New catalytic methods for the synthesis of oxazine natural products

合成恶嗪天然产物的新催化方法

• 批准号: 9232177
• 负责人: Oleg V Larionov
• 金额: $ 11.03万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-11 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9232177
• 关键词: Affect; Antineoplastic Agents; Area; Biological; Biological Assay; Biomedical Research; Catalysis; Categories; Cyclization; Development; Disease; Evaluation; Exhibits; FDA approved; Funding; Future; Generations; Goals; Grant; Health Sciences; Hydrogen Bonding; Hydrophobic Interactions; Inflammation; Lead; Libraries; Life; Malignant Neoplasms; Medicine; Methodology; Methods; Modernization; Modification; Molecular Bank; NCI Center for Cancer Research; Natural Products; Oximes; Pharmaceutical Preparations; Play; Positioning Attribute; Property; Quinones; Reaction; Research; Research Personnel; Role; Route; Sampling; Source; Structure-Activity Relationship; Therapeutic; United States National Institutes of Health; analog; base; cancer therapy; career; cost; design; drug candidate; drug discovery; enantiomer; exhaustion; flexibility; improved; innovation; member; metal complex; multidisciplinary; novel; public health relevance; repository; screening; small molecule; small molecule libraries

DESCRIPTION (provided by applicant): Natural products have played a pivotal role in the discovery and development of modern chemotherapeutics. Thus, the genesis of more than 70% of all small molecule anti-cancer medicines approved in the last 70 years can be traced to natural products. Although the key role of natural products in drug discovery remains uncontested few of them have undergone comprehensive structure-activity relationship (SAR) studies and exhaustive bioactivity screenings. This is primarily due to the prevailing scarcity of the natural products compounded with limited options for structural modifications which are necessary for the SAR studies. Synthesis of these natural products offers the opportunity to access the natural product and its numerous congeners through changes in the synthetic strategy. Due to the limited number of reliable enantioselective catalytic reactions many syntheses rely on the elaboration of chiral starting materials along circuitous synthetic routes. This affects the efficiency and narrows flexibility and applicability of the syntheses. The 1,2-oxazine natural products have been particularly affected by this shortcoming. This is a serious limitation for the discovery of new chemotherapeutics since many of these natural products possess unique and exciting biological activities. We aim to make the 1,2-oxazine core readily accessible through rational design of a novel enantioselective and catalytic cyclization reaction. We will also develop a straightforward methodology for the conversion of the cyclization products to the 1,2-oxazine natural products and their structural analogs that are unattainable using currently available methods. This methodology will then be employed for the synthesis of two 1,2-oxazine natural products that possess unique anti-cancer activities. This approach is based on the unprecedented catalytic enantioselective cyclization reaction and is innovative because (a) it has the potential to combine the undisputed efficiency and practicality of a catalytic asymmetric method with the ready availability of both precursors; and (b) the asymmetric cyclization reaction will allow rapid access to a variety of structurally related natura products by way of simple structural editing. These studies will improve our understanding of their biological properties and will potentially provide new leads for anti-cancer drug discovery.

描述（由申请人提供）：天然产物在现代化疗药物的发现和开发中发挥了关键作用。因此，在过去70年中批准的所有小分子抗癌药物中，超过70%的起源可以追溯到天然产物。虽然天然产物在药物发现中的关键作用仍然是无可争议的，但很少有天然产物进行了全面的构效关系（SAR）研究和详尽的生物活性筛选。这主要是由于天然产品的普遍稀缺，加上SAR研究所需的结构修饰的选择有限。这些天然产物的合成提供了通过改变合成策略获得天然产物及其众多同系物的机会。由于可靠的对映体选择性催化反应的数量有限，许多合成依赖于沿着迂回的合成路线对手性起始材料的精细加工。这影响了合成的效率并缩小了合成的灵活性和适用性。1，2-恶嗪天然产物尤其受到这一缺点的影响。这是发现新的化疗药物的严重限制，因为许多这些天然产物具有独特的和令人兴奋的生物活性。我们的目标是通过合理设计一种新型的对映选择性和催化环化反应，使1，2-恶嗪核容易获得。我们还将开发一种简单的方法，用于将环化产物转化为1，2-恶嗪天然产物及其结构类似物，这些天然产物及其结构类似物是使用目前可用的方法无法实现的。该方法将用于合成两种具有独特抗癌活性的1，2-恶嗪天然产物。这种方法是基于前所未有的催化对映选择性环化反应，并且是创新的，因为（a）它具有将催化不对称方法的无可争议的效率和实用性与两种前体的现成可用性结合的联合收割机的潜力;和（B）不对称环化反应将允许通过简单的结构编辑快速获得各种结构相关的天然产物。这些研究将提高我们对其生物学特性的理解，并可能为抗癌药物的发现提供新的线索。

项目成果

Efficient synthesis of 3-sulfolenes from allylic alcohols and 1,3-dienes enabled by sodium metabisulfite as a sulfur dioxide equivalent.

• DOI: 10.1039/c8ob00745d
• 发表时间: 2018-05-15
• 期刊: Organic & biomolecular chemistry
• 影响因子: 3.2
• 作者: Dang HT;Nguyen VT;Nguyen VD;Arman HD;Larionov OV
• 通讯作者: Larionov OV

Recent Advances in the C-H-Functionalization of the Distal Positions in Pyridines and Quinolines.

• DOI: 10.1016/j.tet.2015.08.034
• 发表时间: 2015-11-18
• 期刊: Tetrahedron
• 影响因子: 2.1
• 作者: Stephens DE;Larionov OV
• 通讯作者: Larionov OV

Highly Regio- and Stereoselective Catalytic Synthesis of Conjugated Dienes and Polyenes.

• DOI: 10.1021/jacs.8b05421
• 发表时间: 2018-07-11
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Nguyen VT;Dang HT;Pham HH;Nguyen VD;Flores-Hansen C;Arman HD;Larionov OV
• 通讯作者: Larionov OV

Metal- and additive-free photoinduced borylation of haloarenes.

• DOI: 10.1038/nprot.2016.184
• 发表时间: 2017-03
• 期刊: Nature protocols
• 影响因子: 14.8
• 作者: Mfuh AM;Schneider BD;Cruces W;Larionov OV
• 通讯作者: Larionov OV

Hexahydropyrrolo[2,3-b]indole Compounds as Potential Therapeutics for Alzheimer's Disease.

• DOI: 10.1021/acschemneuro.9b00297
• 发表时间: 2019-10-16
• 期刊: ACS chemical neuroscience
• 影响因子: 5
• 作者: Doens D;Valdés-Tresanco ME;Vasquez V;Carreira MB;De La Guardia Y;Stephens DE;Nguyen VD;Nguyen VT;Gu J;Hegde ML;Larionov OV;Valiente PA;Lleonart R;Fernández PL
• 通讯作者: Fernández PL