Enantioselective C-H Bond Functionalizations by 3d Transition-Metal Catalysts

Direct catalytic modifications of carbon-hydrogen (C-H) bonds, ubiquitous in organic molecules, represent a powerful strategy in organic synthesis. In the past decade, chemists have focused on the development of sustainable methods for functionalization of inert C-H bonds using cost-effective earthabundant 3d transition-metal catalysts. To fully harness the potential of this technology, however, it is essential to control the stereoselectivity of the C-H functionalization processes. This review describes developments in the emerging area of enantioselective functionalization of C-H bonds by 3d transitionmetal catalysts proceeding via inner-sphere C-H activation.

Catalytic Enantioselective Functionalizations of C-H Bonds by Chiral Iridium Complexes

Nicolai Cramer, Adrien Jules Louis Madron Du Vigné, Qui-Hien Nguyen, Jin Fay Tan, Lukasz Piotr Wozniak

The development of catalytic enantioselective transformations, enabling the construction of complex molecular scaffolds from simple precursors, has been a long-standing challenge in organic synthesis. Recent achievements in transition-metal catalyzed enantioselective functionalizations of carbon-hydrogen (C-H) bonds represent a promising pathway toward this goal. Over the last two decades, iridium catalysis has evolved as a valuable tool enabling the stereocontrolled synthesis of chiral molecules via C-H activation. The development of iridium-based systems with various chiral ligand classes, as well as studies of their reaction mechanisms, has resulted in dynamic progress in this area. This review aims to present a comprehensive picture of the enantioselective functionalizations of C-H bonds by chiral iridium complexes with emphasis on the mechanisms of the C-H activation step.

2020

Ligand synthesis for homogeneous catalysis

Michael Maurin

Organophosphorus compounds found applications in varied fields of the organic chemistry: they are particularly present in natural compounds such as the deoxyribonucleic acid (DNA) and in the field of catalysis in which their utility is also proven. Thus, this thesis work first focused on the preparation of various phosphorus ligands utilizable in transition metal catalysed reactions. Being given the importance of this type of reaction in organic synthesis, it appears essential to have many ligands at disposal in order to fine-tune and to optimize the reaction conditions as much as possible. Thus, the first objective of this work was to propose a simple and general method for the preparation of monodentate phosphorus ligands. Based on the use of phosphites in substitution for the usual phosphorus trihalides, this method was initially tested during the preparation of different simple triarylphosphines. Thereafter, this method was extended to the synthesis of new ligands having more complex structures. The yields obtained for the latter as well as the variety of the substrates authorized by this method confirmed its value and suggested its application to the synthesis of new heteroaromatic phosphines. The preparation of bidentate phosphorus ligands based on chiral biphenyl motifs was then addressed. For that purpose, the 2,2',6,6' -tetrabromobiphenyl was chosen as a pivot substrate for the development of a modular synthetic approach. Indeed, by means of successive halogen/metal permutational exchanges and after treatment with the suitable electrophile, it was possible to functionalize this substrate, isolate each atropisomer in enantiomerically pure form, and finally convert each one of those into chiral biphenylbisphosphines. In addition, it was also possible, during the synthesis of these ligands, to evaluate the rotational stability of some enantiomerically pure dilithiobiphenyls by means of dynamic nuclear magnetic resonance experiments.

EPFL2007

Palladium Catalysed Intramolecular Carbo-oxygenation of Propargylic Amines to Access 1,2-Amino Alcohols and alpha-Amino Ketones via in situ Tether Formation

Phillip Gulliver Dominic Greenwood

a-Amino ketones and 1,2-amino alcohols are important structural motifs in organic chemistry, that can be observed in natural products, pharmaceutically and bioactive compounds. For these reasons, they constitute privileged targets for the development of new and effective synthetic methods. The dual-functionalisation of unsaturated carbon-carbon bonds is a powerful approach to access these crucial motifs. In this context, Pd catalysis has been comprehensively investigated and has consistently demonstrated its capability. Methods enabling the concomitant formation of a carbonâ heteroatom and a carbonâcarbon bond are highly valuable, but the challenges of intermolecular reactions have led to the development of tether systems that require additional steps for their introduction and removal. In situ tethering strategies have previously been explored within the Waser group to circumvent these limitations. This approach relies on a one-pot, three component, Pd catalysed carboetherification or amination reaction, leading to rapidly increase in complexity of simple substrates. So far, the in situ methodologies developed by the Waser group have focused on the functionalisation of alkenes from allylic amines and alcohols. In this regard, the goal of my PhD was to expand the in situ tethering methodologies established within the Waser group, to the synthesis of a-amino ketones and 1,2-amino alcohols. Specifically, my focus was on the formation a trifluoromethyl hemiaminal with a propargylic amine and using the resulting aminal to direct the oxyalkynylation and oxyarylation of the alkyne substrate via a Pd catalysed transformation. Upon optimisation, the reaction of a protected terminal propargylamine, trifluoroacetaldehyde ethyl hemiacetal and silylbromoacetylene using a Pd0 complex with DPEPhos as the catalytic system and Cs2CO3 as the base gave the desired oxazolidine alkenes in high yields and E:Z selectivity. Substrates with substitution on the terminal position and at the propargylic required a change of ligand and base. The transformation was broadly tolerant towards substitution on the nitrogen and the alkyne. An oxyarylative variant was also developed, using Ruphos as ligand, and worked well with a range of iodoarene partners. The obtained oxazolidines could be conveniently orthogonally deprotected to access the a-amino ketone and terminal alkyne; the hydrogenation of the unsaturated oxazolidines has allowed access to 1,2-amino alcohol scaffolds and the application of gold catalysis converted the enyne-oxazolidine system into trisubstituted silyl furans. The identification of a sideproduct of the oxyalkynylation process led to the development of a carboxy-alkynylation reaction using a "CO2" unit derived from the carbonate base. Optimisation established CsHCO3 to the best base/"CO2" source, using DPEPhos as ligand. This transformation gave convenient access to diverse library of cyclic carbamates. Work is ongoing to achieve an enantioselective oxyarylation using chiral phosphine ligands. The asymmetric synthesis of oxazolidines, followed by the diastereoselective alkene hydrogenation and subsequent tether removal would allow the stereodivergent access to interesting diarylalkyl-1,2- amino alcohols. Most recently, the product was synthesised in 66% yield, with 66%ee using commercially available Trost ligand.