Chiral ligand-controlled asymmetric conjugate addition of lithium amides to enoates

Article abstract of DOI:10.1021/ja029633z

The external chiral ligand-controlled asymmetric conjugate addition reaction of lithium amides with α,β-unsaturated esters provided β-amino esters in high yields and high enantioselectivities. Copyright

Full text of DOI:10.1021/ja029633z

Published on Web 02/12/2003
Chiral Ligand-Controlled Asymmetric Conjugate Addition of Lithium Amides
to Enoates
Hirohisa Doi, Takeo Sakai, Mayu Iguchi, Ken-ichi Yamada, and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received December 8, 2002 ; E-mail: tomioka@pharm.kyoto-u.ac.jp
Table 1. Chiral Ligand 1-Controlled Asymmetric Addition of
The conjugate addition of nucleophiles to R,â-unsaturated
2 to 3a
carbonyl compounds is one of the most powerful bond forming
reactions and has been widely utilized as a key reaction in organic
synthesis.1 We have been engaged in the chiral ligand-controlled2
asymmetric reactions of various types of nucleophiles such as
organolithiums,3 organocoppers,4 organoboranes,5 and arylthiols.6
Asymmetric conjugate addition of nitrogen nucleophiles to enoates
1
2
entry
2a
R
R
1 (equiv) T (°C)
t (h)
yield (%) eeb (%)
provides chiral â-amino acid equivalents that, although less
abundant than their R-analogues,7 occur in nature as components
of peptidic natural products with potent pharmacological activities.8
The most well-known, medicinally important class of nonpeptidic
â-amino acids is found in â-lactams.9 Among several strategies
for the synthesis of optically active â-amino acid derivatives,10 the
conjugate addition of nitrogen nucleophiles to R,â-unsaturated
carboxylic acid derivatives is one of the most attractive and versatile
methods. Three major ways have been described to achieve
asymmetric conjugate addition of nitrogen nucleophiles by using
chiral acceptors,11 chiral amines,12 and chiral catalysts.13 We
describe herein that the conjugate addition reaction of lithium
N-benzyltrimethylsilylamide with enoates is controlled or catalyzed
by an external chiral ligand 114 to produce â-amino esters in high
enantioselectivities up to 99% ee and high yields. To the best of
our knowledge, this is the first success in an external chiral ligand-
controlled asymmetric conjugate addition of lithium amides to
enoates.
At the outset of our study, we examined the reaction efficiency
of lithium amides 2a-d with tert-butyl cinnamate 3a. The reaction
of lithium diisopropylamide 2a with 3a under the mediation of a
slight excess of 1 in toluene at -20 °C for 1 h gave â-amino ester
4a (R1 ) R2 ) i-Pr) with 68% ee in 45% yield (Table 1, entry 1).
Delighted by this promising result, we next examined lithium
dibenzylamide 2b, which is an ammonia equivalent convertible by
hydrogenolysis, to afford, after 3 h at -78 °C, 4b (R1 ) R2 ) Bn)
with a disappointing 4% ee in 48% yield. Fortunately, lithium
N-benzyltrimethylsilylamide 2c15 was an ammonia equivalent of
choice, after 0.7 h at -78 °C, producing protodesilylated 4c (R1 )
H, R2 ) Bn) with an excellent 93% ee in 92% yield (entry 3).
Unfortunately, 2d gave no conjugate addition product 4d, recovering
3a unchanged (entry 6). (-)-Sparteine16 was not the choice as a
chiral ligand to give 4c from 2c with a miserable 3% ee in 25%
yield.
1
2
3
a (2.2) i-Pr
b (3.0) Bn
c (3.0) TMS Bn
c (1.5) TMS Bn
c (1.5) TMS Bn
d (3.0) TMS TMS
i-Pr
Bn
2.6
3.6
3.6
1.8
1.8
3.6
-20
-20
-78
-78
-78
1.0
0.2
0.7
2.0
5.0
45
48
92c
81c
97c
0
68
4
93
82
97
4
5d
6
-20 12.0
a Numbers in parentheses represent the equivalents of 2. b The ee was
determined by a chiral stationary phase HPLC. c The isolated product was
a protodesilylated 4c (R1 ) H, R2 ) Bn). d Five equivalents of TMSCl
was added together with 3a.
