Catalytic enantioselective alkylative aldol reaction: efficient multicomponent assembly of dialkylzincs, allenic esters, and ketones toward highly functionalized delta-lactones with tetrasubstituted chiral centers.
A general catalytic asymmetric alkylative aldol reaction is described as a new entry to the catalytic asymmetric multicomponent reaction (CAMCR). Highly functionalized delta-lactones were produced in the presence of a catalytic amount of the Cu(OAc)2-DIFLUORPHOS complex through three-component assembly of dialkylzincs, allenic esters, and unactivated ketones. This CAMCR constructs two C-C bonds and one tetrasubstituted chiral center simultaneously. Conjugate addition of alkylcopper species to an allenic ester produced highly active copper enolate in situ, and the successive asymmetric aldol addition to ketones followed by lactonization afforded the desired products. The addition of MS4A and Lewis base (Ph2S=O, DMSO, or HMPA) is important for obtaining a high yield, with suppression of the undesired alpha-addition pathway. Control/crossover experiments suggest that the addition of a Lewis base facilitated the retro-aldol reaction of the alpha-adducts (proofreading effect). The ketone and copper enolate generated through the retro-aldol reaction were converted to the desired lactone through the gamma-aldol pathway, which was trapped by irreversible lactone formation.
Oisaki
Kounosuke
K
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0013, Japan.
Zhao
Dongbo
D
Kanai
Motomu
M
Shibasaki
Masakatsu
M
D000447:Aldehydes / Q000737:chemistry*; D000478:Alkylation; D002384:Catalysis; D003300:Copper / Q000737:chemistry*; D004952:Esters / Q000737:chemistry*; D007659:Ketones / Q000737:chemistry*; D007783:Lactones / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry; D009942:Organometallic Compounds / Q000737:chemistry; D013237:Stereoisomerism; D015032:Zinc / Q000737:chemistry*
D000447:Aldehydes; D004952:Esters; D007659:Ketones; D007783:Lactones; D009281:Naphthalenes; D009942:Organometallic Compounds; D003300:Copper; C116609:3-hydroxybutanal; C110055:allenolic acid; D015032:Zinc