Huth Susannah E, Stone Elizabeth A, Miller Scott J
Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States.
Department of Chemistry and Biochemistry, Fairfield University, Fairfield, Connecticut 06824, United States.
Acc Chem Res. 2025 Jun 18. doi: 10.1021/acs.accounts.5c00247.
ConspectusAs drug molecules become increasingly complex, the need to develop new or improved strategies for the efficient and selective synthesis and editing of bioactive compounds grows. Inspired by the high selectivity and fast rates exhibited in many enzymatic reactions to assemble complex natural products, our group and others have developed peptide-based catalysts to mediate synthetically relevant transformations that can be orthogonal, or akin to, native enzymatic reactivity. Peptide catalysts offer several useful features, such as modularity, ease of synthesis, and often enhanced compatibility with synthetic reaction conditions.In one intriguing area, our group has employed the proteinogenic amino acid aspartic acid (Asp) as a catalytic residue embedded within short peptide sequences to selectively introduce a singular oxygen atom into increasingly complex scaffolds, which might constitute a type of single atom editing. Our strategy has involved the development of an aspartic acid/peracid catalytic shuttle, a mechanism that, to our knowledge, has not yet been documented in enzymes.Our foray into Asp-catalyzed oxidation began with the discovery of a peptide sequence to impart enantioselectivity in the epoxidation of minimal olefins. This platform was then extended to include nucleophilic Baeyer-Villiger oxidations and electrophilic - and -atom oxidations. Of note, these reactions all use hydrogen peroxide as the stoichiometric oxidant; the appended peptide sequence dictates the selectivity on a per-reaction-type basis. Lead peptides for each transformation were identified using both combinatorial and rational design approaches, and mechanistic studies were used to guide our development along the way or to elucidate modes of action after the fact. In all cases, selectivity was achieved through critical noncovalent interactions between the substrate and peptide catalyst.We have always endeavored to test these catalysts in increasingly complex settings, facing difficult challenges in chemo-, site-, and stereoselectivity in a variety of molecular scaffolds. In a particularly forward-looking example, Asp-peptides were used to perform late-stage molecular editing of geldanamycin, a quintessentially complex and bioactive natural product. Asp-peptides have now also been used to edit the three-dimensional structure of loratadine, the active ingredient in Claritin, to generate helically chiral -oxide analogues with chemo- and stereoselectivity. In the case of both geldanamycin and loratadine, the oxidized bioactive analogues underwent biological testing, providing insight into the development of future medicinally relevant molecules. Taken together, this Account details the power of Asp-catalysts to address challenges in asymmetric catalysis while also contributing to the need for rapid access to drug analogues.
概述
随着药物分子变得越来越复杂，开发新的或改进的策略以高效、选择性地合成和编辑生物活性化合物的需求也在增加。受许多酶促反应中表现出的高选择性和快速反应速率的启发，我们小组和其他研究团队开发了基于肽的催化剂，以介导与合成相关的转化反应，这些反应可以是正交的，或者类似于天然酶的反应活性。肽催化剂具有几个有用的特性，例如模块化、易于合成，并且通常与合成反应条件具有更好的兼容性。
在一个有趣的领域，我们小组使用蛋白质原性氨基酸天冬氨酸（Asp）作为嵌入短肽序列中的催化残基，将单个氧原子选择性地引入到越来越复杂的支架中，这可能构成一种单原子编辑方式。我们的策略涉及开发天冬氨酸/过酸催化穿梭机制，据我们所知，这种机制尚未在酶中被记录。
我们对天冬氨酸催化氧化的探索始于发现一种肽序列，该序列能在最小烯烃的环氧化反应中赋予对映选择性。然后，这个平台被扩展到包括亲核的拜耳 - 维利格氧化反应和亲电的 - 原子氧化反应。值得注意的是，这些反应都使用过氧化氢作为化学计量氧化剂；附加的肽序列决定了每种反应类型的选择性。通过组合设计和理性设计方法确定了每种转化反应的先导肽，并利用机理研究来指导我们的开发过程，或者在事后阐明作用方式。在所有情况下，选择性都是通过底物与肽催化剂之间关键的非共价相互作用实现的。
我们一直致力于在越来越复杂的环境中测试这些催化剂，在各种分子支架的化学选择性、位点选择性和立体选择性方面面临着艰巨的挑战。在一个特别有前瞻性的例子中，天冬氨酸肽被用于对格尔德霉素进行后期分子编辑，格尔德霉素是一种典型的复杂且具有生物活性的天然产物。天冬氨酸肽现在也被用于编辑氯雷他定（开瑞坦的活性成分）的三维结构，以生成具有化学选择性和立体选择性的螺旋手性 - 氧化物类似物。在格尔德霉素和氯雷他定的案例中，氧化后的生物活性类似物都进行了生物学测试，为未来医学相关分子的开发提供了见解。综上所述，本综述详细阐述了天冬氨酸催化剂在应对不对称催化挑战方面的能力，同时也满足了快速获得药物类似物的需求。
