N-tert-Butanesulfinyl imine and aromatic tertiary amide derived non-biaryl atropisomers as chiral ligands for silver-catalyzed endo-selective [3+2] cycloaddition of azomethine ylides with maleimides

Article abstract of DOI:10.1016/j.tet.2015.09.068

Simple modifications of our novel ligand (Xing-Phos) were presented in this work, and a series of aromatic tertiary amide derived non-biaryl atropisomers were successfully synthesized in good yields. In addition, it was found that the multifunctional arom

Full text of DOI:10.1016/j.tet.2015.09.068

Tetrahedron xxx (2015) 1e10
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Tetrahedron
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N-tert-Butanesulfinyl imine and aromatic tertiary amide derived
non-biaryl atropisomers as chiral ligands for silver-catalyzed endo-
selective [3þ2] cycloaddition of azomethine ylides with maleimides
,
,
b
a,b,
*
Xing-Feng Bai a b, Jin Zhang b, Chun-Gu Xia a , Jian-Xing Xu , Li-Wen Xu
*
a State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics (CAS), and University of the Chinese Academy of
Sciences, PR China
b Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education Hangzhou Normal University, No 1378, Wenyi West
Road, Science Park of HZNU, Hangzhou 311121, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Simple modifications of our novel ligand (Xing-Phos) were presented in this work, and a series of aro-
matic tertiary amide derived non-biaryl atropisomers were successfully synthesized in good yields. In
addition, it was found that the multifunctional aromatic tertiary amide derived non-biaryl atropisomers
exhibited an excellent endo-selectivity in the silver-catalyzed [3þ2]-cycloaddition of azomethine ylides
with N-aromatic maleimide. And especially, good to high levels of enantioselectivity (up to 98% ee) was
obtained with a wide range of substrates in the presence of syn-(R, RS)-2a (Xing-Phos). Furthermore, on
the basis of the experimental data, it was demonstrated that a trace amount of water play an important
role in the enhancement of enantioselectivity.
Received 24 August 2015
Received in revised form 20 September 2015
Accepted 29 September 2015
Available online xxx
Keywords:
Cycloaddition
Asymmetric catalysis
Sliver
Ó 2015 Elsevier Ltd. All rights reserved.
Azomethine ylide
Phosphine
Atropisomer
1. Introduction
challenge in asymmetric catalysis. In this context, we became in-
terested in the synthesis of chiral phosphine ligands with sulfinyl
During the past decades, intense research efforts have been
devoted to develop highly effective silver-based catalyst systems
with functional chiral ligands, including S-ligands and P-ligands.1
Especially, the chiral silver complexes have been attracted much
attention from organic chemists because of its privileged catalytic
activity in many organic reactions, which provided versatile and
powerful potential for the synthesis of synthetically useful and
optically active molecules.2 Despite numerous elegant methods
have been established for the construction of the highly efficient
silver-based catalyst system, the development of novel silver
complex with new chiral ligands as an effective catalyst is highly
desired in comparison to that of other transition metals, such as
palladium, rhodium, etc. In addition, the crucial role of chiral ligand
promoted the chemists to design functional ligands to control the
catalytic activity of silver complex.1e3 However, the synthesis of
chiral ligands, including chiral phosphine ligands, with good cata-
lytic activity is not an easy task and still be recognized as a great
groups and its potential application as a controlled element in the
catalytic asymmetric [3þ2] cycloaddition of azomethine ylides
with maleimides, for the preparation of functional pyrrolidines.
Functionalized pyrrolidines are key units in medicinal chemistry
and also a type of highly valuable synthetic building blocks for
nature products.4 In addition, chiral proline derivatives, similarly to
the basic structure of pyrrolidines, also proved to be useful organic
catalysts in many catalytic asymmetric transformations.5 The great
synthetic potential of this five-membered ring heterocycles in-
spired the huge development of diastereoselective [3þ2] cycload-
ditions of azomethine ylide with activated alkenes, which is an
extremely powerful and atom-economical strategy for the enan-
tioselective construction of pyrrolidine ring.6 Since the pioneering
work of Grigg7 and Zhang,8 much more efficient high diastereo-
and enantioselective catalytic system have been reported with the
efforts of Jørgensen,9 Schreiber,10 Zhou,11 Carrerero,12 Hou,13
Wang,14 Fukuzawa15 and other groups.16 Organocatalyzed 1,3-
dipolar [3þ2] cycloadditions also made progress in MacMillan17
and other chemist’s efforts.18
Very recently, we have reported the design and synthesis of
a kind of novel multifunctional ligand, aromatic tertiary amide
* Corresponding authors. E-mail addresses: cgxia@licp.cas.cn (C.-G. Xia),
liwenxu@hznu.edu.cn (L.-W. Xu).
http://dx.doi.org/10.1016/j.tet.2015.09.068
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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2
X.-F. Bai et al. / Tetrahedron xxx (2015) 1e10
derived non-biaryl atropisomer as phosphine ligand (also called as
Xing-Phos).19 We have also found that the Xing-Phos was a highly
efficient ligand in the AgI-catalyzed exo-selective [3þ2] cycloaddi-
in this 1,2-addition reaction of Grignard reagents or organometallic
reagents to aromatic amide-derived sulfinyl imine 1. Actually, we
observed that the addition of Grignard reagent to sulfinyl imino 1
almost was not occurred until the temperature rose to about
ꢀ20 ꢁC, and the epimerization was quenched when temperature
was below 0 ꢁC. If keep the reaction mixture at room temperature
(20 ꢁC), new isomers produced by epimerization of AreCO bond
would grow as time goes on. Hence, we decreased the reaction
temperature to ꢀ20 ꢁC because of the possible epimerization at
room temperature.
tion of azomethine ylides with trans-b
-nitrostyrene (Scheme 1).19a
Although this protocol has made great success in this field, the
variety of aromatic amide-derived non-biaryl atropisomer de-
rivatives still too limited and the application of aromatic amide-
derived non-biaryl atropisomer with both phosphine and sulfinyl
groups in silver-catalyzed [3þ2] cycloaddition remained to be
widened. It is necessary to synthesis versatile aromatic amide-
derived non-biaryl atropisomer derivatives and figure out
whether high diastereo- and enantioselectivity cloud be obtained
when other dipolarophilic olefins used instead of trans-b-nitro-
styrene. Interesting, previously reported silver-catalyzed [3þ2]
cycloadditions of azomethine ylide are almost endo-selective in
most cases, especially with substituted maleimides.11,16,20 Thus
previous works inspired our curiosity about whether it is possible
to get higher endo-selectivity and high ee value under suitable
conditions in the presence of Xing-Phos and other aromatic tertiary
amide derived non-biaryl atropisomers. We speculated that the
geometrical configuration of olefins might change the mutual effect
of [3þ2] cycloaddition procedure in this Ag/Xing-Phos catalysis
system, and accordingly, we considered that maleimide derivatives
could be used as Z-alkene. Herein, we report the enantioselective
synthesis of aromatic amide-derived non-biaryl atropisomer de-
rivatives, the analogues of Xing-Phos, and investigate their appli-
cation in silver-catalyzed cycloaddition of azomethine ylide with N-
aromatic maleimide. This work reveals that the silver-catalyzed
asymmetric [3þ2] cycloaddition reaction of glycine imino esters
with maleimide can proceed smoothly to give the corresponding
pyrrolidine derivatives in good to excellent enantioselectivity in the
presence of the Xing-Phos under mild conditions.
Scheme 2. Stereodivergent preparation of aromatic amide-derived non-biaryl atro-
pisomers with both phosphine and sulfinyl groups.19
.
As shown in Table 1, the diastereoselectivities were varied under
different reaction conditions, for example, the desired aromatic
amide-derived non-biaryl atropisomer could be obtained in a di-
astereoisomer ratio of 67/33 when phenyl Grignard reagent as
Table 1
Optimization of the 1,2-addition of aromatic amide derivative 1 with phenyl metal
reagentsa
Scheme 1. Silver-catalyzed [3þ2] cycloaddition of azomethine in the presence of Xing-
Phos: exo-selectivity or endo-selectivity for the silver-catalyzed cycloaddition of
maleimide?
Entry
Solvent
Additive
PhMgBr or PhLi
2/3b
2. Results and discussion
1
2
3
4
5
6
7
8
9
DCM
DCM
THF
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
d
PhMgBr in THF (1.0M)
PhLi in THF (1.7M)
PhLi in THF (1.7M)
PhLi in THF (1.7M)
PhLi in ether (1.5M)
PhMgBr in THF (1.0M)
PhLi in THF (1.7M)
PhMgBr in THF (1.0M)
PhMgBr in THF (1.0M)
67/33
56/44
69/31
56/44
54/46
71/29
53/47
56/43
49/51
d
We initiated our studies by synthesizing a series of novel aro-
matic amide-derived non-atropisomer derivatives bearing both
axial and sp3 central chirality. We had prepared a special aromatic
amide-derived non-biaryl atropisomer, also called as Xing-Phos,
started with N,N-diisopropylbenzamide in four steps (Scheme
2).19 All the first three steps were simple and classic trans-
formations with high yield, while the fourth step was frustrating, in
which 43% yield of syn-(R, RS)-2a and 35% yield of syn-(S, RS)-3a was
achieved in this 1,2-addition reaction. Not only the stereocontrol of
diastereoselectivity but also the epimerization should be cautious
d
d
d
d
Me3Al
HMPA
TMEDA
a
The reaction was carried out under N2 atmosphere and solvents were dried
before use in all cases.
b
The ratio of syn-(R, RS)-2a/syn-(S, RS)-3a was determined by chiral HPLC with
chiarlpark AD-H column (Hexane:i-PrOH¼96:4, 1 mL/min).
