Catalyst- and Reagent-Guided Selective Alkyl C-H Bond Functionalization
催化剂和试剂引导的选择性烷基 C-H 键官能化
基本信息
- 批准号:10607409
- 负责人:
- 金额:$ 6.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-02-15 至 2026-02-14
- 项目状态:未结题
- 来源:
- 关键词:AlcoholsAmidesBindingBinding SitesBoranesCarbonComplexDevelopmentDiseaseDockingElementsEvaluationExhibitsFamilyGoalsHydrogen BondingIntuitionIridiumLaboratoriesLeadLigand BindingLigandsMedicineMentorsMetabolismMethodsModificationOrganic SynthesisPositioning AttributePropertyReactionReagentResearchRouteScientistSiteSolubilityStructureTechnologyTestingTimeTransition ElementsWorkcatalystclinical candidatedesigndiboraneexperimental studyfunctional grouphuman diseaseimprovedinnovationlead optimizationmethod developmentpreferenceprogramsthree dimensional structure
项目摘要
PROJECT SUMMARY
Identifying just one new clinical candidate for the treatment of human disease usually requires the design,
synthesis, testing, and redesign of thousands upon thousands of organic compounds. Improvements to synthetic
technologies therefore have a major impact on the time required to identify clinical candidates by maximizing the
number of compounds that can be accessed from a single precursor. In particular, adjusting key properties such
as bioactivity, solubility, metabolism, and stability are best accomplished by methods that are capable of
preparing a wide variety of new compounds with a minimal number of steps. Late-stage functionalization of
carbon-hydrogen bonds offers medicinal chemists this coveted opportunity by facilitating the introduction of
numerous types of functional groups into a given lead structure. Recent efforts have demonstrated that transition-
metal catalysts can enable the diverse functionalization of strong alkyl C–H bonds within organic compounds via
the intermediacy of an organoboron compound. However, methods to achieve control over the site- and
stereoselectivity of alkyl C–H bond functionalization are limited by their strength and ubiquity in complex
molecules. The proposed research focuses on the development of a broadly applicable strategy to achieve
selectivity in the functionalization of C(sp3)–H bonds that is independent of inherent substrate preferences. The
impact of this work is to enable practitioners to make precise structural edits to bioactive compounds without
lengthy synthetic manipulation. The proposed approach converts a major challenge in complex molecule
functionalization, the presence of potentially intervening groups, into an opportunity to localize reactivity of a
transition metal catalyst to convert specific C–H bonds into C–B bonds. Specifically, the proposed research will
create catalysts and reagents that bind an existing polar functional group, such an alcohol or amide, thereby
guiding functionalization to an adjacent site. Synthetic routes are presented to access a suite of catalysts and
reagents. In conjunction with experiments to evaluate their suitably for guided functionalization, they will be
refined iteratively for application to target structures. Subsequent studies of the functionalization of complex,
biologically active compounds will demonstrate the applicability and generality of the proposed method to lead
optimization. To control stereoselectivity, a key consideration in alkyl C–H bond functionalization, chiral diborane
reagents derived from readily available precursors will be employed. By differentiating the energies of
diastereomeric intermediates and transition states en route to the alkylboronate products, new derivatives can
be accessed with well-defined three-dimensional structures. An integrated component of the proposed research
program are mechanistic experiments that will form the basis of informed improvements to the overall approach,
as defined by metrics that include reaction efficiency, site-selectivity, and stereo-selectivity. Achieving the
specific aims of the proposed research will expand the opportunities available to scientists to make precise edits
to complex organic compounds at alkyl C–H bonds, facilitating access to new bioactive compounds.
PROJECT SUMMARY
Identifying just one new clinical candidate for the treatment of human disease usually requires the design,
synthesis, testing, and redesign of thousands upon thousands of organic compounds. Improvements to synthetic
technologies therefore have a major impact on the time required to identify clinical candidates by maximizing the
number of compounds that can be accessed from a single precursor. In particular, adjusting key properties such
as bioactivity, solubility, metabolism, and stability are best accomplished by methods that are capable of
preparing a wide variety of new compounds with a minimal number of steps. Late-stage functionalization of
carbon-hydrogen bonds offers medicinal chemists this coveted opportunity by facilitating the introduction of
numerous types of functional groups into a given lead structure. Recent efforts have demonstrated that transition-
metal catalysts can enable the diverse functionalization of strong alkyl C–H bonds within organic compounds via
the intermediacy of an organoboron compound. However, methods to achieve control over the site- and
stereoselectivity of alkyl C–H bond functionalization are limited by their strength and ubiquity in complex
molecules. The proposed research focuses on the development of a broadly applicable strategy to achieve
selectivity in the functionalization of C(sp3)–H bonds that is independent of inherent substrate preferences. The
impact of this work is to enable practitioners to make precise structural edits to bioactive compounds without
lengthy synthetic manipulation. The proposed approach converts a major challenge in complex molecule
functionalization, the presence of potentially intervening groups, into an opportunity to localize reactivity of a
transition metal catalyst to convert specific C–H bonds into C–B bonds. Specifically, the proposed research will
create catalysts and reagents that bind an existing polar functional group, such an alcohol or amide, thereby
guiding functionalization to an adjacent site. Synthetic routes are presented to access a suite of catalysts and
reagents. In conjunction with experiments to evaluate their suitably for guided functionalization, they will be
refined iteratively for application to target structures. Subsequent studies of the functionalization of complex,
biologically active compounds will demonstrate the applicability and generality of the proposed method to lead
optimization. To control stereoselectivity, a key consideration in alkyl C–H bond functionalization, chiral diborane
reagents derived from readily available precursors will be employed. By differentiating the energies of
diastereomeric intermediates and transition states en route to the alkylboronate products, new derivatives can
be accessed with well-defined three-dimensional structures. An integrated component of the proposed research
program are mechanistic experiments that will form the basis of informed improvements to the overall approach,
as defined by metrics that include reaction efficiency, site-selectivity, and stereo-selectivity. Achieving the
specific aims of the proposed research will expand the opportunities available to scientists to make precise edits
to complex organic compounds at alkyl C–H bonds, facilitating access to new bioactive compounds.
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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Kyan Anthony D'Angelo的其他文献
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