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    Home > Angelw: a new method of asymmetric synthesis of α - arylpyrrolidine and benzoaza heterocyclic compounds reported by Buchwald group of MIT

    Angelw: a new method of asymmetric synthesis of α - arylpyrrolidine and benzoaza heterocyclic compounds reported by Buchwald group of MIT

    • Last Update: 2019-03-04
    • Source: Internet
    • Author: User
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    Saturated nitrogen heterocycle is a common structural unit in drug molecules and active alkaloids (Figure 1a) Among them, chiral α - arylpyrrolidine is not only a kind of therapeutic agent, but also a commonly used chiral control agent in asymmetric catalysis At present, the asymmetric synthesis strategies of α - arylpyrrolidine include: direct C-H bond arylation, hydrogenation of cycloeneamines, [3 + 2] cycloaddition, arylation / cyclization series reaction and reduction cyclization reaction However, there are only two methods that can selectively introduce heteroaryl groups at the α position of pyrrolidine, which are reported by Campos et al (Figure 1BA) and Zhang et al (Figure 1BB) Therefore, it is of great significance to develop a new asymmetric synthesis method of α - arylpyrrolidine for drug discovery and development (source: angelw Chem Int ed.) recently, Stephen L Buchwald group of Massachusetts Institute of Technology reported a two-step method for the synthesis of chiral α - arylpyrrolidine, involving Suzuki miyaara cross coupling and copper catalyzed enantioselective intramolecular hydrogen amination (Figure 1c) This intramolecular hydrogen amination strategy can be used for asymmetric synthesis of tetrahydroisoquinoline and dibenzo-n-heterocyclic compounds The related research results were published in angelw Chem Int ed (DOI: 10.1002/anie.201814331) Firstly, the reaction conditions were optimized (Table 1) With 1AA as the substrate, Cu (OAC) 2 as the catalyst, and s-dtbm-segphos (L1) as the ligand, pyrrolidine product 2a was obtained in 78% yield, and a large number of N-O bond reduction cracking by-products (entry1) were produced In order to reduce the formation of by-products, the electron rich hydroxylamine ester was selected as the substrate, and the yield and enantioselectivity of the reaction were improved (entries2-3) The optimal ligand for the reaction was (R, R) - ph-bpe (L3) (entry6) (source: angelw Chem Int ed.) next, the author studied the substrate range of the reaction (Table 2) Firstly, a series of substrates were synthesized by Suzuki miyaara cross coupling Pyrazoles (1F), pyrimidines (1g, 1H), azaindoles (1I, 1J), furans (1K), pyridines (1L), thiazoles (1m) or imidazoles (1n, 1o) were all tolerable The subsequent intramolecular hydrogen amination reaction can also tolerate various functional groups and α - heteroaryl substituents α - arylpyrrolidine products are obtained with good yield (62-83%) and excellent enantioselectivity The absolute configuration of 2l was confirmed by single crystal X-ray diffraction (source: angelw Chem Int ed.) later, the author explored the asymmetric synthesis of other nitrogen heterocycles (scheme 1) Compared with α - arylpyrrolidine, the synthesis rate of four and six membered nitrogen heterocycles is slower Even if the conditions of ligand, solvent and temperature were changed, the yield could not be improved significantly In order to promote the cyclization process, the author introduced aryl group between alkenyl and side chain of valerate, and the target product 7 can be obtained with good yield and enantioselectivity (source: angelw Chem Int ed.) dibenzo nitrogen heterocycles are widely found in drug molecules and biologically active bases Therefore, the author tried to synthesize other dibenzo-n-heterocyclic compounds The results showed that the target compounds could be obtained by four or five steps (source: angelw Chem Int ed.) conclusion: Stephen L Buchwald group of Massachusetts Institute of Technology reported the asymmetric synthesis of α - arylpyrrolidine compounds by Suzuki miyaara cross coupling and copper catalyzed enantioselective intramolecular hydrogen amination The method is also suitable for the synthesis of benzo 6 - to 9-membered nitrogen heterocyclic compounds.
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