Enantiodivergent Brucine Diol-Catalyzed 1,3-Dipolar Cycloaddition of Azomethine Ylides with α,β-Unsaturated Ketones

Article abstract of DOI:10.1002/adsc.201500958

Enantiodivergent catalyst systems were developed using metals with different ionic radii and a multifunctional brucine diol (BD) ligand. The catalytic use of purported 1:1 Cu-BD complexes in the 1,3-dipolar cycloaddition of azomethine ylides with chalcones resulted in the selective formation of endo-pyrrolidines in 87-96% ees with an absolute stereochemical outcome of (2R,3S,4R,5S). In contrast, an opposite absolute stereochemical outcome was observed by using the catalysts derived from Ag(I) salts and BD. The demonstration of enantiodivergent approaches to a broad class of substrates/reaction types underlines their synthetic value in asymmetric synthesis.

Full text of DOI:10.1002/adsc.201500958

UPDATES
DOI: 10.1002/adsc.201500958
Enantiodivergent Brucine Diol-Catalyzed 1,3-Dipolar Cycloaddi-
tion of Azomethine Ylides with a,b-Unsaturated Ketones
Jian-Yuan Li,a Hun Young Kim,b and Kyungsoo Ohb,*
a
Department of Chemistry and Chemical Biology, Indiana University Purdue University Indianapolis, Indianapolis,
Indiana 46202, USA
b
Center for Metareceptome Research, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak, Seoul
156-756, Republic of Korea
Fax: (+82)-2-816-7338; e-mail: kyungsoooh@cau.ac.kr
Received: October 13, 2015; Revised: December 5, 2015; Published online: February 24, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500958.
Abstract: Enantiodivergent catalyst systems were
developed using metals with different ionic radii
and a multifunctional brucine diol (BD) ligand. The
catalytic use of purported 1:1 Cu-BD complexes in
the 1,3-dipolar cycloaddition of azomethine ylides
with chalcones resulted in the selective formation
of endo-pyrrolidines in 87–96% ees with an absolute
stereochemical outcome of (2R,3S,4R,5S). In con-
trast, an opposite absolute stereochemical outcome
was observed by using the catalysts derived from
Ag(I) salts and BD. The demonstration of enantio-
divergent approaches to a broad class of substrates/
reaction types underlines their synthetic value in
asymmetric synthesis.
a single chiral source.[2] While recent years have wit-
nessed the emergence of several successful enantiodi-
vergent catalyst systems, most of these catalyst sys-
tems lack the generality to be applied to new asym-
metric reactions due to the specific chemotypes asso-
ciated with given asymmetric reactions.[3] Consequent-
ly, the application of enantiodivergent reactions to
a broad class of substrates is a much-needed step
toward their entry into the mainstream of asymmetric
catalysis.
Previously, we reported an enantiodivergent 1,3-di-
polar cycloaddition reaction of imino esters with
acrylates using Cu(I)-BD and Ag(I)-BD complexes
derived from a single chiral source, brucine diol (BD)
(Scheme 1).[4] The underlying concept of our earlier
approach was based on the possible formation of dif-
ferent metal-BD complexes in the presence of metals
with different ionic radii. With the aim of broadening
the enantiodivergent approaches in asymmetric catal-
ysis,[5] we investigated the substrate generality in the
1,3-dipolar cycloaddition reactions of imino esters
with chalcone derivatives. Herein, we report the use
of Cu(I)-BD and Ag(I)-BD complexes as orthogonal
Keywords: asymmetric catalysis; copper; enantiodi-
vergence; pyrrolidines; silver
Introduction
Transition metal-catalyzed asymmetric reactions are enantioselective catalysts for the 1,3-dipolar cycload-
one of the most powerful and practical synthetic dition of imino esters with chalcones, demonstrating
methods in organic synthesis.[1] The unique advantag- the generality of enantiodivergent asymmetric cataly-
es of such chiral metal complex catalysts lie in the sis.
fact that the reactivity as well as the selectivity of cat-
alysts can be readily modulated by using (i) the modi-
fications of the ligand, (ii) the different natures of the Results and Discussion
metals, and (iii) other reaction parameters such as sol-
vent, reaction temperature, and additives. Collective- The catalytic asymmetric 1,3-dipolar cycloaddition of
ly, the combination of one or more experimental pa- azomethine ylides with a,b-unsaturated ketones was
rameters leads to a drastic change in the reactivity first pioneered by the group of Carretero using Cu(I)-
and selectivity of a given asymmetric reaction. The Fesulphos complexes,[6] where the preferential forma-
recent development of enantiodivergent asymmetric tion of exo-pyrrolidines was observed. Subsequent
catalysis essentially captures the concept of stereocon- studies by the groups of Zheng,[7] Wang,[8] and Wald-
trol using multiple reaction parameters to induce the mann[9] established the Cu(I)-catalyzed endo-selective
respective enantiomeric products on demand using 1,3-dipolar cycloaddition reactions of various a,b-un-
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Enantiodivergent Brucine Diol-Catalyzed 1,3-Dipolar Cycloaddition
Scheme 1. Enantiodivergent Cu-BD and Ag-BD catalyst systems.
saturated ketones. In related studies, the groups of
Cossío,[10] Fukuzawa,[11] Wang,[12] and Singh[13] report-
ed the use of chiral Ag(I) complexes in the endo-se-
lective 1,3-dipolar cycloaddition of azomethine ylides
with cyclic and acyclic enones. While it is abundantly
clear that both chiral Cu(I) and Ag(I) complexes are
effective catalysts for the 1,3-dipolar cycloaddition of
azomethine ylides with enones,[14] the possibility of
developing enantiodivergent Cu(I) and Ag(I) cata-
lysts has not been explored in spite of extensive
screenings using various Cu(I) and Ag(I) salts during
the optimization processes. To explore the effect of
different metal-BD molecularities to the stereochemi-
Table 1. Optimization of Cu(I)-BD-catalyzed 1,3-dipolar cy-
cloaddition reaction.
Entry Metal/
Solvent Additive[a] Yield ee
Base
[%][b] [%][c]
cal outcome of 1,3-dipolar cycloaddition of azome-
thine ylides and enones, we first examined various
Cu-BD catalysts in the reaction between methyl
imino ester 1a and chalcone 2a (Table 1). The use of
Cu-BD catalysts derived from CuOAc led to the ex-
clusive formation of endo-pyrrolidine 3a with 75% ee
(Table 1, entry 1). Next, we opted for the use of other
Cu-BD catalysts to improve the enantioselectivity as
well as the reaction conversion. The change of copper
salts marginally improved the enantioselectivity to
80–83% ee (Table 1, entries 2–5). However, the reac-
tion conversion remained <30%. The examination of
solvent effects revealed that the use of chlorinated
solvents such as CHCl3 and 1,1,2-trichloroethane was
better suited for consistent results (Table 1, entry 6).
The beneficial effect of alcohol additives has been
noted in the previous metal-BD-catalyzed asymmetric
reactions.[5] While such additive effects are not
a common optimization parameter in the asymmetric
1,3-dipolar cycloaddition reaction, the use of achiral
and meso ligands in enantioselective catalysis has
been widely reported.[15] Our efforts to improve the
reaction conversion using protic additives were quite
1
2
3
4
5
6
7
8
CuOAc/–
CuCl/Et3N
CuI/DBU
CH2Cl2
CH2Cl2
CH2Cl2
–
–
–
–
–
–
9
75
83
80
82
83
83
80
82
83
88
91
91
82
87
20
22
26
30
28
47
25
54
79
80
95
99
70
CuOTf/DBN CH2Cl2
CuOTf/DBU CH2Cl2
CuOTf/DBU TCE
CuOTf/DBU TCE
CuOTf/DBU TCE
CuOTf/DBU TCE
CuOTf/DBU TCE
CuOTf/DBU TCE
EtOH
t-BuOH
TFE
PhOH
PhOH
PhOH
PhOH
PhOH
9
10
11[d]
12[d,e] CuOTf/DBU TCE
13[f]
14[g]
CuOTf/DBU TCE
CuOTf/DBU TCE
[a]
Unless otherwise stated, 20 mol% of additive were
added.
