Vindolinine

Catharanthus roseus (L.) G. Don Chang Chun Hua (Madagascar periwinkle) (whole plant) Vinblastine, vincristine, carosine, vinrosidine, lenrosine, lenrosivine, rovidine, perivine, perividine, vindolinine, pericalline.33 This herb is toxic. Anticancer in chronic lymphocytic leukemia and Hodgkin s disease, in acute lymphocytic leukemia. 

The endocyclic homoallyl effect (see C(21) in 1437] and 14381) is not noted on changing structure from vindolinine [439] to 14,15-dihydro-vindolinine [(5 C(21) in vindoline 78-0, 8 C(21) in dihydrovindolinine 78-8]. In addition the C(3) and C(21) shifts in vindolinine are abnormal and this has been attributed to the strain induced by the presence of the norbornane moiety. Comparison of the C(2) and C(20) shifts in vindolinine with those in venalstonine [440] shows the deshielding of ca. 

The spin-lattice relaxation times of essentially all the protons in vindoline, measured by a Fourier transform method, show values reflecting the degree of steric interaction with other protons. (276) A wealth of coupling constant data has been made available by first order analysis of the 300 MHz NMR spectrum of vindolinine [458]. (277) H NMR shifts for the metabolite of vindoline [459] (278) are shown on the structure. 

In the H NMR spectrum of haplophytine 1454] the C(16) methoxyl group protons absorb at unusually low frequency (8 3-00) and the 11 -protons at 8 6-27. The 11 -proton is shielded by the aspidophytine aromatic ring and the 16-methoxyl protons by the haplophytine aromatic ring in the preferred conformation of the molecule. (273) Additional examples of variations in H NMR parameters with stereochemistry are provided by the spectra of the compounds [460]-[468]. In the vindolinine derivatives [460]—[463] (279) the pair of compounds [460] and [461] show the influence of the aromatic ring on... 

The structure of 14, 15 -dihydropycnanthine has been revised to [533] from a comparison of its 13C NMR spectrum with that of villalstonine [530] and of vindolinine [439]. That [533] belongs to the 19 S series is shown by the similarity of its 18 -proton and carbon parameters to those in 19 -epivindolinine [534] (compare values in vindolinine [535]). The similarity of C(21 ) shifts in 19 -epivindolinine and in 14, 15 -dihydropycnanthine shows the absence of the endocyclic homoallyl effect. (319)... 

Details of the X-ray crystal structure determination of vindolinine hemihydro-chloride hemiperchlorate have now been published.116... 

Yet another rearrangement of a tabersonine derivative has been reported. 19-Iodotabersonine (202), prepared from vindolinine, when heated with diazabi-cycloundecene in DMSO, gives mainly the expected A18-tabersonine, together with the cyclobutane derivative (203) and an optically inactive non-basic indole derivative, for which the structure (204) has been proposed.118 A much-improved yield of (204) (78%) can be obtained if the reaction is conducted in DMF in the presence of sodium acetate. One of the possible mechanisms for the formation of (204) is illustrated if correct, this requires the presence of water in the reaction mixture. 

The structure of baloxine (236) has been confirmed by partial synthesis from vindolinine,110 which has previously been converted into 19-hydroxytabersonine (237). The tetrahydropyranyl ether (238) of the (19.S)-epimer, on hydroboration-oxidation, gave a mixture of C-14 epimeric alcohols (239) on oxidation and removal of the tetrahydropyranyl ether grouping, these gave baloxine (236) (Scheme 34). Its formulation as (19S)-hydroxy-14-oxovincadifformine is thus confirmed. 

The alkaloids isolated from V. rosea are listed in Table I the well-known yohimbinoid bases, including lochneridine (I) and lochnericine, will not be discussed catharanthine (II) and lochnerine (O-methyl-sarpagine) belong to the iboga and ajmaline-sarpagine chapters, respectively. And vindoline (III) and vindolinine (IV) are special cases of... 

Cylindrocarpine, LXXV Vindoline, CIII Dihydrovindoline, CXI 16-Methoxy-.Va-methyl-4-oxoaspido-spermidine, CV Vindolinine, CVI... 

Examination of the mass spectrum (Table V, 7) showed that the correct molecular formula was C21H24N2O2, excluding a C20 akuam-micine-like skeleton, and peaks at m/e 92, 107, and 135 were similar to those encountered in vindolinine (CVI, 3) which has an aspidospermine-like skeleton with 6,7-double bond. The presence of such a nonconjugated double bond had already been shown by catalytic hydrogenation to 6,7-dihydrotabersonine (XCIII, an optically active form of vincadiffor-mine which has identical IR-, NMR-, and mass spectra) in which the UV-spectrum remained similar to that of the parent alkaloid (64, 7). Moreover, the NMR-spectrum of tabersonine (XCII) showed a peak due to two vinyl protons which disappeared in the dihydro derivative... 

A number of alkaloids with the aspidospermine skeleton occur in the genus Vinca and are dealt with in detail in Chapter 12. They include the very important base vindoline (CIII) which not only occurs as the free base in Vinca rosea (= Lochnera rosea = Catharanthus roseus) but also as part of the dimeric alkaloids vinblastine (vincaleucoblastine) and leurosine, whereas the Aa-formyl analog, CIV, forms part of the dimeric alkaloid leurocristine (5, 72a). These dimeric alkaloids have been used successfully for the treatment of certain forms of cancer in man (5). Vindolinine (CVI) has also been isolated from V. rosea and its dihydro-decarbomethoxy derivative, tuboxenin (CVI-A), which is the parent member of the series, occurs in a Pleiocarpa species (53). ( + )-Vincadif-formine (XCIII, 6, 74) has already been mentioned as the racemic form of (— )-6,7-dihydrotabersonine (Section II, O). It has been found in V. difformis and in Rhazya stricta (51b) where the (+) form also occurs. 

The presence of an additional ring connected to the tryptamine bridge changes the aspidospermidine fragmentation pattern drastically, as was demonstrated for kopsine142 and vindolinine.143,144... 

This knowledge of the fragmentation pattern of vindolinine enabled the structure determination of the related alkaloid tuboxenine.145... 

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