Regioselective organocatalyzed asymmetric bromolactonization of aryl acrylate-type carboxylic acids: a new approach towards enantioenriched 3-substituted isobenzofuranones

Article abstract of DOI:10.1016/j.tetasy.2016.07.010

The enantioselective synthesis of several 3-substituted isobenzofuranones has been developed through a new and flexible route. When combined with a catalytic amount of benzoic acid, quinidine thiocarbamate bifunctional catalysts have demonstrated their efficiency for the highly regioselective organocatalyzed asymmetric bromolactonization reaction of aryl acrylate-type carboxylic acids.

Full text of DOI:10.1016/j.tetasy.2016.07.010

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Regioselective organocatalyzed asymmetric bromolactonization
of aryl acrylate-type carboxylic acids: a new approach towards
enantioenriched 3-substituted isobenzofuranones
⇑
Fabien Gelat, Michaël Coffinet, Stéphane Lebrun, Francine Agbossou-Niedercorn, Christophe Michon ,
Eric Deniau
⇑
Univ. Lille, CNRS, Centrale Lille, ENSCL, Univ. Artois, UMR 8181-UCCS-Unité de Catalyse et Chimie du Solide, F-59000 Lille, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective synthesis of several 3-substituted isobenzofuranones has been developed through a
new and flexible route. When combined with a catalytic amount of benzoic acid, quinidine thiocarbamate
bifunctional catalysts have demonstrated their efficiency for the highly regioselective organocatalyzed
asymmetric bromolactonization reaction of aryl acrylate-type carboxylic acids.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 18 July 2016
Accepted 29 July 2016
Available online xxxx
1. Introduction
O
O
O
O
Y
Electrophilic halocyclization reactions of unsaturated acids are
versatile synthetic transformations, which represent an important
class of reactions in organic synthesis.1 In particular, halolactoniza-
tions have been widely used in organic chemistry for the synthesis
of natural products and/or biologically active compounds.2 In addi-
tion to constructing lactone ring system, halolactonization reac-
tions introduce halogen atoms into intermediates, which can be
utilized in further synthetic transformations. Halolactonization
reactions generally consist of the initial formation of a halonium
ion intermediate via an initial electrophilic addition of the halogen
to the olefin (Scheme 1).
Subsequent antiperiplanar intramolecular cyclization through
substitution by an internal oxygenated nucleophile on the carbon
of the halonium ion leads to the formation of the halolactones.
Halolactonization reactions usually proceed with a high degree of
diastereoselectivity in a highly predictable manner. However, they
can suffer from a lack of regioselectivity and they may also produce
constitutional isomers arising from an exo or endo cyclization1k,3
(Scheme 1). In comparison with the number of examples of
substrate-controlled diastereoselective halolactonizations,4 enan-
tioselective versions under reagent or catalyst control have proven
more difficult to realize and have only emerged recently (vide
infra).5 This can be attributed mainly to the difficulty in identifying
X-Y
O
O
OH
OH
or
R
1
R
X
X
X
2
R
R
exo-tet
Scheme 1. General scheme of halolactonization.
endo-tet
a suitable catalytic system, which allows for the effective transfer
of the chiral information during lactonization. Moreover, the enan-
tiomerically enriched halonium-olefin intermediate may racemize
through a rapid olefin-olefin halogen exchange.6 Since 2010,
intense research efforts have led to the development of organocat-
alyzed enantioselective halolactonization reactions in which the
stereochemistry can be controlled by a chiral carboxylate anion
and/or chiral positive halogen ion. In this context, a wide array of
organocatalysts, including biscinchona alkaloids, aminoureas,
aminothiocarbamates, S-alkylthiocarbamates, squaramides, ami-
dine-phenol, and a trisimidazoline has been reported to induce
highly enantioselective processes. On the other hand, the range
of studied substrates is still limited because only alkyl and aryl-
substituted pentenoic or hexenoic acid derivatives have been
examined in most cases. Hence, despite the huge synthetic poten-
tial, enantioselective halolactonizations of styrene-type carboxylic
acids have not elicited many synthetic efforts from the scientific
community and remained poorly explored.5k,t,x,y Moreover,
halocyclization of such unsaturated compounds is challenging
⇑
Corresponding authors. Tel.: +33 (0)3 20 43 68 63 (C.M.); tel.: +33 (0)3 20 33 71
48; fax: +33 (0)3 20 33 63 09 (E.D.).
E-mail addresses: Christophe.Michon@ensc-lille.fr (C. Michon), Eric.Deniau@
univ-lille1.fr (E. Deniau).
http://dx.doi.org/10.1016/j.tetasy.2016.07.010
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Gelat, F.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.07.010

2
F. Gelat et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
O
O
since the presence of an aryl ring significantly reduces the
regioselectivity of the reaction, with both 6-endo or 5-exo
cyclization pathways being possible depending on the
O
R1
R2
R1
R2
R1
R2
OH
Y
O
stereoelectronic
factors.
The
regioselectivity
of
the
halocyclization reaction is mainly governed by the electronic
effects of the substituents connected to the styrenic carbon–
carbon double bond.5k,x For instance, electron-rich groups
connected at C2 favored the 6-endo product while more electron
deficient groups gave higher 5-exo selectivity due to the
destabilization of the 6-endo cyclization pathway.5k The solvent,
catalyst and additives seem to have a minor impact on the
regioselectivity but their roles remains unclear and are still
under investigation.7 Since considerable work has been achieved
in our laboratory on the synthesis of enantioenriched isoin-
dolinones,8 we recently extended our interest to their oxygenated
analogues i.e. isobenzofuranones I. These chiral bicyclic lactones
display a wide array of biological activities9 and constitute the
main core of a minor group of natural products such as isoochraci-
nic II10 or herbaric acids III11 bearing a carboxymethyl group at the
3 position of the lactone ring system (Fig. 1).
CO2R3
CO2R3
CO2R3
Br
1-4
5-8
9,10 Y=Ot-Bu
11-13
Y=H
Scheme 2. Retrosynthetic analysis.
O
O
R1
R2
PdCl2(PPh3)3
(5 mol%)
R1
R2
Y
Y
+
CO2R3
19a-e
(2 equiv.)
Et3N (5 equiv.)
DMSO, 100 °C
15 h
Br
CO2R3
14,15 Y=Ot-Bu
16-18 Y=H
9,10
11-13 Y=H
Y=Ot-Bu
TFA, CH2Cl2, rt
O
Y=Ot-Bu
R1
R2
OH
OH
O
O
O
OH
NaClO2, NaH2PO4
1
O2
O
O
, t-BuOH, rt, 2 h
HO
Y=H
CO2R3
3
CO2H
5-8
Scheme 3. Synthesis of unsaturated benzoic acids 5–8.
CO2H
isoochracinic acid II
herbaric acid III
I
isobenzofuranone
Figure 1. Natural 3-substituted bioactive isobenzofuranones.
Table 1
Compounds 5–8, 9–13 prepared
Organic chemists have a variety of strategies at their disposal
for the racemic synthesis of functionalized isobenzofuranone bear-
ing a carboxymethyl group at C3, which are mainly based upon the
lactone ring construction.12 Otherwise, starting from racemic 3-
substitued phthalides, the synthesis of enantioenriched 3,3-disub-
stituted benzofuranones has been reported using organocatalyzed
reactions such as Mannich, allylic alkylation or Michael addi-
tions.13 However, a few efforts have been devoted to the asymmet-
ric synthesis of 3-carboxy isobenzofuranones and, to the best of
our knowledge, only two stereoselective synthesis of such com-
pounds have been developed so far.14 Consequently, the develop-
ment of highly regioselective organocatalyzed asymmetric
synthetic methodologies for the elaboration of 3-substituted
isobenzofuranones constitutes an area of current interest.
Entry
Y
R1
R2
R3
Yield (%)a
Yield (%)a
1
2
3
4
5
6
7
8
9
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
H
H
H
H
H
H
H
H
NO2
H
H
H
OBn
OMe
H
H
H
H
H
H
H
H
Me
Et
Bn
Et
Bu
Ph
t-Bu
Et
9a 73
9b 91
9c 84
10b 81
11d 72
11e 34
11f 56
12b 62
13b 88
5a 94
5b 87
5c 88
6b 91
5d 89
5e 94
5f 90
7b 91
8b 98
OMe
Et
a
Isolated yield.
acid and Pinnick oxidation of aldehydes 11–13 furnished the tar-
geted benzoic acids 5–8 with good yields (87–98%) (Scheme 3)
(Table 1). From these readily available aryl acrylate-type benzoic
acids, a study of their stereoselective halocyclization was then ini-
tiated. The asymmetric halocyclization reaction of compound 5b
was first studied as a representative model to screen various priv-
ileged organo-catalysts1h (Fig. 2) (Table 2).
Since halolactonization reactions could be achieved without the
use of any catalyst or additional reagent, we performed first a con-
trol experiment. If stilbene carboxylic acid derivatives were previ-
ously shown to lead mainly to 6-endo halolactones,5k the
introduction of an ester electron withdrawing group in our
substrates was important in controlling the 5-exo regioselectivity
of the bromolactonization.
