Development of catalytic asymmetric 1,4-addition and [3 + 2] cycloaddition reactions using chiral calcium complexes

Article abstract of DOI:10.1021/ja8032058

Catalytic asymmetric 1,4-addition and [3 + 2] cycloaddition reactions using chiral calcium species prepared from calcium isopropoxide and chiral bisoxazoline ligands have been developed. Glycine Schiff bases reacted with acrylic esters to afford 1,4-addition products, glutamic acid derivatives, in high yields with high enantioselectivities. During the investigation of the 1,4-addition reactions, we unexpectedly found that a [3 + 2] cycloaddition occurred in the reactions with crotonate derivatives, affording substituted pyrrolidine derivatives in high yields with high enantioselectivities. On the basis of this finding, we investigated asymmetric [3 + 2] cycloadditions, and it was revealed that several kinds of optically active substituted pyrrolidine derivatives containing contiguous stereogenic tertiary and quaternary carbon centers were obtained with high diastereo- and enantioselectivities. In addition, optically active pyrrolidine cores of hepatitis C virus RNA-dependent polymerase inhibitors and potential effective antiviral agents have been synthesized using this [3 + 2] cycloaddition reaction. NMR spectroscopic analysis and observation of nonamplification of enantioselectivity in nonlinear effect experiments suggested that a monomeric calcium species with an anionic ligand was formed as an active catalyst. A stepwise mechanism of the [3 + 2] cycloaddition, consisting of 1,4-addition and successive intramolecular Mannich-type reaction was suggested. Furthermore, modification of the Schiff base structure resulted in a modification of the reaction course from a [3 + 2] cycloaddition to a 1,4-addition, affording 3-substituted glutamic acid derivatives with high diasterero- and enantioselectivities.

Full text of DOI:10.1021/ja8032058

Published on Web 09/11/2008
Development of Catalytic Asymmetric 1,4-Addition and [3 + 2]
Cycloaddition Reactions Using Chiral Calcium Complexes
Tetsu Tsubogo, Susumu Saito, Kazutaka Seki, Yasuhiro Yamashita, and
Shuj Kobayashi*
Department of Chemistry, School of Science and Graduate School of Pharmaceutical Sciences,
The UniVersity of Tokyo, and The HFRE DiVision, ERATO, Japan Science and Technology
Agency (JST), Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received April 30, 2008; E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Abstract: Catalytic asymmetric 1,4-addition and [3 + 2] cycloaddition reactions using chiral calcium
species prepared from calcium isopropoxide and chiral bisoxazoline ligands have been developed. Glycine
Schiff bases reacted with acrylic esters to afford 1,4-addition products, glutamic acid derivatives, in high
yields with high enantioselectivities. During the investigation of the 1,4-addition reactions, we unexpectedly
found that a [3 + 2] cycloaddition occurred in the reactions with crotonate derivatives, affording substituted
pyrrolidine derivatives in high yields with high enantioselectivities. On the basis of this finding, we investigated
asymmetric [3 + 2] cycloadditions, and it was revealed that several kinds of optically active substituted
pyrrolidine derivatives containing contiguous stereogenic tertiary and quaternary carbon centers were
obtained with high diastereo- and enantioselectivities. In addition, optically active pyrrolidine cores of hepatitis
C virus RNA-dependent polymerase inhibitors and potential effective antiviral agents have been synthesized
using this [3 + 2] cycloaddition reaction. NMR spectroscopic analysis and observation of nonamplification
of enantioselectivity in nonlinear effect experiments suggested that a monomeric calcium species with an
anionic ligand was formed as an active catalyst. A stepwise mechanism of the [3 + 2] cycloaddition,
consisting of 1,4-addition and successive intramolecular Mannich-type reaction was suggested. Furthermore,
modification of the Schiff base structure resulted in a modification of the reaction course from a [3 + 2]
cycloaddition to a 1,4-addition, affording 3-substituted glutamic acid derivatives with high diasterero- and
enantioselectivities.
Introduction
Asymmetric transformations are one of the most important
topics in modern organic chemistry,4 and asymmetric catalysis
is of great current interest.5 In development of highly enanti-
oselective metal catalysts, strict control of the asymmetric
environment around the metal bound by chiral ligands is a very
important subject. Alkaline-earth metals have a larger ionic
radius compared to other elements, such as the transition metals
which are often employed in asymmetric catalysis. The metals
with larger ionic radius have larger coordination sites, which
usually mean that chiral modification of the metals is nontrivial
since flexible coordination geometries are possible. Thus, while
only very few chiral barium catalysts, including our efforts, have
been reported, highly enantioselsctive reactions have not yet
been realized. Not only barium bases6 but also calcium and
strontium bases have been less attractive to asymmetric cataly-
sis.7
Group 2 alkaline-earth metals calcium, strontium, and barium
are recognized as being among the most abundant elements in
the natural world, for example, in the sea or in the earth’s crust.1
While they are familiar to our life, their application to organic
synthesis has been limited. Characteristic points of these
elements are (1) lower electron negativity, (2) stable oxidation
state of 2, which means two covalent bonds with anions are
possible, and (3) various coordination sites.1 Among them, the
lower electronegativity is interesting from the viewpoint of
synthetic chemistry, because it usually leads to stronger Brønsted
basicity of their counteranions. We have recently investigated
organic reactions using barium catalysts and found that barium
aryl oxides work as excellent catalysts in direct-type aldol and
Mannich-type reactions of imides.2 However, the other alkaline-
earth-metal bases, calcium, strontium, and radium, are relatively
understudied.3
Chiral modification of alkaline-earth-metal catalysts has not
been well investigated. In the barium case, previous reports of
chiral diol ligands such as BINOL derivatives were used;
however, the enantioselectivities have not yet reached sufficient
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P. L., Eds.; Wiley: New York, 1995.
(4) (a) Brown, J. M.; Davies, S. G. Nature 1989, 342, 631. (b)
StereoselectiVe Synthesis; Atkinson, R. S., Ed.; Wiley-VCH: Chich-
ester, U.K., 1995.
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Yamamoto, H., Eds.; Springer: Heidelberg, Germany, 1999. (b)
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New York, 2000.
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Saito, S.; Tsubogo, T.; Kobayashi, S. Chem. Commun. 2007, 1236.
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9
10.1021/ja8032058 CCC: $40.75
2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 13321–13332 13321

