A C=O⋅⋅⋅Isothiouronium Interaction Dictates Enantiodiscrimination in Acylative Kinetic Resolutions of Tertiary Heterocyclic Alcohols

Abstract

A combination of experimental and computational studies have identified a C=O⋅⋅⋅isothiouronium interaction as key to efficient enantiodiscrimination in the kinetic resolution of tertiary heterocyclic alcohols bearing up to three potential recognition motifs at the stereogenic tertiary carbinol center. This discrimination was exploited in the isothiourea-catalyzed acylative kinetic resolution of tertiary heterocyclic alcohols (38 examples, s factors up to >200). The reaction proceeds at low catalyst loadings (generally 1 mol %) with either isobutyric or acetic anhydride as the acylating agent under mild conditions.

The Importance of 1,5‐Oxygen⋅⋅⋅Chalcogen Interactions in Enantioselective Isochalcogenourea Catalysis

“…Next, the challenging kinetic resolution of tertiary heterocyclic alcohol 12 was performed (Figure B) . While isourea 1 ‐O gave no conversion into ester 13 , isoselenourea 1 ‐Se gave good conversion ( c =45 %) and selectivity ( s =60) comparable to the isothiourea 1 ‐S ( c =54 %, s =60).…”

Understanding the Reactivity and Selectivity of Fluxional Chiral DMAP‐Catalyzed Kinetic Resolutions of Axially Chiral Biaryls

“…[91,[114][115][116][117][118] First, even though the catalysti tself is highly fluxional, exhibiting two interconverting conformations at room temperature, the active, acylated form of the catalyst is conformationally rigid due to p···p + interactions. This rigidity,c om- bined with an etwork of other non-covalenti nteractions, underlies the high degree of stereoselectivity.O ur data also support an ucleophilic mode of catalysis,w hich is rendered more favorable than alternative, base-catalyzed mechanisms due to the impacts of non-covalenti nteractions.F inally,w es howed near quantitative reproduction of experimental selectivities for six substrates and developed as tereochemical model of this reactioni nw hich p···p + interactions, ah ydrogen-bonding network involving the counteranion, and ak ey CH···O interaction between the a-hydrogens of substituents independently control the stereoselectivity.T hese latteri nteractions can be used to explain the selectivity of other substrates, including those that have not yet been tested experimentally.W hile similar non-covalent interactions have been shown to play important roles in KRs, [32,33,81,119] the reaction in Scheme 1i su nique in that these interactions control essentially all aspects of the reaction:t he rigidity of the active catalyst, the preferred mechanism, and the stereoselectivity.T his rich interplay of competing non-covalent interactions underscoret he resemblanceo fs ome organocatalytic systemst oe nzymes, in which selectivity,r eactivity,a nd mechanism are all modulated through the subtle effects of myriad stabilizing non-covalent interactions. [91] We hope that the molecular level insights provided by this study will help guide experimental chemists in the careful choice of substrates while also aiding in the designo fb etter catalysts.…”

Kinetic Resolution of Tertiary 2‐Alkoxycarboxamido‐Substituted Allylic Alcohols by Chiral Phosphoric Acid Catalyzed Intramolecular Transesterification

“…For example, List and co‐workers reported an excellent chiral Brønsted acid catalyzed kinetic resolution of homoaldol compounds and diols with tertiary hydroxy groups that is based on intra‐ and intermolecular acetalizations and generated the both tertiary alcohol starting materials and acetal products with high enantioselectivities . The groups of Zhao and Smith reported highly efficient kinetic resolutions of tertiary heterocyclic alcohols based on asymmetric acylation reactions enabled by NHC and isothiourea catalysis, respectively. Recently, Oestreich and co‐workers developed a kinetic resolution of tertiary propargylic alcohols by enantioselective Cu−H‐catalyzed Si−O coupling with a broad substrate scope …”