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X.-F. Bai et al. / Tetrahedron xxx (2015) 1e10
3
organometallic substrate (Table 1, entry 1). The effects of different
phenyl-metallic reagents, solvent and Lewis acid auxiliaries also
carried out in this work.21 The diastereoselectivity of this 1, 2-
addition was almost reached at a moderate level no matter the
phenyl-metallic reagent changed or the auxiliaries added. So far,
the best result in term of diastereoselectivity we got in this work
was carried out in toluene with PhMgBr (2/3¼71/29, entry 6).
Then we used different organometallic reagent to expand the
diversity of this aromatic amide derived non-biaryl atropisomers.
As shown in Fig. 1, both aromatic and aliphatic Grignard reagents
were investigated in the 1,2-addition of organometallic reagents to
aromatic amide-derived sulfinyl imide 1. In all cases, two isolable
isomers were detected by TLC and the small polar ones could be
isolated as pure atropisomers successively. Although the isolated
yields (varied from 28 to 55%) were not good enough, the type of
present multifunctional aromatic amide derived non-biaryl atro-
piosmers enlarged the scope of optically pure atropisomers, and
accordingly, the high level of enantioselective inductivity of these
aromatic amide-derived atropisomers could be desired in various
organic transformations.
(80% ee, entry 3). However, the enantioselectivity was not improved
when the reaction temperature was decreased to ꢀ40 ꢁC (77% ee,
entry 5). We also evaluated the effect of both organic and inorganic
bases on the silver-catalyzed cycloaddition (Entries 9e13). It tuned
out that inorganic bases work against the enantioselectivity (<53%
ee when HCOONa or K2CO3 was used in this case), while most of
organic bases slightly result in decreased enantioselectivity of
endo-6a. And unexpectedly, the ee of endo-6a decreased dramati-
cally to 22% when DBU was added. The negative effect of these
bases might be aroused from the disturbing intermolecular in-
teraction of catalyst-substrate in the catalytic asymmetric [3þ2]
cycloaddition.
Table 2
Ag(I)-catalyzed [3þ2] cycloaddition of 4a with 5a in presence of aromatic amide-
derived non-biaryl atropisomer 2ha
Entry
Ag
Additive
Solvent
endo/exob
Yield (%)b
Ee (%)c
1
2
3
4
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
d
THF
DCM
EtOH
95:5
70
75
80
90
91
74
85
82
83
90
95
75
88
91
92
92
70
62
80
82
77
71
74
60
47
53
79
22
78
81
81
83
76
77
75
d
d
80:20
88:12
>98:2
>98:2
>98:2
94:6
d
d
Toluene
Toluene
Toluene
Toluene
Xylene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
5d
6d,e
7f
d
d
d
8
9
d
95:5
HCOONa
K2CO3
Et3N
DBU
i-Pr2NEt
Urea
TFE
H2O
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
d
10
11
12
13
14
15
16g
17
18
19
20
21
22
AgClO4
AgOAc
AgOTf
Cu(OAc)2
CuF2
CuCl
93
89
90
Trace
Trace
Trace
Fig. 1. The synthesis of aromatic amide-derived non-biaryl atropisomers 2aeh.
d
d
d
d
a
The metal salt (2.5 mol %) was dissolved in corresponding solvent (2 mL), then
the ligand was added. The mixture was stirred at ꢀ20 ꢁC for 15 min before 1a
(0.4 mmol) was added. Then base (10 mol %) and 2a (0.2 mmol) was added suc-
cessively and stirred for 5 h.
Subsequently, we began to evaluate the catalytic activity and
enantioselectivity of the aromatic amide-derived non-biaryl atro-
pisomers 2aeh in silver-catalyzed [3þ2] cycloaddition of azome-
thine ylides with N-aromatic maleimide. Initially, the cycloaddition
of N-benzylideneglycine ethyl ester 4a with N-phenyl maleimide 5a
was selected as the model reaction. We first examined the reaction
at ꢀ20 ꢁC in THF for 5 h with 2.5 mol % AgF and 5.5 mol % syn-(R,
RS)-2h19, which was the optimized reaction condition for the cy-
b
Measured by 1H NMR spectroscopy of the crude reaction mixture with 4-
dimethylaminopyridine as internal standard.
c
Enantiomeric excesses were determined by chiral HPLC.
d
The reaction was carried out at ꢀ40 ꢁC.
e
The reaction was carried out under N2 atmosphere in this case.
f
The reaction was carried out at ꢀ5 ꢁC.
g
The AgF was dissolved with a trace amount of H2O (0.1 mL), then the reaction
cloaddition of N- benzyl-ideneglycine methyl ester with trans-b-
was carried out in 2 mL of toluene.
nitrostyrene (exo: endo¼>99: <1, up to 97% ee). To our delight, the
diastereoselectivity successfully reversed to endo-selectivity
(endo:exo¼>95:<5), however, the enantioseclectivity dropped
obviously (70% ee, Table 2, entry 1) in comparison to that of
nitrostyrene. Then we investigate the solvent effect because of the
possibly significant impacts of solvent on 1,3-dipolar cycloaddi-
tion.22 As the data summarized in Table 1 illustrated, when DCM
was used as solvent, the ee of endo-6aa decreased to 62% (Entry 2).
Fortunately, the endo-selectivity kept in a high level and the endo-
6aa was obtained in 82% ee in toluene (Entry 4). Similarly, the same
diastereoselectivity was obtained in xylene but this solvent was not
in favour of enantiselectivity (60% ee, entry 8). Despite the cyclo-
addition processed smoothly when protic solvent EtOH was
employed, the diastereo- and enantioselectivity were unsatisfying
The finding that there is no improvement in enantioselectivity
in anhydrous toluene (Entry 6 of Table 1, 71% ee) promoted us to
evaluate the possible activation by the hydrogen-bonding in-
teraction. Notably, the addition of trace amount of water to the
solvent, endo-6a was obtained in higher enantioselectivity (83% ee,
Entry 16). However, urea and trifluoroethanol (TFE) were not nec-
essary for this reaction in term of catalytic activity and enantiose-
lectivity (Entries 14e15). In addition, as shown in Table 1, other
silver Lewis acid, such as AgOAc, AgClO4 and AgOTf, gave a slight
lower ee (Entries 17e19). To support the powerful of silver-based
catalyst system with 2h, the copper salts was used as a catalyst in
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4
X.-F. Bai et al. / Tetrahedron xxx (2015) 1e10
this reaction (Entries 20e22). Unfortunately, the Cu/2h exhibited
almost no activity in this reaction (below 10% even extension the
reaction time to 24 h).
a not obvious effect on the enantioselectivity (from 74% to 83% ee
when under nitrogen atmosphere) in the silver-catalyzed cyclo-
addition, but really effected the air-stability of these aromatic ter-
tiary amide derived non-biaryl atropisomers. In general, a bulky
and rigid aromatic group (e.g., phenyl) was beneficial to improve
the stability and then keep the enantioselectivity under air-
atmosphere. We also evaluated ligands 2aeh in the silver-
catalyzed [3þ2] cycloaddition under nitrogen atmosphere (see
Fig. S1 of Supplementary data), and we found that the diaster-
eoselectivities of all the desired products were also obtained in
quite high level (endo:exo>98:2). And as shown in Fig. S1, the same
level of enantioselectivities (74e83%ee) was achieved with these
aromatic amide-derived atropisomers (2aeh). Although the
enantioselectivity of present [3þ2] cycloaddition remained to be
improved, this endo-selective AgF/Xing-Phos catalyst system
proved to a valuable find because of the paradoxical diaster-
eoselectivity compared with the exo-selectivity in the cycloaddition
of azomethine ylide with nitroolefins, chalcones, or methyl
cinnamates.19
Next, we evaluated the catalytic or enantioselective activity of
the aromatic amide-derived non-biaryl atropisomers (Fig. 1) and
ligand 2i19 in this AgF-catalyzed [3þ2] cycloaddition under the
optimized condition. The catalytic activity of silver-Xing-Phos (2a)
was compared to those of aromatic amide-derived phosphines
bearing analogous groups (2bei), and the results are shown in
Fig. 2. As expected, the enantioselectivity of Xing-Phos (2a)
remained the best level in this reaction (84% ee), while other aro-
matic amide-derived non-biaryl atropisomers 2bei only gave
lower enantioselectvities (46e80% ee) albeit the diaster-
eoselectivities were high for every cases under the optimized re-
action conditions (endo:exo>95:5). Notably, on the basis of
characterization or experimental data, the stability of ligands 2beg
was not as good as that of ligand 2a and 2h in solution, which
supported the partial oxidation of phosphine center on the aro-
matic amide-derived atropisomers. Thus accordingly, these ligands
2beg exhibited the decreased enantioselectivity in comparison to
that of 2a in this reaction. Furthermore, two major finding can be
drawn from the experiment data: 1) the phosphine contained
multifunctional non-biaryl atropisomers performed an excellent
endo-selectivity in the silver-catalyzed [3þ2] cycloaddition of
azomethine ylide with N-phenyl maleimide; 2) the R-group exerted
Next, under the optimized experimental conditions with Xing-
Phos, we explored the catalytic asymmetric 1,3-dipolar [3þ2]
cycloaddition of a series of representative imino esters with N-
substituted maleimides. As seen from the results listed in Table 3,
a wide variety of sterically and electronically different aromatic a-
imino esters on aryl rings, reacted smoothly with N-arylmalei-
mides, affording the desired products in good enantioselectivities
and excellent yields. In most cases, the moisture solvent was
beneficial to the silver-Xing-Phos promoted [3þ2] cycloaddition
of imino esters with maleimides because most of corresponding
products 6aez were obtained with a high level of endo-selectivity
(>98:<2 dr) and good enantioselectivity (up to 98% ee) within
10 h. However, the diastereoselectivities of products 6k (92:8 dr,
entry 11) and 6r (95:5 dr, entry 18) were not enough good, which
would be probably arose from the steric repulsion of ortho-
substituted group of aryl imino esters (e.g., 4c). It was also ob-
served that the level of enantioselectivity obtained from moderate
to excellent with different substituent group. As expected, the
change of substituent group on the phenyl of N-phenyl maleimide
has little influence on the ee of corresponding product endo-6cej
(Entries 3e7, 80e85% ee). When a-imino methyl ester was used
instead of ethyl ester, the enantioselectivity was slightly rose to
86e88% ee (Entries 6 and 9). Then we extended the study of the
cycloaddition to various substituted aromatic
a-imino methyl
ester. 2-methoxyl-phenyl substituted imino ester gave endo-6k in
only a moderate diastereoselectivity, and accordingly the ee was
decreased to 80% (Entry 11). When methoxyl substituted at meta-
position, high level of diastereoselectivity was achieved, but
enantioselectivity remained at a moderate level (81% ee, entry 12).