A R T I C L E S
Tsubogo et al.
pure R-amino acid derivatives.10 Since the first report on
asymmetric alkylation using a chiral phase-transfer catalyst by
O’Donnell et al. in 1978,11 many highly stereoselective reactions
have been developed.10 Among them, asymmetric Michael-type
1,4-addition of Schiff bases of glycine esters to R,ꢀ-unsaturated
carbonyl compounds provides an efficient route to optically
active glutamic acid derivatives.10 Although some successful
examples have been reported in this reaction, excess amounts
of bases or substrates are required to realize high conversions
in most cases.12 However, conceptually a catalytic amount of a
Brønsted base should work effectively in this reaction. We
envisioned that the alkaline-earth metals were suitable for this
reaction and started our investigation to develop asymmetric
1,4-addition reactions of glycine derivatives to R,ꢀ-unsaturated
carbonyl compounds using a chiral-alkaline-earth metal cata-
lyst.13 In this system, a catalytic amount of a Brønsted base
was found to work effectively, which means that this reaction
system is highly atom economical. On the other hand, in the
course of our research, we found that a [3 + 2] cycloaddition
unexpectedly proceeded under similar reaction conditions to
afford optically active pyrrolidine derivatives in good to high
enentioselectivities. It was revealed that small differences in
the substrate structure changed the reaction course dramatically.
Here, we describe full details of our investigation into the
development of catalytic asymmetric 1,4-additions and catalytic
asymmetric [3 + 2] cycloadditions of glycine esters with R,ꢀ-
unsaturated carbonyl compounds using chiral alkaline-earth-
metal-bisoxazoline complexes.
Scheme 1. Alkaline-earth-metal complexes prepared from
bisoxazolidine ligands.
levels.6,7 We turned our attention to the chiral bisoxazoline
skeleton as a model chiral ligand. Bisoxazoline derivatives are
one of the most efficient and often employed chiral ligands in
asymmetric catalysis.8 When the methylene-tethered bisoxazo-
line ligand (e.g., 1-5) is used, the alkaline-earth-metal base
could deprotonate the methylene moiety of the ligand to form
a rigid chiral complex where two nitrogen atoms coordinate
the metal center in a bidentate fashion (Scheme 1).
Furthermore, the other basic site, the remaining alkoxide,
could also deprotonate active protons of substrates to form
optically active carbanions. These types of complexes are known
in asymmetric carbon-carbon bond forming reactions using
stoichiometric amounts of chiral complexes prepared from alkyl
zinc or Grignard reagents, although use of these complexes as
chiral catalysts has been limited.9
Results and Discussion
We started our examination of the 1,4-addition of N-
(diphenylmethylidene)glycine tert-butyl ester (7a) to methyl
acrylate (6a) in THF using alkaline-earth-metal alkoxides.
Except for low activity of the magnesium alkoxide, the calcium,
strontium, and barium alkoxides showed good catalytic activity
(Table 1). In particular, the strontium and barium alkoxides
promoted the reaction smoothly to afford the desired product
in high yields. Addition of 5 Å molecular sieves (MS 5Å) was
very effective, and the calcium alkoxide catalyst also gave a
good yield in a shorter reaction time in the presence of MS 5Å.
With those good results in hand, we decided to examine
asymmetric 1,4-addition using chiral alkaline-earth-metal catalysts.
In our initial investigation, BINOL derivatives were examined
by combining them with calcium isopropoxide; unfortunately,
Recently, catalytic asymmetric carbon-carbon bond forming
reactions using glycine ester derivatives are receiving a lot of
attention since they provide efficient synthetic routes to optically
(6) For use of the Ba catalyst see: (a) Yamada, Y. M. A.; Shibasaki, M.
Tetrahedron Lett. 1998, 39, 5561. (b) Yamaguchi, A.; Aoyama, N.;
Matsunaga, S.; Shibasaki, M. Org. Lett. 2007, 9, 3387.
(7) For use of the Ca catalyst see: (a) Suzuki, T.; Yamagiwa, N.; Matsuo,
Y.; Sakamato, S.; Yamaguchi, K.; Shibasaki, M.; Noyori, R. Tetra-
hedron Lett. 2001, 42, 4669. (b) Kumaraswamy, G.; Sastry, M. N. V.;
Jena, N. Tetrahedron Lett. 2001, 42, 8515. (c) Kumaraswamy, G.;
Jena, N.; Sastry, M. N. V.; Padmaja, M.; Markondaiah, B. AdV. Synth.
Catal. 2005, 347, 867. (d) Kumaraswamy, G.; Jena, N.; Sastry,
M. N. V.; Ramakrishna, G. ARKIVOC 2005, 53. (e) For use of the Sr
catalyst see: Agostinho, M.; Kobayashi, S. J. Am. Chem. Soc. 2008,
130, 2430.
(10) Synthesis of R-amino acid derivatives: (a) Maruoka, K.; Ooi, T. Chem.
ReV. 2003, 103, 3013. (b) O’Donnel, M. J. Acc. Chem. Res. 2004, 37,
506. (c) Nájera, C.; Sansano, J. M. Chem. ReV. 2007, 107, 4584. (d)
Calaza, M. I.; Cativiela, C. Eur. J. Org. Chem. 2008, 3427.
(11) O’Donnell, M. J.; Boniece, J. M.; Earp, S. E. Tetrahedron Lett. 1978,
30, 2641.
(8) Asymmetric reactions using the Box ligand: Desimoni, G.; Faita, G.;
Jørgensen, K. A. Chem. ReV. 2006, 106, 3561.
(9) (a) Lowenthal, R. E.; Abiko, A.; Masamune, S. Tetrahedron Lett. 1990,
31, 6005. (b) Hall, J.; Lehn, J.-M.; DeCian, A.; Fischer, J. HelV. Chim.
Acta 1991, 74, 1. (c) Corey, E. J.; Wang, Z. Tetrahedron Lett. 1993,
34, 4001. (d) Brown, J. M.; Guiry, P. J.; Price, D. W.; Hursthouse,
M. B.; Karalulov, S. Tetrahedron: Asymmetry 1994, 5, 561. (e)
Nakamura, M.; Arai, M.; Nakamura, E. J. Am. Chem. Soc. 1995, 117,
1179. (f) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc.
1996, 118, 8489. (g) Hoffmann, R. W.; Nell, P. G. Angew. Chem.,
Int. Ed. 1999, 38, 338. (h) Schulze, V.; Hoffmann, R. W. Chem.sEur.
J. 1999, 5, 337. (i) Görlitzer, H. W.; Spiegler, M.; Anwander, R.
J. Chem. Soc., Dalton Trans. 1999, 4287. (j) Ward, D. E.; Sales, M.;
Hrapchak, M. J. Can. J. Chem. 2001, 79, 1775. (k) Nakamura, M.;
Hara, K.; Hatakeyama, T.; Nakamura, E. Org. Lett. 2001, 3, 3137. (l)
Hong, S.; Tian, S.; Metz, M. V.; Marks, T. J. J. Am. Chem. Soc. 2003,
125, 14768. (m) Hong, S.; Kawaoka, A. M.; Marks, T. J. J. Am. Chem.
Soc. 2003, 125, 15878. (n) Schulze, V.; Nell, P. G.; Burton, A.;
Hoffmann, R. W. J. Org. Chem. 2003, 68, 4546.
(12) (a) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39, 5347.
(b) Zhang, F.-Y.; Corey, E. J. Org. Lett. 2000, 2, 1097. (c) Ishikawa,
T.; Araki, Y.; Kumamoto, T.; Seki, H.; Fukuda; Isobe, T. Chem.
Commun. 2001, 245. (d) O’Donnell, M. J.; Delgado, F. Tetrahedron
2001, 57, 6641. (e) Shibuguchi, T.; Fukuta, Y.; Akachi, Y.; Sekine,
A.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2002, 43, 9539. (f)
Arai, S.; Tsuji, R.; Nishida, A. Tetrahedron Lett. 2002, 43, 9535. (g)
Akiyama, T.; Hara, M.; Fuchibe, K.; Sakamoto, S.; Yamaguchi, K.
Chem. Commun. 2003, 1734. (h) Ohshima, T.; Shibuguchi, T.; Fukuta,
Y.; Shibasaki, M. Tetrahedron 2004, 60, 7743. (i) Lygo, B.; Allbutt,
B.; Kirton, E. H. M. Tetrahedron Lett. 2005, 46, 4461. (j) Arai, S.;
Takahashi, F.; Tsuji, R.; Nishida, A. Heterocycles 2006, 67, 495. (k)
Ryoda, A.; Yajima, N.; Haga, T.; Kumamoto, T.; Nakanishi, W.;
Kawahata, M.; Yamaguchi, K.; Ishikawa, T. J. Org. Chem. 2008, 73,
133.
(13) Saito, S.; Tsubogo, T.; Kobayashi, S. J. Am. Chem. Soc. 2007, 129,
5364.
9
13322 J. AM. CHEM. SOC. VOL. 130, NO. 40, 2008