Table 2. Asymmetric Conjugate Addition of 2c to 3 Giving 5
entry
method
3
R
t (h)
yield (%)
ee (%)a
1
2
A
B
A
B
A
B
A
B
A
B
A
b
Me
0.25
0.25
2.0
0.5
3.0
3.0
3.0
1.0
3.0
1.0
1.0
92
90
70
68
73
85
99
97
97
96
99
61
98
90
91
92
94
91
92
97
3b
4
c
d
e
f
i-Pr
5
6
7
8
(E)-MeCHdCH
1-naphthyl
9
2-naphthyl
90
98
10
11
g
cis 61
trans 9
12
B
2.0
cis 87
trans 6
85
73
a The ee was determined by a chiral stationary phase HPLC. b Three
equivalents of 2c was used.
of 2c with methyl crotonate gave the corresponding aminated
product with 82% ee (85%) and 49% ee (78%), depending on the
presence and absence of TMSCl, respectively, indicating the
advantageous generality of the simultaneous addition of TMSCl.
We then examined the reaction of 2c with a variety of enoates
3. To a toluene solution of 1.8 equiv of 1 and 1.5 equiv of 2c was
added a mixture of 3 and 5.0 equiv of TMSCl (method A). For
comparison, the reaction of 3.0 equiv of 2c with 3 in the presence
of 3.6 equiv of 1 was examined without addition of TMSCl (method
B). With tert-butyl crotonate 3b, which has deprotonatable methyl
protons at the â-position, the reaction gave 5b with 97% ee in 92%
yield under method A (Table 2, entry 1). In the absence of TMSCl
(method B), comparable selectivity and yield (96% ee, 90%) were
The amount of 2c is one of the critical factors affecting the
reaction efficiency. The reduced amount of 2c to 1.5 equiv from
3.0 equiv gave 4c with a diminished 82% ee in 81% yield (entry
4). Because the lithium ester enolate, generated by the reaction of
2c with 3a, could possibly interfere with the reaction efficiency of
1-2c by forming a ternary complex,17 conversion of a lithium ester
enolate into an inert silyl enol ether may improve the efficiency.
Thus, trimethylchlorosilane (TMSCl) was added together with 3a
to a solution of 1 and 2c in toluene, giving 4c with a satisfactorily
high 97% ee in 97% yield (5 h at -78 °C) (entry 5). The reaction
9
2886
J. AM. CHEM. SOC. 2003, 125, 2886-2887
10.1021/ja029633z CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
ReV. 1992, 92, 771-806. (c) Tomioka, K.; Nagaoka, Y. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; Vol. III, Chapter 31.1. (d) Tomioka, K. In Modern
Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000;
Chapter 12. (e) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033-
8061. (f) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171-196.
obtained (entry 2). The reaction of 3c, having an isopropyl group,
gave 5c with an excellent high 99% ee in 70% yield by method A
(entry 3). The reaction of tert-butyl sorbate 3d, having a propenyl
group at the â-position, regioselectively gave a 1,4-addition product
5d with 98% ee in 73% yield (entry 5). In the reactions of 3c and
3d without TMSCl (method B), 5c and 5d were obtained with lower
61 and 90% ee, respectively (entries 4 and 6). The reaction of 3e
and 3f, having a 1- or 2-naphthyl group at the â-position, under
method A, gave 5e and 5f with 91 and 94% ee in 99 and 90%
yields, respectively (entries 7 and 9). The reaction of cyclic enoate
3g under method A gave cis-5g with 92% ee in 61% yield along
with trans-5g with 97% ee in 9% yield (entry 11). Without TMSCl,
the selectivity of the reaction was lower, giving cis-5g with 85%
ee in 87% yield and trans-5g in 6% yield (entry 12).
The stereochemistry of the asymmetric reaction was determined
by hydrogenolytic debenzylation of (+)-4c (R1 ) H, R2 ) Bn)
with Pearlman’s catalyst under hydrogen in methanol at room
temperature to furnish (+)-R-4 (R1, R2 ) H) of the established
absolute configuration18 in 94% yield. The cyclic (-)-cis-5g
undertook isomerization with potassium tert-butoxide in THF at
room temperature for 5d to afford (+)-trans-5g in 60% yield, and
then debenzylated to the corresponding (-)-(1R,2S)-tert-butyl
2-aminocyclohexanecarboxylate19 in 77% yield. Thus, the same
sense of the stereochemical approach of 2c to acyclic and cyclic 3
was operative in the reaction.
