Phosphine Oxide Catalyzed, Tetrachlorosilane-Mediated Enantioselective Direct Aldol Reactions of Thioesters

Article abstract of DOI:10.1055/s-0034-1379914

The stereoselective direct aldol reaction of S-phenyl thioesters and aromatic aldehydes promoted by tetrachlorosilane was realized for the first time; the proposed mechanism involves the formation of a chiral cationic hypervalent silicon species and requi

Full text of DOI:10.1055/s-0034-1379914

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2015, 47, 2113–2124
2113
paper
Synthesis
S. Rossi et al.
Paper
Phosphine Oxide Catalyzed, Tetrachlorosilane-Mediated Enantio-
selective Direct Aldol Reactions of Thioesters
Ar1
Ar1
O
SiCl4 (3 equiv)
cat. (0.1 equiv)
Sergio Rossi*
S
R
n
Ar1
Ar2
Ar2
S
R
S
R
n
+
Rita Annunziata
Franco Cozzi
Ar2
H
n
O
CH2Cl2
OH
anti
O
OH
O
Laura Maria Raimondi
n = 0, 1
syn
Dipartimento di Chimica, Universita degli Studi di Milano,
via Golgi 19, 20133 Milano, Italy
sergio.rossi@unimi.it
O
S
O
PPh2
PPh2
PPh2
O
PPh2
O
S
(R)-BINAPO
(S)-TetraMe-BITIOPO
Received: 09.02.2015
Accepted after revision: 24.03.2015
Published online: 13.05.2015
of the chiral Lewis base to SiCl generates a new hyperva-
lent silicon species of increased acid character, responsible
4
4
DOI: 10.1055/s-0034-1379914; Art ID: ss-2015-t0066-op
for the addition of different nucleophiles to carbonyl com-
pounds with high chemical and stereochemical efficiency.
These studies opened the way to the so-called ‘Lewis base
catalyzed Lewis acid mediated reactions’ where chiral
Abstract The stereoselective direct aldol reaction of S-phenyl thio-
esters and aromatic aldehydes promoted by tetrachlorosilane was real-
ized for the first time; the proposed mechanism involves the formation
of a chiral cationic hypervalent silicon species and requires the presence
of catalytic amounts of a Lewis base, like a chiral phosphine oxide. The
reaction affords syn β-hydroxy thioesters as major isomers in good
yields, high diastereoselectivity (up to 99:1), and up to 92% enantio-
meric excess. The absolute configuration of the major isomer was es-
tablished by converting the product into the corresponding β-hydroxy
ester. The scope of the reaction was also investigated by employing dif-
ferently substituted thioesters in combination with different aromatic
aldehydes.
phosphoroamides,1 phosphine oxides,
a,5
1b,c,6
and sulfoxides
7
have found extensive application as Lewis bases for the ac-
tivation of trichlorosilyl derivatives, including tetrachlorosi-
lane.
In 2011, our group reported the first organocatalytic di-
rect aldol addition of activated thioesters to aldehydes, cat-
alyzed by phosphine oxides and mediated by the presence
8
of SiCl . Based on this method, activated fluorinated thio-
4
esters act as nucleophiles and react with aromatic alde-
hydes, leading to the formation of β-hydroxy thioesters in
good yield and high diastereo- and enantioselectivity, up to
Key words asymmetric catalysis, direct aldol reaction, hypercoordi-
nate silicon, phosphine oxides, thioesters
95% ee (Scheme 1, a).
The use of tetrachlorosilane in combination with cata-
lytic amounts of chiral Lewis bases to promote stereoselec-
tive reactions is nowadays a well-established method.1
Generally, the coordination of a Lewis base to a Lewis acid
leads to the formation of a stable and less reactive adduct.
However, in some circumstances, this adduct presents en-
hanced reactivity, as in the case of the coordination of a chi-
Before our contribution, the use of activated fluorinated
9
10
thioesters or malonic acid half thioesters as ester mimics
was limited only to a few examples of nonstereoselective
Mannich transformations and enantioselective Michael-
type reactions, and no examples of direct aldol-type reac-
tion were known. On the other hand, a few examples of or-
ganocatalytic, nonstereoselective, direct aldol reaction with
11
ral Lewis base to a molecule of SiCl , where a new silicon
carboxylic acid derivatives were known. In 2013, List and
4
species with increased Lewis acidity is generated in situ.2
Due to its low cost and ready availability, the activation
of tetrachlorosilane through the generation of hypervalent,
highly reactive, silicate species can play an important role
in the development of new, highly chemically and stereo-
chemically efficient catalytic systems of low environmental
Song reported an organocatalytic enantioselective decar-
12
boxylative aldol reaction of malonic acid half thioesters
with aldehydes using a cinchona-based sulfonamide, and
very recently Wang13 reported an enantioselective cascade
reaction between α,β-unsaturated aldehydes and malonic
half thioesters for the synthesis of chiral δ-lactones pro-
moted by a prolinol-derived catalyst.
3
impact.
In this field, a real breakthrough was achieved by
Denmark, who developed phosphoramide-catalyzed and
The use of activated fluorinated thioesters rather than
malonic half thioesters offers the possibility to obtain high-
ly functionalized products with more efficient atom econo-
1a
SiCl -mediated stereoselective reactions. The coordination
4
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S. Rossi et al.
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a) previous work
O
SiCl4 (3 equiv)
cat. (0.1 equiv)
OH
O
OH
O
O
Ar1
Ar2
+
CF3
Ar2
S
S
CF3
Ar2
S
CF3
H
Ar1
Ar1
syn
anti
b) this work
Ar1
Ar1
SiCl4 (3 equiv)
cat. (0.1 equiv)
O
S
R
n
Ar1
Ar2
Ar2
S
R
n
S
R
n
+
Ar2
H
O
OH
O
OH
anti
O
n = 0,1
syn
O
S
S
O
PPh2
PPh2
PPh2
O
PPh2
O
1
2
(
R)-BINAPO
(S)-TetraMe-BITIOPO
Scheme 1 Direct aldol reaction of thioesters with aromatic aldehydes catalyzed by phosphine oxides
my through a straightforward procedure. Despite its poten-
tiality, the direct aldol reaction of thioesters suffers mainly
from two drawbacks: (1) trifluoroethanethiol used to syn-
thetize the thioester is expensive and (2) the presence of an
aryl group at the α-position is necessary to activate the
substrate and make the organocatalytic approach feasible.
