Synthesis of Cyclic Hydroxamic Acids

The following discussion of hydroxamic acids includes saturated systems, e.g., 2, compounds such as 3, derived from aromatic systems, 7V-hydroxyimides such as 7V-hydroxyglutarimide (78), and certain of their derivatives including thiohydroxamic acids. Naturally occurring cyclic hydroxamic acids are discussed to show the range of structural types that has been found, hut macrocyclic polyhydroxamic acids are mentioned very briefly, because several comprehensive reviews of these compounds are already available. The main purpose of this review is to summarize the methods available for the synthesis of cyclic hydroxamic acids, to outline their characteristic reactions, and to present some useful physical data. Their synthesis and some biological properties have previously been reviewed by Coutts. ... 

Several reactions are particularly applicable to the synthesis of cyclic hydroxamic acids as they involve some kind of ring expansion. Some are quite general reactions which are of high preparative utility, whereas others exist as fairly isolated examples which have not as yet been generalized. 

The ring cleavage behavior of cyclopentyl nitrite has been used in an interesting synthesis of cyclic hydroxamic acids. Thus steroidal 17/8-nitrites (81) on photolysis yield the corresponding hydroxamic acids (82).29 This conversion can be rationalized in the following way (83 to... 

Scherlitz-Hofmann, I. Dubs, M. Krieg, R. Schoenecker, B. Kluge, M. Sicker, D. Hybrids of Natural Products. Synthesis of Cyclic Hydroxamic Acids of the Estra-l,3,5(10)-triene Series, Helv. Chim. Acta 1998,80, 2345. 

Heilmann, D. Sicker, D. Synthesis of Cyclic Hydroxamic Acids Derived From the Structure of l-Hydroxypyrido[2,3-b][l,4]oxazin-2(lH)-one, /. Prakt. Chem. 1990, 332, 265. 

Tays, K. and Atkinson, J. 1998. An improved synthesis of cyclic hydroxamic acids from Gramineae. Synth. Commun. 28, 903-912... 

Oxidation of secondary amines, such as piperidine (94), with dimethyldioxirane (95) led to synthesis of cyclic hydroxamic acids (Scheme 52) (93ACS(47)1141). 

From a pharmaceutical discovery perspective, it could be fruitful to embark on a library synthesis using cyclic hydroxamic acid templates. There are several reports describing interesting bioactivities for such compounds, particularly as inhibitors of metal-dependent enzymes 48-52 However, only three a-mercapto acid monomers are currently available from commercial sources hence the structural diversity of products that could be easily prepared is limited. Several approaches to introducing additional points of diversity into the benzothiazinone scaffold are currently under investigation. 

A general synthetic method for acyclic a-alkoxynitrones (196) involves the alkylation with triflates of hydroxamic acids (195) in neutral conditions (Scheme 2.69) (352). Similarly, the synthesis of cyclic methoxynitrone of pyrrolines (197) has been carried out (353). 

In a very interesting paper Hu and Miller have described the synthesis of a L-lysine-derived cyclic hydroxamic acid 174 starting by the oxidation of protected Z-L-lysine 171 (formed from 170) with dimethyldioxirane (DMD) in acetone, followed by nitrone... 

Chittari, P. Thomas, A. Rajappa, S. Synthesis of Novel Cyclic Hydroxamic Acids, Tetrahedron Lett. 1994, 35, 3793. 

The cyclohexene 121, which was readily accessible from the Diels-Alder reaction of methyl hexa-3,5-dienoate and 3,4-methylenedioxy-(3-nitrostyrene (108), served as the starting point for another formal total synthesis of ( )-lycorine (1) (Scheme 11) (113). In the event dissolving metal reduction of 121 with zinc followed by reduction of the intermediate cyclic hydroxamic acid with lithium diethoxyaluminum hydride provided the secondary amine 122. Transformation of 122 to the tetracyclic lactam 123 was achieved by sequential treatment with ethyl chloroformate and Bischler-Napieralski cyclization of the resulting carbamate with phosphorus oxychloride. Since attempts to effect cleanly the direct allylic oxidation of 123 to provide an intermediate suitable for subsequent elaboration to ( )-lycorine (1) were unsuccessful, a stepwise protocol was devised. Namely, addition of phenylselenyl bromide to 123 in acetic acid followed by hydrolysis of the intermediate acetates gave a mixture of two hydroxy se-lenides. Oxidative elimination of phenylselenous acid from the minor product afforded the allylic alcohol 124, whereas the major hydroxy selenide was resistant to oxidation and elimination. When 124 was treated with a small amount of acetic anhydride and sulfuric acid in acetic acid, the main product was the rearranged acetate 67, which had been previously converted to ( )-lycorine (108). 

A new synthesis of ( )-crinane (13) (Scheme 2) may be applicable to Amaryllidaceae alkaloids.5 Key features of the synthesis are the preparation of the acid (10) by Claisen rearrangement of the allylic acetate (9) and intramolecular ene reaction of a protected acylnitroso-enophile (11) to give the cyclic hydroxamic acid (12). 

The challenge in the synthesis of an aglucone like e.g. DIMBOA consists in accomplishing the direct combination of a cyclic hydroxamic acid with a cyclic hemiacetal unit together with a donor substituent in para position to the N atom keeping in mind the principle tendency of the 2,4-di-hydroxy-2//-l,4-benzoxazin-3(4//)-one skeleton to undergo in solution degradation to a benzoxazolin-2(3/7)-one as discussed recently [108] and above. 

Homolytic substitution of heteroaromatic compounds, 16, 123 Hydantoins, chemistry of, 38, 177 Hydrogen cyanide derivatives, synthesis of heterocycles from, 41, 1 Hydrogen exchange base-catalyzed, 16, 1 one-step (labeling) methods, 15, 137 Hydrogenated porphyrin derivatives hydroporphyrins, 43, 73 Hydroxamic acids, cyclic, 10, 199 1 -Hydroxyindoles, 1 -hydroxytryptophans, and 1-hydroxytryptamines,... 

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