The reaction of 5b with NBS as the halogen source, in toluene at
À20 °C led selectively to the racemic isobenzofuranone 1b via a 5-
exo-tet cyclization pathway as a single diastereomer but in low
yield (32%) (Table 2, entry 1). It is worth noting that 3,4-dihy-
droisocoumarin resulting from a 6-endo-tet cyclization could not
be observed. According to a widely accepted mechanism, we
assumed that the halolactone 1b was obtained from the (E)-1,2-
disubstituted olefin 5b with an ester–halogen anti relationship.1h
2. Results and discussion
Our synthetic strategy is based upon a regio- and stereoselec-
tive organocatalyzed halolactonization reaction of aryl acrylate-
type carboxylic acids 5–8 for the construction of the lactone ring
with concomitant control of the stereogenic center at C3
(Scheme 2). In order to both increase the efficiency and control
the regioselectivity of the cyclization process, we decided to incor-
porate an electron withdrawing group in our models on the styre-
nic carbon–carbon double bond. From a retrosynthetic point of
view, the parent poly-substituted unsaturated benzoic acids 5–8
could be readily prepared from the corresponding t-butyl esters
9 and 10 or benzaldehydes 11–13 depending upon the nature
and the position of the substituents connected to the aryl moiety.
t-Butyl esters 9 and 10 and benzaldehydes 11–13 were first
readily prepared via a palladium-catalyzed Heck cross-coupling
between the corresponding aryl bromides 14–18 and an array of
acrylates 19a–e (Scheme 3) (Table 1). Removal of the t-butyl pro-
tecting group in esters 9 and 10 by treatment with trifluoroacetic
Please cite this article in press as: Gelat, F.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.07.010

F. Gelat et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
OMe
OMe
N
OMe
OH
O
OH
N
N
N
N
O
DHQ
N
N
N
DHQD
quinidine
cinchonine
DHQD
DHQ
OMe
N
N
N
N
N
N
N
OH
OH
DHQD
DHQ
N
(DHQD)2PHAL
DHQ
(DHQ)2PHAL
quinine
cinchonidine
O
H
N
R=
R=
QDTC 4-OMe
OMe
S
S
OMe
OMe
O
DHQ
OR
OMe
OMe
H
N
N
(DHQ)2AQN
QDTC 2,4-OMe
N
Ph
Ph
Ph
DHQD
DHQD
DHQ
DHQ
N
N
N
N
OMe
H
N
Ph
(DHQ)2PYR
N
QTC 2,4-OMe
R=
S
(DHQD)2PYR
OMe
OR
N
Figure 2. Organo-catalysts used in this study.
Table 2
in toluene at À20 °C, the desired bromolactone 1b was formed in
good yields but with low enantiomeric excesses (5–21% ee)
(entries 2–5). Under the same reaction conditions, the use of
dimeric catalysts, such as (DHQ)2PYR, (DHQD)2PYR, (DHQ)2AQN
and (DHQD)2PHAL did not improve the enantioselectivity (entries
6–9) through their dual activation of NBS and substrate.1e,g,h We
were encouraged by the discovery that bifunctional catalysts
developed by Yeung et al.5c such as catalyst QDTC 4-OMe
provided good conversion and improved enantioselectivity (24%
ee) (entry 10). Indeed, while the NBS reagent was activated by
the thiocarbamate unit of the catalyst, its protonated quinidine
part may interact with the carboxylic acid fragment of the
substrate.5k,r
Lowering the reaction temperature (Table 3, entries 1–5) led to
lower enantioselectivities independently of the catalyst used, but a
solvent screening (entries 6–9) subsequently revealed that CHCl3/
toluene (1/2) was the best solvent system and afforded the bromo-
lactone 1b with an improved selectivity of 35% (entry 9). An addi-
tional study confirmed that a 10 mol % catalyst loading was the
best and a concentration of 0.1 M was preferred (see Supporting
information Tables S1 and S2).
In order to improve the enantioselectivity of 1b, various acidic
or basic additives (Fig. 3) were screened in CHCl3/toluene (1/2)
with NBS as the bromine source at À20 °C in the presence of
10 mol % of a quinidine thiocarbamate catalyst (Table 4). When
no catalyst or additive were used, a background reaction afforded
product 1b in a 25% yield (Entry 1 and see the Supporting informa-
tion Fig. S1). The use of QDTC 4-OMe catalyst led to 88% yield and a
31% ee (Entry 2). If a stoichiometric amount of benzoic acid
afforded a 29% ee (Entry 5), the switch to catalytic amounts led
to similar or better results (entries 3, 4). When a 20 mol % loading
of benzoic acid was combined with QDTC 4-OMe catalyst, the
desired bromolactone 1b was obtained with the highest enantios-
Screening of various catalysts for enantioselective bromolactonization of 5ba
O
O
NBS (1.5 equiv.)
catalyst (10 mol%)
OH
O
toluene
-20 °C, 15 h
CO2Et
5b
1b
Br
CO2Et
Entry
Catalyst
None
Cinchonine
Quinidine
Cinchonidine
Quinine
(DHQ)2PYR
(DHQD)2PYR
(DHQ)2AQN
(DHQD)2PHAL
QDTC 4-OMe
QDTC 2,4-OMe
QTC 2,4-OMe
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
32
82
79
84
94
87
80
85
73
81
78
89
—
5 (R,R)
16 (R,R)
6 (S,S)
21 (S,S)
2 (R,R)
6 (S,S)
2 (R,R)
12 (S,S)
24 (S,S)
18 (S,S)
15 (R,R)
9
10
11
12
a
Reactions were carried out with acid 5b (0.1 mmol), catalyst (0.01 mmol) and
NBS (0.15 mmol) in toluene (9 ml).
b
Isolated yield.
c
Measured by HPLC, absolute configurations of major enantiomer determined
after the debromination reaction (see text).
At the outset of our investigations we were drawn to the use of
cinchona and bis-cinchona alkaloid derivatives as potential
catalysts for bromolactonization reactions due to their
availability. Cinchonine, quinidine as well as their pseudo-
enantiomers cinchonidine and quinine (Fig. 2) were first engaged
into the bromolactonization of benzoic acid 5b. When compound
5b was reacted with 10 mol % of catalyst in the presence of NBS
Please cite this article in press as: Gelat, F.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.07.010

4
F. Gelat et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Table 3
Table 4
Enantioselective bromolactonization of 5b using different solventsa
Enantioselective halolactonization of 5b with various additivesa
O
O
O
O
NBS (1.5 equiv.)
NBS (1.5 equiv.), additive
OH
catalyst (10 mol%)
OH
catalyst (10 mol%)
O
O
solvent
temperature, 15 h
CHCl /toluene (1/2)
3
CO2Et
CO2Et
-20 °C, 15 h
Br
CO2Et
CO2Et
Br
1b
5b
1b
5b
T (°C) Yield (%)b ee (%)c
Entry
Catalyst
Additive
Yield (%)b
ee (%)c
Entry Catalyst
Solvent
1
2
3
4
5
6
7
8
None
None
None
25
88
84
92
91
77
60
65
88
74
88
74
79
76
83
70
77
—
31
33
43
29
36
8
6
33
6
1
2
3
4
5
6
7
8
9
QDTC 4-OMe
QDTC 4-OMe
QDTC 4-OMe
QDTC 2,4-OMe Toluene
QDTC 2,4-OMe Toluene
QDTC 4-OMe
QDTC 4-OMe
QDTC 4-OMe
Toluene
Toluene
Toluene
À20
À40
À70
À20
À40
À20
À20
À30
À20
81
76
70
78
80
77
89
88
79
24
22
7
18
23
13
31
25
35
QDTC 4-OMe
QDTC 4-OMe
QDTC 4-OMe
QDTC 4-OMe
QDTC 4-OMe
QDTC 4-OMe
QDTC 4-OMe
QDTC 4-OMe
QDTC 4-OMe
QDTC 4-OMe
QDTC 4-OMe
QDTC 2,4-OMe
QDTC 2,4-OMe
QDTC 2,4-OMe
QDTC 2,4-OMe
QDTC 2,4-OMe
BA (10 mol %)
BA (20 mol %)
BA (100 mol %)
NsNH2 (20 mol %)
(R)-MA (20 mol %)
(S)-MA (20 mol %)
(R)-TRIP (20 mol %)
(S)-TRIP (20 mol %)
(R)-TIPSY (20 mol %)
(S)-TIPSY (20 mol %)
—
CHCl3
CHCl3/toluene (1/2)
CHCl3/toluene (1/2)
9
QDTC 2,4-OMe CHCl3/toluene (1/2)
10
11
12
13
14
15
16
17
a
33
6
Reactions were carried out with acid 5b (0.1 mmol), catalyst (0.01 mmol) and
NBS (0.15 mmol) in solvent (9 ml).
b
Isolated yield.
Measured by HPLC.
35
38
36
23
16
c
BA (20 mol %)
NsNH2 (20 mol %)
(R)-MA (20 mol %)
(S)-MA (20 mol %)
electivity (43% ee) (entry 4). Following the reaction course con-
firmed 15 h was the best reaction time for acrylate type carboxylic
acids (see Supporting information, Fig. S1). Hence reactions were
rather fast in comparison with the 3–7 days required for halolac-
tonization of stilbene derivatives.5k It was worth to note the
same trend was observed using (DHQD)2PHAL catalyst but lower
enantioselectivities were obtained (see the Supporting
information Table S3). By using 10 mol % of QDTC 4-OMe and
20 mol % of benzoic acid, our catalytic system was showing
significant improvements. In the past, only Braddock and
a
Reactions were carried out with acid 5b (0.1 mmol), catalyst (0.01 mmol),
additive (0.02 mmol) and NBS (0.15 mmol) in toluene (6 ml)/CHCl3 (3 ml).
b
Isolated yield.
Measured by HPLC.
c
With the optimized reaction conditions in hand, QDTC 4-OMe
catalyst was used in the asymmetric bromolactonization of several
substituted benzoic acids 5–8 (Table 6). Overall, the desired prod-
ucts 1–4 were formed in excellent yields except for compounds 3b
and 4b bearing electron donating alkoxy groups on the aryl moiety
(entries 8 and 9). Fortunately, an increase of the reaction temper-
ature led to compounds 3b and 4b with good yields without a sig-
nificant loss of enantioselectivity. As it could be expected, the
nature of the substrates plays an important role in this reaction
in term of stereoselectivity. As highlighted in Table 6, electron
donating alkoxy groups dramatically decreased the stereoselectiv-
ity of the bromolactonization process (entries 8 and 9). However,
the bulkier the R3 substituent was, the higher the enantioselectiv-
ity. Bromolactones 1a–e were obtained with good yields and aver-
age enantioselectivities (entries 1–6) except for the less hindered
methyl ester 1a (entry 1). These average ee’s most probably result
coworkers5t combined efficiently
benzoic acid with (DHQD)2PHAL
a
stoichiometric amount of
catalyst for the
bromolactonization of various alkenoic acids. Moreover, if NsNH2
additive had no effect on the reaction (entries 6, 15), the use of
Mosher acid (entries 7, 8, 16, 17), TRIP or TIPSY (entries 9–12)
had a negative effect.
