Multiple absolute stereocontrol in Pd-catalyzed [3+2] cycloaddition of oxazolidinones and trisubstituted alkenes using chiral ammoniumphosphine hybrid ligands

Article abstract of DOI:10.1246/bcsj.20160053

The development of a Pd-catalyzed highly enantio- and diastereoselective [3+2] cycloaddition of 5-vinyloxazolidinones and activated trisubstituted alkenes is described in detail. This protocol for the single-step construction of densely functionalized pyrrolidines with three contiguous stereocenters including vicinal quaternary stereocenters depends on the remarkable ability of phosphine ligands possessing a chiral ammonium ion to promote intermolecular cycloaddition reactions with a precise control of absolute stereochemistry. A series of control experiments show that a chiral ammoniumphosphine hybrid ligand enabled the individual, yet simultaneous stereocontrol of each chiral center in the annulation reaction. The reaction mechanism is also discussed with particular focus on the stereodetermining processes.

Full text of DOI:10.1246/bcsj.20160053

BCSJ Award Article
Multiple Absolute Stereocontrol in Pd-Catalyzed [3+2] Cycloaddition
of Oxazolidinones and Trisubstituted Alkenes Using
Chiral Ammonium-Phosphine Hybrid Ligands
Naomichi Imagawa,1 Yuya Nagato,1 Kohsuke Ohmatsu,1 and Takashi Ooi*1,2
1Institute of Transformative Bio-Molecules (WPI-ITbM), and Graduate School of Engineering, Nagoya University,
Nagoya, Aichi 464-8601
2CREST, Japan Science and Technology Agency (JST), Nagoya, Aichi 464-8601
E-mail: tooi@apchem.nagoya-u.ac.jp
Received: February 16, 2016; Accepted: February 26, 2016; Web Released: March 4, 2016
Takashi Ooi
Takashi Ooi received his B.S. in 1989 and his Ph.D. in 1994 from Nagoya University under the guidance of
Prof. H. Yamamoto. After postdoctoral work with Prof. J. Rebek, Jr. (MIT, Cambridge), he joined the group of
Prof. K. Maruoka in Hokkaido University as an assistant professor in 1995, became a lecturer in 1998, and
then moved to Kyoto University as an associate professor in 2001. In 2006, he moved to Nagoya University
as a full professor. Since 2013, he has been a principle investigator at the Institute of Transformative Bio-
Molecules (WPI-ITbM) in Nagoya University.
Abstract
tion mediated by a zwitterionic π-allylpalladium intermedi-
ate offers a powerful tool for the stereoselective synthesis of
highly substituted carbocycles and heterocycles.7 The prom-
inent feature of this methodology is that it allows the facile
construction of multiple stereocenters in a single synthetic
operation. An increase in the number of target stereogenic
centers and the complexity of molecular scaffolds make this
type of transformation more valuable, yet more difficult with
respect to absolute stereocontrol. In fact, while the development
of catalytic stereoselective cycloaddition reactions that enable
the installation of three or more contiguous stereocenters is in
demand, viable strategies to address this challenge have been
limited.8-15
The Pd-catalyzed [3+2] cycloaddition of 5-vinyloxazolidi-
nones and activated trisubstituted alkenes16 provides a straight-
forward method to construct highly functionalized pyrrolidines,
a ubiquitous core structure of natural products and pharma-
ceuticals.17-19 When readily accessible, differently trisubstitut-
ed alkenes are used as the coupling partner for the cyclo-
addition, the initial intermolecular addition of allylpalladium
species to the alkene generates a zwitterionic intermediate
possessing a trisubstituted prochiral carbanion site (Figure 1).
At the same time, this intermediate is endowed with a 1,1-
disubstituted allylpalladium moiety by using vinyloxazolidi-
nones with a tetrasubstituted chiral carbon. The subsequent
The development of a Pd-catalyzed highly enantio- and
diastereoselective [3+2] cycloaddition of 5-vinyloxazolidi-
nones and activated trisubstituted alkenes is described in detail.
This protocol for the single-step construction of densely
functionalized pyrrolidines with three contiguous stereocenters
including vicinal quaternary stereocenters depends on the
remarkable ability of phosphine ligands possessing a chiral
ammonium ion to promote intermolecular cycloaddition reac-
tions with a precise control of absolute stereochemistry. A
series of control experiments show that a chiral ammonium-
phosphine hybrid ligand enabled the individual, yet simulta-
neous stereocontrol of each chiral center in the annulation reac-
tion. The reaction mechanism is also discussed with particular
focus on the stereodetermining processes.