Isolated yields of products after column chromatography
(unreacted chalcones were recovered).
Determined by HPLC using a chiral column.
60 mol% of PhOH additive.
Reaction for 48 h.
Reaction at 08C.
Use of 5 mol% catalyst for 120 h.
[b]
[c]
[d]
[e]
[f]
[g]
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Jian-Yuan Li et al.
Scheme 2. Scope of Cu(I)-BD-catalyzed 1,3-dipolar cycloaddition reaction.
rewarding (Table 1, entries 7–11), leading to 80% con- give endo-pyrrolidine (3p) in 85% yield with 93% ee.
version in the presence of 20 mol% of PhOH. Ulti- The absolute stereochemistry of endo-3 was con-
mately, the use of 60 mol% of PhOH in conjunction firmed to be (2R,3S,4R,5S) by comparison of its
with a longer reaction time of 48 h led to the forma- HPLC retention times with that of authentic samples
tion of endo-3a in 95% yield with 91% ee (Table 1, (see the Supporting Information for details).
entry 12). Control experiments either under elevated
To investigate the scope of enantiodivergent ap-
reaction temperature (08C) or with less catalyst load- proaches in the 1,3-dipolar cycloaddition of azome-
ing (5 mol%) confirmed the optimal reaction temper- thine ylides and enones, we next examined various
ature of À158C and the catalyst loading of 10 mol% Ag-BD catalysts. The screening of silver salts swiftly
for the observed reactivity and enantioselectivity resulted in the identification of AgF as an optimal
(Table 1, entries 13 and 14).
silver source (Table 2, entries 1–7), leading to the ex-
The optimized CuOTf-BD-catalyzed 1,3-dipolar cy- clusive formation of endo-4a, the mirror image form
cloaddition conditions were further investigated using of endo-3a, in 74% ee (Table 2, entry 7). It is worth
other imino esters and chalcone derivatives noting that the use of silver salts provides endo-4a as
(Scheme 2). A wide range of imino esters and chal- a major enantiomer regardless of the nature of the
cones with different electronic and steric effect pro- counter anions, clearly demonstrating the viability of
vided the desired endo-3a–p in high yields with excel- our enantiodivergent approaches based on metals
lent enantioselectivities (87–98% ees). In particular, with different ionic radii. An examination of the sol-
the imino ester with a coordinating heteroarene vent effect was next conducted (Table 2, entries 8–11),
moiety, thiophene, did not need the protic additives, where a coordinating solvent, THF, emerged as an op-
providing endo-pyrrolidine (3o) in 98% yield with timal solvent to provide endo-4a in 91% yield with
91% ee. In addition, the imino ester derived from ala- 79% ee (Table 2, entry 11). While the use of an addi-
nine smoothly underwent the cycloaddition at 08C to tional amount of BD could improve the observed
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Enantiodivergent Brucine Diol-Catalyzed 1,3-Dipolar Cycloaddition
Table 2. Optimization of Ag(I)-BD-catalyzed 1,3-dipolar cy-
cloaddition reaction.
AgF-BD-catalyzed 1,3-dipolar cycloaddition was evi-
dent upon using the imino ester derived from alanine;
the reaction was sluggish and low yielding.[16] While
there exists room for improvement in the enantiose-
lectivity of the AgF-BD-catalyzed reactions, the goal
of developing the enantiodivergent catalyst systems is
within reach with different metal-BD complexes in
the presence of metals with different ionic radii, re-
sulting endo-4 with the opposite absolute stereochem-
ical outcome to the CuOTf-BD-catalyzed reactions.
The absolute stereochemical outcomes of both Cu-
BD-catalyzed and Ag-BD-catalyzed reactions of chal-
cones are identical to those of our previous enantiodi-
vergent approaches in the 1,3-dipolar cycloaddition
using acrylates.[4] Previously, we proposed that a differ-
ent stoichiometry between metals and ligand was re-
sponsible for the enantiodivergent catalyst behav-
iours. Thus, since the reported ionic radius of Cu(I)
metal with a coordination number four is about
0.60 Š, and the corresponding Ag(I) metal is around
1.00 Š, the formations of 1:1 Cu-BD complexes and
1:2 Ag-BD complexes were proposed.[17] Likewise, the
current enantiodivergent 1,3-dipolar cycloaddition of
enones could be explained using the different molecu-
larity of the catalysts (Scheme 4). Thus, a smaller
metal, Cu(I), forms a five-membered metallocycle
with the tertiary amine moiety (N-19) and the tertiary
alcohol (C-21) of BD, whereas a metal with relatively
large ionic radius, Ag(I), complexes with two BD li-
gands through the highly Lewis basic tertiary amine
moiety (N-19). While more detailed mechanistic work
is needed, our preliminary data were consistent with
the proposed molecularity of the catalysts. Thus,
while the optimal ratio between Cu(I) salts and BD
ligand in the Cu-BD catalysts was 1:1, the Ag-BD cat-
Entry Metal
Solvent Additive[a] Yield ee
[%][b] [%][c]
1
2
3
4
5
6
7
8
AgOAc
AgOTf
AgTFA
Ag(2-EHA) CH2Cl2
AgPF6
AgI
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
AgF
CH2Cl2
CH2Cl2
CH2Cl2
–
–
–
–
–
–
–
–
60
76
46
93
88
11
85
3
16
46
91
82
50
91
89
38
71
60
64
59
30
74
35
56
58
79
84
64
79
87
CH2Cl2
CH2Cl2
CH2Cl2
DCE
TCE
CHCl3
THF
THF
9
–
–
–
BD
BD
PhOH
t-BuOH
10
11
12
13[d]
14
15
THF
THF
THF
[a]
Unless otherwise stated, 10 mol% of additive were
added.
Isolated yields of products after column chromatography
(unreacted chalcones were recovered).
Determined by HPLC using a chiral column.
Use of 50 mol% BD. 2-EHA=2-ethylhexanoic acid.
[b]
[c]
[d]
enantioselectivity to 84% (Table 2, entries 12 and 13), alysts well tolerated the ratio between Ag(I) salts and
the subsequent protic additive screening revealed that BD ligand upto 1:3 without a significant decrease in
the use of 10 mol% of t-BuOH could also provide enantioselectivity. In particular, the addition of t-
endo-4a in 89% yield with 87% ee (Table 2, entry 15). BuOH in place of BD provided the products with
The scope of the AgF-BD-catalyzed 1,3-dipolar cy- consistent enantioselectivities, suggesting an intricate
cloaddition was examined using a series of imino H-bonding network in the multiple ligands binding to
esters and chalcone derivatives (Scheme 3). Thus, the Ag(I) metal center. Nevertheless, the possible in-
under the two different sets of optimal conditions volvement of a metallo-azomethine ylide-chiral base
(with or without protic additives, t-BuOH), the facile ion pair, originally proposed by Jørgensen in the
formation of endo-4 was observed albeit with slightly AgF-hydrocinchonine catalyst system,[18] cannot be
varying the scope of substrates. For instance, the elec- completely ruled out. At present time, we postulate
tronic nature of the chalconeꢁs b-aryl substituent det- that the protic additive in the Cu-BD catalyst system
rimentally influenced the observed enantioselectivi- takes on the role of proton shuttle to improve catalyst
ties of endo-pyrrolidine to 22–55% ees (4b–4e). How- turnover as their effect on the observed enantioselec-
ever, the aryl substituent on the imino esters did not tivity was insignificant in the Cu-BD catalyst system.
exert a significant effect on the observed enantiose-
lectivities, providing endo-4f–i in 83–90% ees. In addi-
tion, the effect of the chalconeꢁs b-aryl substituent Conclusions
could be minimized with the introduction of electron-
withdrawing groups to the imino esters and chalcones, In summary, we have developed enantiodivergent cat-
whereby endo-pyrrolidines (4j–o) were obtained in alyst systems for the 1,3-dipolar cycloaddition of azo-
61–98% ees. An additional limitation of the current methine ylides with chalcone derivatives. The differ-
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Scheme 3. Scope of Ag(I)-BD-catalyzed 1,3-dipolar cycloaddition reaction.
