ABSTRACT
The Ni-catalyzed hydroboration of dienols occurs in a 1,4 fashion and delivers a syn-propionate motif in high diastereoselectivity and with a stereodefined trisubstituted crotylboronic ester. The boronic ester can be further manipulated to provide carbon-carbon or carbon-oxygen bonds.
ABSTRACT
The marine natural product (+)-discodermolide was first isolated in 1990 and, to this day, remains a compelling synthesis target. Not only does the compound possess fascinating biological activity, but it also presents an opportunity to test current methods for chemical synthesis and provides an inspiration for new reaction development. A new synthesis of discodermolide employs a previously undisclosed stereoselective catalytic diene hydroboration and also establishes a strategy for the alkylation of chiral enolates. Furthermore, this synthesis of discodermolide provides the first examples of the asymmetric 1,4-diboration of dienes and borylative diene-aldehyde couplings in complex-molecule synthesis.
Subject(s)
Alkanes/chemical synthesis , Boron/chemistry , Carbamates/chemical synthesis , Lactones/chemical synthesis , Pyrones/chemical synthesis , Alkanes/chemistry , Alkylation , Carbamates/chemistry , Catalysis , Lactones/chemistry , Pyrones/chemistry , StereoisomerismABSTRACT
The development of inhibitors of B-Raf(V600E) serine-threonine kinase is described. Various head-groups were examined to optimize inhibitor activity and ADME properties. Several of the head-groups explored, including naphthol, phenol and hydroxyamidine, possessed good activity but had poor pharmacokinetic exposure in mice. Exposure was improved by incorporating more metabolically stable groups such as indazole and tricyclic pyrazole, while indazole could also be optimized for good cellular activity.
Subject(s)
Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Amino Acid Substitution , Animals , Binding Sites , Cell Line, Tumor , Crystallography, X-Ray , Humans , Indazoles/chemistry , Mice , Microsomes, Liver/metabolism , Mutation , Oximes/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Pyrazoles/chemistry , Structure-Activity RelationshipABSTRACT
A catalytic stereoselective 1,4-diboration of conjugated dienes with B(2)(pin)(2) was accomplished with Ni(cod)(2) and PCy(3) as the catalyst. This reaction broadens the substrate scope of current methods for catalytic diene diboration by including internal and sterically hindered dienes, and it proceeds efficiently at low catalyst loadings. The intermediate allylboronate was oxidized to the stereodefined allylic 1,4-diol.
Subject(s)
Boron Compounds/chemistry , Nickel/chemistry , Catalysis , Ligands , Molecular Structure , StereoisomerismABSTRACT
A catalytic regio- and stereoselective 1,4-hydroboration of 1,3-dienes was accomplished with pinacolborane in the presence of Ni(cod)(2) and PCy(3). This reaction exhibits broad substrate scope operating on a range of substituted dienes and occurs with generally high levels of selectivity and efficiency. Reactivity patterns suggest that the reactive conformation of the diene is the S-cis form. The intermediate allylboronate can be oxidized to stereodefined allylic alcohols or can be used in stereoselective carbonyl addition reactions.