Catalytic Addition Reactions Using Chiral Ca Complexes
A R T I C L E S
Table 1. Catalytic 1,4-Addition Reaction of Glycine Schiff Base 7a
to Methyl Acrylate (6a)
Table 3. Optimization of Reaction Conditions in the 1,4-Addition
Reactiona
entry
metal
additivea
time (h)
yield (%)
entry
temp (°C)
additive
solvent
yield (%)
ee (%)
1b
2
3
4
5
6
7
8
9
MS 5Å
24
18
2
18
2
18
2
18
2
no reaction
trace
no reaction
16
76
82
81
91
95
1
2
3
4
5
6
7
8
0
-10
-20
-30
-45
-78
-30
-30
-30
-30
-30
-30
-30
-30
-30
-30
-30
-30
-30
MS 5Å
MS 5Å
MS 5Å
MS 5Å
MS 5Å
MS 5Å
none
MS 3Å
MS 4Å
MS 13X
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
TBME
toluene
CH2Cl2
DME
CH3CN
THF
48
56
56
63
46
36
6
77
71
15
70
23
20
34
44
15
4
82
85
87
87
82
80
2
83
90
3
92
14
11
28
23
<1
28
92
94
Mg(OPr)2
Mg(OPr)2
Ca(OiPr)2
Ca(OiPr)2
Sr(OiPr)2
Sr(OiPr)2
Ba(OtBu)2
Ba(OtBu)2
MS 5Å
MS 5Å
MS 5Å
MS 5Å
9
a 100 mg/0.3 mmol. b 0 °C (8 h) to room temperature (rt).
10
11b
12b
13b
14b
15b
16b
17b
18b,c
19b-d
Table 2. Asymmetric 1,4-Addition Reaction of 7a with 6a Using
Chiral Alkaline-Earth-Metal Complexes
85
88
THF
a The catalyst was prepared at rt for 15 h. b The catalyst was
prepared at rt for 2 h. c The reaction time was 12 h, and 1.2 equiv of the
entry
metal
ligand
yield (%)
ee (%)
i
1
2
3
4
5
6
7
8
Mg(OEt)2
Ca(OiPr)2
Sr(OiPr)2
Ba(OtBu)2
Ca(OiPr)2
Ca(OiPr)2
Ca(OiPr)2
Ca(OiPr)2
1
1
1
1
2
3
4
5
no reaction
glycine derivative was used. d Without removal of PrOH in the catalyst
39
76
79
24
19
54
31
73a
29a
17a
71
preparation step.
sluggishly in their absence (entry 7). MS 3Å to 5Å were
generally effective; 90% ee was obtained in the reaction with
MS 4Å (entry 9), but MS 13X was not effective (entry 10).
The conditions for the catalyst preparation were also examined,
and finally it was found that a shorter preparation time gave a
slight improvement in selectivity (entry 11). The solvent effect
was then studied, and THF was revealed to be the best solvent
for this reaction. Surprisingly, almost all other solvents inves-
tigated gave disappointing results (entries 12-17). For further
improvement of the yield, use of a slightly excess amount of
the glycine derivative over a longer reaction time gave a higher
6a
82
44
a The (S)-enantiomer was obtained.
no significant chiral induction was observed. We then conducted
the reaction using bisoxazoline (Box) ligand 1 (Table 2). To
our delight, the reaction proceeded in moderate to good yields
in the presence of the catalysts prepared from alkaline-earth-
metal alkoxides and ligand 1, and a good enantioselectivity was
observed in the reaction using calcium isopropoxide (entry 2).
While strontium and barium alkoxides showed higher reactivi-
ties, enantioselectivities were insufficient (entries 3 and 4). Those
results indicated that the metal with smaller ionic radius,
calcium, formed a better chiral environment for asymmetric
induction in the reaction. Next, other Box ligands were
investigated. The Box ligand 2 synthesized from 2-amino-1-
indanol showed a little lower selectivity. Among the Box ligands
tested, ligand 4 gave the best result (82% ee).
Optimization of the reaction conditions using calcium iso-
propoxide and ligand 4 was conducted, and the results are
summarized in Table 3. The Ca catalyst was prepared by mixing
Ca(OiPr)2 and ligand 4 in THF at room temperature for 15 h in
the presence of molecular sieves, and then all volatile materials
(THF and iPrOH) were removed under reduced pressure before
the reaction was conducted. First, the effect of the reaction
temperature was examined. In the presence of MS 5Å, the yield
and selectivity were improved at lower temperature, and high
enantioselectivities were obtained at -20 and -30 °C (87%
ee, entries 3 and 4). However, the reactivity and selectivity
decreased at lower temperature (entries 5 and 6). Molecular
sieves were necessary for this reaction; the reaction proceeded
i
yield (entry 18). Moreover, removal of THF and PrOH from
the catalyst system was found not to be necessary at the catalyst
preparation stage, and finally the enantiomeric excess reached
94% under optimized reaction conditions (entry 19).
Next, we investigated the substrate scope of this asymmetric
1,4-addition reaction (Table 4). The effect of the ester parts of
the Schiff bases was examined in the reaction with methyl
acrylate (6a). While the methyl and ethyl (7b) esters showed
higher reactivity, enantioselectivity was lower than the reaction
using the tert-butyl ester (entries 1 and 2). The ester part of the
acrylate was also examined. Ethyl acrylate (6b) and tert-butyl
acrylate (6c) reacted with the Schiff base to afford the desired
products in moderate to good yields with high selectivities
(entries 3 and 4). The acrylamide 6d with a methoxy group on
the N atom (Weinreb amide)14 also reacted with good enanti-
oselectivity (entry 5). Next, the effect of substituents at the
2-position of the acrylates was investigated.15 The reaction of
2-methylacrylate 6e with the glycine ester proceeded smoothly
(14) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815. (b)
Khlestkin, V. K.; Mazhukin, D. G. Curr. Org. Chem. 2003, 7, 967.
(15) Stereoselective synthesis of 4-substituted glutamic acid derivatives:
Belokon, Y. N.; et al. J. Am. Chem. Soc. 2003, 125, 12860.
9
J. AM. CHEM. SOC. VOL. 130, NO. 40, 2008 13323

A R T I C L E S
Tsubogo et al.
Table 4. Substrate Scope of the 1,4-Addition Reactions
Scheme 2. Unexpected Highly Stereoselective [3 + 2]
Cycloaddition Reaction
entry
R1
EWG
R2
product yield (%) 2,4-syn/anti
ee (%)
1
2
H
CO2Me
tBu 8aa
Me 8ac
88
quant
94
83
95
92
H
H
H
H
CO2Me
CO2Et
3a,c
4a,c
5a
6b
7
tBu 8ba 56
t
CO2 Bu
tBu 8ca
74
CONMeOMe tBu 8da 46
87
Me CO2Me
tBu 8ea
tBu 8fa
tBu 8ga
93
quant
81
61/39
63/37
55/45
67/33
91/9
99d/94e
86d/91e
92d/80e
90d/86e
84d
Et
CO2Me
8
iPr CO2Me
iBu CO2Me
Ph CO2Me
9
tBu 8ha quant
10a
11a
tBu 8ia
tBu 8ja
quant
95
Cl
CO2Me
83/17
91/9
81d
12a,c Me CONMeOMe tBu 8ka 83
85d
tBu 8la
43
52
product indicated that [3 + 2] cycloaddition proceeded with
high diastereo- and enantioselectivity (Scheme 2). This result
is remarkable since only one small structural difference,
hydrogen or methyl, on the terminal position of the acrylate
determined the reaction course decisively.
13
H
SO2Ph
a 24 h. b 7a (1.5 equiv) was used. c 6k (1.5 equiv) was used. d ee of
the major product. e ee of the minor product.
to afford two diastereomers in high yield with moderate
diastereoselectivity and excellent enantioselectivities (entry 6).
2-Ethylacrylate 6f, 2-isopropylacrylate 6g, and 2-isobutylacrylate
6h reacted smoothly with high enantioselectivities (entries 7-9).
It was found that the size of the substituents at the 2-position
of the acrylates affected the diastereoselectivity; substrates with
larger groups, 2-phenylacrylate 6i and 2-chloroacrylate 6j,
showed higher syn/anti ratios (entries 10 and 11). 2-Methy-
lacrylamide 6k with an N-methoxy group reacted with the
glycine Schiff base 7a to afford the 1,4-addition product in high
yield with high diastero- and enantioselectivity (entry 12).
Phenyl vinyl sulfone (6l) also worked as an acceptor to afford
the desired 1,4-adduct in moderate yield and selectivity (entry
13). In general, it was revealed that asymmetric 1,4-addition of
glycine esters to acrylate derivatives proceeded well with high
enantioselectivities.
This interesting finding prompted us to investigate catalytic
asymmetric [3 + 2] cycloaddition of glycine esters using the
chiral calcium catalyst.17 At the outset, the ester part of the
crotonates was examined. It was found that substrates with larger
ester groups also reacted to afford the products, but the yields
and selectivities decreased (Table 5, entries 1-3). Notably, the
chiral calcium catalyst worked well at only 0.1 mol % loading
(entry 1). Other ꢀ-substituted acrylates reacted in high enanti-
oselectivities (entries 4-6). Not only crotonates and their
derivatives but also acrylamides afforded [3 + 2] cycloadducts
9 in good yields with very high enantioselectivities (entries
7-9). Substrates with bulkier amide substituents showed slightly
lower selectivities (entry 10). It is noted that single diastereoi-
somers were obtained in all cases and that this is a rare example
Next we planned the asymmetric 1,4-addition reactions of
crotonates using the chiral calcium catalyst. Successful diastereo-
and enantioselective 1,4-addition of glycine enolates to croto-
nates has not yet been reported.16 When the glycine tert-butyl
ester 7a was treated with methyl crotonate (6m) under the
optimized reaction conditions, the reaction proceeded and the
starting material was consumed rapidly; however, the desired
1,4-addition product 8ma was not obtained, but a substituted
pyrrolidine derivative (9ma) as a single diastereomer unexpect-
edly resulted. The structure was unambiguously determined by
X-ray crystallographic analysis.13 Moreover, the enantioselec-
tivity of the product was extremely high. The structure of the
(17) For some recent reviews and examples on catalytic asymmetric [3 +
2] cycloaddion reactions see: (a) Padwa, A.; Pearson, W. H. In
Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry toward
Heterocycles and Natural Products; John Wiley & Sons: New York,
2002. (b) Gothelf, K. V.; Jørgensen, K. A. Chem. ReV. 1998, 98, 863.
(c) Coldham, I.; Hufton, R. Chem. ReV. 2005, 105, 2765. (d) Pandey,
G.; Banerjee, P.; Gadre, S. R. Chem. ReV. 2006, 106, 4484. (e) Gothelf,
A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2002, 41, 4236. (f) Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.;
Kasano, Y.; Minakata, S.; Komatsu, M. Org. Lett. 2003, 5, 5043. (g)
Alemparte, C.; Blay, G.; Jørgensen, K. A. Org. Lett. 2005, 7, 4569.
(h) Gao, W.; Zhang, X.; Raghunath, M. Org. Lett. 2005, 7, 4241. (i)
Husinec, S.; Savic, V. Tetrahedron: Asymmetry 2005, 16, 2047. (j)
Na´jera, C.; Sansano, J. M. Angew. Chem., Int. Ed. 2005, 44, 6272.
(k) Yan, X.-X.; Peng, Q.; Zhang, Y.; Zhang, K.; Hong, W.; Hou, X.-
L.; Wu, Y.-D. Angew. Chem., Int. Ed. 2006, 45, 1979. Syntheses of
quaternary carbon centers in asymmetric [3 + 2] cycloaddition
reactions: (l) Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc.
2003, 125, 10174. (m) Cabrera, S.; Arraya´s, R. G.; Carretero, J. C.
J. Am. Chem. Soc. 2005, 127, 16394. (n) Llamas, T.; Arraya´s, R. G.;
Carretero, J. C. Org. Lett. 2006, 8, 1795. (o) Cabrera, S.; Arraya´s,
R. G.; Mart´ın-Matute, B.; Coss´ıo, F. P.; Carretero, J. C. Tetrahedron
2007, 63, 6587. (p) Na´jera, C.; de Gracia Retamosa, M.; Sansano,
J. M. Org. Lett. 2007, 9, 4025. (q) Fukuzawa, S.-i.; Oki, H. Org. Lett.
2008, 10, 1747. Intramolecular symmetric [3 + 2] cycloadditon
reaction: (r) Stohler, R.; Wahl, F.; Pfaltz, A. Synthesis 2005, 1431.
Organocatalytic asymmetric [3 + 2] cycloaddition reactions: (s)
Vicario, J. L.; Reboredo, S.; Bad´ıa, D.; Carrillo, L. Angew. Chem.,
Int. Ed. 2007, 46, 5168. (t) Xue, M.-X.; Zang, X.-M.; Gong, L.-Z.
Synlett 2008, 691.
(16) (a) Stereoselective synthesis of 3-substituted glutamic acid derivatives:
Soloshonok, V. A. Curr. Org. Chem. 2002, 6, 341. Other representative
examples: (b) Mauger, A. B. J. Org. Chem. 1981, 46, 1032. (c) Achqar,
A. E.; Boumzebra, M.; Roumestant, M, L.; Viallefont, P. Tetrahedron
1988, 44, 5319. (d) Kanemasa, S.; Tatsukawa, A.; Wada, E.; Tsuge,
O. Chem. Lett. 1989, 1301. (e) Kanemasa, S.; Tatsukawa, A.; Wada,
E. J. Org. Chem. 1991, 56, 2875. (f) Alvarez-Ibarra, C.; Csákÿ, A. G.;
Maroto, M.; Quiroga, M. L. J. Org. Chem. 1995, 60, 6700. (g)
Soloshonok, V. A.; Cai, C.; Hruby, V. J. Tetrahedron 1999, 55, 12031.
(h) Ezquerra, J.; Pedregal, C. J. Org. Chem. 1999, 64, 6554. (i)
Soloshonok, V. A.; Cai, C.; Hruby, V. J. Org. Lett. 2000, 2, 747. (j)
Herdeis, C.; Kelm, B. Tetrahedron 2003, 59, 217. (k) Soloshonok,
V. A.; Cai, C.; Yamada, T.; Ueki, H.; Ohfune, Y.; Hruby, V. J. J. Am.
Chem. Soc. 2005, 127, 15296.
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13324 J. AM. CHEM. SOC. VOL. 130, NO. 40, 2008

