Vincristine methiodide

X-Ray diffraction analyses of vincristine methiodide (39) and vinzoli-dine 1-naphthalene sulfonate (40) provide atomic coordinates of compounds that are either modified in the velbanamine portion (alkylation at N-6, Fig. 3) or in the vindoline portion (a spiro-fused oxazolidinedione at C-3 and C-23, Fig. 4). These structures show a chair-boat conformation for ring C with C-8 exhibiting an endo pucker. Ring D is clearly in a chair conformation, but, in contrast to the conclusions drawn from C-NMR studies, the N-6 -C-7 bond is axial relative to the piperidine ring. 

Fig. 3. X-Ray crystal structure of vincristine methiodide [coordinates from Moncrief and Lipscomb (39)].

Along with velbanamine (173) the reductive acid cleavage of vinblastine and vincristine gives some cleavamine (176). This latter is presumably formed by acid-catalysed elimination of water from (173). It therefore follows that in velbanamine (173) and cleavamine (176) centre 2 has the same chirality. The absolute configuration of centre 4 was determined from the previously mentioned X-ray analysis of vincristine methiodide, as well as by the reductive acid cleavage of the hydrazide (177) to velbanamine (see later). 

The structures thus elucidated have been confirmed by Z-ray analysis of vincristine methiodide ° this led also to the absolute stereochemistry of the alkaloids which is depicted in (169) and (170). As far as is known, partial syntheses of these dimeric alkaloids have not been achieved (see ref. 74). 

The X-ray crystal structure determination of vincristine methiodide dihydrate (3) defined the absolute stereochemistry of vincristine vinblastine should therefore has the above absolute structure in view of the known relationship between these two alkaloids. 

The absolute configuration of the stereo centers of vinblastine (1) was determined from the X-ray crystal structure of vincristine (2) methiodide (79,80) in view of the known relationship between 1 and 2. The absolute stereochemistry at C-I8 in vinblastine (1) and related derivatives can also be deduced by means of ORD and CD spectroscopy (81,82). The determination was made possible by the synthesis and structure elucidation of several compounds possessing the unnatural configuration at C-18 (82,84). Because this stereo center controls the relative geometry of the... 

Vincristine (leurocristine) (2) is present in C. roseus in approximately 0.0003% yield, the lowest level of any medicinally useful alkaloid produced on commercial basis. Since the initial isolation of 2 45), its structure elucidation has been reviewed 1,3). The final confirmation of structure 2 and the determination of the absolute configurations of the stereo centers of vincristine (2) were achieved by X-ray crystallography of its methiodide derivative 79,80). 

There is little mention of N-6 quatemerization reactions in the literature. N -Methylvincristine, a methiodide of 2, was prepared by reaction of vincristine (2) with iodomethane, but few experimental details are available (59). 

Moncrief JW, Lipscomb WN. Structures of leurocristine vincristine and vincaleukoblastine. 1 X-Ray analysis of leurocristine methiodide. J. Am. Chem. Soc. 1965 87 4963-4964. 

A-Ray Analysis.—The structures of the following bisindole alkaloids or bisindole alkaloid derivatives have been either determined or confirmed by X-ray analysis calycanthine (1) dihydrobromide,chimonanthine (7) dihydrobromide, hodgkinsine (20) trimethiodide, caracurine II dimethiodide (50), C-calebassine (55) di-iodide, anhydro-isocalebassine methyl ether di-iodide (64), haplo-phytine (99) dihydrobromide (absolute configuration), vincristine (170) methiodide (absolute configuration), and villalstonine (213). ... 

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