Construction of Vicinal Quaternary Carbon Stereocenters Through Diastereo‐ and Enantioselective Oxidative 1,6‐Conjugate Addition

Abstract

The asymmetric construction of vicinal quaternary carbon stereocenters with at least one moiety in acyclic systems is a formidable challenge. We disclose a solution involving diastereo‐ and enantioselective oxidative 1,6‐conjugate addition. The practical asymmetric cross‐dehydrogenative coupling of 2,2‐diarylacetonitriles and diverse α‐substituted cyclic 1,3‐dicarbonyls proceeds, for vicinal quaternary carbon stereocenters with one center in acyclic systems, in excellent yields and stereoselectivities. The generality of the approach is further demonstrated by the stereoselective creation of vicinal quaternary carbon stereocenters with both centers in acyclic systems using acyclic β‐ketoesters as coupling partners. Computational studies elucidate the origins of both diastereo‐ and enantioselectivity.

Recent Advances in Non-Precious Metal Catalysis

“…The use of a bulky and electron-rich diazonium salt was crucial to achieve efficient iodine activation, presumably due to the enhanced stability of the aryl radical. Other notable advances in Cu-catalyzed reactions include the following publications: (1) Cu-catalyzed diazidation reactions; 54 (2) Diastereo-and enantioselective oxidative 1,6conjugate addition; 55 (3) C−H amination of 8-aminoquinoline-directed ferrocenes; 56 (4) Cu-catalyzed hydroxymethylation of alkynes with formic acid; 57 (5) Cu-catalyzed synthesis of indolyl benzo[b]carbazoles; 58 (6) Cu-catalyzed tandem cross-coupling and alkynylogous aldol reaction to access exocyclic α-allenols; 59 (7) Tandem Cu-and Rh-catalysis for oxidation of hydrazones and enantioselective cyclopropanation; 60 (8) Cu-catalyzed CF 2 H-substituted 2-amidofurans; 61 (9) Cu-catalyzed annulation of indolyl α-diazocarbonyl to access carbazoles; 62 (10) Cu-catalyzed enantioselective 1,2reduction of cycloalkenones; 63 (11) Cu-catalyzed enantiodivergent alkynylation of isatins; 64 (12) Cu-catalyzed β-lactam formation from oximes and methyl propiolate; 65 (13) Cucatalyzed aminosulfonylation of O-homoallyl benzimidates; 66 (14) Cu-catalyzed multicomponent trifluoromethylphosphorothiolation of alkenes; 67 (15) Cu-catalyzed chloroarylsulfonylation of styrene derivatives; 68 (16) Cu-catalyzed synthesis of 5-carboxyl-4-perfluoroalkyl triazoles; 69 (17) Crossnucleophile coupling of β-allenyl silanes with tertiary C−H bonds to access 1,3-dienes; 70 (18) Cu-catalyzed C(sp 3 )−H functionalization of O-pentafluorobenzoyl ketone oximes; 71 (19) Total regioselectivity of hydrobromination of alkenes controlled by Fe or Cu catalyst; 72 (20) Enantioselective synthesis of trifluoromethyl cyclopropylboronates by Cu catalysis; 73 (21) Cu-catalyzed asymmetric cyclization of alkenyl diynes; 74 (22) Synergistic Ir/Cu catalysis for asymmetric allylic alkylation of oxindoles; 75…”

