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.

Access to Skipped Polyene Macrolides through Ring‐Closing Metathesis: Total Synthesis of the RNA Polymerase Inhibitor Ripostatin B

“…By using Jones oxidation conditions (excess Jones-reagent diluted in acetone, 0 8C) [38] the TBS ether on the primary alcohol of 24 was cleaved and effected rapid oxidation to the carboxylic acid in 70-85 % yield, thereby avoiding doublebond isomerization and decomposition observed upon isolation of aldehyde intermediates (e.g., TEMPO-based oxidations). The C11 TBS ether was removed by using HF•py (76 %), and finally selective reductive cleavage of the propionate ester [39] in presence of the a,b-unsaturated lactone and the carboxylic acid moiety afforded ripostatin B (1) in 42 % yield (68 % based on unreacted starting material). The spectroscopic data including the optical rotation ( a ½ 20 D ¼ + 26 (c = 5, MeOH), published + 35.7 (c = 1, MeOH)) was in good [40] agreement with that reported in the literature.…”

Access to Skipped Polyene Macrolides through Ring‐Closing Metathesis: Total Synthesis of the RNA Polymerase Inhibitor Ripostatin B

“…By using Jones oxidation conditions (excess Jones‐reagent diluted in acetone, 0 °C)38 the TBS ether on the primary alcohol of 24 was cleaved and effected rapid oxidation to the carboxylic acid in 70–85 % yield, thereby avoiding double‐bond isomerization and decomposition observed upon isolation of aldehyde intermediates (e.g., TEMPO‐based oxidations). The C11 TBS ether was removed by using HF⋅py (76 %), and finally selective reductive cleavage of the propionate ester39 in presence of the α,β‐unsaturated lactone and the carboxylic acid moiety afforded ripostatin B ( 1 ) in 42 % yield (68 % based on unreacted starting material). The spectroscopic data including the optical rotation (${\left[ \alpha \right]_{\rm{D}}^{20} = }$ +26 ( c =5, MeOH), published +35.7 ( c =1, MeOH)) was in good40 agreement with that reported in the literature.…”

Functionality Propagation by Alkylative Oxidation of Cross‐Conjugated Cycloheptadienyl Sulfones

“…Concanamycin F ( 49 ) has been synthesized by the groups of Paterson in 2000 and Toshima in 2001 in 44 and 53 steps, respectively 28. 29…”