Hydroxamic acids, derivatives

In the Lossen reaction a hydroxamic acid derivative (usually an 0-acyl derivative) is deprotonated by base, and rearranges via migration of the group R to give an isocyanate 2. Under the usual reaction conditions—i.e. aqueous alkaline solution—the isocyanate reacts further to yield the amine 3. The Lossen reaction is closely related to the Hofmann rearrangement and the Curtins reaction. 

The Lossen reaction is of limited importance in synthetic organic chemistry one reason for that is the poor availability of the required hydroxamic acid derivatives. Some hydroxamic acids are even unreactive." ... 

They give rise to N,0-diacylhydroxylamine derivatives (Eq. 1) or hydroxamic acid derivatives (Eq. 2). 

Isoxazole-3-hydroxamic Acid Derivatives as Potential PDF Inhibitors. . . 193... 

Scheme 29 Synthesis of isoxazole-3-hydroxamic acid derivatives...

Abstract. The direct scale-up of a solid-phase synthesis has been demonstrated with 4-(2-amino-6-phenylpyrimidin-4-yl)benzamide and an arylsulfonamido-substituted hydroxamic acid derivative as examples. These compounds were obtained through combinatorial chemistry and solution-phase synthesis was used in parallel to provide a comparison. By applying highly loaded polystyrene-derived resins as the solid support, a good ratio between the product and the starting resin is achieved. We have demonstrated that the synthesis can be scaled up directly on the solid support, successfully providing the desired compounds easily and quickly in sufficient quantities for early development demands. 

As second example for the scale-up of solid-phase reactions directly on solid support, we chose an arylsulfonamido-substituted hydroxamic acid derivative stemming from the matrix metalloproteinase inhibitor library (MMP) of our research colleagues (Breitenstein et al. 2001). In this case, there was already a solution-phase synthesis available for comparison (see Scheme 4). The synthesis starts with the inline formation of a benzaldehyde 18 with the glycine methyl ester, which is then reduced to the benzylamine 20 using sodium borohydride in methanol/ THF (2 1). The sulfonamide formation is carried out in dioxane/H20 (2 1) with triethylamine as the base and after neutralisation and evaporation the product 21 can be crystallised from tert. butylmethyl ether. After deprotection with LiOH, the acid is activated by treatment with oxalyl chloride and finally converted into the hyroxamic acid 23 in 33.7% yield overall. 

Scheme 4. Synthesis of a MMP inhibitor, a hydroxamic acid derivative in liquid phase...

Scheme 5. SPS synthesis of the hydroxamic acid derivative via reductive ami-nation a Reduction, b Cl-S02-Ph-R2, NMM, DCM 3M h c 10% or 1-2% TFA in DCM with direct neutralisation with sat. NaHCCb, d without neutralisation...

Scheme 8. New route for the SPSS of hydroxamic acid derivative by nucleophilic substitution...

Breitenstein W, Hayakawa K, Iwasaki G, Kanazawa T, Kasaoka T, Koizumi S, Matsunaga S, Nakajima M, Sakaki J (2001) Preparation of arylsulfonamido-substituted hydroxamic acid derivatives as MMP2 inhibitors. Int Pat Appl... 

Hydroxamic acid derivatives, which belong to a new class of NO donors, have been shown to inhibit the matrix metalloproteinases (MMPs) [112]. MMPs are a family of zinc-dependent endopeptidases, which play a critical role in multiple steps in the metastatic cascade and facilitate neoangiogenesis. Numerous hydroxamic acids, such as marimastat, have been developed, that bind the zinc atom in the active catalytic domain of MMPs. During a randomized Phase III trial, comparing marimastat with placebo in patients with metastatic breast cancer, marimastat was not associated with an improvement in progression-free survival or overall survival. Other studies also indicated no benefit for MMP inhibitors when used either in combination with chemotherapy or sequentially after first-line chemotherapy in a variety of cancers [113]. Currently, many pharmaceutical companies have suspended clinical development of this kind of agent. 

In conclusion, we anticipate that A-Fmoc-aminooxy-2-chlorotrityl polystyrene will prove an indispensable reagent for the solid-phase synthesis of hydroxamic acids by multiple and combinatorial approaches. Not only is its production both efficient and cost effective, but release of the assembled hydroxamic acid derivative is readily accomplished using mild acidolytic reagents. 

TABLE 14. Gas-phase basicities of some hydroxamic acid derivatives (kcal mol-1)... 

