Highly enantioselective Michael Addition of α-Substituted Cyano Ketones to β,γ-unsaturated α-keto esters using bifunctional thiourea-tertiary amine catalysts: An easy access to chiral dihydropyrans

Article abstract of DOI:10.1002/adsc.200900516

An asymmetric Michael addition of α-substituted cyano ketones to β,γ-unsaturated α-keto esters to form chiral dihydropyrans catalyzed by a series of a-amino acid-derived thiourea-tertiary amines is presented. A novel tyrosine-derived thio-urea catalyst was identified as the optimal catalyst providing the desired product in 91-95% yields and with 90-96% ee at a low catalyst loading of 2.0mol%. The utility of the reaction was exempli-fied by facile conversion of the dihydropyran prod-uct into pharmaceutically useful dihydropyridine.

Full text of DOI:10.1002/adsc.200900516

COMMUNICATIONS
DOI: 10.1002/adsc.200900516
Highly Enantioselective Michael Addition of a-Substituted Cyano
Ketones to b,g-Unsaturated a-Keto Esters using Bifunctional
Thiourea-Tertiary Amine Catalysts: An Easy Access to Chiral
Dihydropyrans
Sheng-Li Zhao,a Chang-Wu Zheng,a Hai-Feng Wang,a and Gang Zhaoa,*
a
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 345 Lingling Lu, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-6416-6128; e-mail: zhaog@mail.sioc.ac.cn
Received: July 25, 2009; Published online: November 18, 2009
Abstract: An asymmetric Michael addition of a-
substituted cyano ketones to b,g-unsaturated a-keto
esters to form chiral dihydropyrans catalyzed by a
series of a-amino acid-derived thiourea-tertiary
amines is presented. A novel tyrosine-derived thio-
urea catalyst was identified as the optimal catalyst
providing the desired product in 91–95% yields and
with 90–96% ee at a low catalyst loading of
2.0 mol%. The utility of the reaction was exempli-
fied by facile conversion of the dihydropyran prod-
uct into pharmaceutically useful dihydropyridine.
found that the asymmetric Michael addition of 3-oxo-
3-phenylpropanenitrile (1a) to methyl 2-oxo-4-phenyl-
but-(E)-3-enoate (2a) could be realized to provide a
novel chial dihyropyan product 3a firstly using the
chiral thiourea catalyst 4a, which has been successful-
ly used in a similar reaction by us.[7d] (Figure 1). The
1H and 13C NMR spectra of 3a revealed a rapid equi-
librium[8] between the cyclic hemiketal 3a and the Mi-
chael-type product 3a’ with a ratio of around 5:1
(3a:3a’) (Scheme 1). Preliminary solvent screening
with this catalyst furnished Et2O as the optimal sol-
vent, in which the desired product was obtained in
95% yield and 60% ee value (Table 1, entry 7). This
result promoted us to design and explore new bifunc-
tional thiourea-tertiary amine catalysts for this reac-
tion.
Keywords: enantioseteroselectivity; Michael addi-
tion; organocatalysts; thioureas
With experience in the successful development of
several efficient a-amino acid-derived diamine cata-
The development of carbon-carbon bond formation lysts for the Michael addition of malonates to
reactions for asymmetric synthesis has been an impor- enones,[9] we next focused on the utilization of differ-
tant challenge in organic synthesis.[1,2] In this field, or- ent a-amino acids as the chiral skeletons for catalyst
ganocatalysis as a powerful and environmentally elaboration. Figure 1 lists the bifunctional thiourea-
friendly methodology has achieved great advances in tertiary amine catalysts investigated in this study.
