Pd(II)-SPRIX catalyzed enantioselective construction of pyrrolizines/pyrroloindoles employing molecular oxygen as the sole oxidant

Article abstract of DOI:10.1016/j.tet.2011.02.057

Pd(II)-SPRIX catalyst coupled with an environmentally benign molecular oxygen as the sole oxidant successfully exploited the construction of pyrrolizines/pyrroloindoles, imperative scaffolds of bio-potent molecules through intramolecular C-N and C-C bond

Full text of DOI:10.1016/j.tet.2011.02.057

Tetrahedron 67 (2011) 2889e2894
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pd(II)-SPRIX catalyzed enantioselective construction of pyrrolizines/
pyrroloindoles employing molecular oxygen as the sole oxidant
*
Chennan Ramalingan , Kazuhiro Takenaka, Hiroaki Sasai
The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibaraki, Osaka 567-0047, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 January 2011
Received in revised form 20 February 2011
Accepted 21 February 2011
Available online 26 February 2011
Pd(II)-SPRIX catalyst coupled with an environmentally benign molecular oxygen as the sole oxidant
successfully exploited the construction of pyrrolizines/pyrroloindoles, imperative scaffolds of bio-potent
molecules through intramolecular CeN and CeC bond forming reactions in good yields with appreciable
enantioselectivities.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Spiro bis(Isoxazoline)
Enantioselectivity
Molecular oxygen
Pyrrolizines
Pyrroloindoles
1. Introduction
diketones,7 aminocarbonylation of alkenylureas,8 and oxidative
cyclization of enynes.9 Notably, in all the cases, either benzoqui-
Palladium catalyzed oxidation reactions play vital roles in the
construction of biopertinent organic targets via heteroatom in-
corporation and/functional group manipulation.1 Despite signifi-
cant developments in this area, Pd(II) catalysis employing
molecular oxygen as the sole oxidant is particularly advantageous
because molecular oxygen is not only an inexpensive and envi-
ronmentally benign one but also helps in facilitating product pu-
rification. Further, the use of organic oxidants or cocatalysts, for
instance benzoquinone or copper salts, respectively, to regenerate
Pd (II) species from Pd(0) in oxidative Pd(II) catalysis might impede
the development of efficient asymmetric transformations. Over the
past decade, significant progress has been made in oxidation ca-
talysis exploiting Pd(II) coupled with molecular oxygen as the sole
oxidant.2 Although various chiral ligands have been reported in Pd
(II) catalysis along with molecular oxygen in search for efficient
aerobic asymmetric processes,3 revealing new classes of chiral li-
gands for such aerobic asymmetric processes is highly indispens-
able. Spiro bis(isoxazoline) ligands (SPRIXs), developed by our
group,4 are a class of chiral ligands, which promote various Pd
catalyzed asymmetric processes5 including recent examples, such
as Wacker-type cyclization of geranylphenols6/2-alkenyl-1,3-
none or bis(acetoxy)iodobenzene has been utilized as the stoi-
chiometric oxidant. Disclosed herein is a successful utilization of Pd
(II)-SPRIX catalyst coupled with molecular oxygen as the sole oxi-
dant in an enantioselective construction of pyrrolizines/pyrro-
loindoles, pertinent scaffolds of bio-important targets,10,11 via
intramolecular CeN and CeC bond forming reactions.
2. Results and discussion
Initially, the optimization of the reaction was grouped for which
1a was chosen as a model substrate. It was hypothesized that
a critical choice of Pd (II) source along with an appropriate oxidant
in addition to a chiral SPRIX ligand might efficiently catalyze the
enantioselective construction of 2a through intramolecular CeN
and CeC bond formations (Scheme 1). A preliminary examination
showed that Pd(TFA)2 and (M,S,S)-i-Pr-SPRIX [10 mol % and
40 mol %, respectively (1:4)] along with molecular oxygen (1 atm)
as the sole oxidant in toluene at 50 ꢀC for 24 h effectively catalyzed
the model reaction to produce 2a in 26% yield with 25% ee. It should
be noted that there were no side products formed during the re-
action and 69% of the starting material was recovered (Table 1,
entry 1). To our delight, addition of molecular sieves (25 mg) unless
otherwise identical conditions significantly enhanced not only the
yield but also the enantioselectivity (entry 2). Having the utility of
molecular sieves as one of the common moisture trapping agents in
* Corresponding author. E-mail addresses: ramalinganc@gmail.com, ram@san-
ken.osaka-u.ac.jp (C. Ramalingan).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.057

2890
C. Ramalingan et al. / Tetrahedron 67 (2011) 2889e2894
impacts on the yield and the enantioselectivity of 2a, the scrupu-
lous reason for the remarkable effects is yet to be known.
The attention was then focused toward the effect of solvent on
the yield and the enantioselectivity of 2a (Table 2, entries 7e12).
Use of N,N-dimethylformamide (DMF) resulted in slightly higher
yield but with a complete loss of enantioselectivity by affording
a racemic 2a. Screening with diglyme, acetonitrile (MeCN), 1,2-di-
chloroethane (DCE), and methanol (MeOH) accomplished in lower
both yields as well as enantioselectivities while 1,4-dioxane affor-
ded in slightly higher yield though with less enantioselectivity.
Besides, increasing the temperature from 50 ꢀC to 70 ꢀC provided in
slightly higher both yield as well as enantioselectivity (Table 2,
entry 13) while neither yield nor enantioselectivity improved when
the temperature was further increased to 80 ꢀC (Table 2, entry 14).
At 70 ꢀC, the acceleration of the reaction to provide the improved
yield is due probably to the increased solubility of oxygen in tolu-
ene13 and the reason for the slightly improved enantioselectivity is
yet to be known (Table 2, entry 1 vs entry 13). Noteworthy is that
prolonged reaction period at 70 ꢀC afforded 2a in better yield albeit
with no deprivation in enantioselectivity (Table 2, entry 15).
Having the unique reactivity of SPRIX coupled with Pd sources
for various enantioselective reactions due to their relatively greater
Lewis acidity of the Pd-SPRIX complex14 in mind, various chiral
ligands were screened in place of (M,S,S)-i-Pr-SPRIX. As depicted in
Table 3, none of the ligands coupled with Pd(TFA)2 efficiently
Scheme 1. Enantioselective synthesis of model, 2-methylene-6,6-diphenyltetrahydro-
1H-pyrrolizin-3(2H)-one (2a).