Introduction
Efficient access to complex chiral molecules from simple
materials represents one of the most important objectives in
organic synthesis; numerous efforts have been devoted to the
development of reliable and general methods instrumental in
addressing this issue.1-6 Among the approaches based on
transition-metal catalysis, Pd-catalyzed asymmetric cycloaddi-
Bull. Chem. Soc. Jpn. 2016, 89, 649–656 | doi:10.1246/bcsj.20160053
© 2016 The Chemical Society of Japan | 649

discrimination of prochiral face
of trisubstituted alkene and carbanion
R2
+
R1
R2
R2
R3
[Pd]
R1
R1
R1
R2
R3
R3
R4
R3
R5N
O
R5N
PdL
R4
R4
R5N
R5N
O
PdL
R4
racemic
control of planar chirality
of π-allylpalladium
Figure 1. Multiple stereocontrol in Pd-catalyzed [3+2] cycloaddition of 5-vinyloxazolidinones and trisubstituted alkenes.
Table 1. Optimization of catalytic system for cycloaddition
of 5-vinyloxazolidinone 3 and benzylidenemalononitrile 4a)
ring-closing bond formation between these two reactive sites
gives rise to a cyclic product with three contiguous chiral
carbons including two quaternary carbons. A main obstacle to
achieve this type of annulation reaction in an asymmetric
manner is the need of three simultaneous stereocontrols: (i)
enantiofacial discrimination of the trisubstituted alkene, (ii)
recognition of the prochiral face of the trisubstituted carbanion
site of the zwitterionic intermediate, and (iii) control of the
chirality of its π-allylpalladium moiety.20,21 To establish a
cycloaddition protocol involving such a multiple stereocontrol,
a new type of phosphine ligand bearing a chiral ammonium ion
component was designed; upon coordination to the Pd center,
this was expected to precisely recognize the remote anionic
site of the zwitterionic intermediate through ion pairing. In this
article, we describe a detailed study on the development of
a Pd-catalyzed highly enantio- and diastereoselective [3+2]
cycloaddition of 5-vinyloxazolidinones and activated trisub-
stituted alkenes based on the judicious utilization of the unique
properties of chiral ammonium-phosphine hybrid ligands.22,23
[Pd2(dba)3]·CHCl3
(Pd 2.5 mol%)
ligand (5 mol%)
O
Ph
CN
CN
O
NosN
CN
CN
NosN
+
Ph
toluene, r.t., 1 h
3
4
5
(Nos = 4-NO2C6H4SO2)
Ar1
X
Me
X
Me3N
N
Ph2P
Ar22P
1·X
Ar1
2a·X (Ar1 = Ar2 = Ph)
2b·X (Ar1
2c·X (Ar1
2d·X (Ar1
Ar2
= β-Naph,
= Ph,
= Ph)
Ar2
= 4-CF3C6H4)
Ar2
= β-Naph,
= 4-CF3C6H4)
Entry
Ligand
Yield/%b)
ee/%c)
Results and Discussion
1
2d)
3
4
5
6
7
8
9
PPh3
PPh3
1¢Br
1¢OAc
2a¢Br
2b¢Br
2c¢Br
2d¢Br
2d¢Cl
2d¢I
43
79
99
49
94
99
99
99
99
99
99
®
®
®
®
63
63
57
75
72
90
92
Our initial study was focused on the identification of an
effective ligand for promoting the Pd-catalyzed asymmetric
[3+2] cycloaddition. To this end, we selected N-(4-nitrobenze-
nesulfonyl)-5,5-divinyloxazolidin-2-one (3) and 2-benzylidene-
malononitrile (4) as the model substrates. The reaction between
these substrates would provide a suitable platform to verify our
hypothesis that chiral ammonium phosphines act as a ligand
that could control the absolute stereochemistry in the addition
of the anionic site of the allylpalladium intermediate generated
from 3 to prochiral 4.
10
11e)
2d¢I
First, we investigated the reaction of 3 with 4 under the influ-
ence of the catalyst prepared in situ from tris(dibenzylidene-
acetone)dipalladium-chloroform complex ([Pd2(dba)3]¢CHCl3)
and triphenylphosphine (PPh3) in toluene at room temperature.
After 1 h of stirring, the desired pyrrolidine 5 was obtained in
moderate yield (Table 1, Entry 1). The insufficient reactivity
can be attributed to the reluctant addition of the sulfonamide
ion moiety of the zwitterionic allylpalladium to 4, probably
because of the internal association of this weak nitrogen
nucleophile with the cationic Pd center (Figure 2). This unpro-
ductive interaction could be suppressed by the addition of
an external anion that has a strong coordinating ability to Pd
such as a halide ion,24 as previously observed by Knight
and Aggarwal in related reaction systems.16,25 Indeed, in the
a) Unless otherwise noted, reactions were carried out with 0.10
mmol of 3 and 0.12 mmol of 4 in the presence of [Pd2(dba)3]¢
CHCl3 (Pd, 2.5 mol %) and ligand (5 mol %) in 1.0 mL of tolu-
ene at room temperature for 1 h. b) Isolated yield. c) Deter-
mined by HPLC analysis. d) Performed with 5 mol % of
TBAB. e) Carried out at 0 °C for 3 h.
presence of a catalytic amount of tetrabutylammonium bromide
(TBAB), the cycloaddition proceeded much faster under other-
wise identical conditions, affording 5 in 79% yield (Entry 2).