Hydroxamates have been observed in the water in the Bay of Quinte, a eutrophic bay of Lake Ontario, and are believed to be produced by blue-green algae (76). Simpson and Neilands (77) have identified schizokinen, a hydroxamic acid derivative of citric acid as an extracellular product of the blue-green algae, Anabaena sp. However, not all Anabaena produce hydroxamates, Walsby (78) has shown that Anabaena cylindrica releases a large pigmented, peptide-containing material which complexes iron. As yet these peptides have not been examined for ability to complex the actinides. 

Recently, hydroxamic acid derivatives of common NSAIDs (meclofen-amic acid, indomethacin, sulindac, and ibuprofen) were evaluated at Warner-Lambert [293]. The order of 5-LO inhibitory potency (in RBL-1 cells) for these derivatives was CON(Me)OH > CONHOH > CONH(OMe)-> COOH. The CO potency ranking was exactly opposite, although the best 5-LO inhibitors still possessed significant CO activity. Whether the observed oral activity in CPE was due to carboxyhc acid metabolites or to the intrinsic activity of the hydroxamic acids was not clear. The more active 5-LO inhibitors were less ulcerogenic in fasted rats. 

Hydroxylamine can act as either a N-nucleophile or O-nucleophile, depending on which of the reactive centers is protected. For all reactions Ph-Pybox has been used as ligand, and moderate to high levels of selectivity have been achieved. Hydroxamic acid derivatives and oximes have also been probed as O-nucleophiles [63]. 

The reachons of hydroxamic acid derivatives required carefully optimized reactions conditions that is, 3-arylallyl phosphates were used as substrates in conjunction with PhCFs/water 2 1 as solvent (Scheme 9.35) [69]. The reactivity and selectivity were influenced by base, and the best results were obtained with Ba(OH)2. 

An extensive study focusing on sulfonamide containing hydroxamic acid derivatives as HDAC inhibitors led to the discovery of PXDIOI (Fig. 13) [78-80], which is currently in clinical trials. It was shown that for the meta substituted sulfonamides, the so-called reverse sulfonamides were consistently (2- to 7-fold) more potent HDAC inhibitors than the forward sulfonamides. 

Histone deacetylases are linked to the pathogenesis of malignancy from a mechanistic perspective. The capacity of HDAC inhibitors (HDACi) to interfere with the enzyme fimction has led to the observed prechnical and clinical activity in cancer therapy. Although the exact mechanism of anti-tumor activity is not fully elucidated, various cellular pathways have been shown to be involved. From the first chnical trials involving HDACi with short chain fatty acids to the newer generation hydroxamic acid derivatives and cychc tetrapeptides, a number of structurally diverse compounds have made the transition from the laboratory to the chnical arena. For purposes of this part of the discussion, HDACi are arbitrarily divided into the hydroxamates and nonhydroxamates. 

Nowadays, the most economical way of preparing hydroxamic acid derivatives is the reaction of hydroxylamine with acid chlorides or esters . Unfortunately, the preparation of acid chlorides is often tedious. In addition, it is very difficult to avoid further acylation during the reaction with hydroxylamine. 

Although the simplest route to prepare hydroxamic acid derivatives remains the reaction of hydroxylamine with acid chlorides, this last method cannot be apphed to all Af-protected-a-amino acids. The synthesis of Fmoc-protected amino acid hydroxamates represents the only exception to this rule . In fact, Fmoc-amino acid hydroxamates 98 can be synthesized by the acylation of hydroxylamine using Fmoc-amino acid chlorides 97 in the presence of MgO (Scheme 52). The route is simple, efficient, and affords good yields of products. 

Multicomponent reactions have recently become one of the favored methods to prepare pharmacologically important compounds. Ugi condensations with O-protected hydroxylamines have been successfully performed in THE using ZnCl2 as activating agent (Scheme 56). This synthetic strategy opens up the route to a very convergent assembly of internal hydroxamic acid derivatives (A-acyl-A-hydroxypeptides 109)" . 

In 2000, Szarka and coworkers reported some preliminary results on the facile synthesis of steroidal hydroxamic acid derivatives via the palladium-catalyzed function-ahzation of skeletons (138-141) possessing iodoaikene moieties (Scheme 65). 

Prior to the usage of the Ti-based catalytic system , the Sharpless group had reported their first asymmetric epoxidation of allylic alcohols using a combination of VO(acac)2/ TBHP and the chiral hydroxamic acid 67 (ee < 50%) or derivatives (ee 80%) ". In 1999, Yamamoto and coworkers described an improvement of this oxidation protocol, ee values up to 94%, by using hydroxamic acids derived from binaphthol, 68 being the... 

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