Table 1
Effect of (M,S,S)-i-Pr-SPRIX and molecular sieves a
ꢀ
Entry
Pd(II)-SPRIX (mol %)
MS 3 A
(mg)b
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
10e40
10e40
20e80
10e20
10e15
10e12
10e15
10e15
d
26
34
43
37
36
33
35
28
25
52
32
55
56
53
50
34
25
25
25
25
25
50
100
a
All the yields were isolated ones; all the ee were determined by HPLC analysis;
the reaction time was 24 h.
b
ꢀ
Amount of MS 3 A (mg/0.05 mmol substrate).
a chemical reaction in mind, other dehydrating agents, such as
anhydrous magnesium sulfate (MgSO4) and anhydrous sodium
sulfate (Na2SO4) were also screened in place of molecular sieves,
however, the results were inferior compared to molecular sieves.
Further, the use of benzoquinone (1 equiv) as oxidant afforded
a double bond isomerized product 2a0 (28% yield with 43% ee) along
with the desired 2a (32% yield and 41% ee).12 Tuning the Pd(TFA)2
and (M,S,S)-i-Pr-SPRIX ratio to 1:1.5 further increased the yield and
enantioselectivity (entry 5) while 2:8, 1:2, and 1:1.2 ratios of Pd
(TFA)2 and (M,S,S)-i-Pr-SPRIX afforded the model lower in yield as
well as enantioselectivity (entries 3, 4, and 6). Besides, increasing
the amount of molecular sieves exhibited no significant de-
velopment in both the yield as well as the enantioselectivity (en-
tries 7 and 8).
Table 3
a
Effect of chiral ligand and additive
Entry
Chiral ligand
Additive
(2 equiv)
Yield b(%)
ee c(%)
1
2
3
4
5
6
7
8
3
4
5
6
7
8
9
10
3
3
3
3
3
3
d
42
d
60
d
d
d
<5
d
ND
d
d
d
12
d
14
d
d
d
d
d
d
d
d
9
DIPEA
DIPEAd
Et3N
NaOAc
KOAc
Na2CO3
46
45
40
33
35
47
26
27
20
30
28
52
10
11
12
13
14
Additionally, various Pd(II) sources were screened to investigate
whether counter ions have impact on the yield and/or the enan-
tioselectivity of 2a but none of the other tested Pd(II) sources fur-
nished either better yield or enantioselectivity and infact afforded
much lower yields and enantioselectivities (Table 2, entries 2e6).
ND: Not determined.
a
ꢀ
Reaction conditions: Pd(TFA)2 (10 mol %), Chiral ligand (15 mol %), MS 3 A (25
mg/0.05 mmol substrate), toluene (0.5 mL), O2 (1 atm), 24 h.
b
ꢀ
Although the effect of MS 3 A and TFA counter ions had major
All the yields were isolated ones.
All the ee were determined by HPLC analysis.
DIPEA (1 equiv) was added.
c
Table 2
d
a
Effect of Pd(II) source, solvent, temperature, and reaction time
Entry
Pd(II) source
Solvent
Temp (ꢀC)
Yield b (%)
ee c (%)
1
2
3
4
5
6
7
8
Pd(TFA)2
Pd(OAc)2
PdCl2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
Diglyme
MeCN
DCE
50
50
50
50
50
50
50
50
50
50
50
50
70
80
70
36
12
13
8
16
10
39
12
16
24
9
56
15
12
10
4
14
rac
4
32
12
8
38
60
60
60
Pd(hfacac)2
Pd(MeCN)2Cl2
Pd(PhCN)2Cl2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
9
10
11
12
13
14
15
MeOH
1,4-Dioxane
Toluene
Toluene
Toluene
40
42
41
d
76
a
ꢀ
Reaction conditions: Pd source (10 mol %), (M,S,S)-i-Pr-SPRIX (15 mol %), MS 3 A
(25 mg/0.05 mmol substrate), solvent (0.5 mL), O2 (1 atm), 24 h.
b
All the yields were isolated ones.
All the ee were determined by HPLC analysis.
After prolonged reaction time (120 h).
c
d

C. Ramalingan et al. / Tetrahedron 67 (2011) 2889e2894
2891
promoted the enantioselective construction of 2a and notably the
reaction was inefficient even with the use of higher loading of 53e
(40 mol %) as it provided only trace amount of 2a with the re-
covery of most of the starting material 1a (85%).
reaction; however, unidentified mixture of products were obtained.
Lowering the reaction temperature to 50 ꢀC and 25 ꢀC unless oth-
erwise identical conditions also provided no required targets,
considerable amounts of starting materials were recovered instead
(15% of 1e and <10% of 1f at 50 ꢀC as well as 40% of 1e and 25% of 1f
at 25 ꢀC). In contrast, (E)-configured substrate, N-(2-allylphenyl)
cinnamamide (1g) efficaciously converted into its corresponding
pyrroloindole 2g in (Z)-configuration as evidenced by NOESY in
good yield and enantioselectivity (entry 7). Likewise, (E)-N-(2-
allylphenyl)-3-(2-chlorophenyl)acrylamide (1h) and (E)-N-(2-
allylphenyl)-3-(4-fluorophenyl)acrylamide (1i) also smoothly de-
livered their corresponding pyrroloindoles 2h and 2i, respectively,
both in (Z)-configurations akin to 2g as evidenced by NOESY in
good yields and comparable enantioselectivities (entries 8 and 9).
At the same time, substrates with branched alkene (1j) and ex-
tended methylene (1k) did not react at all under identical model
conditions and it is important to note that most of the starting
materials (w90%) were recovered in those cases.
Further, additive effects on the model reaction were studied
€
(Table 3, entries 9e14). Although addition of Hunig’s base (DIPEA)
and sodium carbonate (Na2CO3) slightly improved the yield of 2a,
the enantioselectivities were unfortunately decreased (entries 9,
10, and 14). Likewise, addition of triethyl amine (Et3N), sodium
acetate (NaOAc), and potassium acetate (KOAc) enhanced neither
the yield nor the enantioselectivity (entries 11e13). Thus, 10 mol %
ꢀ
of Pd(TFA)2, 15 mol % of (M,S,S)-i-Pr-SPRIX, and MS 3 A in toluene at
70 ꢀC under O2 (1 atm) for 120 h is the optimal conditions for the
enantioselective construction of 2a from 1a.