Catalytic Addition Reactions Using Chiral Ca Complexes
A R T I C L E S
Table 5. Asymmetric [3 + 2] Cycloaddition of 7a to Crotonates
and Acrylamides
Table 6. Asymmetric [3 + 2] Cycloaddition of Glycine Schiff Bases
7 with R,ꢀ-Unsaturated Esters 6
entry
R1
R2
R3
ligand
conditions
product yield (%) ee (%)
1
2
3
4
5
6
7
8
9
Me
tBu
tBu
tBu
tBu
tBu
tBu
H
Me
Me
tBu
tBu
tBu
tBu
tBu
4
4
4
4
3
2
4
4
4
4
4
4
-30 °C, 3 h 10ad
-30 °C, 3 h 10cd
-30 °C, 3 h 10ce
73
78
92
92
32
78
98
67
86
89
86
91
46a
66a
76
76
1
66
76
39
70
84
86
61
H
H
H
H
H
H
0 °C, 3 h
10ce
10ce
10ce
10ce
10md
10od
10me
10oe
10we
0 °C, 12 h
0 °C, 12 h
10 °C, 3 h
10 °C, 3 h
10 °C, 3 h
10 °C, 3 h
10 °C, 3 h
10 °C, 3 h
Me Me Me
tBu Me Me
10 Me Me tBu
11 tBu Me tBu
12 Et
Ph tBu
a The absolute configuration is (2R,4R,5S).
Table 7. Asymmetric [3 + 2] Cycloaddition of Various Glycines
a 0.1 mol % catalyst. The reaction was carried out at 20 °C for 72 h.
Ligand 2 was used. The 1,4-adduct was observed in the isolated product
(3%). The detailed experimental procedure is given in the Supporting
Information. b Ligand 2 was used.
of highly stereoselective [3 + 2] cycloaddition of N-diphenyl-
methylene-protected glycine derivatives.18
entry
R
ligand
conditions
product yield (%) ee (%)
We then conducted the reactions of the aldimines of glycine
esters 7 with R,ꢀ-unsaturated carbonyl compounds 6. When the
benzaldehyde imine 7d derived from glycine tert-butyl ester
was treated with methyl acrylate in the presence of the calcium
catalyst prepared from Ca(OiPr)2 and ligand 4, the reaction
proceeded at -30 °C to afford the cycloadduct 10ad in good
yield but with moderate ee (entry 1, Table 6), and no 1,4-
addition product was obtained. Bulkier ester parts of the
substrates showed higher enantioselectivies (entries 2 and 3).
Interestingly, almost the same selectivity was obtained in the
reactions at -30 and 0 °C (entry 4). Next, the effect of the
ligand structure was investigated. While the Box ligand 3 with
a tert-butyl group gave no chiral induction (entry 5), ligand 2
showed almost the same yield with a slightly lower enaniose-
lectivity (entry 6). The yield was improved at 10 °C with almost
the same selectivity (entry 7). We then examined the reactions
of crotonate derivatives. It was found that bulkier substrates
were also effective to get higher selectivity and that the
enantioselectivity reached 86% ee when tert-butyl esters were
employed (entry 11). Ethyl cinnamate was also employed;
however, the ee was moderate (entry 12). It is noted again that
single diastereomers were obtained in all these cases.
1a
2
3
4
5
6
7
8
9
Ph
p-ClC6H4
p-BrC6H4
p-MeC6H4
m-MeC6H4
o-MeC6H4
3,5-(Me)2C6H3
2-naphthyl
p-MeOC6H4
4
2
4
1
2
4
4
4
4
1
2
2
10 °C, 3 h
-20 °C, 8 h
10 °C, 3 h
-30 °C, 12 h 10oh
-20 °C, 12 h 10oi
10 °C, 3 h
10 °C, 12 h
10 °C, 3 h
10 °C, 12 h
-30 °C, 12 h 10on
-20 °C, 12 h 10oo
-20 °C, 12 h 10op
10oe
10of
10og
86
92
95
92
quant
86
quant
97
86
82
86
87b
91
78
94
92
86
90b
38
29
10oj
10ok
10ol
10om 76
10 2-furyl
97
80
97
11 tBu
12 Cy
a A 1.1 equiv sample of glycine ester was used. b The absolute
configuration of the product was reversed.
lectivities (entries 4-6). Bulkier imines showed higher selectivi-
ties, and the enantiomeric excess reached 94% when an imine
prepared from the 3,5-xylene derivative was used (entry 7). An
electron-rich imine also gave good enantioselectivity using
ligand 4 (entry 9), while a 2-furaldehyde-derived imine also
gave high ee using ligand 1 (entry 10). On the other hand,
cyclohexanecarboxyaldehyde- and pivaldehyde-derived imines
showed lower selectivities (entries 11 and 12). It should be noted
that these reactions are the first successful examples of the
asymmetric [3 + 2] cycloaddition of crotonates.19
The fact that the aldimines reacted with tert-butyl crotonate
(6o) in a [3 + 2] cycloaddition manner in high yields with
perfect diastereoselectivities and high enantioselectivities en-
couraged us to investigate the synthesis of pyrrolidine derivatives
with chiral quaternary carbon centers.17l-q On the basis of our
Next, the substrate scope of the imine part of the glycine
ester 7 was examined (Table 7). In this reaction, ligand 4 as
well as ligands 1 and 2 worked well. Halogen-substituted
aromatic imines reacted smoothly to afford the cycloadducts in
good selectivites (entries 2 and 3). In addition, the effect of the
substitution positions was examined, and among the tolyl
substrates, the meta-substituted one gave the highest enantiose-
(18) For an example of a [3 + 2] cycloadditon reaction using N-
(19) For an example of a [3 + 2] cycloaddition reaction using crotonate,
diphenylmethylene-protected glycine, see ref 17m, o.
see ref 17l.
9
J. AM. CHEM. SOC. VOL. 130, NO. 40, 2008 13325

