Colchicine, Eschenmosers synthesis

In the post-World War II years, synthesis attained a different level of sophistication partly as a result of the confluence of five stimuli (1) the formulation of detailed electronic mechanisms for the fundamental organic reactions, (2) the introduction of conformational analysis of organic structures and transition states based on stereochemical principles, (3) the development of spectroscopic and other physical methods for structural analysis, (4) the use of chromatographic methods of analysis and separation, and (5) the discovery and application of new selective chemical reagents. As a result, the period 1945 to 1960 encompassed the synthesis of such complex molecules as vitamin A (O. Isler, 1949), cortisone (R. Woodward, R. Robinson, 1951), strychnine (R. Woodward, 1954), cedrol (G. Stork, 1955), morphine (M. Gates, 1956), reserpine (R. Woodward, 1956), penicillin V (J. Sheehan, 1957), colchicine (A. Eschenmoser, 1959), and chlorophyll (R. Woodward, 1960) (page 5). ... 

Schreiber, J., Leimgruber, W., Pesaro, M., Schudel, R, Eschenmoser, A. (1961) Synthesis of Colchicine. Helvetica Chimica Acta, 44, 540-597. 

In one phase of Eschenmoser s synthesis of colchicine,a Diels-Alder addition of the pyrone derivative (1) with chloromethylmaleic anhydride gave the adduct... 

The coumarin (459), an intermediate in Eschenmoser s synthesis of colchicine (A. Eschenmoser et al., Helv.Chim.Acta,... 

The second example presented here is colchicine, the alkaloid of the meadow saffron (autumn crocus). The structure elucidation of this compound took decades, until a crystal structure analysis unveiled the presence of a tropolone ring [12]. The accumulated knowledge about tropolones at that time offered no hint as to how to approach an anellated tropolone unit such as is present in colchicine. The first synthesis of colchicine by Eschenmoser [13, 14] had to chart new territory. 

This first synthesis of colchicine hy Eschenmoser was followed by 14 further syntheses, which have been comprehensively discussed recently [15]. Four of these syntheses, those by Woodward (Scheme 11.12) [16], Evans (Scheme 11.13) [17], Schmalz (Scheme 11.14) [15, 18, 19], and by Cha (Scheme 11.15) [20] will be presented below. The syntheses by Woodward, Evans, and Schmalz likewise do not offer a solution to the regioselectivity problem associated with colchiceine. That was finally attained by the synthesis of Cha, which is compromised, however, by a protecting group dance from Boc to acetyl and back to Boc at the amino group. 

Michael addition with methyl propiolate led in this case directly to the tricyclic a-pyrone 84, which is a central intermediate in Eschenmoser s colchicine synthesis [35]. 

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