To illustrate the general applicability of the model reaction,
a diverse range of substrates were examined and the results are
shown in Table 4. Replacing sterically bulky gem-diphenyl groups of
1a by a less bulky gem-dimethyl group (i.e., 1b) produced its cor-
responding pyrrolizine 2b in comparable yield; however, a consid-
erable reduction in enantioselectivity was perceived (entry 2).
Switching over to the use of cyclopentyl and cyclohexyl substituted
substrates (1c and 1d, respectively) in place of gem-diphenyl
substituted substrate (1a) also delivered their corresponding pyr-
rolizines 2c and 2d, respectively, in good to better yields despite
their lower enantioselectivities (entries 3 and 4). Further, N-cin-
namoyl and N-(2-chlorocinnamoyl) substituted substrates with (E)-
configuration did not provide their corresponding pyrrolizines 2e
and 2f, respectively (entries 5 and 6). It should be noted that most
of the starting materials of 1e and 1f were consumed during the
A plausible mechanism, as depicted in Scheme 2, consists of an
initial step of a coordination between in situ generated Pd(II)
complex and an alkene as shown in intermediate I. Nucleophilic
attack of amine on internal carbon of the olefin in an intramolecular
fashion provides the cyclized intermediate II via 5-exo-trig mode of
cyclization (CeN bond formation). Subsequent coordination of the
Pd(II) species, thus generated within the intermediate II, to the
olefin of
a,b-unsaturated carbonyl moiety followed by further
intramolecular cyclization (CeC bond formation) through similar 5-
exo-trig mode gives intermediate III, which then emancipates the
target pyrrolizine IV and Pd(II) species V after b-hydride elimina-
tion. Reoxidation of Pd(0) species, liberated from V eventually re-
generates the active Pd(II) species with the utilization of molecular
oxygen and HX.
Table 4
Scope of the Pd(II)-(M,S,S)-i-Pr-SPRIX catalyzed reaction a
Yieldb(%)
eec(%)
60
32
27
28
1
2
3
4
1a: R¼Ph
2a
2b
2c
2d
76
73
69
82
1b: R¼Me
1c: R¼eC4H8e
1d: R¼eC5H10e
5
6
1e: R¼Ph
2e
2f
d
d
d
d
1f: R¼2-CleC6H4
7
8
9
1g: R¼Ph
2gd
2hd
2id
71
79
63
54
61
59
1h: R¼2-CleC6H4
1i: R¼4-FeC6H4
10
1j
2j
d
d
Scheme 2. A plausible mechanism.
11
1k
2k
d
d
a
ꢀ
Reaction conditions: Pd(TFA)2 (10 mol %), (M,S,S)-i-Pr-SPRIX (15 mol %), MS 3 A
(25 mg/0.05 mmol substrate), toluene (0.5 mL), O2 (1 atm), 70 ꢀC, 120 h.
In conclusion, (M,S,S)-i-Pr-SPRIX has efficiently been utilized in
the Pd(II) catalysis employing molecular oxygen as the sole oxidant.
The developed catalytic system manifested its own reactivity on the
b
Isolated yields.
Determined by HPLC analysis.
(Z)-Configurations were confirmed by NOESY.
c
d

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C. Ramalingan et al. / Tetrahedron 67 (2011) 2889e2894
enantioselective construction of pyrrolizines/pyrroloindoles, im-
perative scaffolds of bio-important molecules via intramolecular
CeN and CeC bond forming reactions with good yields and ap-
preciable enantioselectivities. Efficacious utility of this catalytic
system for further development of aerobic asymmetric processes is
currently ongoing in our laboratory and will be reported in due
course.
128.1, 126.7, 126.4, 118.9, 50.4, 46.0, 42.1; HRMS (ESI) calcd for
C
40H42N2NaO2: m/z 605.3144 ([2MþNa]þ), found: m/z 605.3148.
3.2.2. N-(2,2-Dimethylpent-4-enyl)acrylamide
(1b). 2,2-Dime-
thylpent-4-en-1-amine (0.57 g, 5.0 mmol), pyridine (0.44 mL,
5.5 mmol), and acryloyl chloride (0.45 mL, 5.5 mmol) in
dichloromethane (30 mL) produced N-(2,2-dimethylpent-4-
enyl)acrylamide as a white solid (0.56 g, 67%). Mp 108e109 ꢀC; IR
(neat)
NMR (400 MHz, CDCl3)
n ;
3297, 2919, 2360, 1658, 1625, 1554, 1408, 1237 cmꢂ1 1H
3. Experimental
3.1. General
d
6.21 (dd, J¼16.9 Hz; 1.8 Hz, 1H), 6.07
(dd, J¼16.9 Hz; 10.1 Hz, 1H), 5.82e5.72 (m, 2H; NH peak is
merged), 5.57 (dd, J¼10.1 Hz; 1.8 Hz, 1H), 5.01e4.95 (m, 2H), 3.12
(d, J¼6.4 Hz, 2H), 1.93 (d, J¼7.8 Hz, 2H), 0.84 (s, 6H); 13C NMR
All the reported melting points were measured in open capil-
laries with a Laboratory Devices-Mel-Temp II apparatus and are
uncorrected. All the reagents are reagent grade and were used
without further purification. All solvents used herein were either
freshly distilled prior to use or received as anhydrous and were
used without further distillation. Thin Layer Chromatography (TLC)
was performed on a Silica gel 60 F254 plates eluting with the sol-
vents indicated. Column Chromatography was performed on Silica
(100 MHz, CDCl3)
d 165.8, 134.9, 131.1, 126.4, 117.6, 49.1, 44.7,
34.9, 25.0; HRMS (ESI) calcd for C20H34N2NaO2: m/z 357.2518
([2MþNa]þ), found: m/z 357. 2525.
