Synthesis of glutamic acid and highly functionalized pyrrolidine derivatives by utilizing tunable calcium catalysts for chemoselective asymmetric 1,4-addition and [3+2] cycloaddition reactions

Article abstract of DOI:10.1002/adsc.201300171

A current trend in organic chemistry is the development of highly efficient, environmentally friendly and inexpensive catalysts for asymmetric transformations. Alkaline earth metals, due to their specific chemical properties and abundance in nature, provide promising and challenging catalysts in organic synthesis. This article describes the utilization of alkaline earth metals in the development of an effective catalytic system based on calcium salts in combination with Box-type ligands. We disclose asymmetric 1,4-addition and [3+2] cycloaddition reactions using simple catalytic systems consisting of calcium chloride dihydrate, chiral ligands and tetramethylguanidine. Various Box ligands were synthesized and the most effective proved to be that bearing an indane chiral backbone and a cyano group. Depending on the structure of both glycine Schiff bases and α,β-unsaturated compounds, the corresponding Michael adducts or pyrrolidine derivatives were obtained in moderate to high yields with high enantioselectivities. Modification of the catalytic system by using more Lewis acidic calcium salts such as calcium triflate and neutral Pybox-type ligands allows a tuning of the chemoselectivity and leads to suppression of the [3+2] cycloadition reactions. Various β-substituted acrylates provided 1,4-addition adducts exclusively in high yields with moderate to high diastereo- and enantioselectivities. This methodology has broadened a synthetic route to β-branched glutamic acid derivatives and established calcium salts as useful and attractive catalysts for asymmetric catalysis. Copyright

Full text of DOI:10.1002/adsc.201300171

FULL PAPERS
DOI: 10.1002/adsc.201300171
Synthesis of Glutamic Acid and Highly Functionalized Pyrrolidine
Derivatives by Utilizing Tunable Calcium Catalysts for
Chemoselective Asymmetric 1,4-Addition and
[3+2] Cycloaddition Reactions
Martin Hut’ka,a Tetsu Tsubogo,a and Shu¯ Kobayashia,*
a
Department of Chemistry, School of Science, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax : (+81)-3-5684-0634; e-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Received: February 23, 2013; Revised: April 15, 2013; Published online: May 16, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300171.
Abstract: A current trend in organic chemistry is the were obtained in moderate to high yields with high
development of highly efficient, environmentally enantioselectivities. Modification of the catalytic
friendly and inexpensive catalysts for asymmetric system by using more Lewis acidic calcium salts such
transformations. Alkaline earth metals, due to their as calcium triflate and neutral Pybox-type ligands
specific chemical properties and abundance in allows a tuning of the chemoselectivity and leads to
nature, provide promising and challenging catalysts suppression of the [3+2]cycloadition reactions. Vari-
in organic synthesis. This article describes the utiliza- ous b-substituted acrylates provided 1,4-addition ad-
tion of alkaline earth metals in the development of ducts exclusively in high yields with moderate to
an effective catalytic system based on calcium salts high diastereo- and enantioselectivities. This method-
in combination with Box-type ligands. We disclose ology has broadened a synthetic route to b-branched
asymmetric 1,4-addition and [3+2]cycloaddition re- glutamic acid derivatives and established calcium
actions using simple catalytic systems consisting of salts as useful and attractive catalysts for asymmetric
calcium chloride dihydrate, chiral ligands and tetra- catalysis.