This observation led us to envision further reactivity enhance-
ment by the use of a phosphine ligand incorporating a qua-
ternary ammonium halide component in view of not only
assisting the preferable halide-Pd contact, but also recognizing
650 | Bull. Chem. Soc. Jpn. 2016, 89, 649–656 | doi:10.1246/bcsj.20160053
© 2016 The Chemical Society of Japan

NC
Ph
internal association
CN
CN
Ph
PdLn
PdLn
Pd0
CN
slow
NosN
NosN
O
O
NosN
n-Bu4N
NC
CN
Pd0
n-Bu4NBr
Br
Ph
Br
CN
n-Bu4N
Ph
NosN
PdLn
CN
fast
PdLn
NosN
Figure 2. Effect of halide ion.
the anionic site via facile pairing with the ammonium ion.
Therefore, the performance of o-diphenylphosphinobenzyl-
ammonium bromide 1¢Br was evaluated as a ligand.26-29 As
expected, the bond formation was completed within 1 h, afford-
ing 5 quantitatively (Entry 3). Notably, switching the bromide
ion of the ligand to acetate ion caused a substantial decrease in
the reactivity, reinforcing the assumption that the coordinat-
ing ability of the anion is crucial for the catalytic efficiency
(Entry 4). These findings showed that o-diarylphosphino-
benzylammonium halide is a core structure requisite for effec-
tive ligands for promoting the zwitterionic allylpalladium-
mediated cycloaddition. With this information, we sought to
develop chiral ammonium phosphines capable of rigorously
discriminating the prochiral faces of 4 in the conjugate addition
stage of annulation. For this purpose, we chose to introduce a
chiral 1,1¤-binaphthyl-derived azepinium skeleton30 into the
ammonium ion component and fortunately found that 2a¢Br
with simple phenyl appendages at both the 3,3¤-positions of the
binaphthyl unit (Ar1) and phosphorus center (Ar2) induced an
appreciable level of enantiocontrol on 5 without detrimental
effect on the reactivity profile (Entry 5). Subsequent structural
modifications of the aromatic substituents showed that chiral
ammonium phosphine 2d¢Br is a promising candidate for
further optimization (Entries 5-8). Then, we examined the
effect of the identity of halide ion on the competence of the
ligand for stereocontrol. Interestingly, while the use of chloride
variant 2d¢Cl subtly affected the selectivity (Entry 9), a
dramatic improvement in enantioselectivity was attained when
the counter ion was exchanged to iodide 2d¢I (Entry 10). This
indicates the intimate contact of the halide ion with the
positively charged Pd center in the transition state and also
highlights a distinct feature of the chiral ammonium phosphine
ligands. Finally, lowering the reaction temperature to 0 °C
increased the enantioselectivity to 92% ee (Entry 11).
pyrrolidine 7 in good yield (Scheme 1a). This result suggested
that the relative stereochemistry of C(2) and C(3) stereocenters
in 7 originated from the geometry of the starting alkene 6a.
Thus, considering the capability of 2d¢I to precisely discrim-
inate prochiral 6a, we assumed that the use of this chiral ligand
would lead to the formation of stereochemically homogeneous
7. In fact, the reaction of 3 with 6a under the optimized
conditions with 2d¢I as the ligand resulted in the quantitative
production of diastereomerically pure 7 with high enantio-
selectivity. Meanwhile, we interrogated the potential ability of
2d¢I to control the planar chirality of the π-allylpalladium by
subjecting a combination of racemic 5-methyl-5-vinyloxazoli-
dinone 8a and 2-methylidenemalonate 9 to similar annulation.
This trial stereoconvergently produced pyrrolidine 10 with
high efficiency and enantioselectivity (Scheme 1b). These data
manifested the possibility that chiral ammonium phosphine
2d¢I would pave the way to individual, yet simultaneous abso-
lute stereocontrol in multiple bond-forming events in asym-
metric cycloaddition reactions.
