ePrints

Total Synthesis of 8-Hydroxy-dihydroergotamine, the Major Human Metabolite of Dihydroergotamine

Lookup NU author(s): Dr Manuel Monerris Mascaro, Dr Alistair Henderson, Dr Marta Drozdowska, Dr Michael HallORCiD, Alexandra Longcake, Lina Mardiana, Emeritus Professor Bernard Golding

Downloads

• Published version [.pdf]

Licence

This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2026 by the authors. 8-Hydroxy-dihydroergotamine is the major human metabolite of the anti-migraine drug dihydroergotamine and is required, along with a stable isotope-labelled derivative, to aid metabolic studies. An efficient, scalable synthesis of the unlabelled compound is described via the coupling of dihydrolysergic acid to the tricyclic amino compound (2R,5S,8R,10aS,10bS)-2-amino-5-benzyl-10b-hydroxy-8-methoxy-2-methyltetrahydro-8H-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazine-3,6(2H,5H)-dione. The tricycle was obtained by a convergent synthesis combining precursors from suitably protected L-glutamic acid and L-phenylalanine, and 2-bromo-2-methylmalonic acid. For the labelled molecule, the tricyclic precursor contained a pentadeutero benzyl group derived from [2,3,4,5,6-2H5]L-phenylalanine. Considerable experimentation was required to achieve optimal activation of dihydrolysergic acid for efficient amide formation with the tricycle’s amino function affording 8-methoxy-dihydroergotamine. The stereochemical integrity of an intermediate in this synthesis, ethyl (2R,5S,8R,10aS)-5-benzyl-10b-hydroxy-8-methoxy-2-methyl-3,6-dioxooctahydro-8H-oxazolo[3,2-a]pyrrolo[2,1-c]pyrazine-2-carboxylate, was validated by crystal structure analysis. Acid-catalysed hydrolysis of 8-methoxy-dihydroergotamine gave 8-hydroxy-dihydroergotamine. Pentadeuterated 8-hydroxy-dihydroergotamine was obtained in an analogous manner from [2,3,4,5,6-2H5]L-phenylalanine. Both 8-hydroxy-dihydroergotamine and its 2H5-derivative were obtained as an equilibrating mixture of C-8 epimers (diastereomers), with the major isomer having (R)-configuration according to 1H NMR analysis. The syntheses described enable the routine synthesis of 50–100 mg quantities of each target molecule.

Publication metadata

Author(s): Monerris Mascaro M, Henderson AP, Drozdowska M, Richardson R, Nagel-Savage D, Hall MJ, Longcake A, Mardiana L, Golding BT

Publication type: Article

Publication status: Published

Journal: Molecules

Year: 2026

Volume: 31

Issue: 9

Online publication date: 06/05/2026

Acceptance date: 23/04/2026

Date deposited: 26/05/2026

ISSN (electronic): 1420-3049

Publisher: MDPI

URL: https://doi.org/10.3390/molecules31091547

DOI: 10.3390/molecules31091547

Data Access Statement: The original contributions presented in this study are included in the article and Supplementary Materials. Further inquiries can be directed to the corresponding author.

PubMed id: 42123908

Altmetrics

Funding

Share