It seemed that steric effect was generally disfavorable for the
achievement of high diastereoselectivity in this reaction. A series
of electronically different aromatic
a-imino esters and it was
found that the electronic effect of substituted group on the aryl
rings influenced the enantioselectivity obviously. For example, 4-
Me-phenyl substituted imino ester afforded the corresponding
endo-6n with only 65% ee (Entry 14), and in contrast, the para-
halogen substituted phenyl substituted imino ester gave a single
endo-selectivity with 90e91% ee (Entries 15e17). The electron-
withdrawing substituent group also resulted in good enantiose-
lectivity (88% ee, Entries 18 and 19), especially the use of para-
phenyl substituted aromatic a-imino methyl ester led to the for-
mation of the desired product in excellent enantioselectivity and
diastereoselectivity (98% ee and >98:<2 dr, entry 20). In addition,
we found that different N-aromatic maleimides could smoothly
react with 4-Ph substituted N-benzylideneglycine methyl ester to
give corresponding pyrrolidines in excellent enantioselectivities
(89e90% ee).
Fig. 2. Comparison of enantioselective activity of aromatic amide-derived non-biaryl
atropisomers under the optimized reaction condition.
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X.-F. Bai et al. / Tetrahedron xxx (2015) 1e10
5
Table 3
with excellent yields (up to 99% isolated yields) and excellent
diastereoselectivity (>98:2 dr) with endo-selectivity. And the
enantiomeric excesses of desired pyrrolidines derivatives were
also promising and could reach at good level (up to 98% ee),
which offered a simple and unprecedented example that axially
chiral aromatic amide-derived phosphine bearing both axial and
sp3 central chirality exhibited enough good enantiocontrol and
high catalytic performances in enantioselective silver-catalyzed
[3þ2] cycloaddition-type reaction. Furthermore, we believed
that the moisture- and oxygen-resistant Xing-Phos would exhibit
significant application value in various asymmetric organic
transformations. Besides, further development of the new axially
chiral AAAs ligands for catalytic asymmetric reactions to the
synthesis of useful molecules will be the focus of our ongoing
studies in the near future.
Catalytic asymmetric [3þ2] cycloaddition of various imino esters with N-aromatic
maleimides
4. Experimental section
4.1. General
Entry
4/imine
5/maleimide
TM
endo:exo
Yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
4a
4b
4a
4a
4a
4a
4a
4b
4b
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
5a
5a
5b
5c
5d
5e
5f
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
92:8
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
95:5
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
91
93
90
91
85
85
88
93
92
90
89
90
93
87
85
91
86
83
89
99
93
99
83
98
96
99
84
84
84
85
85
80
85
88
86
84
80
81
85
65
91
90
91
88
88
98
90
90
89
92
90
93
Unless specifically stated, all the solvents such as dichloro-
methane (DCM), trifluoroethanol (TFE), toluene, THF and EtOH was
used directly without dried or distilled. Reactions were monitored
by thin layer chromatography (TLC) using silica gel plates. Thin
layer chromatography was performed using silica gel; F254 TLC
plates and visualized with ultraviolet light. Flash column chroma-
tography was performed over silica (200e300 mesh). 1H NMR, and
13C NMR were recorded at 400 (or 500) and 100 (or 125) MHz,
respectively on Advance (Brucker) 400 MHz Nuclear Magnetic
Resonance Spectrometer, and were referenced to the internal sol-
vent signals. HPLC was carried out with a Waters 2695 Millennium
system equipped with a photodiode array detector. EI and CI mass
spectra were performed on a Trace DSQ GC/MS spectrometer. Data
are reported in the form of (m/z).
5d
5g
5h
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5g
5h
5e
5c
5a
5a
9
10
11c
12
13
14
15
16
17
18d
19
20
21
22
23
24
25
26
6s
6t
4l
4l
4l
4l
4m
4n
6u
6v
6w
6x
6y
6z
4.2. General procedure for the synthesis of ligands 2beh
4.2.1. Typical procedure for the synthesis of 2 through the 1,2-
addition of organometallic reagents to sulfinyl imine 1 (Fig. 1). The
synthesis of sulfinyl imine 1 and 2a have been reported in our
previous work and was completed respectively according to the
reported procedure.19 Grignard reagent was added (2.0 equiv) to
a ꢀ20 ꢁC solution of sulfinyl imine 1 (1.0 equiv) in dried toluene
(distilled fresh from CaH2). The mixture was stirred at ꢀ20 ꢁC for
1 h until the reaction was completed. Then the reaction mixture
was quenched with plenty of NH4Cl aqueous solution and extract
with EtOAc. The combined organic layers were dried over Na2SO4,
filtered, concentrated, and purified by flash chromatography
immediately.
a
Isolated yield.
The ee values were determined by chiral HPLC.
The reaction time was 40 h in this case.
The reaction temperature was 0 ꢁC in this case and reacted for 36 h.
b
c
d
3. Conclusions
In summary, we have reported an improved procedure for the
synthesis of a new family of axially chiral aromatic amide derived
non-biaryl atropisomers (AAAs) with the aid of chiral N-tert-
butanesulfinamide (Ellman reagent).23 The novel and air-stable
multifunctional phosphines (AAAs) featured with phosphine
and oxygen-based binding site (P,O-ligands) and an additional
axially aromatic amide and sulfinyl group. And notably, such
aromatic amide-derived chiral phosphine ligands could be syn-
thesized in gram scale. In this work, we determined the enan-
tioselective activity of these axially chiral aromatic amide derived
non-biaryl atropisomers in catalytic asymmetric AgF-catalyzed
[3þ2] cycloaddition of azomethine ylide with substituted mal-
eimides. The enantioselective Ag-catalyzed [3þ2] cycloaddition
reaction of imino esters with maleimides was proved to a prac-
tical and efficient procedure for the synthesis of imide-
containing pyrrolidines in the presence of Xing-Phos, one of
these AAAs ligands. The [3þ2] cycloaddition reaction proceed
4.2.2. 2-((1R)-((tert-Butylsulfinyl)amino) (phenyl)methyl)-6-(diphe-
nylphosphanyl)-N,N-diisopropylbenzamide (2a). 1H NMR (400 MHz,
CDCl3)
d
7.69 (d, J¼7.8 Hz, 1H), 7.56 (d, J¼7.5 Hz, 2H), 7.26 (dd,
J¼19.9, 13.3 Hz, 15H), 7.08 (dd, J¼7.4, 2.9 Hz, 1H), 5.73 (s, 1H),
3.89e3.70 (m, 1H), 3.64e3.59 (m, 2H), 1.71 (dd, J¼30.1, 6.7 Hz, 6H),
1.39e1.23 (m, 15H). 13C NMR (101 MHz, CDCl3)
d 167.81 (d,
J¼4.7 Hz), 143.48 (d, J¼37.7 Hz), 140.62, 138.82 (d, J¼8.9 Hz), 137.89
(d, J¼11.7 Hz), 136.45 (d, J¼11.4 Hz), 134.84 (d, J¼16.8 Hz), 134.53 (d,
J¼2.0 Hz), 133.44 (d, J¼20.3 Hz), 133.02 (d, J¼18.1 Hz), 128.63,
128.51, 128.45, 128.43, 128.38 (d, J¼1.9 Hz), 128.30, 128.17, 127.89,
127.52, 57.76, 55.70, 51.17, 46.39, 22.67, 21.61, 20.97 (d, J¼7.3 Hz),
20.75, 19.94 (d, J¼1.6 Hz). 31P NMR (202 MHz, CDCl3)
¼ꢀ13.94.
d
HRMS (APCI): m/z: [MþH]þ calculated for C36H44N2O2PS: 599.2856,
found: 599.2857. IR (KBr) nmax: 3447, 3297, 3058, 2963, 2927, 2869,
Please cite this article in press as: Bai, X.-F.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.068

6
X.-F. Bai et al. / Tetrahedron xxx (2015) 1e10
1629, 1475, 1446, 1433, 1368, 1339, 1319, 1063, 1037, 763, 743, 695.
CDCl3)
d
ꢀ14.31. HRMS (ESI): m/z: [MþH]þ calculated for
[
a]
30 ꢀ68.2 (c 0.61, CHCl3).
C32H42N2O2PS: 549.2699, found: 549.2693.