the past decade.[3] Particularly, organocatalytic Mi-
Catalysts 4b–4e were prepared from phenylalanine
chael addition of nucleophiles with an activated meth- or tryptophan according to the literature.[10,11] Cata-
ylene group to a,b-unsaturated carbonyl compounds lysts 4f–4i were synthesized from the commercially
has recently been extensively explored because of its available N-Boc (tert-butyloxycarbonyl) protected ty-
offering an extremely effective way to synthesize a va- rosine
riety of useful chiral functionalized organic mole- (Scheme 2). Specifically, 5 was first easily converted
cules.[4]
into amide 6 with dimethylamine hydrochloride in the
5 with a modified procedure as above
Heterocyclic compounds occupy a very important presence of N-methylmorpholine (NMM) and ethyl
place in organic chemistry, agrochemistry and medici- chloroformate, which was then treated with benzyl
nal chemistry due to their omnipresence in nature bromide under basic conditions in acetone to give the
and varied biological properties.[5] The synthesis of product 7. After deprotection of the Boc group fol-
this kind of compounds has been one of the focuses lowed by reduction with lithium aluminium hydride, 7
in organic synthesis.[6] Our group has been interested was converted to diamine 9. Condensation of 9 with
in developing asymmetric reactions using b,g-unsatu- different isothiocyanates then gave rise to the target
rated a-keto esters as substrates for conversion to thiourea catalysts 4f, 4h, 4j and 4k. With similar pro-
useful chiral molecules.[7] During this process, we
Adv. Synth. Catal. 2009, 351, 2811 – 2816
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2811

Sheng-Li Zhao et al.
COMMUNICATIONS
Figure 1. Organocatalysts tested in this study.
Scheme 1. Equilibrium of the product 3a and 3a’.
cedures, catalysts 4g and 4i could also be obtained in
five steps from the starting material 5.
Subsequently, catalysts 4b–4k were evaluated with
this model reaction of 1a and 2a using Et2O as the
solvent (Table 2). In general, better results in terms of
enantioselectivity were obtained with similarly high
yields from these catalysts than that from Takemotoꢀs
catalyst 4a. The inefficiency of catalyst 4h may imply
that large steric hindrance and electron-donating sub-
stituents on the benzene ring of the thiourea moiety
are not favored for this reaction. Moreover, changing
the tertiary amine moiety from a dimethylamine to a
cyclic amine has little influence on this reaction in
that rather similar results were observed when cata-
lysts 4b, 4d, 4f and 4c, 4e, 4g were used, respectively.
Especially, both catalysts 4f and 4g gave the product
with 90% ee at ambient temperature (Table 2, en-
tries 5 and 6). However, replacement of benzyl group
on the tyrosine structure by a sterically larger group
(catalyst 4i) led to a slight drop in the enantioselectiv-
ity (Table 2, entry 8). The C2-symmetrical catalysts 4j
and 4k were also examined, but only moderate enan-
tioselectivities were obtained (Table 2, entries 9 and
10). Then, further optimizing efforts were done with
the best catalyst 4f. Pleasingly, reducing the catalyst
Table 1. Screening of solvents using Takemotoꢀs catalyst
4a.[a]
Entry
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
Toluene
DCM
CH3CN
DMF
THF
1,4-Dioxane
Et2O
94
95
94
78
94
92
95
12
22
31
6
44
57
60
[a]
Unless otherwise noted, the reaction was conducted with
0.1 mmol of 1a and 0.11 mmol of 2a in the presence of
5.0 mol% of 4a in 2.0 mL of solvent at room temperature
for 10 h.
Isolated yields.
Determined by chiral HPLC analysis on a chiralcel OD-
H column.
[b]
[c]
2812
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2811 – 2816

Highly Enantioselective Michael Addition of a-Substituted Cyano Ketones
COMMUNICATIONS
Scheme 2. Preparation of the catalysts 4f and 4j.
Table 2. Evaluation of catalysts with the model reaction.[a]
loading to 2.0 mol% could increase the ee value to
94% while the use of 1 mol% or 10 mol% were not
favored, which exemplified the effect of catalyst con-
centration on the enantioselectivity in the system
(Table 2, entries 11–13).[12] Further investigation with
different volumes of the solvent also revealed the ex-
istence of an optimum concentration for this transfor-
mation (Table 2, entries 14–16). Additionally, no ap-
parent improvement in the enantioselectivity was ob-
served when the reaction was conducted at a lower
temperature (Table 2, entry 17).
