Toward and Around Nitrogen-Containing Molecules: Synthesis, Asymmetric Induction and Mechanistic Studies.

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The global scientific objective of this project is to study the synthesis, biological, and physical properties of various nitrogen-containing molecules. The creation of C–N bonds is still an important challenge in synthetic organic chemistry, especially to produce chiral amines as one stereoisomer. Nitrogen-containing molecules are an important class of compounds to study, as they are ubiquitous components of biologically active molecules; “greater than 75% of drugs and drug candidates incorporate amine functionality.” (Liu, Cogan, Ellman, J. Am. Chem. Soc. 1997, 119, 9913). Furthermore, many novel organic materials that display interesting properties also incorporate nitrogen atoms.My group has been interested at using metal nitrene species to create C–N bonds. Novel metal nitrene precursors, namely N-tosyl- and N-mesyl-oxycarbamates have been developed for the synthesis of oxazolidinones, aziridines, benzylic, allylic, and propargylic amines, as well as sulfilimines. In many cases, stereoselective reactions were achieved to produce the desired chiral nitrogen-containing molecules with high level of diastereoselectivity. There are many aspects of this chemistry that remain unexplored, and this proposal will address these unsolved areas.Intramolecular C–H amination reactions from sulfonyoxycarbamates using rhodium dimer catalysts produced oxazolidinones in good to high yields. However, despite many efforts by us, and others, no general asymmetric version of this reaction has been reported. Furthermore, rhodium is among the most expensive metals. We have recently determined that iron complexes could also catalyze this reaction and we plan to develop novel ligands to induce stereoselectivities. We have recently developed a novel stereoselective method to synthesize chiral sulfimines. Few stereoselective methods have been reported to synthesize sulfilimines, and none furnish aliphatic derivatives in high yield and stereoselectivity. Importantly, the recent discovery of sulfilimine crosslinks in collagen IV networks has shed light on the importance of this class of chemical compounds and highlights the need to develop new synthetic methods around this moiety. We were encouraged to discover that our amination reagents performed well with not only aromatic thioethers, but also with aliphatic thioethers. Both yield and dr were significantly enhanced in the presence of catalytic amount of DMAP and BisDMAPCH2Cl2. An X-ray crystal structure of the Rh2[(S)-nttl]4•(DMAP)2 has been obtained. Mechanistic studies (cyclic voltammetry) suggested the involvement (participation) of a Rh(II)–Rh(III) complex as catalytically active species. We plan to study the reactivity of sulfilimines and sulfoximines and develop new chiral ligands based on these motifs.Finally, continuous flow synthesis will be explored as a technique to achieve chemical reactivity otherwise unattainable through traditional batch methods for both metal nitrene reactions and transition metal-catalyzed olefination reactions with diazo reagents.In summary, the proposed research program aims at making significant discoveries in the area of metal nitrene chemistry to perform C–H and thioether aminations. We plan to focus on first row transition metal complexes and to explore novel chiral ligands. Indeed we envision exploiting the rich chemistry of chiral sulfur nitrogen compounds and exploring these as novel chiral ligands. Finally we plan to make fundamentally new discoveries by taking advantages of the Continuous flow synthesis technology