Leukotriene B4 1 was prepared from two chiral synthons 8 and 14. The chiral secondary alcohols of 8 and 14 were constructed by BINOL/Ti(OiPr)4 catalyzed enantioselective alkynylzinc addition to aldehydes.Download high-res image (44KB)Download full-size image

The first total syntheses of two marine natural products, (R)-strongylodiols C and D, with 99% ee were achieved. The key steps of the strategy include the zipper reaction of an alkyne, the asymmetric alkynylation of an unsaturated aliphatic aldehyde catalyzed with Trost’s ProPhenol ligand, and the Cadiot–Chodkiewicz cross-coupling reaction of a chiral propargylic alcohol with a bromoalkyne.

An efficient total synthesis of natural panaxydol 1a and its seven stereoisomers 1b–h was accomplished; four diastereomers of the natural form were prepared for the first time. Our strategy involves the Cadiot-Chodkiewicz cross-coupling reaction of chiral terminal alkynes with bromoalkynes, the asymmetric alkynylation of aldehydes, and the enantioselective Sharpless epoxidation of allylic alcohols. Preliminary in vitro cytotoxicity evaluation indicated that some synthetic panaxydols possess anticancer activities, and (3S,9R,10S)-panaxydol 1e showed a particularly promising cytotoxic effect.(3R,9R,10S)-9,10-Epoxyheptadec-1-ene-4,6-diyn-3-ol [(3R,9R,10S)-panaxydol]C17H24O2[α]D20 = −94.8 (c 1.1, CHCl3)Source of chirality: (S)-BINOL, (−)-DIPTAbsolute configuration: (3R,9R,10S)(3R,9S,10R)-9,10-Epoxyheptadec-1-ene-4,6-diyn-3-ol [(3R,9S,10R)-panaxydol]C17H24O2[α]D20 = +41.2 (c 1.2, CHCl3)Source of chirality: (S)-BINOL, (+)-DETAbsolute configuration: (3R,9S,10R)(3R,9R,10R)-9,10-Epoxyheptadec-1-ene-4,6-diyn-3-ol [(3R,9R,10R)-panaxydol]C17H24O2[α]D20 = −35.6 (c 0.7, CHCl3)Source of chirality: (S)-BINOL, (−)-DIPTAbsolute configuration: (3R,9R,10R)(3R,9S,10S)-9,10-Epoxyheptadec-1-ene-4,6-diyn-3-ol [(3R,9S,10S)-panaxydol]C17H24O2[α]D20 = −43.0 (c 1.4, CHCl3)Source of chirality: (S)-BINOL, (+)-DETAbsolute configuration: (3R,9S,10S)(3S,9R,10S)-9,10-Epoxyheptadec-1-ene-4,6-diyn-3-ol [(3S,9R,10S)-panaxydol]C17H24O2[α]D20 = −43.4 (c 0.6, CHCl3)Source of chirality: (R)-BINOL, (−)-DIPTAbsolute configuration: (3S,9R,10S)(3S,9S,10R)-9,10-Epoxyheptadec-1-ene-4,6-diyn-3-ol [(3S,9S,10R)-panaxydol]C17H24O2[α]D20 = +90.0 (c 0.5, CHCl3)Source of chirality: (R)-BINOL, (+)-DETAbsolute configuration: (3S,9S,10R)(3S,9R,10R)-9,10-Epoxyheptadec-1-ene-4,6-diyn-3-ol [(3S,9R,10R)-panaxydol]C17H24O2[α]D20 = +45.6 (c 1.2, CHCl3)Source of chirality: (R)-BINOL, (−)-DIPTAbsolute configuration: (3S,9R,10R)(3S,9S,10S)-9,10-Epoxyheptadec-1-ene-4,6-diyn-3-ol [(3S,9S,10S)-panaxydol]C17H24O2[α]D20 = +37.0 (c 1.2, CHCl3)Source of chirality: (R)-BINOL, (+)-DETAbsolute configuration: (3S,9S,10S)

An efficient and concise asymmetric synthesis of (R)-(+)-ar-curcumene, (R)-4,7-dimethyl-l-tetralone, and their enantiomers was accomplished. The key step to construct the stereogenic benzylmethyl centers of these natural products is the cobalt-catalyzed asymmetric Kumada cross-coupling reaction of a racemic α-bromo ester.(R)-1-Methyl-4-(6-methylhept-5-en-2-yl)benzene [(R)-ar-curcumene]C15H22Ee = 90%[α]D20 = −44.6 (c 1.2, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)(R)-4,7-Dimethyl-3,4-dihydronaphthalen-1(2H)-oneC12H14OEe = 90%[α]D20 = +12.8 (c 1.3, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