With the optimal reaction conditions achieved
above, subsequently we examined the reactions of a
range of b,g-unsaturated a-keto esters 1 with 2a to ex-
plore the generality of this reaction, and the results
are summarized in Table 3. Generally, high yields and
excellent enantioselectivities were achieved with b,g-
unsaturated a-keto esters bearing various g-aryl sub-
stituents or segments of ester in 12 h. For substrates
1a–1h, electron-donating or electron-withdrawing sub-
stituents on the meta, para, or ortho positions of the
benzene ring of R1 were equally well-tolerated in the
reaction (Table 3, entries 1–8). Heterocyclic substrate
1i also provided an excellent result (Table 3, entry 9).
Furthermore, substrates 1j–1o with different substitu-
ents on the ester moiety (R2) also gave almost the
same good results (Table 3, entries 10–15). Particular-
ly, the reaction also proceeded smoothly with chain
substrate and 87% ee value was obtained.
Entry
Catalyst
Yield [%][b]
ee [%][c]
1
2
3
4
4b
4c
4d
4e
4f
4g
4h
4i
95
94
94
95
95
93
90
94
91
92
90
93
94
95
94
95
94
73
73
67
68
90
90
42
88
74
78
91
94
87
92
95
90
96
5
6
7[d]
8
9
4j
10
11[e]
12[f]
13[g]
14[h]
15[i]
16[j]
17[k]
4k
4f
4f
4f
4f
4f
4f
4f
[a]
Unless otherwise noted, the reaction was conducted with
0.1 mmol of 1a and 0.11 mmol of 2a in the presence of
5.0 mol% of 4 in 2.0 mL of solvent at room temperature,
10 h.
Isolated yields.
Determined by chiral HPLC analysis on a chiralcel OD-
H column.
The reaction time was extended to 48 h.
1.0 mol% of 4f was used.
2.0 mol% of 4f were used.
10 mol% of 4f were used.
[b]
[c]
Next, the scope examination of the reaction was ex-
tended to different 3-oxo-3-phenylpropanenitrile de-
rivatives with b,g-unsaturated a-keto esters 1a or 1d
(Table 4). When R3 are aromatic groups (2b–2e), the
reactions proceeded smoothly with 1a or 1d to furnish
the desired adducts 3q–3t with high enantioselectivi-
ties and yields (Table 4, entries 1–4). However, when
R3 is an alkyl group (2f, R3 =t-Bu) or an alkoxy (2g,
R3 =EtO), the reaction failed to proceed and only
[d]
[e]
[f]
[g]
[h]
[i]
1.0 mL of Et2O was used.
3.0 mL of Et2O were used.
4.0 mL of Et2O were used.
The reaction was conducted at 08C for 20 h.
[j]
[k]
Adv. Synth. Catal. 2009, 351, 2811 – 2816
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2813

Sheng-Li Zhao et al.
COMMUNICATIONS
Table 3. Reaction of different b,g-unsaturated a-keto esters
1 with 2a catalyzed by 4f.[a]
Table 4. Reaction of different a-substituted cyano ketones 2
with 1 catalyzed by 4f.[a]
Entry R1
R3
Prod- Yield ee
uct
Entry R1 R2 (1)
Prod- Yield ee
uct
[%][b] [%][c]
,
[%][b] [%][c]
1
2
3
Ph (1a)
Ph (1a)
Ph (1a)
4-FC6H4 (2b)
4-BrC6H4 (2c)
4-MeOC6H4
(2d)
3q
3r
3s
95
93
91
96
1
Ph, Me (1a)
3a
3b
3c
3d
3e
3f
94
95
94
94
94
95
92
93
93
95
95
93
94
95
92
70
95
94
94
92
94
94
90
90
92
92
94
94
92
92
90
87
90
90[d]
2
3
4
5
4-F-C6H4, Me (1b)
4-Cl-C6H4, Me (1c)
4-Br-C6H4, Me (1d)
2,4-Cl2-C6H3, Me (1e)
4-NO2-C6H4, Me (1f)
4
4-BrC6H4
(1d)
4-BrC6H4 (2e)
3t
93
94
6
5
6
Ph (1a)
Ph (1a)
t-Bu (2f)
EtO (2g)
–
–
–
–
–
–
7
2,5-(MeO)2-C6H3, Me (1g) 3g
8
9
2-Br-C6H4, Me (1h)
2-Furyl, Me (1i)
Ph, Bn (1j)
Ph, 4-BrBn (1k)
Ph, Et (1l)
Ph, i-Pr (1m)
Ph, allyl (1n)
3h
3i
3j
3k
3l
3m
3n
3o
3p
[a]
Unless otherwise noted, the reaction was conducted with
0.1 mmol of 1 and 0.11 mmol of 2 in the presence of 2.0
mol% of 4f in 3.0 mL of Et2O at room temperature for
12 h.
