A new trifluoromethylated sulfonamide phosphine ligand for Ag(i)-catalyzed enantioselective [3 + 2] cycloaddition of azomethine ylides

Article abstract of DOI:10.1039/C8OB02922A

A newly developed Ming-Phos ligand with a 3,5-bis(trifluoromethyl)phenyl substituent was demonstrated to be highly efficient for Ag-catalyzed asymmetric [3 + 2] cycloaddition reactions of azomethine ylides with maleimides, cyclopentene-1,3-diones, and N-(

Full text of DOI:10.1039/C8OB02922A

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A new trifluoromethylated sulfonamide phosphine
ligand for Ag(I)-catalyzed enantioselective [3 + 2]
cycloaddition of azomethine ylides†
a
Cite this: DOI: 10.1039/c8ob02922a
Yuanqi Wu,a Bing Xu,b Bing Liu,b Zhan-Ming Zhang*c and Yu Liu
*
A newly developed Ming-Phos ligand with a 3,5-bis(trifluoromethyl)phenyl substituent was demonstrated
to be highly efficient for Ag-catalyzed asymmetric [3 + 2] cycloaddition reactions of azomethine ylides
with maleimides, cyclopentene-1,3-diones, and N-(2-t-butylphenyl)maleimide. Being easily prepared on
the gram scale in one step, the ligand in combination with a Ag catalyst enables the synthesis of a variety
of highly functionalized bicyclic pyrrolidine derivatives in good yields and excellent enantioselectivities
under mild conditions.
Received 23rd November 2018,
Accepted 18th December 2018
DOI: 10.1039/c8ob02922a
rsc.li/obc
desymmetrization of N-(2-t-butylphenyl)maleimide via 1,3-
dipolar cycloaddition with in situ generated azomethine ylides
Introduction
Highly substituted pyrrolidine derivatives are prevalent in using (S)-TF-BiphamPhos as the ligand, affording a range of
natural products, and biological and pharmaceutical mole- octahydropyrrolo[3,4-c]pyrrole derivatives (Scheme 1c).11
cules.1 Furthermore, it is also a privileged architecture in
chiral ligands and organocatalysts.2 Catalytic asymmetric 1,3-
dipolar cycloaddition of azomethine ylides with electron-
deficient alkenes is one of the most powerful and diversity-
oriented synthetic methods for the construction of these types
of compounds.3 Various electron-deficient alkenes including
dimethyl malenate,4 tert-butyl acrylate,5 vinylarenes,6 and
nitroalkenes,7 among others have been utilized in such strat-
egies. Internal C–C double bonds in five-membered cyclic
structures are also reactive. In 2005, Carretero et al. reported
an asymmetric 1,3-dipolar cycloaddition reaction of azo-
methine ylide with maleimides, using
a Cu–Fesulphos
complex as the catalyst to produce a series of octahydropyrrolo
[3,4-c]pyrrole derivatives (Scheme 1a).8 Recently, Singh9 and
Wang10 independently reported a Ag(I)-catalyzed desymmetri-
zation of prochiral cyclopentene-1,3-diones via [3 + 2] cyclo-
addition with azomethine ylides using ferrophox and
(S)-TF-BiphamPhos, respectively (Scheme 1b). Later on, Wang
reported
a highly efficient Ag(I)-catalyzed atroposelective
aCollege of Chemistry and Life Science, Advanced Institute of Materials Science,
Changchun University of Technology, Changchun 130012, China.
E-mail: yuliu@ccut.edu.cn
bShanghai Key Laboratory of Green Chemistry and Chemical Processes,
School of Chemistry and Molecular Engineering, East China Normal University,
Shanghai 200062, China
cDepartment of Chemistry, Fudan University, 2005 Songhu Road, Shanghai, 200438,
P.R. China. E-mail: zhanmingzhang@fudan.edu.cn
Scheme 1 Ag(I)-Catalyzed asymmetric 1,3-dipolar cycloaddition of
azomethine ylides with maleimides, cyclopentene-1,3-diones, and N-(2-
t-butylphenyl)maleimide.
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob02922a
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Table 1 Optimization of the reaction conditionsa
Despite the above achievements, it is still highly desirable to
develop new catalyst systems, especially the ones with efficient
and simple chiral ligands for asymmetric 1,3-dipolar cyclo-
addition reactions compatible with broad functional groups
for the synthesis of multi-substituted pyrrolidine derivatives.
