Enantioselective construction of quaternary carbon centre catalysed by bifunctional organocatalyst

Article abstract of DOI:10.1039/b605871j

A highly efficient organocatalytic method for the asymmetric Michael addition of α-substituted cyanoacetates to vinyl sulfones was investigated. It was observed that this reaction was synergistically promoted by readily available bifunctional thiourea-ter

Full text of DOI:10.1039/b605871j

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
Enantioselective construction of quaternary carbon centre catalysed by
bifunctional organocatalyst†
a
a
b
a
b
a
b
a
Tian-Yu Liu, Jun Long, Bang-Jing Li, Lin Jiang, Rui Li, Yong Wu, Li-Sheng Ding and Ying-Chun Chen*
Received 25th April 2006, Accepted 2nd May 2006
First published as an Advance Article on the web 9th May 2006
DOI: 10.1039/b605871j
The bifunctional thiourea–tertiary amine derivatives of sim-
ple chiral diamines serve as highly enantioselective catalysts
for the Michael addition of a-substituted cyanoacetates to
vinyl sulfones, giving an efficient protocol for the construction
of an all-carbon substituted quaternary stereocentre.
In recent years the development of organic molecules capable of
the efficient and enantioselective promotion of carbon–carbon
Fig. 1 Proposed hydrogen-bonding interaction of NH of thiourea with
functional groups.
1
bond-forming reactions has triggered ongoing interest. In partic-
2
ular, bifunctional catalysts possessing a combination of thiourea
3
4
(
or urea) and amine groups have received special attention. The
efficient protocol for the construction of an all-carbon substituted
1
3
8c
double hydrogen-bonding interaction of the N–H of thiourea
quaternary stereocentre at the prochiral nucleophiles. More
importantly, the addition products could be smoothly converted
(
or urea) and a reactant has been generally realized to have a
5
2,2
specific role in efficient catalysis and high enantiocontrol. Several
functionalities, including nitro, carbonyl and imine groups, have
been successfully applied. Nevertheless, expanding the scope of
reactants would be a welcome advance to the insight of the general
synthetic utilities of the thiourea-based catalysts.
to the enantiomerically pure b -amino acids, which still represent
a challenge for synthetic chemists.
Bifunctional catalysts 1a–e (Fig. 2, 20 mol%) with various
14
3–5
4d
chiral scaffolds, which have been previously reported by us
4
and other chemists, were screened in the Michael addition of
ethyl a-phenyl cyanoacetate 2a and phenyl vinyl sulfone 3 in
toluene at room temperature. As summarized in Table 1, all
catalysts could smoothly promote this Michael reaction to give the
addition product 4a. Good to quantitative yields with moderate
enantioselectivities (43–68% ee) were observed for structurally
variable bifunctional catalysts (Table 1, entries 1–5). Catalyst 1e
derived from the more flexible (R,R)-1,2-diphenylethylenediamine
exhibited much better enantioselectivity (68% ee, entry 5), while
the catalytic activity was inferior to the other catalysts 1a–d.
Notably this was the first example that the acyclic catalyst 1e
Nowadays, sulfones are still recognized as significant inter-
mediates in organic synthesis, especially when behaving as the
6
activating group for C–C bond forming reactions. Therefore, it
is not surprising that considerable efforts have been devoted to
the development of enantioselective Michael addition to vinyl
sulfones. However, compared to the extensively studied a,b-
unsaturated carbonyl compounds or nitroolefins, the enantiose-
7,8
lective catalytic reaction of vinyl sulfones is still in its infancy.
In addition, the application of hydrogen-bonding interactions
9
of S=O functionalities in asymmetric synthesis is also rare. In
1
998 Gong et al. reported that a robust 2D sheet could be
was superior to the other thiourea–tertiary amine bifunctional
ꢀ
4a–l
formed from N,N -dibenzylsulfamides through intermolecular
analogues with more rigid scaffolds.
Similar results were
10
hydrogen-bonding of O=S–N–H units (Fig. 1a). We envision
obtained for the modified catalysts 1f and 1g (entries 6 and 7).
Subsequently various solvents were tested (entries 8–11). The
that an efficient double hydrogen-bonding interaction might also
be possible between the N–H of thiourea catalyst and the S=O
11
of vinyl sulfone compounds, as has been observed for nitro
4
a,b,h,j
groups (Fig. 1b vs c).
