Asymmetric Synthesis of Alkaloids Enabled by Novel Methodology

新方法实现生物碱的不对称合成

• 批准号: 1665145
• 负责人: Rodrigo Andrade
• 金额: $ 42万
• 依托单位: Temple University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1665145&HistoricalAwards=false
• 关键词: Asymmetric; Synthesis; Alkaloids; Enabled; Novel

The Chemical Synthesis Program of the Chemistry Division supports the project by Professor Rodrigo B. Andrade. Professor Andrade is a faculty member in the Department of Chemistry at Temple University. He is developing new chemical reactions to quickly build complex nitrogen-containing molecules. The overarching goal is to maximize the efficiency by which complex, three-dimensional molecules are prepared by using new reagents and reactions discovered in his laboratory. Such an approach reduces the time, energy, and cost associated with synthesizing complex molecules composed of carbon and nitrogen atoms. Many such molecules are biologically active, and so they can be employed as molecular probes to better understand biochemical pathways or as therapeutics to be used in medicine. Beyond the training of undergraduate and graduate students, including those from underrepresented groups, the broader impacts of this project touch the fields of organic chemistry (e.g., total synthesis, synthetic methodology), chemical biology, molecular biology, biochemistry, and medicine.N-Sulfinyl metallodienamines (NSMDs) have emerged as powerful asymmetric synthons for chemical synthesis. The focus of this project is to determine both the mechanism and scope of reactions using acyclic NSMDs with a variety of electrophiles, which logically builds from previous efforts on arene-fused congeners. Specifically, in Aim 1 the researchers are studying the scope of the reactions of acyclic NSMDs with electrophilic olefins to afford cycloadducts through a Domino Michael/Mannich (formal Diels-Alder) process. In Aim 2, the research group is applying optimal reaction conditions determined from Aim 1 toward the step-efficient, asymmetric total syntheses of complex Iboga alkaloids (+)-catharanthine, (+)-coronaridine, and (+)-ibogamine. In Aim 3, the research students are systematically investigating the reactions of NSMDs with aldehydes (vinylogous aldol) and imines (vinylogous Mannich). In Aim 4, researchers are probing the reactions of NSMDs with electrophilic oxygen and nitrogen sources to access alpha-functionalized N-sulfinyl imines, which can be further modified to access chiral building blocks for organic synthesis. Computer modeling is used in all mechanistic analyses. Professor Andrade has demonstrated a strong commitment to the inclusion of undergraduates, particularly from underrepresented groups, in his research activities.

化学部化学合成计划支持罗德里戈·B·安德拉德教授的项目。安德拉德教授是坦普尔大学化学系的一名教员。他正在开发新的化学反应，以快速构建复杂的含氮分子。首要目标是通过使用在他的实验室发现的新试剂和反应来最大限度地提高制备复杂三维分子的效率。这种方法减少了与合成由碳和氮原子组成的复杂分子相关的时间、能量和成本。许多这样的分子具有生物活性，因此它们可以用作分子探针，以更好地了解生化途径，或用作医学上的治疗药物。除了对本科生和研究生的培训，包括那些来自未被充分代表的群体的学生，该项目的更广泛的影响涉及有机化学(例如，全合成、合成方法学)、化学生物学、分子生物学、生物化学和医学。N-亚磺基金属二烯胺(NSMD)已成为化学合成的强大的不对称合成子。本项目的重点是确定非环NSMD与各种亲电剂的反应机理和范围，这一点从逻辑上讲是建立在先前对芳烃稠合同系物的研究基础上的。具体地说，在目标1中，研究人员正在研究非环NSMD与亲电烯烃通过Domino Michael/Mannich(正式Diels-Alder)过程生成环加合物的反应范围。在目标2中，研究小组正在将目标1中确定的最佳反应条件应用于复杂的IBOGA生物碱(+)-青蒿素、(+)-冠桂胺和(+)-ibogamine的高效、不对称全合成。在目标3中，研究人员系统地研究了NSMDs与醛(Venylogous Aldol)和亚胺(Venylogous Mannich)的反应。在目标4中，研究人员正在探索NSMD与亲电氧源和氮源的反应，以获得α-功能化的N-亚磺酰亚胺，这些亚胺可以进一步修饰，以获得用于有机合成的手性构建块。在所有的力学分析中都使用计算机建模。安德拉德教授表现出了坚定的承诺，将本科生纳入他的研究活动，特别是来自代表性不足的群体。

项目成果

Synthesis of Bis-Strychnos Alkaloids (–)-Sungucine, (–)-Isosungucine, and (–)-Strychnogucine B from (–)-Strychnine

从 (–)-马钱子碱合成双马钱子生物碱 (–)-Sungucine、(–)-Isosungucine 和 (–)-Strychnogucine B

• DOI: 10.21577/0103-5053.20180217
• 发表时间: 2018
• 期刊: Journal of the Brazilian Chemical Society
• 影响因子: 1.4
• 作者: Zhao, Senzhi;Teijaro, Christiana;Chen, Heng;Sirasani, Gopal;Vaddypally, Shivaiah;O’Sullivan, Owen;Zdilla, Michael;Dobereiner, Graham;Andrade, Rodrigo
• 通讯作者: Andrade, Rodrigo

In vivo Antimalarial and Antitrypanosomal Activity of Strychnogucine B, a Bisindole Alkaloid from Strychnos icaja

马钱子碱 B（一种来自马钱子的双吲哚生物碱）的体内抗疟和抗锥虫活性

• DOI: 10.1055/a-0644-2723
• 发表时间: 2018
• 期刊: Planta Medica
• 影响因子: 2.7
• 作者: Beaufay, Claire;Ledoux, Allison;Jansen, Olivia;Bordignon, Annélise;Zhao, Senzhi;Teijaro, Christiana;Andrade, Rodrigo;Quetin-Leclercq, Joëlle;Frédérich, Michel
• 通讯作者: Frédérich, Michel

The vinylogous aldol reaction of N-Sulfinyl metallodienamines

N-亚磺酰基金属二烯胺的插烯羟醛反应

• DOI: 10.1016/j.tet.2019.130901
• 发表时间: 2020
• 期刊: Tetrahedron
• 影响因子: 2.1
• 作者: Yu, Po-Cheng;Chatare, Vijay K.;Patel, Harsh;DeBrosse, Charles;Andrade, Rodrigo B.
• 通讯作者: Andrade, Rodrigo B.

Elucidating the inhibition of peptidoglycan biosynthesis in Staphylococcus aureus by albocycline, a macrolactone isolated from Streptomyces maizeus.

• DOI: 10.1016/j.bmc.2018.05.017
• 发表时间: 2018-07-23
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Liang H;Zhou G;Ge Y;D'Ambrosio EA;Eidem TM;Blanchard C;Shehatou C;Chatare VK;Dunman PM;Valentine AM;Voelz VA;Grimes CL;Andrade RB
• 通讯作者: Andrade RB

Canvass: A Crowd-Sourced, Natural-Product Screening Library for Exploring Biological Space

• DOI: 10.1021/acscentsci.8b00747
• 发表时间: 2018-12-26
• 期刊: ACS CENTRAL SCIENCE
• 影响因子: 18.2
• 作者: Kearney, Sara E.;Zahoranszky-Kohalmi, Gergely;Rohde, Jason M.
• 通讯作者: Rohde, Jason M.