Calcium-catalyzed diastereo- and enantioselective 1,4-addition of glycine derivatives to α,β-unsaturated esters

Article abstract of DOI:10.1021/ol702958w

The first highly diastereo- and enantioselective catalytic asymmetric 1,4-addition reactions of a glycine Schiff base to β-substituted α, β-unsaturated esters have been developed. The reaction pathway was successfully controlled, and the desired 1,4-addition products were exclusively obtained with high enantioselectivities. The product obtained was converted to a 3-substituted glutamic acid derivative by acid hydrolysis.

Full text of DOI:10.1021/ol702958w

ORGANIC
LETTERS
2008
Vol. 10, No. 5
807-809
Calcium-Catalyzed Diastereo- and
Enantioselective 1,4-Addition of Glycine
Derivatives to
r,â-Unsaturated Esters
Shu¯ Kobayashi,* Tetsu Tsubogo, Susumu Saito, and Yasuhiro Yamashita
Department of Chemistry, School of Science and 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
shu_kobayashi@chem.s.u-tokyo.ac.jp
Received December 6, 2007
ABSTRACT
The first highly diastereo- and enantioselective catalytic asymmetric 1,4-addition reactions of a glycine Schiff base to
â-substituted r,â-
unsaturated esters have been developed. The reaction pathway was successfully controlled, and the desired 1,4-addition products were exclusively
obtained with high enantioselectivities. The product obtained was converted to a 3-substituted glutamic acid derivative by acid hydrolysis.
Efficient synthesis of optically active R-amino acid deriva-
tives is an important topic in current organic synthesis.1 In
particular, unnatural amino acid units are often valuable in
drug design, since mimics of biologically active compounds
containing such unnatural amino acids can work as antago-
nists to receptors in cells.2 Glutamic acid and its derivatives
are biologically important compounds because they work not
only as essential components of peptides and proteins but
also as signal mediators.3 One of the most efficient prepara-
tion methods of glutamic acid derivatives is 1,4-addition of
glycine derivatives to R,â-unsaturated esters or amides.
Asymmetric versions of this reaction have been developed.4,5
However, there are no successful examples of catalytic,
diastereo-, and enantioselectiVe 1,4-additions to afford
3-substituted glutamic acid derivatives. Here, we report the
first example of such reactions using chiral calcium catalysts.
We have recently reported catalytic asymmetric 1,4-
additions and [3 + 2] cycloadditions of a glycine Shiff base
to R,â-unsaturated esters or amides using novel chiral
calcium complexes (Scheme 1).6 Interestingly, the product
structures greatly depended on the R,â-unsaturated com-
pounds used in these reactions. In the reactions with acrylic
(4) Stereoselective synthesis of 3-subsutituted glutamic acid deriva-
tives: Soloshonok, V. A. Curr. Org. Chem. 2007, 6, 341 as a review. Other
representative examples: (a) Soloshonok, V. A.; Cai, C.; Yamada, T.; Ueki,
H.; Ohfune, Y.; Hruby, V. J. J. Am. Chem. Soc. 2005, 127, 15296. (b)
Herdeis, C.; Kelm, B. Tetrahedron 2003, 59, 217. (c) Soloshonok, V. A.;
Cai, C.; Hruby, V. J. Org. Lett. 2000, 2, 747. (d) Soloshonok, V. A.; Cai,
C.; Hruby, V. J. Tetrahedron 1999, 55, 12031. (e) Ezquerra, J.; Pedregal,
C. J. Org. Chem. 1999, 64, 6554. (f) Alvarez-Ibarra, C.; Csa´ky¨, A. G.;
Maroto, M.; Quiroga, M. L. J. Org. Chem. 1995, 60, 6700. (g) Kanemasa,
S.; Tatsukawa, A.; Wada, E. J. Org. Chem. 1991, 56, 2875. (h) Kanemasa,
S.; Tatsukawa, A.; Wada, E.; Tsuge, O. Chem. Lett. 1989, 1301. (i) Achqar,
A. El; Boumzebra, M.; Roumestant, M.-L.; Viallefont, P. Tetrahedron 1988,
44, 5319. (j) Mauger, A. B. J. Org. Chem. 1981, 46, 1032.
(1) Na´jera, C.; Sansano, J. M. Chem. ReV. 2007, 107, 4584 and other
important reviews are cited therein.
(2) (a) Receveur, J.-M.; Guiramand, J.; Re´casens, M.; Roumestant, M.-
L.; Viallefont, P.; Martinez, J. Bioorg. Med. Chem. Lett. 1998, 8, 127. (b)
Hashimoto, M.; Hashimoto, K.; Shirahama, H. Tetrahedron 1996, 52, 1931.
(3) (a) Kotnik, M.; Humljan, J.; Contreras-Martel, C.; Oblak, M.; Kristan,
K.; Herve´, M.; Blanot, D.; Urleb, U.; Gobec, S.; Dessen, A.; Solmajer, T.
J. Mol. Biol. 2007, 370 107. (b) Bra¨uner-Osborne, H.; Egebjerg, J.; Nielsen,
E. Ø.; Madsen, U.; Krogsgaard-Larsen, P. J. Med. Chem. 2000, 43, 2609.
(c) Moloney, M. G. Nat. Prod. Rep. 1998, 15, 205.
10.1021/ol702958w CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/29/2008

