合成路线1

The synthesis of 22-oxacalcitriol labeled with tritium at the 2beta-position has been performed as follows: The condensation of 3beta-(tert-butyldimethylsilyloxy)pregn-5-en-20(S)-ol (XXVI) with N,N-dimethylacrylamide (XV) by means of NaH in THF gives the propionamide derivative (XXVII), which is submitted to a Grignard alkylation with CH3MgBr and CeCl3 in ethyl ether yielding the 3-hydroxy-3-methylbutoxy derivative (XXVIII). The desilylation of (XXVIII) with tetrabutylammonium fluoride in THF affords the 3beta-hydroxy compound (XXIX), which is oxidized with cyclohexanone in refluxing toluene catalyzed by aluminum isopropoxide giving the enone compound (XXX). The dehydrogenation of (XXX) with dichlorodicyanobenzoquinone (DDQ) in refluxing dioxane yields the 1,4-dien-3-one compound (XXXI), which is isomerized by means of sodium ethoxide in DMSO to the 1,5-dien-3-one isomer (XXXII). The reduction of (XXXII) with NaBH4 in methanol affords the corresponding 3beta-hydroxy compound (XXXIII), which is selectively acetylated with acetic anhydride in pyridine to the 3beta-acetoxy compound (XXXIV). The dehydrogenation of (XXXIV) with N-bromosuccinimide (NBS) and tetrabutylammonium fluoride in refluxing CCl4 affords the 1,5,7-triene compound (XXXV), which is deacetylated with LiAlH4/NaOH in THF giving the corresponding 3beta-hydroxy compound (XXXVI). The protection of the conjugated diene system of (XXXVI) by a Diels-Alder cycloaddition with 4-phenyl-2,5-dihydro-1H-1,2,4-triazole-2,5-dione (XXXVII) in dichloromethane yields the adduct (XXXVIII), which is treated with trimethylsilyl chloride and imidazole in DMF (in order to protect the 3beta-hydroxy group) affording (XXXIX). The selective epoxidation of the 1-double bond of (XXXIX) with m-chloroperbenzoic acid (MCPBA) in dichloromethane gives the 1alpha,2alpha-epoxy derivative (XL), which is desilylated with TBAF in THF to the 1alpha,2alpha-epoxy-3beta-hydroxy adduct (XLI). The deprotection of the conjugated diene system of (XLI) by a retro Diels-Alder reaction (heating at 140 C in 1,3-dimethylimidazolidin-2-one) yields 1alpha,2alpha-epoxy-3beta-hydroxy-20(S)-(3-hydroxy-3-methylbutoxy) pregna-5,7-diene (XLII), which is submitted to a epoxy ring opening with tritiated NaB3H4 affording the 2beta-tritiated pregnadiene (XLIII). Finally, this compound is irradiated in ethanol with a 400 W high-pressure mercury lamp provided with a Vycor filter.