Organocascade catalysis - total synthesis of Ochrosamine B

有机级联催化-赭胺B的全合成

• 批准号: 8265325
• 负责人: Eduardas Skucas
• 金额: $ 1.84万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265325
• 关键词: Architecture; Area; Aspidosperma; Biological; Biological Factors; Catalysis; Complex; Development; Disease; Drug Industry; Economics; Exhibits; Family; Indole Alkaloids; Ketones; Molecular; NR1 gene; Natural Product Drug; Process; Property; Reaction; Research; Route; Scheme; Scientist; Source; Strychnos; Supervision; Time; Tryptamines; Universities; Vindoline; aspidosperma alkaloid; catalyst; cost efficient; design; experience; member; novel; programs; public health relevance; skills; tool

DESCRIPTION (provided by applicant): The proposed research will focus on the development of an imidazolidinone catalyzed asymmetric triple organocascade reaction that seeks a successful merger of simple ynones with tryptamine to furnish the well known tetracyclic spiroindoline core, known as B|chi-type ketone, containing four contiguous stereocenters including C3-quaternary stereogenenic center. More importantly chiral imidazolidinone 1 will serve as the sole source of the chiral information. The B|chi-type ketone 2 is a common structural motif of Aspidosperma and Strychnos family indole alkaloids, such as tubifoline, vindoline and ochrosamine B, which exhibit biological properties across a broad spectrum of pharmacological screens. The successful execution of this organocascade would provide the most direct means for accessing this class of natural products in the most time and cost efficient manner, which are key requirements in the current economic settings. More importantly the economic advantages offered by this transformation will potentially allow for its implementation in the pharmaceutical industry. Lastly, to exemplify the power of the proposed organocascade sequence we will undertake the execution of a concise seven-step total synthesis of ochrosamine B, which is a new member of the ever-growing Strychnos family of indole alkaloids. The proposed research will be conducted at Princeton University under the supervision of Dr. David W. C. MacMillan, and is designed to enhance the applicant's research skills, as well as assist him in becoming a competitive leader capable of establishing effective research programs. The applicant will be presented with the opportunity to be educated in the new area of organocatalysis that he has no previous experience in and make him a better-rounded scientist. In summary, the proposed research will help in advancing the field of organocatalysis and supply chemists with a versatile transformation enabling construction of complex molecules. It will also afford the applicant an opportunity to delve into a new area of research. PUBLIC HEALTH RELEVANCE: The ability to prepare therapeutically relevant molecules in expedite fashion is of the great importance for identifying effective cure to various diseases. The objective of this proposal is the development of an enantioselective organocascade reaction enabling a rapid construction of medicinally pertinent molecular architectures from simple achiral materials. This new powerful tool will be implemented for expedited synthesis of Aspidosperma and Strychnos family indole alkaloids, which exhibit biological properties across a broad spectrum of pharmacological screens.

描述（由申请人提供）：拟议的研究将集中于咪唑烷酮催化的不对称三重有机级联反应的开发，该反应寻求简单炔酮与色胺的成功合并，以提供众所周知的四环螺二氢吲哚核，称为B| chi-型酮，含有四个连续的立体中心，包括C3-四级立体中心。更重要的是，手性咪唑烷酮1将作为手性信息的唯一来源。B| α-型酮2是Aspidosperma和Strychnos家族吲哚生物碱（如tubifoline、vindoline和ochrosamine B）的共同结构基序，其在广谱药理学筛选中表现出生物学性质。成功实施这一有机级联将为以最具时间和成本效益的方式获得这类天然产品提供最直接的手段，这是当前经济环境中的关键要求。更重要的是，这种转型所提供的经济优势将有可能使其在制药行业实施。最后，为了证明所提出的有机级联序列的能力，我们将进行一个简洁的七步全合成的ochrosamine B，这是一个新的成员，不断增长的马钱子家族的吲哚生物碱。 这项拟议中的研究将在普林斯顿大学的大卫W博士的监督下进行。C.麦克米伦，旨在提高申请人的研究技能，以及帮助他成为一个有竞争力的领导者，能够建立有效的研究计划。申请人将有机会在有机催化的新领域接受教育，他以前没有经验，使他成为一个更全面的科学家。 总之，拟议的研究将有助于推进有机催化领域，并为化学家提供一个多功能的转换，使复杂分子的构建。它还将为申请人提供一个深入研究新领域的机会。 公共卫生关系：以快速方式制备治疗相关分子的能力对于鉴定各种疾病的有效治疗是非常重要的。本提案的目的是开发一种对映选择性有机级联反应，使简单的非手性材料能够快速构建医学相关的分子结构。这个新的强大的工具将加快Aspidosperma和Strychnos家族吲哚生物碱的合成，这些生物碱在广泛的药理学筛选中表现出生物学特性。