Enantioselective organocatalytic thiol addition to α,β- unsaturated α-amino acid derivatives

Article abstract of DOI:10.1055/s-0032-1317081

A new class of Michael acceptors based on α,β-unsaturated amino acids has been prepared and applied in asymmetric organocatalysis. With the use of thiourea derivatives of cinchona alkaloid-derived catalysts, efficient addition of thiols to the dehydroamin

Full text of DOI:10.1055/s-0032-1317081

LETTER
▌2195
letter
Enantioselective Organocatalytic Thiol Addition to α,β-Unsaturated α-Amino
Acid Derivatives
Enantioselective Organocatalytic Thiol Addition
Arjen C. Breman,a Jan M. M. Smits,b Rene de Gelder,b Jan H. van Maarseveen,a Steen Ingemann,a Henk Hiemstra*a
a
Van’t Hoff Institute for Molecular Sciences, Faculty of Science, University of Amsterdam, Science Park 904, 1098 XH Amsterdam,
The Netherlands
Fax +31(20)5255604; E-mail: h.hiemstra@uva.nl
b
Solid State Chemistry Institute for Molecules and Materials, Radboud University, Nijmegen, Heyendaalseweg 135, 6525 AJ, Nijmegen,
The Netherlands
Received: 21.05.2012; Accepted after revision: 23.07.2012
tion/ring-opening cascade reaction with aromatic thiols as
Abstract: A new class of Michael acceptors based on α,β-unsatu-
nucleophiles and catalyzed by the chiral thiourea-tertiary
rated amino acids has been prepared and applied in asymmetric
amine catalyst developed by Takemoto.6,8
organocatalysis. With the use of thiourea derivatives of cinchona al-
kaloid-derived catalysts, efficient addition of thiols to the
dehydroamino acids occurred with formation of β-thiol functional-
ized α-amino acids in high yields, moderate diastereoselectivities
addition to N-acylated oxazolidin-2-one derivatives of
and ee values up to 95%.
Inspired by the work of Deng and co-workers on asym-
metric synthesis of β-thiol esters,5 we envisioned that thiol
α,β-unsaturated amino acids could serve as a general
Key words: organocatalysis, cinchona alkaloids, amino acids, thi-
method for the preparation of β-thiol amino acids.
ols, conjugate addition
Even though β-thiol functionalized amino acids are of sig-
nificant interest in peptidomimetics, limited attention has
been given to asymmetric synthesis of these compounds.
The reported methods include conjugate addition of thiols
for the preparation of enantiomerically enriched organic
Bifunctional organocatalysis is a widely applied method
to α,β-unsaturated amino acids leading to racemates11 and
mesylation of the hydroxyl group of threonine or ana-
logues followed by nucleophilic substitution by a thiol.12
The latter method leads to formation of enantiomerically
pure unnatural amino acids but is limited to species with a
hydroxyl group at the β-position. In order to extend the
possibilities for asymmetric synthesis of β-thiol function-
alized amino acids, we decided to prepare a novel series
of α,β-unsaturated N-acetylated oxazolidin-2-ones bear-
ing a protected amine group at the α-position. With the use
of cinchona alkaloid derivatives as catalysts, we anticipat-
ed that thiol addition to α,β-unsaturated N-acetylated ox-
azolidin-2-ones (see Scheme 1) could provide enantio-
merically enriched compounds that could be easily con-
verted into β-thiol amino acids.
compounds.1 Succeeding the pioneering work by the
Wynberg2 group on the cinchona alkaloids as bifunctional
catalysts, numerous studies have been reported concern-
ing the design of new and efficient organocatalysts for
enantioselective organic reactions.3 Particular attention
has been paid to the conjugate addition4 of various car-
bon- and heteroatom-based nucleophiles to different
classes of electron-poor alkenes, such as nitroalkenes,
conjugated enones, α,β-unsaturated esters and derivatives
with an oxazolidinone moiety,5 2-pyrrolidinone,6 pyr-
role,7 or a benzamide8 function.
