Bioinspired Enantioselective Catalytic alpha-Alkylation of Aldehydes

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DESCRIPTION (provided by applicant): S-Adenosyl-L-Methionine (a.k.a., SAM, AdoMet) is a cofactor that is crucial to many biological processes. Specifically, SAM is a cationic sulfur-based alkylating agent, and enzymes use SAM to efficiently alkylate oxygen, nitrogen, and carbon atoms in a wide variety of molecules. Direct, enantioselective, catalytic ?-alkylation of carbon is one of the most fundamental ways to form new carbon-carbon bonds. SAM-dependent enzymes manage this transformation with ease, but it remains a challenge for synthetic chemists, despite considerable efforts using neutral, uncharged alkylating agents. The current proposal takes inspiration from nature and aims to develop a chiral small molecule amino-arene catalyst that accomplishes the direct, enantioselective, catalytic ?-alkylation of aldehydes using cationic sulfur-based alkylating agents like SAM. Unlike systems that use neutral alkylating agents, this system exploits the charge on the sulfur-based cation to bring it in close proximity to the activated aldehyde substrate, facilitating the reaction. This pre-binding of substrate and reagent is a hallmark of enzymatic catalysis and should lead to high levels of enantioselectivity, giving a reaction that is applicable to the syntheses of many medicinally important compounds. Finally, this proposal also aims to study this new catalytic system in detail to gain insight into the many key cellular processes involving SAM, potentially shedding light on its various therapeutic uses. PUBLIC HEALTH RELEVANCE: The novel chemical method proposed here offers two major contributions. First, it will allow more rapid and efficient access to pharmaceuticals and other target compounds of medicinal importance. Second, it will provide a model system to better understand the cofactor S-Adenosyl-L-Methionine, which is essential for many cellular functions (including DNA regulation) and is used as a nutritional supplement and as a therapy for depression and osteoarthritis.