Experimental Section
General Procedure for Racemic endo-Selective
Cycloaddition Products
To a stirred solution of methyl (E)-2-(benzylideneamino)a-
cetate derivative (1, 0.5 mmol), (E)-chalcone derivative (2,
0.5 mmol) and silver(I) acetate (0.5 mmol) in dry DCM
(1.0 mL), was added Et3N (0.5 mmol) at ambient tempera-
ture. The resulting solution was stirred for 18 h. After
which, the solution was concentrated under the reduced
pressure and the desired endo-cycloaddition product was
isolated from crude mixture via column chromatograph in
20–35% yield.
General Procedure A for the Cu-BD Complex-
Catalyzed endo-Selective [3+2] Cycloaddition
Reactions
Scheme 4. Stereomodels of enantiodivergent catalyst sys-
tems.
A 10-mL Schlenk flask was charged with (CuOTf)2·C6H6
(10 mol%, 25 mg) and brucine diol (10 mol%, 21 mg). Dry
1,1,2-trichloroethane (2.2 mL) was then added to the flask
at 08C, followed by addition of DBU (10 mol%, 8 mL). The
solution was stirred for 4 h at this temperature. The resulting
solution was cooled to À158C, and methyl (E)-2-(benzyli-
deneamino)acetate derivative (1, 0.5 mmol) was added and
stirring continued for 10 min. After which, (E)-chalcone de-
rivative (2, 0.5 mmol) and phenol additive (60 mol%, 28 mg)
were added. The solution was allowed to stir at À158C until
the reaction was complete by TLC (48–72 h). The reaction
mixture was loaded and chromatographed on a short silica
column (10–20% ethyl acetate in hexanes).
ent stoichiometry of catalysts derived from metals
with different ionic radii and ligands is believed to
effect enantiodivergent pathways, demonstrating the
generality of enantiodivergent approaches to a broad
class of dipolarophile substrates. We are currently in-
vestigating the origin of enantioselectivity in our cata-
lyst systems, and our results will be reported in due
course. Meanwhile, we are eager to encounter the im-
plementation of enantiodivergent approaches to other
synthetic transformations.
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UPDATES
Enantiodivergent Brucine Diol-Catalyzed 1,3-Dipolar Cycloaddition
Methyl (2R,3S,4R,5S)-4-benzoyl-3,5-diphenylpyrrolidine-
2-carboxylate (3a): light yellow solid; yield: 183 mg (95%);
137.3, 134.5, 132.9, 130.1, 128.3, 128.2, 128.1, 127.9, 127.7,
127.5, 127.4, 126.3, 67.4, 66.5, 60.6, 52.4, 51.9; IR (neat): n=
3354, 3060, 3031, 2942, 2914, 1737, 1679, 1597, 1573, 1479,
1448, 1435, 1384, 1331, 1259, 1217, 1179, 1129, 1083, 755,
725, 696 cmÀ1; HR-MS (CI): m/z=420.1343 (M+H)+, calcd.
for C25H23ClNO3: 420.1366.
1
mp 150–1548C; H NMR and 13C NMR spectra for this com-
pound are consistent with previously reported literature
data.[10] 1H NMR (CDCl3, 500 MHz): d=7.52–7.51 (m, 2H),
7.38–7.30 (m, 5H), 7.23–7.20 (m, 3H), 7.12–7.03 (m, 5H),
4.98 (d, J=8.5 Hz, 1H), 4.52–4.49 (m, 1H), 4.19–4.11 (m,
2H), 3.72 (s, 3H), 3.04 (brs, NH); 13C NMR (CDCl3,
125 MHz): d=198.8, 173.4, 140.9, 139.2, 137.5, 132.9, 128.9,
128.3, 128.2, 128.1, 127.8, 127.7, 127.5, 127.2, 67.8, 66.7, 60.7,
52.8, 52.3; IR (neat): n=3345, 3091, 3064, 3032, 3002, 2977,
2953, 1734, 1603, 1553, 1498, 1455, 1435, 1370, 1255, 1221,
1141, 1030, 984, 873, 809, 750, 700, 667 cmÀ1; HR-MS (CI):
m/z=386.1761 (M+H)+, calcd. for C25H24NO3: 386.1751
Methyl (2R,3S,4R,5S)-4-benzoyl-5-phenyl-3-(p-tolyl)pyr-
rolidine-2-carboxylate (3b): light yellow solid; yield: 188 mg
(94%); mp 117–1198C; 1H NMR (CDCl3, 500 MHz): d=
7.52–7.50 (m, 2H), 7.36–7.34 (m, 1H), 7.27–7.19 (m, 4H),
7.13–7.10 (m, 4H), 7.07–7.00 (m, 3H), 4.97 (d, J=9.0 Hz,
1H), 4.48 (t, J=8.0 Hz, 1H), 4.15 (d, J=9.0 Hz, 1H), 4.08
(t, J=8.0 Hz, 1H), 3.71 (s, 3H), 3.07 (brs, NH), 2.29 (s, 3H);
13C NMR (CDCl3, 125 MHz): d=198.8, 173.5, 139.2, 137.8,
137.6, 136.8, 132.8, 129.5, 128.3, 128.1, 128.1, 127.7, 127.6,
127.5, 67.8, 66.7, 60.7, 52.5, 52.3, 21.1; IR (neat): n=3354,
3063, 3027, 2951, 2920, 1736, 1679, 1515, 1448, 1434, 1384,
1334, 1262, 1217, 1178, 1128, 1017, 813, 754, 699 cmÀ1; HR-
MS (CI): m/z= 400.1907 (M+H)+, calcd. for C26H26NO3:
400.1913.
Methyl
(2R,3S,4R,5S)-4-benzoyl-3-(2-chlorophenyl)-5-
phenylpyrrolidine-2-carboxylate (3f): light yellow solid;
yield: 208 mg (99%); mp 99–1028C; 1H NMR (CDCl3,
500 MHz): d=7.52–7.49 (m, 3H), 7.40–7.38 (m, 1H), 7.37–
7.34 (m, 1H), 7.31–7.28 (m, 1H), 7.22–7.18 (m, 3H), 7.13–
7.11 (m, 2H), 7.07–7.00 (m, 3H), 4.96 (d, J=8.5 Hz, 1H),
4.62 (dd, J=8.0, 7.0 Hz, 1H), 4.53 (dd, J=8.5, 7.0 Hz, 1H),
4.22 (d, J=8.0 Hz, 1H), 3.78 (s, 3H), 3.17 (brs, NH);
13C NMR (CDCl3, 125 MHz): d=199.3, 173.4, 138.5, 138.5,
137.5, 134.6, 132.8, 130.2, 128.5, 128.4, 128.3, 128.2, 128.2,
127.8, 127.4, 127.4, 66.7, 66.3, 59.2, 52.6, 50.0; IR (neat): n=
3348, 3066, 3028, 2952, 2923, 1737, 1679, 1596, 1478, 1448,
1435, 1384, 1332, 1262, 1218, 1180, 1128, 1036, 755, 699 cmÀ1
;
HR-MS (CI): m/z=420.1348 (M+H)+, calcd. for
C25H23ClNO3: 420.1366.
