Synthesis of chiral fluorides by sequential organocatalyzed desymmetrization of glutaric anhydrides and photoredox-catalyzed decarboxylic fluorination

Article abstract of DOI:10.1055/s-0040-1707295

We have developed an efficient method for the preparation of chiral fluorinated compounds by sequential organocatalyzed desymmetrization of 3-substituted glutaric anhydrides and photoredox-catalyzed decarboxylic fluorination. Chiral fluorides can be prepa

Full text of DOI:10.1055/s-0040-1707295

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 31, A–D
cluster
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Radicals – by Young Chinese Organic Che-
J.-J. Zhao, S. Yu
Cluster
Synlett
Synthesis of Chiral Fluorides by Sequential Organocatalyzed De-
symmetrization of Glutaric Anhydrides and Photoredox-Catalyzed
Decarboxylic Fluorination
Jia-Jia Zhao
OMe
Shouyun Yu*
0
0
0
0
-
0
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3
-
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9
2
-
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4
H
N
O
O
O
Ar
1. organocatalyst (10 mol%), ROH
State Key Laboratory of Analytical Chemistry for Life Science,
Jiangsu Key Laboratory of Advanced Organic Materials, School
of Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210023, P. R. of China
F
CO2R
NH
Ar
R
H
2. Ir(ppy)2(dtbbpy)PF6 (2 mol%)
Selectfluor, blue LEDs
S
N
O
O
up to 58% yield
98% ee
organocatalyst
R = 3,5-(CF3)2C6H3
yushouyun@nju.edu.cn
Published as part of the Cluster to be replaced
USethMnaoitavueiCelyKroyuserunirytseyYhLs,uaopNbuoaoynnrudjaniitn@oggrny2Aju1ou0.fteh0Ado2nur3a.c,lnyPt.iRca. ol fCChheminiastry for Life Science, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing
Received: 30.06.2020
Accepted after revision: 26.08.2020
Published online: 22.09.2020
chiral 3-substituted glutaric acid monoesters 2 (Scheme
1a).5 On the other hand, because of their stability, operabil-
ity, ready availability, and low cost, carboxylic acids are reg-
ularly used as raw materials in organic synthesis.6 Because
of its excellent site selectivity, decarboxylative functional-
ization has become an important strategy for constructing
new C–C or C–X bonds. The groups of MacMillan7, Sammis8,
Paquin9, and Ye10 have recently developed decarboxylative
fluorinations of alkanoic acids by photoredox catalysis, pro-
viding effective methods for constructing C–F bonds
(Scheme 1b).
DOI: 10.1055/s-0040-1707295; Art ID: st-2020-l0375-c
Abstract We have developed an efficient method for the preparation
of chiral fluorinated compounds by sequential organocatalyzed de-
symmetrization of 3-substituted glutaric anhydrides and photoredox-
catalyzed decarboxylic fluorination. Chiral fluorides can be prepared in
yields of up to 58% and with excellent enantioselectivities of up to 98% ee.
Key words sequential catalysis, organocatalysis, photoredox cataly-
sis, fluoro compounds, asymmetric catalysis, desymmetrization
a) Organocatalyzed alcoholytic desymmetrization of glutaric anhydrides
The pharmaceutical industry has seen a steady increase
in the number of drug candidates containing one or more
fluorine atoms.1 Many fluorinated analogues of natural
products have been synthesized because of the special
properties of the fluorine atom, such as its strong electro-
negativity, its capacity to enhance metabolic stability, its
small size, and the low polarizability of the C–F bond.2 Chi-
ral fluorides have a remarkable record in medicinal chemis-
try, and will play a continuing role in providing lead com-
pounds for therapeutic applications.3 Due to the prevalence
of fluorinated pharmaceuticals and pesticides, asymmetric
incorporation of fluorine into organic molecules has at-
tracted considerable attention from chemists.