3.2.3. N-[(1-Allylcyclopentyl)methyl]acrylamide (1c). (1-Allylcyclo-
pentyl)methanamine (0.70 g, 5.0 mmol), pyridine (0.44 mL,
5.5 mmol), and acryloyl chloride (0.45 mL, 5.5 mmol) in dichloro-
methane (30 mL) gave N-[(1-allylcyclopentyl)methyl]acrylamide as
gel (spherical, 63e200 mm) slurry packed in glass columns with
a white solid (0.57 g, 59%). Mp 112e113 ꢀC; IR (neat)
n
3287, 2951,
eluent system as indicated. All NMR spectra were acquired on
a JEOL JNM-LA400 spectrometer at 25 ꢀC using CDCl3 as a solvent
and tetramethylsilane (TMS) as an internal standard (1H
NMRd400 MHz and 13C NMRd100 MHz). In the 1H NMR, chemical
2359, 1657, 1625, 1554, 1408, 1237 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
6.20 (dd, J¼16.9 Hz; 1.8 Hz, 1H), 6.06 (dd, J¼16.9 Hz; 10.1 Hz, 1H),
5.84e5.73 (m, 2H; NH peak is merged), 5.56 (dd, J¼10.1 Hz; 1.8 Hz,
1H), 5.03e5.01 (m, 1H), 4.99e4.97 (m, 1H), 3.20 (d, J¼6.4 Hz, 2H),
2.04 (d, J¼7.3 Hz, 2H), 1.62e1.50 (m, 4H), 1.41e1.35 (m, 4H); 13C
shifts are reported in d parts per million with reference to TMS and
the multiplicities br s, s, d, dd, t, ddt, and m stand for broad singlet,
singlet, doublet, doublet of doublet, triplet, double doublet of
triplet, and multiplet, respectively. In the 13C NMR, chemical shifts
NMR (100 MHz, CDCl3)
d 165.9, 135.8, 131.2, 126.2, 117.4, 46.5, 42.8,
35.3, 24.9; HRMS (ESI) calcd for C24H38N2NaO2: m/z 409.2831
([2MþNa]þ), found: m/z 409.2839.
are reported in d ppm with relative to CDCl3. ESI mass spectra were
recorded on a Thermo Fisher, LTQ ORBITRAP XL. IR spectra were
recorded on a JASCO FT/IR-4100 instrument. HPLC analyses were
performed on JASCO HPLC system (JASCO PU 2080 pump and MD-
2010 UV/Vis detector). (M,S,S)-i-Pr-SPRIX was synthesized by
adopting our own method.4 The precursors of the substrate (1),
allyl amines were synthesized according to the literature
procedures.3e,15,16
3.2.4. N-[(1-Allylcyclohexyl)methyl]acrylamide (1d). (1-Allylcyclo-
hexyl)methanamine (0.77 g, 5.0 mmol), pyridine (0.44 mL,
5.5 mmol), and acryloyl chloride (0.45 mL, 5.5 mmol) in dichloro-
methane (30 mL) afforded N-[(1-allylcyclohexyl)methyl]acrylam-
ide as a white solid (0.74 g, 71%). Mp 114e115 ꢀC; IR (neat)
n
3266,
2924, 2359, 1654, 1620, 1559, 1413, 1241 cmꢂ1; 1H NMR (400 MHz,
CDCl3)
d
6.27 (dd, J¼16.9 Hz; 1.8 Hz, 1H), 6.09 (dd, J¼16.9 Hz;
10.1 Hz, 1H), 5.93e5.83 (m, 1H), 5.64 (dd, J¼10.1 Hz; 1.4 Hz, 2H; NH
peak is merged), 5.12e5.10 (m, 1H), 5.08e5.06 (m, 1H), 3.28 (d,
J¼6.4 Hz, 2H), 2.08 (d, J¼7.3 Hz, 2H), 1.57e1.40 (m, 6H), 1.36e1.27
3.2. General procedure for the synthesis of substrates (1)
In a dried RB flask, were taken allyl amine (5.0 mmol) in
dichloromethane (20 mL). Pyridine (5.5 mmol) was then added and
the mixture was cooled to 0 ꢀC while stirring. Then a solution of
acryloyl chloride (5.5 mmol) in dichloromethane (10 mL) was
added to the cooled mixture in a drop-wise fashion and allowed to
warm to the room temperature. The stirring was continued for over
night and the organic layer was separated after quenching with
saturated ammonium chloride (30 mL) and the aqueous layer was
extracted thrice with dichloromethane (20 mLꢁ3). The combined
organic layers, after dried over magnesium sulfate were filtered and
concentrated. The residue thus obtained was subjected to silica
gel column chromatography (30% ethyl acetate in n-hexane) to
furnish 1.
(m, 4H); 13C NMR (100 MHz, CDCl3)
d 165.7, 135.0, 131.1, 126.3, 117.5,
45.9, 41.3, 37.2, 33.6, 26.2, 21.5; HRMS (ESI) calcd for C26H42N2NaO2:
m/z 437.3144 ([2MþNa]þ), found: m/z 437.3138.
3.2.5. N-(2-Allylphenyl)cinnamamide (1g). 2-Allylaniline (0.67 g,
5.0 mmol), pyridine (0.44 mL, 5.5 mmol), and cinnamoyl chloride
(0.94 g, 5.5 mmol) in dichloromethane (30 mL) gave N-(2-allyl-
phenyl)cinnamamide as a white solid (1.00 g, 76%). Mp 127e128 ꢀC;
IR (neat)
NMR (400 MHz, CDCl3)
n
3264, 2915, 2349, 1655, 1622, 1533, 1452, 1227 cmꢂ1; 1H
d
7.94 (br.s, 1H), 7.76e7.74 (m, 1H), 7.71 (d,
J¼15.6 Hz, 1H), 7.47 (br.s, 2H), 7.36e7.33 (m, 3H), 7.26e7.22 (m, 1H),
7.17e7.17 (m, 1H), 7.14e7.12 (m, 1H), 6.54 (d, J¼15.6 Hz, 1H),
6.03e5.93 (m, 1H), 5.18 (d, J¼10.1Hz, 1H), 5.12 (d, J¼16.9 Hz, 1H),
3.42 (d, J¼6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 164.2, 142.1,
3.2.1. N-(2,2-Diphenylpent-4-enyl)acrylamide
(1a). 2,2-Diphe-
136.3, 136.1, 134.6, 130.2, 129.9, 128.8, 127.9, 127.4, 125.4, 123.9,
121.0, 116.7, 36.8; HRMS (ESI) calcd for C36H34N2NaO2: m/z
549.2518 ([2MþNa]þ), found: m/z 549.2526.
