Enantioselective synthesis of optically active cis-β-thio-α- amino acid derivatives through an organocatalytic cascade thio-Michael/ring opening process

Article abstract of DOI:10.1039/c2cc30799e

Non-naturally enantioenriched cis-β-thio-α-amino acid derivatives were synthesized through one pot, cascade thio-Michael/ring opening reaction of aromatic thiols with (Z)-olefinic azlactones in good yields with high levels of diastereoselectivities and enantioselectivities, which was catalyzed by a chiral bifunctional thiourea-tertiary amine catalyst.

Full text of DOI:10.1039/c2cc30799e

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COMMUNICATION
Enantioselective synthesis of optically active cis-b-thio-a-amino acid
derivatives through an organocatalytic cascade thio-Michael/ring opening
processwz
Zhi-Cong Geng, Ning Li, Jian Chen, Xiao-Fei Huang, Bin Wu, Guo-Gui Liu and
Xing-Wang Wang*
Received 4th February 2012, Accepted 6th March 2012
DOI: 10.1039/c2cc30799e
Non-naturally enantioenriched cis-b-thio-a-amino acid derivatives
were synthesized through one pot, cascade thio-Michael/ring
opening reaction of aromatic thiols with (Z)-olefinic azlactones
in good yields with high levels of diastereoselectivities and
enantioselectivities, which was catalyzed by a chiral bifunctional
thiourea–tertiary amine catalyst.
Enantiomerically pure natural and non-natural a-amino acids
occurred in many compounds such as chiral ligands, catalysts,
pharmaceuticals, peptides and many other valuable target molecules
with important biological activity.1 Thus, the development of
Scheme 1 The synthesis of non-naturally protected a-amino acids.
(Z)-olefinic azlactones,11 compared with oxazolones, as dual-
practical methods for the synthesis of enantiomerically enriched
non-natural amino acids is of considerable practical importance.2
electrophilic reagents is less explored in the literature reported.
For the Michael addition of aromatic thiols to olefinic azlactones,
The ring opening of azlactones by nucleophilic reagents is one
straightforward route to the synthesis of protected a-amino acids.3
only non-asymmetric version was reported as early as in 1955 by
Because of different reactive sites existing in the oxazolones,4
the oxazolones have been extensively studied as nucleophilic
or electrophilic reagents in asymmetric catalysis using both
organometallic catalysts and organocatalysts.5,6
Mustafa et al., in which achiral b-thio-a-amino acid derivatives
could be synthesized in moderate yields.12 The non-naturally
optically active b-thio-a-amino acid derivatives are the core
structural elements prevalent in many very important compounds.
For instance, the glutathione (GSH) plays a critical role in
maintaining an intracellular reducing environment and serves
many other important metabolic functions. Besides, some
b-thio-a-amino acid derivatives have been reported as potent
MMP inhibitors (Fig. 1).13 Thus, we have been interested in
studying the organocatalytic tandem Michael/ring opening
transformation between alkylidene azlactones and aromatic
thiols for enantioselective synthesis of two contiguous stereogenic
b-thio-a-amino acid derivatives (Scheme 1, b). Presently, we
reported our preliminary results on the divergent one pot,
cascade thio-Michael/ring opening reaction, furnishing
enantioenriched b-thio-a-amino acids with two vicinal stereo-
centers in good yield and high stereocontrol in the presence of
chiral bifunctional thiourea–tertiary amine catalyst.
In 1998, Fu and co-workers have firstly established that
chiral DMAP derivatives catalyzed the deracemization/ring
opening of racemic azlactones, designated as a dynamic kinetic
resolution (DKR) process, affording protected a-amino acids in
high yield with moderate enantioselectivity.7,8 Since then, the
deracemization/ring opening of racemic azlactones through
organocatalysis has attracted much attention. In the last seven
years, numerous literature studies have been reported on this
transformation for the asymmetric synthesis of a-amino acid
derivatives with excellent enantioselectivities through organo-
catalysis (Scheme 1, a).9,10 However, it has been disclosed that
the asymmetric synthesis of the protected a-amino acids using
Key Laboratory of Organic Synthesis of Jiangsu Province,
College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, P. R. China.