A R T I C L E S
Tsubogo et al.
Table 8. Asymmetric [3 + 2] Cycloaddition of Schiff Bases Derived
from R-Amino Acids
Table 9. Asymmetric Synthesis of Contiguous Tertiary and
Quaternary Carbon Centers
entry R1
R2
R3
R4
conditions
product yield (%) ee (%)
entry
R1
R2
R3
ligand temp (°C) product yield (%) ee (%)
1
2
Me Me Me Me
Et Me Me Me
0 °C, 12 h
10 °C, 24 h
0 °C, 12 h
0 °C, 18 h
-20 °C, 24 h 12md
-30 °C, 72 h 12nf
-30 °C, 72 h 12me
12ma
12na
12pa
12ya
79
55
64
81
41
50
98
80
87
96
93
96
98
89
93
85
97
95
1
Me Me Me
tBu Me Me
tBu Et Me
tBu Bn Me
tBu Me Et
tBu tBu Bn
tBu Me nBu
tBu Me iBu
tBu Me iPr
4
4
4
4
2
2
2
2
4
2
2
10
10
10
12aa 95
12ca quant
12cb quant
12cc 93
12cd 82
12ce 90
70
90
91
90
96
92
94
87
59
81
93
2a
3
3
Me Et
Me Me
4a
5
Me nBu Me Me
Me Me Me Et
4
10
5a
6a
7a
8a
9
-30
-30
-20
-30
10
-20
-20
6a
7a
8b
Me Me Me nBu
Me Me tBu Bn
12cf
94
Me Me tBu CH2OtBu 10 °C, 24 h
12mj
12qj
12cg 98
12ch 32
9a,b Me iBu tBu CH2OtBu 0 °C, 24 h
10a tBu Me CH2CH2SMe
11a,b tBu tBu CH2OtBu
12ci
12cj
81
80
a Catalyst (20 mol %) was used. b The L-amino acid derivative was
used.
a 12 h. b The L-amino acid was used.
reaction of an alanine derivative with crotonates was examined.
Remarkably, the desired reaction proceeded smoothly to afford
the desired pyrrolidine derivatives as single diastereomers in
moderate to good yields with excellent enantioselectivity (Table
9, entries 1 and 2). Longer chain R,ꢀ-unsaturated esters methyl
2-pentenoate and methyl 2-heptenoate also reacted with the
alanine derivative, and excellent enantioselectivities were
obtained (entries 3 and 4). Next we studied the reactions of
R-substituted R-amino acid esters. In the reaction of 2-ethylg-
lycine derivative 11d, a moderate yield with high enantiose-
lectivity was observed (entry 5). On the other hand, the reactions
of amino esters with larger substituents proceeded slowly, and
high enantioselectivities were also obtained (entries 6 and 7).
Interestingly, an amino ester derived from a bulky serine
derivative reacted with R,ꢀ-unsaturated esters to afford the
desired products in good yields with excellent enantioselectivi-
ties (entries 8 and 9). These results clearly showed that the chiral
calcium catalysts can construct highly sterically hindered and
complicated carbon centers directly with high stereoselectivities.
This is one of the remarkable features of this chiral calcium
catalyst compared to other chiral catalyst systems reported
previously in asymmetric [3 + 2] cycloaddition.17
As discussed, the present catalytic asymmetric [3 + 2]
cycloaddition reactions have a wide substrate scope with high
diastereo- and enantioselectivities. We then decided to synthesize
optically active pyrrolidine cores of biologically active com-
pounds using this [3 + 2] cycloaddition reaction. Compounds
13ck and 13cl are hepatitis C virus RNA-dependent polymerase
inhibitors and potential effective antiviral agents,21 and quite
recently, two groups have reported asymmetric total syntheses
of these compounds.22 However, their methods were not
necessarily satisfactory in terms of efficiency, especially a
stoichiometric use of a chiral source or moderate enantioselec-
tivity. We conducted the [3 + 2] cycloaddition reaction of 11k
working model, a calcium enolate formed in the reaction of the
glycine ester with calcium isopropoxide, where the nitrogen
atom of the enolate could coordinate to the calcium atom,
resulting in bidentate coordination. Therefore, it was assumed
that the substituent at the R-position of the enolate would not
significantly affect the asymmetric environment. In addition,
since the bulkiness of the imine part improved the enantiose-
lectivity in the earlier system, we envisioned that introduction
of appropriate steric bulk at the R-position of the enolate might
improve the enantioselectivity.
First, we investigated the reactions of alanine derivatives with
R,ꢀ-unsaturated carbonyl compounds. The benzilidene-protected
alanine methyl ester reacted with methyl acrylate to afford the
desired [3 + 2] adduct 12aa in good enantioselectivity (Table
8, entry 1). In this reaction, bulkier ester parts also gave better
effects, and the highest enantioselectivity was obtained using
tert-butyl acrylate (entry 2). In contrast, the selectivity did not
depend on the structure of the alanine ester part (entries 2-4).
Amino acid esters with simple alkyl substituents on their
R-positions were also investigated (entries 5-9). 2-Ethylglycine,
phenylalanine, norleucine, and leucine derivatives also gave
good to high selectivities, although the valine derivative did
not work well presumably due to a steric factor (entry 9). We
also investigated the reactions of the amino acid derivatives with
R-substituents containing heteroatoms. Methionine and O-tert-
butylserine derivatives also worked well, and good to high
enantioselectivities were obtained (entries 10 and 11). In all
cases, single diastereomers were obtained exclusively. It is noted
that this method is superior to other previous chiral pyrrolidine
syntheses17 via asymmetric [3 + 2] cycloaddition in terms of
yields and diastereo- and enantioselectivities and that chiral
quaternary carbon centers have been constructed efficiently.
As a more challenging trial, we further investigated asym-
metric synthesis of pyrrolidine derivatives containing contiguous
chiral tertiary and quaternary carbon centers. This kind of
complex molecule is usually difficult to synthesize, especially
in an enantiomerically pure form, since steric bulk around the
reaction site often prevents strict enantioselection.20 First, the
(21) (a) Slater, M. J.; et al. J. Med. Chem. 2007, 50, 897. (b) Burton, G.;
Ku, T. W.; Carr, T. J.; Kiesow, T.; Sarisky, R. T.; Lin-Goerke, J.;
Baker, A.; Earnshaw, D. L.; Hofmann, G. A.; Keenan, R. M.; Dhanak,
D. Bioorg, Med. Chem. Lett. 2005, 15, 1553. (c) Burton, G.; Ku, T. W.;
Carr, T. J.; Kiesow, T.; Sarisky, R. T.; Lin-Goerke, J.; Hofmann, G. A.;
Slater, M. J.; Haigh, D.; Dhanak, D.; Johnson, V. K.; Parry, N. R.;
Thommes, P. Bioorg. Med. Chem. Lett. 2007, 17, 1930.
(20) Syntheses of contiguous chiral tertiary and quaternary carbon ceters
using ꢀ-substituted acrylates were not reported, but those using
maleimides were reported; see ref 17m,o,p.
(22) (a) Na´jera, C.; de Gracia Retamosa, M.; Sansano, J. M.; de Co´zar,
A.; Coss´ıo, F. P. Eur. J. Org. Chem. 2007, 5038. (b) Agbodjan, A. A.;
et al. J. Org. Chem. 2008, 73, 3094.
9
13326 J. AM. CHEM. SOC. VOL. 130, NO. 40, 2008

