Asymmetric total synthesis of fredericamycin A: an intramolecular cycloaddition pathway.
The asymmetric total synthesis of the potent antitumor antibiotic fredericamycin A ((S)-1) was achieved by the intramolecular [4+2] cycloaddition of the silylene-protected styrene derivative (S)-7 followed by the aromatic Pummerer-type reaction of the sulfoxide (S)-5. Although we had already succeeded in the total synthesis of racemic 1 by the same approach, synthesis of its asymmetric version was more complicated than we had expected due to the difficulties involved in constructing the quaternary carbon center and the tendency of this center to undergo facile racemization. Racemization of this center during the installation of the acetylene moiety on the dione (R)-8 was the most serious aspect. Systematic studies of its DE-ring analogue (R)-25 revealed that racemization of the quaternary carbon center proceeded by a retro-aldol-aldol reaction of the initial adduct, (1R)-39 a-Li, and that the degree of racemization was dependent on the reaction temperature. The racemization process could be completely depressed by keeping the reaction temperature at -78 degrees C. The construction of the stereogenic quaternary carbon center was achieved by the lipase-catalyzed desymmetrization of the prochiral 1,3-diol 9 a bearing the DEF-ring moiety. These studies enabled us to attain the asymmetric total synthesis of (S)-1 while completely retaining the chiral integrity created by the enzymatic reactions.
Akai
Shuji
S
Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Tsujino
Toshiaki
T
Fukuda
Nobuhisa
N
Iio
Kiyosei
K
Takeda
Yoshifumi
Y
Kawaguchi
Ken-ichi
K
Naka
Tadaatsu
T
Higuchi
Kazuhiro
K
Akiyama
Emi
E
Fujioka
Hiromichi
H
Kita
Yasuyuki
Y
D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D018360:Crystallography, X-Ray; D003500:Cyclization; D006868:Hydrolysis; D007202:Indicators and Reagents; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry; D007700:Kinetics; D008049:Lipase / Q000737:chemistry; D013055:Spectrophotometry, Infrared; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry; D013237:Stereoisomerism
D000903:Antibiotics, Antineoplastic; D007202:Indicators and Reagents; D007546:Isoquinolines; D013141:Spiro Compounds; D008049:Lipase; C016660:fredericamycin A