An Approach to the Synthesis of Aspergillic Acid

Ramsay, David W. C (1951) An Approach to the Synthesis of Aspergillic Acid. PhD thesis, University of Glasgow.

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Aspergillic acid, the antibiotic isolated from cultures of the mould Aspergillus flavus, was shown by Dutcher end Wintersteiner to have structure (I) or (IA). Later, Dunn, Newbold and Spring identified the side-chains and showed that aspergillic acid must be either (I; R= Bus, R' = Bui) or (I; R = Bui, R' = Bus). The investigations described in this Thesis were directed towards establishing methods for the synthesis of pyrazine cyclic hydroxamic acids with the synthesis of aspergillic acid as the ultimate objective. Reduction of aspergillic acid gives deoxyaspergillic acid (II), a 2-hydroxy-3:6-disubstituted pyrazine. Thus it appeared possible that oxidation of a suitably substituted pyrazine would lead to a synthesis of aspergillic acid. This route was shown to be impracticable by Baxter, Newbold and Spring who found that when a 2-ethoxy-3:6-disubstituted pyrazine was oxidised, oxidation occurred at the nitrogen remote from the ethoxy group and hence hydrolysis to give a hydroxyl group in the 2-position gave a compound which was not a hydroxamic acid. Although the direct oxidation method had proved unsuccessful for a synthesis of aspergillic acid there was a possibility that it could be used to prepare a pyrazine cyclic hydroxamic acid by the following route:- The oxide (IV) was obtained in low yield. The scheme however, had to be abandoned when difficulty was experienced in hydrolysing the nitrile groups of the oxide as a preliminary to the formation of the required hydroxyl groups. An account is given of the experiments with aminoiminosuecinonitrile (III) which extend its application as a synthetic intermediate. An entirely different approach, namely the formation of the pyrazine ring by ring-closure of an acyclic hydroxamic acid proved more successful. The following general method for the synthesis of 3:6-disubstituted pyrazine cyclic hydroxsmic acids has been developed. This method was applied successfully to three cases including that of a homologue of aspergillic acid (R = R'' = Et) which was isolated in very low yield. The synthesis of one of the possible structures of aspergillic acid (I; R = Bui, R' = Bus) was attempted by this route. After a number of methods for the synthesis of unsaturated alphabeta-aldehydes had been investigated, the required Schiff's base was prepared as follows: A satisfactory cyclisation of the Schiff's base to give (I; R = Bui, R' = Bus) was not achieved. An ultra-violet absorption spectrum showed that the cyclic acid had been formed but only to the extent of 30% of a resinous reaction product isolated in low yield. The difficulties encountered at this ring-closure stage are discussed. An alternative route to 3:6-disubstituted pyrazine cyclic hydroxamic acids has been developed. An a-keto-hydroxamic acid is condensed with an aminoketone to form the cyclic acid in one step thus: In the first instance pyruvchydroxamyl chloride was converted into the bisulphite compound of pyruvohydroxamic acid (V; R = Me). This was condensed with aminoacetone (VI; R' = Me) to give an aspergillic acid homologue (VII; R = R' = Me) in good yield. The structure of the cyclic acid was completely defined when reduction gave 2-hydroxy-3:6-dimethylpyrazine, a known compound. Application of the above method to the aspergillic acid case (VII; R = Bus, R' = Bui) proved less successful. A cyclic acid was not formed when the bisulphite compound of the alpha-keto-hydroxamic acid (V; R = Bus) was treated with the aminoketone (VI; R' = Bui). An experiment in which the alpha-keto-hydroxamic acid was formed by hydrolysis of the hydroxamyl chloride (VIII) with sodium acetate in acetic acid showed more promise. The acid was not isolated but treated directly with the aminoketone. A non-crystalline reaction product had an ultra-violet absorption spectrum from which it was evident that it contained a small proportion of the cyclic acid (VII; R = Bus, R' = Bui).

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Organic chemistry
Date of Award: 1951
Depositing User: Enlighten Team
Unique ID: glathesis:1951-78842
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 30 Jan 2020 14:48
Last Modified: 30 Jan 2020 14:48

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