Lithiation-borylation reactions and their application to the synthesis of vinyl epoxides

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Introduction: One of the main areas of research in Organic Chemistry is the development of new methodologies for the synthesis of valuable intermediates that can be widely used for the creation of agrochemicals, pharmaceuticals and polymers. These intermediates are often referred to as “building blocks”, because they can be seen as “molecular bricks”, which, when put together, are incorporated into the main structure of drugs, natural products and polymers. The ideal building block should 1) be easy to access; 2) be utilizable in new bond forming reactions; 3) have at least one heteroatom; 4) be readily transformed into more advanced intermediates using simple reaction conditions; and 5) be available in enantiopure form. Vinyl epoxides and vinyl aziridines possess such attributes, thus they are widely used synthetic intermediates in organic and polymer chemistry and they are also occasionally encountered in natural products, particularly within the polyketide family.State of the Art: Despite their synthetic value, there is no unified method for the synthesis of both vinyl epoxides and vinyl aziridines from readily accessible starting materials. Moreover, current methods suffer from limitations such as multistep synthesis, harsh conditions, poor functional group tolerance, regioselectivity issues, and the use of highly reactive intermediates. Our research program aims to develop a technology that addresses these shortcomings, thereby greatly expanding the range of accessible vinyl epoxides/aziridines through a highly convergent approach.Objectives (O1-4): We aim to develop a unified synthesis of vinyl epoxides and aziridines through the most unconventional disconnection: between the epoxide and the alkene. We will investigate its scope and apply it to the total synthesis of a revised structure of the polyketide natural product machillene.Research Methodology and Approach: (O1) To develop a unified method for the synthesis of vinyl epoxides and vinyl aziridines. (O2) Assessment of the substrate scope: alkyl, styrenyl and trifluoromethyl epoxides/aziridines.(O3) Synthesis of advanced intermediates from trifluoromethyl vinyl epoxides. (O4) Total synthesis of machillene.