Hydroxamic acids protective groups

In 2002, Couturier and coworkers investigated the possibility of using a dioxazole as an aprotic hydroxamic acid protective group. In this context, the masked hydroxamic acid could be introduced earlier in the synthesis and could perhaps be released in a single operation at the end of the sequence. 

Shaw and McDowellhave prepared imidazolone derivatives by cyclization of a-acylamino amides. In a variation of this reaction the azlactone (30) was gradually converted to the hydroxamic acid (31) by methanolic hydroxylamine. Sodium methoxide and hydroxylamine readily gave the acyclic hydroxamic acid (32) which could be cyclized to 31 by dilute acid. Benzyloxyurea has been used in the sjrnthesis of pyrimidine hydroxamic acids (33) by reaction with /S-diketones followed by catalytic hydrogenation of the benzyl group. Protection... 

Very recently, Mordini and coworkers" have overcome the problems associated with the long reaction times that are normally required for the synthesis of hydroxamic acids from esters by performing these transformations under MW irradiation. The protective groups are also well tolerated under these reaction conditions, though a partial deprotection of the feri-butoxycarbonyl (Boc) group was observed in the reaction with Boc-proline ester. Amidic bonds and ketals also survive without any detectable decomposition. All the reactions go to completion in about six minutes, except in the case of the conversion of Boc-protected phenylalanine methyl ester, which required longer reaction times (12 min). 

The ability of hydroxamic acids to act as bidentate ligands has made this functional group a key component in the design of most matrix metalloproteinase inhibitors. Due to its labile and diprotic nature, the hydroxamate is typically installed in its protected form at the end of the synthetic sequence. ... 

Although several routes have been published for the preparation of hydroxamic acids on solid phase, these generally involve the preparation of a special linker to which hydrox-ylamine is attached. Dankwardt s approach obviates the need for special linkers or protecting groups, by displacing the desired hydroxamic acid from the resin directly using hydroxylamine, as illustrated in Scheme 86. CarboxyUc-acid-ester-linked, polymer-supported, Cbz-protected amino acids 195 (formed from 194) were displaced from the resin with aqueous hydroxylamine to provide the corresponding hydroxamic acids 196. 

Stereospecific synthesis of succinyl derivatives is now commonly carried out as shown in Scheme 7. The tert-butyl ester of the succinyl amino acid methylamides 16 was treated with TFA to deprotect the carboxy group, which was then activated by isobutyl chloroformate and reacted with H2NOTMS.[18] The OTMS protection was removed during the isolation and purification of the hydroxamic acid 17. 

As previously mentioned, 1,4,2-dioxazoline rings may be used as a protected group for hydroxamic acids (see Section 6.04.6.3). In fact, this ring is susceptible to hydrogenolysis conditions (H2/Pd) affording carbonyl compounds <1996CHEC-II(4)525, 2002JOC4833>. 

When 720a is treated with O-benzylhydroxylamine at 0 °C, the hydroxamic acid 724 is produced. The remaining carboxyl group is converted to a tert-hu y ester by the reaction of 725 with tert- m y acetate and perchloric acid. Overall yields for these two steps range from 50-75%. Methanolysis quantitatively removes the two acetate protecting groups to afford diol... 

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