Scheme 1. Catalytic Asymmetric 1,4-Addition of Glycine
Schiff Bases (2) to R,â-Unsaturated Carbonyl Compounds (1)
Table 1. Asymmetric 1,4-Addition of 2 to Methyl Crotonate
(1a) in the Presence of a Chiral Ca Complexa
entry
2
additive (10 mol %) yield (%)
3/4
ee(3/4) (%)
1b 2a
quant
<1/>99
58/42
11/89
8/92
44/56
68/32
56/46
18/82
-/99
0/82
2
3
2a
2a
2a
2a
2a
2a
2b
2c
2d
(CF3)2CHOH
phenol
8a
8b
8c
85
90
46
71
89
78
90
N.P.
95
97
-/95
-/94
19/77
20/68
23/87
96/98
4
5
6
7
8d
8
9
10
>99/<1
>99/<1
72/-
99/-
11c 2d
a All reactions were performed in THF at -30 °C for 12 h by using 1
(0.36 mmol) and 2 (0.30 mmol) in the presence of MS 4Å (100 mg) and a
chiral Ca complex prepared from Ca(OiPr)2 (0.030 mmol) and ligand 6
(0.030 mmol) unless otherwis noted. b The reaction time was 3 h. c Ligand
7 was used and the reaction temperature was -20 °C. 8a ) p-methox-
yphenol, 8b ) 2,6-dimethylphenol, 8c ) 2-phenylphenol, 8d ) 2-(2-
methoxyphenyl)phenol. N.P. ) no desired product.
esters, only 1,4-adducts were obtained, while pyrrolidine
derivatives were exclusively produced in the reactions with
crotonate derivatives. Careful examination of the reaction
mechanism suggested that the reaction might proceed via a
stepwise mechanism; that is, 1,4-addition of 2 to 1a provides
enolate 5, followed by protonation providing 3 or cyclization
giving 4. We envisioned that if enolate 5 prepared from
crotonate derivatives and glycine derivatives 2 were proto-
nated, 3-substituted glutamic acids might be obtained. Based
on this consideration, we started to investigate diastereo- and
enantioselective 1,4-addition of 2 to crotonate derivatives
using a calcium catalyst.
First, we examined a proton source to trap the enolate
intermediate 5 in the reaction of 1a with 2a using a chiral
calcium catalyst prepared from Ca(OiPr)2 and ligand 6. When
1,1,1,3,3,3-hexafluoroisopropyl alcohol was selected as a
proton source, the reaction proceeded in good yield but the
1,4-adduct was racemic (Table 1, entry 2). Phenol derivatives
were then tested as proton sources. When phenol or p-
methoxyphenol were employed, the [3 + 2] cycloaddition
proceeded predominantly (entries 3 and 4). However, the
1,4-addition product was obtained preferentially using bulkier
phenol derivatives albeit with low selectivities (entries 5-7).
Next, we employed glycine derivatives with modified imines
to probe supression of the intramolecular cycloaddition by
controlling its electrophilicity. When a glycine derivative
bearing a bis(p-methoxyphenyl)methylene group (2b) was
employed, the 1,4-addition product was obtained with high
enantioselectivity (entry 8) but still in low yield. To suppress
the intramolecular cyclization further, we conducted the
reaction using bis(methylthio)methylene-protected glycine
derivative (2c). However, the desired reaction did not proceed
at all (entry 9). We then planned to control the reaction
course by altering the steric properties of the substrates.
When a tert-butylphenylmethylene glycine derivative (2d)
was used,7 the desired 1,4-addition adduct was obtained
exclusively with good enantioselectivity (entry 10). Ad-
ditionally, the use of ligand 7 improved the selectivity, and
the desired 1,4-addition adduct was obtained exclusively with
excellent enantioselectivity (entry 11). Moreover, to our
delight, the product obtained was a single diastereoisomer;
notably diastero- and enantioselective 1,4-addition has been
attained.
We then investigate the substrate scope of this 1,4-addition
reaction, summarized in Table 2. In most cases, the reactions
proceeded smoothly to afford the desired glutamic acid
derivatives with excellent diastereo- and enantioselectivities.
The reaction proceeded even in the presence of 2 mol %
catalyst loading (entry 2). Ethyl crotonate (1b) also worked
well; however, the selectivity was a little lower (entry 3).
Methyl or ethyl 2-pentenoate reacted with 2d smoothly, with
excellent yields and enantioselectivities (entries 4 and 5).
The reactivity of R,â-unsaturated esters with longer alkyl
chains was a little lower, and the reaction of 1e proceeded
slowly, but high selectivity was obtained (entry 6). Branched
substrate 1f also gave the corresponding product in moderate
yield with high ee (entry 7). The reaction of 1g, bearing a
benzyloxy group at the terminal position, gave the desired
product as a diastereomeric mixture in good yield. The ee
(5) Catalytic asymmetric 1,4-addition reactions: (a) Arai, S.; Takahashi,
F.; Tsuji, R.; Nishida, A. Heterocycles 2006, 67, 495. (b) Lygo, B.; Allbutt,
B.; Kirton, E. H. M. Tetrahedron Lett. 2005, 46, 4461. (c) O’Donnell, M.
J. Acc. Chem. Res. 2004, 37, 506. (d) Ohshima, T.; Shibuguchi, T.; Fukuta,
Y.; Shibasaki, M. Tetrahedron 2004, 60, 7743. (e) Akiyama, T.; Hara, M.;
Fuchibe, K.; Sakamoto, S.; Yamaguchi, K. Chem. Commun. 2003, 1734.
(f) Shibuguchi, T.; Fukuta, Y.; Akachi, Y.; Sekine, A.; Ohshima, T.;
Shibasaki, M. Tetrahedron Lett. 2002, 43, 9539. (g) Arai, S.; Tsuji, R.;
Nishida, A. Tetrahedron Lett. 2002, 43, 9535. (h) O’Donnell, M. J.; Delgado,
F. Tetrahedron 2001, 57, 6641. (i) Ishikawa, T.; Araki, Y.; Kumamoto, T.;
Seki, H.; Fukuda, K.; Isobe, T. Chem. Commun. 2001, 245. (j) Zhang, F.-
Y., Corey, E. J. Org. Lett. 2000, 2, 1097. (k) Corey, E. J.; Noe, M. C.; Xu,
F. Tetrahedron Lett. 1998, 39, 5347.
(7) (a) 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. (b) Duhamel, P.; Eddine, J. J.; Valonot, J.-Y.
Tetrahedron Lett. 1984, 25, 2355.
(6) Saito, S.; Tsubogo, T.; Kobayashi, S. J. Am. Chem. Soc. 2007, 129,
5364.
808
Org. Lett., Vol. 10, No. 5, 2008