nylpent-4-en-1-amine (1.19 g, 5.0 mmol), pyridine (0.44 mL,
5.5 mmol), and acryloyl chloride (0.45 mL, 5.5 mmol) in
dichloromethane (30 mL) afforded N-(2,2-diphenylpent-4-enyl)
acrylamide as a white solid (1.08 g, 74%). Mp 122e123 ꢀC; IR (neat)
3.2.6. (E)-N-(2-Allylphenyl)-3-(2-chlorophenyl)acrylamide (1h). 2-
Allylaniline (0.67 g, 5.0 mmol), pyridine (0.44 mL, 5.5 mmol), and 2-
chlorocinnamoyl chloride (1.11 g, 5.5 mmol) in dichloromethane
(30 mL) produced (E)-N-(2-allylphenyl)-3-(2-chlorophenyl)acryl-
n
3271, 2954, 2338, 1648, 1611, 1533, 1403, 1233 cmꢂ1
;
1H NMR
(400 MHz, CDCl3)
d 7.34e7.30 (m, 4H), 7.26e7.19 (m, 6H), 6.16 (dd,
J¼16.9 Hz; 1.2 Hz, 1H), 5.90 (dd, J¼16.9 Hz; 10.4 Hz, 1H), 5.56 (dd,
J¼10.4 Hz; 1.2 Hz, 1H), 5.50e5.39 (m, 1H), 5.07 (br.s, 1H), 4.98 (dd,
J¼13.8 Hz; 1.9 Hz, 2H), 4.05 (d, J¼5.8 Hz, 2H), 2.86 (d, J¼7.0 Hz,
amide as a white solid (1.25 g, 84%). Mp 161e162 ꢀC; IR (neat)
n
3254, 2932, 2373, 1655, 1624, 1535, 1454, 1231 cmꢂ1
;
1H NMR
2H); 13C NMR (100 MHz, CDCl3)
d
165.4, 145.3, 133.7, 131.0, 128.5,
(400 MHz, CDCl3)
d
8.08, (d, J¼16.0 Hz, 1H), 8.06 (br.s, 1H),

C. Ramalingan et al. / Tetrahedron 67 (2011) 2889e2894
2893
7.62e7.52 (m, 2H), 7.45e7.42 (m, 1H), 7.37e7.28 (m, 3H), 7.22e7.13
(m, 2H), 6.49 (d, J¼16.0 Hz, 1H), 6.08e5.98 (m, 1H), 5.24 (d,
J¼10.1 Hz, 1H), 5.16 (d, J¼16.9 Hz, 1H), 3.45 (d, J¼6.0 Hz, 2H); 13C
1H), 2.89 (d, J¼11.9 Hz, 1H), 2.43e2.36 (m, 1H), 1.78 (dd, J¼11.9 Hz;
6.0 Hz, 1H), 1.09 (d, J¼10.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
168.6, 142.8, 115.4, 57.6, 55.9, 47.4, 41.6, 32.6, 28.8, 28.3; HRMS
NMR (100 MHz, CDCl3)
d
163.6, 144.4, 137.8, 136.4, 136.2, 135.0,
(ESI) calcd for C20H30N2NaO2: m/z 353.2205 ([2MþNa]þ), found:
m/z 353.2197. The enantiomeric excess was determined by HPLC
analysis using Daicel Chiralcel OD as a chiral stationary phase col-
umn with n-hexane/i-PrOH (100:1) mixture as an eluent (flow
133.1, 130.8, 130.3, 127.7, 127.6, 127.1, 117.0, 37.1; HRMS (ESI) calcd
for C36H32Cl2N2NaO2: m/z 617.1739 ([2MþNa]þ), found: m/z
617.1743.
rate¼0.6 mL/min;
l
¼240 nm; 19.3 min and 24.3 min; 32% ee); [
a]
D20
3.2.7. (E)-N-(2-Allylphenyl)-3-(4-fluorophenyl)acrylamide
(1i). 2-Allylaniline (0.67 g, 5.0 mmol), pyridine (0.44 mL,
5.5 mmol), and 4-fluorocinnamoyl chloride (1.04 g, 5.5 mmol) in
dichloromethane (30 mL) afforded (E)-N-(2-allylphenyl)-3-(4-flu-
ꢂ32.4 (c 0.1, CHCl3).
3.3.3. 60-Methylenetetrahydrospiro[cyclopentane-1,20-pyrrolizin]-50
(30H)-one (2c). N-[(1-Allylcyclopentyl)methyl]acrylamide (9.7 mg,
0.05 mmol), Pd(TFA)2 (1.7 mg, 0.005 mmol), (M,S,S)-i-Pr-SPRIX
orophenyl)acrylamide as
156e157 ꢀC; IR (neat)
3257, 2945, 2334, 1652, 1621, 1527, 1448,
1246 cmꢂ1 1H NMR (400 MHz, CDCl3)
8.01 (br.s, 1H), 7.69 (d,
a white solid (0.99 g, 70%). Mp
ꢀ
n
(2.81 mg, 0.0075 mmol), and 3 A molecular sieves (25 mg) in tol-
;
d
uene (0.5 mL) gave 60-methylenetetrahydrospiro[cyclopentane-
J¼15.6 Hz, 1H), 7.53e7.49 (m, 2H), 7.42e7.38 (m, 1H), 7.31e7.27
(m, 1H), 7.21e7.13 (m, 2H), 7.07 (t, J¼8.7 Hz, 2H), 6.38 (d,
J¼15.6 Hz, 1H), 6.06e5.96 (m, 1H), 5.22 (d, J¼9.6 Hz, 1H), 5.13 (d,
J¼16.9 Hz, 1H), 3.43 (d, J¼6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3)
1,20-pyrrolizin]-50(30H)-one as a colorless oil (6.6 mg, 69%). IR (neat)
n
2950, 2353, 1689, 1657, 1411, 1295 cmꢂ1 1H NMR (400 MHz,
;
CDCl3)
d
5.85 (t, J¼2.8 HZ, 1H), 5.20 (t, J¼2.3 Hz, 1H), 3.90e3.83 (m,
1H), 3.48 (d, J¼11.9 Hz, 1H), 3.00 (d, J¼11.9 Hz, 1H), 2.92 (ddt,
J¼16.0 Hz; 7.3 Hz; 2.1 Hz, 1H), 2.44e2.37 (m, 1H), 1.86 (dd,
J¼11.9 Hz; 5.5 Hz, 1H), 1.67e1.47 (m, 8H), 1.26 (dd, J¼11.9 Hz;
d
165.0, 162.5, 141.1, 136.4, 136.2, 130.4, 129.9, 129.8, 127.7, 116.9,
116.2, 116.0, 37.1; HRMS (ESI) calcd for C36H32F2N2NaO2: m/z
585.2330 ([2MþNa]þ), found: m/z 585.2338.
