Chiral calcium complexes as bronsted base catalysts for asymmetric addition of α-amino acid derivatives to α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1021/ja0709730

A novel catalyst system based on complexes of calcium which promote the catalytic asymmetric 1,4-addition reactions and [3+2] cycloaddition reactions of α-amino acid derivatives with α,β-unsaturated carbonyl compounds have been developed. The reactions proceeded smoothly in the presence of 5-10 mol % of the chiral calcium catalyst to afford the desired adducts in high yields with high diastereo- and enantioselectivities. A wide range of α,β-unsaturated esters and amides were applicable, and other glycine and even dl-alanine derivatives reacted with several α,β-unsaturated carbonyl compounds to afford the corresponding substituted pyrrolodine derivatives in high yields with excellent diastereo- and enantioselectivities. In the reactions with dl-alanine derivatives, quaternary asymmetric carbons were constructed efficiently. Copyright

Full text of DOI:10.1021/ja0709730

Published on Web 04/11/2007
Chiral Calcium Complexes as Brønsted Base Catalysts for Asymmetric
Addition of r-Amino Acid Derivatives to r,â-Unsaturated Carbonyl Compounds
Susumu Saito, Tetsu Tsubogo, and Sh uj Kobayashi*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, The HFRE DiVision, ERATO,
Japan Science Technology Agency (JST), Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received February 22, 2007; E-mail: skobayas@mol.f.u-tokyo.ac.jp
The group 2 elements, Mg, Ca, Sr, and Ba, are widely distributed
in minerals and in the sea. However, their use in organic synthesis
Table 1. Effect of Metal Sources and Chiral Ligands
1
is limited except for organomagnesium compounds (Grignard
reagents). As for the area of asymmetric catalysis, while various
types of chiral catalysts have been developed during the past
decades, there are few reports on the use of the group 2 metals
X
temp
C)
time
(h)
yield
(%)
ee
2
except for magnesium Lewis acids. Since these metals are divalent
entry
metal
ligand (equiv)
additive
(
°
(%)
and have high coordination number and low electronegativity, we
1
2
3
4
5
6
7
8
9
Mg(OEt)
2
1
1
1
1
2
3
4
5
4
4
4
4
4
4
4
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.1
1.1
1.1
1.1
1.2
1.1
1.1
MS 5A -45 to 0
MS 5A -45 to 0
MS 5A -45 to 0
MS 5A -45 to 0
MS 5A -45 to 0
MS 5A -45 to 0
MS 5A -45 to 0
24
N.R.a
3
Ca(Oi-Pr)
Sr(Oi-Pr)
Ba(Ot-Bu)2
Ca(Oi-Pr)
Ca(Oi-Pr)
Ca(Oi-Pr)
Ca(Oi-Pr)
Ca(Oi-Pr)
Ca(Oi-Pr)
2
24 39
24 76
24 79
24 24
24 19
24 54
73 (S)
29 (S)
17 (S)
71 (R)
6 (S)
82 (R)
44 (R)
82 (R)
87 (R)
87 (R)
90 (R)
94 (R)
82 (R)
80 (R)
have focused on their use as novel Brønsted base catalysts. In this
2
paper, we report chiral calcium-catalyzed asymmetric 1,4-addition
reactions and [3+2] cycloaddition reactions of R-amino acid
derivatives with R,â-unsaturated carbonyl compounds.
2
2
2
2
2
2
MS 5A -45 to rt 24 31
Catalytic asymmetric 1,4-addition reaction of R-amino acid
derivatives with R,â-unsaturated carbonyl compounds provides
efficient synthetic methods of chiral glutamic acid derivatives.4
While several systems, mainly chiral phase-transfer catalysts, have
MS 5A
0
8
8
8
8
48
56
63
71
1
0
MS 5A -20
MS 5A -30
MS 4A -30
MS 4A -30
MS 5A -45
MS 5A -78
11
Ca(Oi-Pr)2
1
1
2
3
Ca(Oi-Pr)
Ca(Oi-Pr)
Ca(Oi-Pr)
Ca(Oi-Pr)
2
2
2
2
b
12 88
8
8
5
been developed for this purpose, the reactions need excess amounts
14
46
36
15
of substrates and additional bases in most cases. Therefore, a
versatile reaction system, which affords glutamic acid derivatives
with high enantioselectivity only using a catalytic amount of a
Brønsted base catalyst would be highly desirable.
