Files in this item



application/pdfLAFFOON-DISSERTATION-2020.pdf (13MB)
(no description provided)PDF


Title:Part I. Rhodium-catalyzed asymmetric functionalization of allylic amines Part II. Harnessing kinetic driving forces in alkyne metathesis for the synthesis of complex molecular architectures
Author(s):Laffoon, Joshua Donn
Director of Research:Moore, Jeffrey S
Doctoral Committee Chair(s):Moore, Jeffrey S
Doctoral Committee Member(s):Denmark, Scott E; Zimmerman, Steven C; Fout, Alison R
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
transition metal
asymmetric catalysis
chiral amides
chiral esters
chiral amines
mobius strip
alkyne metathesis
dynamic covalent chemistry
Abstract:Part I of this Dissertation describes the rhodium catalyzed asymmetric functionalization of allylic amines to form chiral products such as β-branched amides and esters, and γ-branched amines. We developed a modular synthetic strategy that enables the diversification of a single allylic amine scaffold into many value-added products. Chiral, β-branched carbonyl compounds are valuable bioactive products as well as useful intermediates in synthetic pathways toward complex chiral products. Inspired by the work of Noyori and Otsuka, we envisioned that the rhodium-catalyzed isomerization of allylic amines to chiral enamines would serve as a powerful platform for the modular functionalization of a general electrophile. Nucleophilic attack onto an enamine in the presence of water leads to the formation of a hemiaminal or hemiacetal depending on the nucleophile. The hydrogen on the methine carbon in the resulting intermediate is hydridic in nature. We hypothesized that the Rh(I) catalyst could perform a dual role in the reaction where after the allylic isomerization, it could then reengage the hemiaminal or hemiacetal intermediate and dehydrogenate leading to an amide or ester respectively. We found that this reaction proceeded with high efficiency in the presence of a suitable hydrogen acceptor and base. The conditions were elaborated with a series of nucleophiles to demonstrate the modularity of this synthetic tool. Designing a method with modularity in mind, we were motivated to find an allylic amine substrate that could be general with a variety of exogenous amine and alcohol nucleophiles. Noyori established that the steric bulk of the diethyl amine group was necessary for good stereoselectivity in the allylic isomerization of geranyl diethyl amine, but we found that it prevented the rhodium-catalyzed dehydrogenation of the resulting intermediate. When using diethyl allylic amines, the oxidized amide product was not observed; however, saturated aldehyde was observed, indicating that the isomerization did proceed. We hypothesized that an exogenous, less sterically hindered amine could exchange with the diethyl iminium intermediate to allow the oxidation to the amide to occur. When we added morpholine to the reaction, we observed formation of a single morpholino amide, with no detectable diethyl amide. Diethyl amine is non-competitive even with alcohols or hindered -branched amines as nucleophiles. This modularity allows rapid diversification of a single prochiral allylic amine into a variety of enantioenriched (90% to 99.9% e.e.) amides and esters via largely commercially available nucleophiles. The reaction generally affords good yields where yield trends correlate with nucleophile strength. Suitable nucleophiles include primary and cyclic secondary amines, anilines, α-branched chiral amines with excellent diastereoselectivity, and alkyl and benzyl alcohols. We also explored reductive conditions. By introducing formic acid as a hydrogen donor, γ-branched, chiral amines formed as the major product. We demonstrated this method for the synthesis of pharmaceuticals such as (R)-Tolterodine and Terikalant. The development of this synthetic strategy also contributes to a broader understanding of the tolerance and scope of rhodium hydride transfer methods. Part II of this Dissertation describes the synthesis of a molecular Möbius strip under alkyne metathesis with kinetic diastereoselectivity. In 1858, mathematicians Möbius and Listing discovered the Möbius strip, a single-sided, unorientable surface. The intriguing Möbius topology would eventually make its way into the consciousness of chemists as a hypothetical molecular topology that had never been observed in nature. The first successful synthesis of a Möbius aromatic hydrocarbon was not achieved until 2003 by Herges and co-workers, paving the way for experimental validation of what was previously only a theoretical understanding of Möbius aromaticity. Over the past 17 years, other macrocycles with Möbius topology have been synthesized while researchers developed new tools for experimentally probing the aromaticity of these structurally fascinating molecules. Unfortunately, the syntheses of Möbius macrocycles to date have been limited by lengthy routes with low overall yields. We demonstrate that a cyclooligomerization strategy with alkyne metathesis provides high yields of a Möbius macrocycle in up to 84% in a single step. Of two possible diastereomers, only one was observed as a product of the reaction. Intriguingly, the major product was kinetically, rather than thermodynamically, favored, an unexpected result considering that alkyne metathesis is a reversible process. We provide computational justification for the kinetic selectivity which arises from differences in strain energy in the transition state of metallacyclobutadiene formation. Through the aid of calculations such as electron density of delocalized bonds (EDDB) and anisotropic induced current density (ACID), we observed that the Möbius macrocycle does not have global aromaticity but rather localized aromaticity in the helicene subunits. This work will facilitate future syntheses of Möbius macrocycles for structure-aromaticity studies and other applications.
Issue Date:2020-11-30
Rights Information:Copyright 2020 Joshua Donn Laffoon
Date Available in IDEALS:2021-03-05
Date Deposited:2020-12

This item appears in the following Collection(s)

Item Statistics