Scheme 2. Transformation to 3-Methylglutamic Acid (11)
Table 2. Asymmetric 1,4-Addition of 2d to 1 in the Presence
of a Chiral Ca Comlplex Prepared Using Ligand 7a
entry
1
product
yield (%)
dr
ee of 3 (%)
1
1a
1a
1b
1c
1d
1e
1f
3ad
3ad
3bd
3cd
3dd
3ed
3fd
97
93
95
96
97
73
56
82
94
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
82/18
>99:1
99
99
93
96
94
91
82
96e
98
2b
3
4
5
6c
7d
8
1g
1h
3gd
3hd
9
a All reactions were performed in THF at -20 °C for 12 h by using 1
(0.36 mmol) and 2d (0.30 mmol) in the presence of MS 4Å (100 mg) and
a chiral Ca complex prepared from Ca(OiPr)2 (0.030 mmol) and ligand 7
(0.030 mmol) unless otherwise noted. b 2 mol % of catalyst was used. c For
48 h. d For 24 h. e ee of the major product.
gave 3-methyl glutamic acid 11 in high yield (physical data
corresponds to the reported values).9
In summary, we have developed the first diastereo- and
enantioselective 1,4-addition of glycine derivatives to R,â-
unsaturated esters. A chiral calcium catalyst displayed
excellent results for the synthesis of enantiomerically en-
riched 3-substituted glutamic acids in good ee. The product
could be converted to the free glutamic acid derivatives in
good yields. Further studies of the catalyst system and its
application to other reactions are in progress.
of the major product was excellent. Furthermore, when a
crotonamide with N-methoxy and N-methyl groups (Weinreb
amide) was employed, the reaction proceeded smoothly and
the desired product was obtained in high yield with excellent
diastereo- and enantioselectivity (entry 9).
Transformation of the product 3ad was conducted as
follows (Scheme 2). The imine of 3ad was easily cleaved
by acidic hydrolysis to afford the corresponding amino ester
9 in quantitative yield.8 Cyclization occurred under neat
conditions to afford the lactam 10 in 98% yield. The physical
data for product 10 correspond to those previously reported
for the 2R,3R stereochemical relationship.9 NOE experiments
revealed that the protons appended to the stereogenic carbons
are cis to one another. Further acid treatment of the lactam
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from Japan Society
of the Promotion of Sciences (JSPS). S.S. thanks the JSPS
Research Fellowship for Young Scientists.
Supporting Information Available: Experimental pro-
cedures and product characterization. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(8) Ooi, T.; Kameda, M.; Taniguchi, M.; Maruoka, K. J. Am. Chem.
Soc. 2004, 126, 9685.
(9) Wehbe, J.; Rolland, V.; Roumestant, M. L.; Martinez, J. Tetrahe-
dron: Asymmetry 2003, 14, 1123.
OL702958W
Org. Lett., Vol. 10, No. 5, 2008
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