Positional and Facial Selectivity in Diels‐Alder Reactions of (−)‐(aS,7S)‐Colchicine: Synthesis of Novel Analogues of the Alkaloid

Abstract

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,...

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 .…”

Reactions of hexadehydro-Diels–Alder benzynes with structurally complex multifunctional natural products

“…5). Colchicine ( 42 ) is known to undergo [4+2] cycloaddition reactions with many dienophiles across the 1,3-diene subunit terminated by carbons C8 and C12 2,28 . However, when heated in the presence of the HDDA substrate 6 , colchicine (1.5 equiv) was engaged by benzyne 8 in a new type of tropolone cycloaddition, giving rise to the benzofuran derivative 45 in good yield (59%, Fig.…”

Nitroso Diels–Alder (NDA) reaction as an efficient tool for the functionalization of diene-containing natural products

“…The regio- and stereoselectivity of the reaction was consistent with previous studies on the cycloaddition of thebaine with symmetrical dienophiles. 86 The biological activity of cycloadduct 29 was not investigated.…”

“…153 Several modifications of the structure of colchicine and isocolchicine (the inactive analog) have been performed, in order to obtain potential new drugs with a more favorable biological profile. 154 Ring C is characterized by two facially differentiated diene moieties and this characteristic has been used to functionalize the molecule at this position through Diels-Alder reactions. Reactions with several hetero- and carbo-dienophiles has been reported 154b but the biological activity of the resulting cycloadducts was not investigated.…”

“…154c Aryl-, acyl- and pyridylnitroso compounds were used as the dienophiles but only the pyridylnitroso compounds afforded optimal results, because of their ideal combination of stability and reactivity ( Table 7 ).…”