New, chiral phase transfer catalysts for effecting asymmetric conjugate additions of α-alkyl-α-cyanoacetates to acetylenic esters

Article abstract of DOI:10.1021/ja068119g

A new, chiral phase transfer catalyst has been designed for the development of a general and useful procedure on the hitherto unknown, asymmetric conjugate additions of α-substituted-α-cyanoacetates to acetylenic esters with high enantioselectivity and mo

Full text of DOI:10.1021/ja068119g

Published on Web 01/17/2007
New, Chiral Phase Transfer Catalysts for Effecting Asymmetric Conjugate
Additions of r-Alkyl-r-cyanoacetates to Acetylenic Esters
Xisheng Wang, Masanori Kitamura, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto UniVersitySakyo, Kyoto 606-8502, Japan
Received November 13, 2006; E-mail: maruoka@kuchem.kyoto-u.ac.jp
Asymmetric conjugate additions of carbon nucleophiles to R,â-
unsaturated carbonyl systems constitute a highly valuable carbon-
carbon bond formation in asymmetric synthesis, and hence con-
siderable efforts have been devoted to the development of such
asymmetric conjugate additions.1 Accordingly, we have been
intrigued for some time in the possibility of developing a hitherto
unknown asymmetric conjugate addition of R-substituted-R-cy-
anoacetates to acetylenic esters under phase-transfer conditions. The
combination of these substrates is quite appealing, because both
R-substituted-R-cyanoacetates and acetylenic esters have been a
difficult class of nucleophiles and electrophiles, respectively, in
current asymmetric stereochemical control.2 Indeed, even now there
are only several very successful examples using R-substituted-R-
cyanoacetates to effect certain asymmetric Michael reactions.3 In
addition, despite numerous examples of the conjugate additions to
alkenoic esters, so far there are no successful asymmetric conjugate
additions to acetylenic esters.4 Furthermore, an all-carbon quaternary
stereocenter can be constructed in this asymmetric transformation.5
Table 1. Effect of Ar and R Substituents in Chiral Phase Transfer
Catalyst (S)-1 in the Enantioselective Conjugate Addition of
Cyanoacetates to Acetylenic Estersa
entry
ester (R3)
catalyst
condition (
°
C, h)
% yieldb (E/Z) c
% eed
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
OEt
OEt
OEt
OEt
Oet
OEt
Oet
OEt
OEt
OBut
OBut
(S)-1a
(S)-1b
(S)-1c
(S)-1d
(S)-1e
(S)-1f
(S)-1g
(S)-1h
(S)-1i
(S)-1i
(S)-1i
0, 2
0, 2
0, 2
0, 2
0, 2
0, 2
0, 2
0, 2
0, 2
99 (1.7:1)
99 (3.2:1)
99 (3.7:1)
99 (4.4:1)
99 (2.2:1)
99 (2.8:1)
99 (2.7:1)
99 (2.7:1)
99 (2.8:1)
99 (2.9:1)
99 (3.1:1)
99 (3.4:1)
99 (3.5:1)
72 (4.5:1)
99 (3.6:1)
97 (4.0:1)
90 (4.1:1)
55/72
48/45
10/11
31/35
53/39
47/65
41/47
58/54
77/71
90/85
91/82
92/86
92/88
92/75
94/84
94/80
93/87
Our strategy is based on our recent finding of a very active chiral
phase-transfer catalyst of type (S)-1 (Ar ) 3,4,5-F3-C6H2; R ) Bu)
for the asymmetric alkylation of N-(diphenylmethylene)glycine tert-
butyl ester.6 Since the catalyst (S)-1 can be readily prepared from
three components, that is, a chiral binaphthyl part (S)-2, an
arylboronic acid (ArB(OH)2), and a secondary amine (R2NH)
(Scheme 1) as described previously,6a the appropriate modification
of ArB(OH)2 and R2NH parts should give a newly designed catalyst
for the development of a novel asymmetric transformation.
0, 2
-20, 3
-20, 4e
-20, 12f
-20, 12g
-40, 6
OBut
(S)-1i
-40, 16e
-40, 44f
Scheme 1
a Unless otherwise specified, the reaction was carried out with 2 equiv
of acetylenic ester in the presence of 1 mol % of (S)-1 and 1.2 equiv of
Cs2CO3 in toluene under the given reaction conditions. b Isolated yield.
c Determined by 1H NMR analysis. d Enantiopurity of the conjugate adducts
was determined by HPLC analysis using a chiral column. e Use of 0.5 equiv
of Cs2CO3. f Cs2CO3 (0.2 equiv). g Cs2CO3 (0.1 equiv).