From this standpoint, we assessed the viability of the asym-
metric construction of three contiguous stereocenters including
vicinal all-carbon quaternary stereocenters8,12,31-35 through the
[3+2] annulation of racemic 5-vinyloxazolidinone 8a and 2-
cyano-3-phenylacrylate 6a (Table 2). Thus, the reaction of 8a
with 6a catalyzed by [Pd2(dba)3]¢CHCl3 and 2d¢I in toluene
at 0 °C furnished the desired densely substituted pyrrolidine
11a in an almost stereochemically pure form (Entry 1).36 Then,
several control experiments were carried out to figure out
the crucial elements for the catalytic system to facilitate this
cycloaddition with satisfactory levels of efficiency and multiple
stereocontrol. As shown in Table 2, the reaction of 8a with 6a
using tris(4-trifluoromethyl)phenylphosphine as the ligand in
the presence of chiral ammonium bromide 1237 proceeded at
room temperature to afford 11a quantitatively, but as a 1:1 mix-
ture of diastereomers of low enantiopurity (Entry 2). Important
comparison was that the annulation with the same phosphine
ligand in the absence of 12 showed no indication of the product
formation (Entry 3). While the combined use of common
chiral phosphine ligands, such as MOP38 (13) or BINAP39 (14)
with TBAB was ineffective in promoting the cycloaddition
(Entry 4) or inducing stereoselectivity (Entry 5), BINOL-
derived phosphoramidite40,41 15 could impart sufficient cata-
With the optimal ligand 2d¢I and reaction conditions, we
turned our attention to the stereoselective construction of con-
secutive tertiary and all-carbon quaternary stereocenters with a
trisubstituted alkene bearing different geminal substituents as
the substrate. We initially attempted the reaction of oxazolidi-
none 3 with (E)-ethyl 2-cyano-3-phenylacrylate (6a) under the
catalysis of the Pd complex bearing an achiral ligand 1¢Br
at room temperature, which afforded diastereomerically pure
Bull. Chem. Soc. Jpn. 2016, 89, 649–656 | doi:10.1246/bcsj.20160053
© 2016 The Chemical Society of Japan | 651

a
[Pd2(dba)3]·CHCl3
(Pd 2.5 mol%)
O
Ph
NosN
CN
CO2Et
O
ligand (5 mol%)
NosN
CN
CO2Et
+
Ph
toluene
3
7
6a (3 equiv)
with 1·Br at r.t., 24 h: 75% yield, dr = >20:1
with 2d·I at 0 °C, 24 h: 99% yield, dr = >20:1, 93% ee
b
O
[Pd2(dba)3]·CHCl3
(Pd 2.5 mol%)
2d·I (5 mol%)
CO2t-Bu
CO2t-Bu
Me
O
NosN
CO2t-Bu
CO2t-Bu
9 (3 equiv)
NosN
Me
+
toluene
8a
racemic
0 °C, 8 h
10
99% yield, 94% ee
Scheme 1. Examinations of individual absolute stereocontrol.
lytic activity to the corresponding Pd complex (Entry 6).12
However, the observed poor stereoselectivity could not be
improved by a further screening of structurally different chiral
phosphoramidites. These results emphasize the critical impor-
tance of the molecular architecture of 2¢X that features the tri-
arylphosphine incorporating chiral ammonium ion component
paired with an appropriate halide ion for achieving an other-
wise difficult multiple stereocontrol in the Pd-catalyzed [3+2]
cycloaddition.
Table 2. Attempt at asymmetric construction of contiguous
all-carbon quaternary stereocentersa)
[Pd2(dba)3]·CHCl3
O
Ph
NosN
CN
CO2Et
Me
(Pd 2.5 mol%)
ligand (5 mol%)
additive (5 mol%)
O
NosN
CN
CO2Et
Me
Ph
+
toluene
0 °C, 10 h
8a
racemic
6a
11a
Next, the substrate scope of this asymmetric [3+2] cyclo-
addition of racemic 5-vinyloxazolidinones 8 and geometrically
pure trisubstituted alkenes 6 was explored, and the representa-
tive results are listed in Figure 3. In the reactions of 8a with 2-
cyanoacrylates 6 possessing aromatic or heteroaromatic sub-
stituents at the 3-positions, excellent chemical yield and almost
complete enantio- and diastereoselectivity were uniformly
observed (11b-11e). A significant variation in the structure of
the 5-alkyl substituent of 8 was feasible, and the corresponding
cycloadducts were obtained in a virtually stereochemically pure
form 11f-11i. The reaction also tolerated the 5-aromatic groups
on 8, producing N-protected pyrrolidines 11j-11l quantitatively
with high levels of relative and absolute stereocontrol.36
To further expand the potential of our strategy for multiple
absolute stereocontrol, the annulation reactions of oxazolidi-
nones with a geometrical mixture of trisubstituted alkenes
were investigated in detail. We reasoned that, if the absolute
stereochemistry in the construction of C(3) chiral carbon of
annulation product can be established individually by the virtue
of chiral ammonium-phosphine ligand 2d¢I (Figure 4), this
ligand-controlled catalysis would override the geometrical
nature of trisubstituted alkenes. For obtaining a vital clue to
validate this possibility, the cycloaddition of oxazolidinone 3
and ethyl 2-cyanoacrylate (16) was performed. Although a
complex mixture was obtained due to the strong tendency of 16
towards polymerization, the desired pyrrolidine 17 was isolated
in 25% yield with moderate enantioselectivity (Scheme 2).
