Regioselective Synthesis of Nitrones by Decarboxylative Oxidation of N-Alkyl-α-amino Acids and Application to the Synthesis of 1-Azabicyclic Alkaloids

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Abstract Tungstate-catalyzed oxidation of N-alkyl-α-amino acids with 30% H2O2 solution under phase-transfer conditions gives nitrones regioselectively in good yields. Using this method, stereodivergent synthesis of (R)- and (S)-4-(t-butyldimethylsilyloxy)-1-pyrroline N-oxides ((R)-17a and (S)-17a) was achieved. In addition, (R)- and (S)-3-(t-butyldimethylsilyloxy)-1-pyrroline N-oxides ((R)-45 and (S)-45) were prepared by catalytic oxidation of the corresponding chiral pyrrolidines in a regioselective manner. These chiral cyclic nitrones, 17 and 45 are versatile intermediates for the synthesis of optically active nitrogen heterocycles, since stereoselective additions of carbon nucleophiles to these chiral nitrones can be readily performed. Typically, ZnI2-mediated addition of ketene t-butyldimethylsilyl methyl acetal (29a) to (R)-17a gave the cis-adduct, methyl (2R,4R)-[1,4-bis(t-butyldimethylsilyloxy)pyrrolidin-2-yl]acetate (cis-30). In contrast, the addition of lithium acetylides 34 to the nitrone (R)-17a gave the trans-adducts, (2S,4R)-2-(1-alkynyl)-4-(t-butyldimethylsilyloxy)-1-hydroxypyrrolidines trans-35. These adducts are useful intermediates for syntheses of the nitrogen heterocycles (3R,5R)-1-aza-3-hydroxybicyclo[3.3.0]octane (37) and (6R,8R)-1-aza-8-hydroxybicyclo[4.3.0]nonane (38), respectively. The ZnI2-mediated addition of ketene silyl acetal 29a to the nitrone (R)-45 gave methyl (2S,3R)-[1,3-bis(t-butyldimethylsilyloxy)pyrrolidin-2-yl]acetate (trans-50a), which was used for asymmetric synthesis of the Geissman–Waiss lactone ((−)-49).