3,5-bis(trifluoromethyl)phenyl-substituted catalyst (S)-1b (entry 2),
and a sterically more hindered (S)-1c significantly lowered the
enantioselectivity (entry 3). Among 3,4,5-trifluorophenyl-substituted
spiro-type catalysts, (S)-1d-f, morphorine-derived (S)-1e gives
better enantioselectivity (entry 5 vs entries 4 and 6). Again, 3,5-
bis(trifluoromethyl)phenyl-substituted catalyst (S)-1g lowered the
enantioselectivity to some extent (entry 7). With this catalyst, the
solvent effect was investigated and the enantioselectivity found to
decrease gradually from toluene to ether, m-xylene, and CPME. In
contrast, 3,5-bis[3,5-bis(trifluoromethyl)phenyl]phenyl-substituted
catalyst (S)-1i showed the better enantioselectivity than catalyst (S)-
1h (entry 9 vs 8). A noticeable increase in enantiomeric excess to
The attempted reaction of t-butyl R-(2-phenylethyl)-R-cyanoac-
etate (3a) and ethyl propiolate with Cs2CO3 in the presence of a
catalytic amount (1 mol %) of spiro-type (S,S)-3,4,5-trifluorophenyl-
NAS-bromide7 in toluene at 0 °C for 2 h afforded conjugate adducts
4aa in 96% yield (E/Z ratio ) 2.1:1). The enantiomeric excesses
of (E)- and (Z)-4aa were found to be 18 and 23%, respectively.
The catalyst (S)-1a, which is found to be very active in the
asymmetric alkylation of glycine derivative,6a showed higher
enantioselectivity (55 and 72% ee’s for (E)- and (Z)-4aa) (entry 1,
Table 1). A somewhat lower enantioselectivity is observed with
9
1038
J. AM. CHEM. SOC. 2007, 129, 1038-1039
10.1021/ja068119g CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Enantioselective Conjugate Addition of
Cyanoacetates to Acetylenic Esters with (S)-1i under Phase
Transfer Conditiona
This approach is also applicable to the asymmetric conjugate
addition of t-butyl R-(2-phenylethyl)-R-cyanoacetate (3a) to 2-cy-
clohexenone with Cs2CO3 in the presence of a catalytic amount (1
mol %) of the catalyst (S)-1i in toluene at 0 °C for 2 h to afford
the corresponding conjugate adduct 6 in 99% yield (diastereomeric
ratio, 85:15; 91% ee for the major diastereomer).
entry
cyanoacetate (R1)
% yieldb
E/Z ratioc
% eed (confign)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
PhCH2CH2 (3a)
99
97e
90f
99
99
99
99e
99
80e
99
99
99
96
72e
99
89
3.6/1
4.0/1
3.8/1
4.6/1
4.6/1
6.7/1
6.5/1
5.4/1
7.5/1
3.3/1
6.2/1
3.8/1
5.1/1
5.8/1
3.7/1
2.2/1
94/84
94/80
95/95
94/93
CH3CH2CH2CH2 (3b)
CH3CH2CH2 (3c)
CH3CH2 (3d)
95/-
CH3 (3e)
93 (S)/-
93 (S)/-
96/-
(CH3)2CH (3f)
96/-
92/89
92/81
95/93
95 (S)/93
97 (S)/90
95 (S)/91 (S)
18/-
CH2dCHCH2CH2 (3g)
CH2dCHCH2 (3h)
(CH3)2CHCH2CH2 (3i)
(CH3)3SiCH2CH2 (3j)
In conclusion, we succeeded in designing a new, chiral phase
transfer catalyst of type (S)-1i to realize a general and useful
procedure for the asymmetric conjugate addition of various t-butyl
R-alkyl-R-cyanoacetates to t-butyl propiolate.
p-Br-PhCH2CH2 (3k)
Ph (3l)
Acknowledgment. This work was supported by a Grant-in-Aid
for Scientific Research on Priority Areas “Advanced Molecular
Transformation of Carbon Resources” from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan. M.K. is
grateful to the Japan Society for the Promotion of Science for Young
Scientists for a Research Fellowship.
a Unless otherwise specified, the reaction was carried out with 2 equiv
of t-butyl propiolate in the presence of 1 mol % of (S)-1i and 1.2 equiv of
Cs2CO3 in toluene under the given reaction conditions. b Isolated yield.
c Determined by 1H NMR analysis. d Enantiopurity of the adducts 4a-k
was determined by HPLC analysis using a chiral column. e Catalytic use
(0.5 equiv) of Cs2CO3 at -40 °C for 16-24 h. f At -40 °C for 20 h.
