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Title:Asymmetric allylic C–H functionalization via palladium(II)/sulfoxide-oxazoline catalysis
Author(s):Liu, Wei
Director of Research:White, Maria Christina
Doctoral Committee Chair(s):White, Maria Christina
Doctoral Committee Member(s):Denmark, Scott E; Hergenrother, Paul J; Fout, Alison R
Department / Program:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):C–H Activation
Asymmetric Catalysis
Abstract:Asymmetric C–H functionalization could deliver a highly efficient transformation by installing both oxidized functionality and absolute stereochemistry simultaneously. In this context, palladium(II)-catalyzed asymmetric allylic C–H functionalization of terminal olefins through the intermediacy of π-allyl/Pd(II) complex represents a viable platform. Traditionally, the asymmetric functionalization of π-allyl/Pd(II) intermediate generally proceeded with phosphine-based ligands, under redox-neutral and basic conditions. Current efforts to develop the oxidative allylic C–H functionalization reaction have focused on the adaptation of phosphine-based ligands, which are prone to oxidation. As such, these systems suffer from limited substrate scope (activated olefins, e.g. allylarenes) and modest enantioselectivity. Alternatively, the oxidatively stable bis-sulfoxide ligand has shown to promote general reactivity with broad scope. However, its underlying mechanism, known as “serial ligand catalysis”, is challenging for asymmetric catalysis, due to the highly dynamic and fluxional binding environment of palladium. This work describes the development of oxidatively stable, chiral sulfoxide-oxazoline ligands for palladium(II)-catalyzed asymmetric allylic C–H oxidations and alkylations. The design principle is to combine the sulfoxide moiety, known to promote C–H cleavage, with a strongly coordinately oxazoline moiety that can anchor the ligand to the metal and thereby provide a stable chiral environment. Additionally, the σ-donation from oxazoline could promote the formation of a cationic π-allyl/Pd(II) intermediate, which becomes more reactive towards functionalization. The first chapter of this dissertation describes the development of a general intermolecular allylic C–H alkylation with tertiary nucleophiles under palladium(II)/bis-sulfoxide catalysis. This work laid the foundation for asymmetric processes with the resultant quaternary stereogenic centers that would not be prone to racemization. This reaction incorporates a broad scope of terminal olefins (e.g. aromatic, aliphatic) and tertiary nucleophiles (e.g. nitroketones, β-ketoesters) with good yields and excellent selectivities (>20:1 linear:branched, >20:1 E:Z). The use of tertiary nucleophiles allows for strategic incorporation of latent functionality into the alkylation partner, which can be exploited for further elaboration to generate molecular complexity. This concept is demonstrated in a tandem allylic C–H alkylation/Diels-Alder reaction sequence: a reactive diene is generated upon the alkylation of a terminal olefin and trapped by a dienophile contained within the tertiary nucleophile to afford a complex tricyclic core structure. The second chapter describes the development of chiral sulfoxide-oxazoline (SOX) ligands for Pd(II)-catalyzed enantioselective allylic C–H oxidation. Chiral isochromans are formed by the intramolecular cyclization between alcohol and terminal olefin, leading to good yields and high enantioselectivities (>90% ee). Pd(II)/trans-SOX catalysts are found to be significantly more selective than Pd(II)/cis-SOX. Systematic ligand modification reveals bulky para-substituents (tert-butyl or trifluoromethyl) on the aryl sulfoxide moiety to be optimal. The synthetic utility of this reaction is demonstrated in the synthesis of a chiral amide-containing isochroman, which is a known pharmacophore found in selective 5HT1d agonist. Finally, Pd(II)/SOX catalysis is applied to the development of asymmetric allylic C–H alkyation. A significant challenge is that the intermolecular alkylation of π-allyl/Pd(II) intermediate generally procceds with linear regioselectivity, where the approach of the prochiral nucleophile is relatively remote from the ligand environment. As a solution, the π-π interaction between the substituents on the sulfoxide and the oxazoline in the cis-SOX ligand is exploited to achieve an orientation that projects the steric element towards the approach of the nucleophile. The modular SOX scaffold enables the successful alkylation of a diverse array of nucleophiles, including α-nitrotetralones and β-ketoesters, all in good yields and high enantioselectivies (>90% ee). The Pd(II)/cis-SOX catalysis has also demonstrated the ability to achieve catalyst-controlled diastereoselectivity in the alkylation of chiral aliphatic olefins.
Issue Date:2018-11-15
Rights Information:Copyright 2018 Wei Liu
Date Available in IDEALS:2019-02-06
Date Deposited:2018-12

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