Methyl (2R,3S,4R,5S)-4-(4-chlorobenzoyl)-3,5-diphenyl-
pyrrolidine-2-carboxylate (3g): light yellow solid; yield:
1
207 mg (99%); mp 115–1198C; H NMR (CDCl3, 500 MHz):
d=7.44–7.42 (m, 2H), 7.37–7.30 (m, 4H), 7.24–7.21 (m,
1H), 7.18–7.16 (m, 2H), 7.11–7.03 (m, 5H), 4.96 (d, J=
9.0 Hz, 1H), 4.41 (dd, J=8.5, 7.5 Hz, 1H), 4.17–4.10 (m,
2H), 3.72 (s, 3H), 3.04 (brs, NH); 13C NMR (CDCl3,
125 MHz): d=197.7, 173.3, 140.8, 139.2, 138.9, 135.9, 129.5,
128.9, 128.6, 128.3, 127.8, 127.8, 127.4, 127.3, 67.7, 66.7, 60.7,
52.8, 52.4; IR (neat): n=3360, 3091, 3060, 3025, 2949, 2914,
1736, 1681, 1588, 1495, 1455, 1434, 1401, 1384, 1261, 1216,
Methyl
(2R,3S,4R,5S)-4-benzoyl-3-(4-chlorophenyl)-5-
phenylpyrrolidine-2-carboxylate (3c): yellow solid; yield:
1
202 mg (96%); mp 115–1178C; H NMR (CDCl3, 500 MHz):
d=7.52–7.50 (m, 2H), 7.38–7.35 (m, 1H), 7.31–7.25 (m,
4H), 7.23–7.20 (m, 2H), 7.09–7.02 (m, 5H), 4.97 (d, J=
9.0 Hz, 1H), 4.47–4.44 (m, 1H), 4.14–4.08 (m, 2H), 3.70 (s,
3H), 3.00 (brs, NH); 13C NMR (CDCl3, 125 MHz): d=198.1,
173.2, 139.2, 139.0, 137.3, 132.9, 132.9, 129.2, 128.9, 128.3,
128.1, 128.0, 127.7, 127.5, 67.4, 66.4, 60.7, 52.3, 51.6; IR
(neat): n=3354, 3088, 3056, 3018, 2952, 2927, 1737, 1679,
1597, 1493, 1448, 1434, 1373, 1333, 1261, 1217, 1178, 1129,
1092, 1014, 825, 755, 719, 698 cmÀ1; HR-MS (CI): m/z=
420.1362 (M+H)+, calcd. for C25H23ClNO3: 420.1366.
Methyl (2R,3S,4R,5S)-4-benzoyl-5-phenyl-3-(m-tolyl)pyr-
rolidine-2-carboxylate (3d): light yellow solid; yield: 148 mg
(74%); mp 125–1288C; 1H NMR (CDCl3, 500 MHz): d=
7.53–7.51 (m, 2H), 7.37–7.34 (m, 1H), 7.23–7.16 (m, 5H),
7.12–7.10 (m, 2H), 7.07–7.01 (m, 4H), 4.98 (d, J=9.0 Hz,
1H), 4.50–4.47 (m, 1H), 4.17 (d, J=9.0 Hz, 1H), 4.10–4.07
(m, 1H), 3.73 (s, 3H), 3.07 (brs, NH), 2.32 (s, 3H);
13C NMR (CDCl3, 125 MHz): d=198.9, 173.5, 140.9, 139.1,
138.4, 137.5, 132.8, 128.7, 128.6, 128.2, 128.2, 128.1, 128.0,
127.6, 127.5, 124.8, 67.8, 66.8, 60.6, 52.8, 52.3, 21.6; IR
(neat): n=3345, 3063, 3028, 2917, 1736, 1680, 1596, 1492,
1448, 1434, 1384, 1331, 1263, 1216, 1178, 1128, 784, 754, 700,
668 cmÀ1; HR-MS (CI): m/z=400.1906 (M+H)+, calcd. for
C26H26NO3: 400.1913.
1176, 1092, 1011, 757, 700 cmÀ1
; HR-MS (CI): m/z=
420.1346 (M+H)+, calcd. for C25H23ClNO3: 420.1366.
Methyl (2R,3R,4R,5S)-4-benzoyl-3-(furan-2-yl)-5-phenyl-
pyrrolidine-2-carboxylate (3h): light yellow solid; yield:
139 mg (74%); mp: 139–1438C; 1H NMR (CDCl3,
500 MHz): d=7.58–7.56 (m, 2H), 7.42–7.38 (m, 2H), 7.27–
7.23 (m, 2H), 7.12–7.02 (m, 5H), 6.32 (dd, J=3.0, 2.0 Hz,
1H), 6.24 (d, J=3.0 Hz, 1H), 4.93 (d, J=8.0 Hz, 1H), 4.58
(dd, J=8.0, 6.0 Hz, 1H), 4.26 (d, J=8.0 Hz, 1H), 4.20 (dd,
J=8.0, 6.0 Hz, 1H), 3.83 (s, 3H), 3.52 (brs, NH); 13C NMR
(CDCl3, 125 MHz): d=199.3, 172.8, 153.7, 142.2, 138.1,
137.4, 133.0, 128.4, 128.3, 128.3, 127.8, 127.4, 110.6, 107.0,
66.6, 65.1, 57.1, 52.7, 46.5; IR (neat): n=3338, 3060, 3031,
3006, 2958, 2920, 1740, 1682, 1596, 1448, 1435, 1384, 1328,
1217, 1180, 1148, 1013, 754, 699 cmÀ1; HR-MS (CI): m/z=
376.1530 (M+H)+, calcd. for C23H22NO4: 376.1549.
Methyl (2R,3S,4R,5S)-4-benzoyl-3-phenyl-5-(p-tolyl)pyr-
rolidine-2-carboxylate (3i): light yellow solid; yield: 192 mg
1
(96%); mp 167–1698C; H NMR and 13C NMR spectra for
this compound are consistent with previously reported liter-
ature data;[10] 1H NMR (CDCl3, 500 MHz): d=7.55–7.53 (m,
2H), 7.39–7.36 (m, 3H), 7.33–7.30 (m, 2H), 7.25–7.20 (m,
3H), 6.99 (d, J=8.0 Hz, 2H), 6.87 (d, J=8.0 Hz, 2H), 4.96
(d, J=9.0 Hz, 1H), 4.51–4.48 (m, 1H), 4.16 (d, J=9.0 Hz,
1H), 4.12–4.09 (m, 1H), 3.72 (s, 3H), 2.96 (brs, NH), 2.16 (s,
3H); 13C NMR (CDCl3, 125 MHz): d=198.8, 173.5, 140.9,
137.6, 137.3, 136.2, 132.8, 128.9. 128.9, 128.3, 128.2, 127.9,
127.4, 127.2, 67.8, 66.6, 60.8, 52.8, 52.3, 21.1; IR (neat): n=
3351, 3066, 3015, 3009, 2942, 2911, 1737, 1676, 1448, 1433,
Methyl
(2R,3S,4R,5S)-4-benzoyl-3-(3-chlorophenyl)-5-
phenylpyrrolidine-2-carboxylate (3e): yellow solid; yield:
1
208 mg (99%); mp 117–1208C; H NMR (CDCl3, 500 MHz):
d=7.52–7.51 (m, 2H), 7.38–7.35 (m, 2H), 7.26–7.17 (m,
5H), 7.09–7.02 (m, 5H), 4.97 (d, J=9.0 Hz, 1H), 4.48–4.45
(m, 1H), 4.15–4.08 (m, 2H), 3.71 (s, 3H), 3.02 (brs, NH);
13C NMR (CDCl3, 125 MHz): d=198.1, 173.1, 142.8, 139.1,
1384, 1261, 1212, 1177, 820, 760, 734, 701, 686, 528 cmÀ1
;
Adv. Synth. Catal. 2016, 358, 984 – 993
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
989

UPDATES
Jian-Yuan Li et al.
