Investigation of the Reaction between Amino Acids or Amino Acid Esters and 9-Formylfluorene and Its Equivalents. Possible Utility of the Derived Enamines as Amino Group Protectants

Article abstract of DOI:10.1021/jo00279a015

Treatment of 9-(hydroxymethylene)fluorene/9-formylfluorene (storable as the hemiacetal with methanol, 7) with amino acids and amino acid esters yields the corresponding enamines 8, which may be considered to be hydrocarbon analogues of N-formyl amino acid derivatives.Attempted coupling of the free acids 8 (R'=H) with amino acid esters failed, suggesting insufficient reduction in basicity of the amino group due to the enamine residue.The introduction of electron-withdrawing substituents into the fluorene ring decreases the basicity sufficiently to allow normal peptide coupling reactions, as for example with the 2,7-dichloro analogues derived from 17.Thus phenylalanine derivative 18 treated with leucine methyl ester and DCC gave dipeptide 19.The DC-FM-bar group could be removed by catalytic transfer hydrogenolysis.Mild acid hydrolysis represents a second general deblocking technique for the FM-bar function.It was demonstrated in a model study involving the highly sensitive amino acid α-phenylglycine that the FM-bar protecting group was less prone to cause racemization than the benzyloxycarbonyl function.It was demonstrated that the simple pentapeptide leucine enkephalin 29 could be synthesized using α-DC-FM-bar protection along with tert-butyl-based side chain protecting groups.