Optically pure dihydrocolchicine‐8,12‐endoperoxide 2 is used as the starting material for the synthesis of some bioactive allocolchicinoids. Depending on the reaction conditions and reagents employed, different modifications of the C ring of colchicine (1) are achieved. Triphenylphosphane deoxygenation of 2 leads to the well known N‐acetylcolchinol O‐methyl ether (NCME, 6, 40% yield from 1). Treatment of the endoperoxide 2 with CH3OH/CH2Cl2/silica gel provides the plant alkaloid androbiphenyline (11) in a yield of 60% from 1. Triethylamine‐catalysed transformation of 2 yields (−)‐colchicine‐8,12‐dione (12) (17% yield), together with a mixture of interconverting tetracyclic hemiketals 8a and 8b. For the formation of the allo colchicinoids 6 and 11 plausible reaction pathways are suggested. In contrast to what is found in the literature, the assignment of the absolute configuration of natural (−)‐colchicine (1), and the allo‐congeners 6 and 11, should be (M,7S) or (aR,7S) instead of (aS,7S).

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Keywords: Colchicine, diene properties of / Positional selectivity / Stabilized exciplex through hydrogen bonding / 71-Facial diastereoselectivity / Photooxygenation / Solvent effects / CycloadditionsPositional and facial selectivity in Diels-Alder reactions of several hetero-and carbodienophiles with (-)-(aS,7S)-colchicine (1) has been examined. In all cases, cycloaddition occurred with high positional selectivity at the 8,12-positions of the alkaloid and preferentially from the diene face syn to the allylic substituent at the stereogenic center C-7. The observed high rr-facial diastereoselectivity is independent of the polarity of the solvent used and is therefore probably a consequence of steric factors. The structures of the Diels Alderadducts of 1 with singlet oxygen, N-phenyl-l,2,4-triazolinedione (PTAD) and trans-cyclooctene, 4 3 , and 15, respectively, were assigned on the basis of spectral data and verified by X-ray crystallography.Natural (-)-(aS,7S)-colchicine (1)['1, the major alkaloid isolated from Colclzicurn uutunznale L. (Liliaceae), is an old drug, medicinally used for the treatment of gout. It is best known for its antimitotic effects, but also shows antitumor activity and anti-inflammatory properties, is useful in the treatment of familial Mediterranean fever and shows some beneficial effects in combating liver cirrhosis. Because the toxicity of the alkaloid has limited its use. several research groups, attracted by its unique modes of action, have devoted their efforts to the synthesis of new derivatives with improved pharmacological profiles, especially with enhanced antitumor properties. Thus, during the last 15 years numerous analogues of colchicine have been synthesized in the hope of developing novel, useful drugs with more favourable pharmacological profilesr2-'I.Recent findings concerning the structure of colchicine (1) have revealed that the tropolonic ring C and the benzenoid ring A (see Scheme 1) are twisted out of the plane, being arranged in a counter-clockwise helicity, which implies an (aS) absolute configuration [']. In addition, ring C is characterized by two facially differentiated 1,3-diene moieties, most suitable for hitherto unknown [4 + 21 cycloaddition reactions of the alkaloid['2]. Because the regiochemistry of a cycloaddition reaction may be controlled by the steric demand and electronic nature of the sub~tituents["~'~] attached to the two diene systems in the tropolonic ring Cthe 10,12-and 8,12a-diene moieties -one cannot predict which of the two 4n-systems will react preferentially with an appropriate dienophile X = X in a HOMOdi,,,/ LUMOd,enoph,le controlled Diels-Alder reaction, to furnish products of type l a , b and/or l c , d["].Secondly, the topography (endo or e m selectivity) of the cycloaddition is of interest because it may be mainly dependent on the electronic nature of the groups attached to the dienophile. In addition, colchicine is an enantiomerically pure substance with a single stereogenic center at C-7 in an allylic position of the 8,12a-diene moiety,...

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Photooxygenation of the helimeric mixture of (-)-(M,7S)/(P,7S)-isocolchicine (6) with the superdienophile singlet oxygen has been studied. Cycloaddition occurred with high regioselectivity at the 7a,11-positions of the alkaloid and predominantly at the diene face anti to the amidic substituent at the stereogenic center C-7, leading to two endoperoxides 7 (syn) and 8 (anti) with an 1:7 ratio. The structure of the minor product 7 was established by X-ray analysis. Investigation of the triethylamine induced transformation of the predominant endoperoxide 8 furnished a mixture of two isomers (M,7S)-10a/(M,7S)-10b in a 2:1 ratio possibly with constitutional interconversion and with (M,7S)-9 as plausible intermediate. Treatment of this mixture with silica gel/ethyl acetate at ambient temperature surprisingly led to an atropenantiomerically pure colchicinoid (M,7S)-12 characterized by an eightmembered oxocine B-ring, the structure and absolute configuration of which could be determined by X-ray analysis. For the unprecedented formation of the novel colchicinoid (M,7S)-12 a plausible reaction pathway is suggested, involving a complete transfer of the (M) helical asymmetry of the intermediate (M)-11 into (S) asymmetry of the newly formed carbon center of (M,7S)-12. Prerequisite for such a scenario is the configurational stability of the intermediate pseudobiaryl (M)-11, under the conditions employed, allowing to transmit the axial chirality onto the chiral center of the product (M,7S)-12.