Thiols are known to be well suited as nucleophiles for
enantioselective organocatalytic conjugate additions usu-
ally referred to as sulfa-Michael additions.9,10 In most of
the reported studies of organocatalytic sulfa-Michael re-
actions aromatic thiols were employed as nucleophiles.9a
In a recent study Deng and co-workers5 described the en-
antioselective formation of β-thiol esters by addition of
aliphatic thiols to α,β-unsaturated N-acylated oxazolidin-
2-ones catalyzed by a C6′-thiourea-substituted cinchona
alkaloid derivative. More recently, Connon and co-work-
R1
SR2
R1
R2SH, cinchona alkaloid
catalyst
∗
O
∗
O
PG
N
PG
N
N
H
N
H
O
O
O
O
1
2
ers reported that a C5′ urea substituted cinchona alkaloid Scheme 1 Thiol addition to dehydroamino acid derivatives;
PG = protective group
derivative efficiently catalyzes the sulfa-Michael reaction
between aliphatic thiols and nitro alkenes with the forma-
tion of the products in excellent enantioselectivity.9a Late-
Initially, we prepared 1 with an acetyl group at the en-
ly, Wang and co-workers9b reported an enantioselective
amine nitrogen atom by the Erlenmeyer–Plöchl azlactone
synthesis13 followed by ring opening with oxazolidinone.
Subsequently, this substrate was reacted with thiophenol
in the presence of a C6′ thiourea cinchona alkaloid deriv-
ative described previously.14 However, no product of thiol
addition could be observed, indicating a low reactivity of
synthesis of cis-β-thio-α-amino acids by a 1,4-addi-
SYNLETT 2012, 23, 2195–2200
Advanced online publication: 24.08.2012
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3
6
-
5
2
1
4
1
4
3
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2
0
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DOI: 10.1055/s-0032-1317081; Art ID: ST-2012-B0441-L
© Georg Thieme Verlag Stuttgart · New York

2196
A. C. Breman et al.
LETTER
the β-carbon atom in the substrate, possibly as a result of
the pronounced enamine character at this position. In or-
der to increase the susceptibility of the β-carbon atom for
nucleophilic attack, we decided to introduce a trifluoro-
acetyl group as the protective group at the enamine nitro-
gen atom in 1.
O
Br
O
O
O
HN
R
R
O
O
NaH, THF
N
N
H
CF3
CF3
The Erlenmeyer–Plöchl azlactone synthesis of azlactones
with trifluoroacetic acid anhydride (TFAA) is known,
however, to lead to unstable products.15 Our attempts to
prepare the trifluoromethyl-substituted azlactones by this
strategy also failed to give isolable products as required
for the reaction with oxazolidinone under basic condi-
tions. We decided, therefore, to prepare the desired
α,β-unsaturated N-trifluoacetylated oxazolidin-2-ones by
treatment of amino acids 3a–d with TFAA thus leading to
the stable pseudoazlactones 4a–d in high yields (Scheme
2).16,17 Bromination in 1,2-dichloroethane (DCE) resulted
in the formation of 5a–d in good to excellent yields. In
agreement with the literature, small amounts of dibromi-
nated compounds were formed in the reaction of pseudo-
azlactones derived from norleucine and norvaline.18
5a–d
6
R
a R = Ph 62%, E/Z = 1:10
b R = Et 29%, E/Z = 1:2
c R = Pr 31%, E/Z = 1:3
d R = Bn 33%, E/Z = 1:2
O
O
N
F3C
N
H
O
O
7a–d
Scheme 3 Preparation of the dehydroamino acid derivatives with tri-
fluoroacetyl-substituted azlactones formed in situ
keeping with a decrease in electron density at the β-posi-
tion upon introduction of a trifluoroacetyl group at the en-
amine nitrogen atom as revealed also by the fact that the
13C NMR chemical shift of this carbon atom is 132.19 ppm
for 7a but only 112.47 ppm if an acetyl group is present.
Br
O
O
R
R
R
(TFA)2O
reflux
O
Br2, DCE
O
N
N
With CHCl3 as the solvent, full conversion was also ob-
served after 12 hours. The diastereoselectivity was almost
the same as in CH2Cl2 but the enantioselectivity was low
for both diastereoisomers (entry 2). A reasonable enantio-
selectivity was observed in THF, even though the conver-
sion was not more than 70% (entry 3). A further increase
in enantioselectivity was seen in toluene, but again the
conversion was low after 12 hours (entry 4). Addition of
2.0 equivalents of thiophenol instead of 1.2 equivalents
gave full conversion after 12 hours. However, a signifi-
cant decrease in the enantioselectivity was observed.
H
H2N
3a–d
CO2H
H
CF3
4a–d
CF3
5a–d
a R = Ph
b R = Et
c R = Pr
d R = Bn
a R = Ph 86%
b R = Et 97%
c R = Pr 88 %
d R = Bn 91%
a R = Ph 100%
b R = Et 89%
c R = Pr 78%
d R = Bn 85%
Scheme 2 Synthesis of brominated pseudoazlactones 5a–d
Treatment of brominated pseudoazlactones 5a–d with
two equivalents of aniline were reported previously to re-
sult in elimination of HBr with formation of azlactones in
situ prior to ring opening to afford dehydroamino acid
anilides.17 Thus, we decided to treat 5a–d with 2.2 equiv-
alents of the sodium salt of oxazolidinone in THF. This re-
sulted in the formation of dehydroamino acids 7a–d in
poor to reasonable yields and with a preference for the
Z-isomer (Scheme 3).19 The E-and Z-isomers were subse-
quently separated by recrystallization from a mixture of
petroleum ether and ethyl acetate or by column chroma-
tography.
