(–)-(M,7S)-Colchicine and (–)-(M,7S)-10-Ethylthiocolchicide/Alkyne Cycloaddition Reactions: Synthesis of Novel Colchicine Derivatives by Consecutive [4+2] and [3+2] Cycloadditions

Abstract

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.

Photooxygenation of the Helimers of (−)-Isocolchicine: Regio- and Facial Selectivity of the [4 + 2] Cycloaddition with Singlet Oxygen and Surprising Endoperoxide Transformations

“…1.60. 12 The predominant endoperoxide 8, obtained in sufficient amounts, was supposed to be a promising starting material in our attempts to obtain novel semisynthetic structural modifications of (-)-colchicine (1). Thus, we first tried to investigate the triethylamine-induced transformations of this intriguing tetracyclic compound.…”

“…For general procedures, see ref . Standard vacuum techniques were used in handling of air-sensitive materials.…”

β-Phenylethylamines and the isoquinoline alkaloids (July 1998 to June 1999)

“…In marked contrast, ethylthiocochicide undergoes a [3 + 2] cycloaddition of benzyne to the enol thioether system to give 212 (not isolated) which suffers hydrogen shift and cleavage of the carbon-sulfur bond to give 213. 399 Thiocolchicine has been demethylated to 214a, 214b and 214c, and of these 214a and 214b have been oxidised to the 1,4-quinone 215 and the quinomethane 216 respectively. 400 Colchicinoid and isocolchicinoid compounds react with amidines in dry benzene to give 1,3-diazazulenes, of type 217 from ring deactivated compounds such as colchicine and of type 218 from ring activated compounds such as 9-tolylsulfonylisocolchicine.…”

Design of an aryne-platform for the synthesis of non-racemic heterocyclic allocolchicinoids

“…Like its precursors 3 or 4 , the aryne 5 possesses both a center and an axis of chirality and can be considered a highly reactive chiral building block available in non-racemic form. The method proposed complements the Diels–Alder addition of benzynes to colchicines and the preparation of allocolchcines by Brecht et al 19…”

“…C, and19 F NMR spectra were recorded at r.t. in DMSO-d 6 or CD 3 OD on Bruker AV 400 and 500 instruments. Chemical shifts (δ) are reported in parts per million (ppm) from TMS using the residual solvent resonance (DMSO-d 6 : 2.50 ppm for 1 H NMR, 39.52 ppm for13 C NMR; CD Boc) 13.…”