The possibility to use cheaper and more environmental-
ly friendly starting materials for this fundamental transfor-
mation is of course very attractive; we now wish to report
the results of our investigation on the use of simple, easily
available thioester substrates in the organocatalytic direct
aldol reaction (Scheme 1, b).
It is known that esters are generally unreactive in or-
ganocatalysis due to the relatively low acidity of the proton
at the α-position of the ester function (pK = 18.7 for com-
a
pound 6), and can be activated only by the presence of
strong electron-withdrawing groups (as the SCH CF group
2
3
for compound 3). However, no information is reported
about the reactivity of compounds 4 and 5 as potential nuc-
leophiles in direct aldol addition reaction catalyzed by Lewis
bases and promoted by silicon tetrachloride.
Following this approach, the S-(3,3,3-trifluoro)ethyl
group of 3 was initially replaced with an S-pyridin-2-yl
moiety. Thioester 4 was synthesized and employed in the
direct aldol reaction with aromatic aldehydes in the pres-
ence of 3 equivalents of SiCl , 10 equivalents of i-Pr NEt and
In order to extend the applicability of the direct aldol
reaction of thioesters with aldehydes, the substitution of
the activating trifluoroethylthio moiety with other substit-
uents was performed, taking into consideration the reactiv-
4
2
10 mol% of (R)-BINAPO at 5 °C in CH Cl as solvent (Scheme
2
2
2).
9b,14
ity scale depicted in Figure 1.
Disappointingly, β-hydroxy thioesters 7a,b were ob-
tained with high diastereoselectivity, but in very low yields
and no enantioselectivity. Hypothesizing that these unsat-
isfactory results could derive from the coordination of the
O
O
O
O
Ph
Ph
Py Ph
Ph Ph
S
CF3
S
S
OPh
pyridyl residue of the substrate to SiCl (causing a competi-
H
H
H
H
4
tive interference with the formation of the catalytic hyper-
valent species),15 we envisioned that the replacement of the
S-pyridin-2-yl moiety with the S-phenyl moiety could avoid
this competitive coordination process. Thioester 5 was then
synthesized in 80% yield by reaction of acyl chloride with
thiophenol and reacted with benzaldehyde, in the presence
of catalytic amounts of chiral phosphine oxide, under stan-
dard reaction conditions.16 Selected results are reported in
Table 1.
3
4
5
16.9
6
18.7
<
< 16.9
<16.9
pKa in DMSO (decreasing reactivity)
Figure 1 pK values of the α-protons of carboxylic acid derivatives in
a
DMSO9
b,14
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SiCl4 (3 equiv)
cat. 2 (10 mol%)
i-Pr2NEt (10 equiv)
O
O
OH
O
OH
O
Ph
S
N
Ar
H
Ar
S
N
CH2Cl2, 5 °C, 24 h
Ar
S
N
Ph
Ph
4
Ar = Ph
Ar = 4-ClC6H4
7a: 14% > 98:2 dr, rac
7b: 15% 80:20 dr, rac
Scheme 2 Direct aldol reaction of pyridin-2-yl thioester with aromatic aldehydes
The reaction promoted by (R)-BINAPO (1) led to the for-
mation of the β-hydroxy thioester 8a in 70% yield, 66:34
syn/anti ratio, and 27% ee for the syn-enantiomer (Table 1,
entry 1). Lowering the temperature decreased the yield, but
improved the enantioselection (entries 1 vs 2 and 3 vs 4). In
addition, these preliminary studies confirmed that catalyst,
mation of corresponding β-hydroxy thioesters with syn/an-
ti ratio ranging from 91:9 to >99:1, even if in lower yields
(Table 2, entries 6, 8, 9, 12).
The temperature plays an important role for the chemi-
cal and stereochemical outcome of the reaction: lowering
the temperature increases the value of enantiomeric excess,
but depresses the yield, and only with 20 mol% of catalyst 2
satisfactory results were obtained (Table 2, entry 3). Con-
sidering that yields are modest at 0 °C, no further attempts
were performed in terms of temperature variation.
3-Methylbenzaldehyde afforded the hydroxy thioester
8e in 80% yield, modest diastereoselectivity and 73% ee for
the syn-diastereosiomer (Table 2, entry 7). 4-Trifluoro-
methylbenzaldehyde gave the product 8i in 76% yield and
41% ee (entry 11), while the analogous 4-fluoro derivative
8h was isolated in 59% yield and 68% ee (entry 10).
Heteroaromatic aldehydes were also investigated and
proved to be suitable substrates for the present method;
product 8n derived by furfural was obtained in 76% yield,
84:16 syn/anti ratio and with 92% enantiomeric excess for
the syn-distereoisomer. Finally, this method was applied to
aliphatic aldehydes: as expected, no product was obtained
with isobutyraldehyde (Table 2, entry 15), confirming that
(
S)-TetraMe-BITIOPO (2), catalyzes the reaction with better
chemical and stereochemical efficiency than (R)-BINAPO
1), even if this difference could be observed only at lower
(
8a
temperature. Notably, at 0 °C, the electron-rich dithio-
phene phosphine oxide 2 was able to promote the addition
of the readily available S-phenyl thioester of phenylacetic
acid 5 to benzaldehyde with good syn selectivity and 74%
enantioselectivity for the major isomer (entry 4). Consider-
ing the small difference in terms of reactivity of the two
catalysts, we decided to employ phosphine oxide 2 in the
survey of direct aldol addition of thioester 5 to substituted
aromatic aldehydes.
