Catalytic chiral aziridination with earth abundant metals The aziridine functional group, which is a three-membered heterocycle with one nitrogen and two carbons, is critically important in biology and, therefore, also in synthetic medicinal chemistry. Aziridines are found in natural products, such as mitomycins, azinomycins, ficellomycins, and thiotepa, that have antitumor and antibiotic properties. Additionally, the strained aziridine, which stores ~27 kcal/mol of energy, can be ring opened with a wide variety of nucleophiles, including N-, O-, and C-based examples, in a manner analogous to epoxides. Furthermore, aziridines can undergo an extensive variety of ring expansion reactions including, recently, the first [3+2] annulation. Yet one can only take advantage of these ring opening and ring expansion reactions if there is an easy way to prepare aziridines in a manner similar to epoxides and cyclopropanes. Despite lying between carbon and oxygen on the periodic table, the nitrogenous version of this ring forming reaction, aziridination, lags far behind by any number of metrics, specifically in their ability to be synthesized catalytically. In fact, the most common methods for forming aziridines are stoichiometric ring closing reactions, such as the Wenker synthesis (developed almost a century ago) which is the closing of a linear 1,2-amino-alcohol under acidic conditions. To date, there are no commercially available, broadly effective catalysts for aziridination between an alkene and nitrene moiety. Our objective is to develop a general catalytic cycle with earth abundant metals for a C2 + N1 aziridination reaction featuring a wide variety of alkenes (C2) and organic azides (N1). Crucially, earth abundant metals, such as iron, will reduce costs during both synthesis and the purification steps to remove metals during drug development since earth abundant metals are less toxic than heavy metals. In this proposal, we continue our research on catalytic aziridination to include new directions relevant to the medicinal chemistry community. Two specific limitations of our current catalyst system that render it inexpedient for medicinal chemistry will be addressed. These limitations include the necessity for excess alkene relative to organic azide and the lack of an enantioselective version of our catalytic system. Since most leading drug candidates with aziridine intermediates feature chiral aziridines, this breakthrough will revolutionize C2 + N1 aziridination for medicinal chemistry.
Catalytic chiral N2 + C1 aziridination with earth abundant metals Project Narrative Despite the myriad uses for aziridines in pharmaceutical products as well as synthetic intermediates, their synthesis has languished far behind epoxides, their oxygen analogue. In this proposal, we extend our research on catalytic aziridination with earth abundant metals (e.g. iron) to include critical advances relevant to the medicinal chemistry community. In particular, we are developing the catalytic synthesis of chiral aziridines from organic azides and alkenes.
| Keller, C Luke; Kern, Jesse L; Terry, Bradley D et al. (2018) Catalytic aziridination with alcoholic substrates via a chromium tetracarbene catalyst. Chem Commun (Camb) 54:1429-1432 |