D
4.2.3. 2-((1R)-((tert-Butylsulfinyl)amino) (4-methoxyphenyl)methyl)-
6-(diphenylphosphanyl)-N,N-diisopropylbenzamide (2b). 1H NMR
4.2.7. 2-((1R)-1-((tert-Butylsulfinyl)amino)-2-methylallyl)-6-(diphe-
nylphosphanyl)-N,N-diisopropylbenzamide (2f). 1H NMR (500 MHz,
(500 MHz, CDCl3)
d
7.72 (d, J¼7.8 Hz, 1H), 7.47 (d, J¼8.2 Hz, 2H),
CDCl3)
d
7.57 (d, J¼7.7 Hz, 1H), 7.32e7.16 (m, 12H), 5.17 (s, 1H), 5.10
7.37e7.15 (m, 11H), 7.11 (d, J¼7.3 Hz, 1H), 6.82 (d, J¼8.1 Hz, 2H),
5.69 (s, 1H), 3.89e3.76 (m, 1H), 3.75 (s, 3H), 3.71e3.58 (m, 2H),
1.76 (d, J¼6.6 Hz, 3H), 1.69 (d, J¼6.6 Hz, 3H), 1.35 (d, J¼6.5 Hz, 4H),
1.30 (s, 9H), 1.26 (d, J¼6.9 Hz, 3H). 13C NMR (126 MHz, CDCl3)
(s, 1H), 5.02 (s, 1H), 3.80e3.69 (m, 1H), 3.59e3.55 (m, 1H), 3.40 (s,
1H), 1.70 (s, 3H), 1.66 (d, J¼6.6 Hz, 3H), 1.29e1.27 (m, 12H), 1.23 (d,
J¼6.2 Hz, 3H). 13C NMR (126 MHz, CDCl3)
d
167.43 (d, J¼4.7 Hz),
144.29 (d, J¼37.8 Hz), 142.60, 137.99 (d, J¼11.8 Hz), 136.69 (d,
J¼3.5 Hz), 136.61, 134.89 (d, J¼16.7 Hz), 134.76 (d, J¼2.0 Hz), 133.54,
133.38, 133.07, 132.93, 128.60, 128.45, 128.40, 128.33, 128.14, 127.90,
116.33, 59.82, 55.50, 51.03, 46.27, 22.67, 21.43, 20.98 (d, J¼6.9 Hz),
20.73, 19.91 (d, J¼1.9 Hz), 18.80. 31P NMR (202 MHz, CDCl3)
d
167.86 (d, J¼4.7 Hz), 158.94, 143.39 (d, J¼38.0 Hz), 139.03 (d,
J¼6.6 Hz), 137.88 (d, J¼11.7 Hz), 136.46 (d, J¼11.4 Hz), 134.74 (d,
J¼16.7 Hz), 134.52 (d, J¼1.9 Hz), 133.47 (d, J¼20.3 Hz), 132.99 (d,
J¼18.1 Hz), 132.50 (d, J¼5.3 Hz), 129.07, 128.64, 128.53, 128.43 (d,
J¼5.7 Hz), 128.35 (d, J¼7.3 Hz), 128.20, 128.16, 113.84, 57.22 (d,
J¼17.5 Hz), 55.60 (d, J¼2.6 Hz), 55.12, 51.19, 46.37, 22.67, 21.56,
20.92 (d, J¼7.0 Hz), 20.76, 19.94. 31P NMR (202 MHz, CDCl3)
d
ꢀ14.23. HRMS (ESI): m/z: [MþH]þ calculated for C33H44N2O2PS:
563.2856, found: 563.2861.
d
¼ꢀ14.13. HRMS (ESI): m/z: [MþH]þ calculated for C37H46N2O3PS:
4.2.8. 2-((1R)-1-((tert-Butylsulfinyl)amino)-2-methylpropyl)-6-(di-
phenylphosphanyl)-N,N-diisopropylbenzamide
(400 MHz, CDCl3)
629.2961, found: 629.2956.
(2g). 1H
NMR
d
7.42 (d, J¼7.7 Hz, 1H), 7.32e7.20 (m, 11H),
4.2.4. 2-((1R)-((tert-Butylsulfinyl)amino)(3-methoxyphenyl)methyl)-
6-(diphenylphosphanyl)-N,N-diisopropylbenzamide (2c). 1H NMR
(400 MHz, CDCl3)
7.10e7.07 (m, 1H), 4.49 (s, 1H), 3.85e3.80 (m, 1H), 3.64e3.53 (m,
1H), 3.46 (s, 1H), 2.52e2.34 (m, 1H), 1.65 (d, J¼6.8 Hz, 3H), 1.57 (d,
J¼6.8 Hz, 3H), 1.34e1.25 (m, 15H), 1.04 (d, J¼7.0 Hz, 3H), 0.70 (d,
d
¼7.67 (d, J¼7.8 Hz, 1H), 7.33e7.12 (m, 14H),
7.10e7.06 (m, 1H), 6.80e6.69 (m, 1H), 5.70 (s, 1H), 3.81e3.76 (m,
1H), 3.74 (s, 3H), 3.64 (s, 1H), 3.63e3.55 (m, 1H), 1.74 (d, J¼6.8 Hz,
3H),1.66 (d, J¼6.8 Hz, 3H),1.33 (d, J¼6.7 Hz, 3H),1.30 (s, 9H),1.25 (d,
J¼7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d
168.11 (d, J¼4.7 Hz),
143.81 (d, J¼37.3 Hz), 138.35 (d, J¼8.6 Hz), 138.11 (d, J¼11.8 Hz),
136.80 (d, J¼11.4 Hz), 134.78 (d, J¼16.2 Hz), 133.49 (d, J¼2.0 Hz),
133.09 (d, J¼18.1 Hz), 131.99 (d, J¼35.6 Hz), 128.62, 128.57, 128.39,
128.33, 128.26, 128.09, 127.08, 56.12, 51.10, 46.13, 33.33, 22.78,
J¼6.5 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d
167.81 (d, J¼4.7 Hz),
159.57, 143.53 (d, J¼37.9 Hz), 142.29, 138.72 (d, J¼8.9 Hz), 137.89 (d,
J¼11.8 Hz), 136.57 (d, J¼11.4 Hz), 134.84 (d, J¼16.9 Hz), 134.62 (d,
J¼2.1 Hz), 133.55, 133.35, 133.18, 133.00, 129.41, 128.57, 128.51,
128.47, 128.42, 128.34, 128.27, 128.22, 120.40, 113.22 (d, J¼13.8 Hz),
57.70, 55.77, 55.19, 51.14, 46.37, 22.70, 21.61, 21.02 (d, J¼7.2 Hz),
21.55, 21.12 (d, J¼8.0 Hz), 20.76, 20.60, 19.91 (d, J¼2.3 Hz), 14.62.31
P
NMR (202 MHz, CDCl3)
d
ꢀ13.94. HRMS (ESI): m/z: [MþH]þ cal-
culated for C33H46N2O2PS: 565.3012, found: 565.3018.
20.76, 20.01 (d, J¼1.8 Hz). 31P NMR (202 MHz, CDCl3)
d
¼ꢀ13.90.
4.2.9. 2-((1R)-1-((tert-Butylsulfinyl)amino)ethyl)-6-(diphenylphos-
phanyl)-N,N-diisopropylbenzamide (2h). 1H NMR (400 MHz, CDCl3)
HRMS (ESI): m/z: [MþH]þ calculated for C37H46N2O3PS: 629.2961,
found: 629.2968.
d
7.51 (d, J¼7.5 Hz, 1H), 7.34e7.20 (m, 11H), 7.11 (ddd, J¼7.6, 3.4,
1.0 Hz, 1H), 4.64 (qd, J¼6.3, 2.2 Hz, 1H), 3.77 (dt, J¼13.2, 6.6 Hz,
1H), 3.55 (dt, J¼13.6, 6.8 Hz, 1H), 3.36 (d, J¼2.1 Hz, 1H), 1.61 (dd,
J¼12.5, 6.8 Hz, 6H), 1.47 (d, J¼6.3 Hz, 3H), 1.26 (s, 9H), 1.20 (dd,
4.2.5. 2-((1R)-1-((tert-Butylsulfinyl)amino)-2-phenylethyl)-6-(di-
phenylphosphanyl)-N,N-diisopropylbenzamide
(400 MHz, CDCl3)
(2d). 1H
NMR
7.37 (d, J¼7.8 Hz, 1H), 7.35e7.27 (m, 8H),
d
J¼9.5, 6.7 Hz, 6H). 13C NMR (101 MHz, CDCl3)
d 166.89 (d,
7.24e7.17 (m, 6H), 7.09 (dd, J¼6.6, 5.0 Hz, 3H), 4.69e4.65 (m, 1H),
3.96e3.85 (m, 1H), 3.73 (d, J¼6.1 Hz, 1H), 3.64e3.58 (m, 1H), 3.42
(dd, J¼13.8, 3.3 Hz, 1H), 2.73 (dd, J¼13.8, 9.0 Hz, 1H), 1.69 (dd, J¼6.8,
3.2 Hz, 6H), 1.24 (dd, J¼16.1, 6.6 Hz, 6H), 1.02 (s, 9H). 13C NMR
J¼4.7 Hz), 142.51 (d, J¼37.8 Hz), 139.87 (d, J¼9.0 Hz), 136.78 (d,
J¼11.7 Hz), 135.79 (d, J¼11.5 Hz), 133.48 (d, J¼16.3 Hz), 133.24 (d,
J¼2.0 Hz), 132.58 (d, J¼20.2 Hz), 132.12 (d, J¼18.3 Hz), 127.66,
127.52, 127.47, 127.42, 127.35, 127.25, 126.03, 54.46, 50.16, 50.06 (d,
J¼2.0 Hz), 45.24, 22.82, 21.72, 21.58, 20.32, 19.87 (d, J¼6.7 Hz),
(101 MHz, CDCl3)
d
168.47 (d, J¼4.8 Hz), 143.02 (d, J¼37.3 Hz),
138.71 (d, J¼8.6 Hz), 137.85, 137.74, 136.88 (d, J¼11.5 Hz), 134.32,
134.16, 133.61, 133.41, 133.13, 132.95, 129.84, 128.67, 128.45 (d,
J¼5.7 Hz), 128.37 (d, J¼7.4 Hz), 128.25, 128.18, 128.05, 126.60, 58.96,
56.61, 51.05, 46.27, 44.43, 22.26, 21.91, 21.30, 20.73 (d, J¼7.6 Hz),
19.43, 19.07 (d, J¼1.5 Hz). 31P NMR (202 MHz, CDCl3)
d
ꢀ14.40.
