The stereodivergent asymmetric synthesis of a range of 2-(1′-hydroxyalkyl)phenols

The use of the (S)-α-methylbenzyl group as a chiral auxiliary has allowed the diastereoselective ortho-deprotonation of a chromium tricarbonyl complexed phenoxy ring. When the resultant ortho-anion is treated with an aldehyde two diastereoisomeric complexes are formed, in relatively poor dr, which differ in the configuration of the newly formed benzylic stereogenic centre. However, both ortho-formylation followed by treatment with Grignard reagents and ortho-acylation followed by reduction with Super-Hydride® were found to be completely diastereoselective, giving access to either epimer of the corresponding benzylic alcohol complexes in >99:1 dr. Subsequent oxidative removal of the chromium tricarbonyl unit, followed by cleavage of the O-α-methylbenzyl chiral auxiliary gives enantiopure 2-(1′-hydroxyalkyl)phenols. Following this stereodivergent procedure, either enantiomer of the product may be accessed from a single antipode of [(α-methylbenzyloxy)benzene]Cr(CO)3.

Diastereoselective ortho-formylation or ortho-acylation of [(S)-(α-methylbenzyloxy)benzene]Cr(CO)3 followed by Grignard addition or hydride reduction, respectively, gives access to either antipode of the corresponding 2-(1′-hydroxyalkyl)phenols in good yield and >99:1 er, after decomplexation and auxiliary cleavage.Figure optionsDownload as PowerPoint slide