10.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 168.5, 143.0, 115.3, 58.0,
54.6, 52.7, 45.2, 39.3, 38.7, 32.6, 24.4, 24.3; HRMS (ESI) calcd for
C24H34N2NaO2: m/z 405.2518 ([2MþNa]þ), found: m/z 405.2510.
The enantiomeric excess was determined by HPLC analysis using
Daicel Chiralcel OD as a chiral stationary phase column with
n-hexane/i-PrOH (100:1) mixture as an eluent (flow rate¼0.6 mL/
3.3. Catalysis: general procedure for the synthesis of
pyrrolizines/pyrroloindoles (2)
Under argon atmosphere,
a solution of (M,S,S)-i-Pr-SPRIX
ꢀ
D20
(15 mol %), Pd(TFA)2 (10 mol %), and activated molecular sieves (3 A;
25 mg) in dry toluene (0.3 mL) was stirred at room temperature for
2 h. Substrate 1 (0.05 mmol) followed by dry toluene (0.2 mL) were
then added. The reaction vessel was then connected to oxygen
(1 atm) and heated to 70 ꢀC for a total period of 120 h. It was cooled
to room temperature and then concentrated after passing through
a short pad of silica gel followed by rinsing with ethyl acetate. The
crude residue thus obtained was purified by silica gel column
chromatography (30% ethyl acetate in n-hexane) to afford 2a.
min;
CHCl3).
l
¼246 nm; 21.9 min and 26.9 min; 27% ee); [
a
]
ꢂ18.8 (c 0.1,
3.3.4. 60-Methylenetetrahydrospiro[cyclohexane-1,20-pyrrolizin]-50
(30H)-one (2d). N-[(1-Allylcyclohexyl)methyl]acrylamide (10.4 mg,
0.05 mmol), Pd(TFA)2 (1.7 mg, 0.005 mmol), (M,S,S)-i-Pr-SPRIX
ꢀ
(2.81 mg, 0.0075 mmol), and 3 A molecular sieves (25 mg) in tol-
uene (0.5 mL) afforded 60-methylenetetrahydrospiro[cyclohexane-
1,20-pyrrolizin]-50(30H)-one as a colorless oil (8.4 mg, 82%). IR (neat)
n
2925, 2355, 1687, 1656, 1446, 1295 cmꢂ1 1H NMR (400 MHz,
;
3.3.1. 2-Methylene-6,6-diphenyltetrahydro-1H-pyrrolizin-3(2H)-one
CDCl3)
d
5.84 (t, J¼2.8 Hz, 1H), 5.20 (t, J¼2.1 Hz, 1H), 3.86 (m, 1H),
(2a). N-(2,2-Diphenylpent-4-enyl)acrylamide
(14.6
mg,
3.44 (d, J¼12.4 Hz, 1H), 2.94 (d, J¼11.9 Hz, 1H), 2.91 (ddt, J¼16.0 Hz;
7.3 Hz; 2.1 Hz, 1H), 2.41e2.34 (m, 1H), 1.91 (dd, J¼12.4 Hz; 6.0 Hz,
1H), 1.52e1.45 (m, 2H), 1.42e1.32 (m, 8H), 1.07 (dd, J¼11.9 Hz;
0.05 mmol), Pd(TFA)2 (1.7 mg, 0.005 mmol), (M,S,S)-i-Pr-SPRIX
ꢀ
(2.81 mg, 0.0075 mmol), and 3 A molecular sieves (25 mg) in tol-
uene (0.5 mL) afforded 2-methylene-6,6-diphenyltetrahydro-1H-
10.5 Hz); 13C NMR (100 MHz, CDCl3)
d 168.2, 143.0, 115.3, 56.9, 53.6,
pyrrolizin-3(2H)-one as
110e111 ꢀC; IR (neat) 2925, 2345, 1689, 1657, 1495, 1300 cmꢂ1; 1H
NMR (400 MHz, CDCl3) 7.25e7.20 (m, 4H), 7.16e7.11 (m, 6H), 5.89
a
white solid (11.0 mg, 76%). Mp
45.8, 38.5, 36.8, 32.4, 25.8, 25.6, 23.9, 23.2; HRMS (ESI) calcd for
C26H38N2NaO2: m/z 433.2831 ([2MþNa]þ), found: m/z 433.2822.
The enantiomeric excess was determined by HPLC analysis using
Daicel Chiralcel OD as a chiral stationary phase column with n-
hexane/i-PrOH (100:1) mixture as an eluent (flow rate¼0.6 mL/
n
d
(t, J¼2.7 Hz, 1H), 5.23 (t, J¼2.3 Hz, 1H), 4.23 (d, J¼12.6 Hz, 1H), 3.89
(d, J¼12.3 Hz, 1H), 3.86e3.82 (m, 1H), 2.91 (ddt, J¼15.8 Hz; 7.3 Hz;
1.9 Hz, 1H), 2.54e2.46 (m, 2H), 2.09 (t, J¼11.2 Hz, 1H); 13C NMR
D20
min;
l
¼250 nm; 36.0 min and 64.0 min; 28% ee); [
a
]
ꢂ12.8 (c 0.1,
(100 MHz, CDCl3)
d 169.3, 146.3, 142.8, 128.6, 128.5, 126.9, 126.7,
CHCl3).
