25,37 synthesis Ergotamine

Acyl azides may loose N2 on heating and rearrange to isocyanates (Curtius rearrangement), which may be solvolyzed. Some of the possibilities of classical carboxyl conversions are exemplified in the schemes below, which are taken from a triquinacene synthesis (R. Russo, 1971 C. Merder, 1973) and the ergotamine synthesis of A. Hofmann (1963). 

There are currently two medicinally valuable alkaloids of commercial import obtained from ergot. Commercial production involves generation parasiticaHy on rye in the field or production in culture because a commercially useful synthesis is unavailable. The common technique today (65) is to grow the fungus in submerged culture. Clavicepspaspali (Stevens and Hall) is said to be more productive than C. purpurea (Fries). In this way, ergotamine (100,... 

Ergotamine Ergotamine, 3, 6, 18 -trione,12 -hydroxy-2 -methyl-5 -benzyl-(5 a)-ergota-mine (12.2.14), is obtained via microbiological synthesis [52]. 

Since the publication of the synthesis of ergotamine (34) all naturally occurring peptide alkaloids have been synthesized by analogous routes. Moreover, it has been shown that they all have the same stereochemistry and differ from each other only in their L-amino acid units and the chain length of the a-hydroxy-a-amino acid moiety at the peptidic site. An X-ray study of a key intermediate has provided additional evidence for the correctness of the proposed absolute configuration of ergotamine (34a). 

The total synthesis of ergotamine (34) opened new possibilities for the preparation of new stereoisomers. Theoretically, almost every isomer now became accessible. 

Finally, two synthetic peptide-type alkaloids may be briefly mentioned in this chapter since both show promising pharmacological activities. Replacing L-phenylalanine in the peptide part of ergotamine by a-methylalanine, a new peptide alkaloid (75) called 5 -methyl-ergoalanine was obtained in analogy to the synthesis of ergotamine... 

Protoplasts of C. purpurea have been prepared which are able to synthesize the peptidic ergot alkaloids ergotamine (69) and ergocryptine de novo.63 Various radioactive amino-acids were incorporated into the alkaloids, and D-lysergic acid (70) stimulated their utilization. It was the only precursor to stimulate the synthesis of alkaloids, and the proposal was made that the concentration of (70) in the cells is a rate-limiting factor in alkaloid synthesis. 

With the preparation of pure ergotamine, chemical research on ergot also entered a new phase so that, after many decades, it finally became possible to elucidate the structure of the ergot alkaloids and to achieve their total synthesis. This will be shown in the remainder of this chapter. 

Owing to the complete elucidation of the constitution of the compounds obtained by total reduction with LiAlH4 and by thermocleavage, it was possible to propose structural formulas for the peptide alkaloids as early as 1951 (89). These formulas were confirmed by total synthesis of ergotamine after a further 10 years of intensive laboratory research (92). 

Conversion of isomer Lilia with lysergic acid chloride hydrochloride (IVa) in chloroform, with the addition of tributylamine, yielded a compound whose chemical, physical, and pharmacological properties were identical with those of the natural alkaloid ergotamine. Thus, the total synthesis of this alkaloid was accomplished, lysergic acid having already been synthesized at an earlier date (50). 

Scheme 43. Total synthesis of ergotamine by Hofmann and co-workers (209).

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