The first asymmetric catalytic synthesis of (−)-oudemanisin A 1a and its diastereomer 1b has been achieved. The key steps of our strategy involved the asymmetric alkynylation of an unsaturated aliphatic aldehyde catalyzed by Trost’s ProPhenol ligand, chemoselective oxidation of the olefinic diol, base-induced ring opening of the lactone, and acylation–alkylation of the ester.Download high-res image (59KB)Download full-size image

Four new cyclopropane-based bisoxazolines were synthesized and applied to cobalt-catalyzed cross-coupling reactions between racemic α-bromo esters and aryl Grignard reagents. The reaction afforded a series of chiral α-arylalkanoic esters with high yields and good enantioselectivities (up to 93% yield, 92:8 er). This research focuses on the cross-coupling between racemic α-bromopropanoate and p-isobutylphenyl Grignard reagent’s which provides ibuprofen ester efficiently. Furthermore, ibuprofen ester 7e was transformed into (S)-ibuprofen (99:1 er) via hydrolysis and recrystallization.(4S,4′S)-2,2′-((1S,2R)-3,3-Dimethylcyclopropane-1,2-diyl)bis(4-ethyl-4,5-dihydrooxazole)C15H24N2O2[α]D20 = −107.8 (c 1.13, CHCl3)Source of chirality: (S)-2-aminobutan-1-olAbsolute configuration: (4S,4′S)(4S,4′S)-2,2′-((1S,2R)-3,3-Dimethylcyclopropane-1,2-diyl)bis(4-isobutyl-4,5-dihydrooxazole)C19H32N2O2[α]D20 = −141.6 (c 1.22, CHCl3)Source of chirality: (S)-2-amino-4-methylpentan-1-olAbsolute configuration: (4S,4′S)(4S,4′S)-2,2′-((1S,2R)-3,3-Dimethylcyclopropane-1,2-diyl)bis(4-sec-butyl)-4,5-dihydrooxazole)C19H32N2O2[α]D20 = −125.4 (c 1.11, CHCl3)Source of chirality: (2S)-2-amino-3-methylpentan-1-olAbsolute configuration: (4S,4′S)(4S,4′S)-2,2′-((1S,2R)-3,3-Dimethylcyclopropane-1,2-diyl)bis(4-phenethyl-4,5-dihydrooxazole)C27H32N2O2[α]D20 = −134.8 (c 1.36, CHCl3)Source of chirality: (S)-2-amino-4-phenylbutan-1-olAbsolute configuration: (4S,4′S)(S)-2-(4-Isobutylphenyl)propanoic acid [(S)-ibuprofen]C13H18O2Er = 99:1[α]D20 = +52.3 (c 1.0, CHCl3)Source of chirality: Ligand 2bAbsolute configuration: (S)

The first cobalt-catalyzed asymmetric Kumada cross-coupling with high enantioselectivity has been developed. The reaction affords a unique strategy for the enantioselective arylation of α-bromo esters catalyzed by a cobalt–bisoxazoline complex. A variety of chiral α-arylalkanoic esters were prepared in excellent enantioselectivity and yield (up to 97% ee and 96% yield). The arylated products were transformed into α-arylcarboxylic acids and primary alcohols without erosion of ee. The new enantioenriched α-arylpropionic esters synthesized herein are potentially useful in the development of nonsteroidal anti-inflammatory drugs. This method was conducted on gram-scale and applied to the synthesis of highly enantioenriched (S)-fenoprofen and (S)-ar-turmerone.