TY - JOUR
T1 - The total synthesis of the antitumor macrolide, rhizoxin
AU - Nakada, Masahisa
PY - 1995
Y1 - 1995
N2 - The first total synthesis of the antitumor macrolide rhizoxin in a highly stereocontrolled manner has been achieved. The efficient construction of optically pure key building fragments designed based on rational retrosynthetic analysis was accomplished in a concise manner. Synthesis of the Right-Wing started from the chiral half-ester generated by asymmetric hydrolysis of the corresponding meso-diester using pig liver esterase. The remaining chiral centers of the fragment were constructed by cyclic hydroboration. Synthesis of the Left-Wing was accomplished starting from methyl (S) -3-hydroxy-2-methylpropionate which in turn had been prepared again by enzyme mediated transformation. Coupling of Right-Wing and Left-Wing was carried out by Julia condensation, and the macrocyclic lactone was constructed by intramolecular Horner-Emmons reaction. Finally, the stereoselective epoxidation was achieved cleanly after formation of unsaturated 16-membered macrocyclic lactone. Chromophore-side-chain moiety was constructed at final stage by reaction of the phosphineoxide in 80% yield with high selectivity (E/Z= >20/1). The present methodology will be useful for the synthesis of the homologues or man-made rhizoxins.
AB - The first total synthesis of the antitumor macrolide rhizoxin in a highly stereocontrolled manner has been achieved. The efficient construction of optically pure key building fragments designed based on rational retrosynthetic analysis was accomplished in a concise manner. Synthesis of the Right-Wing started from the chiral half-ester generated by asymmetric hydrolysis of the corresponding meso-diester using pig liver esterase. The remaining chiral centers of the fragment were constructed by cyclic hydroboration. Synthesis of the Left-Wing was accomplished starting from methyl (S) -3-hydroxy-2-methylpropionate which in turn had been prepared again by enzyme mediated transformation. Coupling of Right-Wing and Left-Wing was carried out by Julia condensation, and the macrocyclic lactone was constructed by intramolecular Horner-Emmons reaction. Finally, the stereoselective epoxidation was achieved cleanly after formation of unsaturated 16-membered macrocyclic lactone. Chromophore-side-chain moiety was constructed at final stage by reaction of the phosphineoxide in 80% yield with high selectivity (E/Z= >20/1). The present methodology will be useful for the synthesis of the homologues or man-made rhizoxins.
KW - Antitumor macrolide
KW - Asymmetric hydrolysis
KW - Chiral half ester
KW - Cyclic hydroboration
KW - First total synthesis
KW - Intramolecular Horner Emmons reaction
KW - Julia condensation
KW - Meso-diester
KW - Pig liver esterase
KW - Stereoselective epoxidation
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U2 - 10.5059/yukigoseikyokaishi.53.122
DO - 10.5059/yukigoseikyokaishi.53.122
M3 - Article
AN - SCOPUS:0029241602
VL - 53
SP - 122
EP - 137
JO - Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry
JF - Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry
SN - 0037-9980
IS - 2
ER -