RESUMEN
The catalytic enantioselective synthesis of α-chiral alkenes and alkynes represents a powerful strategy for rapid generation of molecular complexity. Herein, we report a transient directing group (TDG) strategy to facilitate site-selective palladium-catalyzed reductive Heck-type hydroalkenylation and hydroalkynylation of alkenylaldehyes using alkenyl and alkynyl bromides, respectively, allowing for construction of a stereocenter at the δ-position with respect to the aldehyde. Computational studies reveal the dual beneficial roles of rigid TDGs, such as L-tert-leucine, in promoting TDG binding and inducing high levels of enantioselectivity in alkene insertion with a variety of migrating groups.
RESUMEN
The site-selective palladium-catalyzed three-component coupling of unactivated alkenyl carbonyl compounds, aryl- or alkenylboronic acids, and N-fluorobenzenesulfonimide is described herein. Tuning of the steric environment on the bidentate directing auxiliary enhances regioselectivity and facilitates challenging C(sp3 )-F reductive elimination from a PdIV intermediate to afford 1,2-carbofluorination products in moderate to good yields.
Asunto(s)
Alquenos , Paladio , CatálisisRESUMEN
The vicinal fluorofunctionalization of alkenes represents an expedient strategy for converting feedstock olefins into valuable fluorinated molecules and as such has garnered significant attention from the synthetic community; however, current methods remain limited in terms of scope and selectivity. Here we report the site-selective palladium-catalyzed three-component coupling of alkenylbenzaldehydes, arylboronic acids, and N-fluoro-2,4,6-trimethylpyridinium hexafluorophosphate facilitated by a transient directing group. The synthetically enabling methodology constructs vicinal stereocenters with excellent regio-, diastereo-, and enantioselectivities, forging products that map onto bioactive compounds.
Asunto(s)
Fluorocarburos/síntesis química , Paladio/química , Catálisis , Fluorocarburos/química , Estructura Molecular , EstereoisomerismoRESUMEN
Metal-coordinating directing groups have seen extensive use in the field of transition-metal-catalyzed alkene functionalization; however, their waste-generating installation and removal steps limit the efficiency and practicality of reactions that rely on their use. Inspired by developments in asymmetric organocatalysis, where reactions rely on reversible covalent interactions between an organic substrate and a chiral mediator, we have developed a transient-directing-group approach to reductive Heck hydroarylation of alkenyl benzaldehyde substrates that proceeds under mild conditions. Highly stereoselective migratory insertion is facilitated by inâ situ formation of an imine from catalytic amounts of a commercially available amino acid additive. Computational studies reveal an unusual mode of enantioinduction by the remote chiral center in the transient directing group.
Asunto(s)
Alquenos/química , Benzaldehídos/química , Catálisis , Estereoisomerismo , Temperatura , Elementos de Transición/químicaRESUMEN
The Mizoroki-Heck reaction is one of the most studied palladium-catalyzed cross-coupling reactions, representing a powerful method for forming C-C bonds between diverse substrates with broad functional group compatibility. However, the reductive variant has received considerably less attention. In this Review, we summarize distinct mechanistic aspects of the reductive Heck reaction, highlight recent contributions to the field, and discuss potential applications of the reductive Heck reaction in the pharmaceutical industry. With the potential to have a large impact in both academic and industrial settings, further development of the reductive Heck reaction is a promising area of future investigation.
RESUMEN
The incorporation of fluorine into organic scaffolds often improves the bioactivity of pharmaceutically relevant compounds. C-F/C-N/C-O stereotriad motifs are prevalent in antivirals, neuraminidase inhibitors, and modulators of androgen receptors, but are challenging to install. An oxidative allene amination strategy using Selectfluor rapidly delivers triply functionalized triads of the form C-F/C-N/C-O, exhibiting good scope and diastereoselectivity for all syn products. The resulting stereotriads are readily transformed into fluorinated pyrrolidines and protected α-, ß-, and γ-amino acids.