Vinblastine ether

Transformations of the dimeric alkaloid vinblastine (46) by Streptomyces species have been reported which involve N-demethylation (51), aromatic hydroxylation (55), and intramolecular ether formation (53). With Streptomyces albogriseolus, N-demethylation occurs in an undisclosed yield to produce 47 (51). The same organism in the hands of the same workers is also reported to lead to the formation of vinblastine ether (50) in low yield, along... 

Scheme 14. The structures of vindoline (46) and derivatives, vinblastine and vincristine (52 and 53), and dihydrovindoline ether (54).

About 10 g of VLB (vincaleucoblastine or simply vinblastine) sulfate were converted by standard procedures to VLB free base. The free base, obtained as a residue after evaporation of the dried ethereal solvent, was dissolved in about 200 ml of anhydrous methanol. Anhydrous liquid ammonia (300 ml) was added, and the reaction mixture sealed and maintained at about 100°C for 60 hours. The reaction vessel was opened, and the contents removed and evaporated to dryness in vacuo. The resulting residue, containing 4-desacetyI VLB C-3 carboxamide, as shown by thin layer chromatography, were combined and the solvent evaporated therefrom in vacuo, yielding asa residue purified 4-desacetyl VLB C-3 carboxamide free base. The NMR and IR spectra of the solid free base confirmed the structure indicated. The free base showed a band in the infrared at 1,687 cm-1, characteristic of the amide function. The molecular weight of the free base determined by mass spectroscopy was 753 which is in agreement with theoretical value calculated for C43H55N5O7. 

One part of vinblastine sulfate is soluble in 10 parts of water in 50 parts of chloroform very slightly soluble in ethanol (96%) practically insoluble in ether (6). 

Scheme 13 5. Additional work along to path to building the catharanthine-Uke piece of (+)-vinblastine. After Yokoshima, S. Ueda, T. Kobayashi, S. Sato, A. Kuboyama, T. Tokuyama, H. Fukuyama,T. Pure Appl. Chem., 2003,75,29. OTBDPS = f-butyldiphenylsilyl ether TESO = triethylsilyl ether OTMS = trimethylsilyl ether OTHP = tetrahydropyranyl acetal OTES = triethylsilyl ether.

A transannular 4 + 2-cycloaddition initiates the tandem 4 + 2/3+2-cycloaddion cascade of 1,3,4-oxadiazoles (1) to yield cycloadduct intermediates (2) used for the synthesis of analogues of vinblastine (Scheme 1)." The multi-component 4+ 2/3+2-domino cycloaddition reactions of 3-nitroindole derivatives with vinyl ethers and acrylates were studied computationally and experimentally. The 4+2-reaction follows a classical concerted asynchronous process while the 3 + 2-addition involves an electron donation by an electron-deficient reaction partner. ... 

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