Bioinspired Enantioselective Catalytic alpha-Alkylation of Aldehydes

性状（由申请人提供）：S-腺苷-L-甲硫氨酸（又名，SAM、AdoMet）是一种对许多生物过程至关重要的辅因子。具体地，SAM是阳离子硫基烷基化剂，并且酶使用SAM有效地烷基化各种分子中的氧、氮和碳原子。直接，对映选择性，催化？-碳的烷基化是形成新的碳-碳键的最基本的方法之一。SAM依赖性酶可以轻松地管理这种转化，但它仍然是合成化学家的一个挑战，尽管使用中性，不带电荷的烷基化剂进行了相当大的努力。目前的建议从自然界中获得灵感，旨在开发一种手性小分子氨基芳烃催化剂，实现直接，对映选择性，催化？使用阳离子硫基烷基化剂如SAM将醛烷基化。与使用中性烷基化剂的系统不同，该系统利用硫基阳离子上的电荷使其靠近活化的醛底物，从而促进反应。这种底物和试剂的预结合是酶催化的标志，并且应该导致高水平的对映体选择性，给出适用于许多医学上重要的化合物的合成的反应。最后，该提案还旨在详细研究这种新的催化系统，以深入了解涉及SAM的许多关键细胞过程，从而可能揭示其各种治疗用途。

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.