Hydroxamates Miller hydroxamate

One of the first HDAC inhibitors to be identified and characterized was sodium butyrate, where it was found to alter the histone acetylation state (Riggs et al, 1977), and further determined to inhibit HDAC activity both in vitro and in vivo (Candido et al, 1978). Almost a decade later trichostatin A (TSA), a fungistatic antibiotic, was found to induce murine erythroleukemia cell differentiation (Yoshida et al, 1987). To date, a wide range of molecules have been described that inhibit the activity of Class I and Class II HDAC enzymes, and with a few exceptions, can be divided into structural classes including (1) small-molecule hydroxamates, such as TSA, suberoylanilide hydroxamic acid (SAHA), scriptaid and oxamflatin (2) short-chain fatty-acids, such as sodium butyrate, sodium phenylbutyrate and valproic acid (VPA) (3) cyclic tetrapeptides, such as apicidin, trapoxin and the depsipeptide FK-228 and (4) benzamides, such as MS-275 and Cl-994 (for reviews see Remiszewski et al, 2002 Miller et al, 2003). Some of these molecules are represented in Fig. 4. 

The resulting estimated average polarizabilities for the hydroxylamines, oximes and hydroxamic acids that we have discussed are given in Table 8. (It should be noted that Miller s approach does not distinguish between oxime isomers.) As anticipated from the correlation between average polarizability and volume (equation 10), the a in Table 8 increase with molecular size. 

In this context Miller " has demonstrated that all these issues could be overcome by hydroxamic-acids-based heteroatom activation.Therefore, S-halo or /S-hydroxy carboxylic acids 148a and 148b are converted to the corresponding hydroxamates 149a and 149b by active ester condensation with 0-substituted hydroxylamines (Scheme 69). Since chiral... 

Later, ICrook and Miller found that /3-mesylates of benzyl hydroxamate of a-acylserine (149c X = OMs R = = H R = CHiPh) can be directly cyclized under... 

Making use of a O-trityl-hydroxylamine linker, Meloni and Taddei reported the first example of Miller hydroxamate on solid phase (161, Scheme 73). /1-Lactams 162 and 163 were prepared on solid support starting from serine, threonine or other / -hydroxyacids derived from naturally occurring amino acids and a resin bonnd hydroxylamine 159. The ring closure of 160 was carried out under Mitsunobu conditions. 

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... 

M.J. Miller, Synthesis and therapeutic potential of hydroxamic acid based siderophores and analogues, Chem. Rev., 89, 1563, 1989. 

Solid-Phase Synthesis of (3-Lactams by Miller s Hydroxamate Approach. 292... 

Scheme 42 [S-Lactams on solid phase using the Miller s hydroxamate approach...

The majority of reported solid-phase combinatorial syntheses of the lactam core utilize a [2-i-2] cycloaddition reaction of ketenes with resin-bound imines [33-41]. A further development of the Staudinger reaction was reported by Mata and coworkers using Mukaiyama s reagent [42]. In addition, a stereoselective synthesis of chi-rally pure P-lactams has been performed as a first utilization of polymer-supported oxazolidine aldehydes [43]. Other strategies include an ester enolate-imine condensation [44], an Hg(OCOCF3)2-mediated intramolecular cydization [45], and Miller hydroxamate synthesis [46]. Because of the variability derived from the scaffold synthesis, not many attempts have been made to derivatize the resin-bound lactam template [47]. One of the most detailed descriptions of a versatile (3-lactam synthesis on a resin employed amino acids tethered as esters on Sasrin resin [48]. 

The Miller group [71] continued investigation on the cychzation of /3-hydroxy-O-benzyl hydroxamates in the presence of the Mitsimobu reagent leading to N-benzyloxy- -lactams. The Perrier rearrangement of o-glucal 91 followed by formation of hydroxamate and deacetylation provided a substrate 92 suitable for cychzation. hi the Mitsunobu reaction conditions 92 was converted into the -lactam 93, which was oxidized to the lactone 94 (Scheme 24). 