Isolated yields.
Determined by HPLC analysis on
column.
10
11
12
13
14
15
16[d]
[b]
[c]
a chiral OD-H
Ph, t-Bu (1o)
Phenethyl, Et (1p)
[d]
Determined by HPLC analysis on chiral OD-H+AD
columns.
[a]
Unless otherwise noted, the reaction was conducted with
0.1 mmol of 1 and 0.11 mmol of 2a in the presence of 2.0
mol% of 4f in 3.0 mL of Et2O at room temperature for
12 h.
Isolated yields.
Determined by HPLC analysis on
column.
[b]
[c]
a chiral OD-H
[d]
The reaction time was extended to 48 h.
most of the starting material was recovered after 12 h.
(Table 4, entries 5 and 6).
Scheme 3. Conversion of 3a to 11.
The highly enantiomerically enriched dihyropyrans
3 obtained by this method can be easily converted
into dihydropyridines (DHPs),[13] which have been
recognized as an important class of organic calcium-
channel modulators for the treatment of cardiovascu-
lar diseases[14,15] and recent biological assays disclosed
that this kind of compounds also have a broad range
of other pharmaceutical activities[16]. As an example,
3a was converted to dihydropyridine 11 in high yield
and 92% ee by
a simple one-step treatment
(Scheme 3).[17] The absolute configuration of the prod-
uct 3k was determined to be 2S,4R by X-ray crystallo-
graphic analysis (Figure 2)[18] and the rest of the prod-
ucts were assigned by analogy.
In conclusion, we have firstly developed an enantio-
selective organocatalytic Michael addition of a-substi-
tuted cyano ketones to b,g-unsaturated a-keto esters
using novel amino acid-derived thiourea-tertiary
amine catalysts. With a low catalyst loading of Figure 2. X-ray structure of compound 3k.
2814
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2811 – 2816

Highly Enantioselective Michael Addition of a-Substituted Cyano Ketones
COMMUNICATIONS
7496; g) C. Palomo , A. Mielgo, Angew. Chem. 2006,
118, 8042; Angew. Chem. Int. Ed. 2006, 45, 7876.
[4] For recent reviews on organocatalytic asymmetric Mi-
chael addition, see: a) P. I. Dalko, L. Moisan, Angew.
Chem. 2001, 113, 3840; Angew. Chem. Int. Ed. 2001, 40,
3726; b) O. M. Berner, L. Tedeschi, D. Enders, Eur. J.
Org. Chem. 2002, 1877; c) J. Christoffers, A. Baro,
Angew. Chem. 2003, 115, 1726; Angew. Chem. Int. Ed.
2003, 42, 1688; d) D. Almas¸i, D. A. Alonso, C. Nꢂjera,
Tetrahedron: Asymmetry 2007, 18, 299; e) S. B. Tsogoe-
va, Eur. J. Org. Chem. 2007, 1701.
[5] a) T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem.
Soc. 2003, 125, 12672; b) Y. Hoashi, T. Yabuta, Y. Take-
moto, Tetrahedron Lett. 2004, 45, 9185; c) T. Okino, Y.
Hoashi, T. Furukawa, X. Xu, Y. Takemoto, J. Am.