The observed asymmetric induction could be accounted for
by assuming the doubly ion-pairing intermediate, where the
β-Naph
Br
OMe
PPh2
n-Bu
n-Bu
N
β-Naph
12
13
Ph
PPh2
PPh2
O
Me
P
N
O
Me
Ph
14
15
Entry Ligand
2d¢I
Additive Yield/%b) drc)
ee/%d)
1
®
98
99
0
trace
13
95
>20:1
98/nd
14/¹33
®
2e) P(4-CF3C6H4)3 12
1:1
®
3e) P(4-CF3C6H4)3
4e) 13
®
TBAB
TBAB
TBAB
®
1:1.9
®
<1/<1
5e),f) 14
6e) 15
1:1.2 ¹15/¹23
a) Unless otherwise noted, reactions were carried out with 0.10
mmol of 8a and 0.30 mmol of 6a in the presence of [Pd2(dba)3¢
CHCl3] (Pd, 2.5 mol %), ligand (5 mol %), and additive
(5 mol %) in 1.0 mL of toluene at 0 °C for 10 h. b) Isolated
yield. c) Determined based on 1H NMR analysis of crude
reaction mixture. d) Determined by HPLC analysis. nd: not
detected. e) Carried out at r.t. for 24 h. f) With 2.5 mol % of 14.
652 | Bull. Chem. Soc. Jpn. 2016, 89, 649–656 | doi:10.1246/bcsj.20160053
© 2016 The Chemical Society of Japan

conformation of the C(3) carbanion is controlled by the ligand,
particularly the chiral ammonium ion component.
Based on this prospect, this catalytic system was applied to
the reactions of racemic 5-vinyloxazolidinones 8 with 2-nitro-
3-arylacrylates 18 that are difficult to prepare in a geometrically
pure form because of their facile E/Z isomerization (Table 3).
Initially, the cycloaddition of 8a and ethyl 2-nitro-3-phenyl-
acrylate (18a; E/Z = 1:2) was attempted using achiral ammo-
nium phosphine 1¢Br. The reaction turned out to be sluggish
even at room temperature, furnishing cycloadduct 19a in low
yield and as a 5:8:3:1 mixture of four diastereomers (Entry 1).
This indicates the difficulty of controlling the stereochemical
outcome of this cycloaddition. In contrast, however, the use of
2d¢I as the ligand led to the quantitative formation of 19a with
high diastereo- (11:1.4:1:<1) and excellent enantioselectivity
(95% ee) (Entry 2). It should be noted that the E/Z ratio of the
remaining 18a was confirmed to be almost unchanged. These
observations demonstrate the inherent power of chiral ammo-
nium phosphine 2d¢I for enabling efficient individual absolute
stereocontrol over the array of three contiguous stereocenters
in the single annulation. Further experiments were carried out
to probe the scope of this protocol. With respect to 2-nitro-
acrylates 18, the incorporation of diverse 3-aryl substituents
including fused and heteroaromatic substituents was tolerated,
and the corresponding pyrrolidines were obtained almost quan-
titatively with high diastereo- and enantioselectivity (Entries 3-
6). The reaction accommodated oxazolidinones with various 5-
alkyl substituents without a considerable loss of chemical yield
and stereoselectivity (Entries 7-11). Moreover, 5-aryloxazoli-
dinones were also employable with a similar degree of effi-
ciency and diastereoselectivity, albeit a certain decrease in
enantioselectivity was detected (Entries 12-14).
O
R2
NosN
CN
CO2Et
R1
[Pd2(dba)3]·CHCl3
(Pd 2.5 mol%)
O
NosN
CN
CO2Et
R1
+
2d·I
(5 mol%)
R2
toluene
(temp., time)
8
6
11
(3 equiv)
racemic
Br
MeO
CN
CN
CN
CO2Et
CO2Et
CO2Et
NosN
NosN
NosN
Me
Me
Me
11b (0 °C, 10 h)
11c (0 °C, 10 h)
11d (0 °C, 10 h)
99% yield, dr = 17:1
97% ee
99% yield, dr = >20:1
99% ee
94% yield, dr = >20:1
99% ee
O
Ph
Ph
CN
CN
CN
CO2Et
CO2Et
CO2Et
NosN
NosN
NosN
Me
Et
11e (0 °C, 10 h)
11f (0 °C, 10 h)
11g (0 °C, 10 h)
99% yield, dr = >20:1
97% ee
99% yield, dr = >20:1
98% ee
99% yield, dr = >20:1
99% ee
As clearly shown by this study, chiral ammonium-phosphine
hybrid ligand 2d¢I played a pivotal role in achieving rigorous
multiple absolute stereocontrol over the [3+2] annulation
