Rapid access to functionalized cyclobutanes via ring expansion strategies

Project Information

RACING

Grant agreement ID: 840000

DOI

10.3030/840000

Project terminated on 15 April 2021

EC signature date 22 March 2019

Start date 1 April 2019

End date 11 June 2021

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 224 933,76

EU contribution

€ 224 933,76

Coordinated by

UNIVERSITY OF BRISTOL
United Kingdom

Periodic Reporting for period 1 - RACING (Rapid access to functionalized cyclobutanes via ring expansion strategies)

Reporting period: 2019-04-01 to 2021-03-31

Summary of the context and overall objectives of the project

We are highly grateful to Marie-Curie Actions for enabling us to establish fundamentally a new method to trigger 1,2-metalate rearrangements of boronate complexes. This process affords cyclobutyl boronic esters with high levels of diastereoselectivity. The following project objectives were correctly achieved.
1. Synthesis of vinyl cyclopropyl boronate complexes
2. Realization of ring expansion-induced 1,2-metalate rearrangement using photoredox methods
3. Development of asymmetric palladium-catalyzed ring expansion-induced 1,2-metalate rearrangements.
Overall, the developed methodology not only benefits from the formation of highly functionalized cyclobutanes, but also lays a solid foundation for the development of other ring-expansion induced 1,2-metalate rearrangements. The discoveries are expected to significantly impact the chemical and the pharmaceutical industry introducing new avenues to synthesize previously inaccessible compounds. As a result of the career development enabled by this fellowship, the Fellow secured an academic position in one of the renowned Universities in India (IISc Bangalore), and he started his academic career in May 2021.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The project has completed most of the proposed objectives and milestones within the given period with only a few minor deviations. This project aims to establish new strategies to access versatile boronic esters containing cyclobutanes via ring expansion strategies that would open up significant opportunities in organic synthesis. Vinylcyclopropyl boronic esters are unknown in the literature. In work-page 1, we developed an efficient for synthesizing vinylcyclopropyl boronic esters. In work-package 2, we established a fundamentally new method for accessing cyclobutyl boronic esters with high levels of diastereoselectivity. In work-package 3, we attempted metal-induced 1,2-metalate rearrangement for diasterero/enantioselective synthesis of cyclobutyl boronic esters. Work packages 1 and 2 have been published: Ring-Expansion Induced 1,2-Metalate Rearrangements: Highly Diastereoselective Synthesis of Cyclobutyl Boronic Esters (J. Am. Chem. Soc. 2020, 142, 5515-5520).

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Cyclobutanes are common motifs in natural products and are increasingly important in medicinal chemistry discovery programmes owing to their defined spatial arrangement, a highly desirable feature in drug discovery. The chemistry discovered during this project opened a new chemical space. We believe that this novel methodology lays a solid foundation for the development of other ring expansion induced 1,2-metalate rearrangements to access small rings bearing bioactive compounds. The discoveries are expected to significantly impact the chemical and the pharmaceutical industry introducing new avenues to synthesize previously inaccessible compounds.
This will play a major part in drawing the next generation of outstanding scientists to European institutions, thus increasing the competitiveness of European Science and resulting in long-term benefits for the European economy and the quality of life of all Europeans.

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