“…Other notable advances in Cu-catalyzed reactions include the following publications: (1) Cu-catalyzed diazidation reactions; (2) Diastereo-and enantioselective oxidative 1,6-conjugate addition; (3) C–H amination of 8-aminoquinoline-directed ferrocenes; (4) Cu-catalyzed hydroxymethylation of alkynes with formic acid; (5) Cu-catalyzed synthesis of indolyl benzo­[ b ]­carbazoles; (6) Cu-catalyzed tandem cross-coupling and alkynylogous aldol reaction to access exocyclic α-allenols; (7) Tandem Cu- and Rh-catalysis for oxidation of hydrazones and enantioselective cyclopropanation; (8) Cu-catalyzed CF 2 H-substituted 2-amidofurans; (9) Cu-catalyzed annulation of indolyl α-diazocarbonyl to access carbazoles; (10) Cu-catalyzed enantioselective 1,2-reduction of cycloalkenones; (11) Cu-catalyzed enantiodivergent alkynylation of isatins; (12) Cu-catalyzed β-lactam formation from oximes and methyl propiolate; (13) Cu-catalyzed aminosulfonylation of O -homoallyl benzimidates; (14) Cu-catalyzed multicomponent trifluoromethyl­phosphorothiolation of alkenes; (15) Cu-catalyzed chloro-arylsulfonylation of styrene derivatives; (16) Cu-catalyzed synthesis of 5-carboxyl-4-perfluoroalkyl triazoles; (17) Cross-nucleophile coupling of β-allenyl silanes with tertiary C–H bonds to access 1,3-dienes; (18) Cu-catalyzed C­( sp 3 )–H functionalization of O -pentafluorobenzoyl ketone oximes; (19) Total regioselectivity of hydrobromination of alkenes controlled by Fe or Cu catalyst; (20) Enantioselective synthesis of trifluoromethyl cyclopropylboronates by Cu catalysis; (21) Cu-catalyzed asymmetric cyclization of alkenyl diynes; (22) Synergistic Ir/Cu catalysis for asymmetric allylic alkylation of oxindoles; (23) Hydrosilylation of alkynes and alkenes with Cu-photocatalysis under continuous flow conditions; (24) Cu-based water oxidation catalysts with consecutive ligand-based electron transfer; (25) Heteroleptic copper-based complexes for energy-transfer processes: E → Z isomerization and tandem photocatalytic sequences; (26) Copper-catalyzed aminoheteroarylation of unactivated alkenes through distal heteroaryl migration; (27) Copper-catalyzed syntheses of multiple functionalized allenes via three-component reaction of enynes; (28) Unified mechanistic concept of the copper-catalyzed and amide-oxazoline-directed C­(sp 2 )–H bond functionalization; (29) Cu-catalyzed C–H allylation of benzimidazoles with allenes; (30) Synthesis of 1,2-aminoalcohols through enantioselective aminoallylation of ketones by Cu-catalyzed reductive coupling; (31) Copper-catalyzed N-directed distal C­(sp 3 )–H sulfonylation and thiolation with sulfinate salts; and (32) Dehydrogenative aza-[4 + 2] cycloaddition of amines with 1,3-dienes via dual catalysis …”

Cu(I)-Catalyzed Highly Diastereo- and Enantioselective Constructions of Boron/Carbon Vicinal Stereogenic Centers via Insertion Reaction

“…Despite their significance, the assembly of vicinal stereogenic centers in a single-vessel reaction is much more difficult than the catalytic construction of chiral molecules, which have only one stereogenic center on the scaffolds due to the additional diastereocontrol requirement . The strategies for the construction of vicinal carbon–carbon stereocenters are relatively abundant and have been well developed; however, the construction of vicinal carbon–heteroatom stereocenters is extremely limited (Figure a) . The lack of efficient synthetic approaches in this regard has restricted the potential application of these chiral compounds bearing vicinal stereocenters in medicine, materials, and other related fields .…”

Stereodivergent Construction of Vicinal Acyclic Quaternary–Tertiary Carbon Stereocenters by Michael-Type Alkylation of α,α-Disubstituted N-tert-Butanesulfinyl Ketimines

“…Quaternary carbon stereocenters are often found in natural products or bioactive compounds, and several stereoselective methods have been developed for their preparation . In recent years, great progress has been achieved in the construction of vicinal quaternary–tertiary and quaternary–quaternary carbon stereocenters. To set up quaternary stereocenters at the α-position in carbonyl compounds, C–C bond formation via facially selective nucleophilic addition of geometrically defined, fully substituted enolates to carbon-centered electrophiles is appealing.…”