Total Synthesis of Bafilomycin A(1).
The highly stereoselective total synthesis of the macrolide antibiotic, bafilomycin A(1) (1), the first specific potent inhibitor of vacuolar H(+)-ATPase, has been achieved by a convergent route involving the synthesis and coupling of its 16-membered tetraenic lactone and beta-hydroxyl hemiacetal side-chain subunits. The C1-C17 16-membered lactone aldehyde 2 was synthesized through the coupling of the C5-C11 vinyl iodide 4 and the C12-C17 vinylstannane 5, followed by construction of the C1-C4 diene and macrolactonization. The aldol coupling of 2 and the C18-C25 ethyl ketone 3 followed by desilylation provided 1, which was identical with natural bafilomycin A(1). The key synthetic segments 3-5 were effectively synthesized from the readily available chiral materials, D-glucose, ethyl (S)-lactate, and methyl (S)-3-hydroxy-2-methylpropionate, respectively.
Toshima
Kazunobu
K
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223, Japan.
Jyojima
Takaaki
T
Yamaguchi
Hiroyuki
H
Noguchi
Yasunobu
Y
Yoshida
Takehito
T
Murase
Hidekazu
H
Nakata
Masaya
M
Matsumura
Shuichi
S