R1
alcoholytic
desymmetrization
O
R1
O
or
ent-2
HO
OR2
chiral organocatalysts
O
O
O
R2 = alkyl, aryl, OSiR3
3
1
2
b) Photoredox-catalyzed decarboxylic fluorination of aliphatic carboxylic acids
photoredox catalysis
Alkyl-COOH
(MacMillan, Sammis, Paquin, and Ye)
Alkyl-F
c) Synthesis of chiral fluorides by sequential catalysis: this work
Ar
organocatalytic
PC
Ar
O
Ar
O
desymmetrization
F
CO2R
Selectfluor
OR
ROH
HO
O
O
O
Enantioselective desymmetrization is a powerful meth-
od for generating complex chiral compounds from relatively
simple achiral or meso starting materials.4 Cyclic meso-an-
hydrides are frequently used as substrates for enantioselec-
tive desymmetrization by nucleophilic ring-opening reac-
tions. A variety of nucleophiles, including alcohols and
amines, have been widely used in this reaction. The resul-
tant chiral carboxylic acids can undergo a variety of trans-
formations. Over the past two decades, various organocata-
lytic systems have been employed for the alcoholytic de-
symmetrization of meso-glutaric anhydrides 1 to produce
1
2
3
Scheme 1 Synthesis of chiral fluorides by sequential catalysis
Inspired by organocatalyzed desymmetrization and
photoredox-catalyzed decarboxylic fluorination, we at-
tempted to synthesize chiral fluorides by sequential or-
ganocatalyzed desymmetrization of 3-substituted glutaric
anhydrides and photoredox-catalyzed decarboxylic fluori-
nation of the resultant chiral carboxylic acids (Scheme
1c).11
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
J.-J. Zhao, S. Yu
Cluster
Synlett
This project started with the conversion of 3-phenylglu-
taric anhydride (1a) into the chiral fluoride 3a in a two-step
one-pot manner. Enantioselective methanolysis of anhy-
dride 1a with MeOH (10 equiv) in MTBE at –20 °C for 24
hours was catalyzed by organocatalyst A (10 mol%). When
the first step of the reaction was complete, the solvent was
evaporated and the resultant chiral acid 2a was redissolved
in a 1:1 mixture of acetonitrile and water. The mixture was
irradiated by 45 W blue LEDs in the presence of an Ir or Ru
photocatalyst (2 mol%), Selectfluor (3 equiv), and a base (2
equiv) for 12 hours at ambient temperature under N2. The
final chiral fluoride 3a was isolated upon purification. In at-
tempts to improve this result, organocatalysts A1–4 (Table
1, entries 1–4), photocatalysts I–V (entries 4–8), and sever-
al bases (entries 8–10) were tested [for the comprehensive
optimization of the conditions, see the Supporting Informa-
tion (SI)]. We found that a combination of sulfonamide A45c
as the organocatalyst, iridium complex I7 as the photocata-
lyst, and Na2HPO4 as the base gave the optimal results in
terms of yield and enantioselectivity (36% yield, 92% ee; en-
try 4). The yield was further improved to 58% without af-
fecting the enantioselectivity when the reaction was irradi-
ated by 40 W blue LEDs at the precise wavelength of 456
nm for 12 hours at 25 °C (entry 11).12,13 No reaction was ob-
served without visible-light irradiation (entry 12), and both
the bifunctional organocatalyst A4 and the Ir-based photo-
catalyst I were necessary to this transformation (entries 13
and 14).
We next investigated the generality and limitations of
this reaction under the optimized reaction conditions. A va-
riety of 3-substituted glutaric anhydrides 1 were converted
into the corresponding chiral fluorinated compounds 3a–h
in good yields (41–58%) and excellent enantioselectivities
(82–98% ee) (Scheme 2a). Substituted 3-phenylglutaric an-
hydrides with an electron-donating group (MeO) or an elec-
tron-withdrawing group (Cl) in the para-position of the
phenyl ring gave products 3b and 3c, respectively, with ex-
cellent enantioselectivities. 3-Phenylglutaric anhydrides
with substituents in the meta (3d and 3e) or ortho (3f and
3g) positions of the phenyl ring were also amenable to this
transformation, affording the corresponding products in
satisfactory yields (52–55%) and good enantioselectivities
(82–92% ee). 3-(3,4-Dichlorophenyl)glutaric anhydride was
also compatible with this reaction, and provided the prod-
uct 3h in good yield (56%) and high enantioselectivity (90%
ee). We then examined desymmetrization of 3-phenylglu-
taric anhydride (1a) with various alcohols (Scheme 2b).
