Asymmetric Synthesis of 3-Substituted 4-Oxoesters Using the SAMP-/RAMP-Hydrazone Method

Based on aldehydes 1a—f or ketone 1g , 3-substituted 4-oxo esters 6a—g were synthesized in three steps in moderate to good overall yield (12—50%) and in excellent enantiomeric excesses ( ee >90—>95%) by an Umpolung-strategy employing the SAMP-/RAMP-hydrazone method. The key step in the synthesis is the highly diastereoselective alkylation of lithiated SAMP-hydrazones 3a—g (chiral d 2 -nucleophiles) with tert-butyl bromoacetate ( 4 ) (a 2 -electrophile) to furnish the alkylated 3-hydrazono tert -butylesters 5a—g in good yields (58—91%) and in excellent diastereomeric excesses ( de >90—>98%). Regeneration of the carbonyl functionality by cleavage of the hydrazones 5a—g was accomplished either by acidic hydrolysis or ozonolysis to give the acid labile and oxidation-sensitive 3-substituted 4-oxo esters 6a—g in moderate yields (19—63%) and in excellent enantiomeric excesses (ee >90—>95%). The absolute configuration of compounds 6a—g were assigned by conversion of 4-oxo esters ( S )- 6d and ( R )- 6e into their corresponding known 3-substituted λ-butyrolactones (S)-7 d and ( R )- 7e .