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    Home > [organic] JACS: asymmetric synthesis of α, β - unsaturated δ - aryl lactam by palladium catalyzed transfer Heck reaction

    [organic] JACS: asymmetric synthesis of α, β - unsaturated δ - aryl lactam by palladium catalyzed transfer Heck reaction

    • Last Update: 2018-05-28
    • Source: Internet
    • Author: User
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    Chiral δ - lactam is widely found in bioactive compounds and natural products Among them, as a CGRP receptor antagonist, lactam a can be used to treat or prevent migraine, and as an NK1 antagonist, lactam B can be used to treat nausea and vomiting caused by chemotherapy At present, there are many enantioselective synthesis methods of δ - lactam precursors, such as Cu catalyzed aza Diels alder reaction, N-heterocyclic carbene catalyzed cyclization of α, β - unsaturated carbonyl compounds with sulfonamide, and transition metal catalyzed asymmetric hydrogenation of n-aryl-imine or n-tert-butylsulfonyl imine The traditional Heck reaction can also complete the single or double arylation of enamide, but it is difficult to realize the chiral synthesis (source: J am Chem SOC.) Professor Matthew s Sigman of the University of Utah has made a series of important achievements in the field of research on the transitive Heck reaction Recently, on the basis of previous research results, the research group put forward a new idea for the heck arylation of enamide: under the catalysis of palladium, selective addition of enamide 1 site and elimination of β - h to obtain intermediate D, whether migration insertion and elimination of β - H B can occur again has not been reported In order to verify this assumption, the research group has developed a method for asymmetric synthesis of α, β - unsaturated δ - aryl lactam through the transfer Heck reaction of enamide for the first time This method has mild conditions and high enantioselectivity The related research results were published on j.am Chem SOC (DOI: 10.1021 / JACS 8b02752) Firstly, the reaction conditions were optimized with 1A as the substrate, Pd (CH3CN) 2 (OTS) 2 as the catalyst and pyrox as the ligand When two equivalent phenylboric acid is used as coupling agent, the target product 2A can be obtained with 78% yield and 99:1 Er value Under the reaction conditions, different N-substituted alkenylamides have good to excellent yields and extremely high er value to the corresponding target products (source: J am Chem SOC.) then, the substrate suitability of arylboric acid was investigated The target product (2G - 2J) can be obtained by high yield and enantioselectivity reaction of alkyl substituted boric acid The arylboric acid substituted by electron donor or electron acceptor is well tolerated under the reaction conditions Naphthalene ring and all kinds of heterocycles, such as benzodioxolane, pyridine, n-methylindole, pyrrole and furan, can react, but the electron rich boric acid will reduce the ER value (2L, 2Y, 2Z, 2AA) (source: J am Chem SOC.) in addition, seven membered ring and δ - trisubstituted lactam can produce transfer Heck reaction at higher catalyst dosage, but the yield is reduced (Table 3 and 4) (source: J am Chem SOC.) the author found that the olefinamide 1D can be coupled with phenylboronic acid at gram scale, and the yield and ER value did not decrease Derivatization experiments show that chiral 6-substituted δ - lactam can be easily derived into various useful heterocyclic structural units For example, PMB protected lactam 2D can be converted to piperidine 7 or rhodium catalyzed arylation to produce product 8 In addition, 2A can be transformed into lactam 10 by two steps, and the compound can be further transformed into bioactive compounds a and F Conclusion: Professor Matthew s Sigman of the University of Utah has developed a method for asymmetric synthesis of α, β - unsaturated δ - aryl lactam by the transfer Heck reaction of enamide This method has mild conditions, easy to obtain raw materials and high corresponding selectivity.
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