methylguanidine. Various Box ligands were synthe-
sized and the most effective proved to be that bear-
ing an indane chiral backbone and a cyano group. Keywords: asymmetric addition reactions; b-
Depending on the structure of both glycine Schiff branched glutamic acid derivatives; chiral calcium
bases and a,b-unsaturated compounds, the corre- complexes; pyrrolidine derivatives; tuning of the
sponding Michael adducts or pyrrolidine derivatives chemoselectivity
Introduction
ing block for the synthesis of drugs and their precur-
sors,[5,6] dendrimeric drug carriers,[7] as well as for
The biological importance of natural and unnatural a- useful materials such as gelators and supramolecular
amino acid derivatives has been increasing over the columnar liquid crystals.[8,9] Recent synthetic methods
past few years, and their synthesis in optically pure have offered numerous attractive approaches towards
form continues to be of great interest. In particular, structurally diverse b-substituted a-amino acids pre-
glutamic acid and its b-substituted derivatives, which cursors. The most effective methodologies involve
are found in virtually all living organisms, are impor- diastereoselective synthesis and stereoselective alkyla-
tant not only as essential structural components of tion of glycine Schiff bases.[10,11] Catalytic asymmetric
peptides and proteins,[1] but also due to their biologi- 1,4-additions of glycine derivatives to a,b-unsaturated
cal activities.[2] l-Glutamate is an important nutrient carbonyl compounds or other Michael acceptors were
involved in several biochemical pathways such as glu- often mediated by structurally diverse chiral phase-
coneogenesis and ammonia detoxification, and it is transfer catalysts,[12] metal salts combined with various
also the most abundant neurotransmitter in the cen- enantiopure ligands,[13] and more recently, a chiral or-
tral nervous systems of mammalian organisms.[3,4] ganic base was also successfully used as a catalyst for
Equally, glutamic acid is utilized as a valuable build- this transformation.[14] The current trend to develop
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highly efficient and enantioselective reactions is the
use of ubiquitous and green catalysts. Despite alkaline
earth metals (Ca, Sr, Ba) being one of the most abun-
dant elements on the earth, their utilization in organic
chemistry, especially in catalysis, is limited. Due to
their specific chemical properties and their abundance
in nature, chiral complexes of these metals are prom-
ising and challenging catalysts in organic synthesis. In
particular, calcium, as the fifth most frequent and
easily accessible element in the earthꢁs crust and sea-
water, represents a great potential for synthetic utili-
ty.[15]
So far, chiral complexes of alkaline earth metals
have been successfully utilized as catalysts in several
asymmetric bond forming reactions.[16] Previously, in
our laboratory, an effective catalyst system based on
chiral calcium alkoxides was developed and applied
Figure 1. Employed chiral ligands
for the asymmetric additions of azomethine imines to tions, we employed common tertiary amines in THF
various a,b-unsaturated compounds. This methodolo- with molecular sieves at À308C, but could not obtain
gy has extensively widened the field of synthesis of the desired 1,4-adducts. We hypothesized that the ba-
glutamic acid derivatives.[16b] However, calcium alkox- sicity of the tertiary amines were insufficient to either
ides, phenoxides, and hexamethyldisilylamide, which deprotonate 2a and/or the chiral Box ligands, which is
are commonly used as basic precursors for the prepa- a critical step for the formation of the chiral calcium
ration of chiral calcium complexes, are relatively complexes responsible for the stereoselective cataly-
moisture sensitive. Moreover, calcium alkoxides-cata- sis. Guanidines are well known to be relatively strong
lyzed 1,4-additions of glycine Schiff bases are limited bases and, in the last decade, have found wide utility
to a-substituted acrylates due to the undesired [3+2] in organic synthesis.[18] After initial trials, tetramethyl-
cycloaddition that predominates when crotonates and guanidine (TMG) was found to be an effective base
other b-substituted a,b-unsaturated esters are em- and was subsequently utilized in our optimization
ployed. We report here the development of an effec- studies (Table 1). We screened various Box ligands
tive catalytic system based on calcium chloride dihy- and found that the 1,4-addition reaction proceeded
drate as an inexpensive, harmless, and environmental smoothly, but unfortunately, almost no stereoselective
friendly metal source.[17] In combination with bis(oxa- induction was observed in most cases. Low enantiose-
zoline) (Box) ligands and organic bases, this innova- lectivity was obtained with (S)-Ph-Box (1a) as well as
tive methodology was applied to the asymmetric Mi- with its methylated (R)-analogues 1b–1d (entries 1–4).
