Stereocontrolled Syntheses for the Six Diastereomeric l,2-Dihydroxy-4,5-diaminocyclohexanes

PtIIComplexes and P-388 Antitumor Properties

Donald T. Witiak, David Rotella, Joyce A. Filppi, Judith Gallucci

Research output: Contribution to journalArticleResearchpeer-review

22 Citations (Scopus)

Abstract

Stereocontrolled syntheses for the six diastereomeric l,2-dihydroxy-4,5-diaminocyclohexanes 3a-f from cyclohexene diamines cis-4 and trans-5 are described. Cbz-protected species cis-9 and trans-11, respectively, served as a source of stable Cbz-protected precursors to these cyclohexanediol diamines (CDD), which were liberated upon catalytic (H2, Pd/C) hydrogenation. Catalytic osmylation of 9 afforded a mixture of diastereomeric diols 13 and 14, which served as precursors to cis-anti-cis CDD 3b and cis-syn-cis CDD 3a, respectively, whereas osmylation of 11 yielded the expected single product 12, the precursor to cis-anti-trans CDD 3d. Epoxidation of olefins 9 and 11 afforded oxiranes 15 and 17, respectively, which upon acid-catalyzed hydrolysis produced the corresponding Cbz-protected diols 16 and 18, which served as precursors to CDD trans-anti-cis 3c, and trans-anti-trans 3e. Formation of diol 18 from oxirane 17 was accompanied by formation of 2-oxa-4-azabicyclo[3.3.1]nonan-3-one 19. CDD trans-syn-trans 3f was prepared from diol 12 via regioselective monoacetylation, yielding 22, followed by oxidation to afford ketone 24. Sodium borohydride reduction and acetylation produced diacetate precursor 26. PtIICl2complexes of five of the diamines (3a-d,f) are described, and their activities were compared with cisplatin (1) by employing P-388 leukemia implanted CDF1mice. The data indicate that stereochemistry of the amino groups on the cyclohexanediamine ligand modulate the expression of toxic effects, and depending upon hydroxyl and amino group stereochemistry, there is a marked effect on complex formation (e.g., Cl2PtII-3e) and solubility characteristics (e.g., Cl2PtII-3c). Acetylation of the hydroxyl functions in selected isomers (28a-c) rendered the PtIIcomplexes inactive. A single-crystal X-ray structure of compound 3a was determined at room temperature and indicated the cis-syn-cis arrangement of the OH and NH2groups.

Original languageEnglish
Pages (from-to)1327-1336
Number of pages10
JournalJournal of Medicinal Chemistry
Volume30
Issue number8
DOIs
StatePublished - 1 Aug 1987

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Diamines
Acetylation
Hydroxyl Radical
Ethylene Oxide
Hydrogenation
Poisons
Epoxy Compounds
Alkenes
Ketones
Solubility
Cisplatin
Leukemia
Hydrolysis
X-Rays
Ligands
Temperature
Acids

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@article{cfeb0db7c2d74d18b73c68a60d3b6e59,
title = "Stereocontrolled Syntheses for the Six Diastereomeric l,2-Dihydroxy-4,5-diaminocyclohexanes: PtIIComplexes and P-388 Antitumor Properties",
abstract = "Stereocontrolled syntheses for the six diastereomeric l,2-dihydroxy-4,5-diaminocyclohexanes 3a-f from cyclohexene diamines cis-4 and trans-5 are described. Cbz-protected species cis-9 and trans-11, respectively, served as a source of stable Cbz-protected precursors to these cyclohexanediol diamines (CDD), which were liberated upon catalytic (H2, Pd/C) hydrogenation. Catalytic osmylation of 9 afforded a mixture of diastereomeric diols 13 and 14, which served as precursors to cis-anti-cis CDD 3b and cis-syn-cis CDD 3a, respectively, whereas osmylation of 11 yielded the expected single product 12, the precursor to cis-anti-trans CDD 3d. Epoxidation of olefins 9 and 11 afforded oxiranes 15 and 17, respectively, which upon acid-catalyzed hydrolysis produced the corresponding Cbz-protected diols 16 and 18, which served as precursors to CDD trans-anti-cis 3c, and trans-anti-trans 3e. Formation of diol 18 from oxirane 17 was accompanied by formation of 2-oxa-4-azabicyclo[3.3.1]nonan-3-one 19. CDD trans-syn-trans 3f was prepared from diol 12 via regioselective monoacetylation, yielding 22, followed by oxidation to afford ketone 24. Sodium borohydride reduction and acetylation produced diacetate precursor 26. PtIICl2complexes of five of the diamines (3a-d,f) are described, and their activities were compared with cisplatin (1) by employing P-388 leukemia implanted CDF1mice. The data indicate that stereochemistry of the amino groups on the cyclohexanediamine ligand modulate the expression of toxic effects, and depending upon hydroxyl and amino group stereochemistry, there is a marked effect on complex formation (e.g., Cl2PtII-3e) and solubility characteristics (e.g., Cl2PtII-3c). Acetylation of the hydroxyl functions in selected isomers (28a-c) rendered the PtIIcomplexes inactive. A single-crystal X-ray structure of compound 3a was determined at room temperature and indicated the cis-syn-cis arrangement of the OH and NH2groups.",
author = "Witiak, {Donald T.} and David Rotella and Filppi, {Joyce A.} and Judith Gallucci",
year = "1987",
month = "8",
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doi = "10.1021/jm00391a011",
language = "English",
volume = "30",
pages = "1327--1336",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
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}

Stereocontrolled Syntheses for the Six Diastereomeric l,2-Dihydroxy-4,5-diaminocyclohexanes : PtIIComplexes and P-388 Antitumor Properties. / Witiak, Donald T.; Rotella, David; Filppi, Joyce A.; Gallucci, Judith.

