Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to Heterocyclic Acceptors

摘要

Palladium-catalyzed asymmetric conjugate additions are an increasingly versatile class of enantioselective reactions that allow stereoselective alkylation and arylation of a,b-unsaturated conjugate acceptors.~([1]) These processes often utilize easily-handled, air- and water-stable boron nucleophiles that render these reactions highly tolerant of oxygen and moisture.~([2]) Recently, our group disclosed the asymmetric conjugate addition of arylboronic acids to cyclic enones facilitated by a palladium catalyst derived in situ from palladium(II) trifluoroacetate and a chiral pyridinooxazoline (PyOX) ligand (5).~([3]) Notably, our catalyst system was generally applicable for five-, six-, and seven-membered carbocyclic enones. The numerous advantages of this system encouraged us to seek application to heterocyclic molecules to demonstrate the broad utility of this reaction for the synthesis of pharmaceutically relevant molecules. Herein, we report the first general enantioselective conjugate addition of arylboronic acids to heterocyclic conjugate acceptors derived from chromones and 4-quinolones utilizing the Pd/ PyOX catalyst system. These reactions are performed under an atmosphere of air and deliver a large variety of asymmetric products with high enantioselectivity in moderate to excellent yields. The stereoselective conversion of chromones through conjugate addition renders access to flavanones, a class of heterocyclic molecules that has demonstrated numerous medicinal properties.~([4]) Recent literature suggests that intramolecular oxa-Michael additions are among the best-studied synthetic methods for asymmetric flavanone synthesis.~([5]) However, examples for the retrosynthetic disconnection of flavanones by conjugate addition of an aryl moiety to a chromone derivative remain scarce.~([6, 7]) While chromones have been successfully employed in rhodium-catalyzed conjugate addition,~([7])) to the best of our knowledge, no palladium-catalyzed asymmetric conjugate addition syntheses of flavanones have been reported.~([8]) We identified chromone as a functioning conjugate acceptor with our Pd/ PyOX system during a screen developed to analyze the effect of a b-substituent on reactivity and enantioselectivity (Table 1). As reported in our initial communication,~([3])) 3-methylcyclohexenone reacts with phenylboronic acid to give nearly quantitative yield of the conjugate addition adduct 2 in 93% ee (Table 1, entry 2). With only hydrogen in the β-position, enantioselectivity drops precipitously to 18% ee (Table 1, entry 1). Interestingly, 2-methyl-4-chromone reacts poorly, with only trace conjugate addition adduct detected by ~1H NMR spectroscopy (Table 1, entry 4), yet chromone reacts with high yield and excellent enantioselectivity (94% ee, Table 1, entry 3).