Total Synthesis of (+)-Concanamycin F

Abstract

The concanamycin group of macrolides, first isolated from a culture of Streptomyces diastatochromogenes Sp. S45 by Kinashi and co-workers and typified by concanamycin A (1, Figure 1) [1a±d] and its aglycone, concanamycin F 2), [1e,f] exhibit potent inhibition of vacuolar (H ) ATPase activity. [2] The of a variety of sluggishly reactive and/or sparsely soluble hypervalent iodine reagents in water under neutral conditions. Further studies on the application of this system are now in progress. Experimental SectionMethod A (for primary alcohols): PhIO (0.44 mmol; Tokyo Chemical Industry Co., Ltd.) was added at room temperature to a stirred mixture of 1 (0.20 mmol) and KBr (0.04 mmol) in water (1.0 mL), and the mixture was stirred for 2 h. The resulting mixture was extracted with AcOEt, washed with brine, dried over Na 2 SO 4 , evaporated in vacuo, and the residue was purified by column chromatography (EtOAc/n-hexane) to give pure 2. Intermolecular esterification through nucleophilic attack on the initially formed aldehyde also proceeds under the conditions of Method B.Method B (for secondary alcohols): Water (2.0 mmol) was added dropwise to a stirred mixture of 1 (0.2 mmol), PhIO (0.22 mmol), and KBr (0.2 mmol). The mixture was stirred or sonicated for several hours while checking the reaction progress by gas or thin-layer chromatography. After completion, n-hexane was added to the mixture, and then filtered. Evaporation of the solvent under vacuum afforded a crude product that was further purified by column chromatography (Et 2 O/n-hexane) to give pure 2.Method C (for the oxidation with PSDIB): PSDIB (22 mmol), used without any pretreatment, was added at room temperature to a stirred suspension of 1 (20 mmol) and KBr (14 mmol) in water (40 mL), and the mixture was then sonicated for several hours. The resulting mixture was filtered and the residue containing 2 was washed with water to remove KBr, then extracted with n-hexane or MeOH, and the filtrate was evaporated to give 2. The product was purified by column chromatography, when necessary. benzaldehyde quantitatively, however, only a trace amount of 2 e was obtained even after 48 h under their reaction conditions (PSDIB in CH 2 Cl 2 ). [14] PSDIB was prepared from polystyrene standard (M w 44 000) (Aldrich) via poly(iodostyrene) (78 % iodinated) following known procedures. Elemental analysis (C 45.86, H 3.93, I 37.41) revealed the resin loading to be 2.0 mmol g À1 , which indicated that 68 % of the iodophenyl rings in the resin was converted into (diacetoxyiodo)phenyl rings: Y. Yamada, M. Okawara, Makromol. Chem. 1972, 152, 153 ± 162. [15] J. J. Parlow, B. L. Case, M. S. South, Tetrahedron 1999, 55, 6785 ± 6796.[16] Intermolecular homoesterification mainly proceeds to give Ph(CH 2 ) 3 OCO(CH 2 ) 2 Ph (51 %) in the absence of NaHCO 3 (2 k: 38 %).[17] Even after stirring PSDIB in water for 4 d, the addition of 1 e and KBr to this suspension gave 2 e in 68 % yield.[18] 2 e was obtained only in 8 % yield, when the reaction was performed with PSDIB in CH 2 Cl 2 (cont...