HRMS (APCI): m/z: [MþH]þ calculated for C31H42N2O2PS:
537.2699, found: 537.2681. IR (KBr)nmax: 3434, 3054, 2971, 2931,
1627, 1476, 1435, 1369, 1327, 1302, 1091, 1072, 751, 700. [
(c 0.32, CHCl3).
a
]
30 ꢀ63.8
D
19.85 (d, J¼2.6 Hz). 31P NMR (202 MHz, CDCl3)
d
ꢀ14.46. HRMS
(ESI): m/z: [MþH]þ calculated for C37H46N2O2PS: 613.3012, found:
613.3019.
4.3. Typical procedure for the synthesis of 6 through the
silver-catalyzed [3D2] cycloaddtion of azomethine ylides
4aen with N-aromatic maleimides 5aeh
4.2.6. 2-((1R)-1-((tert-Butylsulfinyl)amino)allyl)-6-(diphenylphos-
phanyl)-N,N-diisopropylbenzamide (2e). 1H NMR (400 MHz, CDCl3)
d
7.51 (d, J¼7.3 Hz, 1H), 7.34e7.19 (m, 12H), 7.16e7.10 (m, 1H),
To the AgF (0. 8 mg, 0.0063 mmol, 2.5 mmol%) catalysis in
reaction tube, 100 mL H2O was added to dissolve the AgF. Toluene
5.83e5.76 (m, 1H), 5.34 (d, J¼17.1 Hz, 1H), 5.18 (d, J¼10.1 Hz, 1H),
5.08 (d, J¼6.8 Hz, 1H), 3.83e3.72 (m, 1H), 3.60e3.53 (m, 1H), 3.43
(d, J¼1.6 Hz, 1H), 1.64 (dd, J¼6.8, 2.9 Hz, 6H), 1.27e1.25 (m, 12H),
(2 mL) was added and the resulting mixture was stirred
for 5 min. Then sys-(R, Rs)-2a (0.0082 g, 0.0138 mmol, 5.5 mmol
%) was added. The mixture was stirred at ꢀ20 ꢁC for 15 min, then
iminoester (0.6 mmol, 1.2 equiv) and maleimide (0.5 mmol,
1.0 equiv) were added successively. The reaction was allowed
to proceed for 10 h at ꢀ20 ꢁC, after which 5 mL H2O was added
to quench the reaction. The organic layer was diluted with 10 mL
EtOAc and water layer was extracted with EtOAc (5mLꢂ2).
1.20 (d, J¼6.6 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 167.54 (d,
J¼4.7 Hz), 143.78 (d, J¼38.1 Hz), 137.87 (d, J¼3.3 Hz), 137.77, 137.36,
136.63 (d, J¼11.5 Hz), 134.89 (d, J¼16.6 Hz), 134.67 (d, J¼2.2 Hz),
133.63,133.43,133.12,132.94,128.63,128.48,128.46,128.42,128.40,
128.33, 127.89, 118.37, 57.66, 57.64, 55.51, 51.12, 46.29, 22.63, 21.43,
20.90 (d, J¼6.7 Hz), 20.50, 19.99 (d, J¼1.6 Hz). 31P NMR (202 MHz,
Please cite this article in press as: Bai, X.-F.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.068

X.-F. Bai et al. / Tetrahedron xxx (2015) 1e10
7
The combined organic layer was dried with Na2SO4 and con-
centrated. A portion of the cured was analysed with 1H NMR to
determine the diastereomeric ratio and recovered. The structures
of some products were known16 and confirmed by NMR, IR and
MS. The enantiomeric excesses of the products were determined
by chiral stationary phase HPLC using a chiral column after
purification.
0.7 mL/min, 210 nm); minor enantiomer tr¼12.7 min, major en-
antiomer tr¼27.6 min.
4.3.6. Ethyl(1S,3R,3aS,6aR)-5-(4-ethoxyphenyl)-4,6-dioxo-3-phenyl-
octahydropyrrolo[3,4-c]pyrrole-1-carboxylate (6f). ½a D25
ꢀ78.2 (c
ꢃ
2.8, CHCl3). 1H NMR (500 MHz, CDCl3)
d
7.46 (d, J¼7.2 Hz, 2H), 7.38
(dd, J¼10.1, 4.7 Hz, 2H), 7.35e7.30 (m, 1H), 7.11e7.04 (m, 2H),
6.94e6.85 (m, 2H), 4.62 (d, J¼8.7 Hz, 1H), 4.45e4.29 (m, 2H), 4.14
(d, J¼6.7 Hz,1H), 4.02 (q, J¼7.0 Hz, 2H), 3.73 (t, J¼7.2 Hz,1H), 3.57 (t,
J¼8.3 Hz, 1H), 1.41 (t, J¼7.0 Hz, 3H), 1.39 (t, J¼7.5 Hz, 3H). 13C NMR
4.3.1. Ethyl (1S,3R,3aS,6aR)-4,6-dioxo-3,5-diphenyloctahydropyrrolo
[3,4-c] pyrrole-1-carboxylate (6a).16a 1H NMR (400 MHz, CDCl3)
d
7.37 (d, J¼7.6 Hz, 2H), 7.32e7.22 (m, 6H), 7.07 (d, J¼7.6 Hz, 2H),
(126 MHz, CDCl3) d 175.13, 173.83, 169.62, 158.76, 136.72, 128.47,
4.53 (d, J¼8.7 Hz, 1H), 4.31e4.21 (m, 2H), 4.05 (d, J¼6.6 Hz, 1H),
3.68e3.63 (m, 1H), 3.52e3.46 (m, 1H), 1.29 (t, J¼7.2 Hz, 3H). En-
antiomeric excess was determined by HPLC with a Chiralpak AS-H
column (hexanes: 2-propanol¼50:50, 0.7 mL/min, 210 nm); minor
enantiomer tr¼12.5 min, major enantiomer tr¼27.8 min.
128.39, 127.33, 127.12, 124.22, 114.89, 64.35, 63.68, 62.15, 61.52,
49.57, 48.35, 14.72, 14.16. Enantiomeric excess was determined by
HPLC with a Chiralpak AS-H column (hexanes: 2-propanol¼50:50,
0.7 mL/min, 210 nm); minor enantiomer tr¼18.7 min, major en-
antiomer tr¼28.2 min.
4.3.2. Methyl (1S,3R,3aS,6aR)-4,6-dioxo-3,5-diphenyloctahydro-pyr-
4.3.7. Ethyl(1S,3R,3aS,6aR)-5-(4-methoxyphenyl)-4,6-dioxo-3-
rolo [3,4-c]pyrrole-1-carboxylate (6b).16b 1H NMR (400 MHz, CDCl3)
phenyl -octahydropyrrolo[3,4-c]pyrrole-1-carboxylate (6g). ½a D25
ꢃ
d
7.45 (d, J¼7.1 Hz, 2H), 7.42e7.28 (m, 6H), 7.14 (dd, J¼5.4, 3.5 Hz,
ꢀ79.2 (c 1.9, CHCl3). 1H NMR (500 MHz, CDCl3)
d
7.46 (d, J¼7.2 Hz,
2H), 4.62 (d, J¼8.6 Hz,1H), 4.15 (d, J¼6.6 Hz,1H), 3.87 (s, 3H), 3.73 (t,
J¼7.2 Hz, 1H), 3.57 (t, J¼8.3 Hz, 1H), 2.35 (s, 1H). Enantiomeric ex-
cess was determined by HPLC with a Chiralpak AS-H column
(hexanes: 2-propanol¼50:50, 0.7 mL/min, 210 nm); minor enan-
tiomer tr¼12.2 min, major enantiomer tr¼20.9 min.
2H), 7.38 (dd, J¼8.1, 6.7 Hz, 2H), 7.34 (dd, J¼4.8, 3.6 Hz, 1H),
7.14e7.04 (m, 2H), 6.94e6.86 (m, 2H), 4.62 (d, J¼8.8 Hz, 1H),
4.44e4.29 (m, 2H), 4.14 (d, J¼6.7 Hz,1H), 3.80 (s, 3H), 3.77e3.68 (m,
1H), 3.66e3.53 (m, 1H), 2.53 (s, 1H), 1.39 (t, J¼7.2 Hz, 3H). 13C NMR
(126 MHz, CDCl3)
d 175.13, 173.83, 169.62, 159.38, 136.74, 128.47,
128.39, 127.39, 127.12, 124.41, 114.36, 64.33, 62.14, 61.52, 55.45,
49.56, 48.35, 14.17. Enantiomeric excess was determined by HPLC
4.3.3. Ethyl(1S,3R,3aS,6aR)-5-(3-chlorophenyl)-4,6-dioxo-3-phenyl-
octahydropyrrolo[3,4-c]pyrrole-1-carboxylate (6c). ½a D25
ꢃ
ꢀ69.9 (c
with
a
Chiralpak AS-H column (hexanes: 2-propanol¼50:50,
3.0, CHCl3). 1H NMR (500 MHz, CDCl3)
d
7.49e7.44 (m, 2H),
0.7 mL/min, 210 nm); minor enantiomer tr¼18.6 min, major en-
7.42e7.31 (m, 5H), 7.21 (t, J¼1.9 Hz, 1H), 7.12e7.07 (m, 1H), 4.63 (d,
J¼8.8 Hz, 1H), 4.43e4.32 (m, 2H), 4.14 (d, J¼6.7 Hz, 1H), 3.74 (t,
J¼7.2 Hz, 1H), 3.58 (t, J¼8.3 Hz, 1H), 2.38 (s, 1H), 1.40 (t, J¼7.2 Hz,
antiomer tr¼31.9 min.