The reaction of (Z)-tert-butyl cinnamate20 instead of (E)-3a
(method A) is interesting to note in that (+)-4c (R1 ) H, R2 ) Bn)
of the same absolute configuration was obtained in 98% ee and
50% yield, along with R-trimethylsilylated trans-cinnamate21 in 44%
yield. With method B, (+)-4c was again obtained in 95% ee and
91% yield. These indicate that Z- to E-isomerization22 takes place
by the action of 2c as a base, supplying (E)-3a as a final substrate
of the conjugate addition reaction.
The reaction of 2c in the absence of 1 in a toluene solvent was
sluggish, producing racemic 4c in 40% yield at -78 °C after 17 h.
Taking advantage of the accelerating effect by a chiral ligand 1,
we conducted the catalytic reaction of 1.5 equiv of 2c with 3a at
-78 °C for 17 h in the presence of 5.0 equiv of TMSCl and 0.3
equiv of 1 in toluene to afford 4c with 70% ee in 75% yield. This
preliminary result shows that the catalytic reaction is promising.
In summary, we have developed the highly efficient external
chiral ligand-mediated asymmetric conjugate addition of lithium
amides to enoates, which provides a powerful new methodology
for the construction of chiral â-amino carbonyl moieties. Currently,
our focus is on the development of the catalytic asymmetric version.
(2) Tomioka, K. Synthesis 1991, 541-549.
(3) (a) Shindo, M.; Koga, K.; Tomioka, K. J. Am. Chem. Soc. 1992, 114,
8732-8733. (b) Asano, Y.; Iida, A.; Tomioka, K. Tetrahedron Lett. 1997,
38, 8973-8976. (c) Asano, Y.; Yamashita, M.; Nagai, K.; Kuriyama, M.;
Yamada, K.; Tomioka, K. Tetrahedron Lett. 2001, 42, 8493-8495.
(4) (a) Kanai, M.; Tomioka, K. Tetrahedron Lett. 1995, 36, 4275-4278. (b)
Fujihara, H.; Nagai, K.; Tomioka, K. J. Am. Chem. Soc. 2000, 122,
12055-12056.
(5) Kuriyama, M.; Nagai, K.; Yamada, K.; Miwa, Y.; Taga, T.; Tomioka, K.
J. Am. Chem. Soc. 2002, 124, 8932-8939.
(6) (a) Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K. J. Am. Chem.
Soc. 1997, 119, 12974-12975. (b) Nishimura, K.; Ono, M.; Nagaoka,
Y.; Tomioka, K. Angew. Chem., Int. Ed. 2001, 40, 429-431. (c)
Nishimura, K.; Tomioka, K. J. Org. Chem. 2002, 67, 431-434. (d)
Nishimura, K.; Tomioka, K. Yakugaku Zasshi 2003, 123, 9-18.
(7) Williams, R. M. Synthesis of Optically ActiVe R-Amino Acids; Pergamon
Press: Oxford, 1989.
(8) (a) Drey, C. N. C. Chemistry and Biochemistry of the Amino Acids;
Chapman and Hall: London, 1985. (b) Hecht, S. M. Acc. Chem. Res.
1986, 19, 383-391. (c) EnantioselectiVe Synthesis of â-Amino Acids;
Juaristi, E., Ed.; Wiley-VCH: New York, 1997.
(9) Recent Progress in the Chemical Synthesis of Antibiotics; Lukacs, G.,
Ohno, M., Eds.; Springer-Verlag: Berlin, 1990.
(10) (a) Cole, D. C. Tetrahedron 1994, 50, 9517-9582. (b) Juaristi, E.;
Quintana, D.; Escalante, J. Aldrichimica Acta 1994, 27, 3-11. (c) Cardillo,
G.; Tomasini, C. Chem. Soc. ReV. 1996, 117-128. (d) Liu, M.; Sibi, M.
P. Tetrahedron 2002, 58, 7991-8035.
(11) (a) Shimano, M.; Meyers, A. I. J. Am. Chem. Soc. 1994, 116, 6437-
6438. (b) Dumas, F.; Mezrhab, B.; d’Angelo, J. J. Org. Chem. 1996, 61,
2293-2304. (c) Asao, N.; Shimada, T.; Sudo, T.; Tsukada, N.; Yazawa,
K.; Gyoung, Y. S.; Uyehara, T.; Yamamoto, Y. J. Org. Chem. 1997, 62,
6274-6282.
