Periodic Reporting for period 4 - OLECAT (Development of Stereoselective Olefin Functionalization Methods)
Période du rapport: 2024-03-01 au 2025-02-28
Olefins are common, readily available starting points for the synthesis of value added products such as medicines and novel materials. The ERC grant is focused on the discovery and development of novel transformations of olefins that provide value-added products. The problem addressed is thus: expanding the scope of robust, conveniently executed reactions that are amenable with olefins. In doing so we aim to provide ready access to key building blocks that are specifically useful in the drug discovery process. We have accomplished this during the funding period covered by this report. The work has been focused on the key objective which is to invent olefin functionalization reactions that are convenient to execute and provide difunctionalized products. This represents an important development in the field which had previously been focused on hydrofunctionalization of alkenes, providing in the transformation two new functional groups.
We have reported two key results. The first of these involves a general, intramolecular cycloisomerization of unactivated olefins with a variety of appended nucleophiles. It is remarkable that the reactions proceed under mild conditions and are tolerant of functional groups such as ethers, esters, protected amines, acetals, pyrazoles, carbamates, and arenes. The types of nucleophiles that can be employed in the cycloisomerization include N-, O-, as well as C-nucleophiles. This yields a large variety of heterocycles including, but not limited to, pyrrolidines, piperidines, oxazolidinones, and lactones. Key to the success of the reaction was the discovery of the use of both a benzothiazinoquinoxaline as organophotocatalyst and a Co-salen catalyst, which obviates the need for stoichiometric oxidant or reductant. In line with the broad objectives, we highlight the protocol in the execution of late-stage drug diversification and synthesis of several small natural products. The second key output involves the discovery of a photo-semipinacol rearrangement of unactivated allylic alcohols. Thus tertiary allylic alcohols undergo rearrangement to give a large collection of ketones. We observe the migration of aliphatic as well as aromatic groups. The operationally simple conditions prescribe 1 mol % benzothiazinoquinoxaline as organophotocatalyst, 0.5 mol % Co-salen, and 10 mol % lutidinium triflate and, importantly, display distinct reactivity complementary to procedures that employ Brønsted acid. It is particularly noteworthy that the semipinacol rearrangement cannot be executed using standard acid conditions. In control experiments we have executed, we show that under such conditions the tertiary alcohol gets protonated and leads the starting material through a very different reaction pathway that affords allylic alcohols or chlorides. The work we have summarized is published in leading a journal in chemistry, Angew. Chem. Int. Ed., as an open access publication.
In the final stages of the project we expect two accomplish a number of key objectives: (1) further exploration of photoHAT transformations for the functionalization of olefins, and (2) applications in complex settings to include carbon-carbon bond formation. In particular, the study of the reaction in complex settings enables us to examine the robustness of the procedure. This will assure broad usage of the methods we have developed in the context of the grant.