Dihydrocolchicine 8,12‐Endoperoxide: A Novel Starting Material for Convenient Syntheses of the Allocolchicinoids N‐Acetylcolchinol O‐Methyl Ether and Androbiphenyline

Abstract

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).

Asymmetric synthesis of the allocolchicinoid natural product N-acetylcolchinol methyl ether (suhailamine), solid state and solution phase conformational analysis

“…When our sample of NCME (21) was recorded in CDCl3, a 69:24:7 ratio of three species, 21a:21b:21c was observed. The 1 H and 13 C NMR spectroscopic data for two of these species matched with those reported by Brecht et al (71:29, 21a:21b) 22 and all three of those reported by Takubo [α −88.6 (c 0.67, MeOH)}.…”

“…21 As expected, the 1 H and 13 C NMR spectroscopic data recorded for the sample of NCME (21) prepared in this study using DMSO-d6 as the solvent matched well with these other, previously reported data. A smaller number of synthetic samples of NCME have 1 H and 13 C NMR spectroscopic data using CDCl3 as the solvent: Brecht et al 22 reported a 71:29 ratio of species for NCME in CDCl3, whilst Takubo et al 23 reported a 65:25:10 ratio of species. When our sample of NCME (21) was recorded in CDCl3, a 69:24:7 ratio of three species, 21a:21b:21c was observed.…”

“…(2) The 1 H and 13 C NMR spectroscopic data of the natural allocolchicinoid that has been dubbed suhailamine were acquired using CDCl3 as the solvent. 2 Comparison of the data sets of Brecht et al 22…”

Synthesis of Cyclic Peroxides

“…These, and additional results from experiments with carbonyl, cyclic ketal and thioketal derivatives were attributed to electrostatic interaction between approaching singlet oxygen and the heteroatom 416,417 . Similar electronic effects were observed in studies on singlet oxygen [4 + 2]-cycloaddition to the naturally occurring alkaloid (−)-colchicine 418,419 , but the opposite facial selectivity was reported for the isomeric (−)-isocolchicine 420 .…”

The Photochemical Behavior of Colchicone and Thiocolchicone

“…From the chemical point of view, the methyl tropolone ring is the most intriguing portion of the molecule, on which a large number of reactions can be performed, such as facile acid and alkaline hydrolysis (4), benzylic acid rearrangement (5), ipso-and telenucleophilic substitutions (6,7), Diels-Alder cycloadditions with several hetero-and carbodienophiles (8), singlet oxygen addition (9) and photochemical rear-*To whom correspondence should be addressed at: Dipartimento di Chimica, Universitá della Basilicata, Via N. Sauro 85, 85100 Potenza, Italy. Fax: ϩ39 0971 202223; e-mail: dauria@unibas.it rangement (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25).…”