(12) (a) Furukawa, M.; Okawara, T.; Terawaki, Y. Chem. Pharm. Bull. 1977,
25, 1319-1325. (b) Hawkins, J. M.; Fu, G. C. J. Org. Chem. 1986, 51,
2820-2822. (c) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991,
2, 183-186. (d) Rico, J. G.; Lindmark, R. J.; Rogers, T. E.; Bovy, P. R.
J. Org. Chem. 1993, 58, 7948-7951. (e) Enders, D.; Wahl, H.; Bettray,
W. Angew. Chem., Int. Ed. Engl. 1995, 34, 455-457. (f) Sewald, N.;
Hiller, K. D.; Helmreich, B. Liebigs Ann. 1995, 925-928. (g) Leroux,
M.-L.; Gall, T.; Mioskowski, C. Tetrahedron: Asymmetry 2001, 12,
1817-1823. (h) Bull, S. D.; Davies, S. G.; Robert, P. M.; Savory, E. D.;
Smith, A. D. Tetrahedron 2002, 58, 4629-4642.
(13) (a) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc.
1998, 120, 6615-6616. (b) Myers, J. K.; Jacobsen, E. N. J. Am. Chem.
Soc. 1999, 121, 8959-8960. (c) Nelson, S. G.; Spencer, K. L. Angew.
Chem., Int. Ed. 2000, 39, 1323-1325. (d) Zhuang, W.; Hazell, R. G.;
Jorgensen, K. A. Chem. Commun. 2001, 1240-1241. (e) Sundararajan,
G.; Prabagaran, N. Org. Lett. 2001, 3, 389-392. (f) Nakama, K.; Seki,
S.; Kanemasa, S. Tetrahedron Lett. 2001, 42, 6719-6722. (g) Cardillo,
G.; Gentilucci, L.; Gianotti, M.; Kim, H.; Perciaccante, R.; Tolomelli, A.
Tetrahedron: Asymmetry 2001, 12, 2395-2398. (h) Sugihara, H.; Daikai,
K.; Jin, X. L.; Furuno, H.; Inanaga, J. Tetrahedron Lett. 2002, 43, 2735-
2739. (i) Guerin, D. J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124, 2134-
2136.
(14) Tomioka, K.; Shindo, M.; Koga, K. J. Org. Chem. 1989, 54, 8266-8268.
(15) (a) Uyehara, T.; Asano, N.; Yamamoto, Y. J. Chem. Soc., Chem. Commun.
1987, 1410-1411. (b) Yamamoto, Y.; Asano, N.; Uyehara, T. J. Am.
Chem. Soc. 1992, 114, 5427-5429.
(16) Johnson, T. A.; Curtis, M. D.; Beak, P. J. Am. Chem. Soc. 2001, 123,
1004-1005.
(17) Fujieda, H.; Kanai, M.; Kambara, T.; Iida, A.; Tomioka, K. J. Am. Chem.
Soc. 1997, 119, 2060-2061.
(18) Davies, S. G.; Garrido, N. M.; Ichihara, O.; Walters, I. A. S. J. Chem.
Soc., Perkin Trans. 1 1993, 1153-1155.
(19) Davies, S. G.; Ichihara, O.; Walters, I. A. S. J. Chem. Soc., Perkin Trans.
1 1994, 1141-1147.
Acknowledgment. This research was supported by a Grant-in-
Aid for Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
Supporting Information Available: The general procedure, char-
acterization data, NMR spectra, and HPLC traces (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
(20) Ando, K. J. Org. Chem. 1999, 64, 8406-8408.
(21) Sato, Y.; Takeuchi, S. Synthesis 1983, 734-735.
(22) Feit, B. A.; Melamed, U.; Schumidt, R. R.; Speer, H. J. Chem. Soc., Perkin
Trans. 1 1981, 1329-1338.
References
(1) (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1992. (b) Rossiter, B. E.; Swingle, N. M. Chem.
JA029633Z
9
J. AM. CHEM. SOC. VOL. 125, NO. 10, 2003 2887