Dr. Stephane P. Roche

Research

Research in my laboratory aims to challenge modern synthetic chemistry: developing catalytic, enantioselective and more chemoselective methodologies by considering biomimetic inspirations. Our research program will focus on establishing new methodologies using organocatalysis, which will be directly applied in total synthesis of complex targets. The total Synthesis campaigns will be gravitating around the development of innovative methodologies on chirality and peptide chemistry as tools for the preparation of complex non-proteinogenic amino acids, peptides and alkaloids.

Method: Mimic of Acetoacetate Decarboxylase.

We aim to mimic the acetoacetate decarboxylase enzyme in a reaction vessel. This organocatalytic strategy will allow the regiospecific formation of an enol intermediate, which will enable a broad range of chemistry to be evaluated. Basically, all previously reported organocatalytic transformation on aldehydes using proline or imidazolidinone will be addressed and applied, for the first time, to ketones.

Method: Memory of Chirality; Total Synthesis of Alkaloid DX-52-1 and Analogs.

Our research will focus on a very important class of reactions: [3+2] and [4+3] cycloadditions. We will study the possibility of 'chiral memory' through a relay of chiral information. ?-Amino acids will be condensed with methyl glyoxylate and spontaneously decarboxylated to form an azomethine ylide intermediate. Azomethine ylide intermediates are envisioned to transfer chirality through atropoisomerism, thus preserving the chiral integrity and inducing highly diastereoselective [3+2] and [4+3] cycloadditions. This strategy was actually inspired by the natural product DX-52-1 structure, metabolite having important anticancer properties. DX-52-1 core is envisioned to be accessed in the context of total synthesis using diastereoselective [4+3] cycloaddition.

Method: Renaissance for Peptide Synthesis (CH-activation); Total Synthesis of Sorbicillactone A.

This project will examine formal ?-functionalization of glycine derivatives to prepare, in three steps, enantioenriched non-proteinogenic ?-amino acids and ultimately develop a desirable large scale process. This study should reveal new possibilities for asymmetric crafting of glycine ?-iminoesters by employing H-bond donor catalysis and visible light mediated CH-oxidation. This strategy will enable the transformation of a glycine residue into any desired chiral non-racemic ?-amino acid. Thus, merging photochemistry (CH-oxidation) of the appropriate glycine derivative with enantioselective Mannich reaction upon Brønsted catalysis should enable us to prepare a broad range of enantioenriched ?-amino esters, ?-disubstituted-aminoesters and dipeptides. In light of the potential impact of this methodology to prepare complex enantioenriched ?-amino esters, particular attention will be given to selective addition of carbon-centre nucleophiles (Nu-H) to the transient ?-iminoester intermediate. This methodology will then be applied to the total synthesis of celogenamide A, a potent angiotensin II antagonist and sorbicillactone A (anticancer agent).