Ergotamine, structure

Such a cyclol structure is a part of the ergotamine structure.211,212 Compound 185 has been isolated213 from a fermentation residue. 

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). 

Hydrogenation of the double bond in position 9-10 of the lysergic acid moiety results in fundamental changes in the pharmacodynamic action, as a comparison of the activity spectra of ergotamine (Fig. 7a) and dihydroergotamine (Fig. 7c) makes evident. The vasoconstrictor and uterotonic effects of the dihydrogenated derivative have been markedly attenuated, as has the stimulation of central structures, so that these effects are hardly elicited by therapeutic doses. On the other hand the adrenolytic effect and the central inhibition of the vasomotor centers are markedly enhanced. This is manifested clinically in vasodilatation, hypotension, and a certain sedative action. 

Ergotamine. LSA indicates the lysergic acid moiety. The dashed line indicates that the cleavage takes place between the a-nitrogen atom and the a-carbon atom of the amino acid involved, namely a-hydroxyalanine. This results in a pyruvoyl precursor of phenylalanine-proline lactam which can have structure 2 or 3. Structure 3 is that of pynoergotamine, a reference sample of which showed the same GC and MS behaviour as the above pyruvoyl precursor. However, this does not preclude structure 2 (which is more stable) for this precursor, but for which no reference sample was available. Structure 4 is the phenylalanine-proline lactam, which is obtained in two forms, namely L-phe-D-pro lactam and L-phe-L-pro lactam. 

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