Inside-out design and synthesis of spiroligomers for transesterification reactions

Abstract

This work describes the application of spiroligomers as serine hydrolases mimetics. Through collaboration with Kendall Houk's group, for the first time in the Schafmeister lab, we demonstrate that "theozymes" can be successfully used as models to design highly functionalized spiroligomer constructs for organocatalysis. We demonstrate a structure-function relationship between the structure of a series of bi-functional and tri-functional spiroligomer based transesterification catalysts and their catalytic activity. First, we designed and synthesized a series of stereochemically and regiochemically diverse bi-functional spiroligozymes to identify the best arrangement of a pyridine as a general base catalyst and an alcohol nucleophile to accelerate attack on vinyl trifluoroacetate as an electrophile. The best bifunctional spiroligozyme reacts with vinyl trifluoroacetate to form an acyl-spiroligozyme conjugate 2.7x103-fold faster than the background reaction with benzyl alcohol. We then incorporated an additional urea functional group to activate the acyl-spiroligozyme intermediate through hydrogen bonds and enable acyl transfer to methanol. The best trifunctional spiroligozyme carries out multiple turnovers and acts as a transesterification catalyst with k1/kuncat of 2.2x103 and k2/kuncat of 1.3x102. Quantum mechanical calculations identified four transition states in the catalytic cycle and provided a detailed view of every stage of the transesterification reaction. With the aim of accelerating the k2, we sought to design better oxyanion holes that hold multiple hydrogen bonding groups in close proximity of the catalytic groups. A macrocyclic motif would be a good candidate to force the oxyanion hole arm to arrange hydrogen-bonding groups in a precise three-dimensional constellation for transition state stabilization. In Chapter 4, we introduce an in silico designed macrocyclic spiroligomer, which overlays well with catalytic active site of an inhibitor bound-esterase. Finally, we detail our effort to develop new methodologies for rapidly synthesizing spiroligomers on solid-support. This would allow us to efficiently permute their structures for diverse applications such as organocatalysts, host molecules, and biologically related applications such as inhibiting protein-protein interactions.