Initially, we studied the model reaction of benzenethiol 2a
and phenyl-substituted olefinic azlactone 3a by the catalysis of
E-mail: wangxw@suda.edu.cn
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures, characterization and spectral data of the Michael addition
products. CCDC 862831. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2cc30799e
Fig. 1 Examples of important b-thio-a-amino acid derivatives.
Chem. Commun., 2012, 48, 4713–4715 4713
c
This journal is The Royal Society of Chemistry 2012

Table 1 Optimization of reaction conditions
Table 2 Asymmetric thio-Michael/ring opening of thiols 2 to 3
Time/ Yieldb
eed
(%)
Entrya R1/R2
h
(%)
drc
1
2
3
4
5
6
7
8
Ph (2a)/Ph (3a)
24
36
16
36
18
18
18
24
16
16
4a/96 95/5 87
4b/92 97/3 85
4c/96 97/3 89
4d/90 96/4 75
4e/93 95/5 88
Ph (2a)/2-MeOC6H4 (3b)
Ph (2a)/3-MeOC6H4 (3c)
Ph (2a)/3-MeC6H4 (3d)
Ph (2a)/3-NO2C6H4 (3e)
Ph (2a)/4-FC6H4 (3f)
Ph (2a)/2,4-Cl2C6H3 (3g)
Ph (2a)/2-naphthyl (3h)
4-MeC6H4 (2b)/Ph (3a)
4-MeC6H4 (2b)/3-BrC6H4 (3i)
4-MeC6H4 (2b)/3-NO2C6H4 (3e) 16
4-MeC6H4 (2b)/2,4-Cl2C6H3 (3g) 16
4-i-PrC6H4 (2c)/3-BrC6H4 (3i)
4-ClC6H4 (2d)/3-MeOC6H4 (3c) 16
4-BrC6H4 (2e)/3-MeOC6H4 (3c) 16
Entrya Sol.
Temp./1C Time/h Yield (%)c drd
eee (%)
1
2
3
4
5
6
7
8
PhMe
PhMe
rt
ꢀ20
6
18
18
18
18
18
48
48
48
18
74
93
92
83
73
95
90
91
95
96
85/15 49
95/5 82
95/5 83
94/6 79
92/8 81
95/5 84
92/8 78
94/6 84
93/7 81
95/5 87
4f/98
96/4 88
m-Xylene ꢀ20
4g/97 98/2 87
4h/98 96/4 85
CHCl3
DCE
PhCl
ꢀ20
ꢀ20
ꢀ20
ꢀ40
9
4i/93
4j/98
94/6 85
92/8 83
10
11
12
13
14
15
CHCl3
4k/94 92/8 85
4l/95 96/4 84
4m/96 92/8 84
4n/98 94/6 82
4o/93 95/5 83
m-Xylene ꢀ40
9
PhCl
PhCl
ꢀ40
16
10b
ꢀ20
a
Unless noted, reactions were carried out with 2a (1.5 mmol), 3a
b
(0.3 mmol), 1h (2.5 mol%), and in solvent (2.0 mL). Run in 4.0 mL
a
Unless noted, reactions were carried out with 2 (0.75 mmol), 3
(0.15 mmol), 1h (2.5 mol%), and in chlorobenzene (2.0 mL) at ꢀ20 1C.
c
of chlorobenzene. Isolated yield. Determined by chiral HPLC
e
analysis. Determined by chiral HPLC analysis.
d
b
c
Isolated yield. Determined by chiral HPLC analysis. Determined
d
by chiral HPLC analysis.
