Symmetry-Assisted Synthesis of C₂-Symmetric trans-α,α‘-Bis(hydroxymethyl)pyrrolidine and -piperidine Derivatives via Double Sharpless Asymmetric Dihydroxylation of α,ω-Terminal Dienes

A new strategy has been developed for the synthesis of C 2 -symmetric trans -α,α‘-bis(hydroxymethyl)pyrrolidine and piperidine derivatives 1 − 3 starting from symmetric α,ω-terminal dienes 4 − 6 . The double-asymmetric dihydroxylation (AD) reaction of 4 − 6 gave C 2 -symmetric tetrols, which were converted in a four-step sequence to C 2 -symmetric azacycloalkanes 17, 9, and 22, respectively. These azacycloalkanes were transformed into 1 − 3 in high enantiomeric excess (82% → 98%ee). The double AD reaction proved to cause enantiomeric enhancement, even though the asymmetric induction for the first AD reaction is moderate. In addition, it was observed that the chromatography on silica gel of several C 2 -symmetric azacycloalkanes ( 17, 20, and 22 ) of varying ee's resulted in marked enantiomeric fractionation.