We then investigated the scope of the halogen source (Table 5,
Fig. 3). NBS was found to be the best brominating agent (entries 1–
5). However, no reaction was observed with chlorinating agents
such as N-chlorosuccinimide (NCS) or 1,3-dichloro-5,5-dimethyl-
hydantoin (DCDMH) (entries 7 and 8). Halolactonization of 5b with
NIS instead of NBS led to the targeted iodolactone in good yield and
with a lower enantioselectivity (entry 6).
O
O
O
O
Me
O
Br
Br
Me
Br
Br
N
X
N
Br
N
Br
Me
N
H
N
O
O
O
Br
Br
NBA
NXS
(X=Cl, Br, I)
DXDMH
(X=Cl, Br)
TBCO
NBP
R
SO2NH2
MeO CF3
CO2H
O
CO2H
O
O
P
OH
NO2
R
(S)-TRIP
R= 2,4,6-tri-i-PrC6H2
NsNH2
(S)-MA
BA
(S)-TiPSY
R= SiPh3
Figure 3. Halogen sources and additives used in this study.
Please cite this article in press as: Gelat, F.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.07.010

F. Gelat et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
Table 5
O
O
Enantioselective halolactonization of 5b with various halogen sourcesa
TTMSS (1.2 equiv.), hν
O
O
halogene source (1.5 equiv.)
PhCO2H (20 mol%)
QDTC 4-OMe (10 mol%)
toluene
r.t., 15 min
93% yield
O
O
(R)
CO2Et
CO2Et
OH
Br
(40% e.e.)
Scheme 4. Radical debromination of bromophthalide 1b.
O
CHCl3/toluene (1/2)
-20 °C, 15 h
1b
20b
(38% e.e.)
CO2Et
X
CO2Et
1b
5b
Entry
Halogen source
X
Yield (%)b
ee (%)c
The absolute configuration of 20b was inferred by comparison
1
2
3
4
5
6
7
8
NBS
NBP
DBDMH
TBCO
NBA
NIS
NCS
DCDMH
Br
Br
Br
Br
Br
I
89
54
88
74
87
89
0
43
1
of the specific rotation with the literature data, [a]D = +6.9 for
(3R)-20b (c 0.92 in CHCl3) (Ee 86%),13b +3.8 for (3R)-20b (c 3.3,
CHCl3) (Ee 38%). This debromination reaction allowed for the
determination of the absolute configurations of all isolated
halolactones.
28
37
21
27
—
Cl
Cl
0
—
3. Conclusion
a
Reactions were carried out with acid 5b (0.1 mmol), QDTC 4-OMe catalyst
(0.01 mmol), PhCO2H (0.02 mmol) and halogen source (0.15 mmol) in toluene
(6 ml)/CHCl3 (3 ml).
In conclusion, we have developed an efficient and highly regio-
and diastereoselective route to enantioenriched brominated
isobenzofuranones. The key step of our methodology is based upon
the first organocatalyzed enantioselective bromolactonization
reaction of aryl acrylate-type carboxylic acids. When combined
with a catalytic amount of benzoic acid, quinidine thiocarbamate
bifunctional catalysts have demonstrated their efficiency and
allowed us to obtain the target bromolactones with promising
enantioselectivities (up to 53%). A more efficient catalytic system
may enable a faster bromolactonization with respect to the
observed background reaction. Moreover, new catalysts are
required to direct and activate at once the ester fragment, the car-
boxylic acid unit and the NBS reagent and to achieve a complete
transfer of the chiral information during the halolactonization
reaction for higher enantioselectivities.
b
Isolated yield.
Measured by HPLC.
c
Table 6
Enantioselective halolactonization of 5-8a
O
NBS (1.5 equiv.)
QDTC 4-OMe (10 mol%)
PhCO2H (20 mol%)
O
R1
R2
R1
R2
OH
O
CHCl3/toluene (1/2)
-20 °C, 15 h
CO2R3
CO2R3
Br
5-8
1-4
Entry
R1
R2
R3
Yield (%)b
ee (%)c
4. Experimental
4.1. General
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
NO2
OBn
OMe
H
H
H
H
H
H
H
H
Me
Et
1a93
1b89
1c94
1d91
1e80
1f86
20
43
44
44
32
53
49d
10
22
Bn
Bu
Ph
t-Bu
Et
1H NMR spectra were recorded on a 300-MHz Bruker spectrom-
eter. Chemical shifts for 1H NMR spectra (in parts per million) rel-
ative to internal tetramethylsilane (Me4Si, d = 0.00 ppm) with
deuterated chloroform. 13C NMR spectra were recorded at
75 MHz. Chemical shifts for 13C NMR spectra are reported (in parts
per million) relative to CDCl3 (d = 77.0 ppm). Flash chromatogra-
phy experiments were carried out on Silica Gel premium Rf grade
2b98e
3b30(68)e
4b22(72)e
Et
Et
OMe
a
Reactions were carried out with acid 5b (0.1 mmol), QDTC 4-OMe catalyst
(0.01 mmol), PhCO2H (0.02 mmol) and halogen source (0.15 mmol) in toluene
(6 ml)/CHCl3 (3 ml).
b
(40–75 lm). Ethyl acetate/petroleum ether mixtures, dichloro-
Isolated yield.
Measured by HPLC.
c
methane/acetone or dichloromethane/methanol mixtures were
used as the eluent for chromatographic purifications. TLC plates
were visualized by UV or immersion in permanganate potassium
(3 g KMnO4, 20 g K2CO3, 5 mL 5% aq NaOH and 300 mL of water)
followed by heating. Melting points were obtained on a capillary
apparatus and are uncorrected. High resolution mass spectra
(HRMS) were obtained by electrospray using a ThermoExactive
spectrometer. Enantiomeric excesses were determined by chiral
HPLC equipped with a photodiode array detector (200–300 nm)
and one of the following Daicel CSP (4.6 5 250 mm) columns:
OD, IA and IC. Optical rotations were measured at room tempera-
ture (20–23 °C) on a polarimeter using a 1 mL cell with a 1 dm path
length at 589 nm (sodium D light). Dry CH2Cl2 and toluene were
displayed by a passage down an activated alumina column. DMSO
and Et3N were distilled over molecular sieve 4 Å.
Determined by 1H NMR using europium tris[3-(heptafluoropropylhydrox-
d
ymethylene)-(+)-camphorate.
e
Reaction carried out at rt.
from the combination of the uncatalyzed background reaction and
the catalyzed enantioselective transformation. The kinetics of
these two reactions (see Supporting information Fig. S1) are relying
on the substrate electronic and steric properties on the one side
(ground and catalyzed transformations) and on the efficiency and
selectivity of the catalyst to assist the cyclization on the other side.
In order to determine the absolute configuration at C3, radical
debromination of bromophthalide 1b was performed by tris
(trimethylsilyl)silane (TTMSS) under irradiation in toluene
(Scheme 4). Bromide was cleanly removed to afford the debromi-
nated compound 20b in high yield (93%) without a significant loss
of enantiopurity.
Bromobenzoic acid tert-butyl ester 15, 2-Bromobenzaldehyde
16 and acrylates 19a–e were purchased from commercial sources
and used as received. Aryl bromides 14,15 1716 and 1817 were pre-
Please cite this article in press as: Gelat, F.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.07.010

6
F. Gelat et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
pared according to reported procedures. QDTC 4-OMe, QDTC 2,4-
OMe and QTC 4-OMe catalysts were prepared according to the lit-
erature.5c The other catalysts used herein were purchased from
commercial sources.
as a colorless oil. 1H NMR (300 MHz, CDCl3): d = 10.28 (s, 1H),
8.54 (d, J = 15.9 Hz, 1H), 7.90–7.84 (m, 1H), 7.67–7.52 (m, 3H),
6.39 (d, J = 15.9 Hz, 1H), 4.23 (t, J = 6.7 Hz, 2H), 1.77–1.63 (m,
2H), 1.52–1.32 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H).
4.2. General Heck procedure. Synthesis of compounds 9,13
4.2.6. (E)-3-(2-Formylphenyl)acrylic acid phenyl ester 11e
General Heck procedure using 2-bromobenzaldehyde 16
(185 mg, 1 mmol, 2 equiv) and phenyl acrylate 19e (296 mg,
2 mmol, 2 equiv) affords 11e (86 mg, 0.34 mmol, yield = 34%) as a
colorless oil. 1H NMR (300 MHz, CDCl3): d = 10.20 (s, 1H), 8.65 (d,
J = 15.9 Hz, 1H), 7.83–7.72 (m, 1H), 7.65–7.46 (m, 3H), 7.36–7.26
(m, 2H), 7.19–7.06 (m, 3H), 6.48 (d, J = 15.9 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d = 191.8, 164.6, 150.8, 143.1, 136.2, 134.0 (2 sig-
nals), 132.8, 130.3, 129.5 (2C), 128.1, 125.9 (2C), 122.2, 121.6;
HRMS (ESI+) m/z calcd for C16H13O3 [MH]+ 253.08592, found
253.08644.
A solution of aryl bromide (1 mmol, 1 equiv), acrylate (2 equiv),
PdCl2(PPh3)2 (5 mol %) and Et3N (5 equiv) in DMSO (2 mL) under
argon was heated at 100 °C for 15 h. Water (10 mL) was then added
followed by sodium chloride (until saturation) and the reaction
mixture was extracted with ethyl acetate (3 Â 15 mL). The organic
layers were combined and washed with brine, dried over MgSO4,
filtered and the solvent was removed under reduced pressure.
The residue was purified on a column of silica gel to afford the
desired pure coupling product.
