New Activation Modes in Anion-Binding Catalysis: Enantioselective Synthesis of Amino Esters
Bendelsmith, Andrew James
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CitationBendelsmith, Andrew James. 2019. New Activation Modes in Anion-Binding Catalysis: Enantioselective Synthesis of Amino Esters. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractDual hydrogen-bond donors (HBDs) function as soft Brønsted- or Lewis-acid catalysts. Two principal modes of catalysis have been identified for HBDs: via direct activation of π-electrophiles, or via anion-abstraction binding. In the latter context, the dual N-H’s can associate with leaving groups to generate reactive chiral ion-pairs, which can be intercepted by nucleophiles to form a variety of products. Chiral HBDs have been designed and identified as highly enantioselective catalysts in a broad range of transformations. However, due to the relatively weak nature of hydrogen bonds in typical HBD catalysts, the scope of substrates that can be engaged is limited. The vast majority of successful HBD-catalyzed anion-abstraction reactions involve halide, and specifically chloride, leaving groups. Additionally HBDs generally only heterolyze labile C-Cl bonds to produce heteroatom-stabilized cations, such as N-acyl iminium ions, oxocarbeniums, and 3-membered onium intermediates. These requirements have resulted in important limitations to the substrates that can be activated toward enantioselective substitution reactions. The dissertation presented herein presents three strategies to overcome these limitations to HBD catalysis.
In Chapters 2 and 3, highly enantio- and diastereoselective syntheses of α-allyl and α-aryl amino esters are presented. Kinetic and computational studies provide evidence for an HBD-catalyzed SN2 reaction between the α-chloroglycinate electrophile and allylsilane nucleophile. This represents a new mode of anion-binding catalysis in which catalyst can effect an SN2 substitution to a substrate for which ionization is energetically inaccessible, potentially expanding the range of substrates amenable to activation. Computational and regression modeling indicate that catalyst achieves enantioinduction by preferentially stabilizing the pathway to the major enantiomer of product through a precisely controlled network of attractive non-covalent interactions.
The ability to achieve strong rate enhancements by chiral HBDs in Lewis acid promoted reactions would greatly expand the scope of enantioselctive anion-abstraction chemistry. In Chapter 4, an HBD and BF3·OEt co-catalyzed allylation of α-aryl-α-methoxy glycinates for the synthesis α,α-disubstituted amino esters is described. The HBD catalyst does not sufficiently accelerate an enantioselective pathway over the racemic background reaction catalyzed by just BF3·OEt2, and thus the product could not be obtained in high enantioselectivity. A Sakurai model reaction and Gutmann-Beckett NMR study were developed to screen for synergistic HBD and Lewis acid combinations in which the complex is more active than the Lewis acid alone. This study determined BCl3 and squaramides as a viable combination with promising preliminary results.
The ability to use chiral HBD catalysts in mineral acid-promoted transformations would open new avenues in asymmetric catalysis. In Chapter 5, an HBD and HCl co-catalyzed semi-pinacol rearrangement to synthesize α-quaternary cyclobutanones is described. The HBD promotes the model reaction in moderate enantioselectivities and is proposed to stabilize the chloride anion, perturbing the HCl dissociation equilibrium, Ka. Enantioselectivity then arises from this HCl-HBD adduct, which serves as a more acidic, chiral H+ source.
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