chael addition and [3+2]cycloaddition of glycine Comparable low enantioselectivity was also observed
Schiff bases to a,b-unsaturated carbonyl compounds. when methylene-substituted derivative 1e was used
Structurally variable substrates, even secondary (entry 5). On the other hand, a breakthrough was ach-
amides bearing an acidic proton, can be employed ieved when commercially available (4S)-(+)-phenyl-
with high efficiency by using only 5 mol% of the cata- a-[(4S)-phenyloxazolidin-ylidene]-2-oxazoline-aceto-
lyst. Notably, slight modification of the catalytic sys- nitrile [(S)-CN-Ph-Box, (S)-1f] provided the desired
tems facilitates chemoselective 1,4-addition reactions glutamic acid derivative 4aa with moderate enantio-
of glycine Schiff bases with crotonates. Suppression of purity (entry 6).[19] These results suggested that an
the [3+2]cycloaddition pathway broadens the sub- electron-withdrawing substituent on the methylene
strate scope of this methodology to include b-substi- bridge of the bis(oxazoline) framework is necessary
tuted a,b-unsaturated esters to provide b-branched to facilitate its deprotonation and subsequent forma-
glutamic acid derivatives in a facile manner with ex- tion of the desired chiral calcium complex. The for-
cellent enantiopurity.
mation of the anionic ligand is a key requirement for
the strong coordination of the chiral ligand to the
metal center, and chiral calcium complexes derived
from 1a–e were most likely not formed due to the in-
sufficient acidity of the ligand. Based on this assump-
Results and Discussion
We initiated our investigation for the enantioselective tion, we performed control studies and found that
1,4-addition reaction of Schiff base 2a with methyl ac- a competitive background reaction proceeded in the
rylate (3a) by using 10 mol% of calcium chloride di- absence of a ligand and that the 1,4-addition reaction
hydrate in combination with various optically active also proceeded with catalytic amounts of TMG. In ad-
Box ligands (Figure 1). In our preliminary investiga- dition to the background reaction, a second undesired
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Synthesis of Glutamic Acid and Highly Functionalized Pyrrolidine Derivatives
Table 1. Screening of bis(oxazoline) ligands and the optimi-
zation of reaction conditions.
and amides was investigated (Table 2). The reactions
of 2a with both methyl acrylate (3a) and benzyl acry-
late (3b) proceeded in high yields with excellent enan-
tioselectivities (entries 1 and 2). Under the same con-
ditions, lower reactivity was observed with Weinreb
amide 3c, but the product was obtained with high
enantioselectivity (entry 3). In comparison with 2a,
Schiff base 2b bearing a methyl ester group turned
out to be less reactive. However, reducing the steric
bulk on the ester did not affect the enantioselectivity
significantly, and the reaction of 2b with 3a provided
the corresponding dimethyl pentanedioate (4ba) with
high ee. A similar result was also obtained for the 1,4-
Entry
Ligand
Yield [%]
ee [%]
1[a]
2
3
4
5
1a
1b
1c
1d
1e
(S)-1f
1f
1g
1h
1h
1h
1h
70
78
85
74
62
64
64
39
73
77
73
87
4
8
0
0
Table 2. Substrate scope of 1,4-addition and [3+2]cycloaddi-
tion reactions.
8
6[a]
7[b]
8[b]
9[a,b]
10[a]
11[a,c]
12[a,c,d]
44
77
0
96
95
96
98
[a]
Opposite enantiomer of the product.
[b]
3a (0.54M) was added over 10 h using a syringe pump
and the resulting mixture was stirred for 6 h.
5 mol% of CaCl2·2H2O, 5 mol% of 1h and 10 mol% of
TMG were used, and the reaction was carried out at
À208C for 24 h.
[c]
[d]
Reversed ratio of reagents 2a/3a.
Michael addition of the product 4aa to methyl acry-
late also took place. Despite these discouraging re-
sults, we continued our investigation and began a de-
tailed exploration on the use of cyano-Box derivatives
as chiral ligands.[20] With the aim to suppress the pre-
dominant background reaction, the effect of slow ad-
dition of 3a was examined. To our delight, when 3a
was added to the reaction mixture over 10 h at
À308C, the enantioselectivity increased dramatically
(entry 7). Further effort to improve both the enantio-
selectivity and the yield by employing ligand 1g failed
(entry 8). However, when 1h, bearing an indane back-
bone, was employed, the desired 1,4-adduct was ob-
tained in good yield with excellent enantioselectivity
(entry 9). By utilizing 1h, the reaction proceeded
smoothly without the slow addition of 3a (entry 10),
and the catalyst loading could be reduced to 5 mol%
at À208C without any significant drop in the yield
and the enantioselectivity (entry 11). The yield of 4aa
was improved further by the addition of a slight
excess of 2a to suppress the undesired second Michael
reaction (entry 12).
