Lithium Hexamethyldisilazide-Mediated Enolization of Highly Substituted Aryl Ketones: Structural and Mechanistic Basis of the <i>E</i>/<i>Z</i> Selectivities

Enolizations of highly substituted acyclic ketones used in the syntheses of tetrasubstituted olefin-based anticancer agents are described. Lithium hexamethyldisilazide (LiHMDS)-mediated enolizations are moderately <i>Z</i>-selective in neat tetrahydrofuran (THF) and <i>E</i>-selective in 2.0 M THF/hexane. The results of NMR spectroscopy show the resulting enolates to be statistically distributed ensembles of <i>E</i>,<i>E</i>-, <i>E</i>,<i>Z</i>-, and <i>Z</i>,<i>Z</i>-enolate dimers with subunits that reflect the selectivities. The results of rate studies trace the preference for <i>E</i> and <i>Z</i> isomers to tetrasolvated- and pentasolvated-monomer-based transition structures, respectively. Enolization using LiHMDS in <i>N</i>,<i>N</i>-dimethylethylamine or triethylamine in toluene affords a 65:1 mixture of LiHMDS–lithium enolate mixed dimers containing <i>E</i> and <i>Z</i> isomers, respectively. Spectroscopic studies show that condition-dependent complexation of ketone to LiHMDS occurs in trialkylamine/toluene. Rate data attribute the high selectivity exclusively to monosolvated-dimer-based transition structures

Development of an Efficient, Safe, and Environmentally Friendly Process for the Manufacture of GDC-0084

An improved, efficient process with a significantly reduced process mass intensity (PMI) led to the multikilogram synthesis of a brain penetrant PI3K inhibitor GDC-0084. Highlights of the synthesis include a phase transfer catalyzed annulation in water, an efficient Suzuki-Miyaura cross-coupling of a chloropyrimidine with an arylboronic acid using a low palladium catalyst loading, and the development of a controlled crystallization to provide the API. The process delivered GDC-0084 with low levels of both impurities and residual metals

Highly Stereoselective Synthesis of Tetrasubstituted Acyclic All-Carbon Olefins via Enol Tosylation and Suzuki–Miyaura Coupling

A highly stereocontrolled synthesis of tetrasubstituted acyclic all-carbon olefins has been developed via a stereoselective enolization and tosylate formation, followed by a palladium-catalyzed Suzuki–Miyaura cross-coupling of the tosylates and pinacol boronic esters in the presence of a Pd­(OAc)₂/RuPhos catalytic system. Both the enol tosylation and Suzuki–Miyaura coupling reactions tolerate an array of electronically and sterically diverse substituents and generate high yield and stereoselectivity of the olefin products. Judicious choice of substrate and coupling partner provides access to either the <i>E</i>- or <i>Z</i>-olefin with excellent yield and stereochemical fidelity. Olefin isomerization was observed during the Suzuki–Miyaura coupling. However, under the optimized cross-coupling reaction conditions, the isomerization was suppressed to <5% in most cases. Mechanistic probes indicate that the olefin isomerization occurs via an intermediate, possibly a zwitterionic palladium carbenoid species