Enantioselective Synthesis of Trisubstituted Allenyl–B(pin) Compounds by Phosphine–Cu-Catalyzed 1,3-Enyne Hydroboration. Insights Regarding Stereochemical Integrity of Cu–Allenyl Intermediates

Abstract

Catalytic enantioselective boron-hydride additions to 1,3-enynes, which afford allenyl-B(pin) (pin = pinacolato) products, are disclosed. Transformations are promoted by a readily accessible bis-phosphine-Cu complex and involve commercially available HB(pin). The method is applicable to aryl- and alkyl-substituted 1,3-enynes. Trisubstituted allenyl-B(pin) products were generated in 52-80% yield and, in most cases, in >98:2 allenyl:propargyl and 92:8-99:1 enantiomeric ratio. Utility is highlighted through a highly diastereoselective addition to an aldehyde, and a stereospecific catalytic cross-coupling process that delivers an enantiomerically enriched allene with three carbon-based substituents. The following key mechanistic attributes are elucidated: (1) Spectroscopic and computational investigations indicate that low enantioselectivity can arise from loss of kinetic stereoselectivity, which, as suggested by experimental evidence, may occur by formation of a propargylic anion generated by heterolytic Cu-C cleavage. This is particularly a problem when trapping of the Cu-allenyl intermediate is slow, namely, when an electron deficient 1,3-enyne or a less reactive boron-hydride reagent (e.g., HB(dan) (dan = naphthalene-1,8-diaminato)) is used or under non-optimal conditions (e.g., lower boron-hydride concentration causing slower trapping). (2) With enynes that contain a sterically demanding o-aryl substituent considerable amounts of the propargyl-B(pin) isomer may be generated (25-96%) because a less sterically demanding transition state for Cu/B exchange becomes favorable. (3) The phosphine ligand can promote isomerization of the enantiomerically enriched allenyl-B(pin) product; accordingly, lower ligand loading might at times be optimal. (4) Catalytic cross-coupling with an enantiomerically enriched allenyl-B(pin) compound might proceed with high stereospecificity (e.g., phosphine-Pd-catalyzed cross-coupling) or lead to considerable racemization (e.g., phosphine-Cu-catalyzed allylic substitution).

Enantio‐ and Diastereoselective Synthesis of Homopropargyl Amines by Copper‐Catalyzed Coupling of Imines, 1,3‐Enynes, and Diborons

“…We propose that intermediate B is the major allenyl–copper isomer in the reaction . Coupling of the allenyl–copper intermediate B with imine 1 b ( C re , 3) gives chiral homopropargylic amine D and closes the catalytic cycle (4) –. Scheme B provides an explanation for the anti ‐diastereoselectivity observed in the reaction.…”

“…Regioselective borocupration provides intermediate A (1), which is proposed to undergo propargyl‐to‐allenyl isomerization to B (2) (Scheme A) . We propose that intermediate B is the major allenyl–copper isomer in the reaction .…”

“…Regioselective borocupration provides intermediate A (1), which is proposed to undergo propargyl‐to‐allenyl isomerization to B (2) (Scheme A) . We propose that intermediate B is the major allenyl–copper isomer in the reaction . Coupling of the allenyl–copper intermediate B with imine 1 b ( C re , 3) gives chiral homopropargylic amine D and closes the catalytic cycle (4) –.…”

Copper Hydride-Catalyzed Enantioselective Synthesis of Axially Chiral 1,3-Disubstituted Allenes

“…Based on previous mechanistic studies and DFT calculations, 11,22 we propose the following mechanism detailed in Figure 2. After generation of the chiral LCuH complex I, enantioselective hydrocupration of enyne II affords a chiral propargylic copper species (III).…”

Catalytic asymmetric synthesis of chiral trisubstituted heteroaromatic allenes from 1,3-enynes

“…Very recently, Hoveyda, Engle, and Ge groups have independently reported enantioselective copper-catalyzed hydroboration of 1,3-enynes through trapping of allenyl copper species with pinacolborane ( Fig. 1b) [57][58][59][60] .…”