Products Cited in Publications Worldwide Computational and Experimental Studies in Selective Organocatalysis

Computational and Experimental Studies in Selective Organocatalysis

Corin Wagen

Abstract

Chemical synthesis has transformed the ability of scientists and engineers to interact with themolecular world. Yet despite almost two centuries of considerable effort, small-molecule synthesisremains a challenging task. Hundreds ofnew reactions are discovered every year, but few possessthe requisite selectivity and generality needed to be use ful for routine synthesis, and elucidation ofthe ir mechanism and underlying catalytic principles is rarely conducted. In this work, we describea variety of efforts at the interface of organic, computational, and analytical chemistry which seekto address the linked problems of discovering selective organocatalysts and understanding themechanism by which they operate. In Chapter 1, we report the development of a new analytical method that combines chiralstationary phase supercritical fluid chromatography wih mass spectrometry-based detection toenable enantiodetermination of pooled crude reaction mixtures, greatly increasing analyticalthroughput. This advance allows us to perform multi-substrate screening to discover catalystspossessing good substrate scope, which we demonstrate in the optimization of a Bronsted acidcatalyst for the enantioselective Pictet-Spengler reaction.In Chapter 2, we disclose the results of a mechanistic study aimed at understanding a hydrogenchloride/hydrogen-bond donor co-catalyzed Prins cyclization of alkenyl aldehydes whichexhibited dramatic rate acceleration compared to the background reaction. Our studies reveal that the catalyst reacts with hydrogen chloride to form a new chiral acid in siu with a higher pK, thanhydrogen chloride, which nevertheless reacts faster owing to favorable catalyst-controlledpositioning ofthe chloride anion to electrostatically stabilize the major transition state In Chapter 3, we report a computational study of our group's regio- and stereoselectiveglycosylation of` minimally protected glycosyl acceptors. The computational model describedthe first of` hydrogen-bond-donor-catalyzed glycosylation of glycosyl phosphate donors containsfeatures of the transition state previously hypothesized on the basis of experimental results, andlends support to the proposed “4H” binding mechanism. In Chapter 4, we describe the development of an enantioselective protio-semipinacol reactionof unactivated vinylic cyclopropanols. Motivated by the question of how high enantioselectivitycan be achieved in a low-barrier 1,2-rearrangement, we conduct an experimental andcomputational mechanistic investigation and come to the surprising conclusion that protonation toform a formally achiral carbocation in fact exerts stereocontrol over the subsequent rearrangementstep: the rearrangement is so rapid that the carbocation is locked in a given chiral conformationrendering the rearrangement efectively stereospecific. Finally, in chapter 5 we detail a spectroscopic and computational study of solutions ofhydrogen chloride in diethyl ether, aimed at assigning the solution structure ofhydrogen chlorideIn situ IR spectroscopy, combined with density-functional theory and molecular dynamicsprovides evidence for the existence of oxonium ions formed from complete proton transfer todiethyl ether. This observation explains the often-inhibitory effect of diethyl ether on hydrogenchloride-catalyzed reactions and has intriguing implications for catalyst design.

Purchased from AmBeed

Methyl 4-oxobutanoate

A22400713865-19-595% (stabilized with Citric acid)

Methyl 4-oxobutanoate

24.0/250mg

Detail
4-Fluorobenzaldehyde

A781101459-57-495%

4-Fluorobenzaldehyde

78.0/500g

Detail