抄録
(-)-Lemonomycin (1) belongs to a large family of tetrahydroisoquinoline (THIQ) alkaloids, and was isolated from fermentation broth of Streptomyces candidus (LL-AP191) in 1964. In 2000, researchers at Wyeth-Ayerst discovered that 1 shows antibacterial activity against MRSA and VREF. The compound features a tetracyclic ring system including a 3,8-diazabicyclo[3.2.1]octane core, which is typical of quinocarcin alkaloids. Moreover, 1 contains a 2,6-dideoxy-4-amino sugar (lemonose) that is rare in nature. Herein, we present the enantioselective total synthesis of 1. The preparation of aglycon 18 was started from glycine derivative 8 having Oppolzer's chiral auxiliary. The synthesis of 9 was achieved via Perkin-type condensation reaction. We then focused on the construction of the bicyclo[3.2.1]octane ring system. Upon treatment of 10 with TFA, generation of the conjugated acyliminium cation and subsequent intramolecular attack of the allylsilane proceeded immediately to provide 11 with complete stereoselectivity. Stereoselective formation of B ring was achieved via thermodynamically controlled Pictet-Spengler reaction. The equilibrium presumably occurs via acid-induced ring-opening reaction to form a quinonemethide intermediate 17. Upon treatment of 18 and glycosyl fluoride 22 with TMSOTf, the desired glycosidation proceeded smoothly to give 23 with good stereoselectivity despite the presence of the tertiary amine as well as the amino nitrile functional group. Finally, further transformations of 23 eventually furnished (-)-lemonomycin (1).