Supporting Information Available: Experimental details and
physical characterization data of the catalysts and all new compounds
including the X-ray analysis. This material is available free of charge
via the Internet at http://pubs.acs.org.
94% ee was finally attained when the lower temperature was
employed with (S)-1i in combination with the use of t-butyl
propiolate (entries 10-12). The amount of Cs2CO3 base can be
reduced to 0.2 equiv without decreasing the yield and enantiose-
lectivity (entries 12, 13, 16, and 17).
References
(1) (a) ComprehensiVe Asymmetric Catalysis I-III; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Berlin, 1999. (b) Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000. (c)
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; Springer: Berlin, 2004; (Suppl. 1).
With the optimal condition at hand, we further studied the
generality of the asymmetric conjugate addition to t-butyl propiolate
using various t-butyl R-substituted-R-cyanoacetates as shown in
Table 2, where excellent enantioselectivity is observable in the
catalytic enantioselective synthesis of polyfunctional molecules with
an all-carbon quaternary stereocenter. Among R-substituted-R-
cyanoacetates, both R-(prim-alkyl)- and R-(sec-alkyl)-R-cyanoac-
etates exhibited high enantioselection. However, use of R-phenyl-
R-cyanoacetate 3l resulted in the low enantioselectivity for 4l (entry
16). Catalytic Cs2CO3 (0.5 equiv) is also employable (entries 2, 7,
9, and 14). Although the observed E/Z selectivity is moderate, these
(E)- and (Z)-4a-k can be easily separated by simple column
chromatography.
The absolute configuration of the conjugate adduct (E)-4e was
firmly determined to be S by conversion to the known dimethyl
ester 5 with the sequence of (i) catalytic hydrogenation (catalyst
Pd/C, H2, MeOH); (ii) acid hydrolysis (CF3CO2H/CH2Cl2); and (iii)
methylation (CH2N2/ether).8 The absolute configuration of other
conjugate adducts, (E)-4j, (E)-4k, and (Z)-4k was also determined
by X-ray crystallographic analysis (Table 2).
(2) Grossman, R. B.; Comesse, S.; Rasne, R. M.; Hattori, K.; Delong, M. N.
J. Org. Chem. 2003, 68, 871.
(3) (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 11204.
(b) Taylor, M. S.; Zalatan, D. N.; Lerchner, A. M.; Jacobsen, E. N. J.
Am. Chem. Soc. 2005, 127, 1313. (c) Li, H.; Song, J.; Liu, X.; Deng, L.
J. Am. Chem. Soc. 2005, 127, 8948. (d) Wang, Y.; Liu, X.; Deng, L. J.
Am. Chem. Soc. 2006, 128, 3928. (e) Wu, F.; Hong, R.; Khan, J.; Liu,
X.; Deng, L. Angew. Chem., Int. Ed. 2006, 45, 4301. See also related
references in ref 3.
(4) Successful example of asymmetric conjugate addition of â-diketones to
alkynones: Bella, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126,
5672.
(5) (a) Quaternary Stereocenters: Challenges and Solutions for Organic
Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim,
Germany, 2005. (b) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5363. (c) Denissova, I.; Barriault, L. Tetrahedron
2003, 59, 10105.
(6) (a) Kitamura, M.; Shirakawa, S.; Maruoka, K. Angew. Chem. Int. Ed.
2005, 44, 1549. (b) Han, Z.; Yamaguchi, Y.; Kitamura, M.; Maruoka, K.
Tetrahedron Lett. 2005, 46, 8555.
(7) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 5139.
(8) Sawamura, M.; Hamashima, H.; Ito, Y. Tetrahedron 1994, 50, 4439.
JA068119G
9
J. AM. CHEM. SOC. VOL. 129, NO. 5, 2007 1039