EtOH, BuOH, and BnOH gave the desired products 3i, 3k,
and 3l in good yields of 55, 50, and 47%, respectively, and
with high enantioselectivities (86, 76, and 94% ee, respec-
tively). Bulky isobutanol also gave a good yield of the corre-
sponding product 3j (52%), but with a lower enantioselec-
Table 1 Optimization of the Reaction Conditionsa
O
organocatalyst A
Ph
Ph
photocatalyst
MeOH
O
O
F
CO2Me
HO2C
CO2Me
Ph
MTBE, –20 °C
Selectfluor, base
MeCN–H2O (1:1)
2a
3a
1a
Organocatalyst
Ar = 3,5-(F3C)2C6H3
OMe
OMe
H
OMe
H
N
Ph
Ph
N
H
N
H
N
H
N
Ar
H
N
H
OH
O
NH
NH
Ar
NH2
Ar
H
H
S
N
N
N
O
S
O
A1
A2
A3
A4
Photocatalyst
2+
2+
R1
2Cl
2PF6
N
N
R2
PF6
tBu
tBu
N
N
N
N
N
N
N
N
N
N
N
N
N
R2
R2
Ru
N
Ru
N
Ir
N
N
N
N
R2
R1
N
Ru(bpz)3(PF6)2 (IV)
Ru(bpy)3Cl2 (V)
Ir(ppy)2(dtbbpy)PF6 (I): R1 = R2 = H
Ir(dFCF3ppy)2(dtbbpy)PF6 (II): R1 = CF3; R2 = F
Ir(dFppy)2(dtbbpy)PF6 (III): R1 = H; R2 = F
Entry
Catalyst
Photocatalyst Base
Yieldb (%) eec (%)
1
2
A1
A2
A3
A4
A4
A4
A4
A4
A4
A4
A4
A4
–
I
Na2HPO4
12
11
17
36
35
35
25
13
17
9
–14
26
82
92
90
90
90
90
92
90
92
–
I
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
K2HPO4
3
I
4
I
5
II
III
IV
V
I
6
7
8
9
10
11d
12e
13
14
I
Na2CO3
I
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
58
NRf
NR
NR
I
I
–
A4
–
–
a Reaction conditions: 1a (0.10 mmol), MeOH (1 mmol), organocatalyst A
(0.01 mmol, 10 mol%), MTBE (3.0 mL), –20 °C, 24 h. After solvent removal,
2a, photocatalyst (0.002 mmol, 2 mol%), Selectfluor (0.3 mmol), base (0.2
mmol), 1:1 MeCN–H2O (1.0 mL), 45 W blue LEDs, r.t., 12 h.
b Isolated yield.
c Determined by HPLC on a chiral stationary phase.
d 40 W blue LEDs (456 nm) at 25 °C.
e In darkness.
f NR = no reaction.
tivity (68% ee). Substrates with electron-deficient aromatic,
furyl, or alkyl substituents were not successful (For the de-
tails, see the SI). This reaction of 3a was scaled up to 5
mmol scale with only slight decrease in yield (51%) and en-
antioselectivity (90% ee).
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

C
J.-J. Zhao, S. Yu
Cluster
Synlett
tional organocatalyst A4, gives the chiral glutaric acid mon-
oester 2a. Concurrently, photoexcitation of the ground-
state photocatalyst Ir(III) by visible light leads to excited
*Ir(III). Excited *Ir(III) undergoes oxidative quenching in the
presence of a sacrificial quantity of Selectfluor reagent, af-
fording the Ir(IV). The chiral glutaric acid monoester 2a un-
dergoes deprotonation, oxidation, and sequential elimina-
tion of CO2 with the assistance of the Na2HPO4 and oxidized
photocatalyst Ir(IV), delivering the alkyl radical intermedi-
ate 8 and regenerating the photocatalyst. After fluorine
transfer from Selectfluor to the alkyl radical species 8, the
chiral fluorinated product 3a is ultimately produced, to-
gether with radical cation 6.