As part of our continuous study
4d
on thiourea-based organocatalysis, here we wish to report
the highly enantioselective Michael addition of a-substituted
12
cyanoacetates and vinyl sulfones synergistically promoted by
bifunctional thiourea–tertiary amine organocatalysts, giving an
a
Key Laboratory of Drug-Targeting of Education Ministry and Depart-
ment of Medicinal Chemistry, West China School of Pharmacy, Sichuan
University, Chengdu, 610041, China. E-mail: ycchenhuaxi@yahoo.com.cn.;
Fax: 86 28 85502609; Tel: 86 28 85502609
b
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu,
6
10041, China
†
Electronic supplementary information (ESI) available: Experimental
procedures, structural proofs, NMR, HRMS and HPLC spectra of the
products. See DOI: 10.1039/b605871j
Fig. 2 Structures of various chiral thiourea–tertiary amine catalysts.
Org. Biomol. Chem., 2006, 4, 2097–2099 | 2097
This journal is © The Royal Society of Chemistry 2006

View Article Online
Table 1 Screening studies of the Michael addition of a-phenyl cyanoac-
Table 2 Asymmetric Michael addition of a-aryl cyanoacetates 2 to phenyl
a
a
etates 2 to phenyl vinyl sulfone 3
vinyl sulfone 3
b
c
Entry
R
Product
Yield (%)
ee (%)
◦
b
c
Entry Catalyst Solvent
T ( C) Time/h Yield (%) ee (%)
1
2
3
4
5
6
7
Ph (2a)
4a
4d
4e
4f
4g
4h
4i
83
90
93
92
92
73
96
94
95
96
93
91
94
95
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
1g
1e
1e
1e
1e
1e
1e
1a
1d
1e
1f
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCM
20
20
20
20
20
20
20
20
20
20
20
20
20
−40
−40
−40
−40
5
5
5
6
8
8
6
10
13
13
8
95
96
95
94
75
75
81
62
47
61
73
76
77
90
89
83
75
54
43
53
52
68
66
62
48
31
8
66
64
63
72
81
94
81
p-Cl–Ph (2d)
p-Br–Ph (2e)
p-F–Ph (2f)
d
m-CF
p-CH
2-thienyl (2i)
3
–Ph (2g)
3
O–Ph (2h)
a
Reaction conditions: 2 (0.2 mmol), 3 (0.1 mmol) and catalyst 1e
b
(
0.02 mmol) were stirred in toluene (1 mL) for 96 h. Isolated yield.
THF
c
Determined by chiral HPLC analysis. The absolute configurations have
1
1
1
1
1
1
1
1
CH
3
CN
d
◦
not been assigned yet. At −50 C for 96 h.
Benzene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
d
e
7
10
48
48
96
96
◦
at −40 C, and up to 73% ee was received in excellent isolated
yield in the presence of the more rigid catalyst 1d (Table 3, entry
16
1
). Nevertheless, the enantioselectivity could not been further
increased at lower temperature. When a-n-butyl cyanoacetate 2k
a
Reaction conditions: 2 (0.2 mmol), 3 (0.1 mmol) and catalyst 1
0.02 mmol) were stirred in a solvent (1 mL). Isolated yield. Determined
d e
was applied, the enantioselectivity was elevated to 82% ee (entry
b
c
(
2
). In addition, good ee was obtained in the case of a-benzyl
by chiral HPLC analysis. 2b was used. 2c was used.
substrate 2l (entry 3), and almost enantiomerically pure product
was received after recrystallization (data in bracket). Notably the
◦
enantioselectivities decreased dramatically in non-arene solvents
acetal-functionalised cyanoacetate 2m gave excellent ee at −50 C
(
entries 8–10). In addition, similar results were gained for the other
while the isolated yield was moderate (entry 4).
cyanoacetates 2b and 2c (entries 12 and 13). Finally, we conducted
the Michael reaction at lower temperature in order to improve the
enantioselectivity. It was quite inspiring that the ees were greatly
Deng et al. have successfully developed an approach for the
synthesis of chiral a,a-disubstituted a-amino acids from the
addition products of vinyl sulfone. Here the a,a-disubstituted
8c
◦
elevated at −40 C in the reactions catalysed by organocatalysts
cyanoacetates were smoothly converted to the biologically impor-
2
,2
1a, 1d–f (entries 14–17), and up to 94% ee was obtained in good
tant b -amino acids, which have not been easily accessible in an
14
isolated yield after 96 h in the case of 1e (entry 16).