Chem. Soc. 2005, 127, 119; d) S. H. McCooey, S. J.
Connon, Angew. Chem. 2005, 117, 6525; Angew. Chem.
Int. Ed. 2005, 44, 6367; e) B. Vakulya, S. Varga, A.
Csꢂmpai, T. Soꢃs, Org. Lett. 2005, 7, 1967; f) J. Wang,
H. Li, W. Duan, L. Zu, W. Wang, Org. Lett. 2005, 7,
4713; g) J. Ye, D. J. Dixon, P. S. Hynes, Chem.
Commun. 2005, 4481; h) S. B. Tsogoeva, D. A. Yalalov,
M. J. Hateley, C. Weckbecker, K. Huthmacher, Eur. J.
Org. Chem. 2005, 4995; i) D. J. Dixon, R. D. Richard-
son, Synlett 2006, 81; j) Y. Hoashi, T. Yabuta, P. Yuan,
H. Miyabe, Y. Takemoto, Tetrahedron 2006, 62, 365.
[6] a) K. Ishihara, K. Nakano, J. Am. Chem. Soc. 2005,
127, 10504; b) J. M. Andrꢄs, R. M. Anzano, R. Pedrosa,
Chem. Eur. J. 2008, 14, 5116.
2.0 mol%, a series of synthetically useful chiral dihy-
dropyrans were obtained with high yields and up to
96% ee. Further elaboration of the products and ap-
plication of the novel catalysts to other reactions are
now under investigation in our group.
Experimental Section
Typical Procedure for the Michael Reaction using
Catalyst 4f in Diethyl Ether at Ambient Temperature
To a solution of b,g-unsaturated a-keto ester 1a (0.11 mmol)
and 3-oxo-3-phenylpropanenitrile 2a (0.10 mmol) in 3.0 mL
of diethyl ether (Et2O), 4f (0.002 mmol, 2.0 mol%) was
added. The mixture was stirred at room temperature for
12 h. After removal of the solvent under reduced pressure,
the crude product was purified directly by column chroma-
tography on silica gel (hexanes/EtOAc=6/1) to afford the
product 3a as a colorless oil; yield: 94%; [a]2D2:1: À11.3 (c
1.70, EtOH); IR (KBr): n=3342, 2210, 1750, 1617 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=7.74–7.76 (m, 2H), 7.32–
7.45 (m, 8H), 5.21 (brs, 1H), 3.95–4.01 (m, 1H), 3.84–3.88
(m, 3H), 2.32–2.36 (m, 2H); 13C NMR (100 MHz, CDCl3):
d=169.2, 162.5, 140.2, 132.6, 131.0, 129.3, 128.8, 128.6, 127.8,
118.6, 95.2, 89.8, 53.9, 36.9, 36.0; HR-MS (EI): m/z=
335.1160; calcd. for C20H17NO4: 335.1158. HPLC (separation
conditions: Chiralcel OD-H column, 208C, 254 nm, hexane/
i-PrOH=80/20, flow rate 0.5 mLminÀ1): tmajor =18.4 min,
[7] a) H. F. Wang, C. W. Zheng, Y. Q. Yang, Z. Chai, G.
Zhao, Tetrahedron: Asymmetry 2008, 19, 2608; b) X. S.
Wang, C. W. Zheng, S. L. Zhao, Z. Chai, G. Zhao, G. S.
Yang, Tetrahedron: Asymmetry 2008, 19, 2699; c) C. W.
Zheng, Y. Y. Wu, X. S. Wang, G. Zhao, Adv. Synth.
Catal. 2008, 350, 2690; d) S. L. Zhao, C. W. Zheng, G.
Zhao, Tetrahedron: Asymmetry 2009, 20, 1046; e) C. W.
Zheng, Y. W. Li, Y. Q. Yang, H. F. Wang, H. F. Cui,
J. K. Zhang, G. Zhao, Adv. Synth. Catal. 2009, 351,
1685.
[8] Such an equilibrium is very rapid for that only one pair
of enantiomers is detected by HPLC. For studies on
similar equilibriums of related compounds, see:
a) W. R. Porter, W. F. Trager, J. Heterocycl. Chem.
