Enantioselective conjugate addition of silylketene acetals to β-enamidomalonates. Synthesis of β-amino acid derivatives

Article abstract of DOI:10.1021/ol026333d

(figure presented) Conjugate addition of silylketene acetals or enolsilanes to enamidomalonates proceeds with excellent chemical efficiency and good selectivity using Cu(OTf)₂ and a chiral bisoxazoline. The effect of the Lewis acid, ligand, the

Full text of DOI:10.1021/ol026333d

ORGANIC
LETTERS
2002
Vol. 4, No. 17
2933-2936
Enantioselective Conjugate Addition of
Silylketene Acetals to
â-Enamidomalonates. Synthesis of
â-Amino Acid Derivatives
Mukund P. Sibi* and Jianxie Chen
Department of Chemistry, North Dakota State UniVersity, Fargo, North Dakota, 58105
mukund.sibi@ndsu.nodak.edu
Received June 10, 2002
ABSTRACT
Conjugate addition of silylketene acetals or enolsilanes to enamidomalonates proceeds with excellent chemical efficiency and good selectivity
using Cu(OTf)2 and a chiral bisoxazoline. The effect of the Lewis acid, ligand, the N-acyl substituent, and the nucleophile on yield and selectivity
for the addition product have been evaluated.
New protocols for enantioselective conjugate addition con-
tinue to attract interest.1 In this context, several recent reports
have underscored the utility of malonate-type acceptors in
these reactions. These systems not only provide a new
structural motif for acceptors but also show enhanced
reactivity toward nucleophiles. The addition of chiral ionic
nucleophiles to malonates has been reported by Beak2 and
Alexakis.3 Evans and co-workers reported a highly selective
addition of neutral silyl ketene acetals to alkylidene and
arylidene malonates using catalytic amounts of chiral Lewis
acids.4 Additionally, Jørgensen has shown that indoles add
conjugatively to malonates using chiral Lewis acids.5 The
use of proline as a catalyst in the addition of ketones to
alkylidene malonates has also been demonstrated.6 The
addition of silyl ketene acetals to enamido methylene-
oxobutanoate has been reported by Saito and co-workers.7
A single example of silyl ketene acetal addition to enami-
domalonates in a racemic fashion was also reported in Saito’s
work. We have recently shown8 that chiral ionic nucleophiles
add to enamido malonates with high selectivity, thus provid-
ing a new route for accessing â-amino acid derivatives.9
Analogously, addition of neutral nucleophiles to enamidoma-
(1) For a recent review, see: Sibi, M. P.; Manyem, S. Tetrahedron 2000,
56, 8033. For other reviews in the area, see: Krause, N.; Hoffmann-Ro¨der,
A. Synthesis 2001, 171. Tomioka, K. In Modern Carbonyl Chemistry, Otera,
J., Ed.; Wiley-VCH: Weinheim, Germany, 2000; p 491. Leonard, J.; Diez-
Barra, E.; Merino, S. Eur. J. Org. Chem. 1998, 2051.
(2) (a) Park, Y. S.; Weisenburger, G. A.; Beak, P. J. Am. Chem. Soc.
1997, 119, 10537. (b) Curtis, M. D.; Beak, P. J. Org. Chem. 1999, 64,
2996.
(5) Zhuang, W.; Hansen, T.; Jørgensen, K. A. Chem. Commun. 2001,
347. For other examples, see: Maas, S.; Stamm, A. Kunz, H. Synthesis
1999, 1792. Cahiez, G.; Alami, M. Tetrahedron 1989, 43, 4163. For the
addition of hydroxylamines to alkylidene malonates, see: Cardillo, G.;
Gentilucci, L.; Gianotti, M.; Kim, H.; Perciaccante, R.; Tolomelli, A.
Tetrahedron: Asymmetry 2001, 12, 2395.
(6) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Barbas, C. F.,
III. Tetrahedron Lett. 2001, 42, 4441.
(3) (a) Alexakis, A.; Benhaim, C. Tetrahedron: Asymmetry 2001, 12,
1151. (b) Alexakis, A.; Rosset, S.; Allamand, J.; March, S.; Guillen, F.;
Benhaim, C. Synlett 2001, 1375.
(4) (a) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Downey, C. W.;
Tedrow, J. S. J. Am. Chem. Soc. 2000, 122, 9134. Also see: (b) Evans, D.
A.; Willis, M. C.; Johnston, J. N. Org. Lett. 1999, 1, 865. (c) Evans, D. A.;
Scheidt, K. A.; Johnston, J. S.; Willis, M. C. J. Am. Chem. Soc. 2001, 123,
4480. (d) Kitajima, H.; Ito, K.; Katsuki, T. Tetrahedron 1997, 53, 17015.
(e) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325.
(7) Saito, S.; Uedo, E.; Kato, Y.; Murakami, Y.; Ishikawa, T. Synlett
1996, 1103. For Diels-Alder reactions with ketene acetals and enamido
substrates, see: Nishiuchi, M.; Honda, K.; Nakai, T. Chem. Lett. 1996,
321. Ray, C. A.; Wallace, T. W.; Ward, R. A. Tetrahedron Lett. 2000, 41,
3501.
(8) Sibi, M. P.; Asano, Y. J. Am. Chem. Soc. 2001, 123, 9708.
(9) For synthesis and biology of â-amino acids, see: EnantioselectiVe
Synthesis of â-Amino Acids; Juaristi, E., Ed.; Wiley-VCH: New York, 1997.
For a review, see: Cole, D. C. Tetrahedron 1994, 50, 9517.
10.1021/ol026333d CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/02/2002