Aldehydes bearing electron-donating groups afforded
products with higher levels of diastereo- and enantioselec-
tivity than electron-poor aldehydes. In addition, diastereo-
selection seems to be influenced by steric characteristics of
the substrates: ortho-substituted aldehydes lead to the for-
Table 1 Aldol Condensation between Thioester 5 and Benzaldehyde
SiCl4 (3 equiv)
cat. (10 mol%)
OH
O
OH
O
O
O
i-Pr2NEt (10 equiv)
Ph
Ph
SPh
Ph
SPh
SPh
Ph
H
CH Cl , 24 h
2
2
Ph
Ph
5
8a-syn
8a-anti
Entry
Catalyst
Temp (°C)
Yield (%)a
syn/antib
syn ee (%)c
anti ee (%)c
1
2
3
4
(R)-1
(R)-1
(S)-2
(S)-2
(S)-2
r.t.
0
70
33
67
62
47
66:34
69:31
41:59
71:29
74:26
27 (2R,3R)
30 (2R,3R)
22 (2S,3S)
74 (2S,3S)
50 (2S,3S)
60 (2R,3S)
68 (2R,3S)
16 (2S,3R)
68 (2S,3R)
73 (2S,3R)
r.t.
0
5d
0
a
Yields were determined after chromatographic purification.
Diastereoisomeric ratio was determined on the crude reaction product by H NMR spectroscopy and confirmed by HPLC.
The ee value was determined by HPLC on a chiral column.
b
c
1
d
1
equiv of thioester was used.
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Table 2 Aldol Condensation between Thioester 5 and Different Aldehydes
SiCl4 (3 equiv)
cat. (10 mol%)
O
O
i-Pr2NEt (10 equiv)
OH
O
OH
O
Ph
CH2Cl2, 24 h
SPh
R
H
R
SPh
R
SPh
Ph
8-syn
Ph
8-anti
5
Entry
R
Catalyst
Temp (°C)
Product
Yield (%)a
syn/antib
syn ee (%)c
anti ee (%)c
1
2
3d
4
5
6
7
8
9
4-MeOC
4-MeOC
4-MeOC
6
6
6
H
H
H
4
4
4
(R)-1
(R)-1
(S)-2
(R)-1
(R)-1
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
r.t.
0
8b
8b
8b
8c
8c
8d
8e
8f
41
27
69
66
45
35
80
58
61
59
76
67
44
76
–
62:38
80:20
82:18
65:35
58:42
92:8
7 (2R,3R)
50 (2R,3R)
53 (2S,3S)
6 (2R,3R)
6 (2R,3R)
69 (2S,3S)
73 (2S,3S)
48 (2S,3S)
91 (2S,3S)
68 (2S,3S)
41 (2S,3S)
29 (2S,3S)
51 (2S,3S)
92 (2S,3S)
–
17 (2R,3S)
69 (2R,3S)
66 (2S,3R)
11 (2R,3S)
35 (2R,3S)
75 (2S,3R)
66 (2S,3R)
–
0
4-ClC
4-ClC
6
H
4
r.t.
0
6
H
4
2-MeC
3-MeC
6
6
H
4
0
H
4
0
67:33
>99:1
92:8
2,4,6-Me
2,6-(MeO)
4-FC
4-CF
2-NO
3
C
6
H
2
0
2
C
6
H
3
0
8g
8h
8i
54 (2S,3R)
65 (2S,3R)
15 (2S,3R)
nd
10
11
12
13
14
15
6
H
4
0
69:31
75:25
91:9
3
C
6
H
4
0
2
C
6
H
4
0
8l
1-naphthyl
2-furyl
i-Pr
0
8m
8n
8o
69:31
84:16
–
82 (2S,3R)
66 (2S,3R)
–
0
0
a
b
c
Yields were determined after chromatographic purification.
Diastereoisomeric ratio was determined on the crude reaction product by H NMR spectroscopy and confirmed by HPLC.
The ee value was determined by HPLC on a chiral column.
1
d
1
equiv of thioester was used.
Table 3 Aldol Condensation between Substituted Thioester and Different Aldehydes
SiCl4 (3 equiv)
cat. (10 mol%)
OH
O
OH
O
R
O
i-Pr2NEt (10 equiv)
O
Ar
SPh
Ar
SPh
CH2Cl2, 0 °C, 24 h
Ar
H
SPh
9
R
R
9
9
a R = 4-F
b R = 4-i-Bu
10-anti
10-syn
Entry
R
Ar
Ph
Catalyst
Product
Yield (%)a
syn/antib
syn ee (%)c
anti ee (%) c
1
2
3
4
5
F
(R)-1
(S)-2
(R)-1
(S)-2
(S)-2
(S)-2
10a
10a
10b
10b
10c
10d
44
29
46
47
43
59
66:34
46:54
73:27
61:39
83:17
87:13
70 (2R,3R)
64 (2S,3S)
22 (2R,3R)
87 (2S,3S)
85 (2S,3S)
65 (2S,3S)
13 (2R,3S)
63 (2S,3R)
50 (2R,3S)
43 (2S,3R)
71 (2S,3R)
39 (2S,3R)
F
Ph
Ph
Ph
i-Bu
i-Bu
i-Bu
i-Bu
4-MeOC
6 4
H
6
4-ClC H
6 4
a
Yields were determined after chromatographic purification.
Diastereoisomeric ratio was determined on the crude reaction product by H NMR spectroscopy and confirmed by HPLC.
The ee value was determined by HPLC on a chiral column.
b
c
1
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aliphatic aldehydes are less reactive in Lewis base catalyzed
reactions.
On the basis of these results we focused our attention
on the use of substituted S-phenyl thioesters of arylacetic
acids 9a,b as substrates in the direct aldol reaction promot-
ed by phosphine oxides (Table 3).
