A Case Study in Catalyst Generality: Simultaneous, Highly-Enantioselective Brønsted- and Lewis-Acid Mechanisms in Hydrogen-Bond-Donor Catalyzed Oxetane Openings

Abstract

Generality in asymmetric catalysis can be manifested in dramatic and valuable ways, such as high enantioselectivity across a wide assortment of substrates in a given reaction (broad substrate scope) or as applicability of a given chiral framework across a variety of mechanistically distinct reactions (privileged catalysts). Reactions and catalysts that display such generality hold special utility, because they can be applied broadly and sometimes even predictably in new applications. Despite the great value of such systems, the factors that underlie generality are not well understood. Here, we report a detailed investigation of an asymmetric hydrogen-bond-donor catalyzed oxetane opening with TMSBr that is shown to possess unexpected mechanistic generality. Careful analysis of the role of adventitious protic impurities revealed the participation of competing pathways involving addition of either TMSBr or HBr in the enantiodetermining, ring-opening event. The optimal catalyst induces high enantioselectivity in both pathways, thereby achieving precise stereocontrol in fundamentally different mechanisms under the same conditions and with the same chiral framework. The basis for that generality is analyzed using a combination of experimental and computational methods, which indicate that proximally localized catalyst components cooperatively stabilize and precisely orient dipolar enantiodetermining transition states in both pathways. Generality across different mechanisms is rarely considered in catalyst discovery efforts, but we suggest that it may play a role in the identification of so-called privileged catalysts.

Radical Ring-Opening of Oxetanes Enabled by Co-Catalysis

“…Along this line, the Jacobsen group reported enantioselective addition of TMSBr to oxetanes giving silylated bromohydrins. 7,25 This work and the control experiment with TMSOTf corroborate our assumption that silylated bromohydrin 5b is an intermediate in this reaction.…”

Hydrogen Bonding Phase-Transfer Catalysis with Alkali Metal Fluorides and Beyond

“… 45 Notable studies have been reported by Jacobsen and co-workers who reported the thiourea-catalyzed asymmetric ring-opening of aziridines with hydrogen chloride, 46 and more recently the desymmetrization of oxetanes with TMSBr and a chiral squaramide as catalyst. 47 , 48 …”

Activation Modes in Asymmetric Anion-Binding Catalysis

“…72 By using silyl bromide 163 , an enantioselective ring opening of oxetanes 162 upon nucleophilic addition of the bromide was achieved, leading to 1,3-halohydrins 164 , which can serve as valuable precursors for further derivatizations. However, in a mechanistic study, 73 the authors showed that competing Lewis acid and Brønsted acid pathways were possible in this reaction leading to the same product.…”