Productively Legeraging the Acidity of ß-Dicarbonyls in Nontraditional Stereoconvergent Reactions

(I) Enantioconvergent iso-Pictet-Spengler Reactions: Organocatalytic Synthesis of Tetrahydro-γ-Carbolines: Enantioconvergent iso-Pictet-Spengler reactions of chiral racemic β-formyl and β-keto esters are reported, providing complex tetrahydro-γ-carbolines containing two contiguous stereocenters. The reactions are catalyzed by a chiral thiourea and benzoic acid co-catalytic system and constitute a rare non-hydrogenative stereoconvergent addition to racemic α-stereogenic-β-dicarbonyls. Elaboration of the products to chiral amino-alcohols and carbamates is demonstrated. (II) 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. The configurational instability of 1,3-dicarbonyls and nitroalkanes, typically considered a liability in stereoselective synthesis, is productively leveraged by merging enantioselective Brønsted base organocatalysis and thermodynamic stereocontrol via a single convergent crystallization. The synthesis of useful γ-nitro β-keto amides containing three contiguous stereogenic centers is thus achieved from Michael acceptors containing two prochiral centers. (III) Enantio- and Diastereoselective Mannich Reactions of ß-Dicarbonyls Enabled by Second Stage Diastereoconvergent Crystallization: The synthesis of chiral α-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 π-electrophiles are unusual. Herein, we disclose a simple catalytic crystallization-driven enantio- and diastereoselective Mannich reaction for the synthesis of stereodefined α-monosubstituted-ß-keto esters, dissymmetric ß-diesters, dissymmetric ß-diketones, and ß-keto amides that productively leverages product epimerization in solution. Mechanistic studies suggest a scenario where the initial enantioselective, diastereodivergent skeletal assembly is catalyzed by a chiral tertiary amine organocatalyst, which then facilitates second stage crystallization-induced diastereoconvergence to provide the challenging α-stereocenter in excellent stereoselectivity. (IV) Switchable Enantio- and Diastereoselective Michael Additions of ß-Keto Amides to Nitroolefins: Asymmetric catalytic reactions rely on the powerful paradigm that chiral catalysts induce highly-ordered transition states capable of imparting stereoselectivity in the bond forming step. Productive deviations from this paradigm are rare yet hold the untapped potential of accessing different stereoisomers using the same chiral catalyst. Herein, we present a crystallization-driven enantio- and diastereoselective Michael addition of ß-keto amides to nitroolefin electrophiles. Mechanistic studies indicate an unusual scenario where excellent kinetic (catalyst) diastereocontrol can be completely overridden by a crystallization-induced diastereomer transformation to provide the complementary stereoisomer of the acyclic system. By tuning reaction conditions, both product diastereomers can be isolated in excellent enantio- and diastereoselectivity using the same chiral catalyst. This work serves as a blueprint for the design of new stereodivergent reaction platforms enabled by crystallization to synthesize kinetically-inaccessible stereoisomers of acyclic systems.