Synthetic and Mechanistic Studies on Preparatively Significant Reactions
预备性显着反应的合成与机理研究
基本信息
- 批准号:10387451
- 负责人:
- 金额:$ 11.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalBiologicalBiomimeticsBoronCarbonCatalysisCationsCharacteristicsChemicalsCommunitiesComplexCouplingCyclizationDrug IndustryEpoxy CompoundsGenerationsGlycosidesIonsLibrariesManualsMethodsNatureNitrogenOutcomeOxygenPharmaceutical ChemistryPositioning AttributePreparationProcessProductionPropertyPublic HealthReactionReagentResearchResearch ProposalsSteroidsSystemTerpenesTherapeuticTherapeutic Agentsanalogbasechemical synthesisdrug candidatedrug developmentdrug discoveryfunctional groupimprovedinorganic phosphateionizationpi bondprogramsprotonationscreeningsmall moleculesmall molecule therapeuticsstereochemistrythioether
项目摘要
PROJECT SUMMARY/ABSTRACT
This application describes two programs of research aimed at improving the efficiency and selectivity of
chemical synthesis relevant to small molecule drug discovery efforts. The first program seeks to invent biomi-
metic cascade reactions used by Nature to construct complex polycyclic terpenes and steroids many of which
have profound biological activities. The second program seeks to invent stereodefined and functional building
blocks that can be used to optimize therapeutic properties of small molecules at various stages of drug discov-
ery and development efforts.
The primary objective of the first program is to identify a new catalytic system that can initiate a cascade of
ring forming reactions from polyunsaturated precursors. Nature constructs all terpenoids by initiating cationic
cascade cyclizations under exquisite control of stereochemistry through either protonation or ionization of reac-
tive groups (phosphates, epoxides). Chemical analogs of this natural process that have the same ability to cre-
ate polycyclic systems with high levels of stereocontrol have only recently emerged. However, they are limited
in their ability to introduce the requisite functionality needed for the production of the final product. By harness-
ing the potential of chiral Lewis base catalysis, this program seeks to create enantiomerically enriched thiirani-
um ions which will enable the initiation of the cationic cascade by spontaneously engaging the proximal double
bonds in the substrate. The resulting polycyclic product will thus contain a thioether functional group at a stra-
tegically crucial position that will allow subsequent manipulations into oxygen and carbon containing moieties.
Further extensions of this sulfenium ion initiated cyclization strategy target the construction of biologically ac-
tive spiroacetals and glycosides.
The primary objective of second program is the creation of a small library of stereodefined, functionalized,
three-dimensional building blocks that can be introduced as plugins for the optimization and diversification of
small molecule candidates in drug discovery programs. One of the major problems facing the research and
discovery efforts in the pharmaceutical industry is the mismatch between the chemical characteristics of avail-
able screening libraries and the kinds of characteristics needed to intervene by association and interaction with
biomolecular targets. This problem arises from the lack of robust methods that reliably and predictably install
three dimensional carbon centers bearing appropriate functionality (oxygen, nitrogen) in both manual and au-
tomated platforms. By systematic examination of the stereochemical outcome of the coupling of small, ste-
reodefined boron-containing building blocks and a rigorous understanding of the mechanisms of their
introduction, this program will provide the medicinal chemistry community with reagents that constitute “stereo-
centers in a bottle”; namely off the shelf plugins to accelerate discovery programs. The potential impact on pro-
cess research enterprises is also significant by eliminating troublesome byproducts.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Scott Eric Denmark', 18)}}的其他基金
Synthetic and Mechanistic Studies on Preparatively Significant Reactions
预备性显着反应的合成与机理研究
- 批准号:
9895811 - 财政年份:2018
- 资助金额:
$ 11.51万 - 项目类别:
Synthetic and Mechanistic Studies on Preparatively Significant Reactions
预备性显着反应的合成与机理研究
- 批准号:
10398806 - 财政年份:2018
- 资助金额:
$ 11.51万 - 项目类别:
Asymmetric Lewis Base Catalysis in Main Group Chemistry
主族化学中的不对称路易斯碱催化
- 批准号:
8213452 - 财政年份:2010
- 资助金额:
$ 11.51万 - 项目类别:
Asymmetric Lewis Base Catalysis in Main Group Chemistry
主族化学中的不对称路易斯碱催化
- 批准号:
8050550 - 财政年份:2010
- 资助金额:
$ 11.51万 - 项目类别:
Asymmetric Lewis Base Catalysis in Main Group Chemistry
主族化学中的不对称路易斯碱催化
- 批准号:
8414158 - 财政年份:2010
- 资助金额:
$ 11.51万 - 项目类别:
Asymmetric Lewis Base Catalysis in Main Group Chemistry
主族化学中的不对称路易斯碱催化
- 批准号:
7887971 - 财政年份:2010
- 资助金额:
$ 11.51万 - 项目类别:
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