|Keywords:||Cinchona Alkaloid; beta-Hydroxy-alpha-Amino Acid; Asymmetric Catalysis; Direct Aldol Reaction; alpha-Alkyl Azlactone; mycestericin natural products; immunosuppressant; sphingosine analogs|
|Full text PDF:||http://hdl.handle.net/10192/29094http://bir.brandeis.edu/bitstream/10192/29094/2/license.txt|
Optically active beta-hydroxy-alpha-amino acids are an important class of amino acids as they exist as structural components of many biologically active natural products such as vancomycin, katanosins, cyclosporin, ustiloxins, lactacystin, myriocin, mycestericins, threonine and sphingosine. Furthermore, these beta-hydroxy-alpha-amino acids are also useful chiral building blocks in organic synthesis, as illustrated by their transformations into beta-lactams, beta-halo-alpha-amino acids, and aziridines. The catalytic asymmetric synthesis of beta-hydroxy-alpha-amino acids and their derivatives has been realized by different catalytic methods. For the catalytic asymmetric synthesis of beta-hydroxy-alpha-amino acids and their derivatives with tertiary beta-centers and quaternary alpha-centers, there were two unsolved problems: 1) high diastereoselectivity when both tertiary beta-center and quaternary alpha-center have alkyl substituents; 2) high anti-diastereoselectivity. These problems have been solved by our new catalytic asymmetric direct aldol reaction of alpha-alkyl azlactones and aliphatic aldehydes. To the best of our knowledge, this is the first time that a direct aldol reaction of the azlactone and the aldehyde is reported. No similar direct aldol reactions with nucleophilic amino acid equivalents other than azlactones are available for making aldol products with free beta-hydroxy groups. This is also the first time that the protected beta-hydroxy-alpha-amino acid bearing alkyl substituents at both tertiary beta-center and quaternary alpha-center is synthesized by a catalytic asymmetric approach with high enantioselectivity and diastereoselectivity. The high anti-diastereoselectivity obtained for the synthesis of protected beta-hydroxy-alpha-amino acids having tertiary beta-centers and quaternary alpha-centers is unprecedented for a catalytic asymmetric approach with a general scope. This new method has enabled us to achieve an unprecedented scope in the synthesis of protected beta-hydroxy-alpha-amino acids. This promising method could be applied to the synthesis of highly immunosuppressant mycestericin natural products and sphingosine analogs in search of new drug leads.