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1.
Org Lett ; 26(8): 1533-1538, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38363757

RESUMEN

A highly enantioselective organocatalytic aza-Michael addition of 4-nitro-pyrazole to ethyl (E)-2,2-difluoro-5-oxopent-3-enoate has been developed. This reaction enabled a concise, four-step, stereoselective synthesis of highly functionalized 3,3-difluoro-4-pyrazolo-piperidine GSK3901383A, a key intermediate for the synthesis of a leucine-rich repeat kinase 2 inhibitor API. Computational analysis provided insight into the steric requirements of the catalytic system, enabling rational selection of a highly selective catalyst.

2.
Org Lett ; 26(14): 2857-2861, 2024 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-38198695

RESUMEN

The C-aryl-tetrahydropyran motif is prevalent in nature in a number of natural products with biological activity; however, this challenging architecture still requires novel synthetic approaches. We demonstrate the application of a stereoselective Heck redox-relay strategy for the synthesis of functionalized 2,6-trans-tetrahydropyrans in excellent selectivity in a single step from an enantiopure dihydropyranyl alcohol, proceeding through a novel exo-cyclic migration. The strategy has also been applied to the total synthesis of a trans-epimer of the natural product centrolobine in excellent yield and stereoselectivity.

3.
J Am Chem Soc ; 144(33): 15026-15032, 2022 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-35969692

RESUMEN

Axial chirality features prominently in molecules of biological interest as well as chiral catalyst designs, and atropisomeric 2,2'-biphenols are particularly prevalent. Atroposelective metal-catalyzed cross-coupling is an attractive and modular approach to access enantioenriched biphenols, and yet existing protocols cannot achieve this directly. We address this challenge through the use of enantiopure, sulfonated SPhos (sSPhos), an existing ligand that has until now been used only in racemic form and that derives its chirality from an atropisomeric axis that is introduced through sulfonation. We believe that attractive noncovalent interactions involving the ligand sulfonate group are responsible for the high levels of asymmetric induction that we obtain in the 2,2'-biphenol products of Suzuki-Miyaura coupling, and we have developed a highly practical resolution of sSPhos via diastereomeric salt recrystallization.


Asunto(s)
Estereoisomerismo , Catálisis , Ligandos
4.
Chemistry ; 27(1): 158-174, 2021 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-32744766

RESUMEN

Exploration of novel, three-dimensional chemical space is of growing interest in the drug discovery community and with this comes the challenge for synthetic chemists to devise new stereoselective methods to introduce chirality in a rapid and efficient manner. This Minireview provides a timely summary of the development of palladium-catalyzed asymmetric redox-relay Heck-type processes. These reactions represent an important class of transformation for the selective introduction of remote stereocenters, and have risen to prominence over the past decade. Within this Minireview, the vast scope of these transformations will be showcased, alongside applications to pharmaceutically relevant chiral building blocks and drug substances. To complement this overview, a mechanistic summary and discussion of the current limitations of the transformation are presented, followed by an outlook on future areas of investigation.

5.
Chem Sci ; 11(35): 9494-9500, 2020 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-34123174

RESUMEN

We report reductive alkylation reactions of amines using carboxylic acids as nominal electrophiles. The two-step reaction exploits the dual reactivity of phenylsilane and involves a silane-mediated amidation followed by a Zn(OAc)2-catalyzed amide reduction. The reaction is applicable to a wide range of amines and carboxylic acids and has been demonstrated on a large scale (305 mmol of amine). The rate differential between the reduction of tertiary and secondary amide intermediates is exemplified in a convergent synthesis of the antiretroviral medicine maraviroc. Mechanistic studies demonstrate that a residual 0.5 equivalents of carboxylic acid from the amidation step is responsible for the generation of silane reductants with augmented reactivity, which allow secondary amides, previously unreactive in zinc/phenylsilane systems, to be reduced.

