Synthesis of New Chiral Catalysts, Isoquinuclidinylmethanols, for the Enantioselective Addition of Diethylzinc to Aryl Aldehydes

New chiral ligands, isoquinuclidinylmethanols, were prepared and their catalytic abilities of asymmetric induction were examined in the addition of diethylzinc to aldehydes to furnish s e c o n d q alcohols in up to 76% e.e.Catalytic asymmetric synthesis has been a challenging subject in organic synthesis.The development of efficient enantioselective catalysts applying to a wide range of carbon-carbon bond forming reactions1 represents a pivotal challenge to the synthetic community.Among the catalysts, pamino alcohols have proved to be extremely efficient catalysts in asymmetric reaction.l.2Recently, we have also reported that 2-azanorbornylmetbanols2k were effective chiral catalysts for the enantioselective addition of diethylzinc to aldehydes.However, no report using isoquinuclidines, 2-azabicyclo[2.2.2]octanes, as c h i d ligands has appeared in literature, although isoquinuclidines have potential as synthetic intermediates for syntheses of biologically active compounds.3In this paper, we wish to report a synthesis of new chiral ligands, isoquinuclidinylmethanol (5) and its derivatives (3,4, 6a-c), which are sterically constrained pamino alcohols similar to 2-azanorbomylmethanols, and the first use of them as catalysts in the enantioselective addition of diethylzinc to aldehydes.Preparations of chiral ligands (3,4,5, 6a-c) are described in Scheme I. Chiral ligand (3) having a hydroxymethyl substituent was obtained from hicyclic amino acid ethyl ester (I), derived from the reaction of 1,3-cyclohexadiene with an optically active imine,4 followed by catalytic hydrogenation and subsequent reduction with lithium aluminum hydride.The optical purities of bicyclic amino acid ethyl esters (100% e.e.) [ (3s)-1 and (3s)-21 were determined by hplc analysis using chiral column.Furthermore, chiral Dedicated to Dr. Shigeru Oae on the occasion of his 77th birthday.