Over the past few years, we have been focusing on the devel-
opment of new chiral sulfonamide phosphine ligands for tran-
sition metal catalysed asymmetric reactions.12–16 Specifically,
Ming-Phoses have been successfully applied to the Au(I)-cata-
lyzed intermolecular asymmetric cyclization of 2-(1-alkynyl)-2-
alken-1-ones with nitrones and 3-stylindoles,13a–c and Cu(I)-
catalyzed asymmetric [3 + 2] cycloaddition reactions of azo-
methine ylides with β-trifluoromethyl-β,β-disubstituted enones
and α-trifluoromethyl-α,β-unsaturated esters with excellent dia-
stereo- and enantioselectivity.13d–f Considering the simplicity
and modularity in preparation and handling, which leads to a
trivial synthesis of a ligand library, we hope to extend its utili-
zation to other kinds of [3 + 2] cycloaddition reactions,
especially the ones leading to meaningful cyclic structures.
Herein, we describe our results on the application of Ming-
Phos in silver catalyzed asymmetric [3 + 2] cycloaddition reac-
tions of azomethine ylides with maleimides, cyclopentene-1,3-
diones, and N-(2-t-butylphenyl)maleimide (Scheme 1, bottom).
Entry [M]a
Ligand
Solvent Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
[Cu(CH3CN)4]ClO4 (R,Rs)-M7 Xylene
29
91
85
84
83
95
90
95
88
—
82
0
−50
20
75
66
29
93
90
90
—
63
90
86
72
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgCO3
Ag2O
(R,Rs)-M7 Xylene
(R,Rs)-M1 Xylene
(S,Rs)-M1 Xylene
(S,Rs)-M3 Xylene
(S,Rs)-M4 Xylene
(S,Rs)-M8 Xylene
(S,Rs)-M8 Xylene
(S,Rs)-M8 Xylene
(S,Rs)-M8 Xylene
(S,Rs)-M8 DCM
9
10
11
12
13
14
AgBr
AgOAc
AgOAc
AgOAc
AgOAc
(S,Rs)-M8 Toluene 88
(S,Rs)-M8 Et2O
(S,Rs)-M8 THF
99
99
a All reactions were carried out using 0.1 mmol of 1a, 0.11 mmol of 2a,
5 mol% of [M], and 5.5 mol% of ligand in 1.0 mL xylene for 15 h.
b Yields of 3aa were determined by 1H NMR analysis with CH2Br2 as an
internal standard. c The ee values of 3aa were determined by chiral
HPLC analysis.
Results and discussion
In view of its notable performance in [3 + 2] cycloaddition reac-
tions,13d–f Ming-Phos (R,Rs)-M7 was initially evaluated in com-
bination with the [Cu(CH3CN)4]ClO4 catalyst for the reaction
maleimide 1a and azomethine ylide 2a. However, a racemic
cycloadduct 3aa was obtained (Table 1, entry 1). Delightfully, a
dramatically higher yield of 91% was achieved when AgOAc
was used, although the enantioselectivity was moderate
(Table 1, entry 2). Consequently, while (R,Rs)-M1 with a phenyl
group led to poor enantioselectivity (Table 1, entry 3), the iso-
meric ligand (S,Rs)-M1 afforded a much higher ee (Table 1,
entry 4), implying that the aryl group might be more effective
for the asymmetric transformation. Accordingly, ligands with
different aryl substituents were prepared for further investi-
gation. The performances of (S,Rs)-M3 and M4, bearing
4-methoxyphenyl and 1-naphthyl groups, underlined the
importance of the aryl moiety: both ligands failed to improve
the enantioselectivity (Table 1, entries 5 and 6). To our delight,
when (S,Rs)-M8 with a 3,5-bis(trifluoromethyl)phenyl group
was introduced, the reaction proceeded remarkably to give
cycloadduct 3aa in 90% yield and 93% ee (Table 1, entry 7). So
we chose (S,Rs)-M8 as the chiral ligand for further screening.
Changing to other silver catalysts such as AgCO3, Ag2O led to
inferior results (Table 1, entries 8 and 9). The reaction was
completely shut down with AgBr (Table 1, entry 10). Other sol-
vents were also tested, and xylene was proved to be the best
choice (Table 1, entries 11–14).
