Asymmetric Total Synthesis of Octalactins A, B and Their Analogues

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Octalactins A and B were isolated from the marine bacterium Streptomyces sp. in 1991.The structure of these compounds includes an unusual saturated medium-sized lactone moiety, and octalactin A exhibits a potent cytotoxic activity against some tumor cell lines.A method for the synthesis of octalactins A and B is established via a new and quite effective mixedanh ydride lactonization for, the synthesis of an eight-membered ring moiety using 2-methyl-6-nitrobenzoic anhydride (MNBA) with DMAP.Both an optically active linear precursor of the lactone and a side chain of octalactins are prepared by the enantioselective aldol reaction of ketene silyl acetals with aldehydes.The desired 8-membered ring lactone was first synthesized by S-Py ester method after 96 h ; however, the lactonization sluggishly proceeded in refiuxed toluene with the silver salt catalyst.Furthermore, the target cyclized molecule was not produced at all when the reaction was carried out at room temperature.On the other hand, the cyclization reaction of the seco acid was efficiently accelerated by MNBA with DMAP to afford the desired 8-membered ring lactone in 84% yield at room temperature, and the corresponding diolide was not produced.Thus, an efficient method for the preparation of the synthetic precursor of octalactins was established via the effective, construction of the medium-sized ring lactone moiety.