1
HR-MS (CI): m/z=400.1903 (M+H)+, calcd. for
(93%); mp 123–1268C; H NMR and 13C NMR spectra for
this compound are consistent with previously reported liter-
ature data;[7,11] 1H NMR (CDCl3, 500 MHz): d=7.56–7.54
(m, 2H), 7.45–7.41 (m, 1H), 7.31–7.27 (m, 6H), 7.05–7.02
(m, 4H), 4.95 (d, J=8.5 Hz, 1H), 4.61 (t, J=8.5 Hz, 1H),
4.14–4.07 (m, 2H), 3.72 (s, 3H), 2.95 (brs, NH); 13C NMR
(CDCl3, 125 MHz): d=)197.8, 173.2, 138.7, 138.1, 137.3,
133.5, 133.3, 133.1, 129.3, 129.1, 128.9, 128.6, 128.3, 128.1,
67.3, 65.5, 60.5, 52.5, 51.3; IR (neat): n=3345, 3066, 3022,
2946, 2917, 1736, 1678, 1596, 1492, 1448, 1435, 1412, 1384,
1258, 1218, 1179, 1129, 1092, 1014, 824, 771, 693 cmÀ1; HR-
MS (CI): m/z=454.0942 (M+H)+, calcd. for C25H22Cl2NO3:
454.0977.
Methyl (2R,3S,4R,5S)-4-benzoyl-3-phenyl-5-(thiophen-2-
yl)pyrrolidine-2-carboxylate (3o): yellow solid; yield: 192 mg
(98%); mp 165–1678C; 1H NMR (CDCl3, 500 MHz): d=
7.69–7.67 (m, 2H), 7.46–7.42 (m, 1H), 7.38–7.37 (m, 2H),
7.33–7.29 (m, 4H), 7.24–7.20 (m, 1H), 7.01 (dd, J=5.0,
1.5 Hz, 1H), 6.72–6.69 (m, 2H), 5.26 (d, J=8.5 Hz, 1H),
4.53–4.50 (m, 1H), 4.19–4.14 (m, 2H), 3.71 (s, 3H), 3.10
(brs, NH); 13C NMR (CDCl3, 125 MHz): d=197.6, 173.3,
143.2, 140.4, 137.4, 133.1, 128.9, 128.5, 128.2, 127.9, 127.2,
126.6, 125.5, 124.8, 67.3, 61.8, 60.3, 52.4, 51.6; IR (neat): n=
3367, 3066, 3018, 2952, 2920, 1736, 1679, 1448, 1435, 1384,
1272, 1234, 1215, 1179, 760, 699 cmÀ1; HR-MS (CI): m/z=
392.1302 (M+H)+, calcd. for C23H22NO3S: 392.1320.
C26H26NO3: 400.1913.
Methyl
(2R,3S,4R,5S)-4-benzoyl-5-(4-fluorophenyl)-3-
phenylpyrrolidine-2-carboxylate (3j): yellow solid; yield:
135 mg (67%); mp 164–1678C; H NMR (CDCl3, 500 MHz):
1
d=7.54–7.53 (m, 2H), 7.41–7.30 (m, 5H), 7.27–7.21 (m,
3H), 7.10–7.08 (m, 2H), 6.78–6.74 (m, 2H), 4.98 (d, J=
9.0 Hz, 1H), 4.51–4.48 (m, 1H), 4.18–4.11 (m, 2H), 3.72 (s,
3H), 2.95 (brs, NH); 13C NMR (CDCl3, 125 MHz): d=198.5,
173.5, 162.2 (d, J=245.0 Hz), 140.6, 137.5, 135.2 (d, J=
2.5 Hz), 133.1, 129.2 (d, J=7.5 Hz), 128.9, 128.4, 128.1,
127.9, 127.3, 115.1 (d, J=21.3 Hz), 67.6, 65.9, 60.5, 52.4,
52.4; IR (neat): n=3351, 3060, 3022, 2952, 2917, 1735, 1674,
1600, 1509, 1447, 1435, 1384, 1353, 1326, 1262, 1219, 1180,
1158, 1130, 1077, 1013, 986, 836, 823, 760, 699, 687, 605, 533,
512 cmÀ1; HR-MS (CI): m/z=404.1625 (M+H)+, calcd. for
C25H23FNO3: 404.1662.
Methyl
(2R,3S,4R,5S)-4-benzoyl-3,5-di-(p-tolyl)pyrroli-
dine-2-carboxylate (3k): light yellow solid; yield: 149 mg
(72%); mp 153–1568C; 1H NMR (CDCl3, 500 MHz): d=
7.54–7.52 (m, 2H), 7.37–7.34 (m, 1H), 7.26–7.20 (m, 4H),
7.11 (d, J=7.5 Hz, 2H), 6.99 (d, J=8.0 Hz, 2H), 6.86 (d, J=
8.0 Hz, 2H), 4.95 (d, J=9.0 Hz, 1H), 4.49–4.45 (m, 1H),
4.13 (d, J=9.0 Hz, 1H), 4.09–4.05 (m, 1H), 3.71 (s, 3H),
3.04 (brs, NH), 2.28 (s, 3H), 2.15 (s, 3H); 13C NMR (CDCl3,
125 MHz): d=198.8, 173.5, 137.8, 137.6, 137.2, 136.7, 136.3,
132.7, 129.5, 128.8, 128.2, 128.1, 127.7, 127.3, 67.8, 66.5, 60.8,
52.5, 52.3, 21.1, 21.0; IR (neat): n=3351, 3056, 3023, 2951,
2922, 2863, 1736, 1680, 1596, 1580, 1515, 1448, 1434, 1384,
1329, 1261, 1217, 1178, 1128, 1022, 814, 757, 704, 689,
527 cmÀ1; HR-MS (CI): m/z=414.2049 (M+H)+, calcd. for
C27H28NO3: 414.2069.
Methyl
(2R,3S,4R,5S)-4-benzoyl-2-methyl-3,5-diphenyl-
pyrrolidine-2-carboxylate (3p): light yellow solid; yield:
1
170 mg (85%); mp 168–1728C; H NMR (CDCl3, 500 MHz):
d=7.57–7.55 (m, 2H), 7.37–7.34 (m, 1H), 7.28–7.16 (m,
7H), 7.13–7.09 (m, 2H), 7.06–7.01 (m, 3H), 5.02 (d, J=
9.5 Hz, 1H), 4.88 (dd, J=10.0, 9.5 Hz, 1H), 4.46 (d, J=
10.0 Hz, 1H), 3.77 (s, 3H), 3.20 (brs, NH), 1.29 (s, 3H);
13C NMR (CDCl3, 125 MHz): d=197.9, 175.8, 139.8, 137.8,
137.7, 132.7, 128.6, 128.3, 128.3, 128.1, 128.0, 127.8, 127.6,
127.2, 68.7, 64.2, 56.7, 55.1, 52.5; IR (neat): n=3345, 3066,
3029, 2990, 2942, 1728, 1677, 1597, 1496, 1448, 1434, 1384,
1256, 1218, 1177, 1135, 1004, 756, 699 cmÀ1; HR-MS (CI):
m/z=400.1895 (M+H)+, calcd. for C26H26NO3: 400.1913.
