An Efficient Synthesis of a Probe for Protein Function: 2,3-Diaminopropionic Acid with Orthogonal Protecting Groups
Ethan A. Englund, Hosahudya N. Gopi and Daniel H. Appella*
*National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland
20892, Email: appellad
niddk.nih.gov
E. A. Englund, H. N. Gopi, D. H. Appella, Org. Lett., 2004, 6, 213-215.
DOI: 10.1021/ol0361599
Abstract
An efficient synthesis of N(α)-Boc2-N(β)-Cbz-2,3-diaminopropionic acid is reported. The synthesis starts from commercially available N(α)-Boc-Asp(OBn)-OH and employs a Curtius rearrangement to establish the β-nitrogen. The success of the Curtius rearrangement depends on proper protection of the α-nitrogen.
see article for more reactions
Details
The document details an efficient and cost-effective synthesis of N(α)-Boc2-N(β)-Cbz-2,3-diaminopropionic acid (Dap) with orthogonal protecting groups. The synthesis begins with commercially available N(α)-Boc-Asp(OBn)-OH and uses a Curtius rearrangement to establish the β-nitrogen. Proper protection of the α-nitrogen is crucial for the success of this rearrangement. Dap is frequently used to probe peptide and protein structures, particularly in RNA-binding peptides, due to its ability to reduce nonspecific binding and enhance binding affinity and selectivity. The high cost of Dap ($35/mmol) and the need for large quantities prompted the development of this economical synthesis route. The traditional Hoffman rearrangement method was found to be less efficient due to the need for constant protecting group exchanges and high reagent costs. The new method involves a Curtius rearrangement of a protected aspartic acid derivative, followed by trapping the isocyanate intermediate with benzyl alcohol. This synthesis is more cost-effective and suitable for solid-phase peptide synthesis. The document also confirms the enantiomeric purity of the synthesized Dap and discusses potential applications in RNA-binding peptide research. The work was supported by Northwestern University’s Weinberg College of Arts and Sciences, Department of Chemistry, and VP of Research.
Key Words
Curtius Rearrangement, tert-butyl carbamates
ID: J54-Y2004-850