Replacing the benzyl group in catalyst A with a 9-methyl
anthracyl moiety led to the formation of the sterically
more congested catalyst B (Table 1).5 With this catalyst
and CH2Cl2 as the solvent the major diastereomer was ob-
tained with an ee of 90% and the minor diastereomer in
75% ee (entry 6). The enantioselectivity was moderate for
both diastereoisomers in CHCl3 (entry 7) and high in tol-
uene, even though the conversion was only 60% after 12
hours with 1.2 equivalents of thiophenol (entry 8). As ob-
served with catalyst A, addition of 2.0 equivalents of thio-
phenol resulted in full conversion after 12 hours with
formation of the diastereoisomers in poor enantioselectiv-
ity (entry 9). The diastereoisomeric ratio was changed by
the use of catalyst C (entries 10–12). However, full con-
version was not observed and the enantioselectivity was
low for both diastereomers with this catalyst. In conclu-
sion, the best results were obtained in CH2Cl2 with B as
the catalyst (entry 6).21
Subsequently, optimal conditions for asymmetric thiol ad-
dition were established by reacting the pure Z-isomer of
substrate 7a with thiophenol in a series of solvents and in
the presence of one of the three thiourea derivatives of
quinidine shown in Table 1.5,14,20 The reaction proceeded
efficiently to give full conversion after 12 hours in CH2Cl2
and in the presence of 10 mol% of the C6′ thiourea deriv-
ative A (Table 1, entry 1). The product of the 1,4-addition
of thiophenol was formed with moderate diastereoselec-
Having identified the optimal conditions, the catalytic re-
tivity and with good enantioselectivity for the major dia- actions between the substrates 7a–d and a series of thiols
stereoisomer (79%). The higher reactivity of 7a compared
were examined (Table 2). With ethanethiol, 2-propene-1-
to the related N-acetyl protected species (see above) is in
thiol, α-toluenethiol and substituted analogues thereof,
Synlett 2012, 23, 2195–2200
© Georg Thieme Verlag Stuttgart · New York

LETTER
Enantioselective Organocatalytic Thiol Addition
2197
Table 1 Optimization of the Conjugate Addition of Thiolsa
hours with a slight preference for one diastereoisomer (en-
try 3). The major diastereomer was formed with high en-
antioselectivity (94% ee), while the ee for the minor
isomer (47%) was significantly lower also compared with
the results for thiophenol as the nucleophile (Table 1, en-
try 6). The diastereoselectivity was 2:1 with 4-methoxy-
benzylthiol and an excellent enantioselectivity was
obtained for the major isomer (entry 4).21,22
CF3
F3C
NH
OR
N
S
S
NH
CF3
N
N
The reaction of the Z-isomer of the ethyl-substituted sub-
strate 7b with thiophenol gave the products in good dia-
stereoselectivity, and the enantioselectivity was also
relatively high for the major isomer (entry 6). With the
less reactive thiols, 2-propene-1-thiol, α-toluenethiol, and
4-methoxy-α-toluenethiol, an inversion with respect to
the diastereoselectivity was observed (entries 5, 7 and 8).
In these reactions, the highest ee values were observed for
the minor diastereoisomer with only a slight change in en-
antioselectivity as compared with the phenyl-substituted
substrate 7a. In the reactions of the Z-isomer of the n-pro-
pyl-substituted substrate 7c (entries 9 and 10) the ee val-
ues did not exceed 80%, indicating that 1,4-addition is
sterically influenced by the size of the alkyl group at the
β-position. With the pure E-form of 7c, we obtained low
ee values for both diastereoisomers (57% for the major di-
astereomer and 24% for the minor species), and the ee of
the major isomer was only slightly higher (63%; entries
9b and 9c) with the E/Z-mixture.
N
N
N
CF3
H
H
OMe
A R = benzyl
B R = 9-methylanthracyl
C
Ph
Ph
SPh
∗
catalyst (10 mol%)
PhSH
O
O
O
O
∗
N
N
F3C
N
F3C
N
solvent, r.t.
H
H
O
O
O
O
7a
8
Entry Cat.