An efficient synthesis of panaxytriol and its seven stereoisomers was achieved, and four unnatural diastereomers of 2a were prepared. The key steps involved the opening of vicinal hydroxy epoxides, the stereospecific opening of the epoxides with perchloric acid, and the Cadiot–Chodkiewicz cross-coupling of chiral terminal alkynes with bromoalkynes. Preliminary antitumor activity investigations indicated that some synthetic panaxytriols exhibited promising cytotoxic activity against three human cancer cell lines.(3R,9R,10R)-Heptadeca-1-en-4,6-diyne-3,9,10-triolC17H26O3[α]D20 = −18.1 (c 1.1, CHCl3)Absolute configuration: (3R,9R,10R)(3R,9S,10S)-Heptadeca-1-en-4,6-diyne-3,9,10-triolC17H26O3[α]D20 = −43.9 (c 1.1, CHCl3)Absolute configuration: (3R,9S,10S)(3R,9R,10S)-Heptadeca-1-en-4,6-diyne-3,9,10-triolC17H26O3[α]D20 = −31.6 (c 1.1, CHCl3)Absolute configuration: (3R,9R,10S)(3R,9S,10R)-Heptadeca-1-en-4,6-diyne-3,9,10-triolC17H26O3[α]D20 = −28.6 (c 0.8, CHCl3)Absolute configuration: (3R,9S,10R)(3S,9R,10R)-Heptadeca-1-en-4,6-diyne-3,9,10-triolC17H26O3[α]D20 = +50.0 (c 0.7, CHCl3)Absolute configuration: (3S,9R,10R)(3S,9S,10S)-Heptadeca-1-en-4,6-diyne-3,9,10-triolC17H26O3[α]D20 = +19.1 (c 0.7, CHCl3)Absolute configuration: (3S,9S,10S)(3S,9R,10S)-Heptadeca-1-en-4,6-diyne-3,9,10-triolC17H26O3[α]D20 = +29.4 (c 0.8, CHCl3)Absolute configuration: (3S,9R,10S)(3S,9S,10R)-Heptadeca-1-en-4,6-diyne-3,9,10-triolC17H26O3[α]D20 = +29.0 (c 0.8, CHCl3)Absolute configuration: (3S,9S,10R)

A concise and highly enantioselective (>99% ee) synthesis of falcarinol and panaxjapyne A and their enantiomers has been accomplished. The key steps involve the asymmetric addition of alkynylzinc reagent to acrolein and propionaldehyde catalyzed by a BINOL–Ti(OiPr)4 complex and a classic Cadiot–Chodkiewicz cross-coupling reaction. The chiral polyacetylenic alcohols synthesized herein have potential utility in the development of antitumor drugs and antidiabetic agents.(S,Z)-Heptadeca-1,9-diene-4,6-diyn-3-ol[(S)-falcarinol]C17H24OEe = >99%[α]D20 = +37.9 (c 1.0, CHCl3)Source of chirality: (R)-BINOLAbsolute configuration: (S)(S,Z)-Heptadeca-9-ene-4,6-diyn-3-olC17H26OEe = >99%[α]D20 = +11.6 (c 1.0, CH3OH)Source of chirality: (R)-BINOLAbsolute configuration: (S)

An efficient enantioselective total synthesis of an antitumor marine natural product (S,4E,15Z)-docosa-4,15-dien-1-yn-3-ol 1 with 96% ee and 15% overall yield has been achieved; this is the first preparation of 1 via asymmetric catalytic strategy. The key steps involve the asymmetric addition of trimethylsilylacetylene to a diolefinc aldehyde using a (R,R)-ProPhenol ligand and a zipper reaction of an alkyne.(S,4E,15Z)-Docosa-4,15-dien-1-yn-3-olC22H38OEe = 96%[α]D20 = +18.4 (c 0.10, MeOH)Source of chirality: (R,R)-ProPhenolAbsolute 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.

An efficient catalytic asymmetric synthesis of the CPB pheromone [(S)-1,3-dihydroxy-3,7-dimethyl-6-octen-2-one] and its enantiomer was accomplished with 99% ee and in gram quantities from geraniol. The key steps in this procedure involve Sharpless asymmetric epoxidation and recrystallization of the 4-bromobenzoate from the CPB pheromone to improve its enantiomeric purity. Furthermore, the absolute configuration of the CPB pheromone enantiomer was confirmed as (R) for the first time by the X-ray crystallographic structure of its benzoate.(R)-1,3-Dihydroxy-3,7-dimethyl-6-octen-2-oneC10H18O3Ee = 99%[α]D20=-3.7 (c 1.0, CHCl3)Source of chirality: l-(+)-diethyl tartrateAbsolute configuration: (R)

A series of cyclopropane-based bisoxazolines were synthesized from (R)- and (S)-amino alcohols, and applied to copper-catalyzed enantioselective nitroaldol reactions between nitromethane and various aldehydes. The reactions generated β-hydroxy nitroalkanes in high yields (97%) and with good enantioselectivities (up to 87% ee). The effects of the oxazoline stereocenters constructed in the Henry reactions were also studied.(1R,2S)-1,2-Bis[4(S)-isopropyloxazolin-2-yl]-3,3-dimethylcyclopropaneC17H28N2O2[α]D20=-131.3 (c 1.6, CHCl3)Source of chirality: (S)-valinol(1R,2S)-1,2-Bis [4(S)-tert-butyloxazolin-2-yl]-3,3-dimethylcyclopropaneC19H32N2O2[α]D20=-135.8 (c 2.1, CHCl3)Source of chirality: (S)-tert-leucinol(1R,2S)-1,2-Bis[4(S)-benzyloxazolin-2-yl]-3,3-dimethylcyclopropaneC25H28N2O2[α]D20=-56.5 (c 0.78, CHCl3)Source of chirality: (S)-phenylalaninol(1R,2S)-1,2-Bis[4(R)-phenyloxazolin-2-yl]-3,3-dimethylcyclopropaneC23H24N2O2[α]D25=+160.2 (c 1.5, CHCl3)Source of chirality: (R)-phenylglycinol(1R,2S)-1,2-Bis[4(S)-phenyloxazolin-2-yl]-3,3-dimethylcyclopropaneC23H24N2O2[α]D20=-152.3 (c 2.0, CHCl3)Source of chirality: (S)-phenylglycinolAbsolute configuration: (1R,2S)(1R,2S)-1,2-Bis[4(R)-phenyloxazolin-2-yl]-3,3-dimethylcyclopropaneC17H28N2O2[α]D25=+126.5 (c 2.4, CHCl3)Source of chirality: (R)-phenylglycinolAbsolute configuration: (1R,2S)