1982, 19, 475; b) L. D. Heimark, W. F. Trager, J. Med.
Chem. 1984, 27, 1092; c) N. Halland, T. Velgaard, K. A.
Jørgensen, J. Org. Chem. 2003, 68, 5067.
t
minor =24.8 min.
Acknowledgements
The generous financial support from the National Natural
Science Foundation of China (No. 20172064, 203900502,
20532040), QT Program, Shanghai Natural Science Council,
and Excellent Young Scholars Foundation of National Natu-
ral Science Foundation of China (20525208) are gratefully ac-
knowledged.
References
[9] Y. Q. Yang, G. Zhao, Chem. Eur. J. 2008, 14, 10888.
[10] X. S. Wang, G. S. Yang, G. Zhao, Tetrahedron: Asym-
metry 2008, 19, 709.
[11] C. J. Hawker, J. M. J. Frꢄchet, J. Am. Chem. Soc. 1990,
112, 7638.
[12] H. S. Rho, S. H. Oh, J. W. Lee, J. Y. Lee, J. Chinc, C. E.
Song, Chem. Commun. 2008, 1208.
[13] The method used in the elaboration is modified accord-
ing to: K. Palani, D. Thirumalai, P. Ambalavanan,
M. N. Ponnuswamy, V. T. Ramakrishnan, J. Chem.
Crystallogr. 2005, 35, 751.
[1] P. Perlmutter, Conjugate Addition Reactions in Organic
Synthesis, Pergamon Press, Oxford, 1992.
[2] For recent reviews, see: a) M. Yamaguchi, in: Compre-
hensive Asymmetric Catalysis, Vols. I–III, (Eds.: E. N.
Jacobsen, A. Pfaltz, H. E. Yamamoto), Springer-Verlag,
Berlin, Heidelberg, Germany, 1999, Chapter 31.2;
b) M. P. Sibi, S. Manyem, Tetrahedron 2000, 56, 8033;
c) E. R. Jarvo, S. J. Miller, Tetrahedron 2002, 58, 2481.
[3] a) P. I. Dalko, L. Moisan, Acc. Chem. Res. 2004, 37,
487; b) Special issue on organocatalysis: P. I. Dalko, L.
Moisan, Angew. Chem. 2004, 116, 5248; Angew. Chem.
Int. Ed. 2004, 43, 5138; c) J. Seayad, B. List, Org.Bio-
mol. Chem. 2005, 3, 719; d) B. List, Chem. Commun.
2006, 819; e) B. List, Tetrahedron 2006, 62, 243; f) T.
Marcelli, J. H. van Maarseveen, H. Hiemstra, Angew.
Chem. 2006, 118, 7658; Angew. Chem. Int. Ed. 2006, 45,
[14] a) R. A. Janis, P. J. Silver, D. J. Triggle, Adv. Drug Res.
1987, 16, 309; b) F. Bossert, W. Vater, Med. Res. Rev.
1989, 9, 291.
[15] B . Loev, M. Goodman, K. Snader, R. Tedeschi, E.
Macko, J. Med. Chem. 1974, 17, 956.
Adv. Synth. Catal. 2009, 351, 2811 – 2816
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2815

Sheng-Li Zhao et al.
COMMUNICATIONS
[16] C. O. Kappe, Eur. J. Med. Chem. 2000, 35, 1043.
[17] For catalytic asymmetric synthesis of highly enantio-
merically enriched DHPs, see: J. Jiang, J. Yu, X. X.
Sun, Q. Q. Rao, L. Z. Gong, Angew. Chem. 2008, 120,
2492; Angew. Chem. Int. Ed. 2008, 47, 2458.
16.6297(17) ꢅ, space group P21/n] contains the supple-
mentary crystallographic data for this paper. These
data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[18] CCDC 738625 [for 3k, formula: C26H20BrNO4, unit cell
parameters: a=13.6827(14), b=10.3113(10), c=
2816
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2811 – 2816