Direct Formation of Oxocarbenium Ions under Weakly Acidic Conditions: Catalytic Enantioselective Oxa-Pictet–Spengler Reactions

Abstract

Two catalysts, an amine HCl salt and a bisthiourea, work in concert to enable the generation of oxocarbenium ions under mild conditions. The amine catalyst generates an iminium ion of sufficient electrophilicity to enable 1,2-attack by an alcohol. Catalyst turnover is achieved by amine elimination with concomitant formation of an oxocarbenium intermediate. The bisthiourea catalyst accelerates all of the steps of the reaction and controls the stereoselectivity via anion binding/ion pair formation. This new concept was applied to direct catalytic enantioselective oxa-Pictet-Spengler reactions of tryptophol with aldehydes.

Chiral Thioureas Promote Enantioselective Pictet–Spengler Cyclization by Stabilizing Every Intermediate and Transition State in the Carboxylic Acid-Catalyzed Reaction

“…63,64 We hypothesize that the resulting complex exhibits increased acidity relative to free benzoic acid and thus contributes to substrate activation en route to product formation, as proposed in the catalytic cycle outlined in Scheme 2. Consistent with this analysis, added tetrabutylammonium benzoate (NBu 4 OBz), which forms a much stronger complex with thiourea 1a (Figure 2C), 34,49,51,52,65–80 inhibits the reaction. This inhibition is also of significance given that the secondary amine product of the Pictet–Spengler reaction is substantially more basic than the imine substrate, 81,82 thereby introducing the potential for formation of a similarly counterproductive ammonium benzoate complex during the course of the reaction (Scheme 2, step V).…”

“…The cooperative catalysis between weak achiral Brønsted acids and chiral thioureas revealed in this work has subsequently proven to be broadly applicable to a variety of enantioselective transformations of interest. 34,48–52 Motivated by the synthetic utility of the Pictet–Spengler method and the generality of the catalytic approach, 53 we undertook a thorough analysis of this reaction system with the goal of elucidating its mechanism.…”

Deracemisation Processes Employing Organocatalysis and Enzyme Catalysis

“…Chiral 1,3,4,9‐tetrahydropyrano[3,4‐ b ]indoles ( 34 , THPIs) are valuable structures present in many biologically active compounds, but there are very few examples of their enantioselective synthesis . In 2018 the redox deracemisation of a set of α‐substituted THPIs was proposed employing DDQ as oxidant and a chiral phosphoric acid for the asymmetric hydrogenation through chiral anion catalysis (Scheme b) .…”

Iridium‐Catalyzed Enantioselective Hydrogenation of Oxocarbenium Ions: A Case of Ionic Hydrogenation

“…Asymmetric transformations based on oxocarbenium ions have attracted attention in the recent decade. Since Jacobsen and co‐workers reported on the thiourea‐catalyzed addition reaction, many catalytic methodologies based on oxocarbenium ions have been developed, such as nucleophilic addition of enolate, alkynylation, acetalization, the oxa‐Pictet—Spengler reaction, and reduction . A practical and commonly applied method to access oxocarbenium ions is the elimination of a leaving group.…”