Catalytic Addition Reactions Using Chiral Ca Complexes
A R T I C L E S
Scheme 3. Syntheses of Pyrrolidine Derivatives Containing a
Heteroaromatic Ring
Table 10. Asymmetric 1,4-Addition Reactions of Cysteine
Derivative 11m
entry
R
ligand
product
yield (%)
ee (%)
1
2
3
4
OMe
1
4
1
1
15am
15am
15cm
15dm
83
77
66
71
86
86a
83
80
OMe
OtBu
NMeOMe
a The absolute configuration of the product was reversed compared to
that of the other entries.
Scheme 4. Asymmetric 1,4-Addition Reaction Using Calcium
Bisoxazolidine 16
or 11l, which contained heteroaromatic moieties, in the presence
of the chiral calcium catalyst. It was found that under optimized
reaction conditions the desired products were obtained in high
yields with perfect diastereoselectivities and high enantioselec-
tivities (Scheme 3). It was shown that our method was a
powerful tool for construction of these kinds of pyrrolidine
compounds in optically active form.
We also applied the calcium catalyst system to the synthesis
of 1,4-addition products containing a chiral quaternary carbon
center. R-Alkylcysteines are recognized as important building
blocks for biologically active peptide mimics, and asymmetric
synthesis of these compounds is valuable in medicinal chemistry
and pharmaceutical sciences.23 However, few reports concerning
efficient synthesis of chiral R-alkylcysteines by asymmetric 1,4-
addition reactions have appeared.24 We tested the chiral calcium
system in the 1,4-addition reaction. A Schiff base (11m) derived
from cysteine was employed as a substrate, and the reaction
with methyl acrylate (6a) proceeded smoothly to afford the
desired product 15am with high enantioselectivity in the
presence of a 10 mol % concentration of the calcium catalyst
prepared from ligand 1 or 4 (Table 10, entries 1 and 2). Other
acrylic esters and acrylamides also reacted in good to high yields
with high enantioselectivities (entries 3 and 4).
Chart 1. 1H NMR Analysis of a Calcium Complex Prepared from
Ligand 2
Reaction Mechanism. 1. Catalyst Structure. We assume that
the calcium metal is coordinated by the chiral ligand in a
covalent fashion via deprotonation of the tethering methylene
moiety in the resulting calcium complexes.25 This complex
should be completely different from a gem-dimethyl-tethered
Box complex. To confirm this assumption, we conducted the
reaction of 6a with 7a in the presence of Ca(OiPr)2 and Box
ligands 16 with dialkyl groups (no tethered methylene moiety).
It was found that the reactions proceeded sluggishly, and very
low enantioselectivities were obtained (Scheme 4). These results
clearly showed that the active catalyst required the nonsubsti-
tuted methylene moiety and could support the assumption that
the ligand coordinated to the calcium in an anionic manner via
deprotonation.
(23) Goodman, M.; Ro, S. In Burger’s Medicinal Chemistry and Drug
DiscoVery, 5th ed.; Wolff, M. E., Ed.; John Wiley & Sons: New York,
1995; Vol. 1, Chapter 20, pp 803-861.
To obtain further information on the catalyst structure, we
conducted NMR spectroscopic experiments on this calcium
complex. At first, a catalyst solution prepared from Ca(OiPr)2
(24) Asymmetric alkylation of a cysteine Schiff base has been reported:
(a) Kim, T.-S.; Lee, Y.-J.; Jeong, B.-S.; Park, H.-g.; Jew, S.-s. J. Org.
Chem. 2006, 71, 8276. Other related works: (b) Jew, S.-s.; Lee, Y.-J.;
Lee, J.; Kang, M. J.; Jeong, B.-S.; Lee, J.-H.; Yoo, M.-S.; Kim, M.-
J.; Choi, S.-h.; Ku, J.-M.; Park, H.-g. Angew. Chem., Int. Ed. 2004,
43, 2382. (c) Lee, Y.-J.; Lee, J.; Kim, M.-J.; Jeong, B.-S.; Lee, J.-H.;
Kim, T.-S.; Lee, J.; Ku, J.-M.; Jew, S.-s.; Park, H.-g. Org. Lett. 2005,
7, 3207. (d) Lee, Y.-J.; Lee, J.; Kim, M.-J.; Kim, T.-S.; Park, H.-g.;
Jew, S.-s. Org. Lett. 2005, 7, 1557.
1
and ligand 2 in THF-d8 was analyzed by H and 13C NMR.
Expectedly, a pair of peaks appeared in the spectra shown in
Charts 1 and 2, and the chemical shifts of the peaks were
reasonable compared to the data of reported anionic metal
species.9i The peaks observed were the same as to those
9
J. AM. CHEM. SOC. VOL. 130, NO. 40, 2008 13327

A R T I C L E S
Tsubogo et al.
Chart 2. 13C NMR of a Calcium Complex Prepared from Ligand 7
Figure 1. Relationship between the optical purity of the ligand and the ee
of the product.
Scheme 5. Asymmetric [3 + 2] Cycloaddition Using a Chiral
Ca-HMDS Complex
Table 11. Relationship between the Optical Purity of the Ligand
and the ee of the Product
entry
ligand ee (%)
yield (%)
ee (%)
1
2
3
4
5
>99
71
51
31
0
88
84
91
80
85
94
71
52
30
1
weight of the calcium complexes using 1, 2, and 4 were not
successful, we examined the relationship between the product ee
and the optical purity of the ligand.26 The results are shown in
Table 11 and Figure 1. No nonlinear effect was observed, and the
same reactivity was obtained when a racemic ligand was used.
These results might suggest that the calcium catalyst worked as a
monomeric species without significant aggregation to afford the
desired product in high enantioselectivity.
2. Reaction Course and Catalytic Cycle. A possible mecha-
nism of the calcium-catalyzed asymmetric 1,4-addition is shown
in Figure 2. The chiral calcium complex deprotonated the
R-position of the glycine derivative 7 to form a chiral calcium
enolate (1B), in which the imine nitrogen also coordinated to
the calcium atom. The enolate then reacted with an R,ꢀ-
unsaturated carbonyl compound (6) with high enantioselection
to form the 1,4-addition product initially as a calcium enolate
(1C). Further, the enolate 1C was protonated with glycine
derivative 7 to afford the product 8 along with regeneration of
the reactive calcium enolate 1B (pathway 1). Alternatively, the
free alcohol iPrOH quenched 1C to give 8 and the active calcium
complex 1A (pathway 2).
observed in NMR analysis of a complex prepared from calcium
bis(trimethylsilyl)amide (Ca(HMDS)2)25b,c and ligand 2.
We also investigated the asymmetric [3 + 2] cycloaddition
reaction using the chiral Ca-HMDS complex (Scheme 5). The
reaction proceeded well and provided the desired adduct in high
yield with high enantioselectivity. This result also supports the
assumption that ligand 2 coordinated to the calcium in an anionic
manner, and we assured the structures of the active calcium
catalysts are those shown in Scheme 5.25h
Next we investigated an aggregation state of the active calcium
species. It is known that calcium-diimine complexes form dimeric
structures easily in solution.25 While measurements of the molecular
(25) (a) Westerhausen, M.; Digeser, M. H.; No¨th, H.; Seifert, T.; Pfitzner,
A. J. Am. Chem. Soc. 1998, 120, 6722. (b) Brady, E. D.; Hanusa,
T. P.; Pink, M.; Young, V. G., Jr. Inorg. Chem. 2000, 39, 6028. (c)
He, X.; Noll, B. C.; Beatty, A.; Mulvey, R. E.; Henderson, K. W.
J. Am. Chem. Soc. 2004, 126, 7444. (d) Avent, A. G.; Crimmin, M. R.;
Hill, M. S.; Hitchcock, P. B. Dalton Trans. 2004, 3166. (e) Crimmin,
M. R.; Casely, I. J.; Hill, M. S. J. Am. Chem. Soc. 2005, 127, 2042.
(f) Avent, A. G.; Crimmin, M. R.; Hill, M. S.; Hitchcock, P. B. Dalton
Trans. 2005, 278. (g) Ahmed, S. A.; Hill, M. S.; Hitchcock, P. B.
Organometallics 2006, 25, 394. (h) We could not exclude a possibility
that the complexes formed in the catalyst solution were a Ca-ligand
(1:2) complex; however, real active species should be a Ca-ligand
(1:1) complex.
(26) Girard, V.; Kagan, H. B. Angew. Chem., Int. Ed. 1998, 37, 2922.
(27) (a) Tatsukawa, A.; Kawatake, K.; Kanemasa, S.; Rudzin´ski, J. M.
J. Chem. Soc., Perkin Trans. 2 1994, 2525. (b) Neumann, F.; Lambert,
C.; von Rague´ Schleyer, P. J. Am. Chem. Soc. 1998, 120, 3357. (c)
Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.;
Coss´ıo, F. P. J. Am. Chem. Soc. 2000, 122, 6078. (d) Zubia, A.;
Mendoza, L.; Vivanco, S.; Aladaba, E.; Carrascal, T.; Lecea, B.;
Arrieta, A.; Zimmerman, T.; Vidal-Vana-clocha, F.; Coss´ıo, F. P.
Angew. Chem., Int. Ed. 2005, 44, 2903.
9
13328 J. AM. CHEM. SOC. VOL. 130, NO. 40, 2008