4.2.1. 2-((E)-2-Methoxycarbonylvinyl)benzoic acid tert-butyl
ester 9a
4.2.7. (E)-3-(2-Formylphenyl)acrylic acid tert-butyl ester 11f19
General Heck procedure using 2-bromobenzaldehyde 16
(500 mg, 2.70 mmol, 1 equiv) and tert-butyl acrylate 19f
(0.79 mL, 5.4 mmol, 2 equiv) affords 11f (351 mg, 1.51 mmol,
General Heck procedure using tert-butyl 2-bromobenzoate 14
(257 mg, 1 mmol, 1 equiv) and methyl acrylate 19a (0.18 mL,
2 mmol, 2 equiv) affords 9a (192 mg, 0.73 mmol, yield = 73%) as a
colorless oil. 1H NMR (300 MHz, CDCl3): d = 8.43 (d, J = 15.9 Hz,
1H), 7.91–7.84 (m, 1H), 7.56–7.32 (m, 3H), 6.28 (d, J = 15.9 Hz,
1H), 3.81 (s, 3H), 1.61 (s, 9H); 13C NMR (75 MHz, CDCl3):
d = 166.9, 166.0, 144.5, 135.6, 132.0, 131.7, 130.6, 129.3, 127.7,
119.9, 82.0, 51.5, 28.1 (3C); HRMS (ESI+) m/z calcd for C15H19O4
[MH]+ 263.12779, found 263.12744.
yield = 56%) as
a
colorless oil. 1H NMR (300 MHz, CDCl3):
d = 10.33 (s, 1H), 8.42 (d, J = 15.8 Hz, 1H), 7.89–7.86 (m, 1H),
7.66–7.53 (m, 3H), 6.30 (d, J = 15.8 Hz, 1H), 1.55 (s, 9H, tBu).
4.2.8. (E)-3-(4-Benzyloxy-2-formylphenyl)acrylic acid ethyl
ester 12b20
General Heck procedure using 2-bromo-5-benzyloxybenzalde-
hyde 17 (500 mg, 1.72 mmol, 1 equiv) and ethyl acrylate 19b
(0.38 mL, 3.5 mmol, 2 equiv) affords 12b (331 mg, 1.07 mmol,
4.2.2. 2-((E)-2-Ethoxycarbonylvinyl)benzoic acid tert-butyl ester
9b18
yield = 62%) as
a
colorless oil. 1H NMR (300 MHz, CDCl3):
General Heck procedure using tert-butyl 2-bromobenzoate 14
(2.56 g, 10 mmol, 1 equiv) and ethyl acrylate 19b (2.2 mL,
20 mmol, 2 equiv) affords 9b (2.52 g, 9.1 mmol, yield = 91%) as a
colorless oil. 1H NMR (300 MHz, CDCl3): d = 8.30 (d, J = 15.9 Hz,
1H), 7.82–7.76 (m, 1H), 7.48–7.26 (m, 3H), 6.18 (d, J = 15.9 Hz,
1H), 4.18 (q, J = 7.1 Hz, 2H), 1.52 (s, 9H), 1.24 (t, J = 7.1 Hz, 3H).
d = 10.27 (s, 1H), 8.37 (d, J = 15.8 Hz, 1H), 7.55 (d, J = 8.7 Hz, 1H),
7.42–7.24 (m, 6H), 7.17–7.11 (m, 1H), 6.26 (d, J = 15.8 Hz, 1H),
5.09 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H).
4.2.9. (E)-3-(2-Formyl-4,5-dimethoxyphenyl)-acrylic acid ethyl
ester 13b21
General Heck procedure General Heck procedure using 2-
bromo-4,5-dimethoxybenzaldehyde 18 (245 mg, 1 mmol, 1 equiv)
and ethyl acrylate 19b (0.22 mL, 2 mmol, 2 equiv) affords 13b
(232 mg, 0.88 mmol, yield = 88%) as a white solid. Mp 113–
114 °C; 1H NMR (300 MHz, CDCl3): d = 10.25 (s, 1H), 8.42 (d,
J = 15.8 Hz, 1H), 7.33 (s, 1H), 7.07 (s, 1H), 6.35 (d, J = 15.8 Hz, 1H),
4.27 (q, J = 7.1 Hz, 2H), 3.99 (s, 3H), 3.94 (s, 3H), 1.34 (t,
J = 7.1 Hz, 3H).
4.2.3. 2-((E)-2-Benzyloxycarbonylvinyl)benzoic acid tert-butyl
ester 9c8g
General Heck procedure using General Heck procedure using
tert-butyl 2-bromobenzoate 14 (500 mg, 1.95 mmol, 1 equiv) and
benzyl acrylate 19c (0.6 mL, 2 mmol, 2 equiv) affords 9c (552 mg,
1.63 mmol, yield = 84%) as a colorless oil. 1H NMR (300 MHz,
CDCl3): d = 8.49 (d, J = 15.9 Hz, 1H), 7.96–7.91 (m, 1H), 7.62–7.32
(m, 8H), 6.38 (d, J = 15.9 Hz, 1H), 5.31 (s, 2H), 1.62 (s, 9H).
4.3. General tert-butyl ester cleavage procedure
4.2.4. 2-((E)-2-Ethoxycarbonylvinyl)-5-nitro-benzoic acid tert-
butyl ester 10b
To a solution of tert-butyl ester 9,10 (1 mmol, 1 equiv) in CH2Cl2
(1 mL) was added TFA (6 equiv). The reaction mixture was stirred
at room temperature for 6 h (monitored by TLC) and concentrated
to dryness to afford carboxylic acid 5 and 6. Purification on silica
gel may be applied if necessary.
Modified Heck procedure with tert-butyl 2-bromo-5-nitro-ben-
zoate 15 (302 mg, 1 mmol, 1 equiv), ethyl acrylate 19b (0.17 mL,
1.5 mmol, 1.5 equiv) but using Pd(OAc)2 (4.5 mg, 0.02 mmol,
2 mol %) and P(o-Tol)3 (12.2 mg, 0.04 mmol, 4 mol %) as catalyst
affords 10b (260 mg, 0.81 mmol, yield = 81%) as a yellow solid.
Mp 84–85 °C; 1H NMR (300 MHz, CDCl3): d = 8.72 (d, J = 2.5 Hz,
1H), 8.38 (d, J = 15.9 Hz, 1H), 8.32 (dd, J = 8.6 and 2.5 Hz, 1H),
7.71 (d, J = 8.6 Hz, 1H), 6.37 (d, J = 15.9 Hz, 1H), 4.30 (q, J = 7.1 Hz,
2H), 1.64 (s, 9H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d = 165.5, 163.9, 147.8 (2C), 141.6, 133.0, 129.0, 126.0, 125.6, 123.6,
83.5, 60.7, 27.9 (3C), 14.1; Anal. calcd (%) for C16H19NO6: C, 59.86;
H, 5.96; N, 4.36; found C, 59.80; H, 5.96; N, 4.07.
4.3.1. 2-((E)-2-Methoxycarbonylvinyl)benzoic acid 5a22
General cleavage procedure using 9a (183 mg, 0.7 mmol,
1 equiv) affords 5a (135 mg, 0.66 mmol, yield = 94%) as a white
solid. Mp 152–153 °C; 1H NMR (300 MHz, CDCl3): d = 8.56 (d,
J = 15.9 Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.66–7.52 (m, 2H), 7.53–
7.43 (m, 1H), 6.34 (d, J = 15.9 Hz, 1H), 3.84 (s, 3H).
4.3.2. 2-((E)-2-Ethoxycarbonylvinyl)benzoic acid 5b13b
4.2.5. (E)-3-(2-Formylphenyl)acrylic acid butyl ester 11d13b
General Heck procedure using 2-bromobenzaldehyde 16
(500 mg, 2.70 mmol, 1 equiv) and n-butyl acrylate 19d (0.77 mL,
5.4 mmol, 2 equiv) affords 11d (451 mg, 1.94 mmol, yield = 72%)
General cleavage procedure using 9b (2.52 g, 9.1 mmol,
1 equiv) affords 5b (1.75 g, 8.0 mmol, yield = 87%) as a white
solid. Mp 68–69 °C; 1H NMR (300 MHz, CDCl3): d = 8.54 (d,
J = 15.9 Hz, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.66–7.55 (m, 2H),
Please cite this article in press as: Gelat, F.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.07.010

F. Gelat et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7
7.52–7.44 (m, 1H), 6.33 (d, J = 15.9 Hz, 1H), 4.29 (q, J = 7.1 Hz,
2H), 1.35 (t, J = 7.1 Hz, 3H).
solid. Mp 151–152 °C; 1H NMR (300 MHz, CDCl3): d = 8.41 (d,
J = 15.9 Hz, 1H), 7.68 (d, J = 2.7 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H),
7.48–7.33 (m, 6H), 7.18 (dd, J = 8.7 and 2.7 Hz, 1H), 6.28 (d,
J = 15.9 Hz, 1H), 5.14 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.34 (t,
J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d = 171.0, 167.0, 159.6,
143.0, 136.1, 130.0, 129.7, 129.5, 128.7 (2C), 128.3, 127.6 (2C),
120.3, 119.7, 117.0, 70.4, 60.6, 14.3; HRMS (CI+) m/z calcd for
4.3.3. 2-((E)-2-Benzyloxycarbonylvinyl)benzoic acid 5c8g
General cleavage procedure using 9c (552 mg, 1.6 mmol,
1 equiv) affords 5c (407 mg, 1.4 mmol, yield = 88%) as a white
solid. Mp 95–96 °C; 1H NMR (300 MHz, CDCl3): d = 8.63 (d,
J = 15.9 Hz, 1H), 8.12 (d, J = 7.5 Hz, 1H), 7.66–7.55 (m, 2H), 7.52–
7.28 (m, 6H), 6.39 (d, J = 15.9 Hz, 1H), 5.27 (s, 2H).
C
19H19O5 [MH]+ 327.12325, found 327.12271.
