Asymmetric Cycloboration of Homoallylic Amine–Boranes for Stereodefined Amino Scaffolds

Descripción del proyecto

Cicloboración asimétrica para bloques de construcción quirales

Los compuestos organoborados son fundamentales en la síntesis, especialmente en el acoplamiento de Suzuki-Miyaura. Si bien los boronatos de alquilo enriquecidos en enantiómeros están bien consolidados, los boranos de amina con estereostructura definida están poco desarrollados a pesar de ser accesibles. Con el apoyo de las acciones Marie Skłodowska-Curie, el proyecto CYCLOB investiga la cicloboración asimétrica de amino-boranos homoalílicos para crear una nueva clase de amino-boranos cíclicos quirales como bloques de construcción modulares. Este método utiliza un catalizador de rodio para unir átomos de boro y carbono, creando moléculas en forma de anillo con estructuras tridimensionales precisas (estereocontrol). A continuación, estas moléculas pueden transformarse en aminas específicas, compuestos de gran valor para la fabricación de medicamentos. El objetivo es comprender cómo funcionan estas reacciones químicas y utilizarlas para crear nuevos componentes básicos farmacéuticos.

Objetivo

Organoborons are cornerstone intermediates in synthesis, enabling key transformations like the Suzuki-Miyaura coupling. While enantioenriched alkyl boronates are accessible through hydroboration and other methods, stereodefined amine-boranes are entirely absent from the synthetic toolbox. This is striking given their low-cost precursors and stability. Current strategies produce only linear and non-chiral amine-boranes.

This project will establish the first asymmetric cycloboration of homoallylic amine-boranes, unlocking a new class of chiral cyclic amine-boranes as stereodefined, modular building blocks. The transformation relies on [Rh(I)]-catalyzed B–H activation and intramolecular olefin insertion, delivering cyclic organoborons with precise stereocontrol. Crucially, the resulting products are chemically versatile and should undergo stereospecific oxidation and Suzuki-Miyaura cross-coupling, enabling direct conversion into γ-functionalized amines.

The methodology will be advanced through: (1) development and optimisation of enantioselective cycloboration with a diverse library of homoallylic amine-boranes, (2) mechanistic elucidation of B–H activation, migratory insertion, and reductive elimination steps through isotope labelling, ESI-MS, and DFT modelling, (3) exploration of scope across diverse amine and olefin substitution patterns, and (4) demonstration of synthetic utility in the preparation of pharmaceutically relevant scaffolds.

This approach introduces a new retrosynthetic paradigm, positioning amine-boranes as stereodefined chiral synthons. It opens avenues for asymmetric synthesis and expands the role of boron chemistry in high-value molecular synthesis.

Completion of this ambitious project at RWTH Aachen University will be supported by extensive mechanistic expertise, knowledge transfer, and dissemination activities, strongly enhancing the Researcher’s career trajectory toward independence in asymmetric catalysis and organoboron chemistry.