The relative configuration of β-hydroxy thioesters 8 was
17
established by converting the syn/anti mixture of product
8a (Table 1, entry 1) into the corresponding syn/anti mix-
ture of the known β-hydroxy methyl ester 14 by reaction
18
with m-CPBA and methanol in CH Cl2 (Scheme 4). The
2
syn/anti ratio was assigned on the basis of the methoxy
1
These results showed that starting from 4-fluorophenyl
substituted thioester 9a, β-hydroxy thioester 10a was
formed in 44% yield, 66:34 of syn/anti ratio, and 70% of en-
antiomeric excess for the syn-diastereoisomer using (R)-
BINAPO (1) as catalyst (Table 3, entry 1). Comparable enan-
tioselectivity was obtained using (S)-TetraMe-BITIOPO (2),
even if with no diastereoselection (entry 2). Interestingly,
thioester 9b reacts with benzaldehyde to give 10b in com-
parable yields in the presence of (R)-BINAPO (1) and (S)-Te-
traMe-BITIOPO (2). However, aldol products were obtained
in higher enantioselectivity when phosphine oxide 2 was
used (entry 3 vs 4); thus with 2 a remarkable level of enan-
tioselectivity was reached (87% ee, entry 4,) The same high
enantioselectivity was observed in the reaction with an
electron-rich aldehyde (85% ee, entry 5), while the combi-
nation of thioesters 9b with electron-poor aldehydes gave
β-hydroxy thioesters in higher yield and diastereoselection,
but lower enantiocontrol (entry 6). This method was fur-
ther successfully extended to less reactive thioesters, such
as S-benzyl 2-phenylethanethioate (11). In this case, the
formation of the corresponding β-hydroxy thioesters 12
could be achieved in modest diastereo- and enantioselec-
tivity and in low yields. No product was observed instead
when S-phenyl 3,3-dimethylbutanethioate (13) was used.
Therefore, the reaction was not further studied in detail
groups signals in the H NMR spectrum of the crude mix-
ture. The 14-syn and 14-anti compounds were then sepa-
rated by chromatographic purification, and the absolute
configuration was determined to be 2R,3R for the major syn
enantiomer and 2R,3S for the major anti enantiomer by
comparison of the optical rotation values with those re-
ported in literature.19 The configuration of the other com-
pounds was assigned by analogy.
OH
O
mCPBA, MeOH
OH
O
OH
O
(R)
(
R)
Ph
SPh CH2Cl2, 24 h Ph (R)
OMe Ph (S)
OMe
Ph
Ph
Ph
8
a
6
6:34 dr
14-syn (62:38)
14-anti (62:38)
2
6
7% ee major
0% ee minor
24% ee
59% ee
Scheme 4 Determination of relative and absolute configuration of β-
hydroxy thioester 8
After the absolute configuration was determined, sim-
ple computational calculations were performed in order to
elucidate the origin of stereoselectivity. The reaction be-
tween thioester 5 and benzaldehyde in the presence of tet-
rachlorosilane promoted by catalyst 2 was computationally
studied. On the basis of steric considerations, adduct I,
formed upon coordination of thioester 5 with the chlorosi-
lane species, will adopt a ‘pinwheel’ conformation to mini-
(Scheme 3).
20
mize the repulsion between bulky peripheral groups.
SiCl4 (3 equiv)
cat. (10 mol%)
i-Pr2NEt (10 equiv)
OH
O
OH
O
O
O
Ph
Ph
S
Ph
Ph
S
Ph
S
Ph
Ph
H
CH2Cl2, 0 °C, 24 h
Ph
Ph
12-anti
1
1
12-syn
(
R)-BINAPO
5%, 64:36 syn/anti
7% ee syn (2R,3R), 18% anti (2R,3S)
1
(S)-TetraMe-BITIOPO
29%, 59:41 syn/anti
9% ee syn (2S,3S), 30% anti (2S,3R)
6
5
SiCl4 (3 equiv)
cat. (10 mol%)
O
O
i-Pr2NEt (10 equiv)
no reaction
SPh
Ph
H
CH2Cl2, 0 °C, 24 h
1
3
Scheme 3 Aldol condensation of S-benzyl thioester
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Synthesis
S. Rossi et al.
Paper
base
SiCl4(O=PR2)2
O
O
H
SiCl4(O=PR2)2
+ i-Pr2NEt
SiCl4(O=PR2)2
Ph
Ph
S
PhS
O
S
H
Ph
.
Ph
– i-Pr2NEt HCl
Ph
I
pinwheel conformation
SiCl3(O=PR2)2
SiCl3
O
O
Ph
Ph
S
S
Ph
Ph
(
R2P=O)2 = phosphine oxide
II'
II
Scheme 5 Formation of the O-silyl ketene thioacelal derived from compound 5
Deprotonation with a bulky base such as i-Pr NEt will af-
Cl
2
OH
O
LB
LB
ford the O-silyl ketene thioacetal II. In agreement with ex-
perimental observations, DFT calculations at B3LYP-631g
level of theory confirmed that (E)-trichlorosilyl thioacetal
II′ (according to CIP rules) was more stable by 2.48 kcal/mol
than the corresponding Z-isomer (Scheme 5).
Ph Ph
O
Si
Cl
(
S)
O
Ph (S)
SPh
H
H
Ph
PhS
TS-1
syn (2S,3S)
From ketene thioacetal II, the formation of the aldol
product is expected to occur via a Zimmerman–Traxler cat-
ionic chair-like transition structure where the aldehyde is
coordinated – and, thus, activated – by the positively
charged silicon atom (Scheme 6). The two transition states
Cl
OH
O
Ph
LB
21
O
Si
Cl
(R)
O
LB
Ph (R)
SPh
H
Ph
SPh
Ph
H
TS-2
syn (2R,3R)
(TSs) responsible of the formation of syn-β-hydroxy thio-
esters were located and depicted in Scheme 6. Computa-
tionally, a conformational analysis with Monte Carlo tech-
nique was performed using MMFFs as force field with Mac-
LB
=
P=O
P=O
= (S)-TetraMe-BITIOPO
LB
22
romodel Schrodinger suite package on a model of the TSs,
obtained by constraining the two reacting atoms (the alde-
hyde electrophilic carbon and the O-silyl thioketene acetal
nucleophilic α-carbon) at about 2.3 Å distance. In this way,
the best arrangement for the different substituents around
a model of the reaction moiety was obtained.
Scheme 6 Transition states responsible for the syn-stereoselection
ketene thioacetal that would be responsible for the favor-
able attack of the thioacetal onto the Si face of the aldehyde
(Figure 2).