4.3.8. Methyl(1S,3R,3aS,6aR)-5-(3-bromophenyl)-4,6-dioxo-3-
3H). 13C NMR (126 MHz, CDCl3)
d
174.55, 173.25, 169.47, 136.57,
phenyl-octahydropyrrolo[3,4-c]pyrrole-1-carboxylate (6h). 1H NMR
134.52, 132.69, 129.95, 128.66, 128.54, 127.08, 126.44, 124.36, 64.27,
62.12, 61.60, 49.53, 48.31, 14.17. Enantiomeric excess was de-
termined by HPLC with a Chiralpak AS-H column (hexanes: 2-
propanol¼50:50, 0.7 mL/min, 210 nm); minor enantiomer
tr¼11.9 min, major enantiomer tr¼25.5 min.
(500 MHz, CDCl3) d 7.48 (m, 2H), 7.43e7.34 (m, 4H), 7.31e7.26 (m,
2H), 7.14 (d, J¼8.0 Hz, 1H), 4.66 (d, J¼8.8 Hz, 1H), 4.18 (d, J¼6.6 Hz,
1H), 3.91 (s, 3H), 3.76 (dd, J¼7.7, 6.7 Hz, 1H), 3.60 (dd, J¼8.7, 7.9 Hz,
1H), 2.56 (s, 1H). 13C NMR (126 MHz, CDCl3)
d 173.16, 169.91, 132.74,
131.59, 130.19, 129.21, 128.62, 128.57, 127.07, 124.78, 77.26, 77.00,
76.75, 64.28, 61.96, 52.38, 49.44, 48.31. Enantiomeric excess was
determined by HPLC with a Chiralpak AS-H column (hexanes: 2-
propanol¼50:50, 0.7 mL/min, 210 nm); minor enantiomer
tr¼15.5 min, major enantiomer tr¼35.8 min.
4.3.4. Ethyl (1S,3R,3aS,6aR)-4,6-dioxo-3-phenyl-5-(m-tolyl)-ctahy-
dropyrrolo[3,4-c]pyrrole-1-carboxylate (6d). ½a D25
ꢀ78.1 (c 2.6,
ꢃ
CHCl3). 1H NMR (500 MHz, CDCl3)
d
7.48 (d, J¼7.3 Hz, 2H), 7.42e7.26
(m, 4H), 7.15 (d, J¼7.7 Hz, 1H), 6.96 (d, J¼6.3 Hz, 2H), 4.63 (d,
J¼8.8 Hz, 1H), 4.47e4.29 (m, 2H), 4.15 (d, J¼6.7 Hz, 1H), 3.74 (dd,
J¼7.6, 6.9 Hz, 1H), 3.58 (dd, J¼8.6, 8.0 Hz,1H), 2.35 (s, 3H), 2.33 (br s,
4.3.9. Methyl(1S,3R,3aS,6aR)-5-(4-bromophenyl)-4,6-dioxo-3-
phenyl-octahydropyrrolo[3,4-c]pyrrole-1-carboxylate
(6i). ½a 2D5
ꢃ
1H), 1.40 (t, J¼7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3)
d
174.97,
ꢀ91.9 (c 3.0, CHCl3). 1H NMR (400 MHz, CDCl3)
d 7.54e7.47 (m, 2H),
173.68, 169.58, 139.01, 136.68, 131.58, 129.35, 128.84, 128.47, 128.42,
127.15, 126.81, 123.32, 77.29, 77.03, 76.78, 64.34, 62.14, 61.53, 49.61,
48.41, 21.29, 14.16. Enantiomeric excess was determined by HPLC
7.46e7.39 (m, 2H), 7.34 (dt, J¼8.5, 6.8 Hz, 3H), 7.08e6.99 (m, 2H),
4.60 (d, J¼8.8 Hz, 1H), 4.13 (d, J¼6.6 Hz, 1H), 3.87 (s, 3H), 3.76e3.65
(m, 1H), 3.56 (d, J¼8.6 Hz, 1H), 2.35 (s, 1H). 13C NMR (126 MHz,
with
a
Chiralpak AS-H column (hexanes: 2-propanol¼50:50,
CDCl3) d 174.73, 173.25, 169.98, 136.58, 132.19, 130.62, 128.54,
0.7 mL/min, 210 nm); minor enantiomer tr¼11.4 min, major enan-
127.60, 127.07, 122.28, 64.25, 61.93, 52.37, 49.42, 48.30. Enantio-
meric excess was determined by HPLC with a Chiralpak AS-H col-
umn (hexanes: 2-propanol¼50:50, 0.7 mL/min, 210 nm); minor
enantiomer tr¼15.3 min, major enantiomer tr¼26.6 min.
tiomer tr¼26.3 min.
4.3.5. Ethyl(1S,3R,3aS,6aR)-5-(3-bromophenyl)-4,6-dioxo-3-phenyl-
octahydropyrrolo[3,4-c]pyrrole-1-carboxylate (6e). ½a D25
ꢀ68.8 (c
ꢃ
2.8, CHCl3). 1H NMR (500 MHz, CDCl3)
d
7.50e7.44 (m, 3H),
4.3.10. Methyl (1S,3R,3aS,6aR)-5-(3,5-dimethylphenyl)-4,6-dioxo-3-
7.42e7.37 (m, 2H), 7.37e7.33 (m, 2H), 7.27 (t, J¼8.1 Hz, 1H), 7.14
(ddd, J¼8.0, 1.9, 0.9 Hz, 1H), 4.63 (d, J¼8.8 Hz, 1H), 4.43e4.31 (m,
2H), 4.15 (d, J¼6.7 Hz, 1H), 3.74 (dd, J¼7.7, 6.8 Hz, 1H), 3.58 (dd,
J¼8.7, 7.9 Hz, 1H), 2.25 (br s, 1H), 1.40 (t, J¼7.2 Hz, 3H). 13C NMR
phenyl-octahydropyrrolo[3,4-c]pyrrole-1-carboxylate
(6j). ½a 2D5
ꢃ
ꢀ93.2 (c 1.9, CHCl3). 1H NMR (400 MHz, CDCl3)
d
7.45 (d, J¼7.2 Hz,
2H), 7.40e7.27 (m, 3H), 6.94 (s, 1H), 6.71 (s, 2H), 4.60 (d, J¼8.5 Hz,
1H), 4.16e4.08 (m, 1H), 3.87 (s, 3H), 3.70 (t, J¼6.5 Hz, 1H), 3.54 (t,
J¼7.6 Hz,1H), 2.35 (br s, 1H), 2.27 (s, 6H). 13C NMR (126 MHz, CDCl3)
(126 MHz, CDCl3)
d 174.52, 173.23, 169.45, 136.56, 132.79, 131.56,
130.19, 129.24, 128.55, 128.53, 127.06, 124.83, 122.26, 64.26, 62.12,
61.59, 49.53, 48.31, 14.17. Enantiomeric excess was determined by
HPLC with a Chiralpak AS-H column (hexanes: 2-propanol¼50:50,
d 175.17,173.74,170.08,138.79,136.69,131.42,130.38,128.46,127.19,
123.94, 64.30, 61.93, 52.32, 49.51, 48.42, 21.19. Enantiomeric excess
was determined by HPLC with a Chiralpak AS-H column (hexanes:
Please cite this article in press as: Bai, X.-F.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.068

8
X.-F. Bai et al. / Tetrahedron xxx (2015) 1e10
2-propanol¼50:50, 0.7 mL/min, 210 nm); minor enantiomer
tr¼11.1 min, major enantiomer tr¼24.7 min.
2-propanol¼50:50, 0.7 mL/min, 210 nm); minor enantiomer
tr¼16.2 min, major enantiomer tr¼36.2 min.
4.3.11. Methyl
(1S,3R,3aS,6aR)-3-(2-methoxyphenyl)-4,6-dioxo-5-
4.3.16. Methyl(1S,3R,3aS,6aR)-3-(4-chlorophenyl)-4,6-dioxo-5-
phenyl-octahydropyrrolo[3,4-c]pyrrole-1-carboxylate (6k).16c
½
a 2D5
ꢃ
phenyl-octahydropyrrolo[3,4-c]pyrrole-1-carboxylate (6p).16d
½ ꢃ
a 2D5
ꢀ120.2 (c 1.9, CHCl3). 1H NMR (500 MHz, CDCl3)
d
7.45 (dd, J¼7.5,
ꢀ127.9 (c 2.5, CHCl3).1H NMR (500 MHz, CDCl3)
d 7.42e7.37 (m, 4H),
1.1 Hz, 1H), 7.35 (dd, J¼8.2, 6.9 Hz, 2H), 7.31e7.26 (m, 2H), 7.11 (dd,
J¼5.3, 3.3 Hz, 2H), 6.95 (td, J¼7.5, 0.7 Hz, 1H), 6.88 (d, J¼8.2 Hz, 1H),
4.73 (d, J¼7.9 Hz,1H), 4.15 (d, J¼6.6 Hz,1H), 3.87 (s, 3H), 3.83 (s, 3H),
3.77e3.67 (m, 2H), 2.84 (br s, 1H). 13C NMR (126 MHz, CDCl3)
7.33 (t, J¼7.5 Hz, 3H), 7.15e7.11 (m, 2H), 4.57 (d, J¼8.8 Hz, 1H), 4.13
(d, J¼6.8 Hz, 1H), 3.86 (s, 3H), 3.76e3.67 (m, 1H), 3.60e3.49 (m, 1H),
2.35 (s, 1H). 13C NMR (126 MHz, CDCl3)
d 174.85, 173.41, 169.87,
135.21, 134.17, 131.55, 129.10, 128.71, 128.61, 128.52, 126.08, 63.53,
61.83, 52.37, 49.18, 48.04. Enantiomeric excess was determined by
HPLC with a Chiralpak AS-H column (hexanes: 2-propanol¼50:50,
0.7 mL/min, 210 nm); minor enantiomer tr¼15.9 min, major en-
antiomer tr¼47.5 min.
d
175.27, 173.72, 170.38, 157.31, 131.81, 129.23, 128.91, 128.31, 126.87,
126.13, 124.76, 120.67, 110.34, 62.48, 60.78, 55.45, 52.37, 48.96,
48.30. Enantiomeric excess was determined by HPLC with a Chir-
alpak AS-H column (hexanes: 2-propanol¼50:50, 0.7 mL/min,
210 nm); minor enantiomer tr¼15.8 min, major enantiomer
tr¼33.5 min.