Solvent
PhSH
Conv. dr
ee
(equiv) (%)b
(%)c
1
2
A
A
A
A
A
B
B
B
B
C
C
C
CH2Cl2
CHCl3
THF
1.2
1.2
1.2
1.2
2.0
1.2
1.2
1.2
2.0
1.2
1.2
1.2
100
100
70
75:25
80:20
75:25
75:25
75:25
75:25
75:25
67:33
75:25
83:17
85:15
91:9
79/57
47/36
60/45
85/63
2/46
3d
4d
5
toluene
toluene
CH2Cl2
CHCl3
toluene
toluene
CH2Cl2
CHCl3
toluene
50
With the Z-form of substrate 7d (entry 11), a relatively
low yield (75%) was obtained as a result of an isomeriza-
tion of the double bond into conjugation with the phenyl
group. For this substrate, the ee values were moderate to
low for both diastereoisomers.
100
100
100
60
6
90/75
80/60
90/74
42/57
28/45
28/–18
57/30
7
8d
9
In order to determine the absolute configuration at the α-
and β-carbon atoms in the major product of the 1,4-addi-
tion of 4-methoxybenzylthiol to 7a, an X-ray crystal
structure analysis23 was performed of the major isomer
obtained by crystallization of 12 from hexane–EtOAc
(Figure 1). The R-configuration was assigned to the β-car-
bon and the S-configuration to the α-carbon of the amino
acid derivative. Thus, the addition of thiophenol to the
100
75
10d
11d
12d
75
57
a Standard reaction conditions: 0.2 M substrate, room temperature, re-
action time 12 h.
b Conversion as determined by 1H NMR spectroscopic analysis.
c The ee was determined by chiral HPLC (AD column) analysis.
d No improvement of the conversion was observed with a reaction
time of 24 h.
3.0 equivalents were added. This resulted in a decrease in
the reaction time without a dramatic change in the enantio-
selectivity (Table 2).
The reaction of the Z-isomer of the phenyl-substituted
substrate 7a with ethanethiol was slow and gave the dia-
stereoisomers in almost equal amounts (entry 1). High en-
antioselectivity was observed for the major
diastereoisomer while only a moderate ee was obtained
for the minor isomer. A lower enantioselectivity was seen
with allylthiol as the nucleophile (entry 2); that is, the ee
of the major diastereoisomer was 86% but only 25% for
the minor isomer. Benzylthiol reacted with 7a within four
Figure 1 X-ray crystal structure of the major enantiomer of 12
Synlett 2012, 23, 2195–2200
© Georg Thieme Verlag Stuttgart · New York

2198
A. C. Breman et al.
LETTER
Table 2 Scope of the Thiol Addition to Dehydroamino Acid Derivativesa
R1
R1
SR2
O
∗
O
O
catalyst B (10 mol%)
N
R2SH
∗
O
+
F3C
N
N
H
CH2Cl2, r.t.
F3C
N
H
O
O
O
O
9–19
7a–d
Entry
7b
R1
R2
Equiv of thiol Time (h)
Product
Yield (%)c dr
55:45
ee (%)d
1
2
7a
7a
7a
7a
7b
7b
7b
7b
Ph
Ph
Ph
Ph
Et
Et
Et
Et
Et
3.0
3.0
3.0
3.0
3.0
1.2
3.0
3.0
1.2
1.2
1.2
3.0
1.2
16
8
9
10
11
12
13
14
15
16
17
17
17
18
19
96
97
93
99
94
92
95
91
91
92
93
95
75
94/52
86/25
94/47
95/46
80/57
87/51
90/71
80/58
80/65
57/24
63/28
72/44
77/58
allyl
52:48
52:48
67:33
42:58
83:17
48:52
48:52
80:20
70:30
67:33
45:55
71:29
3
Bn
4
4
4-MeOC6H4CH2
6
5
allyl
16
8
6
Ph
7
Bn
16
16
16
16
16
16
8
8
4-MeOC6H4CH2
9a
9b
9c
10
11
(Z)-7c
(E)-7c
(E,Z)-7ce
7c
n-Pr
n-Pr
n-Pr
n-Pr
Bn
Ph
Ph
Ph
Bn
Ph
7d
a Standard conditions: 0.2 M substrate, r.t.
b Experiments were performed with the Z-isomer of the substrates unless otherwise stated.
c The combined yield of both diastereoisomers.
d The ee values were determined by chiral HPLC analysis (AD or ADH column).
e The composition of the mixture was 30% E- and 70% Z-isomer.
phenyl-substituted substrate 7a catalyzed by B leads To examine the applicability of the products for solid-
mainly to the anti-diastereoisomer of the product.
