ABSTRACT
Bicyclo[1.1.1]pentanes (BCPs) are important bioisosteres of 1,4-disubstituted arenes, tert-butyl and acetylenic groups that can impart physicochemical benefits on drug candidates. Here we describe the synthesis of BCPs bearing carbon and halogen substituents under exceptionally mild reaction conditions, via triethylborane-initiated atom-transfer radical addition ring-opening of tricyclo[1.1.1.01,3]pentane (TCP) with alkyl halides. This chemistry displays broad substrate scope and functional group tolerance, enabling application to BCP analogues of biologically-relevant targets such as peptides, nucleosides, and pharmaceuticals. The BCP halide products can be converted to the parent phenyl/tert-butyl surrogates through triethylborane-promoted dehalogenation, or to other derivatives including carbonyls, alcohols, and heterocycles.
ABSTRACT
ortho-Arylation of ortho-substituted benzoic acids is a challenging process due to the tendency of the reaction products toward Pd-catalyzed protodecarboxylation. A simple method for preventing decarboxylation in sterically hindered benzoic acids is reported. The method described represents a reliable and broadly applicable entry to 2-aryl-6-substituted benzoic acids.
Subject(s)
Benzoates/chemistry , Benzoates/chemical synthesis , Carbonates/chemistry , Palladium/chemistry , Potassium/chemistry , Catalysis , Decarboxylation , Molecular StructureABSTRACT
Bicyclic α-iminophosphonates were prepared via the first diastereoselective silver catalyzed [3 + 2] cycloaddition reaction of diethyl isocyanomethylphosphonate and diversely N-substituted maleimides. The reduction of the resulting imine by catalytic hydrogenation led to cyclic α-aminophosphonates, which are α-aminoester surrogates. The relative stereochemistry of the adducts was confirmed by X-ray crystallographic analysis of . The diastereoselectivity of the cycloaddition reaction was rationalised by theoretical studies.
Subject(s)
Bridged Bicyclo Compounds/chemical synthesis , Maleimides/chemistry , Organophosphonates/chemical synthesis , Bridged Bicyclo Compounds/chemistry , Crystallography, X-Ray , Cyclization , Models, Molecular , Molecular Conformation , Organophosphonates/chemistry , Quantum Theory , StereoisomerismABSTRACT
Readily available chiral primary 1,2-aminoalcohols and diamines have been explored as organocatalysts for a domino Michael-aldol reaction. Their application in this organocascade process afforded cyclohexanone A with high levels of reactivity (up to 91% yield) and stereoselectivity (>97 : 3 d.r., up to 93% ee). Depending on the acid cocatalyst different chiral species (cyclic secondary amines vs. acyclic primary amines) might catalyse the process. In order to shed light on the catalytic activation, several experiments were carried out and a detailed possible reaction mechanism is proposed. Theoretical studies support the stereochemical outcome of the process.
Subject(s)
Amino Alcohols/chemistry , Cyclohexanones/chemical synthesis , Catalysis , Cyclohexanones/chemistry , Diamines/chemistry , Molecular Structure , Quantum Theory , StereoisomerismABSTRACT
The double cyclocondensation of symmetric pyridyl bis(oxoacids) 2b and 3b with (R)-phenylglycinol stereoselectively gave access to bis-phenylglycinol-derived oxazolopyrrolidine 9 and oxazolopiperidone 10, respectively. Application of the stereocontrolled cyclocondensation reaction to phenyl bis-γ-oxoacid 4b provided 11, which was converted to the corresponding enantiopure di(pyrrolidinyl)benzene 22. The absolute configuration of the new stereogenic centers generated in the key cyclocondenstion step was unambiguously established by X-ray crystallographic analysis.
