The main goal of contemporary organic synthesis research is to prepare a large number of complex and diverse secondary biological metabolites, genes, proteins and other complex life substances through the development of efficient synthetic routes, as well as to synthesize a large number of substances that do not exist in nature but have unique functions. However, the direct one-step synthesis of complex alkaloid frameworks remains one of the unsolved problems in the core field of organic chemistry.
Recently, based on the concept of inverse hydride shuttle catalysis, a strategy for the one-step direct conversion of dynamically assembled ternary complexes to valuable azabicyclic alkaloid frameworks has been reported (Figure 1). Among them, the ternary complexes are easily constructed in situ from three simple precursors (i.e., cyclic amines, electron-deficient alkenes, and aldehydes), and enable highly modular installations with various substitution patterns. Mechanistic studies reveal that the transition intermediate undergoes an unusual hydride shuttle process initiated by the hydride donor.
Figure 1. Rapid synthesis of alkaloid-like azabicycles catalyzed by hydride shuttle process
Based on the interest in the phenomenon of reversible assembly of complex skeletons by dynamic complexes in the process of multicomponent equilibrium, researchers turned their attention to the reversible addition of enamines to Michael acceptors to generate short-lived intermediates, thereby exploring ring expansion reactions. The results showed that stoichiometric tris-(2,6-difluorophenyl)borane can effectively promote the rearrangement of the skeleton (yield: 90%).
Under optimal conditions, the researchers investigated the range of substrates, and the results showed that ring secondary amines of different sizes, fused ring amines, functionalized ring secondary amines and even non-cyclic secondary amines were compatible with the reaction, and the reaction was moderate to moderate. The corresponding cyclized products were obtained in excellent yields. Second, linear aldehydes and cycloalkane-substituted aldehydes can also achieve this transformation, and obtain the corresponding polysubstituted azabicyclic skeletons and spiro ring structures. Remarkably, the reaction is not affected by the electron properties of the nitroalkenes, which are tolerated by either electron-donating or electron-withdrawing groups, even heteroaryl, alkenyl, and alkynyl substituents.
In addition, the enamine condensation, cyclobutane formation, and hydride catalytic one-step realization is also feasible, and the product yield of this process is comparable to that under standard conditions. It should be pointed out that the change of the sequence of the three steps makes the enantioselective synthesis possible.
Finally, the researchers carried out further applications of the product, for example: 1) The product was further synthesized and a product containing the ceramide skeleton (substructure of more than 250 alkaloids) was obtained with a yield of 86%; 2) The product was introduced the required substituents in various natural products by Polonovski-Potier reaction with high regio- and stereoselectivity; 3) Epiquinamide and Lupine-related frameworks can be obtained after product reduction.
Overall, the researchers propose a concept based on reverse hydride shuttle catalysis to convert dynamically assembled ternary complexes into valuable azabicyclic frameworks, and enable a high degree of modularity with various substitution patterns. Install. Undoubtedly, this approach may change the design of multicomponent reactions, thereby advancing the fields of biology, medicine and related product.
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Reference
- Inverse hydride shuttle catalysis enables the stereoselective one-step synthesis of complex frameworks.
Immo Klose, Giovanni Di Mauro, Dainis Kaldre, Nuno Maulide