In: Journal of Medicinal Chemistry, Vol. 30, No. 8, 01.08.1987, p. 1327-1336.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Stereocontrolled Syntheses for the Six Diastereomeric l,2-Dihydroxy-4,5-diaminocyclohexanes

T2 - PtIIComplexes and P-388 Antitumor Properties

AU - Witiak, Donald T.

AU - Rotella, David

AU - Filppi, Joyce A.

AU - Gallucci, Judith

PY - 1987/8/1

Y1 - 1987/8/1

N2 - Stereocontrolled syntheses for the six diastereomeric l,2-dihydroxy-4,5-diaminocyclohexanes 3a-f from cyclohexene diamines cis-4 and trans-5 are described. Cbz-protected species cis-9 and trans-11, respectively, served as a source of stable Cbz-protected precursors to these cyclohexanediol diamines (CDD), which were liberated upon catalytic (H2, Pd/C) hydrogenation. Catalytic osmylation of 9 afforded a mixture of diastereomeric diols 13 and 14, which served as precursors to cis-anti-cis CDD 3b and cis-syn-cis CDD 3a, respectively, whereas osmylation of 11 yielded the expected single product 12, the precursor to cis-anti-trans CDD 3d. Epoxidation of olefins 9 and 11 afforded oxiranes 15 and 17, respectively, which upon acid-catalyzed hydrolysis produced the corresponding Cbz-protected diols 16 and 18, which served as precursors to CDD trans-anti-cis 3c, and trans-anti-trans 3e. Formation of diol 18 from oxirane 17 was accompanied by formation of 2-oxa-4-azabicyclo[3.3.1]nonan-3-one 19. CDD trans-syn-trans 3f was prepared from diol 12 via regioselective monoacetylation, yielding 22, followed by oxidation to afford ketone 24. Sodium borohydride reduction and acetylation produced diacetate precursor 26. PtIICl2complexes of five of the diamines (3a-d,f) are described, and their activities were compared with cisplatin (1) by employing P-388 leukemia implanted CDF1mice. The data indicate that stereochemistry of the amino groups on the cyclohexanediamine ligand modulate the expression of toxic effects, and depending upon hydroxyl and amino group stereochemistry, there is a marked effect on complex formation (e.g., Cl2PtII-3e) and solubility characteristics (e.g., Cl2PtII-3c). Acetylation of the hydroxyl functions in selected isomers (28a-c) rendered the PtIIcomplexes inactive. A single-crystal X-ray structure of compound 3a was determined at room temperature and indicated the cis-syn-cis arrangement of the OH and NH2groups.

AB - Stereocontrolled syntheses for the six diastereomeric l,2-dihydroxy-4,5-diaminocyclohexanes 3a-f from cyclohexene diamines cis-4 and trans-5 are described. Cbz-protected species cis-9 and trans-11, respectively, served as a source of stable Cbz-protected precursors to these cyclohexanediol diamines (CDD), which were liberated upon catalytic (H2, Pd/C) hydrogenation. Catalytic osmylation of 9 afforded a mixture of diastereomeric diols 13 and 14, which served as precursors to cis-anti-cis CDD 3b and cis-syn-cis CDD 3a, respectively, whereas osmylation of 11 yielded the expected single product 12, the precursor to cis-anti-trans CDD 3d. Epoxidation of olefins 9 and 11 afforded oxiranes 15 and 17, respectively, which upon acid-catalyzed hydrolysis produced the corresponding Cbz-protected diols 16 and 18, which served as precursors to CDD trans-anti-cis 3c, and trans-anti-trans 3e. Formation of diol 18 from oxirane 17 was accompanied by formation of 2-oxa-4-azabicyclo[3.3.1]nonan-3-one 19. CDD trans-syn-trans 3f was prepared from diol 12 via regioselective monoacetylation, yielding 22, followed by oxidation to afford ketone 24. Sodium borohydride reduction and acetylation produced diacetate precursor 26. PtIICl2complexes of five of the diamines (3a-d,f) are described, and their activities were compared with cisplatin (1) by employing P-388 leukemia implanted CDF1mice. The data indicate that stereochemistry of the amino groups on the cyclohexanediamine ligand modulate the expression of toxic effects, and depending upon hydroxyl and amino group stereochemistry, there is a marked effect on complex formation (e.g., Cl2PtII-3e) and solubility characteristics (e.g., Cl2PtII-3c). Acetylation of the hydroxyl functions in selected isomers (28a-c) rendered the PtIIcomplexes inactive. A single-crystal X-ray structure of compound 3a was determined at room temperature and indicated the cis-syn-cis arrangement of the OH and NH2groups.

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U2 - 10.1021/jm00391a011

DO - 10.1021/jm00391a011

M3 - Article

VL - 30

SP - 1327

EP - 1336

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 8

ER -