Hydrazone umpolung at the interface of aqueous chemo- and biocatalysis

Abstract: The formation of C–C bonds via Grignard-type additions enabled access to complex molecules such as pharmaceuticals and agrochemicals. Yet traditional organometallic reagents mandate stoichiometric amounts of metals and are generally intolerant to moisture and air, producing copious waste and limiting their compatibility with one-pot chemoenzymatic process development. And although hydrazones as organometallic equivalents have recently emerged as a general and sustainable approach to bypass these challenges—by generating only water and nitrogen gas as benign by-products—it still presented critical areas for improvement to showcase its applicability as a greener alternative to classical methods. First being the use of scarce and precious metals and the second being the development of methods that are operationally simple, yet robust and highly tolerant to a wide diversity of conditions. To address these, we developed a manganese-based catalyst system for the addition of aldehydes to carbonyl compounds and surrogates, producing secondary and tertiary alcohols with yields of up to 91%. By employing a robust and reproducible method under aqueous and aerobic conditions, we were then able to apply it in several sequential one-pot chemoenzymatic processes. In this talk, we will therefore not only discuss how we leveraged hydrazone umpolung to access a greener solvent and biocatalysis, but also how integrating enzymatic solutions contributed to our broader research projects.