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26 A. J. Birch, R. A. Massy-Westropp, and R. W. Rickards, J. Chem. Soc. p. 3717 (1956).
26 R. B. Bates, J. H. Sehaubie, and M. Soucek, Tetrahedron Letters p. 1683
27 C. Gallina, A. Romeo, G. Tarzia, and V. Tortorella, Oazz. Chim. Ital. 94, 1301 (1964).
28 C. .Gallina, A. Romeo, V. Tortorella, and G. D’Agnelo, Chem. Ind. (London) p. 1300 (1966).
Francis et ul.'la and Snow30 have isolated from Mycobacterium phlei and M. tuberculosis two series of growth factors for M. johnei, containing the mycobactins P (12) and T (13), respectively.
(12) R = CH3, R' = CH3CH2
(13) R = H, R' = CH3
Mild alkaline hydrolysis cleaved the molecules as shown by the dotted line to give the carboxylic cobactic acids and the neutral cobactins. Acidic hydrolysis resulted in complcx fission of the molecule into smaller fragments. No synthetic work in the mycobactin series has been reported, but the structures are based on very extensive degradations.
F. Nocardamine and Ferrioxamine E
The ferrioxamines8- 9 form a large group of ferric trihydroxamates composed ofresidues of acetic acid, succinic acid, l-amino-5-hydroxyl-aminopentane, and l-amino-4-hydroxylaminobutane. Of these, only ferrioxamines E (14) and D2 (15) are formally cyclic hydroxamic acids.
29 J. Francis, H. M. Macturk, S. Madinaveitia, and G. A. Snow, Biochem. J.
55, 596 (1953).
30 G. A. Snow, J. Chem. Soc. p. 2588, 4080 (1954); Biochem. J. 81, 4P (1961);
94, 160 (1965); 97, 166 (1965).
I 4 (C
¹), \ /N-(CH2)5
(14) n = 6
(15) n¦ = 4
The iron-free ligand, deferrioxamine Á, is identical31 with nocard-amine,82 a metabolite from a Nocardia species, which was earlier erroneously formulated as 1683 and then 17.34
Ø. Synthesis of Cyclic Hydroxamic Acids
Because of the great range of structures containing cyclic hydroxamic acid functions it is difficult to give a concise summary of the available synthetic methods. Nevertheless, the vast majority of published syntheses depend on condensation reactions involving only familiar processes of acylation or alkylation of hydroxylamine derivatives. The principles of such syntheses are outlined in a number of typical examples in Section III, A but no attempt has been made to cover all reported cases.
However, the oxidative processes and displacement reactions dealt with in Sections III, Â and Ñ are commonly used only in the synthesis
31 W. Keller-Sehierlein and Y. Prelog, Hein. Chim. Acta 44, 1981 (1961).
32 A. Stoll, A. Brack, and J. Renz, Schweiz. Z. Allgem. Pathol. Bakteriol. 14, 225 (1951).
33 A. Stoll, J. Renz, and A. Brack, Helv. Chim,. Acta 34, 862 (1951).
34 R. F. C. Brown, Gr. Biichi, W. Keller-Sehierlein, V. Prelog, and J. Renz, Helv. Chim. Acta 43, 1868 (1960).
of cyclic hydroxamic acids. The formation of cyclic hydroxamic acids by reactions involving ring expansion is assigned a separate section (Section III, D) because the reaction sequences are frequently complex and deserving of detailed exposition, even though the final steps may involve standard condensation reactions.
A variety of condensation processes can lead to cyclic hydroxamic acids. These involve either the condensation of two molecules or the intramolecular cyclization of a single compound. In some eases, a primary hydroxamic acid function is already present and formation of a cyclic compound can arise by suitable reaction on nitrogen. These processes will be dealt with first.
This type of synthesis has been used extensively in the preparation of hydroxamic acids resembling aspergillic acid. a-Aminohydroxamic acids react85,36 with a-dicarbonyl compounds to yield pyrazine hydroxamic acids (18). Glyoxal and diacetyl react readily, but poor
yields are obtained with benzil. In the case of an unsymmetrical a-dicarbonyl reactant, the hydroxylamino nitrogen atom reacts with the more electrophilic carbonyl group. Condensation35 of alanine hydroxamic acid with methyl glyoxal yielded 19 exclusively and not 20. Because of this result, aspergillic acid analogs cannot be prepared
A. Condensation Reactions
CHa NHj NCH
86 Gr. Dunn, J. A. Elvidge, G. T. Newbold, W. C. Ramsay, F. S. Spring, and W. Sweeny, J. Chem. Soc. p. 2707 (1949).
36 S. R. Safir and J. H. Williams, J. Org. Chem. 17, 1298 (1952).
by this method. The aspergillic acid substitution pattern is obtained in the reaction of an a-aminohydroxamic acid with 2-bromocinnam-aldehyde followed by base-catalyzed cyclization.