Entry
2
3
4
Yield [%]
ee [%]
1
2
3
4
2a
2a
2a
2b
2b
2a
2a
2c
2c
2d
2c
2c
2d
2d
3a
3b
3c
3a
3c
3d
3e
3b
3f
3f
3g
3c
3h
3i
4aa
4ab
4ac
4ba
4bc
5ad
5ae
5cd
5cf
5df
5cg
5cc
5dh
5di
87
90
41
65
66
91
76
86
85
89
71
59
63
98
98
90
94
94
83
99
99
64
95
96
89
89
92
96
5
6[a]
7
8
9[b]
10
11[b,c]
12
13
14
With the optimized conditions in hand, the sub-
strate scope for the chiral calcium-complex catalyzed
asymmetric 1,4-addition of various Schiff bases with
a,b-unsaturated compounds such as acrylic acid esters
[a]
10 mol% of catalyst and ligand were used.
48 h.
À308C.
[b]
[c]
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Martin Hut’ka et al.
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addition reaction with Weinreb amide 3c (entries 4 glutamic acids derivatives, we next focused on other
and 5). During our previous investigation of chiral suitable calcium-based catalytic systems. Due to mild
calcium alkoxide-catalyzed 1,4-addition reactions of Lewis acidity of Ca2+ ions, anionic or strongly coordi-
glycine ester Schiff bases with crotonates, an unex- native ligands are often employed to form stable com-
pected [3+2]cycloaddition reaction occurred,[16c,e] and plexes and used as catalysts for various transforma-
the same tendency was observed when Schiff base 2a tions.[16a,17,27] Based on our previous good results ob-
reacted with acryl amides 3d and 3e using the newly tained with 1h bearing a chiral indane backbone, we
developed CaCl2-based catalytic system. In both decided to investigate the use of a related neutral
cases, the corresponding pyrrolidine derivatives 5ad inda-Pybox ligand 1i (Table 3). In a preliminary
and 5ae were obtained as single diastereoisomers in screening, we found that calcium halides did not work
high yields with extremely high enantioselectivities well as catalysts. On the other hand, the reaction cata-
(entries 6 and 7). [3+2]Cycloaddition of azomethine lyzed by calcium triflate [CaACHTNURTGEN(UNG OTf)2] proceeded
imines with substituted alkenes represents one of the smoothly with high selectivity for the 1,4-adduct as
most efficient methods for the synthesis of optically well as with high diastereoselectivity, albeit with mod-
active polyfunctionalized pyrrolidines,[21] which are erate enantioselectivity (entries 1–3).[28] The use of
common substructures of a number of naturally occur- tetrahydrofuran (THF) instead of tert-butyl methyl
ring and medicinally important compounds.[22,23] Fur- ether (TBME) as a solvent led to a dramatic improve-
thermore, optically active pyrrolidines are widely ment of the enantioselectivity, but the selectivity for
used as chiral inductors and organocatalysts in asym- the 1,4-adduct was decreased. High chemical yield,
metric synthesis.[24] Encouraged by our previous re- 1,4/
ACTHNUTRGNE[NUG 3+2] ratio, diastereo- and enantioselectivity were
sults, we decided to explore the substrates scope of achieved by using 1,2-diethoxyethane (DEE) as sol-
the [3+2]cycloaddition under the conditions that vent. The yield and the selectivities were improved
were optimized for the catalytic 1,4-addition reactions further by lowering the temperature to À208C (en-
(Table 1). Various a,b-unsaturated compounds were tries 4–6). Additional optimization by using calcium
examined for the asymmetric [3+2]cycloaddition re- bis(trifluoromethylsulfonyl)amide [CaACTHNUTRGNE(UNG NTf2)2] led to
actions with Schiff bases 2c and 2d. Benzyl acrylate a higher yield and diastereoselectivity, but the enan-
(3b) gave the corresponding pyrrolidine in high yield tioselectivity was decreased (entry 7).
