Synthesis and epimerization of phenylalanyl 4-aminocyclophosphamides

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

doi:10.1016/j.tet.2007.08.009

Synthesis and epimerization of phenylalanyl 4-aminocyclophosphamides

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

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

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 language	English
Pages (from-to)	10637-10645
Number of pages	9
Journal	Tetrahedron
Volume	63
Issue number	43
DOIs	https://doi.org/10.1016/j.tet.2007.08.009
State	Published - 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.

Keywords

Cyclophosphamide
Epimerization
Prodrug
Proteolysis

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1016/j.tet.2007.08.009

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title = "Synthesis and epimerization of phenylalanyl 4-aminocyclophosphamides",

abstract = "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.",

keywords = "Cyclophosphamide, Epimerization, Prodrug, Proteolysis",

author = "Yongying Jiang and Zhoupeng Zhang and DiPaola, {Robert S.} and Longqin Hu",

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.",

year = "2007",

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doi = "10.1016/j.tet.2007.08.009",

language = "English",

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AU - Jiang, Yongying

AU - Zhang, Zhoupeng

AU - DiPaola, Robert S.

AU - Hu, Longqin

N1 - 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.

PY - 2007/10/22

Y1 - 2007/10/22

N2 - 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.

AB - 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.

KW - Cyclophosphamide

KW - Epimerization

KW - Prodrug

KW - Proteolysis

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Synthesis and epimerization of phenylalanyl 4-aminocyclophosphamides

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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