4.3.17. Methyl(1S,3R,3aS,6aR)-3-(4-bromophenyl)-4,6-dioxo-5-
phenyl-octahydropyrrolo[3,4-c]pyrrole-1-carboxylate (6q).16d
½ ꢃ
a 2D5
4.3.12. Methyl (1S,3R,3aS,6aR)-3-(3-methoxyphenyl)-4,6-dioxo-5-
ꢀ129.9 (c 2.7, CHCl3). 1H NMR (500 MHz, CDCl3)
d 7.49e7.45 (m,
phenyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (6l). ½a D25
ꢃ
ꢀ71.7
2H), 7.42e7.36 (m, 2H), 7.33 (dt, J¼7.5,1.9 Hz, 3H), 7.15e7.11 (m, 2H),
4.54 (d, J¼8.7 Hz, 1H), 4.12 (dd, J¼6.9, 2.1 Hz, 1H), 3.86 (s, 3H), 3.71
(dd, J¼7.6, 6.9 Hz, 1H), 3.59e3.48 (m, 1H), 2.47 (s, 1H). 13C NMR
(c 2.3, CHCl3). 1H NMR (500 MHz, CDCl3)
d 7.44e7.38 (m, 2H),
7.37e7.29 (m, 2H), 7.20e7.16 (m, 2H), 7.04 (dd, J¼14.3, 4.9 Hz, 2H),
6.89e6.84 (m, 1H), 4.62 (d, J¼8.9 Hz, 1H), 4.17 (d, J¼6.7 Hz, 1H), 3.90
(s, 3H), 3.79 (s, 3H), 3.75 (dd, J¼7.8, 6.6 Hz, 1H), 3.59 (dd, J¼8.7,
(126 MHz, CDCl3)
d 174.86, 173.41, 169.89, 135.79, 131.64, 131.55,
129.11, 128.84, 128.61, 126.08, 122.33, 63.58, 61.85, 52.36, 49.13,
48.03. Enantiomeric excess was determined by HPLC with a Chir-
alpak AS-H column (hexanes: 2-propanol¼50:50, 0.7 mL/min,
210 nm); minor enantiomer tr¼13.4 min, major enantiomer
tr¼30.9 min.
7.9 Hz, 1H). 13C NMR (126 MHz, CDCl3)
d 174.96, 173.44, 169.96,
159.79, 138.24, 131.68, 129.54, 129.01, 128.48, 126.12, 119.47, 113.78,
112.94, 64.24, 61.90, 55.21, 52.34, 49.44, 48.33. Enantiomeric excess
was determined by HPLC with a Chiralpak AS-H column (hexanes:
2-propanol¼50:50, 0.7 mL/min, 210 nm); minor enantiomer
tr¼18.1 min, major enantiomer tr¼44.0 min.
4.3.18. Methyl
(1S,3R,3aS,6aR)-3-(naphthalen-2-yl)-4,6-dioxo-5-
phenyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
(6r).16e
½
a 2D5
ꢃ
4.3.13. Methyl (1S,3R,3aS,6aR)-3-(3-bromophenyl)-4,6-dioxo-5-phe-
ꢀ130.1 (c 2.9, CHCl3). 1H NMR (500 MHz, CDCl3)
d 7.93 (s, 1H),
nyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
(6m).16c
½
a 2D5
d 7.65 (s, 1H),
ꢃ
7.84e7.78 (m, 3H), 7.50 (dd, J¼8.5, 1.6 Hz, 1H), 7.48e7.43 (m, 2H),
7.35e7.25 (m, 3H), 7.12e7.07 (m, 2H), 4.69 (d, J¼8.8 Hz, 1H), 4.12 (d,
J¼6.6 Hz, 1H), 3.88 (s, 3H), 3.71 (dd, J¼7.6, 6.8 Hz, 1H), 3.59 (dd,
ꢀ73.4 (c 3.1, CHCl3). 1H NMR (500 MHz, CDCl3)
7.46e7.29 (m, 5H), 7.22 (t, J¼7.8 Hz, 1H), 7.17e7.11 (m, 2H), 4.55 (d,
J¼8.9 Hz, 1H), 4.12 (d, J¼6.6 Hz, 1H), 3.86 (s, 3H), 3.71 (t, J¼7.2 Hz,
1H), 3.54 (t, J¼8.3 Hz, 1H), 2.35 (s, 1H). 13C NMR (126 MHz, CDCl3)
J¼8.6, 7.9 Hz, 1H), 2.35 (s, 1H). 13C NMR (126 MHz, CDCl3)
d 175.08,
173.58, 170.10, 134.35, 133.40, 133.31, 131.64, 129.00, 128.44, 128.13,
127.96, 127.86, 126.30, 126.12, 126.06, 125.65, 125.38, 64.29, 61.93,
52.36, 49.38, 48.40. Enantiomeric excess was determined by HPLC
d
174.84, 173.41, 169.78, 139.21, 131.61, 131.53, 130.11, 130.05,
129.12, 128.62, 126.19, 126.06, 122.79, 63.39, 61.74, 52.37, 49.17,
48.01. Enantiomeric excess was determined by HPLC with a Chir-
alpak AS-H column (hexanes: 2-propanol¼50:50, 0.7 mL/min,
210 nm); minor enantiomer tr¼16.7 min, major enantiomer
tr¼43.9 min.
with
a
Chiralpak AS-H column (hexanes: 2-propanol¼50:50,
0.7 mL/min, 210 nm); minor enantiomer tr¼19.5 min, major en-
antiomer tr¼65.8 min.
4.3.19. Methyl (1S,3R,3aS,6aR)-4,6-dioxo-5-phenyl-3-(4-(trifluoro-
4.3.14. Methyl (1S,3R,3aS,6aR)-4,6-dioxo-5-phenyl-3-(p-tolyl)-octa-
methyl)phenyl)octahydropyrrolo[3,4-c]pyrrole-1-carboxylate
hydropyrrolo[3,4-c]pyrrole-1-carboxylate (6n).16d
½
a 2D5
ꢃ
ꢀ106.8 (c
(6s). ½a 2D5
ꢃ
ꢀ94.9 (c 1.9, CHCl3). 1H NMR (500 MHz, CDCl3)
d 7.60 (q,
2.5, CHCl3). 1H NMR (500 MHz, CDCl3)
d
7.41e7.36 (m, 2H), 7.32 (d,
J¼8.5 Hz, 4H), 7.42e7.38 (m, 2H), 7.36e7.31 (m, 1H), 7.14e7.10 (m,
2H), 4.65 (d, J¼8.6 Hz, 1H), 4.17 (d, J¼6.9 Hz, 1H), 3.87 (s, 3H),
3.78e3.70 (m, 1H), 3.67e3.56 (m, 1H), 2.35 (s, 1H). 13C NMR
J¼7.8 Hz, 3H), 7.18e7.13 (m, 4H), 4.57 (d, J¼8.8 Hz, 1H), 4.16e4.07
(m, 1H), 3.86 (s, 3H), 3.76e3.66 (m, 1H), 3.53 (t, J¼8.3 Hz, 1H),
2.64e2.52 (br s, 1H), 2.33 (s, 3H). 13C NMR (126 MHz, CDCl3)
(126 MHz, CDCl3)
d 174.72, 173.26, 169.81, 131.48, 130.56 (d,
d
175.10, 173.68, 170.09, 138.12, 133.55, 131.70, 129.23, 129.02,
J¼32.4 Hz), 129.14, 129.03, 128.69, 127.61, 126.07, 125.44 (q,
J¼3.7 Hz), 125.08, 63.68, 61.93, 52.41, 49.18, 47.95. Enantiomeric
excess was determined by HPLC with a Chiralpak AS-H column
(hexanes: 2-propanol¼50:50, 0.7 mL/min, 210 nm); minor enan-
tiomer tr¼11.4 min, major enantiomer tr¼29.4 min.
128.46, 127.00, 126.17, 64.28, 61.98, 52.32, 49.53, 48.46, 21.23. En-
antiomeric excess was determined by HPLC with a Chiralpak AS-H
column (hexanes: 2-propanol¼50:50, 0.7 mL/min, 210 nm); minor
enantiomer tr¼14.7 min, major enantiomer tr¼37.8 min.
