Polyketides via C-C Coupling of Alcohols: Green Chemistry

通过醇 C-C 偶联的聚酮化合物:绿色化学

基本信息

  • 批准号:
    9283558
  • 负责人:
  • 金额:
    $ 28.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-05-01 至 2019-05-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Our laboratory has discovered a broad, new class of catalytic processes that promote C-C bond formation via direct alcohol C-H functionalization. In the prior funding period, this technology enabled total syntheses of 6-deoxyerythronolide B, bryostatin 7, trienomycins A and F, cyanolide A, roxaticin, and formal syntheses of rifamycin S and scytophycin C, availing the most concise routes to any member of these respective natural products families. In the proposed funding period, these routes will be adapted to prepare functional analogues of bryostatin and trienomycin. Our bryostatin analogues will be evaluated in an ongoing collaboration with Dr. Peter M. Blumberg, who is Chief, Molecular Mechanisms of Tumor Promotion Section in the Laboratory of Cancer Biology and Genetics at the NCI. The bryostatin analogues also will be evaluated in HIV viral reactivation assays in collaboration with colleagues at GlaxoSmithKline. Trienomycin analogues will be evaluated at the Texas Institute for Drug and Diagnostics Development (TI-3D). Having utilized alcohol C-C coupling to streamline the synthesis of several type I polyketides, we will now begin to evolve a suite of methods to assemble therapeutically relevant type II polyketide natural products, such as (+)-lactonamycin, which displays potent antibacterial activity against MRSA. TYPE I Polyketides Prepared in the Prior Funding Period Me Me Me O HO OAc MeO2C Me OO Me Me OH OH O Me Me OH O OH O O Me Me O OH O Me OH Me Me O CO2Me 6-DEOXYERYTHRONOLIDE B BRYOSTATIN 7 14 Steps (LLS), 3 C-C Bonds Formed 20 Steps (LLS), 5 C-C Bonds Formed via Hydrogen Mediated C-C Coupling via Hydrogen Mediated C-C Coupling 26 Steps (Masamune), 23 Steps (Evans) 41 Steps (Masamune), 43 Steps (Yamamura) 42 Steps (Danishefsky), 23 Steps (White) 42 Steps (Evans), 30 Steps (Keck) 28 Steps (Trost), 25 Steps (Wender) Me OH OH OH OH OH Me Me OH O Me HO O Me (+)-ROXATICIN 20 Steps (LLS), 8 C-C Bonds Formed via Hydrogen Mediated C-C Coupling 45 Steps (Mori), 31 Steps (Rychnovsky) 29 Steps (Evans) HO "The ideal synthesis creates a O O Me complex skeleton... in a sequence Me Me OMe NH only of successive construction MeO O O O OMe Me reactions involving no intermediary HO O refunctionalizations, and leading directly to the structure of the MeO O O O OMe O OMe target, not only its skeleton but OMe Me Me H also its correctly placed O O O N O functionality." Me R Me CYANOLIDE A TRIENOMYCINS A and F Hendrickson, J. B. 6 Steps (LLS), 2 C-C Bonds Formed 16 Steps (LLS), 3 C-C Bonds Formed J. Am. Chem. Soc. via Hydrogen Mediated C-C Coupling via Hydrogen Mediated C-C Coupling 1975, 97, 5784. 14 Steps (Hong), 17 Steps (Reddy) 30 Steps (Smith), 24 Steps (Panek) 14 Steps (She), 17 Steps (Pabbaraja) 35 Steps (Hayashi) 12 Steps (Rychnovsky), 15 Steps (Jennings) TYPE II Polyketides Inspire the Development of Convergent Methods for their Assembly; Functional Bryostatin Analogues Me Me O O OAc MeN OH O O OO O OMe O OH O HO O O Me Me OH OO O O Me OH Me OH OMe C7H15 O (+)-Lactonamycin O Potent activity against vancomycin-resistant Enterococcus (VRE) and methicillin-resistant seco-B-ring Analogue WN-1 Staphylococcus aureus (MRSA) Ki = 16.1 nM, PKC¿ A- and C rings common to analogues that display bryostatin 1-like behavior in U937 histiocytic lymphoma cells, yet PMA-like response is observed. Inhibits the growth of multiple leukemia cell lines Made via H2-mediated C-C coupling in 17 Steps (LLS)
 描述(由申请人提供):我们的实验室发现了一种广泛的新型催化方法,通过直接醇C-H官能化促进C-C键形成。在前一个资助期,该技术能够全合成6-脱氧甘草酸B、苔藓抑素7、三烯霉素A和F、蓝藻菌素A、roxaticin,以及正式合成利福霉素S和scytophycin C,为这些各自的天然产物家族的任何成员提供了最简洁的路线。在拟议的资助期间,这些路线将被调整,以制备苔藓抑素和三烯霉素的功能类似物。我们的苔藓抑素类似物将在与Peter M. Blumberg博士说,他是NCI癌症生物学和遗传学实验室肿瘤促进分子机制科科长。苔藓抑素类似物也将与葛兰素史克的同事合作,在HIV病毒再活化试验中进行评估。三烯霉素类似物将在德克萨斯州药物和诊断开发研究所(TI-3D)进行评价。在利用醇C-C偶联来简化几种I型聚酮化合物的合成后,我们现在将开始发展一套组装治疗相关的II型聚酮化合物天然产物的方法,例如(+)-内酯霉素,其显示出对MRSA的有效抗菌活性。在前一资助期制备的I型聚酮化合物Me Me O HO OAc MeO 2 C Me OO Me OH O Me OH O O O Me O O O Me O O O Me O O O Me O O CO 2 Me 6-脱氧甲状腺素B苔藓抑素7 14步(LLS),形成3个C-C键20步(LLS),5通过氢介导的C-C偶联形成的C-C键通过氢介导的C-C偶联26步骤(Masamune),23步(Evans)41步(Masamune),43步(山村)42级台阶(Danishefsky),23步(白色)42步(埃文斯),30步(凯克)28步(特罗斯特),25步(Wender)Me OH OH OH OH Me OH O Me HO O Me(+)-ROXATICIN 20步(LLS),通过氢介导的C-C偶联形成8个C-C键45步(Mori),31步骤(Rychnovsky)29步骤(Evans)HO“理想的合成创造一个O O Me复杂的骨架.在序列Me Me OMe NH中,只有连续结构的MeO O O O O OMe反应不涉及中间HO O再官能化,并直接导致MeO O O O OMe O OMe靶的结构,不仅是其骨架,而且OMe Me Me H还有其正确放置的O O O N O官能度。“Me R Me Cyanolide A Trienomycins A and F Hendrickson,J. B. 6步(LLS),形成2个C-C键,16步(LLS),形成3个C-C键,J. Am. Chem. Soc. via Hydrogen Mediated C-C Coupling via Hydrogen Mediated C-C Coupling 1975,97,5784. 14步(洪),17步(雷迪)30步(史密斯),24步(潘内克)14步(她),17步(Pabbaraja)35步(Hayashi)12步(Rychnovsky),15步Ⅱ型聚酮化合物:聚合方法的发展功能性苔藓抑素类似物Me O O Ac MeN OH O O OMe O OH O HO O O Me O O Me OH Me OH OMe C7 H15 O(+)-Lactonamycin O对万古霉素耐药肠球菌(VRE)和甲氧西林耐药seco-B-环Ancillin WN-1金黄色葡萄球菌(MRSA)Ki = 16.1 nM,PKC <$A环和C环与在U937组织细胞淋巴瘤细胞中显示苔藓抑素1样行为的类似物相同,但观察到PMA样反应。 抑制多种白血病细胞系的生长,通过H2介导的C-C偶联17步(LLS)制备