with moderate enantioselectivity (entry 8). To our de-
The substrate scope involving different a,b-unsatu-
light, the reaction of a- and b-substituted unsaturated rated compounds was surveyed and is summarized in
esters such as methyl crotonate (3f) and methyl meth-
acrylate (3g), which were unreactive in the previous
Table 3. Preliminary screening of reaction conditions for ad-
1,4-addition, with Schiff bases 2c and 2d proceeded
dition of 2a to 3f.
smoothly to afford the desired products in high yields
with excellent enantioselectivities (entries 9–11). Ter-
tiary amides 3c and 3h provided moderate yields but
high ee of the desired pyrrolidines were achieved (en-
tries 12 and 13). Interestingly, in the case of N-phenyl-
acrylamide (3i), the product was isolated in near
quantitative yield with excellent enantioselectivity
(entry 14). Compounds bearing secondary N-phenyla-
mide group represent a useful class of compounds
with potential biological activity and utilization in in-
dustry.[25] Basic calcium catalysts, such as Ca
and Ca
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Entry
Solvent
Yield [%]
4af/5j
dr[a]
ee [%]
mildly acidic N-phenylamides.[26] Due to the potential
quenching of the catalyst by this acid-base process,
catalytic applications of these complexes are limited.
However, in the case of using the calcium chloride-
based catalyst, the reaction proceeded smoothly with
excellent results.
1[b]
2[c]
3
THF
THF
THF
TBME
DEE
DEE
DEE
<5
<5
76
88
87
–
–
–
–
–
–
94/6
96/4
92/8
96/4
96/4
97/3
85/15
91/9
96/4
98/2
53
91
90
92
70
4
5
6[d]
7[d,e]
89
96
Using the catalytic system consisting of
CaCl2·2H2O and ligand 1h, the reactions of methyl
crotonate (3f) as well as some other b-substituted
a,b-unsaturated esters with Schiff base 2a did not
afford the 1,4-addition products, but gave [3+2]cyclo-
addition products. With an aim to broaden the range
of this methodology for the synthesis of b-substituted
[a]
dr of 4af.
CaCl2·2H2O.
CaI2.
The reaction was carried out at À208C for 48 h.
Ca(NTf2)2.
[b]
[c]
[d]
[e]
AHCTUNGTRENNUNG
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Synthesis of Glutamic Acid and Highly Functionalized Pyrrolidine Derivatives
Table 4. Under the optimized conditions for the reac- ly more demanding substrate 3n proved to be less re-
tion of methyl crotonate ethyl analogue 3j gave the active, and moreover, the yield of the desired 1,4-
desired product with similar selectivities. On the adduct was influenced by [3+2]cycloaddition
other hand, an excellent 1,4/ACHTNUTRGNE[NUG 3+2] ratio was observed (entry 7). According to the assumed reaction mecha-
in the case of vinyl ester 3k, although only moderate nism, the pyrrolidine derivative is formed from an in-
enantioselectivity was obtained. Amide 3l provided termediate of a 1,4-addition product via an intramo-
higher reactivity in comparison with esters, and the lecular Mannich reaction (vide infra). We assumed
product was obtained with reasonable enantioselectiv- that this side reaction could be suppressed in the pres-
ity (entries 1–4). In contrast to the crotonic acid deriv- ence of a suitable proton source. We also attempted
atives, the reaction with (E)-methyl pent-2-enoate to modify the calcium catalyst by using appropriate
(3m) proceeded slowly and even when the reaction additives. It is well established that hexafluorophos-
time was prolonged up to 60 h, the Michael adduct phate additive can significantly affect the properties
4am was obtained in 60% yield with high ee. These of a catalyst by an anion exchange.[29] We screened
results led to further modification of the reaction con- several tetrabutylammonium salts and found that the
ditions. Using Ca
ACHTUNGTRENNUNG(NTf2)2 as the catalyst, the yield and addition of Bu4NPF6 improved the enantioselectivity
the 1,4/[3+2] ratio of the desired adducts were im- of the product (entry 8). The sterically more difficult
ACHTUNGTRENNUNG
proved significantly, but the enantioselectivity drop- substrate 3o provided the desired product with excel-
ped from 95 to 83% ee (entries 5 and 6). The sterical- lent enantioselectivity, but with lower selectivity for
the 1,4-adducts and slightly reduced chemical yield
(entry 9). Finally, the undesired [3+2]cycloaddition
was partially suppressed using [DBUH]OTf as an ad-
ditional proton source (entry 10).