enantioselective catalytic way to date. As illustrated in Scheme 1,
2
,2
With the optimised reaction conditions in hand, the scope
and limitation of the bifunctional organocatalyst 1e promoted
asymmetric Michael reactions were explored. A series of a-aryl
substituted ethyl cyanoacetates were reacted with phenyl vinyl
the protected b -amino acid 6a was obtained in one pot in the
presence of Boc O, employing Raney-Ni catalysed hydrogenation
at 50 psi H pressure. In addition, the protected b -amino acid 6b
2
2
,2
2
was also prepared from the a-benzyl bis(pehnylsulfone) 4l under
the same conditions, while a slight decrease in ee was observed in
the product. The remaining sulfone could behave as the activating
◦
sulfone 3 in the presence of 20 mol% 1e at −40 C for 96 h.
As summarised in Table 2, excellent enantioselectivities with high
yields were obtained for a-aryl cyanoacetates with various halide
substituents (Table 2, entries 2–4). For m-trifluoromethyl substrate
Table 3 aAsymmetric Michael addition of a-alkyl cyanoacetates 2 to vinyl
sulfone 5
2g, better ee could be received at lower temperature (entry 5). In
addition, high enantioselectivity was achieved for aryl substrate 2h
with electron-donating substituent (entry 6). Heteroaryl derivative
2i also gave excellent results under the same conditions (entry 7).
Having presented the reaction scope of a-aryl cyanoacetates
with vinyl sulfone 3, we further investigated the reaction of
a-alkyl cyanoacetates. Unfortunately, very poor reactivity was
observed in the reaction of a-methyl cyanoacetate 2j and 3
even at ambient temperature in the presence of 1e (20 mol%,
b
c
Entry
R
Product
Yield (%)
ee (%)
1
2
3
Me (2j)
4j
4k
4l
96
98
73
82
72 (99)
96
n-Butyl (2k)
Benzyl (2l)
d
d
2
4 h, <30% conversion, 45% ee). However, the reaction could be
98 (70)
e
4
(EtO)
2
CH
2
(2m)
4m
52
considerably accelerated by employing the highly electrophilic 1,1-
8d
bis(benzenesulfonyl)ethylene 5 as the Michael acceptor. Quanti-
tative yield was obtained in the reaction of 2j and 5 catalysed by
a
Reaction conditions: 2 (0.2 mmol), 5 (0.1 mmol) and catalyst 1d
(0.02 mmol) were stirred in toluene (1 mL) for 48 h. Isolated yield.
Determined by chiral HPLC analysis. The absolute configurations have
not been assigned yet. After recrystallization from 2-propanol–hexane.
b
c
1
d or 1e (20 mol%) after 1 h at ambient temperature, but very poor
d
15
enantioselectivity was obtained (<30% ee). Gratifyingly, the
e
◦
At −50 C for 96 h.
result could be greatly improved when the reaction was conducted
2
098 | Org. Biomol. Chem., 2006, 4, 2097–2099
This journal is © The Royal Society of Chemistry 2006

View Article Online
Takemoto, Angew. Chem., Int. Ed., 2005, 44, 4032; (d) B.-J. Li, L. Jiang,
M. Liu, Y.-C. Chen, L.-S. Ding and Y. Wu, SYNLETT, 2005, 603; (e) B.
Vakulya, S. Varga, A. Csampai and T. S o´ os, Org. Lett., 2005, 7, 1967;
(
f) A. Berkessel, F. Cleemann, S. Mukherjee, T. N. M u¨ ller and J. Lex,
Angew. Chem., Int. Ed., 2005, 44, 807; (g) A. Berkessel, S. Mukherjee,
F. Cleemann, T. N. M u¨ ller and J. Lex, Chem. Commun., 2005, 1898;
(
(
(
6
7
h) J. Ye, D. J. Dixon and P. S. Hynes, Chem. Commun., 2005, 4481;
i) A. L. Tillman, J. Ye and D. J. Dixon, Chem. Commun., 2006, 1191;
j) S. H. McCooey and S. J. Connon, Angew. Chem., Int. Ed., 2005, 44,
367; (k) J. Wang, H. Li, X. Yu, L. Zu and W. Wang, Org. Lett., 2005,
, 4293; (l) T. Marcelli, R. N. S. van der Haas, J. H. van Maarseveen
and H. Hiemstra, Angew. Chem., Int. Ed., 2006, 45, 929. For other
bifunctional thiourea organocatalysts, see: (m) T. Honjo, S. Sano, M.