O
O
O
1. A4 (10 mol%), ROH
MTBE, –20 °C, 24 h
Ar
F
CO2R
Ar
2. I (2 mol%), Na2HPO4, Selectfluor
MeCN–H2O (1:1), blue LEDs
25 °C, N2, 12 h
3
1
(a) Variation of meso-glutaric anhydrides
OMe
Cl
F
CO2Me
F
F
CO2Me
CO2Me
3a, 58%, 92% ee
3b, 41%, 98% ee
3c, 52%, 92% ee
(51%, 90% ee)a
Cl
Me
Me
F
CO2Me
F
CO2Me
F
CO2Me
Ph
F
CO2Me
Cl
3d, 55%, 90% ee
3e, 54%, 82% ee
3f, 52%, 92% ee
N
Cl
N
3a
N
Cl
N
7
Cl
6
F
*IrIII
reductant
IrIV
F
CO2Me
F
CO2Me
Cl
oxidant
N
N
3g, 54%, 92% ee
3h, 56%, 90% ee
photoredox
cycle
F
5
(b) Variation of alcohols
Ph
CO2Me
O
8
F
Me
Me
F
CO2Et
O
blue LED
– H+
– CO2
IrIII
3i, 55%, 86% ee
3j, 52%, 68% ee
O
O
Ph
catalyst A4
desymmetrization
HO2C
CO2Me
Ph
O
F
CO2Bn
F
2a
O
Me
O
1a
3k, 50%, 76% ee
3l, 47%, 94% ee
Scheme 4 Proposed mechanism
Scheme 2 Scope of the 3-arylglutaric anhydride. Reagents and condi-
tions: 1 (0.50 mmol), MeOH (5 mmol), A4 (0.05 mmol, 10 mol %),
MTBE (15.0 mL), –20 °C, 24 h; then (after solvent removal), 2, photo-
catalyst I (0.010 mmol, 2 mol %), Selectfluor (1.5 mmol), Na2HPO4 (1
mmol), 1:1 MeCN–H2O (5.0 mL), 40 W blue LEDs (456 nm), 25 °C, 12 h.
a 5 mmol scale.
In conclusion, we have developed a method for the syn-
thesis of chiral fluorides. This method involves sequential
organocatalyzed desymmetrization of 3-substituted glutar-
ic anhydrides and photoredox-catalyzed decarboxylic fluo-
rination of the resultant chiral carboxylic acids. This strate-
gy provides an efficient way to access chiral fluorinated
compounds in a highly enantioselective manner.
The synthetic utility of the present procedure was fur-
ther demonstrated by the reduction of the chiral fluorinat-
ed ester 3a to the fluorinated alcohol 4 without loss of en-
antiopurity (Scheme 3).
Funding Information
Financial support from National Natural Science Foundation of China
LiAlH4, THF
(21732003) is acknowledged.Natio
n
alNaturalScienceFo
u
n
datio
n
o
f
C
h
i
na(2
1
7
3
2
0
0
3)
F
F
CO2Me
3a (90% ee)
OH
4 91% (90% ee)
1 mmol scale
Supporting Information
Scheme 3 Transformation of enantioenriched 3a
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707295. Su
p
p
ortingInformatio
n
Su
p
p
ortingInformatio
n
Based on reported precedents,5c,7 a plausible reaction
pathway is outlined in Scheme 4. Initially, glutaric anhy-
dride 1a, upon alcoholytic desymmetrization by bifunc-
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

D
J.-J. Zhao, S. Yu
Cluster
Synlett
References and Notes
(7) Ventre, S.; Petronijevic, F. R.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2015, 137, 5654.
(1) (a) Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.;
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem.
Rev. 2014, 114, 2432. (b) Mei, H.; Han, J.; Fustero, S.; Medio-
Simon, M.; Sedgwick, D. M.; Santi, C.; Ruzziconi, R.; Soloshonok,
V. A. Chem. Eur. J. 2019, 25, 11797. (c) Zhou, Y.; Wang, J.; Gu, Z.;
Wang, S.; Zhu, W.; Aceña, J. L.; Soloshonok, V. A.; Izawa, K.; Liu,
H. Chem. Rev. 2016, 116, 422.
(2) Bégué, J.-P.; Bonnet-Delpon, D.; Croussea, B.; Legrosa, J. Chem.
Soc. Rev. 2005, 34, 562.
(3) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 320.
(4) For reviews on asymmetric alcoholysis of cyclic anhydrides,
see: (a) Atodiresei, I.; Schiffers, I.; Bolm, C. Chem. Rev. 2007, 107,
5683. (b) Chen, Y.; McDaid, P.; Deng, L. Chem. Rev. 2003, 103,
2965. (c) Spivey, A. C.; Andrews, B. I. Angew. Chem. Int. Ed. 2001,
40, 3131. (d) Rodriguez-Docampo, Z.; Connon, S. J. Chem-
CatChem 2012, 4, 151. (e) Díaz de Villegas, M. D.; Gálvez, J. A.;
Etayo, P.; Badorrey, R.; López-Ram-de-Víu, P. Chem. Soc. Rev.
2011, 40, 5564.
(5) (a) Fryszkowska, A.; Komar, M.; Koszelewskia, D.; Ostaszewski,
R. Tetrahedron: Asymmetry 2005, 16, 2475. (b) Peschiulli, A.;
Gun’k, Y.; Connon, S. J. J. Org. Chem. 2008, 73, 2454. (c) Oh, S. H.;
Rho, H. S.; Lee, J. W.; Lee, J. E.; Youk, S. H.; Chin, J.; Song, C. E.