Subsequently, the two structures leading to the forma-
tion of the two syn products, were fully optimized to the
In conclusion, a direct, organocatalytic addition of read-
ily available thioesters to aldehydes catalyzed by a chiral
cationic hypervalent silicon species has been developed.
The reaction of S-phenyl α-arylthioesters with aromatic al-
dehydes in the presence of a catalytically amount of a chiral
phosphine oxide and a stoichiometric amount of tetrachlo-
rosilane led to the formation of the corresponding β-hy-
droxy thioesters in modest yields (up to 70%), good syn/anti
ratio (up to 82:18), and in up to 87% enantiomeric excess.
Further experiments are ongoing in our group to extend the
applicability of this method, as well as to improve the
chemical efficiency of this transformation.
relative genuine TSs with PM6 semiempirical methods
3
(
both with only one imaginary frequency).2 The calcula-
tions, performed using (S)-TetraMe-BITIOPO as catalyst,
showed that TS-1, responsible of the formation of syn-
(2S,3S)-diastereoisomer, was more stable by 0.40 kcal/mol
than TS-2. A possible explanation of these slight differences
in energy could be ascribed to the steric repulsions, ob-
served in TS-2 between diphenylphosphinoyl group of the
phosphine oxide 2 and the thiophenyl group of the O-silyl
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Figure 2 Calculated transition state geometries (hydrogens are omitted for clarity)
All reactions were carried out in oven-dried glassware with magnetic
stirring under a nitrogen atmosphere, unless otherwise stated. Anhy-
drous solvents were purchased and stored under nitrogen over mo-
lecular sieves (bottles with crown caps). Reactions were monitored by
analytical TLC using silica gel 60 F254 precoated glass plates (0.25
mm thickness) and visualized using UV light or with phosphomolyb-
S-Phenyl 2-(4-Fluorophenyl)ethanethioate (9a)
2-(4-Fluorophenyl)acetic acid (385.3 mg, 2.5 mmol, 1 equiv), thio-
phenol (303.0 mg, 2.75 mmol, 1.1 equiv), DCC (515.8 mg, 2.5 mmol, 1
equiv), and anhydrous THF (5 mL) were used. After workup, the prod-
uct was purified by flash chromatography on silica gel with hexane–
EtOAc (96:4) as eluent; yield: 603.4 mg (98%); white solid; mp 35 °C;
Rf = 0.35 (hexane–EtOAc, 9:1).
1
dic acid. H NMR spectra were recorded on spectrometers operating
1
at 300 MHz (Bruker Fourier 300 or AMX 300). The H NMR chemical
1
H NMR (300 MHz, CDCl ): δ = 7.39 (s, 5 H), 7.28 (t, J = 9.0 Hz, 2 H),
3
shifts are reported in ppm (δ) with the solvent reference relative to
7.06 (t, J = 9.0 Hz, 2 H), 3.89 (s, 2 H).
13
TMS as the internal standard (CDCl , δ = 7.26). C NMR spectra were
3
13
C NMR (75 MHz, CDCl ): δ = 195.2, 162.4 (d, J = 246.3 Hz), 134.5,
recorded on 300 MHz spectrometers (Bruker Fourier 300 or AMX
3
13
131.4, 131.3, 129.6, 129.3, 129.2, 127.7, 115.8, 115.5, 49.6.
3
00) operating at 75 MHz, with complete proton decoupling. C NMR
19
chemical shifts are reported in ppm (δ) relative to TMS with the re-
F NMR (282 MHz, CDCl ): δ = –115.35.
3
spective solvent resonance as the internal standard (CDCl , δ = 77.0).
MS (ESI+): m/z = 247.2 [M + H]+.
3
19
F NMR spectra were recorded on 300 MHz spectrometers (Bruker
19
AMX 300) operating at 282 MHz. F NMR chemical shifts are report-
S-Phenyl 2-(4-Isobutylphenyl)ethanethioate (9b)
ed in ppm (δ) relative to CF Cl. Optical rotations were obtained on a
3
2-(4-Isobutylphenyl)acetic acid (480.6 mg, 2.5 mmol, 1 equiv), thio-
polarimeter at 589 nm using a 5 mL cell with a length of 1 dm. HPLC
for ee determinations was performed under the conditions reported
below using Agilent 1100 or 1200 series. All melting points are uncor-
rected and were obtained using an Electrothermal IA9100 digital
melting point apparatus.
phenol (303.0 mg, 2.75 mmol, 1.1 equiv), DCC (515.8 mg, 2.5 mmol, 1
equiv), and anhydrous THF (5 mL) were used. After workup, the prod-
uct was purified by flash chromatography on silica gel with hexane–
EtOAc (98:2) as eluent; yield: 604.4 mg (85%); pale-yellow solid; mp
3
0 °C; R = 0.51 (hexane–EtOAc, 9:1).
f
1H NMR (300 MHz, CDCl
H), 7.13 (d, J = 7.9 Hz, 2 H), 3.89 (s, 2 H), 2.48 (d, J = 7.2 Hz, 2 H), 1.94–
): δ = 7.30–7.38 (m, 5 H), 7.24 (d, J = 7.9 Hz, 2
Thioester Condensation; General Procedure
3
The acid (1 equiv, 2.5 mmol) and thiophenol (1.1 equiv, 2.75 mmol)
were dissolved in anhydrous THF (5 mL) and cooled to 0 °C; then N,N′-
dicyclohexylcarbodiimide (DCC; 1 equiv, 2.5 mmol) was added. The
reaction was monitored by TLC (eluent: using hexane–EtOAc, 95:5)
and after 24 h, the crude mixture was filtered and the solvent was re-
moved under reduced pressure. The crude product was purified by
flash chromatography.
1.80 (m, 1 H), 0.91 (d, J = 6.6 Hz, 6 H).
13
C NMR (75 MHz, CDCl ): δ = 195.6, 141.1, 134.5, 130.6, 129.4, 129.5,
3
129.4, 129.2, 128.0, 49.8, 45.2, 30.3, 22.5.