phase Fmoc-chemistry, a one-pot procedure was devel-
oped to remove the trifluoroacetyl and the oxazolidinone
groups, followed by protection of the primary amine func-
tion with an Fmoc-group (Scheme 4). This resulted in
60% yield of the corresponding Fmoc-protected amino
acid 20.24 Furthermore, the 4-methoxybenzyl group could
be easily removed with TFA and triisopropylsilane in
CH2Cl2. This resulted in formation of the Fmoc-protected
phenyl-substituted cysteine 21 in 79% yield.25
MeO
MeO
1) 2M KOH, MeOH
2) FMoc-Osu, NH4HCO3
MeCN, H2O
H
H
H
Ph
S
Ph
S
O
60%
O
OH
N
FmocHN
F3C
N
H
H
O
O
O
12
20
In conclusion, we have prepared a new class of substrates
for asymmetric organocatalyzed sulfa-Michael additions.
With the new substrates we were able to perform a cincho-
na alkaloid-catalyzed sulfa-Michael reaction with aromat-
ic as well as aliphatic thiols with good yields, modest to
excellent enantioselectivities, and low to moderate diaste-
reoselectivities. The final products can be converted into
β-thiol-substituted amino acids for application in the syn-
thesis of peptidomimetics.
MeO
TFA, (i-Pr)3SiH
H
H
H
Ph
S
Ph
SH
O
CH2Cl2
79%
OH
OH
FmocHN
FmocHN
H
O
20
21
Scheme 4 Formation of enantiopure β-phenyl-substituted cysteine
protected with a Fmoc group at the amine moiety [FMoc-OSu: N-(9-
fluorenylmethoxycarbonyloxy)succinimide]
Acknowledgment
The NRSCC is gratefully acknowledged for funding this research
project.
Synlett 2012, 23, 2195–2200
© Georg Thieme Verlag Stuttgart · New York

LETTER
Enantioselective Organocatalytic Thiol Addition
purified by column chromatography (PE–EtOAc, 2:1)
2199
References and Notes
yielding a 1:10 mixture of E/Z-isomers 7a (5.3 g, 15.5 mmol,
62%). The Z-isomer was obtained by recrystallization
(EtOAc–PE).
(1) For reviews, see: (a) Doyle, A. G.; Jacobsen, E. N. Chem.
Rev. 2007, 107, 5713. (b) Dondoni, A.; Massi, A. Angew.
Chem. Int. Ed. 2008, 47, 4638. (c) Yu, X. H.; Wang, W.
Chem.–Asian J. 2008, 3, 516. (d) Connon, S. J. Chem.
Commun. 2008, 2499. (e) Bertelsen, S.; Jørgensen, K. A.
Chem. Soc. Rev. 2009, 38, 2178.
(2) (a) Wynberg, H.; Helder, R. Tetrahedron Lett. 1975, 46,
4057. (b) Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc.
1981, 103, 417.
(3) (a) Marcelli, T.; Hiemstra, H. Synthesis 2010, 1229.
(b) Cinchona Alkaloids in Synthesis and Catalysis: Ligands,
Immobilization and Organocatalysis, 1st ed.; Song, C. E.,
Ed.; Wiley-VCH: Weinheim, 2009.
(4) (a) Organocatalytic Enantioselective Conjugate Additions
Reactions, 1st ed.; Vicario, J. L.; Badia, L.; Carrillo, L.;
Reyes, E., Eds.; Royal Society of Chemistry: Cambridge,
2010. (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
(5) Liu, Y.; Sun, B. F.; Wang, B. M.; Wakem, M.; Deng, L.
J. Am. Chem. Soc. 2009, 131, 418.
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2005, 44, 4032.
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3475.
(8) Inokuma, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc.
2006, 128, 9413.
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2849. (b) Geng, C.-G.; Li, N.; Chern, J.; Huang, X.-F.; Eu,
B.; Liu, G.-G.; Wang, X.-W. Chem. Commun. 2012, 48,
4713.
Compound (Z)-7: 1H NMR (400 MHz, CDCl3): δ = 8.64 (s,
1 H), 7.47–7.40 (m, 5 H), 6.94 (s, 1 H), 4.44 (t, J = 7.6 Hz,
2 H), 4.05 (t, J = 7.6 Hz, 2 H); 13C NMR (100 MHz, CDCl3):
δ = 164.5, 155.5 (q, J = 38.0 Hz), 152.9, 132.2, 131.6, 128.8,
129.4, 129.0, 125.6, 115.4 (q, J = 286.0 Hz), 63.0, 42.9.
