抄録
Lactimidomycin (1) is a highly unsaturated 12-membered macrolide possessing a biosynthetically rare glutarimide side chain, isolated from the fermentation broth of Streptomyces amphibiosporus R310-104 by Sugawara and co-workers. It displays strong in vitro cytotoxicity against a number of cancer cell lines including the highly invasive MDA-MB-231 human breast adenocarcinoma, in vivo antitumor activity in mice, and potent antifungal activity. It also inhibits both DNA and protein syntheses by blocking the translation-elongation phase through binding to the 60S ribosome. Its attractive biological activity and intriguing structure prompted our synthetic efforts toward lactimidomycin. Synthesis of 23 has been achieved from acetaldehyde and known oxazolidinone derivative 6 in 13 steps through vinylogous Mukaiyama aldol reaction (VMAR), chiral diamine-catalyzed asymmetric aldol reaction, Stile coupling, Yamaguchi macrolactonization, and E-selective double bond installation. Since a three-step conversion of 23 into 1 is known, the present synthesis constitutes a formal total synthesis of 1. In our effort toward the total synthesis of 1, we set known glutarimide-carboxylic acid 24 as our starting material. This compound was converted to aldehyde 30 in 6 steps via thiol esterification, TMSE protection of the nitrogen of the imide group under Mitsunobu conditions, Fukuyama reduction, Maruoka asymmetric allylation, and ozonolysis. The VMAR of 30 with 6 and subsequent protection and reductive removal of the chiral auxiliary of the resulting product 31 gave olefinic aldehyde 32. The aldehyde was subjected to asymmetric aldol reaction, reduction and Wittig olefination to furnish vinyl iodide 33 as a single isomer. After coupling of 33 with vinyl stannane 12, the resulting ester 34 was hydrolyzed and then exposed to Yamaguchi macrolactonization conditions to give 36 in moderate yield. Finally, NaIO_4-oxidation of 36 afforded key intermediate 37 bearing the complete carbon skeleton of 1, in good yield and geometrical selectivity.
