Computational Design of Enhanced Enantioselectivity in Chiral Phosphoric Acid-Catalyzed Oxidative Desymmetrization of 1,3-Diol Acetals

Abstract

A general method for the highly enantio­selective desymmetrization of 2-alkyl-substituted 1,3-diols is presented. A combination of computational and experimental studies has been utilized to understand the origin of the stereo­control of oxidative desymmetrization of 1,3-diol benzylidene­acetals. DFT calculations demonstrate that the acetal protecting group is highly influential for high enantio­selectivity, and a simple but effective new protecting group has been designed. The desymmetrization reactions proceed with high enantio­selectivity for a variety of substrates. Moreover, the reaction conditions are also shown to be effective for desymmetrization of 2,2-dialkyl-substituted 1,3-diols, which provides chiral products bearing acyclic all-carbon quaternary stereo­centers. The method has been applied to the formal synthesis of indoline alkaloids.

Chemoselective Dual Functionalization of Phenols via Relay Catalysis of Borane with Different Forms

“…The actual aromatization occured in steps III-IV, during which the C=O acted as a proton accepter to promote aromatization and produce intermediate IV. Remarkably, the catalyst served as a proton shuttle [60][61][62][63] to stabilize the reaction system. It captured the proton of phenolic hydroxyl to present as intramolecular dehydration of gem-diol generating the ultimate lactonized product was 39.4 kcal/mol (V 4 in Figure 4), indicating that gem-diol V 4 cannot undergo dehydration in the gas phase.…”

Organocatalytic enantioselective SN1-type dehydrative nucleophilic substitution: access to bis(indolyl)methanes bearing quaternary carbon stereocenters

“…To initiate our investigation, racemic α-indolyl-α-trifluoromethyl propargylic alcohol 1a was selected as the model substrate in consideration of the privileged role of the CF 3 group in medicinal chemistry 14,15 and the versatile alkynyl handle for further diversification. 16 Moreover, we envisioned that the Brønsted acid catalyst 17 could activate the tertiary alkyl alcohol 1a via dehydration to form the corresponding tertiary carbocation intermediate, which is stabilized by its iminium type resonance form. Furthermore, the chiral Brønsted acid catalyst is expected to achieve efficient chiral induction through ion-pair or hydrogen-bonding with the corresponding carbocation and indole nucleophile simultaneously, to deliver the desired all-carbon quaternary stereocenter.…”

Recent advances towards organocatalytic enantioselective desymmetrizing reactions

“…Consequently, substantial endeavors have been devoted to this burgeoning domain during the last 5 years and a diverse number of novel desymmetric transformations have been successively exploited. Apart from aforementioned cases, other readily available substrates have been studied as well, such as diesters [101], acetals [102], and diamines [103,104]. These remarkable advances not only combine the respective advantages of organocatalysis with desymmetrization, which accelerates the development of related methodologies, but also open up new avenues for synthetic community.…”