+
+
MS (ESI+): m/z = 285.2 [M + H] and 307.0 [M + Na] .
Enantioselective Direct Aldol Reaction between Thioesters and Al-
dehydes; General Procedure
To a stirred solution of catalyst 1 or 2 (0.1 equiv) in CH Cl2 (2 mL)
2
were added the thioester (0.6 mmol, 2 equiv) and i-Pr NEt (6 mmol,
2
10 equiv). The mixture was then cooled to 0 °C and freshly distilled
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Synthesis
S. Rossi et al.
Paper
SiCl4 (0.9 mmol, 3 equiv) was added dropwise via syringe. After 15
min, freshly purified aldehyde (0.3 mmol, 1 equiv) was added. The
mixture was stirred for 24 h, then quenched by the addition of sat. aq
NaHCO3 (3 mL). The mixture was allowed to warm up to r.t., stirred
S-Phenyl 3-Hydroxy-2,3-diphenylpropanethioate (8a)
Thioester 5 (137 mg, 0.6 mmol, 2 equiv), catalyst 1 (18 mg, 0.03
mmol, 0.1 equiv), benzaldehyde (32 mg, 0.3 mmol, 1 equiv), i-Pr NEt
2
(775 mg, 6 mmol, 10 equiv), SiCl4
(153 mg, 0.9 mmol, 3 equiv), and
for 30 min, and partitioned between H O (5 mL) and EtOAc (15 mL).
2
anhydrous CH Cl (2 mL) were used. After workup, the product was
2
2
The organic layer was separated and the aqueous layer was extracted
with EtOAc (15 mL). The combined organic layers were washed with
purified by flash chromatography on silica gel with hexane–EtOAc
9:1) as eluent. This purification furnished a mixture of syn- and anti-
(
sat. aq NH Cl (10 mL) and brine (10 mL), dried (Na SO ), filtered, and
4
2
4
diastereoisomers; yield: 70.2 mg (70%); white solid; mp 107–109 °C;
Rf = 0.14 (hexane–EtOAc, 9:1, stained with phosphomolybdic acid).
concentrated under vacuum at r.t. The crude product was purified by
column chromatography with 9:1 hexane–EtOAc mixture as eluent
HPLC: Chiralcel OD-H; eluent: hexane–i-PrOH (93:7); flux: 0.8
mL/min; detection: 230 nm; (2S,3R)-anti-enantiomer, tR = 19.7 min;
(see below) to afford the pure aldol adducts. Yields and ee for each re-
action are indicated in Tables 1–3. The syn/anti ratio was determined
2
S
,
3
S
)
-
s
y
n
-
e
n
a
n
t
i
o
m
e
r
,
t
=
2
2
.
8
m
i
n
;
(
2
R
,
3
S
)
-
a
n
t
i
-
e
n
a
n
t
i
o
m
e
r
,
t
1
R
R
by H NMR spectroscopy of the crude product; the enantiomeric ex-
2
7.1 min; (2R,3R)-syn-enantiomer, t = 29.8 min.
R
cess was determined by HPLC on a chiral stationary phase.
1
H NMR (300 MHz, CDCl ): δ = 7.44–7.08 (m, 15 H), 5.38 (d, J = 8.0 Hz,
3
1
H, syn), 5.31 (d, J = 9.0 Hz, 1 H, anti), 4.21 (d, J = 9.0 Hz, 1 H, anti),
S-(Pyridin-2-yl) 3-Hydroxy-2,3-diphenylpropanethioate (7a)
4.16 (d, J = 8.0 Hz, 1 H, syn), 3.00 (br, 1 H, syn) 2.48 (br, 1 H, syn).
Thioester 4 (137 mg, 0.6 mmol, 2 equiv), catalyst 2 (19 mg, 0.03
mmol, 0.1 equiv), benzaldehyde (32 mg, 0.3 mmol, 1 equiv), i-Pr NEt
13
C NMR (75 MHz, CDCl ): δ = 199.1 (anti), 197.7 (syn), 140.6, 140.5,
3
2
1
1
34.5, 134.4, 134.3, 134.2, 129.6, 129.4, 129.2, 129.1, 128.9, 128.8,
28.7, 128.3, 128.1, 127.9, 126.8, 126.6, 75.4, 67.7.
(775 mg, 6 mmol, 10 equiv), SiCl4 (153 mg, 0.9 mmol, 3 equiv), and
anhydrous CH Cl (2 mL) were used. After workup, the product was
2
2
purified by flash chromatography on silica gel with hexane–EtOAc
7:3) as eluent. This purification furnished only one diastereoisomer;
MS (ESI+): m/z = 357.2 [M + Na]+.
(
yield: 14.1 mg (14%); yellow solid; mp 38–40 °C; R = 0.48 (hexane–
EtOAc, 6:4, stained with phosphomolybdic acid).
f
S-Phenyl 3-Hydroxy-3-(4-methoxyphenyl)-2-phenylpropanethio-
ate (8b)
HPLC: Chiralcel OD-H; eluent: hexane–i-PrOH (85:15); flux: 0.8
mL/min; detection: 230 nm; t = 24.0 min, t = 30.6 min.
Thioester 5 (137 mg, 0.6 mmol, 2 equiv), catalyst 2 (19 mg, 0.03
mmol, 0.1 equiv), 4-methoxybenzaldehyde (41 mg, 0.3 mmol, 1
R
R
1
equiv), i-Pr NEt (775 mg, 6 mmol, 10 equiv), SiCl (153 mg, 0.9 mmol,
H NMR (300 MHz, CDCl ): δ = 8.59 (d, J = 4.4 Hz, 1 H) 7.72 (t, J = 7.7
2
4
3
3
equiv), and anhydrous CH Cl (2 mL) were used. After workup, the
2 2
Hz, 1 H), 7.60 (d, J = 7.7 Hz, 1 H), 7.35–7.08 (m, 11 H), 5.31 (d, J = 9.3
Hz, 1 H), 4.20 (d, J = 9.3 Hz, 1 H).
product was purified by flash chromatography on silica gel with hex-
ane–EtOAc (9:1) as eluent. This purification furnished a mixture of
syn- and anti-diastereoisomers; yield: 75.5 mg (69%); white solid, mp
13
C NMR (75 MHz, CDCl ): δ = 197.9, 151.2, 150.3, 140.5, 137.5, 137.3,
3
1
34.2, 130.1, 129.0, 128.7, 128.1, 127.9, 126.6, 123.7, 77.2, 68.4.
