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Synthesis and conformational properties of 3,4-difluoro-L-prolines

Synthesis and conformational properties of 3,4-difluoro-L-prolines
Synthesis and conformational properties of 3,4-difluoro-L-prolines
Fluorinated proline derivatives have found diverse applications in areas ranging from medicinal chemistry over structural biochemistry to organocatalysis. Depending on the stereochemistry of monofluorination at the proline 3- or 4-position, different effects on the conformational properties of proline (ring pucker, cis/trans isomerization) are introduced. Simultaneous fluorination at the 3- and 4-positions is expected to either reinforce or oppose these effects. Here we report, in full, the syntheses and conformational properties of three out of the four possible 3,4-difluoro-L-proline diastereoisomers. The yet unreported conformational properties are described for (3S,4S)- and (3R,4R)-difluoro-L-proline, which are shown to bias ring pucker and cis-trans ratios on the same order of magnitude as their respective monofluorinated progenitors, although with significantly faster amide cis-trans isomerization rates. The reported analogues thus expand the scope of available fluorinated proline analogues as tools to tailor proline’s distinct conformational and dynamical properties, allowing to interrogate its role in, for instance, protein stability or folding.
0022-3263
Hofman, Gert-Jan
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Ottoy, Emile
d34b7519-7bc5-4f61-8bc8-5a0ec5584b62
Light, Mark
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Kieffer, Bruno
34187faf-4dc3-4d1b-895c-cee8ce760217
Martins, José C.
6ca83d5b-f416-4309-a2ec-fe10d5024881
Kuprov, Ilya
bb07f28a-5038-4524-8146-e3fc8344c065
Sinnaeve, Davy
1bff7c9e-d706-4318-9042-b291807752d6
Linclau, Bruno
19b9cacd-b8e8-4c65-af36-6352cade84ba
Hofman, Gert-Jan
696ede89-26ae-4a7e-88d8-0574fce74d93
Ottoy, Emile
d34b7519-7bc5-4f61-8bc8-5a0ec5584b62
Light, Mark
cf57314e-6856-491b-a8d2-2dffc452e161
Kieffer, Bruno
34187faf-4dc3-4d1b-895c-cee8ce760217
Martins, José C.
6ca83d5b-f416-4309-a2ec-fe10d5024881
Kuprov, Ilya
bb07f28a-5038-4524-8146-e3fc8344c065
Sinnaeve, Davy
1bff7c9e-d706-4318-9042-b291807752d6
Linclau, Bruno
19b9cacd-b8e8-4c65-af36-6352cade84ba

Hofman, Gert-Jan, Ottoy, Emile, Light, Mark, Kieffer, Bruno, Martins, José C., Kuprov, Ilya, Sinnaeve, Davy and Linclau, Bruno (2019) Synthesis and conformational properties of 3,4-difluoro-L-prolines. Journal of Organic Chemistry. (doi:10.1021/acs.joc.8b02920).

Record type: Article

Abstract

Fluorinated proline derivatives have found diverse applications in areas ranging from medicinal chemistry over structural biochemistry to organocatalysis. Depending on the stereochemistry of monofluorination at the proline 3- or 4-position, different effects on the conformational properties of proline (ring pucker, cis/trans isomerization) are introduced. Simultaneous fluorination at the 3- and 4-positions is expected to either reinforce or oppose these effects. Here we report, in full, the syntheses and conformational properties of three out of the four possible 3,4-difluoro-L-proline diastereoisomers. The yet unreported conformational properties are described for (3S,4S)- and (3R,4R)-difluoro-L-proline, which are shown to bias ring pucker and cis-trans ratios on the same order of magnitude as their respective monofluorinated progenitors, although with significantly faster amide cis-trans isomerization rates. The reported analogues thus expand the scope of available fluorinated proline analogues as tools to tailor proline’s distinct conformational and dynamical properties, allowing to interrogate its role in, for instance, protein stability or folding.

Text
Difluoroproline manuscript 2 with corrections v6_acc - Accepted Manuscript
Restricted to Repository staff only until 19 February 2020.
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More information

Accepted/In Press date: 19 February 2019
e-pub ahead of print date: 19 February 2019

Identifiers

Local EPrints ID: 428836
URI: https://eprints.soton.ac.uk/id/eprint/428836
ISSN: 0022-3263
PURE UUID: 8942ddda-4562-4a4f-90fc-6f848b203d84
ORCID for Mark Light: ORCID iD orcid.org/0000-0002-0585-0843
ORCID for Ilya Kuprov: ORCID iD orcid.org/0000-0003-0430-2682
ORCID for Bruno Linclau: ORCID iD orcid.org/0000-0001-8762-0170

Catalogue record

Date deposited: 11 Mar 2019 17:30
Last modified: 20 Jul 2019 01:10

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