Selectively fluorinated citronellol analogues support a hydrogen bonding donor interaction with the human OR1A1 olfactory receptor

Mengfan He; Weihong Liu; Chen Zhang; Yingjian Liu; Hanyi Zhuang; David O'Hagan

doi:10.1021/acs.orglett.2c01635

Selectively fluorinated citronellol analogues support a hydrogen bonding donor interaction with the human OR1A1 olfactory receptor

Mengfan He
, Weihong Liu
, Chen Zhang
, Yingjian Liu
, Hanyi Zhuang^*
, David O'Hagan^*

^*Corresponding author for this work

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

Abstract

C-2 fluorinated and methylated stereoisomers of the fragrance citronellol 1 and its oxalate esters were prepared from (R)-pulegone 11 and explored as agonists of the human olfactory receptor OR1A1 and assayed also against site-specific mutants. There were clear isomer preferences and C-2 difluorination as in 18 led to the most active compound suggesting an important hydrogen bond donor role for citronellol 1. C-2 methylation and the corresponding oxalate ester analogues were less active.

Original language	English
Pages (from-to)	4415-4420
Number of pages	6
Journal	Organic Letters
Volume	24
Issue number	24
Early online date	10 Jun 2022
DOIs	https://doi.org/10.1021/acs.orglett.2c01635
Publication status	Published - 24 Jun 2022

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10.1021/acs.orglett.2c01635Licence: CC BY

He_2022_OL_Selectively-fluorinated-citronellol-analogues_CC
Copyright © 2022 The Authors. Published by American Chemical Society. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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The impact of selective fluorination on the properties of aliphatic and bioactive molecules
He, M. (Author), O'Hagan, D. (Supervisor), 3 Jul 2025
Student thesis: Doctoral Thesis (PhD)

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title = "Selectively fluorinated citronellol analogues support a hydrogen bonding donor interaction with the human OR1A1 olfactory receptor",

abstract = "C-2 fluorinated and methylated stereoisomers of the fragrance citronellol 1 and its oxalate esters were prepared from (R)-pulegone 11 and explored as agonists of the human olfactory receptor OR1A1 and assayed also against site-specific mutants. There were clear isomer preferences and C-2 difluorination as in 18 led to the most active compound suggesting an important hydrogen bond donor role for citronellol 1. C-2 methylation and the corresponding oxalate ester analogues were less active.",

author = "Mengfan He and Weihong Liu and Chen Zhang and Yingjian Liu and Hanyi Zhuang and David O'Hagan",

note = "Authors thank the Chinese Scholarship Council for funding a Studentship (No. 202008060063) at the University of St. Andrews, U.K.",

year = "2022",

month = jun,

day = "24",

doi = "10.1021/acs.orglett.2c01635",

language = "English",

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journal = "Organic Letters",

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T1 - Selectively fluorinated citronellol analogues support a hydrogen bonding donor interaction with the human OR1A1 olfactory receptor

AU - He, Mengfan

AU - Liu, Weihong

AU - Zhang, Chen

AU - Liu, Yingjian

AU - Zhuang, Hanyi

AU - O'Hagan, David

N1 - Authors thank the Chinese Scholarship Council for funding a Studentship (No. 202008060063) at the University of St. Andrews, U.K.

PY - 2022/6/24

Y1 - 2022/6/24

N2 - C-2 fluorinated and methylated stereoisomers of the fragrance citronellol 1 and its oxalate esters were prepared from (R)-pulegone 11 and explored as agonists of the human olfactory receptor OR1A1 and assayed also against site-specific mutants. There were clear isomer preferences and C-2 difluorination as in 18 led to the most active compound suggesting an important hydrogen bond donor role for citronellol 1. C-2 methylation and the corresponding oxalate ester analogues were less active.

AB - C-2 fluorinated and methylated stereoisomers of the fragrance citronellol 1 and its oxalate esters were prepared from (R)-pulegone 11 and explored as agonists of the human olfactory receptor OR1A1 and assayed also against site-specific mutants. There were clear isomer preferences and C-2 difluorination as in 18 led to the most active compound suggesting an important hydrogen bond donor role for citronellol 1. C-2 methylation and the corresponding oxalate ester analogues were less active.

U2 - 10.1021/acs.orglett.2c01635

DO - 10.1021/acs.orglett.2c01635

M3 - Article

SN - 1523-7060

VL - 24

SP - 4415

EP - 4420

JO - Organic Letters

JF - Organic Letters

IS - 24

ER -

Selectively fluorinated citronellol analogues support a hydrogen bonding donor interaction with the human OR1A1 olfactory receptor

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The impact of selective fluorination on the properties of aliphatic and bioactive molecules

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