Copper(I) Hydride-Catalyzed Transformations of π-Electrophiles

Abstract

The studies presented in this dissertation are regarding the development of new methods for copper-catalyzed transformations of π-electrophiles. The first part of this dissertation focuses on the development of broadly applicable protocols for the syntheses of enantioenriched homoallylic alcohols (Chapter 2) and homopropargylic amines (Chapter 3). The second part of this dissertation describes a method for accessing synthetically relevant β, γ-unsaturated acceptors (Chapter 4). — PART I Chapter 2: Regio- and Enantioselective CuH-Catalyzed Allylation of Ketones Using Terminal Allenes An efficient method for the copper-catalyzed allylation of ketones is described using widely available terminal allenes as allylmetal surrogates. Homoallylic alcohols bearing a wide range of functional groups are obtained in high yield and with good regio-, diastereo-, and enantioselectivity. Mechanistic investigations implicate the in situ formation of isomeric copper(I) allyl complexes which undergo addition to ketones with exclusive branched regioselectivity to afford the major isomer of the product. A stereochemical model is provided to explain the high diastereo- and enantioselectivity of this process.

Chapter 3: Asymmetric Synthesis of Homopropargylic Amines by CuH-Catalyzed Coupling of Imines and Enynes A novel method for the synthesis of chiral homopropargylic amines is detailed. Aromatic and aliphatic N-phosphinoyl aldimines possessing a variety of functional groups are coupled with both terminal and internal enynes under mild conditions. The resulting homopropargylic amines are produced in high yields, with moderate diastereoselectivities and generally high enantioselectivities. — PART II Chapter 4: Regio- and Stereoselective Synthesis of β,γUnsaturated Compounds by CuH-Catalyzed 1,6-Semireduction A practical and highly selective preparation of β, γ-unsaturated compounds is reported. This method relies on the CuH-catalyzed 1,6-semireduction of easily accessible α, β, γ, δ-doubly unsaturated acceptors. By using the commercially available wide bite-angle ligand Xantphos, the formation of all undesired isomers and overreduction products is not observed in the majority of cases. The scope of accessible products includes β, γ-unsaturated esters, amides, sulfones, and nitriles with a variety of functional groups. Due to the high volatility of many products, careful purification is required to ensure high yields. — Thesis Supervisor: Stephen L. Buchwald Title: Camille Dreyfus Professor of Chemistry