Shiro and Y. Nagao, Angew. Chem., Int. Ed., 2005, 44, 5838; (n) R. P.
Herrera, V. Sgarzani, L. Bernardi and A. Ricci, Angew. Chem., Int. Ed.,
2
,2
Scheme 1 Synthesis of optically active b -amino acids.
2
005, 44, 6576; (o) Y. Sohtome, Y. Hashimoto and K. Nagasawa, Adv.
Synth. Catal., 2005, 347, 1643.
group for the further C–C bond forming reactions, thus variously
structured b -amino acids might be accessible from the well
5 For reviews on hydrogen-bonding interaction of organocatalysts, see:
(a) P. R. Schreiner, Chem. Soc. Rev., 2003, 32, 289; (b) P. M. Pihko,
Angew. Chem., Int. Ed., 2004, 43, 2062; (c) Y. Takemoto, Org. Biomol.
Chem., 2005, 3, 4299; (d) M. S. Taylor and E. N. Jacobsen, Angew.
Chem., Int. Ed., 2006, 45, 1520.
2
,2
6,8c,d
established procedures.
In conclusion, we have described a highly efficient organocat-
alytic method for the asymmetric Michael addition of a-
substituted cyanoacetates to vinyl sulfones. This reaction was syn-
ergistically promoted by readily available bifunctional thiourea–
tertiary amine organocatalysts, and an all-carbon substituted
quaternary stereocentre was constructed. To the best of our
knowledge, this is the first enantioselective catalytic reaction which
might involve a double-hydrogen bonding interaction between
the NH of thiourea and a sulfone functionality. In addition, the
reaction scope is substantial and a-aryl or alkyl cyanoacetates
could be successfully applied, and excellent enantioselectivities
6 For general reviews, see: (a) C. M. Rayner, Contemp. Org. Synth.,
1
996, 3, 499; (b) C. Najera and J. M. Sansano, Recent Res. Dev. Org.
Chem., 1998, 2, 637; (c) J.-E. B a¨ ckvall, R. Chinchilla, C. Najera and M.
Yus, Chem. Rev., 1998, 98, 2291; (d) R. Dumeunier and I. E. Marko,
Modern Carbonyl Olefination, Wiley-VCH Verlag Gmbh & Co. KGaA,
Weinhein, Germany, 2004, pp. 104–150.
7
For examples by using chiral auxiliary strategy, see: (a) J. d’Angelo and
G. Revial, Tetrahedron: Asymmetry, 1991, 2, 199; (b) D. Enders, S. F.
M u¨ ller, G. Raabe and J. Runsink, Eur. J. Org. Chem., 2000, 879; (c) A. K.
Sanki, C. G. Suresh, U. D. Falgune and T. Pathak, Org. Lett., 2003,
5
5
, 1285; (d) J. J. Reddick, J. Cheng and W. R. Roush, Org. Lett., 2003,
, 1967; (e) D. Desma e¨ le, S. Delarue-Cochin, C. Cave, J. d’Angelo and
G. Morgant, Org. Lett., 2004, 6, 2421; (f) B. Ravindran, K. Sakthivel,
C. G. Suresh and T. Pathak, J. Org. Chem., 2000, 65, 2637; (g) For
recent studies on chiral auxiliary strategy, see: J. Christoffers and A.
Mann, Chem.–Eur. J., 2001, 7, 5 and references therein.
For a Rh-catalysed enantioselective conjugate addition of organo-
boronic acids to vinyl sulfones, see: (a) P. Maule o´ n and J. C. Carretero,
Org. Lett., 2004, 6, 3195; (b) P. Maule o´ n and J. C. Carretero,
Chem. Commun., 2005, 4961. For organocatalysed asymmetric Michael
addition to vinyl sulfones, see: (c) H. Li, J. Song, X. Liu and L. Deng,
J. Am. Chem. Soc., 2005, 127, 8948; (d) S. Moss e´ and A. Alexakis, Org.
Lett., 2005, 7, 4361.
For examples of intramolecular hydrogen bonding of sulfones in
asymmetric synthesis, see: (a) N. Mase, Y. Watanabe and T. Toru,
Tetrahedron Lett., 1999, 40, 2797; (b) N. Mase, Y. Watanabe, T.
Toru, T. Kakumoto and T. Hagiwara, J. Org. Chem., 2000, 65,
7083.
