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

Abstract

An investigation of the mechanism of benzoic acid/thiourea co-catalysis in the asymmetric Pictet–Spengler reaction is reported. Kinetic, computational, and structure–activity relationship studies provide evidence that rearomatization via deprotonation of the pentahydro-β-carbolinium ion intermediate by a chiral thiourea•carboxylate complex is both rate- and enantioselectivity-determining. The thiourea catalyst induces rate acceleration over the background reaction mediated by benzoic acid alone by stabilizing every intermediate and transition state leading to up to and including the final selectivity-determining step. Distortion–interaction analyses of the transition structures for deprotonation predicted using density functional theory indicate that differential π–π and C–H···π interactions within a scaffold organized by multiple hydrogen-bonds dictate stereoselectivity. The principles underlying rate acceleration and enantiocontrol described herein are expected to have general implications for the design of selective transformations involving deprotonation of high-energy intermediates.

Unified Mechanistic Understandings of Pictet-Spengler Reactions

“…Thus, the stereochemistry of the reaction might be irrelevant to both spiroindolization and C2 cyclization processes. 41 This mechanistic spectrum shows that, although the structural perturbation of substrate and the switch of catalyst will alter the profile of Pictet-Spengler reactions significantly, a quick but insightful interpretation of the mechanism of a given Pictet-Spengler reaction can be drawn on the basis of two simple parameters (d and h) in energetics.…”

“…In fact, direct C2 cyclization leads to protonated tetrahydro-b-carbolines II-A (9.4 kcal/mol) and II-B (À12.0 kcal/mol), from which the irreversible proton abstraction by tosylate anion (TS3-A, 15.7 kcal/mol; TS3-B, À10.6 kcal/mol) furnishes tetrahydro-b-carboline as the thermodynamically most stable species in each system (IV-A, À4.2 kcal/mol; IV-B, À27.7 kcal/mol). Notably, the deprotonation is the rate-determining step in series A, 39,41 whereas on the other hand it is kinetically trivial in series B.…”

“…[30][31][32][33][34] Moreover, their mechanistic aspect is intriguing and has been a topic of intensive research for quite a long time. [35][36][37][38][39][40][41][42] In general, two reaction paths are proposed (Scheme 1): the initial iminium ion I generated from the condensation between the corresponding tryptamine and aldehyde might…”

A Structurally Robust Chiral Borate Ion: Molecular Design, Synthesis, and Asymmetric Catalysis

“…This observation led us to evaluate the primary kinetic isotope effect (KIE) in these parallel reactions, and the KIE for 2a/d 2 -2a was determined to be 1.37. 40,41 Judging from the deuterium incorporation into the methyl group of the products (ca.…”

Asymmetric Nazarov Cyclizations of Unactivated Dienones by Hydrogen‐Bond‐Donor/Lewis Acid Co–Catalyzed, Enantioselective Proton‐Transfer

“…Deprotonation by a chiral HBD-anion complex is an unusual mode of enantioinduction, but it finds direct precedent in thiourea/carboxylic acid co-catalyzed Pictet-Spengler reactions, where reversible CÀ C bond formation followed by enantiodetermining deprotonation was also demonstrated. [19] In conclusion, an enantioselective, TMSOTf/HBD co-catalyzed Nazarov cyclization of unactivated dienones was developed. Trisubstituted cyclopentenones were accessed in good yields and high enantioselectivity (up to 76% yield and 95% e.e.).…”