Abstract 1 and 2. Novel Methodologies in Organocatalysis.
Project 1 is a challenging but extremely innovative research program mimicking 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, any kind of reported organocatalytic transformation using aldehydes will be addressed and applied, for the first time, to ketones.
Project 2 will explore an enantioselective transformation of α-amino ester racemic mixtures to produce dipeptides as single diastereomers. For this purpose a Dynamic Kinetic Resolution (DKR) for peptidic backbone construction will be evaluated, highlighting a new organocatalysis maneuver: aldehyde catalysis. Several salicylic aldehydes/pyridoxaldehyde mimics, catalysts based on C2-symmetry frameworks, will be tested to achieve high stereo-differentiation of the two starting α-amino ester enantiomers using a biomimetic racemization process (DKR). The matched enantiomer (R) (see above) should be consumed through a racemization process to increase the production of the mismatched (S)-enantiomer. In the same pot, an activated enantiopure N-protected-α-amino acid will be added to obtain a pure dipeptide diastereomer, in a single step.
Abstract 3 and 4. Methodologies on Chirality and Applications in Total Synthesis
Project 3 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. α-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.
Project 4 will examine formal α-functionalization of glycine derivatives to prepare, in three steps, enantioenriched non-proteinogenic α-amino acids and ultimately develop a desirable large scale process. This study should reveal new possibilities for asymmetric crafting of glycine α-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 α-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 α-amino esters, α-disubstituted-aminoesters and dipeptides. In light of the potential impact of this methodology to prepare complex enantioenriched α-amino esters, particular attention will be given to selective addition of carbon-centre nucleophiles (Nu-H) to the transient α-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).