A Stereoselective Access to Dihydroxylated Pyrrolidines by Reductive Ring Contraction of 1,2-Oxazines

Abstract

Protected dihydroxylated 1,2-oxazine derivatives such as rac-4 were converted into tetrahydro-1,2-oxazines rac-7 by employing BH₃·THF for the stereoselective reduction of the C=N bond. Compound 7a underwent a reductive ring contraction on hydrogenation in the presence of palladium on charcoal to provide rac-5 in good yield. Enantiopure 1,2-oxazine derivatives 13 and 14 were prepared using (-)-menthol as chiral auxiliary. Their diastereo­selective dihydroxylation and BH₃·THF reduction furnished enantiopure tetrahydro-2H-1,2-oxazine derivatives 17 and 18 in good overall yield. Enantiomers (6R)-18 and (6S)-18 were transformed into the two enantiomeric hydroxylated pyrrolidine derivatives 5 in moderate yield.

Key words

cycloaddition - 1,2-oxazines - pyrrolidines - hydrogenation - ring contraction

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13

The hydrogenation of ethoxycarbonyl-substituted rac-4 was carried out in EtOH as solvent. The reaction in MeOH led to transesterification: see ref. 6a.

18

It should be noted that the reduction of the corresponding
3-trifluoromethyl-substituted 1,2-oxazine rac-4c with NaBH₃CN failed. This may be due to the electron-withdrawing ability of the trifluoromethyl group which prevents protonation of the C=N unit.