Compound (E)-7: 1H NMR (400 MHz, CDCl3): δ = 8.21 (s,
1 H), 7.49–7.42 (m, 5 H), 6.65 (s, 1 H), 4.43 (t, J = 8.0 Hz,
2 H), 4.07 (t, J = 8.0 Hz, 2 H); 13C NMR (100 MHz, CDCl3):
δ = 162.3, 155.7 (q, J = 38.0 Hz), 151.9, 132.0, 130.1, 129.7,
129.5, 129.1, 125.9, 115.4 (q, J = 286.0, 62.5, 42.0 Hz); IR
(neat): 3253, 1617, 1717, 1685, 1529, 1388, 1209, 1184,
1155 cm–1; HRMS (FAB): m/z [M + H]+ calcd. for
C14H12F3N2O4: 329.0749; found: 329.0746.
(20) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett.
2005, 7, 1967.
(21) In addition to the cinchona derivatives, we performed a
series of experiments with the thiourea catalyst developed by
Takamoto.6,8 With this organocatalyst, the reaction between
thiophenol and (Z)-7a yielded the products in a
diastereomeric ratio of 95:5 in CH2Cl2 but both isomers were
formed in an unsatisfactory ee (i.e., 70% ee for the major
diastereomer and 36% for the minor isomer). With
4-methoxybenzylthiol as the nucleophile, the reaction with
the (Z)-7a catalyzed by the Takamoto thiourea led to the
formation of products in a diastereomer ratio of 63:37 and in
poor enantioselectivity (25% ee for the major isomer and
24% for the minor isomer).
(10) (a) Enders, D.; Luettgen, K.; Narine, A. A. Synthesis 2007,
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Urakawa, A.; Galzerano, P.; Arceo, E.; Melchiorre, P. J. Am.
Chem. Soc. 2011, 133, 17934. (c) Dai, L.; Yang, H. J.; Chen,
F. Eur. J. Org. Chem. 2011, 5071. (d) Pei, Q.-L.; Sun, H.-
W.; Wu, Z.-J.; Du, X.-L.; Zhang, X.-M.; Yuan, W.-C. J.
Org. Chem. 2011, 76, 7849. (e) Rana, N. K.; Selvakumar, S.;
Singh, V. K. J. Org. Chem. 2010, 75, 2089. (f) Rana, N. K.;
Singh, V. K. Org. Lett. 2011, 13, 6520.
(11) (a) Nagasawa, H. T.; Elberling, J. E.; Roberts, J. C. J. Med.
Chem. 1987, 30, 1373. (b) Nagai, U.; Pavone, V.
Heterocycles 1989, 28, 589. (c) Villeneuve, G.; Dimaio, J.;
Chan, T. H.; Michel, A. J. Chem. Soc., Perkin Trans. 1 1993,
1897.
(12) Crich, D.; Banerjee, A. J. Am. Chem. Soc. 2007, 129, 10064.
(13) (a) Plöchl, J. Ber. Dtsch. Chem. Ges. 1883, 16, 2815.
(b) Erlenmeyer, E. Justus Liebigs Ann. Chem. 1893, 275, 1.
(14) Marcelli, T.; van der Haas, R. N. S.; van Maarseveen, J. H.;
Hiemstra, H. Angew. Chem. Int. Ed. 2006, 45, 929.
(15) Weygand, F. Chem. Ber. 1954, 87, 248.
(16) (a) Weygand, F.; Steglich, W. Angew. Chem. 1961, 73, 433.
(b) Weygand, F.; Steglich, W.; Tanner, H. Justus Liebigs
Ann. Chem. 1962, 658, 128. (c) Weygand, F.; Steglich, W.;
Mayer, D.; von Philipsborn, W. Chem. Ber. 1964, 97, 2023.
(17) Breitholle, E. G.; Stammer, C. H. J. Org. Chem. 1976, 41,
1344.