Table 2 The scope of the reaction between aryl maleimide and azo-
methine ylidea
Entry
Ar1
Ar2/R1
3
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-FC6H4
4-ClC6H4
4-ClC6H4
3-ClC6H4
4-MeC6H4
4-BrC6H4/Me
4-ClC6H4/Me
4-IC6H4/Me
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3ba
3ca
3cm
3da
3ea
90
99
91
85
91
88
93
99
62
81
98
83
95
96
80
>99
93
93
91
90
90
91
98
92
98
84
94
85
95
91
83
96
92
93
3-FC6H4/Me
4-CF3C6H4/Me
4-CNC6H4/Me
4-SMeC6H4/Me
4-PhC6H4/Me
2-MeC6H4/Me
2-MeC6H4/tBu
Ph/Me
4-BrC6H4/Bn
4-BrC6H4/Me
4-BrC6H4/Me
4-BrC6H4/tBu
4-BrC6H4/Me
4-BrC6H4/Me
9
10
11
12
13
14
15
16
17
a All reactions were carried out with 0.165 mmol of 1, 0.15 mmol of
2, 5 mol% of AgOAc, and 5.5 mol% of ligand in 2.0 mL xylene for
12–24 h. b Isolated yield. c The ees of 3 were determined by HPLC
analysis.
With the optimized reaction conditions in hand, we first
investigated the scope of azomethine ylides 2 with maleimide
1a (Table 2). Gratifyingly, all of the halogen atoms located at
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Table 3 The scope of the reaction between cyclopentene-1,3-diones
both 4- and 3- positions of the phenyl groups were untouched,
thus providing opportunities for subsequent manipulation
(entries 1–4). Electron-withdrawing trifluoromethyl and nitrile
groups were well tolerated (entries 5 and 6). The significantly
higher enantioselectivity for the latter might be due to the con-
jugation effect of the nitrile group. The reaction was not
affected by the methylthio group, affording product 3ag in a
high yield and ee value (entry 7). In accordance with the nitrile
substrate, azomethine ylide with a conjugated phenyl group
showed obviously better results, leading to the desired product
3ah with 98% ee in quantitative yield (entry 8). The reactivity
was impaired for a more sterically hindered substrate with an
ortho-methyl group (entry 9), which gave a significantly lower
yield compared with unsubstituted azomethine imine (entry
11). When sterically hindered tert-butyl ester was introduced
instead of the methyl substrate, product 3aj was obtained in
notably higher enantioselectivity (entry 10). Glycine ketoimino
benzyl ester also showed excellent reactivity, providing chiral
bicyclic adduct 3al in high yield and optical purity (entry 12).
As to the scope of maleimide 1, analogues bearing both fluo-
ride and chlorides were well tolerated, leading to halogenated
products efficiently (entries 13–16). Again, the tert-butyl ester
group led to higher enantioselectivity compared with the
methyl substrate (entries 14 and 15). Me-substitution at Ar1
was also accommodated, as pyrrolidinedione 3ea was also
obtained in excellent yield and enantioselectivity with this
strategy (entry 17).
and azomethine ylidesa
Entry
Ar3
Ar2/R1/R2
5
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-BrC6H4/Me/H
4-ClC6H4/Me/H
4-IC6H4/Me/H
5aa
5ab
5ac
5ad
5ae
5af
5ag
5ah
5an
5ao
5ap
5aq
5ar
5ba
5ca
5da
5ea
5fa
86
95
85
62
70
83
70
90
73
82
89
91
80
84
83
81
82
86
96
95
94
90
94
95
94
95
92
94
92
90
91
94
95
95
95
85
3-FC6H4/Me/H
4-CF3C6H4/Me/H
4-CNC6H4/Me/H
4-SMeC6H4/Me/H
4-PhC6H4/Me/H
4-FC6H4/Me/H
4-ClC6H4/Et/H
4-BrC6H4/Me/Me
4-ClC6H4/Me/Me
4-MeC6H4/Me/Me
4-BrC6H4/Me/H
4-BrC6H4/Me/H
4-BrC6H4/Me/H
4-BrC6H4/Me/H
4-BrC6H4/Me/H
9
10
11
12
13
14
15
16
17
18
Ph
4-ClC6H4
4-FC6H4
4-MeC6H4
3-ClC6H4
2-ClC6H4
a All reactions were carried out with 0.165 mmol of 1, 0.15 mmol of
2, 5 mol% of AgOAc, and 5.5 mol% ligand in 2.0 mL xylene for 12–24 h.
b Isolated yield. c The ees of 5 were determined by HPLC analysis.