Methyl (2R,3S,4R,5S)-4-benzoyl-3-(4-chlorophenyl)-5-(p-
tolyl)pyrrolidine-2-carboxylate (3l): yellow solid; yield:
187 mg (86%); mp 140–1438C; H NMR (CDCl3, 500 MHz):
1
d=7.55–7.53 (m, 2H), 7.41–7.38 (m, 1H), 7.31–7.23 (m,
6H), 6.97 (d, J=8.0 Hz, 2H), 6.87 (d, J=8.0 Hz, 2H), 4.95
(d, J=8.5 Hz, 1H), 4.45 (t, J=8.5 Hz, 1H), 4.13–4.07 (m,
2H), 3.71 (s, 3H), 2.96 (brs, NH), 2.16 (s, 3H); 13C NMR
(CDCl3, 125 MHz): d=198.1, 173.3, 139.1, 137.5, 137.4,
136.3, 132.9, 129.3, 129.0, 129.0, 128.9, 128.4, 128.2, 127.4,
67.4, 66.3, 60.9, 52.4, 51.8, 21.1; IR (neat): n=3357, 3053,
3022, 2946, 2920, 1736, 1679, 1596, 1493, 1448, 1434, 1384,
General Procedure B for the Ag-BD Complex-
Catalyzed endo-Selective [3+2] Cycloaddition
Reactions
1329, 1260, 1216, 1179, 1129, 1092, 1014, 819, 758, 691 cmÀ1
;
HR-MS (CI): m/z=434.1498 (M+H)+, calcd. for
C26H25ClNO3: 434.1523.
To a stirred suspension of AgF (10 mol%, 6 mg) and brucine
diol (10 mol%, 21 mg), was added dry THF (2.2 mL) at 08C
under argon. The solution was stirred for 4 h at this temper-
ature. The resulting solution was cooled to À158C, and
methyl (E)-2-(benzylideneamino)acetate derivative (1,
0.5 mmol) was added and stirring continued for 10 min.
After which, (E)-chalcone derivative (2, 0.5 mmol) was
added with t-BuOH as additive (10 mol%, 5 mL). The solu-
tion was stirred at À158C until the reaction was complete
by TLC (48–72 h). The reaction mixture was loaded and
chromatographed on a short silica column (10–20% ethyl
acetate in hexanes).
Methyl (2R,3S,4R,5S)-4-benzoyl-5-(4-chlorophenyl)-3-(p-
tolyl)pyrrolidine-2-carboxylate (3m): light yellow solid;
yield: 180 mg (83%); mp 155–1578C; 1H NMR (CDCl3,
500 MHz): d=7.55–7.53 (m, 2H), 7.41–7.38 (m, 1H), 7.27–
7.23 (m, 4H), 7.12–7.11 (m, 2H), 7.06–7.02 (m, 4H), 4.94 (d,
J=8.5 Hz, 1H), 4.50 À4.47 (m, 1H), 4.15–4.05 (m, 2H), 3.71
(s, 3H), 3.00 (brs, NH), 2.29 (s, 3H); 13C NMR (CDCl3,
125 MHz): d=198.5, 173.5, 138.2, 137.5, 137.4, 136.9, 133.3,
133.1, 129.6, 128.9, 128.5, 128.3, 128.1, 127.7, 67.6, 65.8, 60.4,
52.3, 52.1, 21.1; IR (neat): n=3364, 3060, 3018, 2952, 2927,
2860, 1736, 1679, 1596, 1515, 1491, 1448, 1435, 1384, 1259,
1217, 1178, 1114, 1092, 1014, 816, 757, 690 cmÀ1; HR-MS
(CI): m/z=434.1504 (M+H)+, calcd. for C26H25ClNO3:
434.1523.
Methyl (2S,3R,4S,5R)-4-benzoyl-3,5-diphenylpyrrolidine-
2-carboxylate (4a): light yellow solid; yield: 172 mg (89%);
1
mp 150–1548C; H NMR and 13C NMR spectra for this com-
pound are consistent with previously reported literature
data;[10] 1H NMR (CDCl3, 500 MHz): d=7.52–7.51 (m, 2H),
7.38–7.30 (m, 5H), 7.23–7.20 (m, 3H), 7.12–7.03 (m, 5H),
Methyl (2R,3S,4R,5S)-4-benzoyl-3,5-bis(4-chlorophenyl)-
pyrrolidine-2-carboxylate (3n): yellow solid; yield: 211 mg
990
asc.wiley-vch.de
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2016, 358, 984 – 993

UPDATES
Enantiodivergent Brucine Diol-Catalyzed 1,3-Dipolar Cycloaddition
4.98 (d, J=8.5 Hz, 1H), 4.52–4.49 (m, 1H), 4.19–4.11 (m,
2H), 3.72 (s, 3H), 3.04 (brs, NH); 13C NMR (CDCl3,
125 MHz): d=198.8, 173.4, 140.9, 139.2, 137.5, 132.9, 128.9,
128.3, 128.2, 128.1, 127.8, 127.7, 127.5, 127.2, 67.8, 66.7, 60.7,
52.8, 52.3; IR (neat): n=3345, 3091, 3064, 3032, 3002, 2977,
2953, 1734, 1603, 1553, 1498, 1455, 1435, 1370, 1255, 1221,
1141, 1030, 984, 873, 809, 750, 700, 667 cmÀ1; HR-MS (CI):
m/z=386.1761 (M+H)+, calcd. for C25H24NO3: 386.1751.
Methyl (2S,3R,4S,5R)-4-benzoyl-5-phenyl-3-(p-tolyl)pyr-
rolidine-2-carboxylate (4b): light yellow solid; yield: 184 mg
(92%); mp: 139–1428C; 1H NMR (CDCl3, 500 MHz): d=
7.52–7.50 (m, 2H), 7.36–7.34 (m, 1H), 7.27–7.19 (m, 4H),
7.13–7.10 (m, 4H), 7.07–7.00 (m, 3H), 4.97 (d, J=9.0 Hz,
1H), 4.48 (t, J=8.0 Hz, 1H), 4.15 (d, J=9.0 Hz, 1H), 4.08
(t, J=8.0 Hz, 1H), 3.71 (s, 3H), 3.07 (brs, NH), 2.29 (s, 3H);
13C NMR (CDCl3, 125 MHz): d=198.8, 173.5, 139.2, 137.8,
137.6, 136.8, 132.8, 129.5, 128.3, 128.1, 128.1, 127.7, 127.6,
127.5, 67.8, 66.7, 60.7, 52.5, 52.3, 21.1; IR (neat): n=3364,
3062, 3030, 2952, 2920, 1736, 1676, 1606, 1455, 1434, 1409,
1373, 1336, 1264, 1219, 1179, 1128, 1033, 1016, 824, 756,
700 cmÀ1; HR-MS (CI): m/z=400.1891 (M+H)+, calcd. for
C26H26NO3: 400.1907.
MS (CI): m/z=420.1348 (M+H)+, calcd. for C25H23ClNO3:
420.1366.
Methyl (2S,3R,4S,5R)-4-benzoyl-3-phenyl-5-(p-tolyl)pyr-
rolidine-2-carboxylate (4f): light yellow solid; yield: 197 mg
1
(99%); mp 167–1698C; H NMR and 13C NMR spectra for
this compound are consistent with previously reported liter-
ature data;[10] 1H NMR (CDCl3, 500 MHz): d=7.55–7.53 (m,
2H), 7.39–7.36 (m, 3H), 7.33–7.30 (m, 2H), 7.25–7.20 (m,
3H), 6.99 (d, J=8.0 Hz, 2H), 6.87 (d, J=8.0 Hz, 2H), 4.96
(d, J=9.0 Hz, 1H), 4.51–4.48 (m, 1H), 4.16 (d, J=9.0 Hz,
1H), 4.12–4.09 (m, 1H), 3.72 (s, 3H), 2.96 (brs, NH), 2.16 (s,
3H); 13C NMR (CDCl3, 125 MHz): d=198.8, 173.5, 140.9,
137.6, 137.3, 136.2, 132.8, 128.9. 128.9, 128.3, 128.2, 127.9,
127.4, 127.2, 67.8, 66.6, 60.8, 52.8, 52.3, 21.1; IR (neat): n=
3351, 3066, 3015, 3009, 2942, 2911, 1737, 1676, 1448, 1433,
1384, 1261, 1212, 1177, 820, 760, 734, 701, 686, 528 cmÀ1
;
HR-MS (CI): m/z=400.1903 (M+H)+, calcd. for
C26H26NO3: 400.1913.
