Highly diastereoselective additions to polyhydroxylated pyrrolidine cyclic imines: ready elaboration of aza-sugar scaffolds to create diverse carbohydrate-processing enzyme probes.
Representative diastereomeric, erythritol and threitol polyhydroxylated pyrrolidine imine scaffolds have been rapidly elaborated to diversely functionalized aza-sugars through highly diastereoselective organometallic (RM) additions (R=Me, Et, allyl, hexenyl, Ph, Bn, pMeO-Bn). The yields for these ad...
| Main Authors: | , , , |
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| Format: | Journal article |
| Language: | English |
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2003
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| _version_ | 1797101340828106752 |
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| author | Chapman, T Courtney, S Hay, P Davis, B |
| author_facet | Chapman, T Courtney, S Hay, P Davis, B |
| author_sort | Chapman, T |
| collection | OXFORD |
| description | Representative diastereomeric, erythritol and threitol polyhydroxylated pyrrolidine imine scaffolds have been rapidly elaborated to diversely functionalized aza-sugars through highly diastereoselective organometallic (RM) additions (R=Me, Et, allyl, hexenyl, Ph, Bn, pMeO-Bn). The yields for these additions have all been substantially enhanced from previously optimised levels (<58 %) for normal additions using a reverse addition procedure (e.g. R=Ph; 44 % normal mode --> 78 % reverse mode). The high diastereoselectivities (>98 % de for all except R=Me) are consistent with additions that are controlled by the configuration of the C-2 centre adjacent to the azomethine imine carbon and the conformation of the pyrrolidine imine. The high potential of this method was demonstrated by concise syntheses of 1-epi- and 2-epi-desacetylanisomycins. In addition, the late stage addition of hydrophobic substituents, which this imine addition methodology allows, enabled the preparation of novel aza-sugars with enhanced inhibitory potential. This was highlighted by the screening of a representative selection of these "hydrophobically-modified" aza-sugars against a diverse panel of 12 non-mammalian and human carbohydrate-processing enzymes. This identified a novel nanomolar alpha-galactosidase inhibitor (IC(50)=250 nM) and a novel highly selective glucosylceramide synthase inhibitor (IC(50)=52 microM, no alpha-glucosidase inhibition at 1 mM). Furthermore, analysis of the structure-activity relationships of racemic series of inhibitors allowed some validation of Fleet's mirror-image enzyme active site postulate. |
| first_indexed | 2024-03-07T05:50:29Z |
| format | Journal article |
| id | oxford-uuid:e8b20725-d4ff-4bcb-b811-7a7fc4361675 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:50:29Z |
| publishDate | 2003 |
| record_format | dspace |
| spelling | oxford-uuid:e8b20725-d4ff-4bcb-b811-7a7fc43616752022-03-27T10:48:44ZHighly diastereoselective additions to polyhydroxylated pyrrolidine cyclic imines: ready elaboration of aza-sugar scaffolds to create diverse carbohydrate-processing enzyme probes.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e8b20725-d4ff-4bcb-b811-7a7fc4361675EnglishSymplectic Elements at Oxford2003Chapman, TCourtney, SHay, PDavis, BRepresentative diastereomeric, erythritol and threitol polyhydroxylated pyrrolidine imine scaffolds have been rapidly elaborated to diversely functionalized aza-sugars through highly diastereoselective organometallic (RM) additions (R=Me, Et, allyl, hexenyl, Ph, Bn, pMeO-Bn). The yields for these additions have all been substantially enhanced from previously optimised levels (<58 %) for normal additions using a reverse addition procedure (e.g. R=Ph; 44 % normal mode --> 78 % reverse mode). The high diastereoselectivities (>98 % de for all except R=Me) are consistent with additions that are controlled by the configuration of the C-2 centre adjacent to the azomethine imine carbon and the conformation of the pyrrolidine imine. The high potential of this method was demonstrated by concise syntheses of 1-epi- and 2-epi-desacetylanisomycins. In addition, the late stage addition of hydrophobic substituents, which this imine addition methodology allows, enabled the preparation of novel aza-sugars with enhanced inhibitory potential. This was highlighted by the screening of a representative selection of these "hydrophobically-modified" aza-sugars against a diverse panel of 12 non-mammalian and human carbohydrate-processing enzymes. This identified a novel nanomolar alpha-galactosidase inhibitor (IC(50)=250 nM) and a novel highly selective glucosylceramide synthase inhibitor (IC(50)=52 microM, no alpha-glucosidase inhibition at 1 mM). Furthermore, analysis of the structure-activity relationships of racemic series of inhibitors allowed some validation of Fleet's mirror-image enzyme active site postulate. |
| spellingShingle | Chapman, T Courtney, S Hay, P Davis, B Highly diastereoselective additions to polyhydroxylated pyrrolidine cyclic imines: ready elaboration of aza-sugar scaffolds to create diverse carbohydrate-processing enzyme probes. |
| title | Highly diastereoselective additions to polyhydroxylated pyrrolidine cyclic imines: ready elaboration of aza-sugar scaffolds to create diverse carbohydrate-processing enzyme probes. |
| title_full | Highly diastereoselective additions to polyhydroxylated pyrrolidine cyclic imines: ready elaboration of aza-sugar scaffolds to create diverse carbohydrate-processing enzyme probes. |
| title_fullStr | Highly diastereoselective additions to polyhydroxylated pyrrolidine cyclic imines: ready elaboration of aza-sugar scaffolds to create diverse carbohydrate-processing enzyme probes. |
| title_full_unstemmed | Highly diastereoselective additions to polyhydroxylated pyrrolidine cyclic imines: ready elaboration of aza-sugar scaffolds to create diverse carbohydrate-processing enzyme probes. |
| title_short | Highly diastereoselective additions to polyhydroxylated pyrrolidine cyclic imines: ready elaboration of aza-sugar scaffolds to create diverse carbohydrate-processing enzyme probes. |
| title_sort | highly diastereoselective additions to polyhydroxylated pyrrolidine cyclic imines ready elaboration of aza sugar scaffolds to create diverse carbohydrate processing enzyme probes |
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