Next, we tried to extend this practical methodology to the
synthesis of other types chiral pyrrolidine derivatives. To our
delight, cyclopentene-1,3-dione 4 could be applied to the trans-
formation without the necessity to modify the conditions,
further demonstrating the power of the new ligand. The broad
generality of the reaction is presented in Table 3. Again,
various halogens and the methyl group on the phenyl moieties
in both cyclopentene-1,3-diones (entries 14–18) and azo-
methine ylides (entries 1–4, 9–12) were all untouched, leading
to the corresponding products in high yields and enantio-
selectivities. Other types of electron-donating or electron-with-
drawing groups such as trifluoromethyl-, nitrile-, methylthio-
and phenyl groups were also well tolerated (entries 6–9). Ethyl
ester displayed similar reactivity and selectivity (entry 10).
Moreover, chiral pyrrolidine products with two quaternary
carbon centers could be prepared using more sterically hin-
dered imino esters derived from α-substituted-α-amino acids
(entries 11–13). No erosion on the reactivity was detected for
all of the substrates tested.
Table 4 Substrate scope of azomethine ylides for Ag-catalyzed desym-
metrization of N-(2-t-butylphenyl)maleimidea,b,c
Based on the above work, we envisaged that the Ag(I)/Ming-
Phos complex could be employed as an effective catalyst for
the atroposelective desymmetrization of prochiral N-(2-t-butyl-
phenyl)maleimide with azomethine ylides, affording octa-
hydropyrrolo[3,4-c]pyrrole derivatives decorated with four adja-
cent stereogenic centers and one N–C chiral axis through a 1,3-
dipolar cycloaddition reaction. Fortunately, the above optimal
conditions apply equally well in the cycloaddition of azo-
methine ylide 2 and prochiral N-(2-t-butylphenyl)maleimide 6,
a All reactions were carried out with 0.165 mmol of 1, 0.15 mmol of
2, 5 mol% of AgOAc, and 5.5 mol% of ligand in 2.0 mL xylene for
12–24 h. b Isolated yield of 7. c The ees of 7 were determined by HPLC
analysis.
affording octahydropyrrolo[3,4-c]pyrrole derivatives
7 with
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the application of these ligands in other reaction systems is
underway in our lab.
Experimental section
Materials and methods
All reactions were carried out under an atmosphere of nitrogen
in flame-dried glassware with magnetic stirring. 1H NMR
spectra, 19F NMR spectra, 31P NMR spectra, and 13C NMR
spectra were recorded on a Bruker 300, 400 and 500 MHz
spectrometer in CDCl3. All signals are reported in ppm with
the internal TMS signal at 0 ppm as a standard. Data for 1H
NMR spectra are reported as follows: chemical shift (ppm,
referenced to TMS; s = singlet, d = doublet, t = triplet, q =
quartet, dd = doublet of doublets, dt = doublet of triplets, m =
multiplet), coupling constant (Hz), and integration. Data for
13C NMR are reported in terms of chemical shift (ppm) relative
to a residual solvent peak (CDCl3: 77.0 ppm). Reactions were
monitored by thin layer chromatography (TLC) using silica gel
plates. Flash column chromatography was performed over
silica gel (300–400 mesh). The enantiomeric excesses of the
products were determined by chiral stationary phase HPLC
using a Chiralpak AS-H, AD-H, IE.
Scheme 2 Gram-scale experiment and synthetic transformation.
excellent yield and enantioselectivity. Consequently, we exam-
ined the scope with respect to the azomethine ylide com-
ponent 2 by reaction with 6 (Table 4). A series of electron-rich
and electron-deficient arylaldehyde-derived benzylideneamino
acetates reacted smoothly with 6 delivering the corresponding
chiral axis products bearing halogen atoms (7aa–7ad), nitrile
(7af) and methylthio groups (7ag). Ethyl and benzyl glycine
ketoimino esters were also examined, and the desired cyclo-
adducts were generated without any sacrifice of reactivity or
selectivity (7al, 7ao). Again, α-methyl substituted azomethine
ylides could be applied in the system, affording cycloadducts
7ap–7ar with a quaternary carbon center in high yields and
enantioselectivities.