3
6–39 °C; R = 0.07 (hexane–EtOAc, 9:1, stained with phosphomolyb-
f
MS (ESI+): m/z = 358.2 [M + Na]+.
dic acid).
HPLC: Chiralcel AS-3; eluent: hexane–i-PrOH (8:2); flux: 0.8 mL/min;
detection: 230 nm; anti-enantiomer, tR = 12.8 min; syn-enantiomer,
S-(Pyridin-2-yl) 3-(4-Chlorophenyl)-3-hydroxy-2-phenylpropan-
ethioate (7b)
tR = 14.9 min; anti-enantiomer, tR = 17.8 min; syn-enantiomer, tR
=
Thioester 4 (137 mg, 0.6 mmol, 2 equiv), catalyst 2 (19 mg, 0.03
mmol, 0.1 equiv), 4-chlorobenzaldehyde (42 mg, 0.3 mmol, 1 equiv),
i-Pr NEt (775 mg, 6 mmol, 10 equiv), SiCl (153 mg, 0.9 mmol, 3
30.9 min.
1
H NMR (300 MHz, CDCl ): δ = 7.34–7.11 (m, 10 H), 7.26 (d, J = 7.5 Hz,
3
2
4
2
H, syn), 7.15 (d, J = 7.5 Hz, 2 H, anti), 6.87 (d, J = 7.5 Hz, 2 H, syn),
equiv), and anhydrous CH Cl (2 mL) were used. After workup, the
2
2
6.71 (d, J = 7.5 Hz, 2 H, anti), 5.29 (d, J = 8.0 Hz, 1 H, syn), 5.23 (d,
product was purified by flash chromatography on silica gel with hex-
ane–EtOAc (7:3) as eluent. This purification furnished a mixture of
syn- and anti-diastereoisomers; yield: 16.7 mg (15%); pale-yellow sol-
J = 8.0 Hz, 1 H, anti), 4.15 (d, J = 9.0 Hz, 1 H, anti), 4.12 (d, J = 9.0 Hz, 1
H, syn), 3.81 (s, 3 H, syn), 3.73 (s, 3 H, anti).
13
C NMR (75 MHz, CDCl ): δ = 197.6, 159.4, 134.5, 134.4, 132.7, 129.6,
id; mp 40–43 °C; R = 0.21 (hexane–EtOAc, 6:4, stained with phospho-
3
f
1
7
29.4, 129.2, 128.8, 128.7, 128.3, 128.1, 127.8, 127.2, 113.7, 113.5,
5.1, 67.8, 55.3.
molybdic acid).
HPLC: The two diastereoisomers were separated on Supelco Ascentis
Si column (3u) with hexane–i-PrOH (95:5) (tR = 8.87 min, for minor
diasteroisomer, tR = 9.07 min, for major diastereoisomer). The enan-
tiomeric excess of each separated diastereoisomer was determined on
Chiralpak AD column; eluent: hexane–i-PrOH (7:3); flux: 0.8 mL/min;
detection: 220 nm; t = 13.3 min, t = 18.2 min.
MS (ESI+): m/z = 387.2 [M + Na]+.
S-Phenyl 3-Hydroxy-3-(4-chlorophenyl)-2-phenylpropanethioate
(8c)
R
R
Thioester 5 (137 mg, 0.6 mmol, 2 equiv), catalyst 1 (18 mg, 0.03
1
mmol, 0.1 equiv), 4-chlorobenzaldehyde (42 mg, 0.3 mmol, 1 equiv),
H NMR (300 MHz, CDCl ): δ = 8.59 (d, J = 4.4 Hz, 1 H, major), 8.45 (d,
3
i-Pr NEt (775 mg, 6 mmol, 10 equiv), SiCl (153 mg, 0.9 mmol, 3
J = 3.1 Hz, 1 H, minor), 7.70 (t, J = 7.7 Hz, 1 H, minor), 7.59 (t, J = 6.8
Hz, 1 H, major), 7.31–6.94 (m, 11 H), 5.29 (d, J = 6.3 Hz, 1 H, major),
2
4
equiv), and anhydrous CH Cl (2 mL) were used. After workup, the
2
2
product was purified by flash chromatography on silica gel with hex-
ane–EtOAc (9:1) as eluent. This purification furnished a mixture of
syn- and anti-diastereoisomers; yield: 73.1 mg (66%); white solid; mp
5
.28 (d, J = 3.1 Hz, 1 H, minor), 4.13 (d, J = 5.2 Hz, 1 H, minor), 4.10 (d,
J = 3.0 Hz, 1 H, major).
13
C NMR (75 MHz, CDCl ): δ = 197.9, 150.3, 149.5, 139.0, 137.5, 133.9,
3
1
34–136 °C; R = 0.10 (hexane–EtOAc, 9:1, stained with phosphomo-
f
1
1
33.6, 130.2, 129.0, 128.9, 128.7, 128.3, 128.6, 128.0, 123.8, 121.2,
19.8, 76.0, 68.3.
lybdic acid).
MS (ESI+): m/z = 392.1 [M + Na]+.
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Synthesis
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Paper
HPLC: Chiralcel AS-3; eluent: hexane–i-PrOH (8:2); flux: 0.8 mL/min;
detection: 230 nm; anti-enantiomer, tR = 9.1 min; anti-enantiomer,
MS (ESI+): m/z = 371.1 [M + Na]+.
t = 9.8 min; syn-enantiomer, t = 10.4 min; syn-enantiomer, t = 16.4
min.