(22) Synthesis of 12: Compound 7a (885 mg, 2.69 mmol) and
catalyst B (207 mg, 0.27 mmol) were dissolved in CH2Cl2
(13 mL). 4-methoxybenzylthiol (1.12 mL, 8.07 mmol) was
added and the resulting mixture was stirred overnight. The
product was concentrated and purified by column
chromatography (PE–EtOAc, 2:1), yielding a 33:67 mixture
of syn/anti-isomers of a slowly solidifying oil (1.24 g, 2.58
mmol, 96%). 1H NMR (400 MHz, CDCl3): δ = 7.53 (dd, J =
8.4, 1.6 Hz, 1 H), 7.41–7.32 (m, 3 H), 7.28–7.26 (m, 1 H),
7.16 (dd, J = 6.4, 2 Hz, 1.33 H), 7.10 (dd, J = 6.4, 2 Hz,
0.67 H), 7.00 (d, J = 9.6 Hz, 1 H), 6.87 (dd, J = 6.4, 2 Hz,
0.67 H), 6.84 (dd, J = 6.4, 2 Hz, 1.33 H), 6.33 (t, J = 7.6 Hz,
0.67 H), 6.02 (dd, J = 8.4, 5.2 Hz, 0.33 H), 4.46 (t, J = 8 Hz,
1.33 H), 4.36 (m, 0.33 H), 4.29 (d, J = 5.2 Hz, 0.33 H), 4.23
(d, J = 7.6 Hz, 0.67 H), 4.15 (m, 0.67 H), 4.06 (m, 0.67 H),
3.98–3.92 (m, 1.33 H), 3.83 (s, 1 H), 3.83 (s, 2 H), 3.73 (d,
J = 12.8 Hz, 0.67 H), 3.65–3.60 (m, 0.67 H), 3.34 (d,
J = 13.6 Hz, 0.33 H); 13C NMR (100 MHz, CDCl3): δ =
168.6, 168.2, 158.9, 158.8, 156.6 (q, J = 38 Hz), 156.5 (q,
J = 38 Hz), 152.9, 152.5, 136.8, 136.3, 130.2, 130.1, 129.3,
129.1, 128.9, 128.7, 128.7, 128.6, 128.5, 128.4, 128.3,
121.6, 115.5 (q, J = 286 Hz), 113.9, 62.6, 62.4, 56.4, 55.3,
54.1, 50.7, 49.4, 42.6, 42.5, 35.4, 34.6; IR (neat): 3319,
1779, 1728, 1698, 1537, 1214, 1173, 702 cm–1; HRMS
(FAB): m/z [M + H]+ calcd for C22H22F3N2O5S: 483.1202;
found: 483.1207; HPLC [Daicel Chiralcel AD; i-PrOH–
heptane, 15:85 (0–40 min) then 30:70 (40–120 min); 1.0
mL/min; λ = 220nm]: tR (major diastereoisomer) = 21.5
(minor), 110.8 (major) min; tR (minor diastereoisomer) =
14.9 (minor), 21.5 (major) min. Recrystallization of the
crude product (EtOAc–PE) gave the minor syn-isomer as a
racemate (120 mg, 0.25 mmol, 9%). The mother liquor was
concentrated and further recrystallized (EtOAc–PE) to give
the anti-isomer as a pure enantiomer (503 mg, 1.04 mmol,
39%). Mp 142–144 °C; [α]D –203.4 (c = 0.42, MeOH). 1H
NMR (400 MHz, CDCl3): δ = 7.35 (m, 3 H), 7.28 (m, 2 H),
(18) The same observation was reported by the group of
Stammer, see ref. 17.
(19) Synthesis of 7: Oxazolidinone (5.0 g, 57.4 mmol, 2.3 equiv)
was dissolved in anhydrous THF (250 mL), and NaH (1.3 g,
55 mmol, 2.2 equiv) was added in portions. The resulting
mixture was stirred for 30 min, then a solution of 5a (8.0 g,
25 mmol, 1 equiv) in anhydrous THF (50 mL) was added
dropwise and stirring was continued for 30 min. Saturated
NH4Cl was added and the resulting mixture was extracted
three times with EtOAc. The organic layers were combined,
washed with brine and dried with MgSO4. The product was
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2195–2200

2200
A. C. Breman et al.
LETTER
7.16 (d, J = 8.4 Hz, 1 H), 6.98 (d, J = 8.8 Hz, 1 H), 6.83 (d,
J = 8.8 Hz, 1 H), 6.32 (t, J = 8.4 Hz, 1 H), 4.48 (t,
Beurskens, G.; Strumpel, M.; Nordman, C. E. In Patterson
and Pattersons; Glusker, J. P.; Patterson, B. K.; Rossi, M.,
Eds.; Clarendon Press: Oxford, 1987, 356–367.
(d) Sheldrick, G. M. SHELXL-97; University of Göttingen:
Germany, 1997.
J = 8.0 Hz, 2 H), 4.23 (d, J = 7.2 Hz, 1 H), 4.07–4.01 (m,
1 H), 3.99–3.94 (m, 1 H), 3.81 (s, 3 H), 3.74 (d, J = 8.8 Hz,
1 H), 3.63 (d, J = 8.8 Hz, 1 H); 13C NMR (100 MHz,
CDCl3): δ = 168.6, 158.8, 156.5 (q, J = 38 Hz), 152.8, 136.8,
136.3, 130.2, 129.3, 128.7, 128.6, 128.4, 115.5 (q,
J = 286 Hz), 113.9, 62.4, 55.2, 54.1, 50.7, 42.5, 35.4.
