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

Producción científica: Article › revisión exhaustiva

9 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	10637-10645
Número de páginas	9
Publicación	Tetrahedron
Volumen	63
N.º	43
DOI	https://doi.org/10.1016/j.tet.2007.08.009
Estado	Published - oct 22 2007

Nota bibliográfica

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.

Financiación

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.

Financiadores	Número del financiador
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

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

Acceder al documento

10.1016/j.tet.2007.08.009

Otros archivos y enlaces

Citar esto

@article{1f4f33ed146a4cf3be3628b2cefab2a3,

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",

month = oct,

day = "22",

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

language = "English",

volume = "63",

pages = "10637--10645",

number = "43",

}

TY - JOUR

T1 - Synthesis and epimerization of phenylalanyl 4-aminocyclophosphamides

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

UR - https://www.scopus.com/pages/publications/34548473607

UR - https://www.scopus.com/pages/publications/34548473607#tab=citedBy

U2 - 10.1016/j.tet.2007.08.009

DO - 10.1016/j.tet.2007.08.009

M3 - Article

AN - SCOPUS:34548473607

SN - 0040-4020

VL - 63

SP - 10637

EP - 10645

JO - Tetrahedron

JF - Tetrahedron

IS - 43

ER -

Synthesis and epimerization of phenylalanyl 4-aminocyclophosphamides

Resumen

Nota bibliográfica

Financiación

ASJC Scopus subject areas

Acceder al documento

Otros archivos y enlaces

Huella

Citar esto