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Reports: DNI151707-DNI1: Novel Catalytic Enantioselective [3,3]-Sigmatropic Rearrangements for the Preparation of Highly Substituted Fused Heterocycles and Biaryls

Laszlo Kurti, PhD, University of Texas Southwestern Medical Center at Dallas

The growth of knowledge in the chemical sciences has seen a dramatic increase since the beginning of the 21st century. The advance is particularly significant in synthetic chemistry because of its centrality and value to society. Key to all of this is the constant development of novel C-C and C-heteroatom bond-forming strategies, methods and reagents that expand the toolbox of synthetic organic chemists and enable the environmentally friendly construction of complex molecular structures using the fewest number of chemical steps and generating the least amount waste. At the heart of our research program is the discovery, mechanistic understanding and exploitation of new patterns of reactivity. We aim to design/create synthetic strategies that previously did not exist and enable the practitioner to prepare both existing as well as new structurally complex building blocks/scaffolds quickly and more efficiently than before. The Kürti group is pursuing the development of powerful and practical new methods for the synthesis of N- and O-heterocycles. Ideally these new routes are expected to: (a) be operationally simple; (b) utilize readily available and inexpensive starting materials; (c) avoid the use of TM catalysts, ligands and strong oxidizing agents; (d) achieve C-X bond-formation with controllable and high regioselectivity; (e) build molecular complexity rapidly and with exceptional step-economy (i.e., in one-pot); (f) permit the presence of functional groups that are generally not compatible with TMs (i.e., halogens, that allow further functionalization via the cross-coupling manifold) and (g) be complementary to existing cross-coupling methods by allowing the facile preparation of currently unknown or otherwise inaccessible heterocycles.   The carbazole ring system appears as a motif in a large number of biologically active natural products, active pharmaceutical ingredients (APIs) and novel functional organic materials. Given the tremendous importance of functionalized carbazoles and their derivatives across many fields, it is not surprising that during the past 50 years dozens of synthetic methods have been developed to access this valuable heterocyclic framework with a variety of substitution patterns. However, the overwhelming majority of these methods require harsh reaction conditions which are incompatible with many sensitive functional groups. Thus, we have developed a low-temperature, transition metal-free, rapid and highly regioselective intramolecular amination of arene C(sp2)-H bonds, starting from readily available 2-nitrobiaryls (Figure 1). This transformation has a wide scope as demonstrated by the preparation of a total of 30 fused N-heterocycles, including two bioactive carbazole alkaloids. A preliminary examination of the mechanism using DFT suggests that a stepwise electrophilic aromatic cyclization mechanism may be operative. We anticipate that this transformation may serve as a prototype for related powerful transformations that build molecular complexity rapidly, under mild conditions with exceptional step-economy and in an environmentally friendly fashion.      

The benzofuran structural motif, in particular benzo[b]furan, appears widely in many biologically active natural products, active pharmaceutical ingredients (APIs), and intermediates/ building blocks for the synthesis of complex molecules as well as in functional materials such as dyes, polymers and film-forming compounds.

Given the importance of functionalized benzo[b]furans and their derivatives across several key scientific fields, there is great demand for versatile synthetic methods that allow their rapid, efficient and readily scalable preparation. Thus, it is not surprising that during the past few decades quite a few synthetic approaches have been developed to access these heterocycles from acyclic precursors. The overwhelming majority of these methods utilize transition metal (TM) catalysts (e.g., Cu, Pd, Pt) to form the required C-C and C-O bonds of the benzo[b]furan substructure; most commonly the furan nucleus is assembled on a pre-functionalized benzenoid scaffold (i.e., via cycloisomerization). Even though TM-catalyzed syntheses of benzofurans are currently the most widely used, they often suffer from certain drawbacks such as necessity to employ harsh conditions (e.g., elevated temperatures for extended periods of time) and generation of a toxic heavy metal waste that is expensive to remove especially during the production for APIs in which residual metal contamination needs to meet stringent specifications. In light of the above, there is a clear need for the development of versatile TM-free approaches to functionalized benzo[b]furans that utilize structurally diverse, readily available/inexpensive starting materials and/or reagents. We have developed a scalable, transition-metal-free, direct O-arylation of ketone oximes utilizing structurally diverse and readily available diaryliodonium salts as electrophilic arylating agents (Figure 2). The O-arylation proceeds under mild conditions at ambient temperature and furnishes the corresponding O-aryl oximes in high yield while tolerating both electron-rich and electron-poor substituents on both reactants. The O-arylated ketoxime products can be efficiently converted into substituted benzo[b]furans either under acid-mediated or N-acylation condition if acid-sensitive functionalities are present. We have also developed a one-pot sequence that conveniently affords benzo[b]furans in good isolated yields, while avoiding the preparation and handling of sensitive O-aryloxyamines. Aziridines, the three-membered and equally highly-strained nitrogen analogues of epoxides, are important synthetic intermediates (i.e., building blocks) en route to structurally complex molecules due to their versatility in myriad regio- and stereoselective transformations (ring-openings and -expansions as well as rearrangements). 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, generated using strong external oxidants, 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; removal of these protecting groups is problematic as it often results in the undesired opening 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. We have developed a mild, versatile method for the direct stereospecific conversion of structurally diverse mono-, di-, tri-, and tetrasubstituted olefins to N-H aziridines using O-(2,4-dinitrophenyl)hydroxylamine (DPH) via homogeneous rhodium catalysis with no external oxidants. This method is operationally simple (i.e., one-pot), scalable, and fast at ambient temperature, furnishing N-H aziridines in good-to-excellent yields. Likewise, N-alkyl aziridines are prepared from N-alkylated DPH derivatives. Quantum-mechanical calculations suggest a plausible Rh-nitrene pathway.