Scheme 1
Table 1. Effect of Ligand and Stoichiometry on Conjugate
Addition
yield
(%)a
ee
(%)b
entry substrate:Nu:HFIP:LA ligand time
1c
2
3
4d
5
6
7
8
1:2.2:2:0.1
1:2.2:2:0.1
1:2.2:0:0.1
1:2.2:2:0.1
1:2.2:2:0.3
1:2.2:2:0.1
1:2.2:2:0.1
1:2.2:2:0.1
1:2.2:2:0.1
1:2.2:2:0.1
8
8
8
8
8
5 h
20 h
20 h
55 h
8 h
20 h
20 h
20 h
20 h
20 h
95
96
51
89
95
95
95
87
96
96
80
89
78
72
76
63
68
60
44
32
9
10
11
12
13
9
10
lonates using chiral Lewis acids provides access to â-amino
acid derivatives in an enantioenriched form and also infor-
mation on the nature of the coordination between the
substrate and the Lewis acid. Results from these studies are
reported here (Scheme 1).
a Isolated yield for column-purified material. b Determined by HPLC.
c Reaction carried out at -78 °C and warmed to room temperature.
d Reaction at -50 °C.
The â-heteroatom substituent in the malonate 1 raises
several issues with regard to the conjugate addition. (1) Will
neutral nucleophiles add effectively (1 to 3)? (2) Could these
reactions be carried out using a catalytic amount of a chiral
Lewis acid, and what will be the level of selectivity? (3)
What will be the nature of the coordination between the
amide and the Lewis acid, or will the Lewis acid preferen-
tially coordinate to the 1,3-dicarbonyl unit of the malonate?
(4) Can the product amino acid 4 be obtained easily from 3
by Krapcho decarboxylation?10
tion was carried out by varying the amounts of the Lewis
acid Cu(OTf)2, the nucleophile, and hexafluoro 2-propanol
(HFIP)12 using ligand 8 as the chiral source.13 Adding excess
6 using 10 mol % chiral Lewis acid at -78 °C to the
substrate 5 and warming the reaction to room temperature
gave the conjugate addition product 7 in high yield and 80%
ee (entry 1). This illustrates that conjugate addition of neutral
nucleophiles to enamidomalonates can be carried out with
good selectivity using catalytic amounts of a chiral Lewis
acid. Performing the reaction at -30 °C for a longer time
led to an improvement in selectivity with as high as 89% ee
(entry 2). Omission of HFIP as an additive had a negative
impact on both yield and selectivity (entry 3), although in
contrast to Evans’ results, the HFIP is not absolutely
necessary for turnover. It may be that in the absence of HFIP,
the enamide may function as a proton source. Other
variations in reaction conditions did not lead to an improve-
ment in selectivity (entries 4 and 5). A series of ligands were
evaluated next under the optimal conditions (see entry 2).
In comparison to the cyclopropyl-substituted ligand 8, two
other ligands with variation in the substitution at the
methylene bridge (dibenzylidene (9) or dihydrogen (10))
showed moderate selectivity in the conjugate addition
(compare entry 2 with 6 and 7). Three other bisoxazolines
11-13 were also tested. Evans and co-workers have previ-
ously shown that tert-butyl box ligand 11 in combination
with copper Lewis acids is very effective in conjugate
addition to malonates (>95% ee).11 In contrast, ligand 11
was only marginally effective in conjugate addition to 5
(entry 8). Ligands 12 and 13 were less efficient than 11 in
the addition reaction (compare entry 8 with 9 and 10). These
Our work began with the addition of the O,S-ketene silyl
acetal 6 to the malonate 5 under the reaction conditions
previously reported by Evans and co-workers (Scheme 2,
Scheme 2
(10) Krapcho, A. P.; Weimaster, J. F.; Eldridge, J. M.; Jahngen, E. G.
E., Jr.; Lovey, A. J.; Stephen, W. P. J. Org. Chem. 1978, 43, 138.
(11) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Tedrow, J. S. J. Am.
Chem. Soc. 1999, 121, 1994.
(12) (a) See refs 4 and 11. (b) Bernardi, A.; Colombo, G.; Scolastico,
C. Tetrahedron Lett. 1996, 37, 8921. (c) Kawara, A.; Taguchi, T.
Tetrahedron Lett. 1994, 35, 8805. (d) Kitajima, H.; Katsuki, T. Synlett 1997,
568.
(13) For details on experimental procedures and characterization of the
compounds prepared in this study, see Supporting Information.
Table 1).11 The methyl ester was chosen as the substrate
based on the ease of its preparation as well as the literature
precedent from the Evans group.4,11 Initial reaction optimiza-
2934
Org. Lett., Vol. 4, No. 17, 2002