Catalytic Addition Reactions Using Chiral Ca Complexes
A R T I C L E S
Figure 2. Catalytic cycle of the 1,4-addition reaction.
Scheme 6. Two Possible Reaction Mechanisms of the [3 + 2] Cycloaddition Reaction
Scheme 7. [3 + 2] Cycloaddition with Fumaric or Maleic Esters
On the other hand, two reaction mechanisms are possible for
the [3 + 2] cycloaddition reaction; either a concerted or a
stepwise pathway is plausible (Scheme 6). Until now, few
mechanistic studies of the reaction have been reported; for
example, Kanemasa et al. reported that the [3 + 2] cycloaddition
of a lithium enolate of a glycine derivative to R,ꢀ-unsaturated
carbonyl compounds proceeded in a stepwise mechanism on
the basis of their computational study.27a Other groups have
also described that reactions of glycine enolates with electron-
deficient olefins proceeded in a stepwise mechanism.27b-d
First, we compared the absolute configuration of the 1,4-
adduct 8aa and the [3 + 2] cycloadduct 9ma. It was found that
the absolute configurations of the stereogenic carbons at the
2-positions of both products were the same, which indicated
that the activated olefin approached the calcium enolate from
the same face. Next we investigated the reactions of fumaric
diester (E)-17 and maleic diester (Z)-17 in the [3 + 2]
cycloaddition. If the reaction were to proceed via the concerted
mechanism, only two diastereomers would be formed; namely,
(E)-17 would give a trans product, while (Z)-17 would give a
cis product (Scheme 7).
proceeded to afford only trans diastereomers (trans-18ae), and
the enantioselectivity of the major product was moderate. On
the other hand, the reaction with (Z)-17a gave the products as
a cis and trans mixture with moderate enantioselectivities
(Scheme 8). In the reaction system, isomerization of (Z)-17a to
(E)-17a was not observed by TLC analysis. These results
support the assumption that the reactions proceeded via a
When (E)-17a was treated with 7e in the presence of
Ca(OiPr)2 (10 mol %) and ligand 4 (10 mol %), the reaction
9
J. AM. CHEM. SOC. VOL. 130, NO. 40, 2008 13329

A R T I C L E S
Tsubogo et al.
Figure 3. Proposed catalytic cycle of the [3 + 2] cycloaddition reaction.
Scheme 8. Asymmetric [3 + 2] Cycloadditions with Fumaric or
Maleic Ester
stepwise mechanism, and a proposed catalytic cycle is shown
in Figure 3. The enolate intermediate 3C generated by the initial
1,4-addition would attack the imine part of the same molecule
to form a pyrrolidine derivative with high stereoselectivity.
On the basis of this mechanism, we can reasonably explain
these interesting results. As we have already described, acrylates
gave 1,4-adducts exclusively with high enantioselectivity (Table
4), while acrylamides gave [3 + 2] cycloadducts exclusively
(Table 5). The major difference between these reactions is only
the structure of the ester or amide part. Also the reactions of
aldehyde-protected glycine derivatives 7d-p gave only [3 +
2] cycloadducts (Tables 6 and 7). We could explain these results
by assuming a stepwise mechanism mainly based on the
reactivity of the enolate intermediate in the second cyclization
step. In the reactions of benzophenone derivatives of glycine
7a-c, the nucleophilicity of the generated enolate intermediates
toward the ketimine part is an important factor. The amide
enolates formed by the reactions of acrylamides are more
reactive than the ester enolates formed by the reactions of
acrylates to afford the cyclic adducts. The ester enolates are
less reactive and are protonated by the substrates or the free
alcohol in the reaction system to afford the 1,4-addition products.
In the cases of the aldehyde-protected glycine derivatives 7,
the reactivity of the aldimine part is higher than that of the
ketimine part, and therefore, the less reactive acrylate-derived
enolates could attack the imine to give the [3 + 2] cycloaddition
products 10.
A special case is the [3 + 2] cycloaddition of crotonates,
where the reactions proceeded faster and only [3 + 2] cycload-
ducts were obtained. To further elucidate the reaction mecha-
nism, we investigated the [3 + 2] cycloaddtion reaction of
methyl crotonate (6m) with 7 using bisoxazoline ligands (Table
12). When the reaction was conducted in the absence of ligand,
the product was obtained as a mixture of the 1,4-addition adduct
and the [3 + 2] cycloaddition product (entry 1), while only the
[3 + 2] cycloaddition product was obtained in the reaction using
ligand 2 or 4 (entries 2 and 3). These results suggested that
steric factors of the ligand could affect the reaction course.
Therefore, we performed the reaction using less sterically
demanding ligand 14 bearing isopropyl groups. As predicted,
the product was obtained as a mixture of the 1,4-addition product
and the [3 + 2] cycloadduct with high enantioselesctivities (entry
4). This fact showed that the steric bulk of the chiral ligand
affected the reaction course significantly and that the reactions
of crotonates also proceeded in a stepwise fashion, through 1,4-
addition and cyclization pathways. As further evidence, the
reaction of the glycine derivative bearing a bis(p-methoxyphe-
nyl)methylene group (7r) with methyl crotonate (6m) proceeded
smoothly to afford a mixture of the 1,4-addition product and
the [3 + 2] cycloadduct in high yields with similar excellent
enantioselectivities (entry 5). This result also suggested a
stepwise mechanism because the imine part of the glycine
derivative was less electrophilic and less prone to be attacked
in an intramolecular fashion due to the electron-donating effect
of the methoxy groups. On the basis of these experimental
findings, we concluded that the [3 + 2] reaction of R,ꢀ-
unsaturated carbonyl compounds with glycine Schiff bases
proceeds in a stepwise manner.
As mentioned above, the N-diphenylmethylidene-protected
glycine derivatives reacted with crotonates or acrylamides to
afford [3 + 2] cycloadducts. This is remarkable because only
1,4-addition reaction occurred in combination with these
9
13330 J. AM. CHEM. SOC. VOL. 130, NO. 40, 2008

Catalytic Addition Reactions Using Chiral Ca Complexes
A R T I C L E S
Table 12. Effect of Ligands on the Reaction Courses
Scheme 9. Comparison of the Reaction Rate Using a
Stoichiometric Amount of the Catalyst
entry
Ar
ligand
yield (%)
8/9a
ee (%)
1
2
3
4
5
Ph
Ph
Ph
Ph
none
2
4
14
4
34
95
62/38
9mc only
9mc only
18/82
99
99
>99
quantb
90
98c
p-MeOC6H4
18/82
96/98
a Determined by NMR spectroscopic analysis. 8 was obtained as a
single diastereomer in all cases. b Determined by NMR spectroscopic
analysis using 1,1,2,2,-tetrachloroethane as an internal standard. c ee of
the [3 + 2] cycloaddition product.
Table 13. Effect of Protic Additives
substrates in previously reported cases due to lower reactivity
of the bulky ketimine group as an electrophile; this could be
explained by the reactivity difference of the metal enolates of
the intermediates. Compared to other metal enolates (Co, Ag,
etc.), alkaline-earth-metal enolates show higher reactivity.
Presumably interaction between oxygen anions and alkaline-
earth-metal cations is not strong; that is, the corresponding
enolates would be more reactive than other metal enolates.
Therefore, it is reasonable to assume that the highly reactive
intermediates alkaline-earth-metal enolates can attack the ketimine
parts efficiently to afford the [3 + 2] cycloadducts.
We also observed a significant difference of the reaction rate
between the 1,4-addition to acrylates and [3 + 2] cycloaddition to
crotonates. The [3 + 2] cycloaddition to crotonates proceeded faster
than the 1,4-addition, which seemed counterintuitive since the
sterically hindered crotonate reacted faster than the less hindered
acrylate. In our hypothesis, the chiral calcium-catalyzed reactions
proceed via 1,4-addition and successive intramolecular cyclization;
therefore, the observed reaction rate does not correspond to that
expected in the proposed mechanism. One possible explanation
of this phenomenon is offered by considering the rate difference
of the second steps in the mechanisms (protonation step or
cyclization/protonation steps in Figure 3). If the rate of the second
step, protonation, in the reaction with the acrylate is slower than
the rate of the cyclization/protonation steps in the reaction with
the crotonate, that observation could be made. To clarify this point,
we conducted the reactions of the acrylate and the crotonate in the
presence of a stoichiometric amount of the chiral calcium catalyst
over a shorter reaction time. As a result, the reaction of the acrylate
proceeded faster than that of the crotonate with a significant rate
difference, which supports our hypothesis that the observed rate
difference in the catalytic reactions is caused by efficiency of
the second steps (Schemes 8 and 9). The rate difference of the
second steps, protonation and cyclization/protonation steps, could
be ascribed to the basicity of the intermediates calcium enolate
and calcium amide.
ee of 8ma/ee
of 9ma (%)
entry
additive (mol%)
yield (%) 8maa/9ma
1
2
3
4
5
6
7
quant 9ma only
-/99
0/82
(CF3)2CHOH (10)
PhOH (10)
p-MeOC6H4OH (10)
2,6-Me2C6H3OH (10)
2-phenylphenol (10)
85
90
46
71
89
58/42
11/89
8/92
44/56
68/32
56/46
-/95
-/94
19/77
20/68
23/87
2-(2-methoxyphenyl)phenol (10) 78
a 8ma was obtaind as a single diastereomer in all cases.
R-amino acid derivatives; however, successful examples are very
limited.16 We started an investigation to realize the 1,4-addition
reaction of a ketimine-protected glycine derivative with methyl
crotonate (6m). First, we tried to trap the corresponding intermedi-
ate in the reaction system. Addition of proton sources was
investigated for trapping the 1,4-adduct intermediate (Table 13).
Acidic alcohols and phenol derivatives were examined in the
reaction system; however, in most cases, the [3 + 2] cycloadduct
was obtained preferentially. When 2-substituted phenol derivatives
were employed, the 1,4-adduct was obtained predominantly, but
the enantioselectivities were insufficient.
Next we carried out the reaction of a glycine derivative with a
bulkier substituent at the imine part, which could prevent the second
cyclization step to afford the 1,4-addition product. We synthesized
and employed the glycine derivative 7s with tert-butylphenylm-
ethylidene28 as a protecting group in the reaction with methyl
crotonate (6m). Expectedly, the 1,4-addition products were obtained
exclusively as a single diastereomer with high enantioselectivity
by using calcium-2 catalyst (Table 14, entry 1).13,29
3. Diastereoselective and Enantioselective 1,4-Addition. If the
reaction of crotonates proceeds via a stepwise pathway, we still
have a chance to obtain 1,4-adducts exclusively by optimizing the
reaction conditions. Asymmetric 1,4-addition of glycine derivatives
to crotonates is also an important method for synthesizing branched
By using glycine derivative 7s, we could control the reactions
with crotonate derivatives in favor of the 1,4-addition reaction. As
shown in Table 14, not only crotonates but also 2-pentenoate,
2-heptenoate, and 5-methyl-2-hexenoate reacted with the glycine
9
J. AM. CHEM. SOC. VOL. 130, NO. 40, 2008 13331