reaction. Among the critical stereodetermining events involved
in the asymmetric five-membered ring construction, the C(2)
and C(3) stereocenters of the resulting pyrrolidine framework
would be determined through the enantiofacial discrimination
of the starting trisubstituted alkene in the aza-Michael addi-
tion and of the subsequently generated carbanion in the ring-
closing step, respectively (Figure 1). With regard to the C(4)
stereocenter derived from the C(5) chiral carbon of racemic
oxazolidinone, however, two possible scenarios existed for the
stereoconvergent establishment of this stereocenter (Figure 5):
(i) It was installed through the isomerization of planar chiral π-
allylpalladium via π-σ-π interconversion; (ii) racemic oxazo-
lidinone was directly transformed into a single stereoisomer of
π-allylpalladium intermediate through direct enantioconvergent
mechanism, where one enantiomer of oxazolidinone undergoes
an anti-SN2¤-type addition pathway, and the other reacts via a
syn-SN2¤ pathway.42
Ph
Ph
Ph
CN
CN
CN
CO2Et
NosN
CO2Et
NosN
CO2Et
NosN
Ph
Ph
11h (0 °C, 24 h)
11i (r.t., 96 h)
11j (r.t., 40 h)
99% yield, dr = >20:1
95% ee
70% yield, dr = >20:1
94% ee
99% yield, dr =9.8:1
93% ee
[Pd2(dba)3]·CHCl3
(Pd 5mol%)
2d·I
(10 mol%)
Ph
Ph
CN
CN
CO2Et
CO2Et
NosN
NosN
Cl
OMe
11k (r.t., 40 h)
11l (r.t., 40 h)
94% yield, dr = 8.6:1
94% ee
97% yield, dr = 9.3:1
95% ee
Figure 3. Substrate scope of catalytic asymmetric [3+2]
cycloaddition of oxazolidinones 8 and 2-cyanoacrylates 6.
*
O
R2
R3 Me
R1
NosN
[Pd2(dba)3]·CHCl3
2d·I
R2
O
N
NosN
R1
+
R3
R4
toluene
I
R4
[Pd]
P
Figure 4. Individual stereocontrol in the construction of C(3) chiral carbon.
Bull. Chem. Soc. Jpn. 2016, 89, 649–656 | doi:10.1246/bcsj.20160053
© 2016 The Chemical Society of Japan | 653

O
[Pd2(dba)3]·CHCl3
(Pd 2.5 mol%)
2d·I (5 mol%)
CN
CO2Et
O
CN
CO2Et
16 (3 equiv)
NosN
NosN
+
toluene
r.t., 24 h
3
17
25% yield, 49% ee
Scheme 2. Examination of the construction of C(3) chiral carbon.
Table 3. Asymmetric [3+2] cycloaddition of oxazolidinones 8 and 2-nitro-3-arylacrylates 18a)
O
R2
[Pd2(dba)3]·CHCl3
(Pd 2.5 mol%)
CO2Et
NO2
R1
O
NosN
NO2
NosN
R1
+
2d·I
(5 mol%)
R2
CO2Et
18
toluene
8
19
racemic
Yield
/%b)
ee
/%d)
Entry
R1
8
R2
18
Conditions
19
drc)
1e)
2
3
4
5
6
7
8
9
10
11
12
13
14
Me
Me
Me
Me
Me
Me
Et
n-Bu
8a
8a
8a
8a
8a
8a
8b
8c
8d
8e
8f
Ph
Ph
18a
18a
18b
18c
18d
18e
18a
18a
18a
18a
18a
18a
18a
18a
r.t., 24 h
0 °C, 8 h
0 °C, 10 h
0 °C, 10 h
0 °C, 10 h
r.t., 24 h
0 °C, 24 h
0 °C, 24 h
r.t., 24 h
r.t., 36 h
r.t., 48 h
r.t., 48 h
r.t., 36 h
r.t., 36 h
19a
19a
19b
19c
19d
19e
19f
19g
19h
19i
27
99
99
99
99
97
99
80
83
99
78
92
81
79
5:8:3:1
®
95
92
89
96
94
96
92
97
95
96
71
83
77
11:1.4:1:<1
12:1.1:1:<1
5.9:1.1:1:<1
11:1.2:1:<1
11:1.1:1:<1
15:2.8:1:<1
17:3.8:1:<1
11:1:<1:<1
14:1.3:1:<1
>20:2.6:1:<1
16:1:<1:<1
19:1:<1:<1
17:1:<1:<1
4-Me-C6H4
4-CF3-C6H4
2-naphthyl
2-furyl
Ph
Ph
Ph
Ph
Ph
i-Bu
PhCH2CH2
i-Pr
19j
19k
19l
Ph
8g
8h
8i
Ph
Ph
Ph
4-Cl-C6H4
4-MeO-C6H4
19m
a) Unless otherwise noted, reactions were carried out with 0.10 mmol of 8 and 0.3 mmol of 18 in the presence of
[Pd2(dba)3¢CHCl3] (Pd, 2.5 mol %) and 2d¢I (5 mol %) in 1.0 mL of toluene. b) Isolated yield. c) Determined based on
1H NMR analysis of crude reaction mixture. d) Enantiomeric excesses of the major diastereomer were indicated,
which were analyzed by chiral stationary phase HPLC. The absolute configurations of 19a was confirmed by X-ray
diffraction analysis, and the stereochemistries of other examples were assumed by analogy. e) The reaction was
performed with 1¢Br (5 mol %) instead of 2d¢I.
