RESUMEN
As sp2-sp3 disconnections gain acceptance in the medicinal chemist's toolbox, an increasing number of potential drug candidates containing this motif are moving into the pharmaceutical development pipeline. This raises a new set of questions and challenges around the novel, direct methodologies available for forging these bonds. These questions gain further importance in the context of process chemistry, where the focus is the development of scalable processes that enable the large-scale delivery of clinical supplies. In this paper, we describe our efforts to apply a wide variety of standard, photo-, and electrochemical sp2-sp3 cross-coupling methods to a pharmaceutically relevant intermediate and optimize each through a combination of high throughput and mechanistically guided experimentation. With data regarding the performance, benefits, and limitations of these novel methods, we evaluate them against a more traditional two-step palladium-catalyzed process. This work reveals trends and similarities between these sp2-sp3 bond-forming methods and suggests a path forward for further refinements.
Asunto(s)
Benchmarking , Preparaciones Farmacéuticas , Catálisis , PaladioRESUMEN
Alkyl chlorides and aryl chlorides are among the most abundant and stable carbon electrophiles. Although their coupling with carbon nucleophiles is well developed, the cross-electrophile coupling of aryl chlorides with alkyl chlorides has remained a challenge. We report here the first general approach to this transformation. The key to productive, selective cross-coupling is the use of a small amount of iodide or bromide along with a recently reported ligand, pyridine-2,6-bis(N-cyanocarboxamidine) (PyBCamCN). The scope of the reaction is demonstrated with 35 examples (63 ± 16% average yield), and we show that the Br- and I- additives act as cocatalysts, generating a low, steady-state concentration of more-reactive alkyl bromide/iodide.
Asunto(s)
Hidrocarburos Clorados , Níquel/química , Catálisis , Hidrocarburos Clorados/síntesis química , Hidrocarburos Clorados/química , Estructura MolecularRESUMEN
We report the development of palladium(0)-catalyzed syn-selective 1,2-carboboration and -silylation reactions of alkenes containing cleavable directing groups. With B2 pin2 or PhMe2 Si-Bpin as nucleophiles and aryl/alkenyl triflates as electrophiles, a broad range of mono-, di-, tri- and tetrasubstituted alkenes are compatible in these transformations. We further describe a directed dearomative 1,2-carboboration of electron-rich heteroarenes by employing this approach. Through use of a removable chiral directing group, we demonstrate the viability of achieving stereoinduction in Heck-type alkene 1,2-difunctionalization. This work introduces new avenues to access highly functionalized boronates and silanes with precise regio- and stereocontrol.
Asunto(s)
Alquenos/química , Compuestos Heterocíclicos/química , Paladio/química , Silanos/química , Catálisis , Ciclización , Estructura MolecularRESUMEN
While the use of triphenylphosphine as a reductant is common in organic synthesis, the resulting triphenylphosphine oxide (TPPO) waste can be difficult to separate from the reaction product. While a number of strategies to precipitate TPPO are available, none have been reported to work in more polar solvents. We report here that mixing ZnCl2 with TPPO precipitates a TPPO-Zn complex in high yield in several common polar organic solvents. The solvent compatibility of this procedure and the reliability of the precipitation in the presence of polar functional groups were examined to show the utility and limitations of this method.
Asunto(s)
Acetatos/química , Cloruros/química , Etanol/química , Furanos/química , Compuestos Organofosforados/aislamiento & purificación , Compuestos de Zinc/química , Estructura Molecular , Compuestos Organofosforados/química , Solventes/químicaRESUMEN
The activation of carbodicarbene (CDC)-Rh(I) pincer complexes by secondary binding of metal salts is reported for the catalytic site-selective hydro-heteroarylation of dienes (up to 98% yield and >98:2 γ:α). Reactions are promoted by 5 mol % of a readily available tridentate (CDC)-Rh complex in the presence of an inexpensive lithium salt. The reaction is compatible with a variety of terminal and internal dienes and tolerant of ester, alkyl halide, and boronate ester functional groups. X-ray data and mechanistic experiments provide support for the role of the metal salts on catalyst activation and shed light on the reaction mechanism. The increased efficiency (120 to 22 °C) made available by catalytic amounts of metal salts to catalysts containing C(0) donors is a significant aspect of the disclosed studies.
RESUMEN
A catalytic protocol for the diastereoselective synthesis of anti-1,2-hydroxyboronates is described. The process provides access to secondary alkyl organoborons. The deborylative 1,2-addition reactions of alkyl 1,1-diborons proceed in the presence of a silver(I) salt with either KOtBu or nBuLi as an activator. The catalytic diastereoselective protocol can be extended to aryl, alkenyl, and alkyl aldehydes with up to 99:1 d.r.
RESUMEN
A carbodicarbene (CDC)-based pincer ligand scaffold is reported, along with its application to site-selective Rh(I)-catalyzed intermolecular hydroamination of 1,3-dienes with aryl and alkyl amines. To the best of our knowledge, this is the first example of the use of a well-defined CDC complex as an efficient catalyst. Transformations proceed in the presence of 1.0-5.0 mol % Rh complex at 35-120 °C; allylic amines are obtained in up to 97% yield and with >98:2 site selectivity.
Asunto(s)
Compuestos Alílicos/química , Aminas/síntesis química , Complejos de Coordinación/química , Metano/análogos & derivados , Polienos/química , Rodio/química , Compuestos Alílicos/síntesis química , Aminación , Aminas/química , Catálisis , Metano/química , Modelos Moleculares , Fosfinas/químicaRESUMEN
Catalytic intermolecular hydroalkylation of dienes with silyloxyfuran nucleophiles is reported. Reactions are catalyzed by 5 mol % of a (CDC)-Rh complex and proceed in up to 87% yield and 6:1 dr (syn/anti) to provide allylic butenolides bearing vicinal stereocenters. Reactions proceed with terminal aryl and alkyl dienes and with modified silyl enol ether nucleophiles including a thiophenone variant. Utility of the products is demonstrated in the synthesis of a polypropionate anti,syn-stereotriad.
RESUMEN
An efficient and diastereoselective (CDC)-Rh-catalyzed hydroalkylation of dienes with 1,3-oxazol-5(4H)-ones is reported. Aryl and alkyl substituted dienes are converted to α,α-substituted oxazolones (24 examples) by the formation of N-substituted quaternary carbon stereogenic centers in good yields (up to 96%) and with high diastereoselectivity (>20 : 1 dr). The reaction is tolerant of a range of dienes and oxazolones bearing various functional groups. Utility of the oxazolone products is illustrated through hydrolysis to form α,ß-substituted α-amino acid analogues and stereoselective epoxidation of the resultant alkene to create four contiguous stereocenters.
RESUMEN
Ligand cross-linking is known to improve the colloidal stability of nanoparticles, particularly in aqueous solutions. However, most cross-linking is performed chemically, in which it is difficult to limit interparticle cross-linking, unless performed at low concentrations. Photochemical cross-linking is a promising approach but usually requires ultraviolet (UV) light to initiate. Using such high-energy photons can be harmful to systems in which the ligand-nanoparticle bond is fairly weak, as is the case for the commonly used semiconductor quantum dots (QDs). Here, we introduce a novel approach to cross-link thiolated ligands on QDs by utilizing the photocatalytic activity of QDs upon absorbing visible light. We show that using visible light leads to better ligand cross-linking by avoiding the problem of ligand dissociation that occurs upon UV light exposure. Once cross-linked, the ligands significantly enhance the colloidal stability of those same QDs that facilitated cross-linking.