(
72–96% ee) were achieved. Moreover, the biologically important
2
,2
b -amino acids could be smoothly prepared from the addition
products. Currently, studies are actively underway to investigate
the reaction mechanism and expand the synthetic utility of the
optically active addition products.
We are grateful for financial support from the National Natural
Science Foundation of China (20502018) and Sichuan University.
8
9
Notes and references
1
For recent reviews on organocatalysis, see: (a) P. I. Dalko and L.
Moisan, Angew. Chem., Int. Ed., 2004, 43, 5138; (b) Special issue, see:
Acc. Chem. Res., 2004, 37(8); (c) J. Seayad and B. List, Org. Biomol.
Chem., 2005, 3, 719.
For examples of bifunctional organocatalysts, see: (a) Y. Iwabuchi, M.
Nakatani, N. Yokoyama and S. Hatakeyama, J. Am. Chem. Soc., 1999,
21, 10219; (b) S. Saaby, M. Bella and K. A. Jørgensen, J. Am. Chem.
Soc., 2004, 126, 8120; (c) H. Li, Y. Wang, L. Tang and L. Deng, J. Am.
Chem. Soc., 2004, 126, 9906; (d) K. Matsui, S. Takizawa and H. Sasai,
J. Am. Chem. Soc., 2005, 127, 3680; (e) For a review on bifunctional
organometallic catalysts, see: M. Shibasaki and N. Yoshikawa, Chem.
Rev., 2002, 102, 2187.
10 (a) B. Gong, C. Zheng, E. Skrzypczak-Jankun, Y. Yan and J. Zhang,
J. Am. Chem. Soc., 1998, 120, 11194; (b) B. Gong, C. Zheng, H. Zeng
and J. Zhu, J.Am. Chem. Soc., 1999, 121, 9766.
11 Curran et al. has reported the hydrogen-bonding interaction of
sulfoxide and biarylurea, see: D. P. Curran and L. H. Kuo, J. Org.
Chem., 1994, 59, 3299.
12 For recent examples of enantioselective Michael addition of a-
substituted cyanoacetates, see: (a) M. S. Taylor and E. N. Jacobsen,
J. Am. Chem. Soc., 2003, 125, 11204; (b) M. S. Taylor, D. N. Zalatan,
A. M. Lerchner and E. N. Jacobsen, J. Am. Chem. Soc., 2005, 127,
1313; (c) see ref. 8c.
13 For a recent review on catalytic enantioselective construction of all
carbon quaternary chiral centres, see: J. Christoffers and A. Baro, Adv.
Synth. Catal., 2005, 347, 1473 and references therein.
2
1
3
For pioneering work on thiourea (or urea) organocatalysts, see: (a) M. S.
Sigman and E. N. Jacobsen, J. Am. Chem. Soc., 1998, 120, 4901; (b) P.
Vachal and E. N. Jacobsen, J. Am. Chem. Soc., 2002, 124, 10012;
(
c) A. G. Wenzel and E. N. Jacobsen, J. Am. Chem. Soc., 2002, 124,
1
4
1
2
2
2964; (d) G. D. Joly and E. N. Jacobsen, J. Am. Chem. Soc., 2004, 126,
102; (e) M. S. Taylor and E. N. Jacobsen, J. Am. Chem. Soc., 2004,
26, 10558; (f) T. P. Yoon and E. N. Jacobsen, Angew. Chem., Int. Ed.,
005, 44, 466; (g) D. E. Fuerst and E. N. Jacobsen, J. Am. Chem. Soc.,
005, 127, 8964; (h) M. S. Taylor, N. Tokunaga and E. N. Jacobsen,
14 For a highlight on enantiomerically pure b-amino acids, see: (a) N.
Sewald, Angew. Chem., Int. Ed., 2003, 42, 5794. For a review on the
2,2
synthesis of b -amino acids using chiral auxiliary strategy, see: (b) S.
Abele and D. Seebach, Eur. J. Org. Chem., 2000, 1.
15 It was found that the Michael addition of 2j to 5 could occur without
any catalyst at room temperature.
Angew. Chem., Int. Ed., 2005, 44, 6700.
4
(a) T. Okino, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc., 2003, 125,
1
2672; (b) T. Okino, Y. Hoashi, T. Furukawa, X. Xu and Y. Takemoto,
16 Much poorer results were obtained in the presence of catalyst 1e (84%
J. Am. Chem. Soc., 2005, 127, 119; (c) Y. Hoashi, T. Okino and Y.
yield, 14% ee).
This journal is © The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 2097–2099 | 2099