To gain insight into the course of the determination of C(4)
stereochemistry, the asymmetric cycloaddition with racemic
oxazolidinone 20 bearing a geometrically pure, deuterated
vinyl substituent was investigated. Thus, 20 was treated with 2-
cyano-3-phenylacrylate 6a under the influence of the Pd/2d¢I
complex, which afforded a 1:1 ratio of the geometrical isomers
of pyrrolidine 21 (Scheme 3), indicating that the absolute
stereochemistry of the C(4) carbon was established through the
isomerization of planar chiral π-allylpalladium.
membered heterocycle, allows the straightforward access to
diverse densely functionalized pyrrolidines of high stereo-
chemical purity. This study not only provides an efficient
synthetic protocol, but also offers unprecedented, yet fruitful
opportunities for the molecular design of chiral phosphine
ligands and their applications to the development of previously
elusive, catalytic stereoselective transformations.
Experimental
General. All air- and moisture-sensitive reactions were per-
formed under an atmosphere of argon (Ar) in dried glassware.
The manipulations for Pd-catalyzed reactions were carried out
with standard Schlenk techniques under Ar. Toluene was
supplied from Kanto Chemical Co., Inc. as “Dehydrated” and
further purified by both A2 alumina and Q5 reactant using a
GlassContour solvent dispensing system. [Pd2(dba)3]¢CHCl3
was purchased from Sigma-Aldrich Co. and purified by follow-
ing a literature procedure.43 Ammonium phosphines 2¢X,22
Conclusion
A highly enantio- and diastereoselective [3+2] annulation
reaction of 5-vinyloxazolidinones with trisubstituted alkenes
was successfully developed based on the utilization of a
Pd complex bearing a chiral ammonium-phosphine hybrid
ligand. This asymmetric cycloaddition system, characterized by
ligand-enabled multiple absolute stereocontrol over the single-
step construction of three contiguous stereocenters in a five-
654 | Bull. Chem. Soc. Jpn. 2016, 89, 649–656 | doi:10.1246/bcsj.20160053
© 2016 The Chemical Society of Japan

(i) isomerization of planar chiral π-allylpalladium
O
NNos
[Pd]
HB
HA
NNos
[Pd]
NNos
HA
HB
NosN
O
HB
HA
R4
R4
R4
R4
[Pd]
HB
HA
racemic
(ii) direct enantio-convergent mechanism
O
R1
NosN
R2
R3
R4
NNos
anti-SN2'
NosN
O
R4
R4
[Pd]
'
+
2
SN
-
n
y
s
O
NNos
[Pd]
NosN
O
R4
R4
Figure 5. Two possible scenarios for the determination of C(4) stereocenter.
[Pd2(dba)3]·CHCl3
(Pd 2.5 mol%)
Ph
O
CN
CO2Et
2d·I (5 mol%)
CO2Et
CN
O
NosN
D
NosN
Ph
+
Me
Me
toluene
0 °C, 10 h
D
20
racemic
E/Z = 1:>20
6a (3.0 equiv)
21
99% yield, E/Z = 1:1
dr = >20:1, 98% ee
Scheme 3. Asymmetric cycloaddition of deuterated oxazolidinone 20.
oxazolidinones,22 and alkenes44,45 were synthesized by follow-
17.4 Hz), 5.37 (1H, d, J = 11.0 Hz), 4.33 (1H, d, J = 11.5 Hz),
4.28 (1H, dq, J = 11.0, 7.3 Hz), 4.15 (1H, dq, J = 11.0, 7.3
Hz), 3.76 (1H, d, J = 11.5 Hz), 1.57 (3H, s), 1.28 (3H, t, J =
7.3 Hz); 13C NMR (101 MHz, CDCl3): ¤ 163.4, 149.9, 145.4,
135.2, 134.1, 129.3, 128.8, 128.5, 128.2, 123.9, 118.4, 115.1,
66.9, 65.0, 63.8, 58.3, 50.6, 19.4, 14.2; IR (film): 3105, 3069,
3036, 2984, 2936, 1744, 1531, 1350, 1240, 1165, 1090, 1042,
741, 698, 563 cm¹1; HRMS (ESI): Calcd for C23H23N3O6SNa+
([M + Na]+) 492.1200, Found 492.1200; HPLC OZ3, Hex/
IPA = 80:20, flow rate: 1.0 mL min¹1, - = 254 nm, retention
time: 29.3 min (major), 38.9 min (minor).
