Chemoenzymatic Total Synthesis of Natural Products.
Chemoenzymatic Total Synthesis of Natural Products.
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DOI：
10.1021/acs.accounts.0c00810
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发表时间：
2021-03-16
影响因子：
18.3
通讯作者：
Narayan ARH
中科院分区：
文献类型：
--
作者：
Chakrabarty S;Romero EO;Pyser JB;Yazarians JA;Narayan ARH
结构复杂的天然产物的全合成已经挑战和启发了几代化学家，并且仍然是一个令人兴奋的活跃研究领域。尽管天然产物在历史上是具有丰富生物活性的特殊支架，但在药物发现中的使用已经减少。这一转变是由于其相对较低的丰度阻碍了与自然来源的隔离以及其合成所带来的挑战。生物催化的最新发展导致了酶用于构建复杂分子的应用。自2015年Narayan实验室成立以来，我们一直专注于利用酶的精致选择性以及当代基于小分子的方法，以实现天然产物的简洁化学酶促路线。我们专注于来自不同家族的进行选择性氧化反应的酶。例如，我们通过依赖于化学和位点选择性生物催化羟基化的策略靶向了木缩酮天然产物。木缩酮家族的成员以多环缩酮核心为特征，并表现出有效的神经活性。我们设想组装一个代表性的木缩酮天然产物（木缩酮D），涉及生物催化产生的邻醌甲基化物中间体。非血红素铁（NHI）依赖性单加氧酶ClaD用于进行间苯二酚前体的苄羟基化，其产物可以在温和条件下经历自发失水以形成邻醌甲基化物。使用手性亲二烯体捕获该中间体以完成木缩酮D的全合成。我们在合成中采用的第二类生物催化氧化是使用黄素依赖性单加氧酶（FDMO）的间苯二酚化合物的羟基化脱芳构化。我们预计，催化剂控制的网站和FDMO的立体选择性将使azaphilone天然产物的全合成。氮杂菲酮类化合物是一种具有生物活性的化合物，其特征在于吡喃醌双环核和完全取代的手性碳原子。我们利用FDMOs AzaH和AfoD的立体分散反应性来实现对映体选择性合成阿夫菌素对映体、偏转素1a和月氨酸。我们还利用FDMO构建托酚酮和山梨西林类天然产物。环庚三烯酮是一类结构多样的生物活性分子，其特征在于具有α-羟基酮部分的芳族环庚三烯核。我们开发了一个两步，生物催化级联的托酚酮天然产物stipitatic醛开始使用FDMO TropB和NHI单加氧酶TropC。从索比西林生物合成途径获得的FDMO SorbC用于脲索比西林类天然产物的简明全合成。我们长期以来对使用酶进行C-H羟基化反应的兴趣也被引导到复杂支架的后期多样化。例如，我们已经使用Rieske加氧酶来羟基化麻痹性贝类毒素常见的三环核心。这些化合物的全身毒性可以通过添加羟基和硫酸酯基团来降低，这改善了它们作为治疗剂的性质和潜力。酶SxtT、GxtA、SxtN和SxtSUL用于在石房蛤毒素和相关结构中进行选择性C-H羟基化和O-硫酸化。最后，我们讨论了生物催化中存在的挑战以及我们目前可以解决这些挑战的方法。
The total synthesis of structurally complex natural products has challenged and inspired generations of chemists and remains an exciting area of active research. Despite their history as privileged bioactivity-rich scaffolds, the use of natural products in drug-discovery has waned. This shift is driven by their relatively low abundance hindering isolation from natural sources and the challenges presented by their synthesis. Recent developments in biocatalysis have resulted in the application of enzymes for the construction of complex molecules. From the inception of the Narayan lab in 2015, we have focused on harnessing the exquisite selectivity of enzymes alongside contemporary small molecule-based approaches to enable concise chemoenzymatic routes to natural products. We have focused on enzymes from various families that perform selective oxidation reactions. For example, we have targeted xyloketal natural products through a strategy that relies on a chemo- and site-selective biocatalytic hydroxylation. Members of the xyloketal family are characterized by polycyclic ketal cores and demonstrate potent neurological activity. We envisioned assembling a representative xyloketal natural product (xyloketal D) involving a biocatalytically generated ortho-quinone methide intermediate. The non-heme iron (NHI) dependent monooxygenase ClaD was used to perform the benzylic hydroxylation of a resorcinol precursor, the product of which can undergo spontaneous loss of water to form an ortho-quinone methide under mild conditions. This intermediate was trapped using a chiral dienophile to complete the total synthesis of xyloketal D. A second class of biocatalytic oxidation that we have employed in synthesis is the hydroxylative dearomatization of resorcinol compounds using flavin-dependent monooxygenases (FDMOs). We anticipated that the catalyst-controlled site- and stereoselectivity of FDMOs would enable the total synthesis of azaphilone natural products. Azaphilones are bioactive compounds characterized by a pyranoquinone bicyclic core and a fully substituted chiral carbon atom. We leveraged the stereodivergent reactivity of FDMOs AzaH and AfoD to achieve the enantioselective synthesis of trichoflectin enantiomers, deflectin 1a, and lunatoic acid. We also leveraged FDMOs to construct tropolone and sorbicillinoid natural products. Tropolones are a structurally diverse class of bioactive molecules characterized by an aromatic cycloheptatriene core bearing an α-hydroxyketone moiety. We developed a two-step, biocatalytic cascade to the tropolone natural product stipitatic aldehyde starting using the FDMO TropB and a NHI monooxygenase TropC. The FDMO SorbC obtained from the sorbicillin biosynthetic pathway was used in the concise total synthesis of a urea sorbicillinoid natural product. Our long-standing interest in using enzymes to carry out C–H hydroxylation reactions has also been channeled for the late-stage diversification of complex scaffolds. For example, we have used Rieske oxygenases to hydroxylate the tricyclic core common to paralytic shellfish toxins. The systemic toxicity of these compounds can be reduced by adding hydroxyl and sulfate groups, which improves their properties and potential as therapeutic agents. The enzymes SxtT, GxtA, SxtN, and SxtSUL, were used to carry out selective C–H hydroxylation and O-sulfation in saxitoxin and related structures. We conclude this account with a discussion of existing challenges in biocatalysis and ways we can currently address them.
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影响因子：
15
作者：
Chun SW;Hinze ME;Skiba MA;Narayan ARH
通讯作者：
Narayan ARH
影响因子：
46.2
作者：
Chakrabarty S ;Wang Y ;Perkins JC ;Narayan ARH
通讯作者：
Narayan ARH
影响因子：
18.3
作者：
Bai, Wen-Ju;David, Jonathan G.;Feng, Zhen-Gao;Weaver, Marisa G.;Wu, Kun-Liang;Pettus, Thomas R. R.
通讯作者：
Pettus, Thomas R. R.
影响因子：
12.9
作者：
Benitez, Attabey Rodriguez;Tweedy, Sara E.;Narayan, Alison R. H.
通讯作者：
Narayan, Alison R. H.
影响因子：
15
作者：
Chiang, Y;Kresge, AJ;Zhu, Y
通讯作者：
Zhu, Y