Hydroxamates cleavage

Alicyclic hydroxamic acids undergo several specific oxidative cleavage reactions which may be of diagnostic or preparative value. In the pyrrolidine series compounds of type 66 have been oxidized with sodium hypobromite or with periodates to give y-nitroso acids (113). Ozonolysis gives the corresponding y-nitro acids. The related cyclic aldonitrone.s are also oxidized by periodate to nitroso acids, presumably via the hydroxamic acids.This periodate fission was used in the complex degradation of J -nitrones derived from aconitine. 

Hydroxamic acids are an important class of compounds targeted as potential therapeutic agents. A-Fmoc-aminooxy-2-chlorotrityl polystyrene resin 61 allowed the synthesis and subsequent cleavage under mild conditions of both peptidyl and small molecule hydroxamic acids (Fig. 14) [70]. An alternative hydroxylamine linkage 62 was prepared from trityl chloride resin and tV-hydroxyphthalimide followed by treatment with hydrazine at room temperature (Scheme 30) [71]. A series of hydroxamic acids were prepared by the addition of substituted succinic anhydrides to the resin followed by coupling with a variety of amines, and cleavage with HCOOH-THF(l 3). 

The hydrolysis of sulfate monoesters has been studied increasingly in relation to sulfate group transfer in vivo. In general, the rate-enhancing effect on the sulfate cleavage is small even with hydroxamate- or imidazole-functionalized cationic micelles which are extremely effective for the hydrolysis of phenyl esters. Recently, Kunitake and Sakamoto (1979a) found that zwitterionic hydroxamate [47] cleaved 2,4-dinitrophenyl sulfate effectively in cationic and... 

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... 

Nitro-compounds fRNOj) are isomeric with nitrites, but their electronic structure, excited states and photochemistry are very different. There is no very low-lying (n.jt ) state, and nitroalkanes show n — 3i absorption with a maximum around 275 nm ( —201 mol - cm In cyclohexane solution, nitromethane (CH1NOi) is photoreduced to nitrosomethane(CH,NO, but nitroethane under the same conditions gives rise to a nitroso-dimer derived from the solvent CS.47). The latter process is probably initiated by cleavage of the carbon-nitrogen bond in the nitroalkane. In basic solution (when the nitroalkane is converted to a nitronate anion) irradiation can lead to efficient formation of a hydroxamic acid (S.48), and this reaction most likely proceeds through formation of an intermediate three-mem bered cyclic species. 

Hydroxamic acids and hydrazides can also be prepared by nucleophilic cleavage of resin-bound esters, activated amides, or thiol esters [359] with hydroxylamine and... 

Aldehydes and ketones have also been prepared by nucleophilic cleavage of resin-bound O-alkyl hydroxamic acids (Weinreb amides [744]) with lithium aluminum hydride [745] or Grignard reagents (Entries 1 and 2, Table 3.41). Similarly, support-bound thiol esters can be cleaved with Grignard reagents to yield ketones [272], or with reducing agents to yield aldehydes (Entry 3, Table 3.41). Polystyrene-bound sele-nol esters (RCO-Se-Pol) react with alkynyl cuprates to yield alkynyl ketones [746]. 

The combinatorial approach is attractive for the synthesis of libraries of hydroxamic acids for screening as metalloenzyme inhibitors. A variety of hydroxylamine-linked resins (shown in Schemes 9-12) have been developed that allow peptide condensation reactions followed by cleavage of the hydroxamic acid from the resin. 

Cleavage of one specific functional group, such as a carboxylic ester, hydroxamate or amide. This strategy is especially useful to produce focused or targeted libraries. 

A preparatively satisfactory means of selective enol ester cleavage consists in the treatment with hydroxylamine, which not only induces hydroxylaminolysis of the more reactive enol ester group to form the respective hydroxamic acid, but captures the keto group thus liberated in the form of its stable oxime (29) ... 

Members of a second prominent group of mechanism-based inhibitors contain a peptide isostere, an element mimicking an intermediate formed during amide bond cleavage. Inhibitors of metalloproteases often contain a metal-chelating unit such as hydroxamate or phosphonic acids, which act as a bidentate ligand. 

In the reaction of O-benzoyl hydroxamic acid (56) with Bu3SnH, Bu3Sn adds to the carbonyl oxygen and subsequent p-elimination occurs to form an amidyl radical through the weak N-O bond cleavage, where finally, y-lactam (57) via 5-exo-trig manner is formed (eq. 3.18). 

---