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Asymmetric Total Synthesis of Fredericamycin A: An Intramolecular Cycloaddition Pathway
Author(s) -
Akai Shuji,
Tsujino Toshiaki,
Fukuda Nobuhisa,
Iio Kiyosei,
Takeda Yoshifumi,
Kawaguchi Kenichi,
Naka Tadaatsu,
Higuchi Kazuhiro,
Akiyama Emi,
Fujioka Hiromichi,
Kita Yasuyuki
Publication year - 2005
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200500443
Subject(s) - racemization , chemistry , aldol reaction , stereocenter , moiety , stereochemistry , total synthesis , cycloaddition , enantioselective synthesis , intramolecular force , desymmetrization , asymmetric carbon , sulfoxide , cope rearrangement , medicinal chemistry , organic chemistry , catalysis , optically active
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, (1 R )‐ 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 °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.