Colchicine synthesis step

Electrocyclic closure of butadiene units encased within cycloheptane rings has been used to obtain bicyclo[3.2.0]heptene systems (Scheme 5)12. For example, irradiation of eucarvone 21 led to the formation of adduct 22 in 52% yield via a disrotatory ring closure123. This adduct was used as a key intermediate in the synthesis of the pheromone grandisol, 23, which proceeded in 20% overall yield from 22. In their synthesis of a-lumicolchicine. Chapman and coworkers utilized a photochemically initiated four-electron disrotatory photocyclization of colchicine to produce /Murnicolchicine 24a and its /-isomer 24b in a 2 1 ratio12b. These adducts were then converted, in a second photochemical step, to the anti head-to-head dimer a-lumicolchicine 25. 

Deacetamidocolchicine (18) has served as a key intermediate in several formal total syntheses of colchicine (1) (/). It has to be realized, however, that several additional steps are required for completing the synthesis of 1 from 18 the introduction of an amino group at C-7, the... 

A recent synthesis of colchicine (84) featured the divinylcyclopropane rearrangement as a key step. In a model study, cyclopropane 82 in refluxing xylene gave cycloheptadiene 83 in 93% yield. 3... 

Cyclopropanation.1 The key step in a biomimctic synthesis of (i)-colchicine (4) is a regio- and stereoselective reaction of the tricyclic I, prepared in several steps from 5-bromo-2-methoxyphenol, with dimethylsulfoxonium methylide to give a single product (2) in 75% yield. When treated with trifluoroacclic acid at 25°, this product rearranges in 89% yield to the a-tropolone O-methyl ether 3. This product is converted into ( )-co chicine (4) in four known steps. 

Cha has used this strategy for the synthesis of tropoloisoquinolines <01JA3243> and colchicines <98JOC2804 00T10175> with the conversion of 270 to 271 as the key step. Wright used an intermolecular addition to annulated furan 272 <990L1535> to give 273, an... 

A new synthesis of ( )-colchicine (138 R = Me) has been reported using an elegant methylene-transfer reaction as the key step (Scheme Reduction... 

The elegant synthesis by Woodward 50) is a complete departure from other approaches, since it begins with the construction of an auxiliary ring (representing carbon atoms 6, 7, 7a, 8, 12a, and the nitrogen atom of the future colchicine molecule) upon which the entire structure of colchicine is built. The nitrogen atom is masked in the stable isothiazole system until it is released in the final step. Simple isothiazoles were previously unknown. In the course of this synthesis much was discovered about the chemistry of these interesting compounds. 

Imembrine, a tropolone natural product related to colchicine was also synthesized via an oxazole-acetylene Diels-Alder reaction followed by a [4 -H 3]-oxyallyl cycloaddition.Here, 8-iodo-5,6,7-trimethoxyisoquinoline 269 was converted to 5-substituted oxazole 270 in four steps and 42% overall yield (Fig. 3.81). Thermolysis of 270 in refluxing o-dichlorobenzene effected the desired intramolecular Diels-Alder cycloaddition with concomitant loss of the Boc-protecting group to afford the tetracyclic furan 271 in 90% yield. At this point, 271 was subjected to the [4 + 3] cycloaddition in the presence of l,3,3-trichloro-2-propanone and 2,2,2-trifluoroethanol. Subsequent dechlorination of the intermediate (not shown) with zinc provided the oxabicyclic 272 as a single regioisomer in 73% yield. The synthesis of imembrine was completed in three steps from 272. 

In the following section, Banwell s synthesis of colchicine is discussed in detail [160]. The route features a biomi-metic ring enlargement as key step. The ring system is elaborated via an oxidative coupling approach. Key steps of other approaches that utilize oxidative coupling reactions for the elaboration of the colchicine ring system are briefly outlined. 

SCHEME 12.48 Key steps in Tobinaga s and Evans synthesis of colchicine derivatives. 

Chloromethylcyclohexadiene derivative dissolved in abs. benzene, which is then partly distilled off, cooled, a 0.6 N soln. of K in cr -butanol added, and stirred 2% hrs. at room temp, under Ng cycloheptatriene derivative. Y 92.5%.— This is one step of the total synthesis of colchicine. J. Schreiber et al., Helv. 44, 540 (1961). 

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