Proposal for the Enantioselective Total Synthesis of N-Methylwelwitindolinone C I

N-甲基二氢吲哚啉酮 C I 对映选择性全合成方案

• 批准号: 8384843
• 负责人: John A. Enquist
• 金额: $ 4.31万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-11-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384843
• 关键词: Address; Alkaloids; Antineoplastic Agents; Biological Factors; Breast Cancer Cell; Carbon; Carcinoma; Catalysis; Cell Line; Claisen rearrangement; Complex; Coupling; Development; Drug resistance; Evolution; Goals; Health; Human; Indoles; Inhibitory Concentration 50; Isothiocyanates; MCF7 cell; Malignant Neoplasms; Marines; Methods; Multi-Drug Resistance; Paclitaxel; Phenols; Phenotype; Preparation; Process; Reaction; Reagent; Research; Source; Structure; Techniques; Testing; Transition Elements; aryl halide; chemotherapeutic agent; combat; cyclohexadienone; cytotoxic; decane; fighting; novel; public health relevance; scaffold

DESCRIPTION (provided by applicant): Multiple drug resistant (MDR) carcinomas represent an urgent and growing problem in the field of human health. Because these cancer phenotypes respond poorly to treatment with known chemotherapeutic agents, there exists a need for novel cytotoxic reagents to combat them. The marine alkaloid N-methylwelwitindolinone C isothiocyanate is well poised to address this situation. Not only has this natural product displayed potent cytotoxic activity against MDR breast cancer cells (MCF-7, IC50=130 nM), but it has also been shown to reverse the drug resistant capacity of these cell lines, making them up to one-hundred fold more susceptible to conventional cancer drugs such as taxol. Because its isolation from natural sources is a painstaking process that affords little material, the total synthesis of N-methylwelwitindolinone C isothiocyanate is poised as an effective technique to access additional quantities of this potent bioactive compound. The research proposed herein describes a novel, concise approach toward the preparation of N- methylwelwitindolinone C isothiocyanate. The project will involve the development of an enantioselective oxidative dearomatization reaction for the coupling of aryl halides with ortho-carboxy phenols. This new method will provide access to enantioenriched cyclohexadienone products bearing all-carbon 1-quaternary stereocenters. By applying this technique to the synthesis of the N-methylwelwitindolinone C isothiocyanate it will be possible to rapidly construct the complex tetracyclic carbon scaffold of the natural product, which will in turn allow expedient preparation of this marine alkaloid.

描述（由申请人提供）：多种耐药性（MDR）癌代表了人类健康领域的紧急且日益严重的问题。由于这些癌症表型对已知化学治疗剂的治疗反应不佳，因此需要新型的细胞毒性试剂对抗它们。海洋生物碱N-甲基韦韦替诺酮C偶然氰酸盐有望解决这种情况。这种天然产物不仅对MDR乳腺癌细胞（MCF-7，IC50 = 130 nm）表现出有效的细胞毒性活性，而且还显示出它可以逆转这些细胞系的耐药能力，从而使它们对常规癌症药物（如紫杉醇）的敏感性更高。由于它与自然来源的隔离是一个艰苦的过程，几乎没有材料，因此将N-甲基韦韦替诺酮C的完全合成均具有依从含量，可以作为一种有效的技术，可以访问额外数量的这种有效的生物活性化合物。本文提出的研究描述了一种新颖的简洁方法，用于制备N-甲基韦韦替诺酮C异硫氰酸酯。该项目将涉及开发对对抗氧化的氧化型珍珠化反应，以芳基卤化物与原羧酸酚的偶联。这种新方法将提供对具有全碳1-季度立体中心的包含的对映环的环己酮产品的访问权限。通过将此技术应用于N-甲基韦替旺迪酮C的合成，可以迅速构建天然产物的复杂四环碳支架，这又可以使这种海洋生物碱的方便制备。

项目成果

An enantioselective total synthesis and stereochemical revision of (+)-citrinadin B.

• DOI: 10.1021/ja405548b
• 发表时间: 2013-07-31
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Kong K;Enquist JA Jr;McCallum ME;Smith GM;Matsumaru T;Menhaji-Klotz E;Wood JL
• 通讯作者: Wood JL

Synthetic studies toward citrinadin A: construction of the pentacyclic core.

柑橘素 A 的合成研究：五环核心的构建。

• DOI: 10.1038/ja.2016.25
• 发表时间: 2016
• 期刊: The Journal of antibiotics
• 作者: McCallum,MonicaE;Smith,GenessaM;Matsumaru,Takanori;Kong,Ke;EnquistJr,JohnA;Wood,JohnL
• 通讯作者: Wood,JohnL

Synthetic studies toward the citrinadins: enantioselective preparation of an advanced spirooxindole intermediate.

• DOI: 10.1016/j.tet.2014.02.046
• 发表时间: 2014-07
• 期刊: Tetrahedron
• 影响因子: 2.1
• 作者: Takanori Matsumaru;Monica E. McCallum;J. A. Enquist;Genessa M. Smith;K. Kong;J. Wood