To further explore the practicability of our methodology,
gram-scale reactions were conducted. Both the reaction of 1a
and 4a with 2a could be efficiently scaled up without any loss
of efficiency and selectivity, delivering the cycloadducts 3aa
(Scheme 2, eqn (1)) and 5aa (Scheme 2, eqn (2)) in high yields
and optical purities. Upon oxidation with DDQ, the bicyclic-
pyrrolidine cycloadduct 5aa delivered the enantioenriched
bicyclic pyrrole derivative 8 without any loss of enantio-
selectivity (Scheme 2, eqn (3)).
General procedure for the synthesis of ligand (S,Rs)-M8. To a
solution of (2-bromophenyl)diphenylphosphane (12 mmol) in
dry THF (15 mL) was added n-BuLi (12 mmol, 2.4 M in
hexane) dropwise under argon at −78 °C. After 2 hours at this
temperature, the solution of (R,E)-N-(3,5-bis(trifluoromethyl)
benzylidene)-2-methylpropane-2-sulfinamide (10 mmol) in
THF (10 ml) was added dropwise, and the reaction mixture
was warmed to room temperature overnight. The reaction
mixture was quenched by the addition of NH4Cl (aq.) and
diluted with EtOAc. The organic layer was separated, and the
aqueous layer was extracted twice with EtOAc. The combined
organic layers were dried over Na2SO4, filtered, and concen-
trated. The crude product was then purified by flash column
chromatography on silica gel (petroleum ether : AcOEt = 15 : 1)
to afford (S,Rs)-M8.
(S,Rs)-M8. As a white solid (3.5241 g, 58% yield); [α]D25
=
−40.9 (c = 0.25, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.61 (s, 3
H), 7.49–7.44 (m, 2 H), 7.29–7.25 (m, 4 H), 7.23–7.19 (m, 1 H),
7.14 (dd, J = 13.7, 6.0 Hz, 4 H), 7.05 (dd, J = 6.9, 4.0 Hz, 1 H),
6.98 (t, J = 7.4 Hz, 2 H), 6.66 (s, 1 H), 4.13 (s, 1 H), 1.24 (s, 9 H);
Conclusions
In conclusion, we have reported the asymmetric [3 + 2] cyclo- 19F NMR (282 MHz, CDCl3): δ −62.78. 31P NMR (162 MHz,
addition reaction of azomethine ylides with maleimides, cyclo- CDCl3): δ −18.56; 13C NMR (101 MHz, CDCl3): δ 144.84 (d, J =
pentene-1,3-diones, and N-(2-t-butylphenyl)maleimide with an 24.2 Hz), 144.55, 135.8–135.7 (m), 135.51, 134.70 (d, J = 8.1
easily available Ming-Phos derivative, and firstly realized the Hz), 133.69 (d, J = 12.9 Hz), 133.50 (d, J = 12.3 Hz), 131.53 (q,
silver/Ming-Phos-catalyzed asymmetric reactions. The method- J = 33.3 Hz), 129.74, 128.81 (d, J = 9.4 Hz), 128.50 (dd, J = 7.0,
ology proceeds well over a broad scope of substrates, providing 4.6 Hz), 128.16 (d, J = 5.6 Hz), 122.98 (q, JC–F = 273.0 Hz),
facile access to a series of highly functionalized bicyclic pyrrol- 121.31 (dt, J = 7.3, 3.8 Hz), 60.53, 60.29, 56.41, 22.62. ESI-MS
idines in high yields and excellent enantioselectivities. calculated for C31H29F6NOPS: m/z (%): 608.1606 (M + H+),
Moreover, prochiral cyclopentenedione and N-(2-t-butylphenyl) found: 608.1606.
maleimide could also be introduced into the reaction system.