studies clearly established that a combination of Cu(OTf)2
and ligand 8 can provide excellent chemical yield and high
selectivity in neutral nucleophile addition to enamidoma-
lonates.
A brief study on the effect of Lewis acid on the conjugate
addition was undertaken (Table 2) under the reaction
Table 3. Effect of the N-Acyl Group and the Nucleophile on
Selectivity
entry
R1
Ph
Ph
Ph
Phc
t-Bu
t-Bu
t-Bu
CF3
CF3
nucleophile
time
yield (%)a
ee (%)b
1
2
3
4
5
6
7
8
9
6
16
17
18
6
16
17
6
20 h
7 h
96
98
97
39
97
98
74
74
95
89
30
64
40
83
16
73
54
67
34 h
40 h
36 h
12 h
22 h
20 h
20 h
Table 2. Effect of Lewis Acid on Conjugate Addition
entry
Lewis acid (0.1 equiv)
time
yield (%)a
ee %b
1
2
3
4
5
Cu(OTf)2
Cu(SbF6)2
Zn(OTf)2
Mg(OTf)2
Mg(ClO4)2
20 h
12 h
48 h
48 h
48 h
96
95
30
21
28
89
63
32
36
5
17
a Isolated yield for column-purified material. b Determined by HPLC.
c Reaction at room temperature.
a Isolated yield for column-purified material. b Determined by HPLC.
temperatures and the selectivity was only modest (entry 4).
These results suggest that a variety of nucleophiles can be
used for the conjugate addition with variable selectivity and
good chemical efficiency. Of the four different nucleophiles,
the O,S-ketene silyl acetal gave the highest level of selectivity
in these reactions. These results are consistent with the
observations of Evans and co-workers on nucleophile addi-
tion to arylidene malonates.14
The effect of the N-acyl group on selectivity in the
conjugate addition was also examined (Table 3). The
N-pivaloyl group was equally effective as the N-benzoyl
group in conjugate addition affording similar selectivity and
efficiency (compare entry 1 with 5). The selectivity for the
addition of the silylketene acetal 16 was low irrespective of
the protecting group (compare entry 2 with 6). The enolsilyl
ether 17 showed good reactivity and selectivity in the
addition reaction (entry 7). Reactions with the electron-
withdrawing N-acyl group, the trifluoroacetamide 14b, were
carried out. Addition of the thioketene acetal 6 under the
standard conditions gave product 15g in good yield and
reduced selectivity. As was the case with other N-acyl groups,
addition of 17 to 14b was very successful and selectivity
was good (entry 9). Thus, of the three N-acyl groups
evaluated, the benzoyl and pivaloyl groups were equally
effective with respect to yield and selectivity.
conditions established for Cu(OTf)2. Changing the triflate
counterion to a more ionic antimony hexafluoride led to
improvements in reactivity with a concomitant decrease in
selectivity (compare entry 1 with 2). Magnesium and zinc
Lewis acids were not very effective in the conjugate additions
(entries 3-5).
Having established that the conjugate addition to enami-
domalonates was feasible, we then set out to evaluate the
scope of the reaction with respect to the nucleophile and the
effect of the N-acyl substituent on the reaction (Scheme 3,
Table 3).
Scheme 3
The absolute stereochemistry for one of the conjugate
addition products was established by converting 7 to a known
compound (Scheme 4). Compound 7 was decarboxylated
under Krapcho conditions10 to provide a desymmetrized
glutarate. This established that the conjugate addition product
could be converted to the â-amino acid derivative unevent-
fully. Selective hydrolysis of the thioester to the correspond-
ing acid 19 was carried out using bromine.15 Monodecar-
boxylation of the acid ester 19 using Barton protocol16
In comparison to the O,S-ketene silyl acetal 6 (entry 1),
reaction with the O,O-ketene silyl acetal 16 (entry 2) was
less selective under the optimized conditions for conjugate
addition. Similar enhancement in selectivity with O,S-ketene
silyl acetal was also observed by Evans and co-workers.4
Reaction with enolsilyl ether 17 derived from acetophenone
gave the addition product 15b in excellent yield and moderate
selectivity (entry 3). In contrast, reaction with pinacolone
enolsilyl ether 18 was very slow and required higher
(14) For excellent contributions on the mechanistic aspects of Mu-
kaiyama-Michael additions with silyl ketene acetals, see: Fujita, Y.; Otera,
J.; Fukuzumi, S. Tetrahedron 1996, 52, 9419. Otera, J.; Fujita, Y.; Sakuta,
N.; Fujita, M.; Fukuzumi, S. J. Org. Chem. 1996, 61, 2951.
(15) (a) Minato, H.; Kodama, H.; Miura, T.; Kobayashi, M. Chem. Lett.
1977, 413. (b) Minato, H.; Takeda, K.; Miura, T.; Kobayashi, M. Chem.
Lett. 1977, 1095.
(16) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron 1985,
41, 3901.
Org. Lett., Vol. 4, No. 17, 2002
2935