Methyl
(2S,3R,4S,5R)-4-benzoyl-5-(4-chlorophenyl)-3-
phenylpyrrolidine-2-carboxylate (4g): light yellow solid;
yield: 105 mg (50%); mp: 155–1588C; 1H NMR and
13C NMR spectra for this compound are consistent with pre-
viously reported literature data;[7,11] 1H NMR (CDCl3,
500 MHz): d=7.55–7.54 (m, 2H), 7.43–7.40 (m, 1H), 7.37–
7.31 (m, 4H), 7.28–7.22 (m, 3H), 7.07–7.03 (m, 4H), 4.96 (d,
J=8.5 Hz, 1H), 4.51 (t, J=8.5 Hz, 1H), 4.17 (d, J=9.0 Hz,
1H), 4.12–4.09 (m, 1H), 3.73 (s, 3H), 2.98 (brs, NH);
13C NMR (CDCl3, 125 MHz): d=198.4, 173.4, 140.5, 138.1,
137.5, 133.4, 133.1, 128.9, 128.9, 128.5, 128.3, 128.1, 127.8,
127.3, 67.6, 65.9, 60.4, 52.4 (2C); IR (neat): n=3370, 3060,
3025, 2955, 2914, 1737, 1678, 1596, 1492, 1448, 1435, 1384,
1260, 1217, 1179, 1129, 1091, 1014, 828, 770, 699 cmÀ1; HR-
MS (CI): m/z=420.1356 (M+H)+, calcd. for C25H23ClNO3:
420.1366.
Methyl
(2S,3R,4S,5R)-4-benzoyl-3-(4-chlorophenyl)-5-
phenylpyrrolidine-2-carboxylate (4c): yellow solid; yield:
176 mg (84%); mp: 115–1178C; 1H NMR (CDCl3,
500 MHz): d=7.52–7.50 (m, 2H), 7.38–7.35 (m, 1H), 7.31–
7.25 (m, 4H), 7.23–7.20 (m, 2H), 7.09–7.02 (m, 5H), 4.97 (d,
J=9.0 Hz, 1H), 4.47–4.44 (m, 1H), 4.14–4.08 (m, 2H), 3.70
(s, 3H), 3.00 (brs, NH); 13C NMR (CDCl3, 125 MHz): d=
198.1, 173.2, 139.2, 139.0, 137.3, 132.9, 132.9, 129.2, 128.9,
128.3, 128.1, 128.0, 127.7, 127.5, 67.4, 66.4, 60.7, 52.3, 51.6;
IR (neat): n=3354, 3088, 3056, 3018, 2952, 2927, 1737, 1679,
1597, 1493, 1448, 1434, 1373, 1333, 1261, 1217, 1178, 1129,
1092, 1014, 825, 755, 719, 698 cmÀ1; HR-MS (CI): m/z=
420.1362 (M+H)+, calcd. for C25H23ClNO3: 420.1366.
Methyl
(2S,3R,4S,5R)-4-benzoyl-5-(4-fluorophenyl)-3-
phenylpyrrolidine-2-carboxylate (4h): yellow solid; yield:
Methyl
(2S,3R,4S,5R)-4-benzoyl-3-(3-chlorophenyl)-5-
1
200 mg (99%); mp 164–1678C; H NMR (CDCl3, 500 MHz):
phenylpyrrolidine-2-carboxylate (4d): yellow solid; yield:
d=7.54–7.53 (m, 2H), 7.41–7.30 (m, 5H), 7.27–7.21 (m,
3H), 7.10–7.08 (m, 2H), 6.78–6.74 (m, 2H), 4.98 (d, J=
9.0 Hz, 1H), 4.51–4.48 (m, 1H), 4.18–4.11 (m, 2H), 3.72 (s,
3H), 2.95 (brs, NH); 13C NMR (CDCl3, 125 MHz): d=198.5,
173.5, 162.2 (d, J=245.0 Hz), 140.6, 137.5, 135.2 (d, J=
2.5 Hz), 133.1, 129.2 (d, J=7.5 Hz), 128.9, 128.4, 128.1,
127.9, 127.3, 115.1 (d, J=21.3 Hz), 67.6, 65.9, 60.5, 52.4,
52.4; IR (neat): n=3351, 3060, 3022, 2952, 2917, 1735, 1674,
1600, 1509, 1447, 1435, 1384, 1353, 1326, 1262, 1219, 1180,
1158, 1130, 1077, 1013, 986, 836, 823, 760, 699, 687, 605, 533,
512 cmÀ1; HR-MS (CI): m/z=404.1625 (M+H)+, calcd. for
C25H23FNO3: 404.1662.
1
185 mg (99%); mp 117–1208C; H NMR (CDCl3, 500 MHz):
d=7.52–7.51 (m, 2H), 7.38–7.35 (m, 2H), 7.26–7.17 (m,
5H), 7.09–7.02 (m, 5H), 4.97 (d, J=9.0 Hz, 1H), 4.48–4.45
(m, 1H), 4.15–4.08 (m, 2H), 3.71 (s, 3H), 3.02 (brs, NH);
13C NMR (CDCl3, 125 MHz): d=198.1, 173.1, 142.8, 139.1,
137.3, 134.5, 132.9, 130.1, 128.3, 128.2, 128.1, 127.9, 127.7,
127.5, 127.4, 126.3, 67.4, 66.5, 60.6, 52.4, 51.9; IR (neat): n=
3354, 3060, 3031, 2942, 2914, 1737, 1679, 1597, 1573, 1479,
1448, 1435, 1384, 1331, 1259, 1217, 1179, 1129, 1083, 755,
725, 696 cmÀ1; HR-MS (CI): m/z=420.1343 (M+H)+, calcd.
for C25H23ClNO3: 420.1366.
Methyl
(2S,3R,4S,5R)-4-benzoyl-3-(2-chlorophenyl)-5-
Methyl
(2S,3R,4S,5R)-4-benzoyl-5-(3-bromophenyl)-3-
phenylpyrrolidine-2-carboxylate (4e): light yellow solid;
phenylpyrrolidine-2-carboxylate (4i): yellow solid; yield:
1
1
198 mg (99%); mp: 99–1028C; H NMR (CDCl3, 500 MHz):
227 mg (98%); mp 126–1308C: H NMR (CDCl3, 500 MHz):
d=7.52–7.49 (m, 3H), 7.40–7.38 (m, 1H), 7.37–7.34 (m,
1H), 7.31–7.28 (m, 1H), 7.22–7.18 (m, 3H), 7.13–7.11 (m,
2H), 7.07–7.00 (m, 3H), 4.96 (d, J=8.5 Hz, 1H), 4.62 (dd,
J=8.0, 7.0 Hz, 1H), 4.53 (dd, J=8.5, 7.0 Hz, 1H), 4.22 (d,
J=8.0 Hz, 1H), 3.78 (s, 3H), 3.17 (brs, NH); 13C NMR
(CDCl3, 125 MHz): d=199.3, 173.4, 138.5, 138.5, 137.5,
134.6, 132.8, 130.2, 128.5, 128.4, 128.3, 128.2, 128.2, 127.8,
127.4, 127.4, 66.7, 66.3, 59.2, 52.6, 50.0; IR (neat): n=3348,
3066, 3028, 2952, 2923, 1737, 1679, 1596, 1478, 1448, 1435,
1384, 1332, 1262, 1218, 1180, 1128, 1036, 755, 699 cmÀ1; HR-
d=7.54–7.52 (m, 2H), 7.42–7.15 (m, 10H), 7.1–7.09 (m,
1H), 6.96–6.93 (m, 1H), 4.92 (d, J=9.0 Hz, 1H), 4.51–4.48
(m, 1H), 4.17 (d, J=9.0 Hz, 1H), 4.12–4.09 (m, 1H), 3.72 (s,
3H), 3.09 (brs, NH); 13C NMR (CDCl3, 125 MHz): d=198.4,
173.2, 141.7, 140.6, 137.5, 133.1, 130.8, 130.7, 129.8, 128.9,
128.5, 128.1, 127.8, 127.3, 125.9, 122.2, 67.6, 65.8, 60.2, 52.4,
52.2; IR (neat): n=3373, 3066, 3028, 2946, 1738, 1679, 1596,
1448, 1435, 1384, 1256, 1216, 1178, 757, 692 cmÀ1; HR-MS
(CI): m/z=464.0853 (M+H)+, calcd. for C25H23BrNO3:
464.0861.