2.5 mol% of different bifunctional organic catalysts 1a–l in
toluene. After a preliminary screening of the catalysts and
solvents at room temperature (Tables S1 and S2 in ESIz),14 it
was found that Takemoto’s thiourea catalyst 1h was the
promising catalyst in terms of both reactivity and stereo-
selectivity (Table 1, entry 1). The reaction conditions were
further optimized by adjusting several parameters, including
temperature, solvent, substrate concentration and catalyst
loading. When the reaction was carried out at ꢀ20 1C in
toluene after 18 hours, 95/5 dr and 82% ee were obtained
(Table 1, entry 2). Subsequently, some of other common
solvents were explored. Considering yields, diastereoselectivities
and enantioselectivities, chlorobenzene was the optimal reaction
medium (Table 1, entries 6 vs. 2–5). When the temperature was
dropped to ꢀ40 1C, there was no evident increase in enantio-
selectivity (Table 1, entries 6 vs. 7–9). After investigating the
effects of substrate concentration and catalyst loading (Table S3
in ESIz),14 the best catalytic results (96% yield, 95/5 dr and
87% ee) were obtained with the concentration of 0.08 M and
2.5 mol% catalyst loading (Table 1, entry 10).
aromatic ring were also investigated for this transformation,
and enantiomerically enriched b-thio-a-amino acid derivatives
were efficiently obtained in excellent yields (93–98%) with good
diastereoselectivities (92/8–96/4 drs) and enantioselectivities
(82–85% ees) (Table 2, entries 9–15).
During the investigation of aromatic thiols addition to
alkylidene azlactones, interestingly, it was found that most
of the b-thio-a-amino acid derivatives obtained precipitated
progressively from the initial homogenous reaction mixture of
starting materials consisting of aromatic thiols 2, olefinic
azlactones 3 and catalyst 1h. The further testing experiments
demonstrated that most of the b-thio-a-amino acid derivatives
show very poor solubility in chlorobenzene, and almost no
solubility in petroleum ether. However, aromatic thiols 2 and
olefinic azlactones 3 could be dissolved in chlorobenzene.
Based on these observations, some desired products were
isolated by a simple filtration from the reaction mixture and
then rinsed with sufficient petroleum ether (60–90 1C). With
this strategy, several pure b-thio-a-amino acid derivatives were
obtained in good yields (>70%), excellent diastereomeric
ratios (>98/2 drs) and good to excellent enantioselectivities
(>90% ees) without isolation by column chromatography
(Table 3, entries 1–5). Fortunately, a single crystal of compound
4f was obtained by recrystallization from petroleum ether/ethyl
acetate/CHCl3, and the cis configuration of the two contiguous
stereocenters was unambiguously determined by X-ray analyses.15
To further evaluate the synthetic potential of the catalyst system,
gram-scale syntheses of the product 4a were performed. As shown
in Scheme 2, product 4a was obtained in 74% yield, >99/1 dr and
up to 93% ee by simple filtration and washing procedure without
isolation by column chromatography (Scheme 2).
Having established the optimized reaction conditions, the
scope of the organocatalyzed tandem thio-Michael/ring opening
of arylthiols 2 and alkylidene azlactones 3 was then explored with
thiourea 1h (2.5 mol%) as the catalyst in chlorobenzene at ꢀ20 1C
and the results were summarized in Table 2. When benzenethiol
2a was used as a nucleophilic reagent, a variety of olefinic
azlactones 3 were examined to study the effects of electronic
property and steric hindrance on enantioselectivity, diastereo-
selectivity and reactivity. From the results in Table 2, all the
reactions proceeded smoothly and provided the desired products
in high yields (90–98%) with good diastereoselectivities (92/8–98/
2 drs) and enantioselectivities (75–89% ees) (Table 2, entries 1–8).
Subsequently, thiols 2b–e bearing both electron-rich (-p-iPr,
-p-Me) and electron-deficient (-p-Cl, -p-Br) substituents on the
In conclusion, we have developed the first asymmetric
thio-Michael/ring opening reaction of aromatic thiols with
c
4714 Chem. Commun., 2012, 48, 4713–4715
This journal is The Royal Society of Chemistry 2012

Table 3 Asymmetric thio-Michael/ring opening of thiols 2 to 3
without column chromatography
(e) C. Cativiela and M. D. Diaz-de-Villegas, Tetrahedron: Asymmetry,
1998, 9, 3517.
