Synthesis and epimerization of phenylalanyl 4-aminocyclophosphamides

Yongying Jiang, Zhoupeng Zhang, Robert S. DiPaola, Longqin Hu

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Peptide and amino acid conjugates of (4R)- and (4S)-4-aminocyclophosphamides (4-NH2-CPA, 3) were designed as prodrug forms of phosphoramide mustard. Four diastereomers of Boc-Phe-4-NH-CPA (6) were synthesized stereospecifically from homoserine (R or S) and the protection strategy was optimized for the homoserine hydroxyl group during the construction of the 1,3,2-oxazaphosphorinane ring. The Phe-4-NH-CPA isomers of the trans-configuration ((2S,4R)- and (2R,4S)-) were found to be less stable than the corresponding isomers of the cis-configuration ((2R,4R)- and (2S,4S)-) and to undergo epimerization of the C-4 chiral center in the presence of 25% TFA used during Boc deprotection. The synthetic route developed should be applicable to the synthesis of a variety of peptide and amino acid conjugates of 4-aminocyclophosphamide.

Original languageEnglish
Pages (from-to)10637-10645
Number of pages9
Issue number43
StatePublished - Oct 22 2007

Bibliographical note

Funding Information:
We gratefully acknowledge the financial support of grant SNJ-CCR 700-009 from the State of New Jersey Commission on Cancer Research, a pilot grant from the Gallo Prostate Cancer Center of the Cancer Institute of New Jersey, and grant RSG-03-004-01-CDD from the American Cancer Society.


  • Cyclophosphamide
  • Epimerization
  • Prodrug
  • Proteolysis

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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