General procedure for the asymmetric silver-catalyzed cyclo-
The desymmetrization process allowed for the access of the addition of azomethine ylides with maleimides. A solution of
corresponding chiral products efficiently. The investigation of (S,Rs)-M8 (5.5 mol%) and AgOAc (5 mol%) in xylene (2 mL) was
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stirred at room temperature for 2 h. The reaction mixture was −9.8 (c = 0.25, CHCl3); H NMR (300 MHz, CDCl3): δ 7.46–7.36
cooled to −30 °C and then the imino ester 2 (0.15 mmol), (m, 2 H), 7.18 (dd, J = 5.4, 2.0 Hz, 5 H), 6.92 (dd, J = 6.5,
Cs2CO3 (0.045 mmol) and maleimide 1 (0.165 mmol) were 3.1 Hz, 2 H), 4.29 (d, J = 8.0 Hz, 1 H), 3.91–3.88 (m, 1 H), 3.85
added sequentially. Following complete consumption of the (s, 3 H), 2.83 (s, 2 H), 2.75 (dd, J = 5.2, 2.6 Hz, 2 H), 2.22 (s, 1
imino ester 2, the solvent was removed under reduced H), 1.11 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 217.27, 215.43,
pressure. The crude product was then purified by silica gel 170.51, 136.19, 135.63, 131.28, 129.63, 128.63, 128.51, 127.11,
column chromatography using petroleum ether/ethyl acetate 121.73, 65.41, 63.44, 60.22, 55.79, 54.26, 52.09, 43.84, 18.21.
as the eluent (2/1–1/1) to afford the desired product.
Methyl
(1R,3S,3aR,6aS)-3-(4-bromophenyl)-4,6-dioxo-5- H+), found: 456.0817. Enantiomeric excess was determined by
phenyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (3aa). As HPLC with a Chiralpak ASH column (hexanes : 2-propanol =
a white solid (61.8 mg, 96% yield); mp: 175–176 °C; [α]2D5 50 : 50, 0.8 mL min−1, 210 nm); minor enantiomer tr =
−123.8 (c = 0.25, CHCl3); 1H NMR (500 MHz, CDCl3): δ 7.48 (d, 9.4 min, major enantiomer tr = 13.3 min (96% ee).
J = 8.4 Hz, 2 H), 7.40 (t, J = 7.6 Hz, 2 H), 7.34–7.32 (m, 3 H), Methyl (1R,3S,3aR,5R,6aS)-3-(4-bromophenyl)-5-(4-chloro-
ESI-MS calculated for C23H23BrNO4: m/z (%): 456.0805 (M +
=
7.13 (d, J = 7.5 Hz, 2 H), 4.54 (dd, J = 8.6, 4.8 Hz, 1 H), 4.12 (dd, benzyl)-5-methyl-4,6-dioxooctahydrocyclopenta[c]pyrrole-1-car-
J = 6.4, 4.7 Hz, 1 H), 3.86 (s, 1 H), 3.71 (t, J = 7.2 Hz, 3 H), 3.54 boxylate (5ba). As a white solid (62.0 mg, 84% yield); mp:
1
(t, J = 8.2 Hz, 1 H), 2.48 (s, 1 H); 13C NMR (126 MHz, CDCl3): 170–171 °C; [α]D25 = 5.9 (c = 0.25, CHCl3); H NMR (300 MHz,
δ 174.88, 173.43, 169.88, 135.75, 131.59, 131.45, 129.07, CDCl3): δ 7.44 (d, J = 8.3 Hz, 2 H), 7.16 (dd, J = 11.8, 8.4 Hz, 4
128.79, 128.58, 126.02, 122.27, 63.47, 61.75, 52.34, 49.03, H), 6.84 (d, J = 8.3 Hz, 2 H), 4.32 (d, J = 7.6 Hz, 1 H), 3.93 (d, J =
47.94. ESI-MS calculated for C20H18BrN2O4: m/z (%): 429.0444 6.9 Hz, 1 H), 3.84 (s, 3 H), 2.83–2.79 (m, 4 H), 2.25 (s, 1 H),
(M + H+), found: 429.0449. Enantiomeric excess was deter- 1.11 (s, 3 H); 13C NMR (101 MHz, CDCl3): δ 217.00, 215.17,
mined by HPLC with a Chiralpak ASH column (hexanes : 2-pro- 170.36, 136.00, 134.22, 133.07, 131.30, 131.07, 128.61, 128.57,
panol = 50 : 50, 0.8 mL min−1, 210 nm); minor enantiomer tr = 121.77, 65.46, 63.53, 60.06, 55.77, 54.21, 52.10, 42.42, 18.36.
17.9 min, major enantiomer tr = 39.1 min (93% ee).
