Synthesis of vinca alkaloids and related compounds. Part LVI. 15′,20′-Anhydrovinblastine borane complex. Structural investigations using NMR methods.
✍ Scribed by Csaba Szántay; Mihály Balázs; Hedvig Bölcskei; Csaba Szántay
- Publisher
- Elsevier Science
- Year
- 1991
- Tongue
- French
- Weight
- 652 KB
- Volume
- 47
- Category
- Article
- ISSN
- 0040-4020
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✦ Synopsis
In the course of coupling catharanthine 1 to vindoline 2, the 3 borane complex of anhydrovinblastine, a new diindole derivative was isolated. The structure of this compound was studied by detailed NMR investigations. Full 1H and 13C assignments for both the 3 borane complex and anhydrovinblastine are given.
Vincristine-vinblastine type diindole alkaloids play an important role in cancer chemotherapy. The plant Catharanthus roseus contains these naturally occurring alkaloids, but only in minute concentrations. Many efforts have thus been made to synthesize diindole compounds with the right stereochemistry by coupling the appropriate units. 2 Notably, the modified Polonovski reaction resulted in diindole derivatives with the natural stereochemistry in 40-50% yield. 3 Recently Vukovic et. al. published a new and simple coupling method in aqueous medium in the presence of ferric chloride with even higher yield (77%). 4
Here we report that under slightly modified conditions of the above reaction (room temperature, lower ferric ion concentration, 1-1.2 equiv, of NaBH4) anhydrovinblastine (AVLB) 4 is prepared with at least 80% yield when coupling catharanthine 1 to vindoline 2 (Scheme). More importantly, when using extreme excess of NaBH 4, the borane complex 3 of AVLB is obtained as the final product. This compound has the advantage that it is highly stable as opposed to the AVLB base, which is known to be oxidized quickly and spontaneously by air oxygen into leurosine. 5 However, 3 could be stored at room temperature for weeks without the formation of detectable amounts of leurosine or other sideproducts (see experimental section). The AVLB borane complex 3 may also be prepared under the usual conditions of the Polonovski reaction which, depending on the amount of excess NaBH 4 used, gave either the AVLB base 4, or the borane complex 3. The latter can be easily transformed into 4 using the common procedure. 6 Refluxing 3 in methanol in the presence of Na2CO 3 gave the AVLB base 4 in quantitative yield without any measurable leurosine contamination. All this points to an obvious synthetic utility of 3, and possibly of similar analogs.
Some previous examples of similar borane complexes of "monomeric" cleavamine derivatives were reported in ref. 7 (see below). The formation of an analogous BH 3 complex of the diindol deoxyvinblastine, with a different synthetic aspect, was described in ref. 8. This paper also gives a detailed 1H NMR account of the latter BH 3 compound using decoupling methods and 2D J spectra, but leaving some ambiguities in the assignments (especially concerning assignments of a and /~ geminal proton pairs), and does not give finer stereochemical details.
Here we report full 1H and 13C assignments for both the AVLB BH 3 complex 3 and the AVLB base 4, obtained by a concerted use of 1H{llB} selective decoupling, 1H{1H} NOE difference measurements, 2D 1H-1H (COSY) and 13C-1H
(HETCOR) shift correlation methods.
Assignment of the 1H and 130 NMR spectra
Considering the expected relative basicity of the three sp 3 nitrogens in 4 (relevant pK a values for some closely related "dimers" were reported in ref. 9) it seems plausible to assume that the BH 3 complexation site involves N-4' in the cleavamine unit rather than N-4 or N-1 in the vindoline moiety. However, it is noted that: a) steric influences which may