Asymmetric Carboamination of Alkenylboronates

Lead Research Organisation: University of Bristol
Department Name: Chemistry

Abstract

This proposed Fellowship brings together an Experienced Researcher from China, with expertise in asymmetric catalysis, methodology, and organic synthesis, with an internationally recognized Host Laboratory in the UK under the expert supervision of Prof. Varinder K. Aggarwal FRS. His research interests focus on total synthesis, asymmetric synthesis, photoredox-driven processes, and the development of new reactivity in organic chemistry, in particular, boron chemistry.
The successful realization of this highly interdisciplinary project will:

Enhance European excellence in organic synthesis and catalysis, which are fundamentally important branches of chemistry.

Enable the ER to acquire new skills in the field of organoboron chemistry, asymmetric copper catalysis, and to develop new drug candidates in collaboration with a partner pharmaceutical company, which will expand his scientific knowledge and network.

Amino boronic esters are bioisosteres of amino acids, which can act as protease inhibitors. Indeed several have even progressed to the market with others in clinical development highlighting their growing importance. In this proposal, we aim to access such entities by introducing new methodologies that merge a copper-catalyzed asymmetric functional-group transfer process with the stereospecific 1,2-metallate nitrogen or carbon rearrangement of alkenylboronates. This novel method employs catalytic, chiral copper-oxazoline complexes in combination with 3-iodane reagents, to provide rapid access to highly electrophilic, chiral Cu(III) species, enabling a subsequent 1,2-metallate nitrogen or carbon rearrangement of alkenylboronates while achieving bond carboamination. This ambitious approach will allow for the facile synthesis of enantiomerically enriched and medicinally relevant aminoalkylboron reagents, which will be employed to access new potential drug candidates in collaboration with AstraZeneca.

Publications

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Description We attempted to make amino boronic esters which are bioisosteres of amino acids, and so can act as protease inhibitors. We aimed to access such entities by merging a copper-catalyzed asymmetric functional-group transfer process with the stereospecific 1,2-metallate nitrogen or carbon rearrangement of alkenylboronates. Unfortunately, while some reactions worked in low yield, we were unable to generalise the process or to make it asymmetric. Observing highly efficient reactions of boronate complexes we turned to their reactions with pi-allyl iridium complexes in place of copper and achieved excellent results which were subsequently published. This discovery has led to several high impact publications.
Exploitation Route Carbon-carbon bond formation lies at the heart of chemical synthesis. Whilst it is easy to make sp2-sp2 bonds it is much harder to construct sp3-sp3 bonds since they are more hindered and issues of selectivity arise. We discovered that such bonds could be made through combining enantioenriched boronic esters with racemic allylic carbonates in the presence of iridium catalysis. It is likely that others in the pharmaceutical industry may use this methodology since it shows broad scope is versatile, and shows high selectivity.
Sectors Chemicals

Pharmaceuticals and Medical Biotechnology