ESI-MS calculated for C23H22BrClNO4: m/z (%): 490.0415 (M +
Methyl (1R,3S,3aR,6aS)-3-(4-bromophenyl)-5-(4-fluorophenyl)- H+), found: 490.0426. Enantiomeric excess was determined by
4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (3ba). As a HPLC with a Chiralpak ASH column (hexanes : 2-propanol =
white solid (62.7 mg, 93% yield); mp: 231–232 °C; [α]D25
=
80 : 20, 0.8 mL min−1, 210 nm); minor enantiomer tr =
−119.8 (c = 0.25, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.47 (d, 15.1 min, major enantiomer tr = 18.1 min (94% ee).
J = 8.4 Hz, 2 H), 7.32 (d, J = 8.4 Hz, 2 H), 7.15–7.05 (m, 4 H), General procedure for the asymmetric silver-catalyzed cyclo-
4.55 (d, J = 8.4 Hz, 1 H), 4.13 (d, J = 6.4 Hz, 1 H), 3.86 (s, 3 H), addition of azomethine ylides with N-(2-t-butylphenyl)male-
3.71 (t, J = 7.1 Hz, 1 H), 3.55 (t, J = 8.2 Hz, 1 H), 2.33 (s, 1H); imide. A solution of (S,Rs)-M8 (5.5 mol%) and AgOAc (5 mol%)
19F NMR (282 MHz, CDCl3): δ −112.25–−112.31 (m); 13C NMR in xylene (2 mL) was stirred at room temperature for 2 h. The
(101 MHz, CDCl3): δ 174.78, 173.32, 169.84, 162.08 (d, J = reaction mixture was cooled to −30 °C and then the imino
248.8 Hz), 135.69, 131.61, 128.73, 127.89 (d, J = 8.8 Hz), 127.35 ester 2 (0.15 mmol), Cs2CO3 (0.045 mmol) and N-(2-t-butyl-
(d, J = 3.3 Hz), 122.32, 116.09 (d, J = 23.0 Hz), 63.45, 61.75, phenyl)maleimide 6 (0.165 mmol) were added sequentially.
52.35, 49.01, 47.88. ESI-MS calculated for C20H16BrF5NaO: m/z Following complete consumption of the imino ester 2, the
(%): 469.0197 (M + H+), found: 469.0193. Enantiomeric excess solvent was removed under reduced pressure. The crude
was determined by HPLC with a Chiralpak ASH column product was then purified by silica gel column chromato-
(hexanes : 2-propanol = 50 : 50, 0.8 mL min−1, 210 nm); minor graphy using petroleum ether/ethyl acetate as the eluent
enantiomer tr = 15.7 min, major enantiomer tr = 28.8 min (2/1–1/1) to afford the desired product. The configuration of 7
(93% ee).
was determined by comparison with the literature, see: ref. 11.
General procedure for the asymmetric silver-catalyzed cyclo-
Methyl (1R,3S,3aR,6aS)-3-(4-bromophenyl)-5-(2-(tert-butyl)
addition of azomethine ylides with cyclopentene-1,3-diones. A phenyl)-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
solution of (S,Rs)-M8 (5.5 mol%) and AgOAc (5 mol%) in (7aa). As a white solid (70.2 mg, 96% yield); mp: 196–197 °C;
xylene (2 mL) was stirred at room temperature for 2 h. The [α]2D5 = −102.9 (c = 0.25, CHCl3); 1H NMR (400 MHz, CDCl3):
reaction mixture was cooled to −30 °C and then the imino δ 7.49–7.44 (m, 3 H), 7.35–7.30 (m, 3 H), 7.27–7.23 (m, 1 H),
ester 2 (0.15 mmol), Cs2CO3 (0.045 mmol) and cyclo-pentene- 6.85 (d, J = 1.5 Hz, 1 H), 4.49 (dd, J = 8.2, 4.0 Hz, 1 H),
dione 4 (0.165 mmol) were added sequentially. Following com- 4.11–4.08 (m, 1 H), 3.83 (s, 3 H), 3.67 (dd, J = 14.6, 7.0 Hz, 1
plete consumption of the imino ester 2, the solvent was H), 3.52 (t, J = 8.1 Hz, 1 H), 2.46 (s, 1 H), 1.21 (s, 9 H); 13C NMR
removed under reduced pressure. The crude product was then (101 MHz, CDCl3): δ 176.03, 174.62, 169.86, 147.65, 135.63,
purified by silica gel column chromatography using petroleum 131.44, 130.80, 129.89, 129.79, 128.75, 128.70, 127.55, 122.05,
ether/ethyl acetate as the eluent (2/1–1/1) to afford the desired 63.54, 61.79, 52.29, 48.97, 47.68, 35.58, 31.56. ESI-MS calcu-
product. The configuration of 5 was determined by compari- lated for C24H25BrN2NaO4: m/z (%): 507.0890 (M + H+), found:
son with the literature, see: ref. 9.
