A Route to Artificial Glycoconjugates and Oligosaccharides via Enzymatically Resolved Glycals: Dramatic Effects of the Handedness of the Sugar Domain Upon the Properties of an Anthracycline Drug

David B. Berkowitz, Samuel J. Danishefsky, Gayle K. Schulte

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

Racemic, fully synthetic glycals of considerable structural variety may be kinetically resolved via enzymatically mediated transesterification using Lipase PS-30 from Pseudomonas cepacia as catalyst and vinyl acetate as acyl donor. This methodology provides convenient access to a pool of optically enriched d- and l-glycals. These glycals may be employed as building blocks, both as glycosyl donors and glycosyl acceptors, to generate artificial oligosaccharides. Thus the d-glucal analogue 7, bearing a phenyl group at C-5, was converted to the corresponding 1,2-anhydrosugar(s) 8/9, which could be coupled directly to a second glycal. Alternatively, the 1,2-anhydrosugar could be converted to the corresponding β-glycosyl fluoride 14 or β-glycosyl sulfoxides 18a,b. Both 14 and 18a,b were glycosylated, with a glycal or a terminating sugar, in good yield. Conversely, the l-glucal analogue 3 was employed as a glycosyl acceptor, with l-fucosyl fluoride(s) (α:β = 1:1) as the glycosyl donor, to furnish the artificial “L,L”-disaccharide 17. Enzymatically resolved l- and d-glycals were also used to construct novel glycoconjugates of daunomycinone with di-sym-collidinyliodonium perchlorate as the coupling reagent. By employing each antipode of the 5-phenyl analogue of galactal, (+)- and (-)-25, as glycosyl donor, a pair of diastereomeric 5′-phenyl analogues of daunomycin 22 and 23, was obtained. These two compounds differ only in the handedness (l or d) of their carbohydrate sectors, yet exhibit markedly different biological properties. Interestingly, X-ray crystal structure determinations for 22 and 23 reveal fundamentally different overall molecular shapes for the two compounds.

Original languageEnglish (US)
Pages (from-to)4518-4529
Number of pages12
JournalJournal of the American Chemical Society
Volume114
Issue number12
DOIs
StatePublished - Jun 1 1992

Fingerprint

Bearings (structural)
Oligosaccharides
Functional Laterality
Glycoconjugates
Anthracyclines
Transesterification
Lipases
Carbohydrates
Fluorides
Sugars
Crystal structure
Sulfoxides
Calcium Gluconate
Burkholderia cepacia
X rays
Catalysts
Daunorubicin
Disaccharides
Lipase
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

@article{a690399ce02342209c7b5b44aca31b76,
title = "A Route to Artificial Glycoconjugates and Oligosaccharides via Enzymatically Resolved Glycals: Dramatic Effects of the Handedness of the Sugar Domain Upon the Properties of an Anthracycline Drug",
abstract = "Racemic, fully synthetic glycals of considerable structural variety may be kinetically resolved via enzymatically mediated transesterification using Lipase PS-30 from Pseudomonas cepacia as catalyst and vinyl acetate as acyl donor. This methodology provides convenient access to a pool of optically enriched d- and l-glycals. These glycals may be employed as building blocks, both as glycosyl donors and glycosyl acceptors, to generate artificial oligosaccharides. Thus the d-glucal analogue 7, bearing a phenyl group at C-5, was converted to the corresponding 1,2-anhydrosugar(s) 8/9, which could be coupled directly to a second glycal. Alternatively, the 1,2-anhydrosugar could be converted to the corresponding β-glycosyl fluoride 14 or β-glycosyl sulfoxides 18a,b. Both 14 and 18a,b were glycosylated, with a glycal or a terminating sugar, in good yield. Conversely, the l-glucal analogue 3 was employed as a glycosyl acceptor, with l-fucosyl fluoride(s) (α:β = 1:1) as the glycosyl donor, to furnish the artificial “L,L”-disaccharide 17. Enzymatically resolved l- and d-glycals were also used to construct novel glycoconjugates of daunomycinone with di-sym-collidinyliodonium perchlorate as the coupling reagent. By employing each antipode of the 5-phenyl analogue of galactal, (+)- and (-)-25, as glycosyl donor, a pair of diastereomeric 5′-phenyl analogues of daunomycin 22 and 23, was obtained. These two compounds differ only in the handedness (l or d) of their carbohydrate sectors, yet exhibit markedly different biological properties. Interestingly, X-ray crystal structure determinations for 22 and 23 reveal fundamentally different overall molecular shapes for the two compounds.",
author = "Berkowitz, {David B.} and Danishefsky, {Samuel J.} and Schulte, {Gayle K.}",
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T1 - A Route to Artificial Glycoconjugates and Oligosaccharides via Enzymatically Resolved Glycals