Adv. Synth. Catal. 2016, 358, 984 – 993
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991

UPDATES
Jian-Yuan Li et al.
Methyl (2S,3R,4S,5R)-4-benzoyl-5-(4-chlorophenyl)-3-(p-
tolyl)pyrrolidine-2-carboxylate (4j): light yellow solid; yield:
199 mg (92%); mp 155–1578C; H NMR (CDCl3, 500 MHz):
1.5 Hz, 1H), 6.72–6.69 (m, 2H), 5.26 (d, J=8.5 Hz, 1H),
4.53–4.50 (m, 1H), 4.19–4.14 (m, 2H), 3.71 (s, 3H), 3.10
(brs, NH); 13C NMR (CDCl3, 125 MHz): d=197.6, 173.3,
143.2, 140.4, 137.4, 133.1, 128.9, 128.5, 128.2, 127.9, 127.2,
126.6, 125.5, 124.8, 67.3, 61.8, 60.3, 52.4, 51.6; IR (neat): n=
3367, 3066, 3018, 2952, 2920, 1736, 1679, 1448, 1435, 1384,
1272, 1234, 1215, 1179, 760, 699 cmÀ1; HR-MS (CI): m/z=
392.1302 (M+H)+, calcd. for C23H22NO3S: 392.1320.
1
d=7.55–7.53 (m, 2H), 7.41–7.38 (m, 1H), 7.27–7.23 (m,
4H), 7.12–7.11 (m, 2H), 7.06–7.02 (m, 4H), 4.94 (d, J=
8.5 Hz, 1H), 4.50–4.47 (m, 1H), 4.15–4.05 (m, 2H), 3.71 (s,
3H), 3.00 (brs, NH), 2.29 (s, 3H); 13C NMR (CDCl3,
125 MHz): d=198.5, 173.5, 138.2, 137.5, 137.4, 136.9, 133.3,
133.1, 129.6, 128.9, 128.5, 128.3, 128.1, 127.7, 67.6, 65.8, 60.4,
52.3, 52.1, 21.1; IR (neat): n=3364, 3060, 3018, 2952, 2927,
2860, 1736, 1679, 1596, 1515, 1491, 1448, 1435, 1384, 1259,
1217, 1178, 1114, 1092, 1014, 816, 757, 690 cmÀ1; HR-MS
(CI): m/z=434.1504 (M+H)+, calcd. for C26H25ClNO3:
434.1523.
Methyl
(2S,3R,4S,5R)-4-benzoyl-5-(thiophen-2-yl)-3-(p-
tolyl)pyrrolidine-2-carboxylate (4o): yellow solid; yield:
198 mg (98%); mp: 151–1548C; 1H NMR (CDCl3,
500 MHz): d=7.67–7.65 (m, 2H), 7.43–7.40 (m, 1H), 7.30–
7.22 (m, 4H), 7.11–7.09 (m, 2H), 6.99–6.98 (m, 1H), 6.70–
6.68 (m, 2H), 5.23 (d, J=8.5 Hz, 1H), 4.50–4.47 (m, 1H),
4.15–4.10 (m, 2H), 3.69 (s, 3H), 2.99 (brs, NH), 2.27 (s, 3H);
13C NMR (CDCl3, 125 MHz): d=197.7, 173.3, 143.3, 137.4,
137.3, 136.7, 133.0, 129.5, 128.4, 128.2, 127.7, 126.6, 125.4,
124.7, 67.2, 61.7, 60.3, 52.3, 51.3, 21.1; IR (neat): n=3366,
3065, 3019, 2951, 2920, 1736, 1678, 1447, 1434, 1384, 1261,
Methyl (2S,3R,4S,5R)-4-benzoyl-3,5-bis(4-chlorophenyl)-
pyrrolidine-2-carboxylate (4k): light yellow solid; yield:
1
218 mg (96%); mp 123–1268C; H NMR and 13C NMR spec-
tra for this compound are consistent with previously report-
ed literature data;[7,11] 1H NMR (CDCl3, 500 MHz): d=7.56–
7.54 (m, 2H), 7.45–7.41 (m, 1H), 7.31–7.27 (m, 6H), 7.05–
7.02 (m, 4H), 4.95 (d, J=8.5 Hz, 1H), 4.61 (t, J=8.5 Hz,
1H), 4.14–4.07 (m, 2H), 3.72 (s, 3H), 2.95 (brs, NH);
13C NMR (CDCl3, 125 MHz): d=197.8, 173.2, 138.7, 138.1,
137.3, 133.5, 133.3, 133.1, 129.3, 129.1, 128.9, 128.6, 128.3,
128.1, 67.3, 65.5, 60.5, 52.5, 51.3; IR (neat): n=3345, 3066,
3022, 2946, 2917, 1736, 1678, 1596, 1492, 1448, 1435, 1412,
1216, 1177, 1017, 760, 699 cmÀ1
; HR-MS (CI): m/z=
406,1487 (M+H)+, calcd. for C24H24NO3S: 406.1477.
Acknowledgements
1384, 1258, 1218, 1179, 1129, 1092, 1014, 824, 771, 693 cmÀ1
;
HR-MS (CI): m/z=454.0942 (M+H)+, calcd. for
C25H22Cl2NO3: 454.0977.
This work was supported by the National Research Founda-
tion of Korea (NRF) grant funded by the Korea government
(MSIP) (NRF-2015R1A5A1008958). We thank Dr. Karl Dria
at Indiana University Purdue University Indianapolis
(IUPUI) for his assistance with spectral analysis.
Methyl (2S,3R,4S,5R)-4-benzoyl-3-(4-chlorophenyl)-5-(4-
fluorophenyl)pyrollidine-2-carboxylate (4l): yellow solid;
yield: 208 mg (95%); mp 154–1588C; 1H NMR (CDCl3,
500 MHz): d=7.54–7.53 (m, 2H), 7.43–7.40 (m, 1H), 7.31–
7.25 (m, 6H), 7.08–7.05 (m, 2H), 6.77–6.74 (m, 2H), 4.97 (d,
J=4.0 Hz, 1H), 4.46–4.43 (m, 1H), 4.14–4.09 (m, 2H), 3.72
(s, 3H), 2.75 (brs, NH); 13C NMR (CDCl3, 125 MHz): d=
198.0, 173.3, 162.2 (d, J=246.3 Hz), 138.9, 137.4, 135.3 (d,
J=2.5 Hz), 133.2, 133.1, 129.3, 129.2 (d, J=6.3 Hz), 129.1,
128.5, 128.1, 115.1 (d, J=21.3 Hz), 67.3, 65.6, 60.6, 52.4,
51.4; IR (neat): n=3352, 3059, 3022, 3018, 2951, 2926, 1736,
1674, 1508, 1492, 1448, 1434, 1219, 1179, 1092, 1014, 759,
699 cmÀ1; HR-MS (CI): m/z=438.1282 (M+H)+, calcd. for
C25H22ClFNO3:438.1272.
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