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).

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,...

Wu beschreiben eine Synthese von 3-Methylthiod-trifluormethyl-l,2, hiszin (5) aus Trifluordibromaceton (1) und S-Methylthiosemicarbazid. Nucleophile Substitution der Thiomethylgruppe von 5 durch die Alkoxide von 6a-c bzw. durch das ~Amino-l-alkin 11 f W t m den Triazinen 7 bzw. 12, die uber eine Sauerstoff-bzw. eine NH-Briicke mit dem Seitenkettendienophil verkniipft sind Triazine mit Schwefel als Bindeglied zwischen Dien und Dienophil wie 2 h -c werden aus 1 und dem Isothiosemicarbazid-Salz 17 hergestellt. Die Triazine 7,12 und 20 reagieren beim Erhitzen in Chlorben-Zen bzw. Diphenylether zu den muen kterocyclisch anellierlen Pyridinen 8-10,13 und 23-25. Wie wir kiirzlich fanden", entstehen nach der Reaktionsfolge 1 + 2 -) 4 + 5 die konstitutionsisomeren trifluormethylsubstituierten Triazine 4 und 5 im Verhiiltnis 9 5 :~~) . F3C, /CHBrZ C II 0 **) H e m Prof. Dr. K . Dehnicke mit den besten Wiinschen zum 60. Geburtstag gewidmet. giert. Erst anschlieknd kondensiert die Ketofunktion von 2 8 B 10 Schema 2

Cycloaddition reactions of the facially dissymmetric diene moiety of (–)‐(M,7S)‐colchicine (5) and (–)‐(M,7S)‐10‐ethylthiocolchicide (9) to various alkynes have been studied. With 5 and the dienophilic benzyne (3), dimethyl acetylenedicarboxylate (DMAD) (4) and cyclooctyne (6) as starting materials all cycloadditions could be realized with high regioselectivity at the 8,12‐positions of the alkaloid. The approach of the dienophiles preferentially occurred toward the syn π‐face of the diene. In contrast to the cycloaddition mode of 5 the ethylthiocolchicide 9 surprisingly reacted in a different manner. With benzyne as starting material a novel [3+2] cycloaddition of the thioenol ether moiety of 9 towards the dipolarophilic benzyne is supposed, affording the unexpected colchicide 10 after [1,5]H shift of the primarily formed cycloadduct followed by cleavage of the C–S linkage. With DMAD (4) and cyclooctyne (6) the reaction course is more complex. In a consecutive [4+2]/[3+2] cycloaddition (or vice versa) followed by a thermally induced cycloreversion of a not identified intermediate DMAD (4) gives rise to the polycyclic thiophene derivative 13 and the novel allocolchicinoid 14. In a similar way cyclooctyne (6) yielded three products, the thiophene‐annulated homobarrelenones 18 and 19 and the tetracyclic allocolchicinoid 21. The structures of the novel colchicine derivatives were assigned on the basis of spectral data, those of the cycloadducts 1 and 19 were verified by X‐ray crystallography. For the unprecedented formation of the various allocolchicinoids by consecutive [4+2]/[3+2] cycloadditions plausible reaction pathways are suggested, as far as possible. In addition the inhibitory effects on the tubulin polymerization reaction in vitro of 10, 14, and 21 are reported.

Vinylborane des Types A e B reagieren als Dienophile gleichermaBen rnit elektronenreichen, elektronenarmen und nicht aktivierten Dienenl-'). Sie werden deswegen als "omniphil" bezeichnet7