T2 - Dramatic Effects of the Handedness of the Sugar Domain Upon the Properties of an Anthracycline Drug

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AU - Danishefsky, Samuel J.

AU - Schulte, Gayle K.

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Y1 - 1992/6/1

N2 - Racemic, fully synthetic glycals of considerable structural variety may be kinetically resolved via enzymatically mediated transesterification using Lipase PS-30 from Pseudomonas cepacia as catalyst and vinyl acetate as acyl donor. This methodology provides convenient access to a pool of optically enriched d- and l-glycals. These glycals may be employed as building blocks, both as glycosyl donors and glycosyl acceptors, to generate artificial oligosaccharides. Thus the d-glucal analogue 7, bearing a phenyl group at C-5, was converted to the corresponding 1,2-anhydrosugar(s) 8/9, which could be coupled directly to a second glycal. Alternatively, the 1,2-anhydrosugar could be converted to the corresponding β-glycosyl fluoride 14 or β-glycosyl sulfoxides 18a,b. Both 14 and 18a,b were glycosylated, with a glycal or a terminating sugar, in good yield. Conversely, the l-glucal analogue 3 was employed as a glycosyl acceptor, with l-fucosyl fluoride(s) (α:β = 1:1) as the glycosyl donor, to furnish the artificial “L,L”-disaccharide 17. Enzymatically resolved l- and d-glycals were also used to construct novel glycoconjugates of daunomycinone with di-sym-collidinyliodonium perchlorate as the coupling reagent. By employing each antipode of the 5-phenyl analogue of galactal, (+)- and (-)-25, as glycosyl donor, a pair of diastereomeric 5′-phenyl analogues of daunomycin 22 and 23, was obtained. These two compounds differ only in the handedness (l or d) of their carbohydrate sectors, yet exhibit markedly different biological properties. Interestingly, X-ray crystal structure determinations for 22 and 23 reveal fundamentally different overall molecular shapes for the two compounds.

AB - Racemic, fully synthetic glycals of considerable structural variety may be kinetically resolved via enzymatically mediated transesterification using Lipase PS-30 from Pseudomonas cepacia as catalyst and vinyl acetate as acyl donor. This methodology provides convenient access to a pool of optically enriched d- and l-glycals. These glycals may be employed as building blocks, both as glycosyl donors and glycosyl acceptors, to generate artificial oligosaccharides. Thus the d-glucal analogue 7, bearing a phenyl group at C-5, was converted to the corresponding 1,2-anhydrosugar(s) 8/9, which could be coupled directly to a second glycal. Alternatively, the 1,2-anhydrosugar could be converted to the corresponding β-glycosyl fluoride 14 or β-glycosyl sulfoxides 18a,b. Both 14 and 18a,b were glycosylated, with a glycal or a terminating sugar, in good yield. Conversely, the l-glucal analogue 3 was employed as a glycosyl acceptor, with l-fucosyl fluoride(s) (α:β = 1:1) as the glycosyl donor, to furnish the artificial “L,L”-disaccharide 17. Enzymatically resolved l- and d-glycals were also used to construct novel glycoconjugates of daunomycinone with di-sym-collidinyliodonium perchlorate as the coupling reagent. By employing each antipode of the 5-phenyl analogue of galactal, (+)- and (-)-25, as glycosyl donor, a pair of diastereomeric 5′-phenyl analogues of daunomycin 22 and 23, was obtained. These two compounds differ only in the handedness (l or d) of their carbohydrate sectors, yet exhibit markedly different biological properties. Interestingly, X-ray crystal structure determinations for 22 and 23 reveal fundamentally different overall molecular shapes for the two compounds.

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