126.6, 115.8, 57.3, 56.9, 54.1, 45.0, 32.3; HRMS (ESI) calcd for
C40H38N2NaO2: m/z 601.2831 ([2MþNa]þ), found: m/z 601.2820;
The enantiomeric excess was determined by HPLC analysis using
Daicel Chiralcel OD as a chiral stationary phase column with n-
hexane/i-PrOH (100:1) mixture as an eluent (flow rate¼0.6 mL/
3.3.5. (Z)-2-Benzylidene-9,9a-dihydro-1H-pyrrolo[1,2-a]indol-3(2H)-
one (2g). N-(2-Allylphenyl) cinnamamide (13.2 mg, 0.05 mmol), Pd
(TFA)2 (1.7 mg, 0.005 mmol), (M,S,S)-i-Pr-SPRIX (2.81 mg,
ꢀ
0.0075 mmol), and 3 A molecular sieves (25 mg) in toluene (0.5 mL)
D20
min;
l
¼213 nm; 49.3 min and 56.7 min; 60% ee); [
a
]
ꢂ5.6 (c 0.1,
afforded (Z)-2-benzylidene-9,9a-dihydro-1H-pyrrolo[1,2-a]indol-3
CHCl3).
(2H)-one as a white solid (9.3 mg, 71%). Mp 113e114 ꢀC; IR (neat)
n
2906, 2360, 1686, 1649, 1481, 1302 cmꢂ1; 1H NMR (400 MHz, CDCl3)
3.3.2. 6,6-Dimethyl-2-methylenetetrahydro-1H-pyrrolizin-3(2H)-
one (2b). N-(2,2-Dimethylpent-4-enyl)acrylamide (8.4 mg,
d
7.81 (d, J¼7.3 Hz, 2H), 7.64 (d, J¼7.8 Hz, 1H), 7.29 (t, J¼7.6 Hz, 2H),
7.22 (t, J¼7.3 Hz, 1H), 7.17e7.13 (m, 2H), 6.98 (dt, J¼7.3 Hz; 0.9 Hz,
1H), 6.72 (d, J¼2.3 Hz, 1H), 4.63e4.55 (m, 1H), 3.20e3.11 (m, 2H),
0.05 mmol), Pd(TFA)2 (1.7 mg, 0.005 mmol), (M,S,S)-i-Pr-SPRIX
(2.81 mg, 0.0075 mmol), and 3 A molecular sieves (25 mg) in tol-
2.94e2.84 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 163.8, 140.0, 135.3,
ꢀ
uene (0.5 mL) provided 6,6-dimethyl-2-methylenetetrahydro-1H-
134.5, 133.8, 130.4, 128.6, 128.0, 127.8, 125.2, 124.5, 115.1, 59.4, 39.0,
36.4; HRMS (ESI) calcd for C36H30N2NaO2: m/z 545.2205
([2MþNa]þ), found: m/z 545.2196. The enantiomeric excess was
determined by HPLC analysis using Daicel Chiralcel OD-H as a chiral
stationary phase column with n-hexane/i-PrOH (100:5) mixture as
pyrrolizin-3(2H)-one as a white solid (6.1 mg, 73%). Mp 99e100 ꢀC;
IR (neat)
(400 MHz, CDCl3)
(m, 1H), 3.39 (d, J¼11.9 Hz, 1H), 2.93 (ddt, J¼16.0 Hz; 7.3 Hz; 2.1 Hz,
n ;
2923, 2342, 1687, 1655, 1432, 1236 cmꢂ1 1H NMR
d
5.85 (t, J¼2.8 Hz, 1H), 5.20 (t, J¼2.3 Hz, 1H), 3.92

2894
C. Ramalingan et al. / Tetrahedron 67 (2011) 2889e2894
an eluent (flow rate¼0.5 mL/min;
l
¼312 nm; 40.0 min and
found: m/z 312.1369. The enantiomeric excess was determined by
HPLC analysis using Daicel Chiralcel OD as a chiral stationary phase
column with n-hexane/i-PrOH (100:1) mixture as an eluent (flow
D20
a]
45.3 min; 54% ee); [
ꢂ2.2 (c 0.1, CHCl3).
3.3.6. (Z)-2-(2-Chlorobenzylidene)-9,9a-dihydro-1H-pyrrolo[1,2-a]
indol-3(2H)-one (2h). (E)-N-(2-Allylphenyl)-3-(2-chlorophenyl)ac-
rylamide (14.9 mg, 0.05 mmol), Pd(TFA)2 (1.7 mg, 0.005 mmol),
rate¼0.6 mL/min; ¼216 nm; 45.2 min and 54.6 min; 43% ee).
l
ꢀ
(M,S,S)-i-Pr-SPRIX (2.81 mg, 0.0075 mmol), and 3 A molecular
Acknowledgements
sieves (25 mg) in toluene (0.5 mL) afforded (Z)-2-(2-chlor-
obenzylidene)-9,9a-dihydro-1H-pyrrolo[1,2-a]indol-3(2H)-one as
Financial assistance from Ministry of Culture, Sports, Science
and Technology (MEXT) is gratefully acknowledged. Generous help
from the technical staff of the Comprehensive Analysis Centre of
ISIR is also acknowledged.
a white solid (11.7 mg, 79%). Mp 139e140 ꢀC; IR (neat)
n
2911, 2344,
1686, 1649, 1481, 1302 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
7.95 (dd,
J¼7.3 Hz; 1.8 Hz,1H), 7.65 (d, J¼7.8 Hz,1H), 7.36 (dd, J¼7.3 Hz; 1.8 Hz,
1H), 7.29e7.25 (m, 2H), 7.24e7.18 (m, 2H), 7.05 (dt, J¼7.3 Hz; 0.9 Hz,
1H), 7.00 (d, J¼2.8 Hz, 1H), 4.73e4.64 (m, 1H), 3.32e3.22 (m, 2H),
3.01e2.92 (m, 2H); 13C NMR (100 MHz, CDCl3):
d
163.3, 139.8, 136.2,
References and notes
133.8, 133.5, 132.5, 132.2, 131.4, 129.6, 129.0, 127.9, 126.0, 125.2,
124.7, 115.2, 59.7, 37.8, 36.2; HRMS (ESI) calcd for C36H28Cl2N2NaO2:
m/z 613.1426 ([2MþNa]þ), found: m/z 613.1419. The enantiomeric
excess was determined by HPLC analysis using Daicel Chiralcel OD-
H as a chiral stationary phase column with n-hexane/i-PrOH (100:5)
1. For reviews see: (a) Grigg, R.; Mutton, S. P. Tetrahedron 2010, 66, 5515e5548; (b)
Ferreira, E. M.; Zhang, H.; Stoltz, B. M. Tetrahedron 2008, 64, 5987e6001; (c)
Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107,
5318e5365; (d) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644e4680.
