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

9 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.

Funding

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.

Funders	Funder number
Betty Gallo Prostate Cancer Center
State of New Jersey Commission on Cancer Research
American Cancer Society
Rutgers Cancer Institute of New Jersey	RSG-03-004-01-CDD

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.",

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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

Funding

Keywords

ASJC Scopus subject areas

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