2 (a) R. G. Arrayas and J. C. Carretero, Chem. Soc. Rev., 2009,
38, 1940; (b) S.-Y. Yu, H. Ishida, M. E. J. Garcia and J. W. Bode,
Chem. Sci., 2010, 1, 637.
3 For an authoritative review on the stereoselective syntheses of
quaternary-substituted a-amino acids by using oxazolones, see:
(a) J. S. Fisk, R. A. Mosey and J. J. Tepe, Chem. Soc. Rev., 2007,
36, 1432; (b) N. M. Hewlett, C. D. Hupp and J. J. Tepe, Synthesis,
2009, 2825; (c) A. N. R. Alba and R. Rios, Chem.–Asian J., 2011,
3, 720.
Time/ Yieldb
eed
(%)
Entrya R1/R2
h
(%)
drc
4 A. Padwa and W. H. Pearson, Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural
Products, John Wiley and Sons, Hoboken, NJ, 1st edn, 2002, p. 682.
5 For selected examples on metal catalysis, see: (a) B. M. Trost,
C. Jakel and B. Plietker, J. Am. Chem. Soc., 2003, 125, 4438;
(b) M. Luparia, M. T. Oliveira, D. Audisio, F. Frebault,
R. Goddard and N. Maulide, Angew. Chem., Int. Ed., 2011,
50, 12631.
6 For selected examples on organocatalysis, see: (a) D. Uraguchi,
Y. Ueki and T. Ooi, J. Am. Chem. Soc., 2008, 130, 14088;
(b) J. Jiang, J. Qing and L.-Z. Gong, Chem.–Eur. J., 2009,
15, 7031; (c) D. Rix and J. Lacour, Angew. Chem., Int. Ed.,
2010, 49, 1918; (d) S.-X. Dong, X.-H. Liu, Y.-L. Zhang,
L.-L. Lin and X.-M. Feng, Org. Lett., 2011, 13, 5060.
7 J. Liang, J. C. Ruble and G. C. Fu, J. Org. Chem., 1998, 63, 3154.
8 For recent reviews on dynamic kinetic resolution, see: H. Pellissier,
Tetrahedron, 2011, 67, 3769.
1
2
3
4
5
Ph (2a)/3-NO2C6H4 (3e)
Ph (2a)/4-FC6H4 (3f)
4-MeC6H4 (2b)/Ph (3a)
4-MeC6H4 (2b)/3-BrC6H4 (3i)
18
18
16
16
4e/75
4f/82
4i/70
4j/70
4n/71
98/2 91
99/1 94
99/1 96
99/1 96
99/1 90
4-ClC6H4 (2d)/3-MeOC6H4 (3c) 16
a
Unless noted, reactions were carried out with 2 (5.0 mmol), 3
(1.0 mmol), 1h (2.5 mol%), and in chlorobenzene (13.0 mL) at ꢀ20 1C.
b
Isolated yield by direct filtration and simple washing procedure with
c
petroleum ether (60–90 1C). Determined by chiral HPLC analysis.
Determined by chiral HPLC analysis.
d
9 For selected examples on organocatalysis, see: (a) A. Berkessel,
F. Cleemann, S. Mukherjee, T. N. Muller and J. Lex, Angew.
Chem., Int. Ed., 2005, 44, 807; (b) J. W. Lee, T. H. Ryu, J. S. Oh,
H. Y. Bae, H. B. Jang and C. E. Song, Chem. Commun., 2009,
7224; (c) A. Peschiulli, C. Quigley, S. Tallon, Y. K. Gun’ko and
S. J. Connon, J. Org. Chem., 2008, 73, 6409.
Scheme 2 The gram-scale preparation of 4a by direct filtration and
simple washing procedure.
10 For selected recent reviews on organocatalysis, see: (a) S. Bertelsen
and K. A. Jørgensen, Chem. Soc. Rev., 2009, 38, 2178;
(b) P. Melchiorre, M. Marigo, A. Carlone and G. Bartoli, Angew.
Chem., Int. Ed., 2008, 47, 6138.
