Aziridines, the three-membered and equally highly-strained nitrogen analogues of epoxides, are important synthetic intermediates en route to structurally complex molecules due to their versatility in myriad regio- and stereoselective transformations. The aziridine structural motif, predominantly N-H and to a lesser extent N-alkyl, also appears in natural products which exhibit potent antibiotic, immunomodulatory and anticancer properties. Current direct olefin aziridination methods rely either on the transfer of substituted nitrenes to the C=C bond of olefins or the transfer of substituted carbenes to the C=N bond of imines. Normally, the result is an aziridine bearing a strongly electron-withdrawing N-protecting group whose removal can result in destruction of the aziridine. In addition, the high reactivity of these N-protected nitrenes can give rise to non-productive allylic C-H amination as well as the loss of stereospecificity. This proposal has two main goals: (a) the development of direct, stereospecific and practical syntheses of unprotected (i.e., N-H, N-alkyl) aziridines and (b) bis-functionalization of olefins leading to vicinally functionalized amines using homogeneous transition metal catalysis. These objectives will be developed in three specific aims: (1) Development and optimization of the direct, catalytic enantioselective N-H/N-alkyl aziridination of olefins; (2) Development of transition-metal-catalyzed direct hydro-/carbo-/heteroatom-amino olefin difunctionalizations, affording unprotected amino-alcohols, azido-amines as well as primary, secondary and tertiary amines; (3) Design and synthesis of a family of novel N-H/N-alkyl transfer agents (i.e., aminating agents) that will provide an unprecedented range of chemo- and stereo-selectivities in both direct olefin N-H/N-alkyl aziridinations and hydro-/carbo-/heteroatom-amino olefin difunctionalizations.

Public Health Relevance

This project brings together the complementary expertise of two laboratories to tackle the challenges of developing the direct catalytic enantioselective difunctionalization of readily available olefins to afford unprotected aziridines and vicinally substituted amines. These transformations have eluded chemists for decades. The resulting products are highly prized by the synthetic as well as the medicinal chemistry communities. The new, highly efficient and environmentally friendly chemical transformations (i.e., green chemistry) that will emerge as a result of this project will expedite synthetic access to and reduce the production cost of highly functionalized nitrogen-containing materials. It is anticipate that these novel olefin difunctionalizations will have a profound impact on the conduct of synthetic chemistry.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM114609-04
Application #
9453701
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2015-06-01
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Rice University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
050299031
City
Houston
State
TX
Country
United States
Zip Code
77005
Ma, Zhiwei; Zhou, Zhe; Kürti, László (2017) Direct and Stereospecific Synthesis of N-H and N-Alkyl Aziridines from Unactivated Olefins Using Hydroxylamine-O-Sulfonic Acids. Angew Chem Int Ed Engl 56:9886-9890
Zhou, Zhe; Ma, Zhiwei; Behnke, Nicole Erin et al. (2017) Non-Deprotonative Primary and Secondary Amination of (Hetero)Arylmetals. J Am Chem Soc 139:115-118
Gao, Hongyin; Zhou, Zhe; Kwon, Doo-Hyun et al. (2017) Rapid heteroatom transfer to arylmetals utilizing multifunctional reagent scaffolds. Nat Chem 9:681-688
Wang, Jin-Zheng; Zhou, Jin; Xu, Chang et al. (2016) Symmetry in Cascade Chirality-Transfer Processes: A Catalytic Atroposelective Direct Arylation Approach to BINOL Derivatives. J Am Chem Soc 138:5202-5
Gao, Hongyin; Xu, Qing-Long; Keene, Craig et al. (2016) Practical Organocatalytic Synthesis of Functionalized Non-C2-Symmetrical Atropisomeric Biaryls. Angew Chem Int Ed Engl 55:566-571
Paudyal, Mahesh P; Adebesin, Adeniyi Michael; Burt, Scott R et al. (2016) Dirhodium-catalyzed C-H arene amination using hydroxylamines. Science 353:1144-7