Catalytic C2+N1 Aziridination from Organic and Carbamate Azides The aziridine functional group is critical in biology and synthetic medicinal chemistry. Aziridines are biologically active functional groups in natural products, such as mitomycins and azinomycins, that have antitumor properties. In synthetic chemistry, this strained ring can be opened by a wide variety of nucleophiles in a manner analogous to epoxides. Unlike epoxides, which are often synthesized from an alkene and an O-atom source (a C2 + O1 reaction), aziridines are not typically synthesized by a C2 + N1 approach. These approaches are inefficient and a broadly applicable C2 + N1 synthesis of aziridines would be highly valuable. In this proposal, we extend our research on catalytic aziridination to include new directions relevant to the medicinal chemistry community. Three 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 azide, absence of functional group tolerance, and lack of an enantioselective version of our catalytic system. First, our iron system, like many C2 + N1 aziridination reactions, required excess alkene versus nitrene reagent. While this is acceptable for inexpensive alkenes (e.g. 1-decene), this drawback curtails its application with high value-added intermediates that appear in pharmaceuticals. Recent results from the Jenkins labs have demonstrated that disfavoring formation of a metallotetrazene is key to reducing alkene loading to equivalency with the nitrene source. Second, functional group tolerance must be high for aziridination to be applicable for highly complex molecules. We have been expanding the list of functional groups that are tolerated by our system and, in particular, are adapting it for carbamate azides. Third, to date, there are extremely limited chiral catalysts for C2 + N1 aziridination with aliphatic alkenes. The development of D2-symmetric macrocyclic ligand systems will allow us to facilely form single enantiomer catalysts. Since most leading drug candidates with aziridine intermediates feature chiral aziridines, this breakthrough will revolutionize C2 + N1 aziridination for medicinal chemistry. Once these three barriers have been overcome, an additional task will showcase this catalytic system's significance and effectiveness. We will synthesize pyrroloindolines through a four step process from alkenes and azides. Pyrroloindolines are a bicyclic ring system that contains molecules that are effective for antibiotic and antitumor therapeutics. The ability to systematically prepare a wide variety of these species will be critical for development of drugs on this scaffold.
Catalytic C2+N1 Aziridination from Organic and Carbamate Azides 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 to include new directions relevant to the medicinal chemistry community, in particular, the synthesis of carbamate protected aziridines and chiral aziridines from carbamate and organic azides, respectively.
| 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 |