4.3.15. Methyl(1S,3R,3aS,6aR)-3-(4-fluorophenyl)-4,6-dioxo-5-
4.3.20. Methyl (1S,3R,3aS,6aR)-3-([1,10-biphenyl]-4-yl)-4,6-dioxo-5-
phenyl-octahydropyrrolo[3,4-c]pyrrole-1-carboxylate (6o).16e
½
a 2D5
ꢃ
phenyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
(6t). ½a 2D5
ꢃ
ꢀ100.3 (c 2.4, CHCl3). 1H NMR (500 MHz, CDCl3)
d
7.48e7.39 (m,
ꢀ163.3 (c 2.5, CHCl3). 1H NMR (400 MHz, DMSO)
7.67 (dd, J¼13.5,
d
4H), 7.38e7.32 (m, 1H), 7.16 (d, J¼7.4 Hz, 2H), 7.07 (dd, J¼12.2,
4.9 Hz, 2H), 4.62e4.58 (m, 1H), 4.19e4.09 (m, 1H), 3.93e3.82 (m,
3H), 3.77e3.65 (m, 1H), 3.57e3.52 (m, 1H), 2.38 (s, 1H). 13C NMR
7.8 Hz, 4H), 7.47 (ddd, J¼11.9, 9.6, 6.2 Hz, 6H), 7.37 (dd, J¼14.0,
7.3 Hz, 2H), 7.16e7.08 (m, 2H), 4.53 (dd, J¼8.7, 3.5 Hz, 1H), 4.08 (dd,
J¼6.7, 3.6 Hz, 1H), 3.79 (t, J¼7.3 Hz, 1H), 3.71 (s, 3H), 3.66e3.56 (m,
(126 MHz, CDCl3)
d
174.95, 173.53, 169.94, 162.64 (d, J¼246.8 Hz),
2H). 13C NMR (101 MHz, DMSO)
d 175.74, 174.30, 170.35, 139.88,
132.50, 131.60, 129.08, 128.79 (d, J¼8.1 Hz),128.57, 126.08, 115.46 (d,
J¼21.6 Hz), 63.48, 61.80, 52.34, 49.24, 48.10. Enantiomeric excess
was determined by HPLC with a Chiralpak AS-H column (hexanes:
139.03, 138.07, 132.24, 128.88, 128.80, 128.15, 127.97, 127.29, 126.55
(d, J¼13.0 Hz), 126.04, 62.79, 61.21, 51.37, 49.10, 48.20. Enantiomeric
excess was determined by HPLC with a Chiralpak AS-H column
Please cite this article in press as: Bai, X.-F.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.068

X.-F. Bai et al. / Tetrahedron xxx (2015) 1e10
9
(hexanes: 2-propanol¼50:50, 0.7 mL/min, 210 nm); minor enan-
tiomer tr¼14.4 min, major enantiomer tr¼35.1 min.
a Chiralpak AS-H column (hexanes: 2-propanol¼50:50, 0.7 mL/
min, 210 nm); minor enantiomer tr¼32.7 min, major enantiomer
tr¼89.4 min.
4.3.21. Methyl (1S,3R,3aS,6aR)-3-([1,10-biphenyl]-4-yl)-5-(4-bromo-
phenyl)-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
4.3.26. Methyl (1S,3R,3aS,6aR)-3-(30,50-bis(trifluoromethyl)-[1,10-bi-
phenyl]-4-yl)-4,6-dioxo-5-(m-tolyl)octahydropyrrolo[3,4-c]pyrrole-
(6u). ½a 2D5
ꢃ
ꢀ149.7 (c 3.8, CHCl3). 1H NMR (400 MHz, DMSO)
d
7.72e7.60 (m, 6H), 7.53e7.44 (m, 4H), 7.36 (t, J¼7.3 Hz, 1H), 7.10
1-carboxylate (6z). ½a D25
ꢃ
ꢀ131.2 (c 4.5, CHCl3). 1H NMR (400 MHz,
(dd, J¼9.1, 2.3 Hz, 2H), 4.52 (dd, J¼8.7, 4.4 Hz, 1H), 4.08 (dd, J¼6.9,
CDCl3)
d
8.00 (s, 2H), 7.84 (s, 1H), 7.59 (s, 4H), 7.40 (t, J¼7.5 Hz, 2H),
4.3 Hz,1H), 3.78 (t, J¼7.3 Hz,1H), 3.71 (s, 3H), 3.65e3.57 (m, 2H). 13
C
7.33 (t, J¼7.3 Hz, 1H), 7.16 (d, J¼7.5 Hz, 2H), 4.67 (d, J¼8.6 Hz, 1H),
4.18 (d, J¼6.8 Hz, 1H), 3.89 (s, 3H), 3.76 (t, J¼7.3 Hz, 1H), 3.63 (t,
NMR (101 MHz, DMSO)
d 175.54, 174.08, 170.32, 139.88, 139.07,
138.00, 131.88, 131.45, 128.88, 128.58, 127.94, 127.30, 126.50, 126.07,
121.07, 62.79, 61.22, 51.40, 49.19, 48.29. Enantiomeric excess was
determined by HPLC with a Chiralpak AS-H column (hexanes: 2-
propanol¼50:50, 0.7 mL/min, 210 nm); minor enantiomer
tr¼18.0 min, major enantiomer tr¼43.9 min.
J¼8.2 Hz, 1H), 2.30 (br s, 1H). 13C NMR (101 MHz, CDCl3)
d 174.90,
173.51, 169.97, 142.78, 138.20, 137.64, 132.14 (d, J¼33.2 Hz), 131.63,
129.15, 128.67, 128.18, 127.31, 127.26, 126.18, 124.75, 122.04, 121.00,
63.94, 62.04, 52.43, 49.43, 48.17. Enantiomeric excess was de-
termined by HPLC with a Chiralpak AS-H column (hexanes: 2-
propanol¼50:50, 0.7 mL/min, 210 nm); minor enantiomer
tr¼9.2 min, major enantiomer tr¼19.4 min.
4.3.22. Methyl(1S,3R,3aS,6aR)-3-([1,10-biphenyl]-4-yl)-5-(3,5-
dimethyl-phenyl)-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-
carboxylate (6v). ½a D25
ꢃ
ꢀ146.6 (c 3.2, CHCl3). 1H NMR (400 MHz,
Acknowledgements
DMSO)
d
7.67 (dd, J¼11.5, 7.9 Hz, 4H), 7.54e7.44 (m, 4H), 7.36 (s,1H),
7.01 (s, 1H), 6.71 (s, 2H), 4.52 (dd, J¼8.7, 4.0 Hz, 1H), 4.07 (dd, J¼6.8,
4.0 Hz, 1H), 3.77 (t, J¼7.2 Hz, 1H), 3.71 (s, 3H), 3.62e3.55 (m, 2H),
This project was supported by the National Natural Science
Founder of China (No. 21173064, 21133011, and 21472031), and
Zhejiang Provincial Natural Science Foundation of China
(LR14B030001) is appreciated. The authors thank the group
members, Dr. Zheng Xu, Dr. Zhan-Jiang Zheng, and Dr. Yu-Ming Cui
of HZNU, for their help in this work.
2.27 (s, 6H). 13C NMR (101 MHz, DMSO)
d 175.74, 174.34, 170.36,
139.89, 139.04, 138.12, 137.98, 132.13, 129.52, 128.89, 128.02, 127.29,
126.46, 126.00, 124.21, 62.74, 61.18, 51.36, 49.05, 48.17, 20.68. En-
antiomeric excess was determined by HPLC with a Chiralpak AS-H
column (hexanes: 2-propanol¼50:50, 0.7 mL/min, 210 nm); minor
enantiomer tr¼12.9 min, major enantiomer tr¼50.6 min.
Supplementary data
4.3.23. Methyl (1S,3R,3aS,6aR)-3-([1,10-biphenyl]-4-yl)-5-(4-ethoxy-
phenyl)-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
Supplementary data (General remarks and the procedure of the
synthetic reaction, NMR data diagrams for all the products 2e6)
related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2015.09.068.
(6w). ½a 2D5
ꢃ
ꢀ148.2 (c 2.0, CHCl3). 1H NMR (400 MHz, DMSO)
d 7.65
(dd, J¼16.4, 7.8 Hz, 4H), 7.55e7.42 (m, 4H), 7.35 (t, J¼7.3 Hz, 1H),
6.99 (q, J¼9.1 Hz, 4H), 4.50 (dd, J¼8.7, 4.4 Hz, 1H), 4.06e3.99 (m,
3H), 3.74 (t, J¼7.2 Hz, 1H), 3.69 (s, 3H), 3.57 (dd, J¼10.3, 6.3 Hz, 2H),
References and notes
1.31 (t, J¼7.0 Hz, 3H). 13C NMR (101 MHz, DMSO)
d 175.90, 174.48,
170.37, 158.02, 139.89, 139.01, 138.13, 128.88, 127.97, 127.79, 127.28,
126.49, 126.02, 124.70, 114.52, 63.29, 62.77, 61.18, 51.36, 49.01,
48.09, 14.51. Enantiomeric excess was determined by HPLC with
a Chiralpak AS-H column (hexanes: 2-propanol¼50:50, 0.7 mL/
min, 210 nm); minor enantiomer tr¼36.2 min, major enantiomer
tr¼51.7 min.
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4.3.24. Methyl (1S,3R,3aS,6aR)-3-([1,10-biphenyl]-4-yl)-4,6-dioxo-5-
(m-tolyl)octahydropyrrolo[3,4-c]pyrrole-1-carboxylate
(6x). ½a 2D5
ꢃ
ꢀ152.0 (c 3.9, CHCl3). 1H NMR (400 MHz, DMSO)
7.65 (dd, J¼12.5,
d
7.8 Hz, 4H), 7.53e7.42 (m, 4H), 7.38e7.29 (m, 2H), 7.18 (d, J¼7.6 Hz,
1H), 6.90 (s, 2H), 4.51 (d, J¼8.8 Hz,1H), 4.05 (d, J¼6.9 Hz,1H), 3.76 (t,
J¼7.3 Hz, 1H), 3.70 (s, 3H), 3.64e3.55 (m, 1H), 3.34 (s, 1H), 2.30 (s,
3H). 13C NMR (101 MHz, DMSO)
d 175.75, 174.33, 170.37, 139.88,
139.03, 138.23, 138.10, 132.18, 128.89, 128.79, 128.62, 128.00, 127.29,
127.04, 126.47, 126.02, 123.73, 62.67, 61.11, 51.37, 49.05, 48.16, 20.75.
Enantiomeric excess was determined by HPLC with a Chiralpak AS-
H column (hexanes: 2-propanol¼50:50, 0.7 mL/min, 210 nm);
minor enantiomer tr¼15.1 min, major enantiomer tr¼54.4 min.
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d
7.53 (dt, J¼8.0, 6.3 Hz, 6H), 7.39 (t, J¼7.6 Hz, 2H), 7.32 (t,
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~
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d 174.96,
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Please cite this article in press as: Bai, X.-F.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.068

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Please cite this article in press as: Bai, X.-F.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.068