A R T I C L E S
Tsubogo et al.
Table 14. Asymmetric 1,4-Addition Reactions with ꢀ-Substituted
R,ꢀ-Unsaturated Carbonyl Compounds
that the tert-butylphenylmethylidene group is a useful hindered
protecting group for amino acid derivatives. Intramolecular
cyclization of 21 occurred easily (standing neat at room
temperature) to afford 5-prolinone derivative 22 in high yield.
Further hydrolysis of 22 afforded free 3-methylglutamic acid
(23) in good yield. The absolute configuration of 23 was
determined by comparing the optical rotation of 23 to that
previously reported.31 It is noted that this 1,4-addition reaction
provides a facile preparation of optically active 3-methyl-
glutamic acid derivatives and proline derivatives.
entry
R1
R2
product
dr
yield (%)
ee (%)
1
2
3
Me
Me
Et
OMe
OEt
OMe
OEt
OMe
OMe
20ms
20ns
20ps
20xs
20ys
20qs
20zs
>99/1 97 (93)c 99 (99)a
Conclusion
>99/1 95
>99/1 96
>99/1 97
>99/1 73
>99/1 56
93
96
94
91
82
96
98
96
95
82
51
We have investigated catalytic asymmetric 1,4-addition reactions
of glycine derivatives using chiral alkaline-earth-metal complexes
as catalysts. It was found that chiral anionic calcium-Box
complexes were effective for the reaction, and high yields and high
enantioselectivities have been achieved. Compared to previously
reported reaction systems, this catalyst system is simpler since only
a catalytic amount of Brønsted base is employed. Furthermore, in
the reactions of crotonates, [3 + 2] cycloaddition reactions
proceeded by using the same reaction system to afford the chiral
pyrrolidines in high yields with high diastereo- and enantioselec-
tivities. It is remarkable that small differences in substrate structure
affected the reaction course and changed the product structure
dramatically. Not only aldehyde-protected glycine derivatives but
also ketimine-protected glycine derivatives reacted with active
olefins to afford substituted pyrrolidines. Moreover, the first
successful asymmetric 1,4-addition reactions of crotonates have
been realized by modifying the protecting groups of the amine parts.
Remarkably, the calcium catalyst could construct contiguous chiral
tertiary and quaternary carbon stereocenters with high stereose-
lectivities in the [3 + 2] cycloaddition reactions of R-substituted
R-amino acid derivatives and 3-substituted acrylates. It is noted
that the current chiral calcium catalyst expanded possibilities of
the asymmetric 1,4-addition and [3 + 2] cycloaddition reactions
of R-amino acid derivatives. The reaction mechanism of the [3 +
2] cycloaddition was also investigated, and a stepwise mechanism,
1,4-addition and successive intramolecular cyclization, was pro-
posed. High reactivity of the second alkaline-earth-metal enolates
made the intramolecular cyclization step smooth, thus affording
highly substituted chiral pyrrolidine derivatives.
4
Et
5b
6c
7
nBu
iBu
BnOCH2 OEt
82/18
82
8
Me
Et
NMeOMe 20rs
NMeOMe 20ꢀs
NMeOMe 20γs
NMe2
NMe2
>99/1 94
>99/1 92
>99/1 89
22
9c
10c
11d
12e
iBu
H
20ss
20δs
Me
88/12
2
a 2 mol %. b -20 °C, 48 h. c 24 h. d 0 °C. e 40 h.
Scheme 10. Transformation of 1,4-Adduct 20 ms
derivative in a 1,4-addition manner with good to high enantiose-
lectivities (entries 2-6). A crotonate derivative substituted by a
benzyloxy group at the terminal methyl moiety (6z) also gave high
selectivity (entry 7). On the other hand, reactions with crotonamides
showed a different tendency; for crotonamides with an N-methoxy
group (6r) and ꢀ-substituted acrylamides with an N-methoxy group
(6ꢀ and 6γ) a high yield and high selectivity were obtained (entries
8-10). However, the reactions using N,N-dimethylacrylamide (6s)
and N,N-dimethylcrotonamide (6δ) showed lower conversions
(entries 11 and 12). It should be noted that this is the first example
of catalytic highly stereoselective 1,4-addition of a glycine enolate
to crotonates.
Deprotection of this tert-butylphenylmethylidene group on
the nitrogen atom of the product was also studied.30 Simple
acid hydrolysis was found to be effective for removal of this
group, and the corresponding primary amine product 21 was
obtained in high yield (Scheme 10). This result demonstrates
Calcium is one of the most abundant elements in the natural
world and an easily available metal. Also Box-type ligands are
quite effective for preparing asymmetric environments around metal
centers, and most of them can be prepared from natural chiral amino
acids readily available. The use of these cheap and naturally
abundant metals in fine organic synthesis is quite important from
both economical and environmental points of view. Further
investigations using alkaline-earth metals as effective Brønsted base
catalysts in organic chemistry are in progress.
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research from the Japan Society of the
Promotion of Sciences (JSPS). S.S. thanks the JSPS Research
Fellowship for Young Scientists.
(28) (a) Duhamel, P.; Eddine, J. J.; Valonot, J.-Y. Tetrahedron Lett. 1984,
25, 2355. (b) Tsuge, O.; Kanemasa, S.; Yoshioka, M. J. Org. Chem.
1988, 53, 1384. (c) Duhamel, L.; Duhamel, P.; Fouquay, S.; Eddine,
J. J.; Peschard, O.; Plaquevent, J.-C.; Ravard, A.; Solliard, R.; Valonot,
J.-Y.; Vincens, H. Tetrahedron 1988, 44, 5495. (d) Kanemasa, S.;
Uchida, O.; Wada, E. J. Org. Chem. 1990, 55, 4411. (e) Casas, J.;
Grigg, R.; Na´jera, C.; Sansano, J. M. Eur. J. Org. Chem. 2001, 1971.
(29) Kobayashi, S.; Tsubogo, T.; Saito, S.; Yamashita, Y. Org. Lett. 2008,
10, 807.
Supporting Information Available: Experimental procedures,
product characterization, and complete refs 15, 21a, and 22b.
This material is available free of charge via the Internet at http://
pubs.acs.org.
JA8032058
(30) Ooi, T.; Kameda, M.; Taniguchi, M.; Maruoka, K. J. Am. Chem. Soc.
2004, 126, 9685.
(31) Wehbe, J.; Rolland, V.; Roumestant, M. L.; Martinez, J. Tetrahedron:
Asymmetry 2003, 14, 1123.
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13332 J. AM. CHEM. SOC. VOL. 130, NO. 40, 2008