Solid-phase extraction on C18 silica as a purification strategy in the solution synthesis of a 1-Thio-β-D-galactopyranoside library
(1998) In Bioorganic and Medicinal Chemistry 6(9). p.1563-1575- Abstract
A novel strategy for the purification of carbohydrate-based chemical libraries synthesized in solution was developed. Purification of reaction products was accomplished by means of solid-phase extraction enabled by protecting the 2-, 3-, 4-, and 6-hydroxyl groups of a galactose derivative as their hydrophobic O-laurates. The presence of multiple O-laurates allowed adsorption of reaction products onto C18 silica while reagents and by-products were washed away with MeOH. Products were quantitatively eluted with pentane. Purification of products using solid-phase extraction offers the combined advantages of solution synthesis (normal solution reactivity and ease of reaction monitoring) with those of solid-phase synthesis (facile product... (More)
A novel strategy for the purification of carbohydrate-based chemical libraries synthesized in solution was developed. Purification of reaction products was accomplished by means of solid-phase extraction enabled by protecting the 2-, 3-, 4-, and 6-hydroxyl groups of a galactose derivative as their hydrophobic O-laurates. The presence of multiple O-laurates allowed adsorption of reaction products onto C18 silica while reagents and by-products were washed away with MeOH. Products were quantitatively eluted with pentane. Purification of products using solid-phase extraction offers the combined advantages of solution synthesis (normal solution reactivity and ease of reaction monitoring) with those of solid-phase synthesis (facile product isolation permitting the use of large excesses of reagents). To demonstrate the utility of the hydrophobic recovery-procedure, tetra-O-lauroyl-β-d-galactopyranose-1-thiol was subjected to high-yielding reactions with a panel of Michael-acceptors and an α-chloro ketone. The resulting ketone adducts were then either reduced to the alcohols or reductively aminated with a selection of amino acids to give 30 different 1-thio-β-d-galactosides as mixtures of four diastereomers after removal of protecting groups. At each step, the product was separated from the reagents and their by-products by simple adsorption onto C18 silica, washing with MeOH and elution of product with pentane. After completion of the combinatorial chemistry sequence, the O-laurates were cleaved by methanolysis and the product methyl laurate in turn removed from the desired water-soluble products by C18 adsorption. Individual library members were thus conveniently produced on 10-30mg scales at purity levels of >90%. One of the 1-thio-β-d-galactosides thus produced was found to be a competitive inhibitor of the β-galactosidase from E. coli with K(i) value of 1.7μM.
(Less)
- author
- Nilsson, Ulf J. LU ; Fournier, Eric J.-L. and Hindsgaul, Ole
- publishing date
- 1998-09
- type
- Contribution to journal
- publication status
- published
- keywords
- 1-Thio-β-D-galactopyranoside library, C18, Solid-phase extraction, Solution combinatorial chemistry
- in
- Bioorganic and Medicinal Chemistry
- volume
- 6
- issue
- 9
- pages
- 13 pages
- publisher
- Elsevier
- external identifiers
-
- scopus:0032168143
- pmid:9801828
- ISSN
- 0968-0896
- DOI
- 10.1016/S0968-0896(98)00087-X
- language
- English
- LU publication?
- no
- id
- 2e5fe2a1-6756-449a-b450-1d66762ffa10
- date added to LUP
- 2023-02-07 08:59:43
- date last changed
- 2024-05-30 22:51:29
@article{2e5fe2a1-6756-449a-b450-1d66762ffa10,
abstract = {{<p>A novel strategy for the purification of carbohydrate-based chemical libraries synthesized in solution was developed. Purification of reaction products was accomplished by means of solid-phase extraction enabled by protecting the 2-, 3-, 4-, and 6-hydroxyl groups of a galactose derivative as their hydrophobic O-laurates. The presence of multiple O-laurates allowed adsorption of reaction products onto C18 silica while reagents and by-products were washed away with MeOH. Products were quantitatively eluted with pentane. Purification of products using solid-phase extraction offers the combined advantages of solution synthesis (normal solution reactivity and ease of reaction monitoring) with those of solid-phase synthesis (facile product isolation permitting the use of large excesses of reagents). To demonstrate the utility of the hydrophobic recovery-procedure, tetra-O-lauroyl-β-d-galactopyranose-1-thiol was subjected to high-yielding reactions with a panel of Michael-acceptors and an α-chloro ketone. The resulting ketone adducts were then either reduced to the alcohols or reductively aminated with a selection of amino acids to give 30 different 1-thio-β-d-galactosides as mixtures of four diastereomers after removal of protecting groups. At each step, the product was separated from the reagents and their by-products by simple adsorption onto C18 silica, washing with MeOH and elution of product with pentane. After completion of the combinatorial chemistry sequence, the O-laurates were cleaved by methanolysis and the product methyl laurate in turn removed from the desired water-soluble products by C18 adsorption. Individual library members were thus conveniently produced on 10-30mg scales at purity levels of >90%. One of the 1-thio-β-d-galactosides thus produced was found to be a competitive inhibitor of the β-galactosidase from E. coli with K(i) value of 1.7μM.<br/></p>}},
author = {{Nilsson, Ulf J. and Fournier, Eric J.-L. and Hindsgaul, Ole}},
issn = {{0968-0896}},
keywords = {{1-Thio-β-D-galactopyranoside library; C18; Solid-phase extraction; Solution combinatorial chemistry}},
language = {{eng}},
number = {{9}},
pages = {{1563--1575}},
publisher = {{Elsevier}},
series = {{Bioorganic and Medicinal Chemistry}},
title = {{Solid-phase extraction on C18 silica as a purification strategy in the solution synthesis of a 1-Thio-β-D-galactopyranoside library}},
url = {{http://dx.doi.org/10.1016/S0968-0896(98)00087-X}},
doi = {{10.1016/S0968-0896(98)00087-X}},
volume = {{6}},
year = {{1998}},
}