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Designing catalysis: Nitrogen-carbon ylids as methylene donors

Final Report Summary - DESIGNING CATALYSIS (Designing catalysis: Nitrogen-carbon ylids as methylene donors)

Cyclopropanes are important common structural units in a variety of natural products and pharmaceuticals and are especially interesting due to their well-defined and rigid structure. Cyclopropanes are tailored for synthetic biochemical mechanistic investigation and are warranted as part of pharmaceutical and related bioactive compounds, due to their specific structural features. One of the recent examples of a drug candidate, incorporating a cyclopropane ring in the structure, is eglumegad (LY354740). This compound is designed by the pharmaceutical company Eli Lilly and is in clinical trials for the treatment of anxiety and drug addiction.

A wide variety of methods have been developed for the preparation of cyclopropanes. In spite of the production of an equimolar amount of (toxic) zinc salts as waste, the method of choice for industrial cyclopropane synthesis remains the Simmons-Smith reaction.

Especially methylenation of natural and low cost olefins is an industrially important reaction. A small number of reagents are available for the methylenation of olefins, but all suffer from severe drawbacks. Methyl dihalide reagents, used in the Simmons-Smith reaction, are highly potent greenhouse gasses. Furthermore, these dihalide reagents require activation by (at least) an equimolar amount of (toxic) zinc salt. Finally, the Simmons-Smith reaction suffers at industrial scale from problems related to scale up (i.e. runaway reactions, occasionally leading to explosions). Diazomethane, a reagent used frequently in academia, is highly toxic and explosive; these properties limit the usefulness in industrial settings. Furthermore, several diazomethane precursors are available, although all of them are highly carcinogenic, expensive and suffer from low atom efficiency in the reaction. Finally, methyl S-ylide reagents are potent cyclopropanation reagent, but suffer from a limited substrate scope (only electron poor olefins can be cyclopropanated) and the resulting waste suffers from the characteristic bad S-odour.

The development of new methylene reagents (i.e. methylene analogues) is thus highly warranted. We have developed a new methylene analogue for the cyclopropanation of styrenes and dienes, and methylenation of carbonyls.