(24) Experimental procedure for the conversion of 12 into the
β-phenyl-substituted cysteine 20: Enantiomerically pure
compound 12 (200 mg, 0.41 mmol) was dissolved in a 1:2
mixture of 2 M KOH and MeOH (12 mL total volume) and
stirred overnight. The resulting mixture was neutralized with
2 M HCl and the methanol was removed by evaporation.
Ammonium bicarbonate (328 mg, 4.15 mmol) and a solution
of Fmoc-OSu (138 mg, 0.41 mmol) in MeCN (4 mL) was
added and the resulting mixture was stirred for 4 h. The
mixture was acidified with 2 M HCl until pH 2. The mixture
was extracted three times with EtOAc and the organic layers
were combined, washed with brine and dried with MgSO4.
The solvents were evaporated and the product was purified
by column chromatography (PE–EtOAc–AcOH, 3:2:0.1)
yielding 20 (134 mg, 0.25 mmol, 60%) as a white solid. Mp
60–62 °C; [α]D –72.1 (c = 0.37, MeOH). 1H NMR (400
MHz, CDCl3): δ = 7.80 (d, J = 4.4 Hz, 2 H), 7.58 (t,
J = 8.0 Hz, 2 H), 7.49–7.31 (m, 9 H), 7.18 (d, J = 5.5 Hz,
2 H), 6.82 (d, J = 8.4 Hz, 2 H), 5.27 (d, J = 9.2 Hz, 1 H),
4.94 (m, 1 H), 4.44 (d, J = 6.8 Hz, 1 H), 4.35 (t, J = 7.2 Hz,
1 H), 4.26 (m, 2 H), 3.79 (s, 3 H), 3.68 (d, J = 13.2 Hz, 1 H),
3.56 (d, J = 13.2 Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ
= 174.1, 158.6, 143.7, 141.2, 136.4, 132.5, 130.5, 130.1,
129.7, 129.0, 128.7, 128.6, 128.2, 127.7, 127.1, 125.2,
125.1, 124.9, 119.9, 113.9, 67.4, 57.4, 55.2, 50.5, 47.0, 35.2;
IR (neat): 3063, 3032, 2953, 1710, 1511, 1478, 1247, 1214,
1175, 701 cm–1; HRMS (FAB): m/z [M + H]+ calcd for
C32H30NO5S: 540.1839; found: 540.1877.
(23) (a) Crystal Structure Data for Compound 12:
Mw = 482.27; colorless platelet; 0.27 × 0.22 × 0.06 mm;
orthorhombic; P212121; a = 10.0062(7) Å,
b = 11.8687(4) Å, c = 18.6029(12) Å; V = 2209.3(2) Å3;
Z = 4; D = 1.451 g·cm–3; μ = 0.209 mm–1. 66682 reflections
were measured with a Nonius KappaCCD diffractometer
(Mo radiation, graphite monochromator, λ = 0.71073 Å) up
to a resolution of sinθ/λ = 0.65 Å–1 at 208 K. 5067 reflections
were unique (Rint = 0.0423) of which 4371 were observed
with Io ≥ 2σ(Io). The structure was solved by direct methods
with the PATTY option of the DIRDIF program system23b,c
and refined against F2 using SHELXL.23d All non-hydrogen
atoms were refined with anisotropic temperature factors.
The hydrogen atoms were placed at calculated positions and
refined isotropically in riding mode. The three fluorine
atoms could not be refined adequately because of rotational
disorder. The absolute structure was determined based on the
anomalous dispersion of 2199 Friedel pairs, Flack
parameter = 0.00(12), the Hooft parameter y = 0.014(16).
R1 = 0.0685 [I ≥ 2σ(I)]; R1 = 0.0806 [all reflections];
S = 1.537. Residual electron density between 1.334 and –
0.562 e·Å–3. The data were deposited with the Cambridge
Crystallographic Data Centre (CCDC 882528). More
detailed information can be obtained free of charge from The
Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. (b) Beurskens, P. T.;
Beurskens, G.; Bosman, W. P.; de Gelder, R.; García-
Granda, S.; Gould, R. O.; Israël, R.; Smits, J. M. M.
DIRDIF-96; Crystallography Laboratory: University of
Nijmegen (The Netherlands), 1996. (c) Beurskens, P. T.;
(25) Although the ee values of 20 and 21 could not be readily
measured by using HPLC techniques, the absence of any
epimerization according to 1H HMR spectroscopic analysis
is a strong indication that these compounds are enantiopure.
Synlett 2012, 23, 2195–2200
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