Angew. Chem. Int. Ed. 2008, 47, 7872. (d) Wang, S.-X.; Chen, F.-E.
Adv. Synth. Catal. 2009, 351, 547. (e) Park, S. E.; Nam, E. H.; Jang,
H. B.; Oh, J. S.; Some, S.; Lee, Y. S.; Song, C. E. Adv. Synth. Catal.
2010, 352, 2211. (f) Yan, L.-J.; Wang, H.-F.; Chen, W.-X.; Tao, Y.;
Jin, K.-J.; Chen, F.-E. ChemCatChem 2016, 8, 2249.
(6) For reviews on decarboxylative reactions, see: (a) Dzik, W. I.;
Lange, P. P.; Gooßen, L. J. Chem. Sci. 2012, 3, 2671. (b) Shang, R.;
Liu, L. Sci. China: Chem. 2011, 54, 1670. (c) Weaver, J. D.; Recio,
A. III.; Grenning, A. J.; Tunge, J. A. Chem. Rev. 2011, 111, 1846.
(d) Rodríguez, N.; Gooßen, L. J. Chem. Soc. Rev. 2011, 40, 5030.
(e) Gooßen, L. J.; Rodríguez, N.; Gooßen, K. Angew. Chem. Int. Ed.
2008, 47, 3100.
(8) Leung, J. C. T.; Sammis, G. M. Eur. J. Org. Chem. 2015, 2197.
(9) Rueda-Becerril, M.; Mahé, O.; Drouin, M.; Majewski, M. B.;
West, J. G.; Wolf, M. O.; Sammis, G. M.; Paquin, J.-F. J. Am. Chem.
Soc. 2014, 136, 2637.
(10) Wu, X.; Meng, C.; Yuan, X.; Qian, X.; Jia, X.; Ye, J. Chem. Commun.
2015, 51, 11864.
(11) Chen, D.-F.; Han, Z. Y.; Zhou, X.-L.; Gong, L.-Z. Acc. Chem. Res.
2014, 47, 2365.
(12) Alkyl 3-Aryl-4-fluorobutanoates 3; General Procedure
MTBE (15 mL) was added to a mixture of the appropriate 3-
arylglutaric anhydride 1 (0.5 mmol) and catalyst A4 (0.05
mmol), and the mixture was stirred at –20 °C for 30 min. MeOH
(5 mmol) was added, and stirring was continued at –20 °C for
24 h. When the reaction was complete, the solvent was evapo-
rated under reduced pressure without further purification. The
residue was dissolved in 1:1 MeCN–H2O (5.0 mL) and
Ir(ppy)2(dtbbpy)PF6 (I) (0.010 mmol, 2 mol%), Selectfluor (1.5
mmol), and Na2HPO4 (1 mmol) were added. The mixture was
irradiated by 40 W (456 nm) blue LEDs for 12 h at 25 °C under
N2 until the reaction was complete. The reaction was then
quenched with aq NaCl, the mixture was extracted with Et2O,
and the extracts were purified by preparative TLC.
(13) Methyl (R)-4-Fluoro-3-phenylbutanoate (3a)
Purified by preparative TLC (PE–EtOAc, 10:1) to give a white oil;
yield: 56.8 mg (58%, ee 92%); []D20 = –37.9 (c 2.15, CHCl3). HPLC
[Daicel Chiralpak OD-H, hexane–i-PrOH (98:2), flow rate: 1.0
mL/min, T = 25 °C,  = 220 nm]: tR = 8.292 min (major), tR
=
14.765 min (minor). 1H NMR (400 MHz, CDCl3):  = 7.36–7.29
(m, 2 H), 7.28–7.22 (m, 3 H), 4.68–4.41 (m, 2 H), 3.62 (s, 3 H),
3.59–3.46 (m, 1 H), 2.89 (dd, J = 16.0, 6.9 Hz, 1 H), 2.70 (dd, J =
16.0, 8.0 Hz, 1 H). 13C NMR (100 MHz, CDCl3):  = 172.2, 139.5,
128.7, 127.8, 127.4, 86.1 (J = 173.0 Hz), 51.7, 42.6, 36.3. 19F NMR
(376 MHz, CDCl3):  = –219.8. ESI (FTMS): m/z [M + Na]+ calcd
for C11H13FNaO2: 219.0798; found: 219.0801.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–D