According to the "membrane sensor" hypothesis, the membrane's physical properties and microdomain organization play an initiating role in the heat shock response. Clinical conditions such as cancer, diabetes and neurodegenerative diseases are all coupled with specific changes in the physical state and lipid composition of cellular membranes and characterized by altered heat shock protein levels in cells suggesting that these "membrane defects" can cause suboptimal hsp-gene expression. Such observations provide a new rationale for the introduction of novel, heat shock protein modulating drug candidates. Intercalating compounds can be used to alter membrane properties and by doing so normalize dysregulated expression of heat shock proteins, resulting in a beneficial therapeutic effect for reversing the pathological impact of disease. The membrane (and lipid) interacting hydroximic acid (HA) derivatives discussed in this review physiologically restore the heat shock protein stress response, creating a new class of "membrane-lipid therapy" pharmaceuticals. The diseases that HA derivatives potentially target are diverse and include, among others, insulin resistance and diabetes, neuropathy, atrial fibrillation, and amyotrophic lateral sclerosis. At a molecular level HA derivatives are broad spectrum, multi-target compounds as they fluidize yet stabilize membranes and remodel their lipid rafts while otherwise acting as PARP inhibitors. The HA derivatives have the potential to ameliorate disparate conditions, whether of acute or chronic nature. Many of these diseases presently are either untreatable or inadequately treated with currently available pharmaceuticals. Ultimately, the HA derivatives promise to play a major role in future pharmacotherapy.
Treatment of 2-bromo aldehydes and ethyl nitroacetate with alumina without solvent, or in solution with a tertiary base, at room temperature gives the diastereoisomeric title compounds in fair yields by a tandem nitroaldol reaction-cyclization sequence opening a new route for the preparation of trans and cis 4-hydroxylated 2-isoxazolines in a predictable way.The stereoselective synthesis of 4-hydroxylated isoxazolines 1 is an important task in the context of synthetic strategies toward the preparation of biologically relevant target molecules such as polyhydroxylated amino acids, aminopolyols, and amino sugars. This assumption stems mainly from the synthetic equivalency of 2-isoxazolines 1 and the products 2, which are obtained by hydride addition to C=N and reductive N-0 bond cleavage of 1. This conversion can be effected with preparatively useful diastereoselectivity.1 2 Y = COOH, CHO, CH2OH Nevertheless, 2-isoxazolin-4-ols 2 are not available directly by nitrile oxide cycloaddition to oxygenated alkenes.3-5 In 1981, Jáger and Schwab6,7 devised a route to prepare trons-2-isoxazolin-4-ols by reacting 2-isoxazoline4-anions with borates, followed by oxidative workup. More recently, I to and Sato8 reported the preparation of tnms-5-aryl-and -5-cyclopropyl-2-isoxazolin-4-ols via intramolecular ring opening of ,ß-epoxy ketone oximes. However, both the methods consist in the elaboration of an already constructed carbon skeleton to prepare the trans isomer only and suffer from severe limitations. Thus,
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1994 stereochemistry stereochemistry (general, optical resolution) O 0030
-038Asymmetric 1,3-Dipolar Cycloaddition of Nitrones with Ketene Acetals Catalyzed by Chiral Oxazaborolidines.-The nitrones (III) or (VI) and ketene acetals (II) or (VII) undergo an asym. 1,3-dipolar cycloaddition in the presence of catalytic oxazaborolidines (I) and (V). The resulting isoxazolidines are obtained in high yield and regioselectivity but, in general, with low enantioselectivity. Mild hydrogenolysis of the cycloadducts affords suitable synthons for imporant classes such as the isoquinoline (VIII), intermediate for biologically active compounds. -(SEERDEN, J.-P. G.; SCHOLTE OP REIMER, A. W. A.; SCHEEREN, H. W.; Tetrahedron Lett. 35 (1994) 25, 4419-4422; Dep. Org. Chem., Univ. Nijmegen, NL-6525 ED Nijmegen, Neth.; EN)
1,3-Dipolar Cycloaddition Reactions of Nitrones with Alkyl VinylEthers Catalyzed by Chiral Oxazaborolidines.-It is found that 1,3-dipolar cycloadditions of various nitrones with ethyl vinyl ether are catalyzed by chiral oxazaborolidines. The reaction proceeds with complete regioselectivity but with poor stereoselectivity and very low enantioselectivity (ca. 0% e.e.). With rigid (Z)-alkyl vinyl ether drastically improved stereoselectivity is observed. Starting from the nitrone (VIII) a cycloadduct with moderate enantioselectivity can be obtained. -(SEERDEN, J.-P. G.; BOEREN, M. M. M.; SCHEEREN, H. W.; Tetrahedron 53 (1997) 34, 11843-11852; Dep. Org.
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