N-(9-Phenylfluoren-9-yl)-α-amino Ketones and N-(9-Phenylfluoren-9-yl)-α-amino Aldehydes as Chiral Educts for the Synthesis of Optically Pure 4-Alkyl-3-hydroxy-2-amino Acids. Synthesis of the C-9 Amino Acid MeBmt Present in Cyclosporin

Article abstract of DOI:10.1021/jo00298a025

Serine derived N-(9-phenylfluoren-9-yl)-α-amino ketones were prepared by acylation of primary organometallic reagents with amino acid isoxazolidides.When the amino and hydroxyl functions of serine were constrained in oxazolidine and oxazolidinone rings, alkylation of these ketones as their lithium enolates proceeded regiospecifically with good to excellent diasteroselectivity.Reduction of the oxazolidine and oxazolidinone ketones diastereoselectively led to N-protected 4-alkyl-branched 2-amino 1,3-diols that were subsequently oxidized in two steps, via the N-(9-phenylfluoren-9-yl)-α-amino aldehyde, to produce 4-alkyl-β-hydroxy-α-amino acids.In this way L-(+)-MeBmt (1), the C-9 amino acid of cyclosporin, and its D-(-) enantiomer were prepared in 12 steps from D- and L-serine, respectively, with 22percent overall yield and >99percent enantiomeric purity.N-(9-Phenylfluoren-9-yl)-MeBmt triple-bond and 6Z double-bond analogues 37 and 39 were also prepared.This synthetic route requires only a single chiral source (serine) and provides for configurational choice at all four diastereomeric centres.