Syntheses of TN building blocks Nα-(9- fluorenylmethoxycarbonyl)-O-(3,4,6-tri-O-acetyl-2-azido-2-deoxy-α-D- galactopyranosyl)-L-serine/L-threonine pentafluorophenyl esters: Comparison of protocols and elucidation of side reactions

Mian Liu; Victor G. Young; Sachin Lohani; David Live; George Barany

doi:10.1016/j.carres.2005.02.029

Syntheses of T_N building blocks N^α-(9- fluorenylmethoxycarbonyl)-O-(3,4,6-tri-O-acetyl-2-azido-2-deoxy-α-D- galactopyranosyl)-L-serine/L-threonine pentafluorophenyl esters: Comparison of protocols and elucidation of side reactions

Mian Liu, Victor G. Young, Sachin Lohani, David Live, George Barany

Chemistry (Twin Cities)

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

Abstract

T_N antigen building blocks N^α-(9- fluorenylmethoxycarbonyl)-O-(3,4,6-tri-O-acetyl-2-azido-2-deoxy-α-d- galactopyranosyl)-l-serine/l-threonine pentafluorophenyl ester [Fmoc-l-Ser/l-Thr(Ac₃-α-d-GalN₃)-OPfp, 13/14] have been synthesized by two different routes, which have been compared. Overall isolated yields [three or four chemical steps, and minimal intermediary purification steps] of enantiopure 13 and 14 were 5-18% and 6-10%, respectively, based on 3,4,6-tri-O-acetyl-d-galactal (1). A byproduct of the initial azidonitration reaction of the synthetic sequence, that is, N-acetyl-3,4,6-tri- O-acetyl-2-azido-2-deoxy-α-d-galactopyranosylamine (5), has been characterized by X-ray crystallography, and shown by ¹H NMR spectroscopy to form complexes with lithium bromide, lithium iodide, or sodium iodide in acetonitrile-d₃. Intermediates 3,4,6-tri-O-acetyl-2-azido- 2-deoxy-α-d-galactopyranosyl bromide (6) and 3,4,6-tri-O-acetyl-2-azido-2- deoxy-β-d-galactopyranosyl chloride (7) were used to glycosylate N ^α-(9-fluorenylmethoxycarbonyl)-l-serine/l-threonine pentafluorophenyl esters [Fmoc-l-Ser/l-Thr-OPfp, 11/12]. Previously undescribed low-level dehydration side reactions were observed at this stage; the unwanted byproducts were easily removed by column chromatography.

Original language	English (US)
Pages (from-to)	1273-1285
Number of pages	13
Journal	Carbohydrate Research
Volume	340
Issue number	7
DOIs	https://doi.org/10.1016/j.carres.2005.02.029
State	Published - May 23 2005

Bibliographical note

Funding Information:
We thank Professor Gary R. Gray for critical reading of the manuscript and William W. Brennessel of the X-ray Crystallographic Laboratory of the Department of Chemistry at the University of Minnesota for assistance in solving the structure of 5 . An anonymous referee made several helpful suggestions, which are appreciated insofar as they guided revision of the manuscript. This work was supported by grant GM 66148 from the National Institute of Health.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

Keywords

Dehydroalanine
Glycopeptide synthetic building blocks
Glycosylation
Metal ion-carbohydrate complexes
Side reactions
Z-Dehydrothreonine

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Liu, M., Young, V. G., Lohani, S., Live, D., & Barany, G. (2005). Syntheses of T_N building blocks N^α-(9- fluorenylmethoxycarbonyl)-O-(3,4,6-tri-O-acetyl-2-azido-2-deoxy-α-D- galactopyranosyl)-L-serine/L-threonine pentafluorophenyl esters: Comparison of protocols and elucidation of side reactions. Carbohydrate Research, 340(7), 1273-1285. https://doi.org/10.1016/j.carres.2005.02.029

Syntheses of T_N building blocks N^α-(9- fluorenylmethoxycarbonyl)-O-(3,4,6-tri-O-acetyl-2-azido-2-deoxy-α-D- galactopyranosyl)-L-serine/L-threonine pentafluorophenyl esters: Comparison of protocols and elucidation of side reactions. / Liu, Mian; Young, Victor G.; Lohani, Sachin et al.
In: Carbohydrate Research, Vol. 340, No. 7, 23.05.2005, p. 1273-1285.

Research output: Contribution to journal › Article › peer-review

Liu, M, Young, VG, Lohani, S, Live, D & Barany, G 2005, 'Syntheses of T_N building blocks N^α-(9- fluorenylmethoxycarbonyl)-O-(3,4,6-tri-O-acetyl-2-azido-2-deoxy-α-D- galactopyranosyl)-L-serine/L-threonine pentafluorophenyl esters: Comparison of protocols and elucidation of side reactions', Carbohydrate Research, vol. 340, no. 7, pp. 1273-1285. https://doi.org/10.1016/j.carres.2005.02.029