Table 4. Scope of a,b-unsaturated compounds.
We next monitored the formation of the chiral cal-
cium catalyst by 1H NMR (Figure 2). The first spectral
chart represents ligand 1h in THF-d8 and the second
1H NMR chart represents a mixture of 1h with two
equivalents TMG. No change in the chemical shift of
the ligand was observed with the exception of a broad
Entry
3
4
Yield [%]
4/5
dr[a]
ee [%]
1
2
3
4
3f
3j
3k
3l
3m
3m
3n
3n
3o
3o
4af
4aj
4ak
4al
4am
4am
4an
4an
4ao
4ao
89
50
70
95
60
91
44
88
53
78
96/4
83/17
99/1
98/2
81/19
93/7
72/28
88/12
83/17
90/10
96/4
95/5
87/13
98/2
99/1
92
92
55
75
95
83
93
87
97
91
5[b]
6[c]
7
99/1
85/15
85/15
89/11
89/11
8[d]
9[e]
10[f]
[a]
dr of 4.
[b]
[c]
[d]
Reaction time 60 h.
Ca(NTf2)2 was used as catalyst.
Reaction at À308C using Ca(NTf2)2 as a catalyst with
10 mol% of Bu4NPF6 and 10 mol% of [DBUH]OTf.
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
[e]
[f]
Reaction at À308C using Ca
Reaction at À308C using Ca(NTf2)2 as catalyst, 10 mol%
[DBUH]OTf as an additive for 24 h.
ACHTUNGTREN(NNUG NTf2)2 as catalyst for 24 h.
U
Figure 2. Determination of chiral calcium catalytic species
by 1H NMR analysis.
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Martin Hut’ka et al.
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signal at 5.95 ppm that corresponds to the protonated
tetramethylguanidine (Figure 1, spectra 1 and 2).
Next, following the procedure for the in situ prepara-
tion of our catalyst, the ligand was stirred with two
equivalents of TMG and one equivalent of
CaCl2·2H2O in the presence of MS 4ꢂ at room tem-
perature for 2 h. Under these conditions, new peaks
corresponding to the anticipated catalytic active spe-
cies were detected (dashed protons in spectrum 3). In
the last chart, two equivalents of CaCl2·2H2O were
employed in order to push the complexation of anion-
ic 1h completely. Under these conditions, almost no
peaks corresponding to the free ligand were detected
and this indicates that full coordination of 1h to calci-
um was achieved (spectrum 4.). These results con-
firmed the formation of the catalytic active chiral cal-
cium species and the spectral data are comparable to
those reported by our group previously.[16c]
We assumed a catalytic cycle and reaction mecha-
nism (Figure 3). The first step involves the deprotona-
tion of the ligand and the formation of the chiral cal-
cium complex 1ha, which might be in equilibrium
with either the binuclear complex 1hb or 1hc. All
three of these calcium complexes 1ha–1hc could react
with a deprotonated Schiff base via a counterion ex-
change to form chiral enolate 1hd as a key intermedi-
ate. The next step is the 1,4-addition of 1hd to an a,b-
unsaturated compound to form enolate 1he, which,
after protonation, provides the desired product 4. Pro-
tonation of 1he might proceed through pathway A
with [TMGH]Cl, in which both TMG and calcium
complex are regenerated, or via pathway B, where the
deprotonation of the Schiff base takes place and
chiral enolate 1hd is regenerated. The [3+2]cycload-
dition may proceed through a stepwise mechanism in-
volving enolates 1hd and 1he, but in this case, inter-
mediate 1he undergoes intramolecular Mannich type
reaction to furnish amide 1hf (pathway C). Sequential
protonation, which may proceed via pathway A or B,
affords the corresponding pyrrolidine derivative 5.