contrast to 89% ee observed for the reaction with 5 using
the same chiral Lewis acid. The reaction of 21 and 6 with
the chiral Lewis acid derived from Cu(OTf)2/11 gave a higher
selectivity, and the sense of stereoinduction in the two
experiments was the same.
Scheme 4
A working model for the conjugate addition to 5 is
presented in Figure 1. On the basis of the crystal structure
furnished the known (R)-methyl 3-(benzoylamino)butanoate
20.17 It should be noted that the radical intermediate in the
decarboxylation step is amenable for functionalization such
as labeling (deuterium or tritium) and reactions with allyl-
stannane or other radical acceptors.18
Figure 1.
In an effort to arrive at a stereochemical model for the
observed selectivity in the conjugate addition to 5, two
control experiments were carried out (Scheme 5). The level
and product stereochemistry, Evans and co-workers have
proposed a model (structure A) for ketene acetal addition to
arylidene malonates. The absolute stereochemistry for 7
(Scheme 4) is consistent with malonate 5 also undergoing a
si-face addition. This suggests a similar coordination geom-
etry for the ternary complex between 5 + Cu(OTf)2 + 8
(structure B). The large variation in selectivity in addition
to 5 and 21 using ligand 8 may indicate alternate coordination
geometries (chelation involving the amide functional group
resulting in either six or an eight-membered ring). With the
limited amount of data at hand, it is not possible to
definitively state which of these speculative models (B or
others) are operative in the conjugate additions. Experiments
are underway to gain a better understanding of the coordina-
tion in these systems and to further extend the addition
chemistry to the preparation of more complex amino acids.
Scheme 5
of enantioselectivity and the sense of stereoinduction for the
conjugate addition product from 21 and 6 using Cu(OTf)2
and ligands 8 or 11 were determined. The reaction using
ligand 8 was nonselective affording 22 in 17% ee. This is in
Acknowledgment. This work was supported by a grant
from the National Science Foundation (CHE-9983680).
Supporting Information Available: Characterization
data for compounds 5-22 and experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) (a) Estermann, H.; Seebach, D. HelV. Chim. Acta 1988, 71, 1824.
(b) Cardillo, G.; Tolomelli, A.; Tomasini, C. Eur. J. Org. Chem. 1999,
155.
(18) For a recent review of this area, see: Motherwell, W. B.; Imboden,
C. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-
VCH: Weinheim, Germany, 2001, Chapter 1.7.
OL026333D
2936
Org. Lett., Vol. 4, No. 17, 2002