Chiral iV-acetyloxazolidinones and 3-haloacetyl-2-oxazolidinones have also been employed by Evans and coworkers [93] to synthesize a thienamycin intermediate and monobactam precursors. Thiazolidinethiones have also been used as chiral auxiliaries in the aldol addition to produce optically active monocyclic P-lactams [94]. Miller et al. [95] (Scheme 35), employed such a strategy by using cysteine- and serine-derived thiazolidinethiones 221 and oxazolidinethiones 222 to provide direct access to hydroxamate precursors 224 of bicyclic P-lactams, like 225. 

It is clear that the hydroxamate approach offers an attractive methodology to the preparation of a variety of optically active P-lactam antibiotics through the development of highly controlled aldol additions [101]. Although this methodology is straightforward in the preparation of valuable P-hydroxyhy-droxamates for subsequent cyclization, recently Miller and Rajendra [102] introduced a new stereoselective synthesis of 3,4-substituted P-lactams by bromine-induced oxidative cyclization of 0-acyl P,y-unsaturated hydroxamic acid derivatives (Scheme 41). 

Miller s hydroxamate method [41], widely used for the preparation of mono-bactams, surprisingly scores a single application useful for penem synthesis [42]. Chiral 0-butyl hydroxamate 91 was prepared by aldol reaction of crotonalde-hyde with synthon 90a (Sn(OTf )2/iV-ethylmorpholine), followed by temporary 0-TBDMS protection of obtained 90b and displacement with butoxyamine. Lactamization of 91 under Mitsunobu conditions (PPh3/DEAD) afforded 92, an equivalent (by alkene oxidative cleavage and deprotection) of enantiomerically pure 4-acetoxyazetidinone. 

A soln. of vitamin A acid chloride (prepared from the acid and PC/g) in dioxane added dropwise during 10 min. at 10° to a vigorously stirred soln. of Na-retinoyl-hydroxamate prepared by addition of aq. NaOH to the hydroxamic acid in dioxane, and stirred 3 hrs. at 20° in a closed flask in the dark N,0-diretinoyl-hydroxylamine. Overall Y 73.4%. R. Miller, Chim. Therap. 9, 298 (1974). 

Alkylation of hydroxamic acids as a method of co-N-hydroxyamino acids (2) synthesis was introduced by Maurer and Miller 196), When N- r -butoxycarbonyl-6-hydroxynorleucine benzylhydroxamate (248) or a homologue was treated with triphenylphosphine and diethylazodi-carboxylate (DEAD) under Mitsunobu conditions 197), intramolecular alkylation took place leading to N-hydroxylactams (249) or (250) as well as lesser amounts of hydroximates Z-(251) and -(252) (Scheme 50). The products were separated and distinguished by NMR spectrometry 196,198,199). Derivatives of the seven-membered N-hydroxylactam (253) were applied for the total synthesis of mycobactin S2 (254) 199) (Scheme 51). 

In the latest of a series of papers Miller and coworkers 202) described the alkylation of hydroxamic acids (263) with alcohol (262) under Mitsunobu conditions 197). In this manner, starting from glutamic acid they obtained several derivatives of N -hydroxyornithine (264-269) which were used subsequently in the synthesis of rhodotorulic acid 202) (Scheme 53). 

Considerable advance has recently been made in the purification of bovine thrombin with the demonstration by Rasmussen (1955) that most of the active component of commercial thrombin preparations can be separated from the inactive protein impurities by chromatography on columns of Amberlite IRC-50 resin. This enzyme can be inhibited with diisopropylfluorophosphate (DFP) (Gladner and Laki, 1956 Miller and Van Vunakis, 1956) and reactivated by nucleophilic reagents such as hydroxamic acid (Gladner and Laki, 1956). On the assumption that DFP and thrombin combine in a mole ratio of 1 1 a molecular weight of 13,700 can be calculated (Gladner el al., 1958). The DFP is bound to a seryl residue, the sequence around which bears remarkable similarities to those of other enzymes which combine with DFP, as shown in Table XIII. 

Nickolov, Z. S., Wang, X., and Miller, J. D. 2004. Liquid/air interfacial structure of alcohol-octyl hydroxamic acid mixtmes A study by sum-frequency spectroscopy. Spectrochim. Acta, Part A. 60A 2711. 

Mattingly, P. G., and M. J. Miller Synthesis of 2-Azetidinones from Serine-hydroxamates Approaches to the Synthesis of 3-Aminonocardicinic Acid. J. Org. Chem. 46, 1557 (1981). 

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