Pd-Catalyzed Dynamic Kinetic Asymmetric Cross-Coupling of Heterobiaryl Bromides with -Tosylhydrazones.

A dynamic kinetic asymmetric Pd-catalyzed cross-coupling reaction of heterobiaryl bromides with ketone -tosylhydrazones for the synthesis of heterobiaryl styrenes is described. The combination of Pd(dba) as a precatalyst with a TADDOL-derived phosphoramidite ligand provides the corresponding coupling products in good yields and high enantioselectivities under mild conditions. Racemization-free -oxidation and -alkylation of the products allowed us to obtain appealing functionalized axially chiral heterobiaryl derivatives.

Enantioselective Synthesis of Phthalides and Isochromanones via Heck-Matsuda Arylation of Dihydrofurans.

In this communication, the enantioselective synthesis of phthalides and isochromanones is described through a new palladium-catalyzed Heck-Matsuda arylation/NaBH -reduction/lactonization sequence of 2,3- and 2,5-dihydrofurans in good overall yields and excellent enantioselectivities (up to 98:2 er). This expeditious synthesis of chiral Heck lactol intermediates allowed the diversification of the strategy to obtain medicinally relevant chiral lactones, amines, and olefins. The natural product 3-butylphthalide was obtained in three steps with an overall yield of 33 % yield in 98:2 er.

Enantioselective total synthesis of the highly selective sphingosine-1-receptor VPC01091 by the Heck desymmetrization of a non-activated cyclopentene-fused spiro-pyrrolidinone.

A novel, efficient and enantioselective Heck-Matsuda desymmetrization of non-activated cyclopentene-fused spiro-pyrrolidinones was developed. The reaction provided the Heck products in good to excellent yields and selectivities and tolerated a variety of functional groups in arenediazonium tetrafluoroborates (12 examples) with respect to its electronics and substitution patterns. This methodology was successfully applied in the concise enantioselective total synthesis of VPC01091 (2b), a drug candidate for the treatment of multiple sclerosis.