Colchicine configuration

In addition to effects on biochemical reactions, the inhibitors may influence the permeability of the various cellular membranes and through physical and chemical effects may alter the structure of other subcellular structures such as proteins, nucleic acid, and spindle fibers. Unfortunately, few definite examples can be listed. The action of colchicine and podophyllin in interfering with cell division is well known. The effect of various lactones (coumarin, parasorbic acid, and protoanemonin) on mitotic activity was discussed above. Disturbances to cytoplasmic and vacuolar structure, and the morphology of mitochondria imposed by protoanemonin, were also mentioned. Interference with protein configuration and loss of biological activity was attributed to incorporation of azetidine-2-carboxylic acid into mung bean protein in place of proline. 

Only a few unnatural (+)-colchicinoids with a clockwise arrangement of the phenyltropolone backbone have so far been reported. This includes unnatural (+)-(a/ ,7/ )-colchicine (Fig.l) and (-t-)-deacetamidocolchicine [which lacks the acetamido group of (-t-)-colchicineJ. Both compounds were crucial in determining the absolute (aS) configuration of natural (75)-colchicine. The dibromo compound 16 of the alio series, which was discussed in Section III,B, also belongs to this group of compounds. 

Deacetamidocolchicine (18) was prepared by the classic syntheses of Eschenmoser (38) and van Tamelen (39). The racemate was resolved by medium-pressure liquid chromatography on swollen, microcrystalline cellulose triacetate prepared at 5°C, and the enantiomers were collected at -70°C (32). The (-)-enantiomer with the same biaryl configuration as natural (aS,7S)-colchicine (1) was eluted first and found to be essentially optically pure. Thermal racemization of the optical isomers gave the ther-... 

M. F. Mackay, Department of Chemistry, La Trobe University, Bundoora, Victoria 3083, Australia, personal correspondence. The (a5) configuration of the phenyltro-polone helix in natural (7S)-colchicine is based on rules established by V. Prelog and G. Helmchen, Angew, Chem., Int. Ed. Engl. 21,567 (1988), and adopted by the IUPAC. 

Contrary to most allocolchicinoids which lack a C-ll substituent, compounds 78 and 80 show stable axial chirality. The above study constitutes the first example in the allocolchicinoid series where both configurations at the biaryl axis can be obtained from a given stereochemistry at C-7. In the natural alio series, free rotation around the biaryl axis is often possible at room temperature, and the configuration of the biaryl axis is controlled by the stereochemistry at C-7 due to conformational constraints in the C-ring [14]. While several total enantioselective syntheses of colchicine address the control of the stereochemistry at C-7 [106], no direct enantioselective synthesis of natural allocolchicines has been reported to date. ... 

The optical activity of colchicine is derived from the asymmetry of C7. The absolute configuration of this center is known from the work of Corrodi and Hardegger (357), who obtained W-acetyl-L-glUtamic acid (CXIV) from the strenuous oxidation of colchicine. From the correlation between the absolute configurations of L-amino acids and n-glyceralde-hyde, it is possible to relate the configuration of C7 in colchicine to that of D-glyceraldehyde. The structural work on the minor alkaloids has... 

ORD-studies conducted on colchicine derivatives, colchinols, and ]8-and y-lumicolchicine (Table II) have clarified some of the stereochemical aspects of these molecules (28). Colchinol (XIX) and its derivatives are essentially bridged and skewed biphenyls. They show a single strong negative Cotton effect at 260 mp which implies an S-configuration (XX), also indicated in the X-ray analysis of colchicine (XXI). 

The crucial test for the hypothesis lay in the examination of compounds of type 6.171) and 6.173) as colchicine precursors. In the event [119-121], 0-methylandrocymbine 6.172) was a spectacularly good precursor for colchicine. The phenethylisoquinoline 6.171), called autumnaline, was also clearly implicated in biosynthesis only the (5)-isomer of autumnaline, with the same absolute configuration as colchicine is involved, and oxidative coupling of this base occurs in a para-para sense rather than the alternative, ortho-para. Results of other experiments, together with those discussed here, led to the pathway illustrated in Scheme 6.34. 

DIAD), ttiphenylphosphine, and azide to afford the requisite amine with the correct stereochemical configuration after subsequent Staudinger reduction. Colchicine (54) was isolated after exposure of the amine to acetic anhydride in pyridine. 

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