项目成果

期刊论文数量(0)
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MICHAEL J KRISCHE其他文献

MICHAEL J KRISCHE的其他文献

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{{ truncateString('MICHAEL J KRISCHE', 18)}}的其他基金

Polyketides via C-C Coupling of Alcohols: Green Chemistry
通过醇 C-C 偶联的聚酮化合物:绿色化学
  • 批准号:
    8884268
  • 财政年份:
    2011
  • 资助金额:
    $ 28.75万
  • 项目类别:
Polyketides via C-C Coupling of Alcohols: Green Chemistry.
通过醇的 C-C 偶联的聚酮化合物:绿色化学。
  • 批准号:
    8452719
  • 财政年份:
    2011
  • 资助金额:
    $ 28.75万
  • 项目类别:
Polyketides via Redox-Triggered Alcohol C-H Functionalization.
通过氧化还原触发的醇 C-H 官能化的聚酮化合物。
  • 批准号:
    10155496
  • 财政年份:
    2011
  • 资助金额:
    $ 28.75万
  • 项目类别:
Polyketides via Redox-Triggered Alcohol C-H Functionalization.
通过氧化还原触发的醇 C-H 官能化的聚酮化合物。
  • 批准号:
    10394725
  • 财政年份:
    2011
  • 资助金额:
    $ 28.75万
  • 项目类别:
Polyketides via Redox-Triggered Alcohol C-H Functionalization.
通过氧化还原触发的醇 C-H 官能化的聚酮化合物。
  • 批准号:
    10207982
  • 财政年份:
    2011
  • 资助金额:
    $ 28.75万
  • 项目类别:
Polyketides via Redox-Triggered Alcohol C-H Functionalization.
通过氧化还原触发的醇 C-H 官能化的聚酮化合物。
  • 批准号:
    10619248
  • 财政年份:
    2011
  • 资助金额:
    $ 28.75万
  • 项目类别:
Polyketides via C-C Coupling of Alcohols: Green Chemistry.
通过醇的 C-C 偶联的聚酮化合物:绿色化学。
  • 批准号:
    8651499
  • 财政年份:
    2011
  • 资助金额:
    $ 28.75万
  • 项目类别:
Polyketides via Redox-Triggered Alcohol C-H Functionalization.
通过氧化还原触发的醇 C-H 官能化的聚酮化合物。
  • 批准号:
    9918890
  • 财政年份:
    2011
  • 资助金额:
    $ 28.75万
  • 项目类别:
Polyketides via C-C Coupling of Alcohols: Green Chemistry.
通过醇的 C-C 偶联的聚酮化合物:绿色化学。
  • 批准号:
    8461879
  • 财政年份:
    2011
  • 资助金额:
    $ 28.75万
  • 项目类别:
Polyketides via Redox-Triggered Alcohol C-H Functionalization
通过氧化还原触发醇 C-H 官能化的聚酮化合物
  • 批准号:
    10567345
  • 财政年份:
    2011
  • 资助金额:
    $ 28.75万
  • 项目类别:

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