6.
Angew Chem Int Ed Engl ; 55(29): 8270-4, 2016 07 11.
Artículo en Inglés | MEDLINE | ID: mdl-27206223

RESUMEN

Methods for functionalizing carbon-hydrogen bonds are featured in a new synthesis of the tricyclic core architecture that characterizes the indoxamycin family of secondary metabolites. A unique collaboration between three laboratories has engendered a design for synthesis featuring two sequential C-H functionalization reactions, namely a diastereoselective dirhodium carbene insertion followed by an ester-directed oxidative Heck cyclization, to rapidly assemble the congested tricyclic core of the indoxamycins. This project exemplifies how multi-laboratory collaborations can foster conceptually novel approaches to challenging problems in chemical synthesis.

7.
J Med Chem ; 55(19): 8464-76, 2012 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-22951074

RESUMEN

Human cytochrome P450 aromatase catalyzes with high specificity the synthesis of estrogens from androgens. Aromatase inhibitors (AIs) such as exemestane, 6-methylideneandrosta-1,4-diene-3,17-dione, are preeminent drugs for the treatment of estrogen-dependent breast cancer. The crystal structure of human placental aromatase has shown an androgen-specific active site. By utilization of the structural data, novel C6-substituted androsta-1,4-diene-3,17-dione inhibitors have been designed. Several of the C6-substituted 2-alkynyloxy compounds inhibit purified placental aromatase with IC(50) values in the nanomolar range. Antiproliferation studies in a MCF-7 breast cancer cell line demonstrate that some of these compounds have EC(50) values better than 1 nM, exceeding that for exemestane. X-ray structures of aromatase complexes of two potent compounds reveal that, per their design, the novel side groups protrude into the opening to the access channel unoccupied in the enzyme-substrate/exemestane complexes. The observed structure-activity relationship is borne out by the X-ray data. Structure-guided design permits utilization of the aromatase-specific interactions for the development of next generation AIs.


Asunto(s)
Androstadienos/síntesis química , Antineoplásicos/síntesis química , Inhibidores de la Aromatasa/síntesis química , Androstadienos/química , Androstadienos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Inhibidores de la Aromatasa/química , Inhibidores de la Aromatasa/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Placenta/enzimología , Embarazo , Unión Proteica , Estereoisomerismo , Relación Estructura-Actividad
8.
Angew Chem Int Ed Engl ; 51(34): 8636-9, 2012 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-22807172

RESUMEN

Siloxy group migration: A rhodium(II) carbenoid approach has been developed for the synthesis of alkynoates. This transformation combines the addition of enol ethers at the vinylogous position of ß-siloxy-substituted vinyldiazo derivatives with a siloxy group migration to give the products as single diastereomers.


Asunto(s)
Alquinos/síntesis química , Ésteres/química , Rodio/química , Catálisis , Cristalografía por Rayos X , Éteres/química , Modelos Moleculares , Estructura Molecular , Estereoisomerismo
9.
Org Lett ; 11(22): 5358-61, 2009 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-19856904

RESUMEN

A triflimide-activated oxazaborolidine catalyst successfully promoted the asymmetric Diels-Alder reaction of 9-methylanthracene with methacrolein in high regio- and enantioselectivity. The cycloadduct obtained was subsequently used as a chiral template to access secondary and tertiary allylic alcohols in good to high enantiomeric excess via a cycloreversion by flash vacuum pyrolysis.

10.
J Org Chem ; 70(19): 7578-84, 2005 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-16149786

RESUMEN

[reactions: see text] Palladium hydroxide on carbon (Pearlman's catalyst) effectively catalyzes direct arylation reactions of aryl iodides and bromides, providing excellent arylation-to-hydrodehalogenation ratios (>30:1) with broad scope for both intra- and intermolecular arylation processes. Studies aimed at determining the nature of the active catalyst indicate that an active homogeneous palladium species is produced under the reaction conditions.

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