2. (a) Shi, Z.; Zhang, B.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2010, 49, 4036e4041;
(b) Gligorich, K. M.; Sigman, M. S. Chem. Commun. 2009, 3854e3867 and ref-
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Synth. Catal. 2009, 351, 2491e2495; (d) Shi, Z.; Ding, S.; Cui, Y.; Jiao, N. Angew.
Chem., Int. Ed. 2009, 48, 7895e7898; (e) Wang, J.-L.; He, L.-N.; Miao, C.-X.; Li, Y.-
N. Green Chem. 2009, 11, 1317e1320.
3. (a) He, W.; Yip, K.-T.; Zhu, N.-Y.; Yang, D. Org. Lett. 2009, 11, 5626e5628; (b)
Ebner, D. C.; Trend, R. M.; Genet, C.; McGrath, M. J.; O’Brien, P.; Stoltz, B. M.
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Chem. Soc. 2007, 129, 3076e3077; (d) Yoo, K. S.; Park, C. P.; Yoon, C. H.; Saka-
guchi, S.; O’Neill, J.; Jung, K. W. Org. Lett. 2007, 9, 3933e3935; (e) Yip, K.-T.;
Yang, M.; Law, K.-L.; Zhu, N.-Y.; Yang, D. J. Am. Chem. Soc. 2006, 128, 3130e3131;
(f) Akiyama, K.; Wakabayashi, K.; Mikami, K. Adv. Synth. Catal. 2005, 347,
1569e1575; (g) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123,
7725e7726; (h) Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. J. Am. Chem. Soc. 2001,
123, 7475e7476.
4. Arai, M. A.; Arai, T.; Sasai, H. Org. Lett. 1999, 1, 1795e1797.
5. For a review see: Bajracharya, G. B.; Arai, M. A.; Koranne, P. S.; Suzuki, T.; Ta-
kizawa, S.; Sasai, H. Bull. Chem. Soc. Jpn. 2009, 82, 285e302.
6. Takenaka, K.; Tanigaki, Y.; Patil, M. L.; Rao, C. V. L.; Takizawa, S.; Suzuki, T.; Sasai,
H. Tetrahedron: Asymmetry 2010, 21, 767e770.
7. Takenaka, K.; Mohanta, S. C.; Patil, M. L.; Rao, C. V. L.; Takizawa, S.; Suzuki, T.;
Sasai, H. Org. Lett. 2010, 12, 3480e3483.
8. Tsujihara, T.; Shinohara, T.; Takenaka, K.; Takizawa, S.; Onitsuka, K.; Hatanaka,
M.; Sasai, H. J. Org. Chem. 2009, 74, 9274e9279.
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Nat. Compd. 2009, 45, 677e680; (b) Jiang, T.; Livinghouse, T. Org. Lett. 2010, 12,
4271e4273; (c) Tang, M.; Pyne, S. G. J. Org. Chem. 2003, 68, 7818e7824; (d)
Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash, R. J. Phyto-
chemistry 2001, 56, 265e295.
11. (a) Liu, J.-F.; Jiang, Z.-Y.; Wang, R.-R.; Zeng, Y.-T.; Chen, J.-J.; Zhang, X.-M.; Ma, Y.-
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mixture as an eluent (flow rate¼0.5 mL/min;
l
¼314 nm; 39.8 min
and 41.8 min; 61% ee); [
a
]
D20
ꢂ5.0 (c 0.1, CHCl3).
3.3.7. (Z)-2-(4-Fluorobenzylidene)-9,9a-dihydro-1H-pyrrolo[1,2-a]
indol-3(2H)-one (2i). (E)-N-(2-Allylphenyl)-3-(4-fluorophenyl)ac-
rylamide (14.1 mg, 0.05 mmol), Pd(TFA)2 (1.7 mg, 0.005 mmol),
ꢀ
(M,S,S)-i-Pr-SPRIX (2.81 mg, 0.0075 mmol), and 3 A molecular sieves
(25 mg) in toluene (0.5 mL) afforded (Z)-2-(4-fluorobenzylidene)-
9,9a-dihydro-1H-pyrrolo[1,2-a]indol-3(2H)-one as a white solid
(8.8 mg, 63%). Mp 134e135 ꢀC; IR (neat)
n
3073, 2350, 1666, 1635,
1481, 1301 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
d
7.84 (dd, J¼8.7 Hz;
5.5 Hz, 2H), 7.63 (d, J¼7.8 Hz, 1H), 7.16e7.13 (m, 2H), 7.01e6.94 (m,
3H), 6.66 (d, J¼2.3 Hz, 1H), 4.63e4.54 (m, 1H), 3.20e3.10 (m, 2H),
2.93e2.83 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 163.7, 161.6, 139.9,
134.1, 133.8, 132.5, 132.4, 130.7, 130.6, 127.8, 125.2, 124.6, 115.1, 115.0,
114.8, 59.6, 38.7, 36.3; HRMS (ESI) calcd for C36H28F2N2NaO2: m/z
581.2017 ([2MþNa]þ), found: m/z 581.2009. The enantiomeric ex-
cesswas determined byHPLCanalysis using Daicel ChiralcelOD-H as
a chiral stationary phase column with n-hexane/i-PrOH (100:5)
mixture as an eluent (flow rate¼0.5 mL/min;
l
¼311 nm; 32.1 min
and 35.7 min; 59% ee); [
a
]
D20
ꢂ6.4 (c 0.1, CHCl3).
3.4. Isomerized product of 2a, 6-methyl-2,2-diphenyl-2,3-
dihydro-1H-pyrrolizin-5(7aH)-one (2a0)
Colorless oil; 1H NMR (400 MHz, CDCl3)
d 7.25e7.21 (m, 4H),
7.15e7.09 (m, 6H), 5.62e5.58 (m, 1H), 4.54e4.51 (m, 1H), 4.22 (d,
J¼12.5 Hz, 1H), 3.90 (d, J¼12.3 Hz, 1H), 2.59e2.53 (m, 1H), 2.32 (s,
3H), 2.15e2.11 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 168.5, 146.3,
142.1, 134.9, 128.6, 128.5, 127.0, 126.7, 126.5, 57.3, 54.4, 45.0, 44.8,
19.9; HRMS (ESI) calcd for C20H19NNaO: m/z 312.1364 ([MþNa]þ),