Methyl (1R,3S,3aR,5R,6aS)-5-benzyl-3-(4-bromophenyl)-5-
507.0901. Enantiomeric excess was determined by HPLC with
Chiralpak ASH column (hexanes : 2-propanol 50 : 50,
a
=
methyl-4,6-dioxooctahydrocyclopenta[c]pyrrole-1-carboxylate (5aa). 1.0 mL min−1, 220 nm); minor enantiomer tr = 5.8 min, major
As a white solid (58.8 mg, 86% yield); mp: 153–154 °C; [α]D25
=
enantiomer tr = 9.2 min (96% ee).
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Organic & Biomolecular Chemistry
General procedure for the synthesis of 8. A solution of com-
Wiley-VCH, Weinheim, 2011, p. 409; (c) B. M. Trost and
M. J. Bartlett, Acc. Chem. Res., 2015, 48, 688.
pound 5aa (136.9 mg, 0.3 mmol) in toluene (3 mL) was stirred
at room temperature in a sealed tube. DDQ (1.2 mmol) was
then added. Consumption of the starting material was moni-
tored by TLC analysis. After 5aa was completely consumed, the
reaction mixture was quenched by the addition of NaHCO3
(aq.) and diluted with EtOAc. The organic layer was separated,
and the aqueous layer was extracted twice with EtOAc. The
combined organic layers were dried over Na2SO4, filtered, and
concentrated. The crude product was analyzed by 1H NMR and
19F NMR spectroscopy to determine the diastereomeric ratio.
The crude product was then purified by flash column chrom-
atography on silica gel (petroleum ether : AcOEt = 3 : 1) to
afford the desired product.
3 For reviews about the 1,3-dipolar cycloaddition reactions of
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Methyl (R)-5-benzyl-3-(4-bromophenyl)-5-methyl-4,6-dioxo-
2,4,5,6-tetrahydrocyclopenta[c]pyrrole-1-carboxylate (8). As a
white solid (116.3 mg, 86% yield); mp: 105–106 °C; [α]D25
=
1
199.0 (c = 0.25, CHCl3); H NMR (300 MHz, CDCl3): δ 11.16 (s,
1 H), 8.01 (d, J = 8.6 Hz, 2 H), 7.54 (d, J = 8.6 Hz, 2 H),
7.06–6.99 (m, 5 H), 3.85 (s, 3 H), 3.12 (s, 2 H), 1.40 (s, 3 H); 13
C
NMR (101 MHz, CDCl3): δ 196.71, 196.29, 160.22, 136.30,
134.16, 132.99, 132.23, 129.82, 129.61, 128.27, 127.97, 126.68,
126.54, 124.67, 116.65, 63.22, 52.87, 41.50, 21.30. ESI-MS calcu-
lated for C20H17ClN2NaO4: m/z (%): 407.0774 (M + H+), found:
407.0769. Enantiomeric excess was determined by HPLC with
a Chiralpak ADH column (hexanes : 2-propanol = 90 : 10,
1.0 mL min−1, 254 nm); major enantiomer tr = 13.4 min,
minor enantiomer tr = 17.4 min (96% ee).
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Conflicts of interest
There are no conflicts to declare.
7 (a) X.-X. Yan, Q. Peng, Y. Zhang, K. Zhang, W. Hong,
X.-L. Hou and Y.-D. Wu, Angew. Chem., Int. Ed., 2006, 45,
1979; (b) T. Arai, N. Yokoyama, A. Mishiro and H. Sato,
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L.-W. Xu, Angew. Chem., Int. Ed., 2015, 54, 5255.
Acknowledgements
This work was supported by the grant from the Science and
Technology Development Project of Jilin Province
(20170520137JH) and the National Natural Science Foundation
of China (Grant No. 21602015).
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