7. Imide Synthesis from (R)-Acid & Cyclo(-Pro-Val) (Ergovaline)

(R)-Benzyloxy-methyl-malonate ethyl ester is converted to an acid chloride and then reacted with cyclo-L-pro-L-val to give an unstable imide. The imide is an intermediate in the synthesis of ergovaline.

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Project No. 5042-32630-002-10A

Ergovaline is a common fungus that grows on rye and other grasses with an extensive history dating back centuries. It produces ergot alkaloids, which are a unique class of biological compounds consisting of a cyclic peptide bonded to lysergic acid. Some ergot alkaloids produce beneficial effects in small does, while others produce devastating effects such as necrosis and reproductive abnormalities. In particular, ergovaline is believed to be responsible for a multitude of disorders caused by ergot poisonings. A synthetic source of ergovaline is needed to monitor feedstocks and to carry out biological studies (1).

The first laboratory synthesis of ergovaline was published in 1964 by P. A. Stadler, A. J. Frey, H. Ott, and A. Hofmann working for the Swiss pharmaceutical company Sandoz (2). In 1969, Sandoz patented a general synthetic route to ergot alkaloids which involves the synthesis of a 2-benzyloxy-malonic acid monoalkyl ester to a diketo-piperazine to form a tricyclic ester that is converted to an amine by Curtius degradation and then combined with lysergic acid (3).

Forrest Smith, professor at Auburn University Harrison School of Pharmacy in Auburn, Alabama, has been the sole provider of ergovaline for the past several decades. The procedures in this video are primarily adapted from correspondence with Forrest Smith.

Chemistry Department
Eastern Kentucky University
Richmond, Kentucky 40475

References:
(1) Frontiers Media. doi 10.3389/978-2-88919-551-0
(2) Helv. Chim. Acta 47, 1911, (1964)
(3) US Patent No. 3,428,639 (1969)