Figure 3. Assumed reaction mechanism for 1,4-addition and
[3+2] cycloaddition reactions of glycine Schiff bases with
a,b-unsaturated carbonyl compounds.
portant role. Less steric hindered Schiff bases 2b and
The formation of the cycloadduct may be deter- 2c afforded exclusively the [3+2]cycloadducts
mined by the nature of catalysts, as well as the struc- (Table 2, entries 8–14). However, in reactions of
ture of both substrates. In the case of calcium com- amides 3d and 3e with (diphenylmethylene)amino-
plexes bearing electron-donating ligands such as Schiff base 2a, the corresponding pyrrolidines were
anionic 1h or alkoxides, a more electron rich enolate obtained in high yields (Table 2, entries 6 and 7). Due
1he is formed and this intermediate may be a stronger to the greater stability of amide enolates (compared
nucleophile that can readily undergo intramolecular with esters enolates) and significantly higher nucleo-
Mannich reaction (Figure 4, A). On the other hand, philicity,[30] cyclization of enolates 1he derived from
in the catalytic system consisting of more Lewis acidic the mentioned substrates proceeds smoothly despite
CaACHTUNGTRENNUNG(OTf)2 [or CaACHTUNGTRENNUNG(NTf2)2 ] and 1i, the neutral coordina- of higher steric demand of 2a. Additionally, protona-
tive ligand may not affect electron properties of 1ie tion of enolate 1he may be kinetically favored, while
significantly and the main contribution is probably de- the [3+2]cycloaddition may lead to the more stable
rived from the triflate [or bis(trifluoromethanesulfo- pyrrolidine derivatives and may be thermodynamical-
nyl)amide] anion (Figure 4, B). In this scenario, the ly controlled (especially in the reactions of b-
corresponding enolate is less nucleophilic, rather branched a,b-unsaturated compounds).
basic, and protonation is therefore preferred
(Figure 4, B). Equally, steric factors may play an im-
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Adv. Synth. Catal. 2013, 355, 1561 – 1569

Synthesis of Glutamic Acid and Highly Functionalized Pyrrolidine Derivatives
Experimental Section
Typical Procedure for CaCl2·2H2O-Box-Catalyzed
1,4-Addition and [3+2]Cycloaddition Reactions of
Glycine Schiff Bases with a,b-Unsaturated Carbonyl
Compounds
A typical procedure for 1,4-addition is represented by the
reaction of glycine Schiff base 2a with methyl acrylate (3a).
In the glovebox, CaCl2·2H2O (2 mg, 0.0135 mmol), ligand 1h
(4.9 mg, 0.0135 mmol) and MS 4ꢂ (90 mg) were added into
30-mL flame-dried flask. THF (0.5 mL) was added and after
5 min, TMG (3.4 mL, 0.027 mmol) in THF (0.5 mL) was
added. The resulting mixture was stirred under an argon at-
mosphere for 2 h and then cooled to À208C. 2a (95.7 mg,
0.324 mmol) in THF (0.5 mL) was slowly added, followed
by dropwise addition of 3a (24.1 mL, 0.27 mmol) in THF
(0.5 mL). After the mixture had been stirred at the same
temperature for 24 h, saturated NH4Cl (10 mL) was added
to quench the reaction. Dichloromethane (10 mL) was
added, the organic layer was separated and the aqueous
layer was extracted with dichloromethane (2ꢃ15 mL). The
combined organic layers were dried over anhydrous Na2SO4
and, after filtration, the solvent was evaporated under re-
duced pressure. The crude product was purified by prepara-
tive thin layer chromatography (hexane-ethyl acetate=4:1)
to afford 1,4-adduct 4aa; yield: 90 mg (87%). The enantiose-
lectivity of the product was determined by HPLC.
AHCTUNGTREG[NNNU 3+2]Cycloaddition reactions involve the same experi-
mental procedure. A typical reaction of glycine Schiff base
2c (71 mg, 0.324 mmol) with methyl crotonate (3f) (29 mL,
0.27 mmol) gave the corresponding [3+2] adduct 5cf; yield:
74 mg (85%). The enantioselectivity of the product was de-
termined by HPLC.