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title = "Syntheses of TN building blocks Nα-(9- fluorenylmethoxycarbonyl)-O-(3,4,6-tri-O-acetyl-2-azido-2-deoxy-α-D- galactopyranosyl)-L-serine/L-threonine pentafluorophenyl esters: Comparison of protocols and elucidation of side reactions",

abstract = "TN antigen building blocks Nα-(9- fluorenylmethoxycarbonyl)-O-(3,4,6-tri-O-acetyl-2-azido-2-deoxy-α-d- galactopyranosyl)-l-serine/l-threonine pentafluorophenyl ester [Fmoc-l-Ser/l-Thr(Ac3-α-d-GalN3)-OPfp, 13/14] have been synthesized by two different routes, which have been compared. Overall isolated yields [three or four chemical steps, and minimal intermediary purification steps] of enantiopure 13 and 14 were 5-18% and 6-10%, respectively, based on 3,4,6-tri-O-acetyl-d-galactal (1). A byproduct of the initial azidonitration reaction of the synthetic sequence, that is, N-acetyl-3,4,6-tri- O-acetyl-2-azido-2-deoxy-α-d-galactopyranosylamine (5), has been characterized by X-ray crystallography, and shown by 1H NMR spectroscopy to form complexes with lithium bromide, lithium iodide, or sodium iodide in acetonitrile-d3. Intermediates 3,4,6-tri-O-acetyl-2-azido- 2-deoxy-α-d-galactopyranosyl bromide (6) and 3,4,6-tri-O-acetyl-2-azido-2- deoxy-β-d-galactopyranosyl chloride (7) were used to glycosylate N α-(9-fluorenylmethoxycarbonyl)-l-serine/l-threonine pentafluorophenyl esters [Fmoc-l-Ser/l-Thr-OPfp, 11/12]. Previously undescribed low-level dehydration side reactions were observed at this stage; the unwanted byproducts were easily removed by column chromatography.",

keywords = "Dehydroalanine, Glycopeptide synthetic building blocks, Glycosylation, Metal ion-carbohydrate complexes, Side reactions, Z-Dehydrothreonine",

author = "Mian Liu and Young, {Victor G.} and Sachin Lohani and David Live and George Barany",

note = "Funding Information: We thank Professor Gary R. Gray for critical reading of the manuscript and William W. Brennessel of the X-ray Crystallographic Laboratory of the Department of Chemistry at the University of Minnesota for assistance in solving the structure of 5 . An anonymous referee made several helpful suggestions, which are appreciated insofar as they guided revision of the manuscript. This work was supported by grant GM 66148 from the National Institute of Health. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.",

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T2 - Comparison of protocols and elucidation of side reactions

AU - Liu, Mian

AU - Young, Victor G.

AU - Lohani, Sachin

AU - Live, David

AU - Barany, George

N1 - Funding Information: We thank Professor Gary R. Gray for critical reading of the manuscript and William W. Brennessel of the X-ray Crystallographic Laboratory of the Department of Chemistry at the University of Minnesota for assistance in solving the structure of 5 . An anonymous referee made several helpful suggestions, which are appreciated insofar as they guided revision of the manuscript. This work was supported by grant GM 66148 from the National Institute of Health. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.

PY - 2005/5/23

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N2 - TN antigen building blocks Nα-(9- fluorenylmethoxycarbonyl)-O-(3,4,6-tri-O-acetyl-2-azido-2-deoxy-α-d- galactopyranosyl)-l-serine/l-threonine pentafluorophenyl ester [Fmoc-l-Ser/l-Thr(Ac3-α-d-GalN3)-OPfp, 13/14] have been synthesized by two different routes, which have been compared. Overall isolated yields [three or four chemical steps, and minimal intermediary purification steps] of enantiopure 13 and 14 were 5-18% and 6-10%, respectively, based on 3,4,6-tri-O-acetyl-d-galactal (1). A byproduct of the initial azidonitration reaction of the synthetic sequence, that is, N-acetyl-3,4,6-tri- O-acetyl-2-azido-2-deoxy-α-d-galactopyranosylamine (5), has been characterized by X-ray crystallography, and shown by 1H NMR spectroscopy to form complexes with lithium bromide, lithium iodide, or sodium iodide in acetonitrile-d3. Intermediates 3,4,6-tri-O-acetyl-2-azido- 2-deoxy-α-d-galactopyranosyl bromide (6) and 3,4,6-tri-O-acetyl-2-azido-2- deoxy-β-d-galactopyranosyl chloride (7) were used to glycosylate N α-(9-fluorenylmethoxycarbonyl)-l-serine/l-threonine pentafluorophenyl esters [Fmoc-l-Ser/l-Thr-OPfp, 11/12]. Previously undescribed low-level dehydration side reactions were observed at this stage; the unwanted byproducts were easily removed by column chromatography.

AB - TN antigen building blocks Nα-(9- fluorenylmethoxycarbonyl)-O-(3,4,6-tri-O-acetyl-2-azido-2-deoxy-α-d- galactopyranosyl)-l-serine/l-threonine pentafluorophenyl ester [Fmoc-l-Ser/l-Thr(Ac3-α-d-GalN3)-OPfp, 13/14] have been synthesized by two different routes, which have been compared. Overall isolated yields [three or four chemical steps, and minimal intermediary purification steps] of enantiopure 13 and 14 were 5-18% and 6-10%, respectively, based on 3,4,6-tri-O-acetyl-d-galactal (1). A byproduct of the initial azidonitration reaction of the synthetic sequence, that is, N-acetyl-3,4,6-tri- O-acetyl-2-azido-2-deoxy-α-d-galactopyranosylamine (5), has been characterized by X-ray crystallography, and shown by 1H NMR spectroscopy to form complexes with lithium bromide, lithium iodide, or sodium iodide in acetonitrile-d3. Intermediates 3,4,6-tri-O-acetyl-2-azido- 2-deoxy-α-d-galactopyranosyl bromide (6) and 3,4,6-tri-O-acetyl-2-azido-2- deoxy-β-d-galactopyranosyl chloride (7) were used to glycosylate N α-(9-fluorenylmethoxycarbonyl)-l-serine/l-threonine pentafluorophenyl esters [Fmoc-l-Ser/l-Thr-OPfp, 11/12]. Previously undescribed low-level dehydration side reactions were observed at this stage; the unwanted byproducts were easily removed by column chromatography.

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KW - Glycopeptide synthetic building blocks

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KW - Metal ion-carbohydrate complexes

KW - Side reactions

KW - Z-Dehydrothreonine

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