Representative Procedure for Pd-Catalyzed Asymmetric
Cycloaddition of 5-Vinyloxazolidinones with 2-Nitro-3-
arylacrylates. To a Schlenk flask was added [Pd2(dba)3]¢
CHCl3 (1.29 mg, 1.25 ¯mol) and 2d¢I (5.50 mg, 5 ¯mol) and
the flask was evacuated and refilled with Ar three times. Then,
toluene (1 mL) was introduced, and the resulting catalyst
mixture was degassed by alternating vacuum evacuation/Ar
backfill. The mixture was cooled to 0 °C and 2-nitro-3-phenyl-
acrylate 18a (66.4 mg, 0.3 mmol) and 5-vinyloxazolidinone 8a
(31.2 mg, 0.1 mmol) were successively added into the reaction
flask. After stirring for 8 h, the reaction mixture was filtered
through a pad of short silica gel and rinsed with acetone and
ing procedures described in the literature. Deuterated oxazo-
lidinone 20 was synthesized as described in Supporting Infor-
mation. Other simple chemicals were purchased and used as
such.
Representative Procedure for Pd-Catalyzed Asymmetric
Cycloaddition of 5-Vinyloxazolidinones with Trisubstituted
Alkenes. To a Schlenk flask was added [Pd2(dba)3]¢CHCl3
(1.29 mg, 1.25 ¯mol), 2d¢I (5.50 mg, 5 ¯mol), and ethyl 2-
cyano-3-phenylacrylate (6a) (60.4 mg, 0.3 mmol) and the flask
was evacuated and refilled with Ar three times. Then, toluene
(1 mL) was introduced, and the resulting catalyst mixture was
degassed by alternating vacuum evacuation/Ar backfill. The
mixture was cooled to 0 °C and 5-vinyloxazolidinone 8a (31.2
mg, 0.1 mmol) was successively added into the reaction flask.
After stirring for 10 h, the reaction mixture was filtered through
a pad of short silica gel and washed with acetone. The resulting
filtrates were concentrated and purified by column chromatog-
raphy on silica gel (Hex/Et2O = 9:1 to 3:1 as eluent) to afford
11a (46.1 mg, 0.098 mmol, 98% yield) as a white solid. 11a:
1H NMR (400 MHz, CDCl3): ¤ 8.13 (2H, d, J = 8.9 Hz), 7.59
(2H, d, J = 8.9 Hz), 7.26-7.22 (1H, m), 7.19-7.11 (4H, m),
5.86 (1H, dd, J = 17.4, 11.0 Hz), 5.68 (1H, s), 5.45 (1H, d, J =
Bull. Chem. Soc. Jpn. 2016, 89, 649–656 | doi:10.1246/bcsj.20160053
© 2016 The Chemical Society of Japan | 655

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the filtrates were concentrated. Purification of the residue by
column chromatography on silica gel (H/Et2O = 11:1 to 3:1 as
eluent) gave 19a (48.4 mg, 0.0989 mmol, 99% yield) as a white
1
solid. 19a: H NMR (400 MHz, CDCl3): ¤ 8.12 (2H, d, J =
8.7 Hz), 7.59 (2H, d, J = 8.7 Hz), 7.22-7.17 (1H, m), 7.07-7.05
(4H, m), 6.08 (1H, s), 5.91 (1H, dd, J = 17.2, 11.0 Hz), 5.50
(1H, d, J = 17.2 Hz), 5.38 (1H, d, J = 11.0 Hz), 4.30 (1H, d,
J = 10.5 Hz), 4.21 (1H, d, J = 10.5 Hz), 3.76 (1H, dq, J = 10.5,
7.3 Hz), 3.45 (1H, dq, J = 10.5, 7.3 Hz), 1.56 (3H, s), 0.68
(3H, t, J = 7.3 Hz); 13C NMR (101 MHz, CDCl3): ¤ 163.3,
149.9, 145.7, 136.0, 133.7, 129.1, 128.8, 128.4, 128.0, 123.9,
119.2, 105.0, 66.4, 63.1, 58.2, 50.9, 16.5, 13.2; IR (film): 3105,
3069, 3038, 2984, 2922, 1744, 1557, 1530, 1348, 1236, 1161,
1042, 853, 735, 702, 617, 565 cm¹1; HRMS (ESI): Calcd for
C22H23N3O8SNa+ ([M + Na]+) 512.1098, Found 512.1101;
HPLC IA, H/EtOH = 83.3:16.7, flow rate: 0.5 mL min¹1, - =
254 nm, retention time: 15.8 min (minor), 20.1 min (major).
This work was aided by CREST (JST), Grants-in-Aid
for Scientific Research (C) from JSPS, and the Program for
Leading Graduate Schools “Integrative Graduate Education
and Research Program in Green Natural Sciences” at Nagoya
University.
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© 2016 The Chemical Society of Japan