We first examined alkaline earth metal alkoxides with chiral
ligands as catalysts in the reaction of glycine derivatives 1a with
methyl acrylate (Table 1). Among metal alkoxides tested, Ca(Oi-
a
No reaction. b The catalyst preparation was conducted at room tem-
perature (rt) for 2 h and then the substrates were added without removal of
volatile components.
Pr)
the best enantioselectivity although the yield was moderate (entries
-4). As for chiral ligands, while tert-BuBox 3 gave poor
selectivity, PhBox 4 provided the product in better enantioselectivity
entry 7). We further optimized the reaction conditions and finally
found that the desired product could be obtained in 88% yield with
2
-ligand 1 gave the desired 1,4-addition (Michael) product with
Table 2. Catalytic Asymmetric 1,4-Addition Reactions of Glycine
Derivatives
1
(
2
94% ee when the reaction was conducted using Ca(Oi-Pr) -ligand
4
in THF at -30 °C for 12 h in the presence of MS 4A (entry 13).
Next we investigated the substrate scope of this 1,4-addition
yield
(%)
ee
(%)
entry
R1
R2
R3
product
2,4-syn/anti
reaction under the optimized conditions, (Table 2). Gratifyingly it
was found that acrylate esters reacted with 1a smoothly to afford
the desired Michael products in high yields with high enantiose-
lectivities (entries 3-6). Variation of the ester moiety revealed that
methyl esters gave the product in highest enantioselectivity. It is
1
2
3
H
H
H
H
H
H
Me
Et
Cl
Ph
Me
OMe
OMe
OMe
OEt
Ot-Bu
NMeOMe
OMe
OMe
OMe
Me
Et
6b
6c
6a
6d
6e
6f
6g
6h
6i
quant
quant
88
56
74
46
93
quant
95
quant
83
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
a,d
a,d
a
4
5
6
7
8
9
0
b
c
61/39
63/37
83/17
91/9
6
noteworthy that the Weinreb amide of acrylic acid also gave the
desired Michael adduct in good yield with high enantioselectivity
a
a
1
OMe
NMeOMe
6j
6k
a,d
(entry 6). We further examined the reactions of R-substituted acrylic
11
91/9
acid esters. The methyl, ethyl, and even chloro-substituted R,â-un-
saturated esters also reacted with 1a smoothly to afford the Michael
adducts in high yields with high enantioselectivities (entries 7-11).
During the examination of the substrate scope, we discovered
that when methyl crotonate was allowed to react with 1a under the
standard reaction conditions the reaction also proceeded smoothly;
however, the product was not the expected Michael adduct but the
corresponding pyrrolidine derivative, obtained in excellent yield
and enantioselectivity via a formal [3+2] cycloaddition pathway7
a
4 h. b Glycine derivative (1.5 equiv) was used. c Value represents ee
2
d
of the major product. R,â-Unsaturated ester (1.5 equiv) was used.
that in the cases of amides, even acrylic acid amides reacted with
1a to afford the corresponding [3+2] cycloaddition products
exclusively (entries 3-6). Moreover, only a single diastereomer
of the pyrrolidine derivative was obtained exclusively and the
enantioselectivity was excellent in each case. It should be noted
from a synthetic point of view that other glycine and even DL-
alanine derivatives reacted with several R,â-unsaturated carbonyl
(Table 3, entry 1). We examined other related substrates and found
5364
9
J. AM. CHEM. SOC. 2007, 129, 5364-5365
10.1021/ja0709730 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Catalytic Asymmetric [3+2] Cycloaddition-Type
Reactions of R-Amino Acid Derivatives
occurs to afford the pyrrolidine derivative exclusively. The present
mechanism cannot rule out a possibility of a concerted [3+2]
cycloaddition pathway, especially in the reactions of crotonates.
