3'-functionalization for a broad range of nucleosides and nucleoside mimetics. The synthetic utility of this model was exemplified by demonstration on a broad scope of nucleosides and electrophiles yielding targets that were previously only accessible via a protection/deprotection sequence or an enzymatic approach.
RESUMO
Significant catalyst loading reduction and increased reaction robustness have been achieved for a Pd-catalyzed asymmetric intramolecular C-N coupling through comprehensive mechanistic studies. Detailed kinetic, spectroscopic, and crystallographic analyses revealed that the mono-oxidation of the bis-phosphine ligand is critical for a successful transformation. 31P NMR studies provided an understanding of the inefficient activation of the Pd(OAc)2/(R,R)-QuinoxP* pre-catalyst to form the active bis-phosphine mono-oxide-Pd(0) catalyst with competitive formation of a less active (R,R)-QuinoxP*·PdBr2 complex. Based on these detailed mechanistic studies, a new series of bis-phosphine mono-oxides (BPMO)-ligated Pd(ii) pre-catalysts have been rationally developed that allow for reliable and complete catalyst activation which should have general utility in academic and industrial settings.