The design and synthesis of high-affinity FKBP 12 ligands is described. These compounds potently inhibit the m-rrans-peptidylprolyl isomerase (rotamase) activity catalyzed by FKBP 12 with inhibition constants (Ki,app) as low as 1 nM, yet they possess remarkable structural simplicity relative to FK506 and rapamycin, from which they are conceptually derived. The atomic structures of three FKBP12-ligand complexes and of one unbound ligand were determined by X-ray crystallography and are compared to the FKBP12-FK506 and FKBP12-rapamycin complexes.

Nitronic esters derived from primary nitro ketones, ethyl nitroacetate, and (phenylsulfonyl)nitromethane react with dipolarophiles in the presence of nonaqueous protic and Lewis acids to give nitrile oxide cycloadducts. a-Nitro ketones, ethyl nitroacetate, and (phenylsulfonyl)nitromethane give nitrile oxide cycloadducts in the presence of p-toluenesulfonic acid, although conditions are necessarily more vigorous. The anions of phenylnitromethane and 1-nitropropane react similarly under mild conditions, the latter in poor yield. The methyl nitronic ester of (phenylsulfonyl)nitromethane undergoes direct cycloaddition to 1-hexene in neutral media to give diastereomeric isoxazolidines. 3-(a-Hydroxyalkyl)isoxazolines are readily prepared by reduction of 3-carbethoxyisoxazolines with sodium borohydride and by carbonyl addition to 3-acylisoxazolines with alkyllithium reagents. 3-Alkenylisoxazolines, which can be prepared from either 3-(hydroxyalkyl)isoxazolines or 3-sulfonylisoxazolines, undergo reversible [4 + 2]-cycloaddition with tetracyanoethylene.The diverse reactions of nitro compounds, nitronate salts, and nitronic esters with aqueous acid have been under study for over a century.1 Aldehydes and ketones are most commonly obtained (the Nef reaction). Under strongly acidic conditions, hydroxamic acids are formed instead; these may further hydrolyze to carboxylic acids and hydroxylamine (the Meyer reaction). Hydroxamic acid formation has been shown to proceed through hydrolysis of a nitrile oxide intermediate.2 Surprisingly little synthetic use has been made of this demonstration. Furoxans (1,2,5-oxadiazole 2-oxides) have been prepared from several nitro compounds under strongly acidic conditions,3 but extensive studies of nitrile oxide cycloadditions to added dipolarophiles are conspicuously lacking.

Aus den Nitroverbindungen (I) erhält man mit Diazomethan die Nitronsäuremethylester (III), die über die in situ gebildeten Nitriloxide (IV) durch Cycloadditionsreaktion zu den Dimeren (V) führen.