In summary, we have developed novel Ca-Box catalysts
prepared from calcium alkoxides and methylene bridged Box
ligands. These catalysts effectively promoted two types of catalytic
asymmetric additions of R-amino acid derivatives with R,â-
unsaturated carbonyl compounds; 1,4-addition reactions and [3+2]
cycloaddition recations. This reaction system does not need excess
amounts of electrophiles or the external addition of bases in contrast
with usual methods such as these using phase-transfer catalysts.
Further investigations to clarify the precise mechanism of this
reaction and exact catalyst structure as well as to expand still further
the substrate scope are now in progress.
temp
C) product
yield
(%)
ee
R1
R2
R3
R4
R5
entry
(
°
(%)
a
quant (99)d >99 (99)d
98
83
76
1
2
3
4
OMe
OEt
Me t-Bu
Me t-Bu
H
Ph -30
Ph -30
Ph -30
Ph -30
7a
7b
7c
7d
a
H
H
H
98
95
98
a,c
b,c
NMe
2
H
H
t-Bu
t-Bu
5b,c
6b NCy
H
t-Bu
H
Ph -30
Ph -30
7e
84
97
2
H
H
t-Bu
t-Bu
H
H
H
H
7f
7g
7h
7i
7j
7k
7l
93
98
89
86
quant
quant
93
91
76
84
86
90
91
90
7
8
9
0
1
2
Ot-Bu
OMe
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
H
H
H
H
H
H
10
10
10
10
10
10
Me t-Bu
Me t-Bu
H
H
H
Acknowledgment. This work was partially supported by a
Grant-in-aid for Scientific Research from Japan Society of the
Promotion of Science (JSPS). S.S. thanks the JSPS Research
1
1
1
Me Me
Et Me
Bn Me
Fellowship for Young Scientists.
a
Reaction run in 12 h. b Reaction run in 24 h; Cy, cyclohexyl. c R,â-
Supporting Information Available: Experimental procedures and
product characterization (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
d
Unsaturated amide (1.5 equiv) was used. Reaction run using 5 mol % of
the catalyst.
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(
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(
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Figure 1. Assumed Catalytic Cycle
compounds to afford the corresponding substituted pyrrolodine
derivatives in high yields with excellent diastereo- and enantiose-
lectivities (entries 7-12). In the reactions with dl-alanine deriva-
tives, quaternary asymmetric carbons were constructed efficiently.
As for the structure of the chiral calcium catalyst, we assume
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(
(
that ligand 4 does not work as a neutral ligand but an anionic
ligand.8
-10
Indeed, the structurally related ligand 8 which would
be expected to form a neutral catalyst complex, gave almost no
selectivity when used with Ca(Oi-Pr) (10 mol %) in the reaction
2
of methyl acrylate with 1a, the corresponding Michael adduct being
produced in only 31% yield in racemic form.11
(
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3
(
c) Ward, D. E.; Sales, M.; Hrapchak, M. J. Can. J. Chem. 2001, 79,
A plausible catalytic cycle of this reaction is shown in Figure 1.
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R-proton of the glycine derivative 1 to give chiral calcium enolate
1
775. (d) Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. ReV. 2006,
1
06, 3561.
(
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9
in situ. This chiral calcium enolate formed then reacts with an
R,â-unsaturated carbonyl compound to afford the initial 1,4-addition
adduct 10. While subsequent protonation of the 1,4-addition adduct
with either the proton of the alcohol or the R-proton of the glycine
derivative affords the Michael adduct 6, intramolecular cyclization
of 10 gives pyrrolidine derivative 7. In the reactions of amides,
reactivity of the enolate 10 is high and the intermolecular cyclization
(
10) Chiral zinc reagents: (a) Nakamura, M.; Arai, M.; Nakamura, E. J. Am.
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(
11) The correlation between the ee of the product and the ee of ligand 4 was
shown to be linear, suggesting a monomeric structure of Ca(Oi-Pr)
2
-4.
JA0709730
J. AM. CHEM. SOC.
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VOL. 129, NO. 17, 2007 5365