Switchable Enantio- and Diastereoselective Michael Additions of β-Keto Amides to Nitroolefins: Crystallization-Based Inversion of Kinetic Stereocontrol.

Asymmetric catalytic reactions rely on chiral catalysts that induce highly ordered transition states capable of imparting stereoselectivity in the bond-forming step(s). Productive deviations from this paradigm are rare yet hold the potential for accessing different stereoisomers using the same catalyst. Here, we present an enantio- and diastereoselective Michael addition of β-keto amides to nitroolefin electrophiles proceeding via an unusual scenario where the kinetic diastereocontrol imparted by the catalyst may be overridden by crystallization to provide the complementary stereoisomer of the product.

Enantio- and Diastereoselective Mannich Reactions of ß-Dicarbonyls by Second Stage Diastereoconvergent Crystallization.

The synthesis of chiral -monosubstituted-ß-dicarbonyls is a challenging task in asymmetric catalysis due to the rapid, typically uncontrolled, product racemization or epimerization under most reaction conditions. For this reason, diastereoselective additions of unsubstituted ß-dicarbonyls to -electrophiles are unusual. Herein, we disclose a simple catalytic crystallization-driven enantio- and diastereoselective Mannich reaction for the synthesis of stereodefined -monosubstituted-ß-keto esters, dissymmetric ß-diesters, dissymmetric ß-diketones, and ß-keto amides that productively leverages product epimerization in solution.

Crystallization-Enabled Stereoconvergent Michael Additions of β-Keto Esters to Nitroolefins.

Asymmetric Michael additions are powerful tools to meet the growing need for stereochemically complex products. While 1,3-dicarbonyls are common nucleophiles, the successful use of configurationally unstable β-keto esters in diastereoselective variants remains understudied. In this Letter, crystalline β-keto esters were leveraged in a two-phase, one-pot merger of an asymmetric Michael addition with a crystallization-induced diastereomer transformation.

Enantioconvergent -Pictet-Spengler Reactions: Organocatalytic Synthesis of Chiral Tetrahydro-γ-carbolines.

Enantioconvergent -Pictet-Spengler reactions of chiral racemic ß-formyl esters and a ß-keto ester are reported, providing complex tetrahydro-γ-carbolines containing two contiguous stereocenters. The reactions are catalyzed by a chiral thiourea and benzoic acid cocatalytic system and constitute rare cases of nonhydrogenative stereoconvergent additions to racemic α-stereogenic-ß-dicarbonyls. Elaboration of the products to chiral aminoalcohols and carbamates is demonstrated.

Development of organic reactions that productively leverage physical properties.

Crystallization-induced stereoconvergent Michael additions demonstrate the potential of using physical properties to reveal unique reactivity.

Doubly stereoconvergent crystallization enabled by asymmetric catalysis.

Synthetic methods that enable simultaneous control over multiple stereogenic centers are desirable for the efficient preparation of pharmaceutical compounds. Herein, we report the discovery and development of a catalyst-mediated asymmetric Michael addition/crystallization-induced diastereomer transformation of broad scope. The sequence controls three stereogenic centers, two of which are stereochemically labile.