Computational Prediction and Experimental Validation of a Bridged Cation Intermediate in Akanthomycin Biosynthesis.
Computational Prediction and Experimental Validation of a Bridged Cation Intermediate in Akanthomycin Biosynthesis.
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阿克沙霉素生物合成中桥联阳离子中间体的计算预测和实验验证。
DOI：
10.1021/jacs.2c02288
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发表时间：
2022-03-30
影响因子：
15
通讯作者：
Tang, Yi
中科院分区：
文献类型：
--
作者：
Jamieson, Cooper S.;Ohashi, Masao;Houk, K. N.;Tang, Yi
在这里，我们报告了一个计算驱动的化学酶合成和生物合成的天然产物脱氧棘霉素，阻转异构体吡啶酮的天然产物，具有7元碳环与5个立体中心，其中一个四元中心。从生物合成前体的一步合成是基于计算分析，其预测了形成脱氧棘霉素的σ-桥连阳离子介导的环化机制。σ-桥连阳离子使观察到的底物控制的选择性合理化;非对映选择性是由水对σ-桥连的攻击引起的，如通常在σ-桥连阳离子中发现的。我们的研究还揭示了一个统一的生物合成策略2-吡啶酮天然产物，从一个共同的邻醌甲基化物产生不同的结构。化学家和自然界利用固有的底物反应性来进行立体选择性的无催化剂反应-也许最值得注意的例子是鹳的胚芽合成。更常见的是，化学家和自然界依靠催化剂的发展来控制合成中的立体选择性、区域选择性和化学选择性。在合成中，已经设计和实施了过多的选择复杂分子的反应结果的小分子催化剂。相比之下，自然界进化出了各种酶，通过非共价相互作用来施加选择性。其中一个家族是最近发现的催化周环反应的周环酶。这种酶可以在单一步骤中从非环状中间体选择性地产生复杂的分子结构，例如天然产物的4-羟基2-吡啶酮家族中的结构多样性（图1）。以前，我们的特点是酶催化的周环反应，导致吡啶酮天然产物。在此，我们描述了从排除控制这些反应途径的酶获得的天然产物，并展示了自然界使用固有的底物反应性来合成具有挑战性的分子结构。本工作建立了天然产物脱氧棘霉素（1a和1b）的化学酶合成和生物合成。
Here we report a computation-driven chemoenzymatic synthesis and biosynthesis of the natural product deoxyakanthomycin, an atropisomeric pyridone natural product that features a 7-membered carbocycle with five stereocenters, one of which a quaternary center. The one-step synthesis from a biosynthetic precursor is based on computational analysis that predicted a σ-bridged cation mediated cyclization mechanism to form deoxyakanthomycin. The σ-bridged cation rationalizes the observed substrate-controlled selectivity; diastereoselectivity arises from attack of water anti to the σ-bridging, as is generally found for σ-bridged cations. Our studies also reveal a unifying biosynthetic strategy for 2-pyridone natural products that derive from a common o-quinone methide to create diverse structures. Chemists and nature leverage inherent substrate reactivity to conduct stereoselective catalyst-free reactions – perhaps most notably exemplified by Stork’s synthesis of germine. More commonly, chemists and nature rely on catalyst development to control stereoselectivity, regioselectivity, and chemoselectivity in synthesis. In synthesis, a plethora of small molecule catalysts that select the reaction outcomes of complex molecules have been designed and implemented. In comparison, nature evolved a variety of enzymes to impose selectivity via noncovalent interactions. One such family is the recently discovered pericyclases that catalyze pericyclic reactions. Such enzymes can selectively generate complex molecular architectures from acyclic intermediates in a single step exemplified by the structural diversity in the 4-hydroxy 2-pyridone family of natural products (Figure 1). Previously, we have characterized the enzyme-catalyzed pericyclic reactions that lead to pyridone natural products. Herein, we describe natural products obtained from the exclusion of enzymes that control these reaction pathways and showcase nature’s use of inherent substrate reactivity to synthesize challenging-to-make molecular architectures. This work establishes a chemoenzymatic synthesis and biosynthesis of the natural product deoxyakanthomycin (1a and 1b).
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影响因子：
64.8
作者：
Ohashi M;Jamieson CS;Cai Y;Tan D;Kanayama D;Tang MC;Anthony SM;Chari JV;Barber JS;Picazo E;Kakule TB;Cao S;Garg NK;Zhou J;Houk KN;Tang Y
通讯作者：
Tang Y
影响因子：
5.2
作者：
Liu N;Hung YS;Gao SS;Hang L;Zou Y;Chooi YH;Tang Y
通讯作者：
Tang Y
影响因子：
64.8
作者：
Houk, K. N.;Cheong, Paul Ha-Yeon
通讯作者：
Cheong, Paul Ha-Yeon
影响因子：
15
作者：
McClymont KS;Wang FY;Minakar A;Baran PS
通讯作者：
Baran PS
影响因子：
3.2
作者：
Hong, Young J.;Tantillo, Dean J.
通讯作者：
Tantillo, Dean J.