Figure 4. 1, 4-Addition vs. [3+2] cycloaddition.
Conclusions
Experimental Procedure for Ca-Pybox-Catalyzed
Asymmetric 1,4-Addition Reactions of Glycine Schiff
Base (3a) with b-Substituted Acrylates
In conclusion, highly efficient 1,4-addition and
[3+2]cycloaddition reactions of glycine Schiff bases
with a,b-unsaturated carbonyl compounds using
a simple CaCl2·2H2O-based catalyst have been devel-
oped. The reactions proceeded smoothly at À208C,
and high enantioselectivities of the corresponding
products were achieved with Box-type ligand 1h bear-
ing a chiral indane scaffold. The introduced method-
ology was successfully applied to a broad range of
substrates by employing 5 mol% of the catalyst. Addi-
tionally, modification of the catalytic system by using
more Lewis acidic calcium salts and neutral coordina-
A typical experimental procedure is described for the reac-
tion of glycine Schiff base 2a with methyl crotonate (3f). In
the glovebox, calcium triflate (6.8 mg, 0.02 mmol), ligand 1i
(7.9 mg, 0.02 mmol) and MS 4ꢂ (50 mg) were added to
a 10-mL vial and 1,2-diethoxyethane (0.25 mL) was then
added. The resulting mixture was stirred at room tempera-
ture in the glovebox for 1 h and sequentially tert-butyl 2-
[(diphenylmethylene)amino]acetate (2a) (59 mg, 0.2 mmol,
neat), DBU (3.2 mL, 0.02 mmol, neat) and 1,2-diethoxy-
ethane (0.75 mL) were added in this order. The reaction vial
tive ligand 1i allows for the tuning of the chemoselec- was then transferred out of the glovebox and cooled to
À208C. After 10 min., methyl crotonate (3f) (25.5 mL,
tivity of the reaction and to extend its application for
b-substituted a,b-unsaturated carbonyl compounds.
0.24 mmol, neat) was added dropwise and mixture was
stirred at the same temperature for 24 h. The reaction was
From a practical viewpoint, further investigations and
then quenched by addition of saturated NH4Cl (5 mL) and
applications of calcium-based catalysts in asymmetric
extracted with dichloromethane (3ꢃ10 mL). The combined
transformations is a challenging topic, which is cur-
organic layers were dried over anhydrous Na2SO4 and, after
rently underway in our laboratory.
filtration, the solvent was evaporated. The crude product
was purified by preparative thin layer chromatography
(hexane-ethyl acetate=4:1) to afford 1,4-adduct 4af; yield:
71 mg (89%). Diastereoselectivity and the ratio of 1,4-ad-
duct/ACTHNURGTNE[UNG 3+2] cycloadduct were determined from crude
Adv. Synth. Catal. 2013, 355, 1561 – 1569
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1567

Martin Hut’ka et al.
FULL PAPERS
1H NMR. The enantioselectivity of the product was deter-
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Ca-Pybox-Catalyzed Asymmetric 1,4-Addition of
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of 1,4-adduct/
ACHTUNGTRENNUNG
1H NMR analysis of the crude product (1,4-adduct/
AHCTUNGTRENNUNG
86/14, dr=86/14). HPLC (Daicel Chiralpak AD-H, hexane/
i-PrOH=100/1, flow rate=0.2 mLminÀ1, detection wave-
length=254 nm): tR =43.2 min. (minor), tR =47.8 min.
(major) (83% ee).
A complete Experimental Section is provided in the Sup-
porting Information.
Acknowledgements
This work was partially supported by a Grant-in-Aid for Sci-
ence Research from the Japan Society of the Promotion of
Science (JSPS) and Japan Science and Technology Agency
(JST). M.H. thanks the JSPS Postdoctoral Fellowship for
Foreign Researchers. The authors are grateful to Dr. Yasuhiro
Yamashita (The University of Tokyo) for his helpful discus-
sion throughout this work and Dr. Woo-Jin Yoo (The Univer-
sity of Tokyo) for his assistance in the preparation of this
manuscript.
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