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Synthesis and structural characteristics of all mono- and difluorinated 4,6-dideoxy-d-xylo-hexopyranoses

Synthesis and structural characteristics of all mono- and difluorinated 4,6-dideoxy-d-xylo-hexopyranoses
Synthesis and structural characteristics of all mono- and difluorinated 4,6-dideoxy-d-xylo-hexopyranoses
Protein–carbohydrate interactions are implicated in many biochemical/biological processes that are fundamental to life and to human health. Fluorinated carbohydrate analogues play an important role in the study of these interactions and find application as probes in chemical biology and as drugs/diagnostics in medicine. The availability and/or efficient synthesis of a wide variety of fluorinated carbohydrates is thus of great interest. Here, we report a detailed study on the synthesis of monosaccharides in which the hydroxy groups at their 4- and 6-positions are replaced by all possible mono- and difluorinated motifs. Minimization of protecting group use was a key aim. It was found that introducing electronegative substituents, either as protecting groups or as deoxygenation intermediates, was generally beneficial for increasing deoxyfluorination yields. A detailed structural study of this set of analogues demonstrated that dideoxygenation/fluorination at the 4,6-positions caused very little distortion both in the solid state and in aqueous solution. Unexpected trends in α/β anomeric ratios were identified. Increasing fluorine content always increased the α/β ratio, with very little difference between regio- or stereoisomers, except when 4,6-difluorinated.
0022-3263
7725–7756
Wheatley, David
259931a5-d5a7-4400-80c9-2a7e8d161a74
Fontenelle, Clement Q
c746c5ea-96bc-46c2-849d-47215ab58c03
Kuppala, Rama krishna K
c92bd85a-9009-4d33-99ca-a9ee3b457d44
Szpera, Robert
fc00a238-112f-4646-9783-6f9309456c09
Briggs, Edward L.
17fe16c5-fe04-475a-805c-a8e955bfaea8
Vendeville, Jean B
9f2c6155-cf23-4733-9402-33633fb5bb47
Wells, Neil J.
86312185-007b-495b-86da-4e2e5b9b8025
Light, Mark
cf57314e-6856-491b-a8d2-2dffc452e161
Linclau, Bruno
19b9cacd-b8e8-4c65-af36-6352cade84ba
Wheatley, David
259931a5-d5a7-4400-80c9-2a7e8d161a74
Fontenelle, Clement Q
c746c5ea-96bc-46c2-849d-47215ab58c03
Kuppala, Rama krishna K
c92bd85a-9009-4d33-99ca-a9ee3b457d44
Szpera, Robert
fc00a238-112f-4646-9783-6f9309456c09
Briggs, Edward L.
17fe16c5-fe04-475a-805c-a8e955bfaea8
Vendeville, Jean B
9f2c6155-cf23-4733-9402-33633fb5bb47
Wells, Neil J.
86312185-007b-495b-86da-4e2e5b9b8025
Light, Mark
cf57314e-6856-491b-a8d2-2dffc452e161
Linclau, Bruno
19b9cacd-b8e8-4c65-af36-6352cade84ba

Wheatley, David, Fontenelle, Clement Q, Kuppala, Rama krishna K, Szpera, Robert, Briggs, Edward L., Vendeville, Jean B, Wells, Neil J., Light, Mark and Linclau, Bruno (2021) Synthesis and structural characteristics of all mono- and difluorinated 4,6-dideoxy-d-xylo-hexopyranoses. Journal of Organic Chemistry, 86 (11), 7725–7756. (doi:10.1021/acs.joc.1c00796).

Record type: Article

Abstract

Protein–carbohydrate interactions are implicated in many biochemical/biological processes that are fundamental to life and to human health. Fluorinated carbohydrate analogues play an important role in the study of these interactions and find application as probes in chemical biology and as drugs/diagnostics in medicine. The availability and/or efficient synthesis of a wide variety of fluorinated carbohydrates is thus of great interest. Here, we report a detailed study on the synthesis of monosaccharides in which the hydroxy groups at their 4- and 6-positions are replaced by all possible mono- and difluorinated motifs. Minimization of protecting group use was a key aim. It was found that introducing electronegative substituents, either as protecting groups or as deoxygenation intermediates, was generally beneficial for increasing deoxyfluorination yields. A detailed structural study of this set of analogues demonstrated that dideoxygenation/fluorination at the 4,6-positions caused very little distortion both in the solid state and in aqueous solution. Unexpected trends in α/β anomeric ratios were identified. Increasing fluorine content always increased the α/β ratio, with very little difference between regio- or stereoisomers, except when 4,6-difluorinated.

Text
4,6-dideoxy paper_revision v4acc - Accepted Manuscript
Restricted to Repository staff only until 24 May 2022.
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Accepted/In Press date: 14 May 2021
e-pub ahead of print date: 24 May 2021
Published date: 4 June 2021
Additional Information: Funding Information: This project has been funded by the Industrial Biotechnology Catalyst (Innovate UK, BBSRC, EPSRC, BB/M028941/1) to support the translation, development, and commercialization of innovative Industrial Biotechnology processes. We also thank the EPSRC (core capability EP/K039466/1) for funding. R.S. thanks the Southampton Excel programme for a fellowship. Carbosynth and Dextra are thanked for financial support. Julien Malassis is thanked for the crystallization of 19 . Publisher Copyright: © 2021 American Chemical Society. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

Identifiers

Local EPrints ID: 450092
URI: http://eprints.soton.ac.uk/id/eprint/450092
ISSN: 0022-3263
PURE UUID: 3cb99fcb-a81f-4efb-af2e-6ff80b4acd01
ORCID for Clement Q Fontenelle: ORCID iD orcid.org/0000-0002-1630-3407
ORCID for Neil J. Wells: ORCID iD orcid.org/0000-0002-4607-5791
ORCID for Mark Light: ORCID iD orcid.org/0000-0002-0585-0843
ORCID for Bruno Linclau: ORCID iD orcid.org/0000-0001-8762-0170

Catalogue record

Date deposited: 09 Jul 2021 16:33
Last modified: 26 Nov 2021 02:43

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Contributors

Author: David Wheatley
Author: Clement Q Fontenelle ORCID iD
Author: Rama krishna K Kuppala
Author: Robert Szpera
Author: Edward L. Briggs
Author: Jean B Vendeville
Author: Neil J. Wells ORCID iD
Author: Mark Light ORCID iD
Author: Bruno Linclau ORCID iD

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