Catalytic C(sp3)-H bond functionalization of enolates – EnolFun
Functionalization of unactivated carbon-hydrogen bonds by metallic catalysis
The direct functionalization of carbon-hydrogen bonds is an atom and step-economical alternative to traditional synthetic methods in order to access original functionalized organic molecules. In this context, this project aims at studying a new catalytic method for the direct functionalization of alkane fragments.
Towards the development of shorter and cleaner synthetic methods.
This fundamental research project is positioned in a frontier field of organic synthesis and organometallic catalysis. Its main goal is the development of new methods for the direct functionalization of alkyl groups of organic molecules by organopalladium catalysis, via the chemistry of enolates. This method should allow to easily access functionalized molecules of high added value such as nonnatural amino acids, which have great utility in medicinal chemistry.
The work plan is composed of 3 complementary parts performed in parallel by the two partner teams in a combined experiment/theory approach: 1. development of reaction conditions for the coupling of various types of enolates in beta position or longer range with a variety of aromatic or non aromatic electrophiles; 2. development of an enantioselective version; 3. study of reaction mechanisms and selectivity control.
The long-range arylation of alpha-amino esters with various aryl bromides, occurring selectively at the terminal position of the linear alkyl chain, was performed successfully, in line with our initial results. This method allows to access a great variety of phenylalanine analogues, which are useful building blocks for medicinal and peptide chemistry, in a direct and efficient way. These results were published in Angewandte Chemie International Edition.
Our current work focuses on the extension of these arylation methods to other functional groups, in particular protected amines. Moreover, the development of an efficient asymmetric arylation reaction in the presence of new chiral ligands is under study. In addition, current experimental and theoretical mechanistic work aims at clarifying the role of the ligand structure in order to propose a more rational design.
- Synthesis of aromatic a-amino esters: Pd-catalyzed long-range arylation of primary C(sp3)–H bonds: S. Aspin, A.-S. Goutierre, P. Larini, R. Jazzar, O. Baudoin, Angew. Chem. Int. Ed. 2012, 51, 10808-10811.
- Ligand-controlled ß-selective C(sp3)–H arylation of N-Boc-piperidines: A. Millet, P. Larini, E. Clot, O. Baudoin, Chem. Sci. 2013, 4, 2241-2247.
The transition-metal catalyzed functionalization of carbon-hydrogen bonds is an atom and step-economical approach for the synthesis of valuable organic molecules. This project deals with the study of a new palladium-catalyzed method allowing the direct intermolecular functionalization of unactivated C-H bonds of enolates. The proposal is composed of three complementary parts which will be performed by two partner groups: 1. development of general reaction conditions for the cross-coupling of various types of enolate nucleophiles at their beta or gamma position with a broad range of aromatic, heteroaromatic and non-aromatic electrophiles; 2. development of an efficient enantioselective version, and its application to the synthesis of synthetically useful homochiral amino acids; 3. study of reaction mechanisms and selectivity issues by experiment and theory (DFT calculations).
Project coordination
Olivier Baudoin (UNIVERSITE CLAUDE BERNARD - LYON I)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partnership
ICBMS UNIVERSITE CLAUDE BERNARD - LYON I
ICG CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE LANGUEDOC-ROUSSILLON
Help of the ANR 419,999 euros
Beginning and duration of the scientific project:
September 2011
- 42 Months