4.4.5. 2-((E)-2-Ethoxycarbonylvinyl)-4,5-dimethoxybenzoic acid
8b
4.3.4. 2-((E)-2-Ethoxycarbonylvinyl)-5-nitro-benzoic acid 6b
General cleavage procedure using 10b (240 mg, 0.75 mmol,
1 equiv) affords 6b (180 mg, 0.68 mmol, yield = 91%) as a white
solid. Mp 179–180 °C; 1H NMR (300 MHz, CDCl3): d = 8.94 (d,
J = 2.4 Hz, 1H), 8.55 (d, J = 16.0 Hz, 1H), 8.42 (dd, J = 8.6 and
2.4 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 6.45 (d, J = 16.0 Hz, 1H), 4.33
(q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d = 168.5, 166.0, 148.0, 143.2, 141.4, 129.7, 129.6, 127.5, 126.8,
124.7, 61.3, 14.2; HRMS (ESIÀ) m/z calcd for C12H10NO6 [M]À
264.05026, found 264.04922.
General oxidation procedure using 13b (212 mg, 0.8 mmol,
1 equiv) affords 8b (220 mg, 0.79 mmol, yield = 98%) as a white
solid. Mp 194–195 °C; 1H NMR (300 MHz, CDCl3): d = 8.63 (d,
J = 15.9 Hz, 1H), 7.62 (s, 1H), 7.07 (s, 1H), 6.29 (d, J = 15.8 Hz, 1H),
4.29 (q, J = 7.1 Hz, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 1.35 (t,
J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): d = 171.2, 166.8, 152.7,
149.7, 143.7, 131.6, 121.2, 120.1, 113.9, 110.0, 60.6, 56.2, 56.1,
14.3; HRMS (ESI+) m/z calcd for C14H17O6 [MH]+ 281.10196, found
281.10153.
4.4. General Pinnick oxidation procedure
4.5. General procedure for the halolactonization reaction.
Synthesis of 3-substituted isobenzofuranones 1–4
To a solution of aldehyde 10–12 (1 mmol, 1 equiv) and 2-
methylbut-2-ene (10 equiv) in tert-butanol (30 mL) was added
water (7.5 mL), followed by sodium chlorite (3 equiv) and sodium
hydrogenophosphate (6 equiv). The reaction mixture was stirred at
rt for 15 h (monitored by TLC), then concentrated to dryness. The
residue was diluted in H2O/ethyl acetate. The aqueous layer was
saturated with NaCl, then extracted with ethyl acetate (3 times).
The combined organic layers were washed with brine, dried over
MgSO4, filtered and then concentrated to afford the desired car-
boxylic acid 5–8. Purification on a column of silica gel may be
applied if the purity of the material is not good enough.
General procedure for the racemic version: To a solution of car-
boxylic acid 5–8 (0.1 mmol) in toluene (1 mL) was added NBS or
NIS (0.15 mmol, 1.5 equiv). The reaction mixture was heated at
40 °C for 15 h. The crude mixture was directly purified by column
chromatography on silica gel.
4.5.1. (S⁄)-Bromo-((S⁄)-3-oxo-1,3-dihydroisobenzofuran-1-yl)
acetic acid methyl ester 1a
General procedure using carboxylic acid 5a (20.6 mg, 0.1 mmol,
1 equiv) affords 1a (29 mg, 0.1 mmol, yield = quantitative) as white
solid. Mp 81–82 °C; 1H NMR (300 MHz, CDCl3): d = 7.96–7.90 (m,
1H), 7.87–7.81 (m,1H), 7.72 (dt, J = 1.2 and 7.4 Hz, 1H), 7.65–7.57
(m, 1H), 5.92 (d, J = 6.9 Hz, 1H), 4.52 (d, J = 6.9 Hz, 1H), 3.89 (s,
3H); 13C NMR (75 MHz, CDCl3): d = 168.9, 167.4, 145.8, 134.2,
130.3, 126.6, 125.9, 124.2, 78.7, 53.6, 45.2; HRMS (ESI+) m/z calcd
for C11H10BrO4 [MH]+ 284.97570, found 284.97528.
4.4.1. 2-((E)-2-Butoxycarbonylvinyl)benzoic acid 5d23
General oxidation procedure using 11d (487 mg, 2.1 mmol,
1 equiv) affords 5d (463 mg, 1.87 mmol, yield = 89%) as a white
solid. Mp 61–62 °C; 1H NMR (300 MHz, CDCl3): d = 8.56 (d,
J = 15.9 Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.67–7.55 (m, 2H), 7.52–
7.43 (m, 1H), 6.34 (d, J = 15.9 Hz, 1H), 4.24 (t, J = 6.7 Hz, 2H), 1.71
(quint, J = 6.7 Hz, 2H), 1.46 (sex, J = 7.5 Hz, 2H), 0.97 (t, J = 7.5 Hz,
3H).
4.5.2. (S⁄)-Bromo-((S⁄)-3-oxo-1,3-dihydroisobenzofuran-1-yl)
acetic acid ethyl ester 1b (X = Br25
)
General procedure using carboxylic acid 5b (22 mg, 0.1 mmol,
1 equiv) affords 1b (30 mg, 0.1 mmol, yield = quantitative) as white
solid. Mp 68–69 °C; 1H NMR (300 MHz, CDCl3): d = 7.92 (d,
J = 7.6 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.61
(t, J = 7.6 Hz, 1H), 5.93 (d, J = 6.6 Hz, 1H), 4.55 (d, J = 6.6 Hz, 1H),
4.33 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H).
4.4.2. 2-((E)-2-Phenoxycarbonylvinyl)benzoic acid 5e
General oxidation procedure using 11e (75 mg, 0.3 mmol,
1 equiv) affords 5e (75 mg, 0.28 mmol, yield = 94%) as a white
solid. Mp 129–130 °C; 1H NMR (300 MHz, CDCl3): d = 10.27 (br s,
1H), 8.75 (d, J = 15.9 Hz, 1H), 8.16–8.09 (m, 1H), 7.72–7.457 (m,
2H), 7.54–7.45 (m, 1H), 7.43–7.33 (m, 2H), 7.27–7.15 (m, 3H),
6.51 (d, J = 15.9 Hz, 1H); 13C NMR (75 MHz, CDCl3): d = 171.8,
165.0, 150.9, 145.7, 137.0, 133.3, 131.8, 129.8, 129.4 (2C), 128.8,
128.3, 125.8, 121.7 (2C), 120.5; HRMS (ESI+) m/z calcd for
4.5.3. (S⁄)-Iodo-((S⁄)-3-oxo-1,3-dihydroisobenzofuran-1-yl)
acetic acid ethyl ester 1b (X = I)
General procedure using carboxylic acid 5b (110 mg, 0.5 mmol,
1 equiv) affords 1b (168 mg, 0.49 mmol, yield = 97%) as a white
solid. Mp 35–36 °C; 1H NMR (300 MHz, CDCl3): d = 7.97–7.90 (m,
2H), 7.72 (dt, J = 1.4 and 7.4 Hz, 1H), 7.65–7.57 (m, 1H), 5.66 (d,
J = 3.1 Hz, 1H), 4.78 (d, J = 3.1 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H),
1.32 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d = 168.9,
168.6, 147.3, 134.1, 130.3, 126.6,125.7, 124.5, 79.3, 62.6, 22.1,
13.8; HRMS (ESI+) m/z calcd for C12H12IO4 [MH]+ 346.97750, found
346.97672.
C
16H13O4 [MH]+ 269.08084, found 269.08047.
4.4.3. 2-((E)-2-tert-Butoxycarbonylvinyl)benzoic acid 5f24
General oxidation procedure using 11f (290 mg, 1.25 mmol,
1 equiv) affords 5f (279 mg, 1.12 mmol, yield = 90%) as a white
solid. Mp 125–126 °C; 1H NMR (300 MHz, CDCl3): d = 8.48 (d,
J = 15.9 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.67–7.52 (m, 2H), 7.50–
7.46 (m, 1H), 6.27 (d, J = 15.9 Hz, 1H), 1.55 (s, 9H, tBu).
4.4.4. 5-Benzyloxy-2-((E)-2-ethoxycarbonylvinyl)-benzoic acid
7b
4.5.4. (S⁄)-Bromo-((S⁄)-3-oxo-1,3-dihydroisobenzofuran-1-yl)
acetic acid benzyl ester 1c
General oxidation procedure using 12b (320 mg, 1.0 mmol,
1 equiv) affords 7b (307 mg, 0.94 mmol, yield = 91%) as a white
General procedure using carboxylic acid 5c (28.2 mg, 0.1 mmol,
1 equiv) affords 1c (28 mg, 0.08 mmol, yield = 77%) as a colorless
Please cite this article in press as: Gelat, F.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.07.010

8
F. Gelat et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
oil. 1H NMR (300 MHz, CDCl3): d = 7.83 (d, J = 7.5 Hz, 1H), 7.67–
7.62 (m, 1H), 7.58 (dt, J = 1.2 and 7.2 Hz, 1H), 7.54–7.47 (m, 1H),
7.36–7.24 (m, 5H), 5.85 (d, J = 6.6 Hz, 1H), 5.22 (s, 2H), 4.50 (d,
J = 6.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): d = 168.9, 166.7, 145.8,
134.6, 134.2, 130.3, 128.8 (2 signals overlapped), 128.5, 126.6,
125.9, 124.1, 78.7, 68.5, 45.7; HRMS (ESI+) m/z calcd for C17H14BrO4
[MH]+ 361.00700, found 361.00656.
5.77 (d, J = 6.8 Hz, 1H), 5.06 (s, 2H), 4.37 (d, J = 6.8 Hz, 1H), 4.26
(q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d = 168.9, 167.0, 160.6, 138.5, 135.9, 128.8 (2C), 128.4, 128.1, 127.6
(2C), 125.2, 123.4, 109.0, 78.7, 70.6, 62.9, 45.9, 13.9; HRMS (ESI+)
m/z calcd for C19H18BrO5 [MH]+ 405.03320, found 405.03311.
