10317-14-3Relevant articles and documents
A Case Study in Catalyst Generality: Simultaneous, Highly-Enantioselective Br?nsted- And Lewis-Acid Mechanisms in Hydrogen-Bond-Donor Catalyzed Oxetane Openings
Strassfeld, Daniel A.,Algera, Russell F.,Wickens, Zachary K.,Jacobsen, Eric N.
supporting information, p. 9585 - 9594 (2021/07/19)
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.
Highly Enantioselective, Hydrogen-Bond-Donor Catalyzed Additions to Oxetanes
Strassfeld, Daniel A.,Wickens, Zachary K.,Picazo, Elias,Jacobsen, Eric N.
supporting information, p. 9175 - 9180 (2020/07/13)
A precisely designed chiral squaramide derivative is shown to promote the highly enantioselective addition of trimethylsilyl bromide (TMSBr) to a broad variety of 3-substituted and 3,3-disubstituted oxetanes. The reaction provides direct and general access to synthetically valuable 1,3-bromohydrin building blocks from easily accessed achiral precursors. The products are readily elaborated both by nucleophilic substitution and through transition-metal-catalyzed cross-coupling reactions. The enantioselective catalytic oxetane ring opening was employed as part of a three-step, gram-scale synthesis of pretomanid, a recently approved medication for the treatment of multidrug-resistant tuberculosis. Heavy-atom kinetic isotope effect (KIE) studies are consistent with enantiodetermining delivery of bromide from the H-bond-donor (HBD) catalyst to the activated oxetane. While the nucleophilicity of the bromide ion is expected to be attenuated by association to the HBD, overall rate acceleration is achieved by enhancement of Lewis acidity of the TMSBr reagent through anion abstraction.
