A Practical Method for Enantioselective Synthesis of All‐Carbon Quaternary Stereogenic Centers Through NHC‐Cu‐Catalyzed Conjugate Additions of Alkyl‐ and Arylzinc Reagents to β‐Substituted Cyclic Enones.

Abstract

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Construction of all-carbon quaternary stereocenters by catalytic asymmetric conjugate addition to cyclic enones in natural product synthesis

“…Palladium-catalyzed asymmetric conjugate additions of β-aryl groups, which make use of various commercially available, air-and/or moisture-stable arylboronic acids bearing a wide range of functionalities such as halo and nitro groups, undoubtedly provide a convenient and useful approach to the construction of enantioenriched β-aryl ketones [135][136][137][138]143 (see Schemes 10 and 11). Unlike palladiumcatalyzed asymmetric conjugate additions of boronic acids, the copper-catalyzed counterparts usually require air-and/or moisture-sensitive organometallic nucleophiles generated from arylmagnesium, 125,183 arylaluminum, 47,184,185 and arylzinc reagents, 105,186,187 which are incompatible with many reactive functional groups because of their reactivity with the nucleophiles used. Recently, Zhou achieved asymmetric conjugate addition of organoboron reagents to acyclic enones by combining cost-effective copper catalysts and air-stable organoboron reagents.…”

Access to Functionalized Quaternary Stereocenters via the Copper-Catalyzed Conjugate Addition of Monoorganozinc Bromide Reagents Enabled by N,N-Dimethylacetamide

“…Comparable yields were realized using 20 mol% catalyst, and we proceeded with these conditions as our standard one-pot procedure to explore a broad substrate scope (Scheme 2). Monoorganozinc reagents that incorporate ester functionality at various chain lengths afford addition products in high yields ( The Journal of Organic Chemistry tolerated to afford nitrile (9 and 24), carbamate (10), and phthalimide (25) products in good yields. The addition reaction was efficient with various β-substituted cyclohexenones (11)(12)(13) and cycloheptenone (14).…”

“…The application of sensitive diorganozinc 5,6,7 or mixed diorganozinc 8 reagents has enabled the synthesis of β-quaternary carbonyls that include recent enantioselective achievements. 9,10,11 Monoorganozinc reagents, however, have been underutilized despite the appeal of their simplified preparation via the direct insertion of zinc into a carbon-halogen bond. Examples that leverage the addition of monoorganozinc reagents to sterically demanding β,β-disubstituted α,βunsaturated carbonyls are surprisingly limited and require stoichiometric cyanocuprate reagents.…”

“…7 With optimized conditions in hand, we examined the scope of monoorganozinc and α,β-unsaturated ketones (enones; Scheme 1). A variety of functional monoorganozinc reagents proved effective in this reaction, affording β-quaternary ketones that incorporate ester (6 and 7), chloro (8), nitrile (9), and carbamate (10) groups in high yields. The cyclic enones could also possess alternative β-functionality, with n-butyl (11), benzyl (12), and phenyl (13) groups well-tolerated.…”

“…Monoorganozinc reagents that incorporate ester functionality at various chain lengths afford addition products in high yields (7, 22, and 23), including 6 in 92% yield on a 5.0 mmol scale. Nitrogen-containing monoorganozincs were well tolerated to afford nitrile (9 and 24), carbamate (10), and phthalimide (25) products in good yields. The addition reaction was efficient with various β-substituted cyclohexenones (11−13) and cycloheptenone (14).…”