4.5.10. (S⁄)-Bromo-((S⁄)-5,6-dimethoxy-3-oxo-1,3-dihydro-
isobenzofuran-1-yl)acetic acid methyl ester 4b
4.5.5. (S⁄)-Bromo-((S⁄)-3-oxo-1,3-dihydroisobenzofuran-1-yl)
acetic acid butyl ester 1d
General procedure using carboxylic acid 8b (28 mg, 0.1 mmol,
1 equiv) affords 4b (30 mg, 0.08 mmol, yield = 83%) as white solid.
Mp 111–112 °C; 1H NMR (300 MHz, CDCl3): d = 7.30 (s, 1H), 7.29 (s,
1H), 5.79 (d, J = 6.7 Hz, 1H), 4.48 (d, J = 6.7 Hz, 1H), 4.34 (q,
J = 7.2 Hz, 2H), 3.99 (s, 3H), 3.95 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3): d = 169.2, 167.1, 154.7, 151.3, 140.5,
118.7, 106.1, 105.8, 78.2, 62.8, 56.4, 56.3, 45.8, 13.9; HRMS (ESI+)
m/z calcd for C14H16BrO6 [MH]+ 359.01250, found 359.01233.
General procedure for asymmetric version: To a solution of qui-
nine or quinidine thiocarbamate QD-thio (0.01 mmol, 10 mol %)
and benzoic acid (0.02 mmol, 20 mol %) in toluene (6 mL) was
added NBS or NIS (0.15 mmol, 1.5 equiv). The reaction mixture
was cooled at À20 °C, then a solution of carboxylic acid 5–8
(0.1 mmol, 1 equiv) in chloroform (3 mL) was added dropwise.
After 15 h at À20 °C, the crude mixture was directly purified by
column chromatography on silica gel.
General procedure using carboxylic acid 5d (24.8 mg, 0.1 mmol,
1 equiv) affords 1d (23 mg, 0.07 mmol, yield = 70%) as a colorless
oil. 1H NMR (300 MHz, CDCl3): d = 7.95–7.93 (m, 1H), 7.92–7.81
(m, 1H), 7.71 (dt, J = 1.2 and 7.4 Hz, 1H), 7.64–7.56 (m, 1H), 5.91
(d, J = 6.8 Hz, 1H), 4.51 (d, J = 6.8 Hz, 1H), 4.35–4.23 (m, 2H),
1.75–1.63 (m, 2H), 1.50–1.35 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H); 13C
NMR (75 MHz, CDCl3): d = 168.9, 167.0, 145.9, 134.2, 130.3,
126.6, 125.9, 124.2, 78.8, 66.7, 45.6, 30.4, 19.0, 13.6; HRMS (ESI+)
m/z calcd for C14H16BrO4 [MH]+ 327.02270, found 327.02197.
4.5.6. (S⁄)-Bromo-((S⁄)-3-oxo-1,3-dihydroisobenzofuran-1-yl)
acetic acid phenyl ester 1e
General procedure using carboxylic acid 5e (24.8 mg,
0.05 mmol, 1 equiv) affords 1e (13 mg, 0.04 mmol, yield = 75%) as
a
a
colorless oil.; 1H NMR (300 MHz, CDCl3): d = 7.97 (d,
J = 7.6 Hz, 1H); 7.94–7.89 (m, 1H), 7.74 (dt, J = 1.2 and 7.5 Hz,
1H); 7.67–7.60 (m, 1H), 7.48–7.38 (m, 2H), 7.33–7.26 (m, 1H),
7.21–7.15 (m, 2H), 6.02 (d, J = 7.0 Hz, 1H), 4.70 (d, J = 7.0 Hz, 1H);
13C NMR (75 MHz, CDCl3): d = 168.8, 165.6, 150.2, 145.7, 134.3,
130.5, 129.7 (2C), 126.7, 126.6, 126.0, 124.3, 121.0 (2C), 78.7,
45.2; HRMS (ESI+) m/z calcd for C16H12BrO4 [MH]+ 346.99135,
found 346.99075.
4.5.11. (S⁄)-Bromo-((S⁄)-3-oxo-1,3-dihydroisobenzofuran-1-yl)
acetic acid methyl ester 1a
General asymmetric halolactonization procedure using 5a
(20.6 mg, 0.1 mmol, 1 equiv) with QD-thio affords 1a (26 mg,
0.09 mmol, yield = 93%, 20% ee) as a white solid. HPLC: rt (R)
= 13.8 min, rt (S) = 15.0 min (Daicel ChiralpakTM IA CSP; flow
rate = 1.0 mL minÀ1; heptane/2-propanol 90:10; 25 °C, 225 nm);
[a]
23 = À11.8 (c 1.5, CHCl3).
D
4.5.7. (S⁄)-Bromo-((S⁄)-3-oxo-1,3-dihydroisobenzofuran-1-yl)
acetic acid tert-butyl ester 1f
4.5.12. (S⁄)-Bromo-((S⁄)-3-oxo-1,3-dihydroisobenzofuran-1-yl)
acetic acid ethyl ester 1b (X = Br)
General procedure using carboxylic acid 5f (24.8 mg, 0.1 mmol,
1 equiv) affords 1f (30.4 mg, 0.093 mmol, yield = 93%) as a color-
less oil; 1H NMR (300 MHz, CDCl3): d = 7.95–7.92 (m, 1H), 7.89–
7.82 (m,1H), 7.73 (dt, J = 1.2 and 7.4 Hz, 1H), 7.63–7.57 (m, 1H),
5.88 (d, J = 6.7 Hz, 1H), 4.42 (d, J = 6.7 Hz, 1H), 1.55 (s, 9H, tBu);
13C NMR (75 MHz, CDCl3): d = 169.0, 165.7, 146.1, 134.1, 130.2,
126.7, 125.8, 124.1, 84.1, 79.1, 47.1, 27.7; HRMS (ESI+) m/z calcd
for C10H7BrO4 [MHÀC4H9]+ 270.96005, found 270.95975.
General asymmetric halolactonization procedure using 5b
(22 mg, 0.1 mmol, 1 equiv) with QD-thio affords 1b (30 mg,
0.1 mmol, yield = 89%, 43% ee) as white solid. HPLC: rt (R)
= 12.1 min, rt (S) = 14.7 min (Daicel ChiralpakTM IA CSP; flow
rate = 1.0 mL minÀ1; heptane/2-propanol 90:10; 25 °C, 225 nm);
[a]
23 = À19.6 (c 3.0, CHCl3).
D
4.5.13. (S⁄)-Iodo-((S⁄)-3-oxo-1,3-dihydroisobenzofuran-1-yl)
acetic acid ethyl ester 1b (X = I)
4.5.8. (S⁄)-Bromo-((S⁄)-5-nitro-3-oxo-1,3-dihydroisobenzofu-
ran-1-yl)acetic acid ethyl ester 2b
General asymmetric halolactonization procedure using 5b
(22 mg, 0.1 mmol, 1 equiv) with QD-thio affords 1b (35 mg,
0.1 mmol, yield = 89%, 27% ee) as a white solid. HPLC: rt (R)
= 13.1 min, rt (S) = 17.8 min (Daicel ChiralpakTM IA CSP; flow
rate = 1.0 mL minÀ1; heptane/2-propanol 90:10; 25 °C, 225 nm);
To a solution of carboxylic acid 6b (26.5 mg, 0.1 mmol, 1 equiv)
in toluene (1 mL) was added NBS (0.5 mmol, 5 equiv). The reaction
mixture was heated at 70 °C for 3 days. The crude mixture was
concentrated to dryness. The residue was dissolved in ethyl acet-
ate, washed with a saturated solution of NaHCO3, water then brine
to afford the desired phthalide 2b (27 mg, 0.08 mmol, yield = 78%)
as a pale yellow solid. Mp 133–134 °C; 1H NMR (300 MHz, CDCl3):
d = 8.75 (d, J = 2.1 Hz, 1H), 8.57 (dd, J = 8.5 and 2.1 Hz, 1H), 8.11–
8.06 (m, 1H), 6.04 (d, J = 5.5 Hz, 1H), 4.69 (d, J = 5.5 Hz, 1H), 4.38
(q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d = 166.8, 166.5, 151.1, 149.7, 128.9, 128.7, 126.0, 121.2, 78.9, 63.3,
44.8, 13.9; Anal. calcd (%) for (C12H10O6NBr + 1/6 CH2Cl2): C, 41.14;
H, 2.91; N, 3.94; found C, 41.11; H, 3.53; N, 3.68.
[a]
23 = À16.8 (c 3.0, CHCl3).
D
4.5.14. (S⁄)-Bromo-((S⁄)-3-oxo-1,3-dihydroisobenzofuran-1-yl)
acetic acid benzyl ester 1c
General asymmetric halolactonization procedure using 5c
(28.2 mg, 0.1 mmol, 1 equiv) with QD-thio affords 1c (34 mg,
0.09 mmol, 94% yield, 44% ee) as a white solid. HPLC: rt (R)
= 12.7 min, rt (S) = 31.6 min (Daicel ChiralpakTM IA CSP; flow
rate = 1.0 mL minÀ1; heptane/2-propanol 90:10; 25 °C; 225 nm);
[a]
23 = À11.6 (c 2.9, CHCl3).
D
4.5.9. (S⁄)-((S⁄)-5-Benzyloxy-3-oxo-1,3-dihydroisobenzofuran-1-
yl)bromoacetic acid ethyl ester 3b
4.5.15. (S⁄)-Bromo-((S⁄)-3-oxo-1,3-dihydroisobenzofuran-1-yl)
acetic acid butyl ester 1d
General asymmetric halolactonization procedure using 5d
(24.8 mg, 0.1 mmol, 1 equiv) with QD-thio affords 1d (30 mg,
0.09 mmol, yield = 91%, 44% ee) as a colorless oil. HPLC: rt (R)
General procedure using carboxylic acid General procedure
using carboxylic acid 7b (32.4 mg, 0.1 mmol, 1 equiv) affords 3b
(23 mg, 0.06 mmol, yield = 57%) as
(300 MHz, CDCl3): d = 7.65 (d, J = 8.5 Hz, 1H), 7.39–7.21 (m, 7H),
a
colorless oil. 1H NMR
Please cite this article in press as: Gelat, F.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.07.010

F. Gelat et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
9
= 9.8 min, rt (S) = 18.3 min (Daicel ChiralpakTM IA CSP; flow
rate = 1.0 mL minÀ1; heptane/2-propanol 90:10; 25 °C; 225 nm);
on silica gel to afford the pure desired dehalogenated compound
20b.
