Complex Amines from Simple Amino Acids via Pyridoxal-Mimicking Radical (Photo) Catalysis

Project Summary The overarching five-year goal of the proposed research thrust is to realize a wholly new avenue in biomimetic organic synthesis, whereby rationally designed PLP-mimicking scaffolds can enable open-shell radical pathways, particularly by using visible light, for challenging bond cleavages and formations. This will be enabling in the synthesis of complex primary amines from unprotected amino acids, providing rapid access to molecular complexity, leveraging the inherent sustainability and accessibility of bio-derived precursors. From a mechanistic standpoint, PLP-mimicking synthesis has operated in a single manifold (a-deprotonation) for the past 50 years – albeit with substantial practical advances – mimicking PLP-dependent transaminases. This proposal posits that other PLP-dependent mechanisms can be realized “ex vivo”, provided substantial kinetic barriers, which are overcome in enzyme active sites through exquisite stereoelectronic control, can be subverted through distinct mechanistic pathways. First, a “synthetic photodecarboxylase” platform is described, wherein the natural, but kinetically-difficult, 2e--decarboxylation pathway is diverted to a radical decarboxylation via charge-transfer excitation of a PLP-like amino acid Schiff base, which triggers oxidation to a carboxyl radical, inducing rapid decarboxylation. This provides ambient access to the key quinonoid intermediate common to PLP-dependent mechanisms. From this intermediate, a bevy of functionalizations could be realized, allowing for decarboxylative synthesis of complex 1º amine products. Catalyst SAR demonstrate the necessary components of a catalytic system and control over post-decarboxylation reactions. Elaboration of this platform to asymmetric catalysis is proposed, taking advantage of the wealth of chiral PLP-mimicking catalysts for e.g. Mannich reactions. Second, drawing inspiration from PLP-dependent radical aminomutase enzymes, a platform for amination of C-centered radicals using amino acid esters as a source of “NH3” is described. This platform relies on umpolung via highly polarized imines to trap nucleophilic C-radicals at the electrophilic N-terminus of an imine, followed by ß-scission fragmentation of the amino acid ester to generate the newly aminated product, with simple esters (e.g. EtOAc) as the sole byproduct. This will be applied intramolecularly for a hook-and-slide strategy for the translation of abundant a-amino acids into synthetically challenging ß-, ?-, d-, and e-amino acids. The platform will be realized catalytically for intermolecular amination of C-radicals, with the potential for asymmetric amination via either chirality transfer from abundant chiral amino acid precursors or via asymmetric catalysis. The proposed research is highly innovative, as radical PLP-mimicking catalysis is wholly undescribed in the literature, with just one example of engineered enzymatic catalysis merging radical mechanisms with PLP-dependent enzymes. Furthermore, the studies described herein are significant as they will both open up new avenues of organic synthesis, particularly within organocatalysis, and provide rapid access to complex primary amines of pharmaceutical relevance from simple, abundant amino acids.