Enolic acids toxicity

Apart from the salicylates NSAIDs include several classes of weak acids like propionic acid derivatives such as ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ketorolac, loxoprofen, naproxen, oxaprozin, tiaprofenic acid and suprofen. Phenylbutazone is the most important representative of the pyrazolon derivatives which have a bad reputation for their risk of potentially fatal bone-marrow toxicity. To the acetic acid derivatives belong in-domethacin, diclofenac and sulindac. Sulindac is a pro-drug with less toxicity than indomethacin. The enolic acids include piroxicam, droxicam and tenoxicam. Meloxicam is an analog of piroxicam and has a high selectivity for COX-2. 

The Merck group s efforts to find a more stable substitute for the DKA pharmacophore resulted in the design of 8-hydroxy-[l,6]naphthyridines such as compound 10,19 wherein the keto-enol-acid triad was replaced with a 1,6-naphthyridine ketone bearing a phenolic hydroxyl group. Further refinement of compound 10—replacement of the naphthyridine phenyl ketone with a 4-fluorobenzyl carboxamide and addition of a six-membered sulfonamide at the 5-position of the naphthyridine core—resulted in compound 11, the second IN inhibitor to reach the clinic.20 The discovery of liver toxicity in long-term safety studies of compound 11 in dogs led to the suspension of clinical development21 of this compound. 

Besides the silyl enolate-mediated aldol reactions, organotin(IY) enolates are also versatile nucleophiles toward various aldehydes in the absence or presence of Lewis acid.60 However, this reaction requires a stoichiometric amount of the toxic trialkyl tin compound, which may limit its application. Yanagisawa et al.61 found that in the presence of one equivalent of methanol, the aldol reaction of an aldehyde with a cyclohexenol trichloroacetate proceeds readily at 20°C, providing the aldol product with more than 70% yield. They thus carried out the asymmetric version of this reaction using a BINAP silver(I) complex as chiral catalyst (Scheme 3-34). As shown in Table 3-8, the Sn(IY)-mediated aldol reaction results in a good diastereoselectivity (,anti/syn ratio) and also high enantioselectivity for the major component. 

Uses. Powerful methylating agent for acidic compounds such as carboxylic acids, phenols, enols not manufactured for sale and distribution because of toxicity and explosivity... 

Used as a common alkylating agent acts on acidic and enolic groups rapidly, and more slowly on other groups with replaceable hydrogens (the use of a Lewis acid catalyst such as BF3 is sometimes helpful) all diazoalkanes are toxic and sometimes explosive, and are used in microscale operations only... 

Cadmium enolate chemistry is considerably unexplored compared to that of Zn. These metals have comparable binding to the acetyl isomeric thiophene enolates" . In the case of metal kojic acid complexes the Zn complex is more stable than the corresponding Cd complex regardless of choice of 1 1, 1 2 or 1 3 ratio of the metal and ligand. However, one should not deduce that cadmium always binds ligands less tightly than zinc. Were that the case, Cd(II) would be expected to be rather non toxic. 

Pyrrolizidines compounds have been produced in connection with syntheses of other types of natural products. For example, Gensler and Hu prepared the dioxopyrrolizidine ester (46) as an intermediate in the synthesis of ( + )-slaframine, an indolizidine alkaloid obtained from cultures of Rhizoctonia leguminicola. The pyrrolidone ester (47), prepared from l-glutamic acid [Eq. (14)], was optically active, but the cyclized product, formed in quantitative yield from 47, was completely racemized. The synthesis of 2-acetyl-1,3-dioxopyrrolizidine (48) was carried out by Kruger and Arndt to assist with their investigations on model compounds aimed toward the total synthesis of a-cyclopiazonic acid, the main toxic principle of Penicillium cyclopium The spectra of the product (48) obtained in 30% overall yield was typical of an intramolecularly H-bonded enolized )S-... 

However, none of these reagents seemed to be appropriate for our DALA production because they are either very toxic, water-sensitive or unstable, and have the added disadvantage of low atom efficiency as they generate waste that contains molecular residues of significant size. Because of these factors, we did not spend much time exploring the reactivity of levulinic acid under these conditions. However, a future detailed study of enolate chemistry with levulinic acid using a variety of bulky bases would be worthwhile because of the high functionality of this ketoacid. 

Certain alkane- and arenesulfonic acids are well known and widely used catalysts in organic transformations (27). Metanesulfonic acid, alone or in conjunction with P2O5, is applied in cyclocondensations to form carbocyclic or heterocyclic compounds (28a). p-Toluenesulfonic acid is a toxic compound applied usually as monohydrate (28b). It is most useful in the protection of ketones to form acetals and to transform ketones to enol ethers and acetates. Further uses include esterification, dehydration, rearrangement, and isomerization. 

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