[
a]
D
23 = À14.7 (c 2.5, CHCl3).
4.6.1. ((R)-3-Oxo-1,3-dihydroisobenzofuran-1-yl)-acetic acid
ethyl ester 20b
4.5.16. (S⁄)-Bromo-((S⁄)-3-oxo-1,3-dihydroisobenzofuran-1-yl)
acetic acid phenyl ester 1e
General procedure from bromide 1b (73 mg, 0.24 mmol,
1 equiv, 40% ee) affords (50 mg, 0.23 mmol, 93% yield, 38% ee) as
a white solid. Mp 55–56 °C; 1H NMR (300 MHz, CDCl3): d = 7.95–
7.89 (m, 1H), 7.73–7.65 (m, 1H), 7.60–7.48 (m, 2H), 5.89 (t,
J = 6.5 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 2.94 and 2.88 (AB part of
ABX system, JAB = 16.5 and JAX = JBX = 6.5 Hz, 2H), 1.28 (t,
J = 7.2 Hz, 3H); HPLC: rt (R) = 11.0 min, rt (S) = 12.6 min (Daicel
ChiralpakTM OD CSP; flow rate = 1.0 mL minÀ1; heptane/2-propanol
General asymmetric halolactonization procedure using 5e
(26.8 mg, 0.1 mmol, 1 equiv) with QD-thio affords 1e (28 mg,
0.08 mmol, 80% yield, 32% ee) as a white solid. HPLC: rt (R)
= 12.0 min, rt (S) = 21.0 min (Daicel ChiralpakTM IA CSP; flow
rate = 1.0 mL minÀ1; heptane/2-propanol 90:10; 25 °C; 225 nm);
[
a]
D
23 = À9.6 (c 1.0, CHCl3).
4.5.17. (S⁄)-Bromo-((S⁄)-3-oxo-1,3-dihydroisobenzofuran-1-yl)
acetic acid tert-butyl ester 1f
90:10; 25 °C; 224 nm); [
a]
20 = +3.8 (c 3.3, CHCl3), Lit.14e (R)-enan-
D
tiomer (84% ee), [
a
]
D
23 = +6.9 (0.92, CHCl3).
General asymmetric halolactonization procedure using 5f
(24.8 mg, 0.1 mmol, 1 equiv) with QD-thio affords 1f (28.1 mg,
0.086 mmol, 86% yield, 53% ee) as a colorless oil. HPLC: rt (R)
= 8.6 min, rt (S) = 12.3 min (Daicel ChiralpakTM IA CSP; flow
rate = 1.0 mL minÀ1; heptane/2-propanol 90:10; 25 °C; 225 nm);
Acknowledgments
CNRS, Chevreul Institute (FR 2638), Ministère de l’Enseigne-
ment Supérieur et de la Recherche, Région Nord—Pas de Calais
and FEDER (E.u.) are acknowledged for supporting and funding
partially this work. Mrs C. Méliet (UCCS) is thanked for elemental
analyses. Mrs C. Delabre (UCCS) is thanked for HPLC analyses.
Mrs N. Duhal and C. Lenglart (CUMA, Univ. of Lille) are thanked
for HRMS analyses.
[
a]
D
23 = À15.4 (c 1.0, CHCl3).
4.5.18. (S⁄)-Bromo-((S⁄)-5-nitro-3-oxo-1,3-dihydro-isoben-
zofuran-1-yl)acetic acid ethyl ester 2b
To a solution of quinidine thiocarbamate (4.9 mg, 0.01 mmol,
10 mol %) and benzoic acid (2.4 mg, 0.02 mmol, 20 mol %) in
toluene (6 mL) was added NBS (0.15 mmol, 1.5 equiv). A solution
of carboxylic acid 6b (26.5 mg, 0.1 mmol, 1 equiv) in chloroform
(3 mL) was added dropwise at room temperature. After 15 h, the
crude mixture was concentrated to dryness. The residue was dis-
solved in ethyl acetate, washed with saturated solution of NaHCO3,
water then brine to afford the crude phthalide 2b (34 mg,
0.1 mmol, yield = 98%, 49% ee). Enantiomeric excess was deter-
mined by 1H NMR using europium tris[3-(heptafluoropropylhy-
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.07.
010.
References
droxymethylene)-(+)-camphorate]. [
a]
23 = À2.6 (c 1.0, CHCl3).
D
1. (a) French, A. N.; Bissmire, S.; Wirth, T. Chem. Soc. Rev. 2004, 33, 354–362; (b)
Chen, G.; Ma, S. Angew. Chem., Int. Ed. 2010, 49, 8306–8308; (c) Tan, C. K.; Zhou,
L.; Yeung, Y. Synlett 2011, 1335–1339; (d) Snyder, S. A.; Treitler, D. S.; Brucks, A.
P. Aldrichim. Acta 2011, 44, 27–40; (e) Castellanos, A.; Fletcher, S. P. Chem. Eur. J.
2011, 17, 5766–5776; (f) Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew.
Chem., Int. Ed. 2012, 51, 10938–10953; (g) Hennecke, U. Chem. Asian J. 2012, 7,
456–465; (h) Murai, K.; Fujioka, H. Heterocycles 2013, 87, 763–805; (i) Tan, C.
K.; Yeung, Y.-Y. Chem. Commun. 2013, 7985–7996; (j) Tan, C. K.; Yu, W. Z.;
Yeung, Y.-Y. Chirality 2014, 26, 328–343; (k) Cheng, Y. A.; Yu, W. Z.; Yeung, Y.-Y.
Org. Biomol. Chem. 2014, 12, 2333–2343.
2. (a) Ranganathan, S.; Muraleedharan, K. M.; Vaish, N. K.; Jayaraman, N.
Tetrahedron 2004, 60, 5273–5308; (b) Lava, M. S.; Banerjee, A. K.; Cabrera, E.
V. Curr. Org. Chem. 2009, 13, 720–730; (c) Rodriguez, F.; Fanana, F. J. In
Handbook of Cyclization Reactions; Ma, S., Ed.; Wiley-VCH: New York, 2010; Vol.
4, pp 951–990.
3. Denmark, S. E.; Burk, M. T. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20655–20660.
4. (a) Dowle, M. D.; Davies, D. I. Chem. Soc. Rev. 1979, 8, 171–197; (b) Cardillo, G.;
Orena, M. Tetrahedron 1990, 46, 3321–3408; (c) Moon, H. S.; Eisenberg, S. W. E.;
Wilson, M. E.; Schore, N. E.; Kurth, M. J. J. Org. Chem. 1994, 59, 6504–6505; (d)
Monache, G. D.; Misiti, D.; Salvatore, P.; Zappia, G. Tetrahedron: Asymmetry
2000, 11, 1137–1149; (e) Jiang, X. P.; Fu, C. L.; Ma, S. M. Chem. Eur. J. 2008, 14,
9656–9664.
5. (a) Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B. J. Am. Chem. Soc.
2010, 132, 3298–3300; (b) Zhang, W.; Zheng, S.; Liu, N.; Werness, J. B.; Guzei,
L.; Tang, W. J. Am. Chem. Soc. 2010, 132, 3664–3665; (c) Zhou, L.; Tan, C. K.;
Jiang, X.; Chen, F.; Yeung, Y.-Y. J. Am. Chem. Soc. 2010, 132, 15474–15476; (d)
Veitch, G. E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2010, 49, 7332–7335; (e)
Murai, K.; Matsushita, T.; Nakamura, A.; Fukushima, S.; Shimura, M.; Fujioka, H.
Angew. Chem., Int. Ed. 2010, 49, 9174–9177; (f) Yousefi, R.; Whitehead, D. C.;
Mueller, J. M.; Staples, R. J.; Borhan, B. Org. Lett. 2011, 13, 608–611; (g) Tan, C.
K.; Zhou, L.; Yeung, Y.-Y. Org. Lett. 2011, 13, 2738–2741; (h) Whitehead, D. C.;
Fhaner, M.; Borhan, B. Tetrahedron Lett. 2011, 52, 2288–2291; (i) Tan, C. K.;
Chen, F.; Yeung, Y.-Y. Tetrahedron Lett. 2011, 52, 4892–4895; (j) Tan, C. K.; Zhou,
L.; Yeung, Y.-Y. Synlett 2011, 1335–1339; (k) Chen, J.; Zhou, L.; Tan, C. K.; Yeung,
Y.-Y. J. Org. Chem. 2012, 77, 999–1009; (l) Zhang, W.; Liu, N.; Schienebeck, C. M.;
Decloux, K.; Zheng, S.; Werness, J. B.; Tang, W. Chem. Eur. J. 2012, 18, 7296–
7305; (m) Tungen, J. E.; Nolsoe, J. M. J.; Hansen, T. V. Org. Lett. 2012, 14, 5884–
5887; (n) Ikeuchi, K.; Ido, S.; Yoshimura, S.; Asakawa, T.; Inai, M.; Hamashima,
Y.; Kan, T. Org. Lett. 2012, 14, 6016–6019; (o) Fang, C.; Paull, D. H.; Hethcox, J.