11 For selected chiral examples see: (a) Y.-Q. Zou, C. Li, J. Rong,
H. Yan, J.-R. Chen and W.-J. Xiao, Synlett, 2011, 1000;
(b) H. Jiang, B. Gschwend, Ł. Albrecht, S. G. Hansen and
K. A. Jørgensen, Chem.–Eur. J., 2011, 33, 9032; (c) M. Steurer,
K. L. Jensen, D. Worgull and K. A. Jørgensen, Chem.–Eur. J.,
2012, 18, 76; (d) D. Wang, Y. Wei and M. Shi, Chem. Commun.,
2012, 48, 2764.
(Z)-olefinic azlactones in the presence of a catalytic amount of
chiral bifunctional thiourea–tertiary amine 1h (2.5 mol%) in
chlorobenzene at ꢀ20 1C,16 which provided non-natural cis-b-
thio-a-amino acid derivatives in good yields with high level of
stereoselectivities. This transformation could serve as a general
method for the direct construction of chiral b-thio-a-amino
acid building blocks. Gram-scale products can be easily
obtained by simple filtration without isolation by column
chromatography. Further elucidation of the sequence of
cascade thio-Michael/ring opening reaction and investigation
of synthetic application of this approach are in progress, and
the results will be reported in due course.
12 B. A. Mustafa, A. H. E. Harhash and M. Kamel, J. Am. Chem.
Soc., 1955, 77, 3860.
13 (a) R. C. Fahey and G. L. Newton, in Functions of Glutathione Bio-
chemical, Physiological, Toxicological and Clinical Aspects, ed.
A. Larsson, A. Holmgren, B. Mannervik and S. Orrenius, Raven,
New York, 1983, p. 251; (b) D. P. Becker, T. E. Barta, L. Bedell,
G. DeCrescenzo, J. Freskos, D. P. Getman, S. L. Hockerman,
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C. I. Villamil, Bioorg. Med. Chem. Lett., 2001, 11, 2719;
(c) C. K. Wada, J. H. Holms, M. L. Curtin, Y. Dai,
A. S. Florjancic, R. B. Garland, Y. Guo, H. R. Heyman,
J. R. Stacey, D. H. Steinman, D. H. Albert, J. S. Bouska,
I. N. Elmore, C. L. Goodfellow, P. A. Marcotte, P. Tapang,
D. W. Morgan, M. R. Michaelides and S. K. Davidsen, J. Med.
Chem., 2002, 45, 219.
We are grateful for financial support from the National
Natural Science Foundation of China (21072145), Foundation
for the Author of National Excellent Doctoral Dissertation of
P.R. China (200931), Natural Science Foundation of Jiangsu
Province of China (BK2009115) and the Priority Academic
Program Development of Jiangsu Higher Education Institutions
(PAPD).
14 See the ESIz for details.
Notes and references
15 CCDC 862831 (4f). C28H22FNO2S2, a block crystal (0.80 ꢁ 0.30 ꢁ
0.20 mm), T = 293(2) K, l(Mo-Ka) = 0.71070 A, monoclinic,
space group: P21, a = 5.3494(11) A, b = 10.901(2) A, c =
11.123(2) A, V = 611.9(2) A3, 5973 total reflections, 3680 unique,
Rint = 0.0372, R1 = 0.0551 (I > 2s), wR2 = 0.1424.
16 For selected reviews about thiourea catalysts, see: (a) H. Miyabe
and Y. Takemoto, Bull. Chem. Soc. Jpn., 2008, 81, 785;
(b) S. J. Connon, Chem.–Eur. J., 2006, 12, 5418.
1 For representative reviews on the preparation of optically active
a-amino acids, see: (a) R. M. Williams, in Synthesis of Optically
Active-Amino Acids, ed. J. E. Baldwin, Organic Chemistry
Series, Pergamon Press, Oxford, 1989; (b) R. M. Williams and
J. A. Hendrix, Chem. Rev., 1992, 92, 889; (c) R. O. Duthaler,
Tetrahedron, 1994, 50, 1539; (d) D. Seebach, A. R. Sting and
M. Hoffmann, Angew. Chem., Int. Ed. Engl., 1996, 35, 2708;
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4713–4715 4715