C.; Shugrue, C. R.; Martin, S. F. Org. Lett. 2012, 14, 6290–6293; (p) Paull, D. H.;
Fang, C.; Donald, J. R.; Pansick, A. D.; Martin, S. J. Am. Chem. Soc. 2012, 134,
4.5.19. (S⁄)-((S⁄)-5-Benzyloxy-3-oxo-1,3-dihydro-isobenzofuran-
1-yl)bromoacetic acid ethyl ester 3b
General asymmetric halolactonization procedure using 7b
(32.6 mg, 0.1 mmol, 1 equiv) with QD-thio affords 3b (12 mg,
0.03 mmol, 30% yield, 10% ee) as a colorless oil. HPLC: rt (R)
= 20.6 min, rt (S) = 31.7 min (Daicel ChiralpakTM IA CSP; flow
rate = 1.0 mL minÀ1; heptane/2-propanol 95:5; 25 °C; 212 nm);
[
a]
D
23 = À5.6 (c 0.8, CHCl3).
4.5.20. (S⁄)-Bromo-((S⁄)-5,6-dimethoxy-3-oxo-1,3-dihydro-
isobenzofuran-1-yl)acetic acid methyl ester 4b
To a solution of quinidine thiocarbamate (4.9 mg, 0.01 mmol,
10 mol %) and benzoic acid (2.4 mg, 0.02 mmol, 20 mol %) in
toluene (6 mL) was added NBS (0.15 mmol, 1.5 equiv). A solution
of carboxylic acid 8b (28 mg, 0.1 mmol, 1 equiv) in chloroform
(3 mL) was added dropwise at room temperature. After 15 h, the
crude mixture was directly purified by column chromatography
on silica gel to afford 4b (26 mg, 0.07 mmol, 72% yield, 22% ee)
as a white solid. HPLC: rt (R) = 99.8 min, rt (S) = 106.4 min (Daicel
ChiralpakTM IC CSP; flow rate = 1.0 mL minÀ1; heptane/2-propanol
90:10; 25 °C; 221 nm); [
a]
23 = À9.7 (c 2.0, CHCl3).
D
4.6. General procedure for dehalogenation reaction
A solution of halogenated compound 1b (1 mmol, 1 equiv) in
anhydrous toluene (200 mL) was bubbled with argon for 5 min in
a quartz vessel. TTMSS (1.1 mmol, 1 equiv) was added and the mix-
ture was directly irradiated in
a Rayonet RPR photoreactor
equipped with 254 nm lamps for 15 min. The crude was concen-
trated under vacuum then purified by column chromatography
Please cite this article in press as: Gelat, F.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.07.010

10
F. Gelat et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
11128–11131; (q) Jiang, X.; Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Angew. Chem., Int.
O.; Reed, J. N.; Billedeau, R. J.; Wang, X.; Norris, D. J.; Snieckus, V. Tetrahedron
1992, 48, 4863–4878; (d) Hosoya, T.; Kuriyama, Y.; Suzuki, K. Synlett 1995,
635–638; (e) Giurg, M.; Said, S. B.; Syper, L.; Mlochowski, J. Synth. Commun.
2001, 31, 3151–3159; (f) Giurg, M.; Syper, L.; Mlochowski, J. Pol. J. Chem. 2004,
78, 231–238; (g) Li, G.; Yin, D.; Liang, X.-T. Synth. Commun. 2004, 34, 1183–
1189; (h) Fan, Y. C.; Kwon, O. Org. Lett. 2012, 14, 3264–3267; (i) Petrignet, J.;
Inack Ngi, S.; Abarbri, M.; Thibonnet, J. Tetrahedron Lett. 2014, 55, 982–984; (j)
Parida, K. N.; Jarugu, N. J. Org. Chem. 2015, 80, 8354–8360.
Ed. 2012, 51, 7771–7775; (r) Tan, C. K.; Le, C.; Yeung, Y.-Y. Chem. Commun.
2012, 5793–5795; (s) Lee, H. J.; Kim, D. Y. Tetrahedron Lett. 2012, 53, 6984–
6986; (t) Armstrong, A.; Braddock, D. C.; Jones, A. X.; Clark, S. Tetrahedron Lett.
2013, 54, 7004–7008; (u) Nakatsuji, H.; Sawamura, Y.; Sakakura, A.; Ishihara, K.
Angew. Chem., Int. Ed. 2014, 53, 6974–6977; (v) Murai, K.; Shimizu, N.; Fujioka,
H. Chem. Commun. 2014, 12530–12533; (w) Wilking, M.; Daniliuc, C. G.;
Hennecke, U. Synlett 2014, 1701–1704; (x) Han, X.; Dong, C.; Zhou, H.-B. Adv.
Synth. Catal. 2014, 356, 1275–1280; (y) Egami, H.; Asada, J.; Sato, K.;
Hashizume, D.; Kawato, Y.; Hamashima, Y. J. Am. Chem. Soc. 2015, 137,
10132–10135.
13. (a) Luo, J.; Wang, H.; Zhong, F.; Kwiatkowski, J.; Xu, L.-W.; Lu, Y. Chem.
Commun. 2012, 4707–4709; (b) Zhong, F.; Luo, J.; Chen, G.-Y.; Dou, X.; Lu, Y. J.
Am. Chem. Soc. 2012, 134, 10222–10227; (c) Luo, J.; Jiang, C.; Wang, H.; Xu, L.-
W.; Lu, Y. Tetrahedron Lett. 2013, 54, 5261–5265; (d) Luo, J.; Wang, H.; Zhong,
F.; Kwiatkowski, J.; Xu, L.-W.; Lu, Y. Chem. Commun. 2013, 5775–5777.
14. (a) Choi, P. J.; Sperry, J.; Brimble, M. A. J. Org. Chem. 2010, 75, 7388–7392; (b)
Youn, S. W.; Song, H. S.; Park, J. H. Org. Lett. 2014, 16, 1028–1031.
15. Wiseman, R. L.; Kelker, M. S.; Foss, T.; Wilson, I. A.; Kelly, J. W. J. Am. Chem. Soc.
2005, 127, 5540–5551.
16. Huang, S.; Petersen, T. B.; Lipshutz, B. H. J. Am. Chem. Soc. 2010, 132, 14021–
14023.
17. Arican, D.; Bruckner, R. Org. Lett. 2013, 15, 2582–2585.
18. Wu, N.; Messinis, A.; Batsanov, A. S.; Yang, Z.; Whiting, A.; Marder, T. B. Chem.
Commun. 2012, 9986–9988.
19. Bryan, C. S.; Lautens, M. Org. Lett. 2010, 12, 2754–2757.
20. Madhurima, H.; Krishna, J.; Satyanarayana, G. Synthesis 2015, 47, 1245–1254.
21. Peacock, L. R.; Chapman, R. S. L.; Sedgwick, A. C.; Mahon, M. F.; Amans, D.; Bull,
S. D. Org. Lett. 2015, 17, 994–997.
6. (a) Brown, R. S. Acc. Chem. Res. 1997, 30, 131–137; (b) Denmark, S. E.; Burk, M.
T.; Hoover, A. J. J. Am. Chem. Soc. 2010, 132, 1232–1233.
7. Chen, T.; Yeung, Y.-Y. Org. Biomol. Chem. 2016, 14, 4571–4575.
8. (a) Deniau, E.; Enders, D.; Couture, A.; Grandclaudon, P. Tetrahedron: Asymmetry
2003, 14, 2253–2258; (b) Deniau, E.; Enders, D.; Couture, A.; Grandclaudon, P.
Tetrahedron: Asymmetry 2005, 16, 875–881; (c) Lanblin, M.; Couture, A.;
Deniau, E.; Grandclaudon, P. Tetrahedron: Asymmetry 2008, 19, 111–123; (d)
Deniau, E.; Couture, A.; Grandclaudon, P. Tetrahedron: Asymmetry 2008, 19,
2735–2740; (e) Agouridas, V.; Capet, F.; Couture, A.; Deniau, E.; Grandclaudon,
P. Tetrahedron: Asymmetry 2011, 22, 1441–1447; (f) Sallio, R.; Lebrun, S.;
Schifano-Faux, N.; Goossens, J.-F.; Agbossou-Niedercorn, F.; Deniau, E.; Michon,
C. Synlett 2013, 1785–1790; (g) Lebrun, S.; Sallio, R.; Dubois, M.; Agbossou-
Niedercorn, F.; Deniau, E.; Michon, C. Eur. J. Org. Chem. 2015, 1995–2004.
9. (a) Sato, H.; Yorozu, H.; Yamaoka, S. Biomed. Res. 1993, 14, 385–390; (b) Zheng,
G. Q.; Zhang, J.; Kenney, P. M.; Lam, L. K. T. ACS Symp. Ser. 1994, 546, 230–238;
(c) Zhu, X. Z.; Li, X.-Y.; Liu, J. Eur. J. Pharmacol. 2004, 495, 221–230; (d) Beck, J. J.;
Chou, S.-C. J. Nat. Prod. 2007, 70, 891–900; (e) Lin, G.; Chan, S. S.-K.; Chung, H.-
S.; Li, S. L. Stud. Nat. Prod. Chem. 2005, 32, 611–669.
22. Nalivela, K. S.; Tilley, M.; McGuire, M. A.; Organ, M. G. Chem. Eur. J. 2014, 20,
6603–6607.
23. Wrigglesworth, J. W.; Cox, B.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. Org. Lett.
2011, 13, 5326–5329.
10. Kameda, K.; Namiki, M. Chem. Lett. 1974, 12, 1491–1492.
11. Jadulco, R.; Brauers, G.; Edrada, R. A.; Ebel, R.; Wray, V.; Proksch, S.; Proksch, P.
J. Nat. Prod. 2002, 65, 730–733.
24. Yasmin, N.; Ray, J. K. RSC Adv. 2013, 3, 25631–25635.
25. Narasimhan, N. S.; Kusurkar, S. S. Indian J. Chem., Sect. B 1983, 22B, 345–348.
12. (a) Yeola, S. N.; Mali, R. S. Indian J. Chem, Sect. B 1986, 25B, 804–806; (b) Donati,
C.; Prager, R. H.; Weber, B. Australian J. Chem. 1989, 42, 787–795; (c) De Silva, S.
Please cite this article in press as: Gelat, F.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.07.010