R
R
R
S-Phenyl 3-Hydroxy-3-(mesityl)-2-phenylpropanethioate (8f)
Thioester 5 (91 mg, 0.4 mmol, 2 equiv), catalyst 2 (12 mg, 0.02 mmol,
1
H NMR (300 MHz, CDCl ): δ = 7.39–6.99 (m, 14 H), 5.36 (d, J = 7.0 Hz,
0.1 equiv), mesitaldehyde (30 mg, 0.2 mmol, 1 equiv), i-Pr NEt (517
3
2
1
H, syn), 5.27 (d, J = 9.1 Hz, 1 H, anti), 4.12 (d, J = 9.0 Hz, 1 H, anti),
mg, 4 mmol, 10 equiv), SiCl (102 mg, 0.6 mmol, 3 equiv), and anhy-
4
4.10 (d, J = 7.0 Hz, 1 H, syn), 3.07 (d, J = 3.8 Hz, 1 H, anti), 2.57 (d,
drous CH Cl (1.3 mL) were used. After workup, the product was puri-
2
2
J = 2.3 Hz, 1 H, syn).
fied by flash chromatography on silica gel with hexane–EtOAc (9:1)
1
3
as eluent. This purification furnished only the syn-diastereoisomer;
C NMR (75 MHz, CDCl ): δ = 199.1 (anti), 197.8 (syn), 139.2, 134.5,
3
yield: 44.0 mg (58%); pale-yellow solid; mp 57–60 °C; R = 0.16 (hex-
1
1
34.4, 133.6, 129.7, 129.5, 129.3, 128.9, 128.8, 128.5, 128.3, 128.1,
28.0, 127.3, 76.1 (anti), 74.6 (syn), 67.7 (anti), 67.4 (syn).
f
ane–EtOAc, 9:1, stained with phosphomolybdic acid).
MS (ESI+): m/z = 391.1 [M + Na]+.
HPLC: Phenomenex Lux-3u cellulose-1 equipped with security guard
filter; eluent: hexane–i-PrOH (95:5); flux: 0.8 mL/min; detection:
2
10 nm; syn-minor enantiomer, t = 4.51 min; syn-major enantiomer,
R
S-Phenyl 3-Hydroxy-2-phenyl-3-(2-methylphenyl)propanethioate
tR = 0 6.1 min.
(
8d)
Thioester 5 (91 mg, 0.4 mmol, 2 equiv), catalyst 2 (12 mg, 0.02 mmol,
.1 equiv), 2-methylbenzaldehyde (24 mg, 0.2 mmol, 1 equiv), i-
Pr NEt (517 mg, 4 mmol, 10 equiv), SiCl (102 mg, 0.6 mmol, 3 equiv),
1
H NMR (300 MHz, CDCl ): δ = 7.59 (d, J = 7.1 Hz, 2 H), 7.50–7.21 (m, 6
3
H), 7.04 (d, J = 6.9 Hz, 2 H), 6.92 (s, 2 H), 5.72 (d, J = 9.3 Hz, 1 H), 4.68
0
(d, J = 9.4 Hz, 1 H), 2.55 (s, 6 H), 2.33 (s, 3 H), 1.88 (br, 1 H).
2
4
13
and anhydrous CH Cl (1.3 mL) were used. After workup, the product
C NMR (75 MHz, CDCl ): δ = 196.3, 137.5, 137.1, 135.6, 134.3, 132.8,
2
2
3
was purified by flash chromatography on silica gel with hexane–EtO-
Ac (9:1) as eluent. This purification furnished a mixture of syn- and
anti-diastereoisomers; yield: 24.7 mg (35%); pale-yellow solid; mp
130.3, 129.4, 129.1, 129.0, 128.2, 127.4, 73.0, 64.5, 20.9.
MS (ESI+): m/z = 399.1 [M + Na]+.
3
0–32 °C; R = 0.14 (hexane–EtOAc, 9:1, stained with phosphomolyb-
f
S-Phenyl 3-(2,6-Dimethoxyphenyl)-3-hydroxy-2-phenylpropane-
thioate (8g)
dic acid).
HPLC: Chiralcel OD-H; eluent: hexane–i-PrOH (9:1); flux: 0.8
mL/min; detection: 254 nm; syn-enantiomer, tR = 10.6 min; anti-en-
antiomer, tR = 12.3; syn-enantiomer; tR = 13.4 min; anti-enantiomer,
tR = 14.4 min.
Thioester 5 (91 mg, 0.4 mmol, 2 equiv), catalyst 2 (12 mg, 0.02 mmol,
0.1 equiv), 2,6-dimethoxybenzaldehyde (33 mg, 0.2 mmol, 1 equiv), i-
Pr NEt (517 mg, 4 mmol, 10 equiv), SiCl (102 mg, 0.6 mmol, 3 equiv),
2
4
and anhydrous CH Cl (1.3 mL) were used. After workup, the product
2
2
1
H NMR (300 MHz, CDCl ): δ = 7.45–7.31 (m, 8 H), 7.31–7.00 (m, 7 H),
was purified by flash chromatography on silica gel with hexane–
EtOAc (9:1) as eluent. This purification furnished a mixture of syn-
and anti-diastereoisomers; yield: 48.4 mg (61%); pale-yellow solid;
3
5.62 (d, J = 6.8 Hz, 1 H, anti), 5.55 (d, J = 8.8 Hz, 1 H, syn), 4.32 (d,
J = 8.8 Hz, 1 H, syn), 4.26 (d, J = 6.8 Hz, 2 H, anti), 2.47 (s, 3 H).
1
3
mp 77–80 °C; R = 0.10 (hexane–EtOAc, 9:1, stained with phosphomo-
lybdic acid).
C NMR (75 MHz, CDCl ): δ = 197.7, 138.4, 135.0, 134.3, 130.4, 129.6,
f
3
1
29.1, 128.7, 128.2, 127.9, 127.2, 126.9, 126.1, 71.6, 65.9, 19.4.
MS (ESI+): m/z = 371.1 [M + Na]+.
HPLC: Phenomenex Lux-3u cellulose-2; eluent: hexane–EtOH
(65:35); flux: 0.8 mL/min; detection: 230 nm; syn-enantiomer, tR
=
8
.3 min; syn-enantiomer, tR = 10.1 min; anti-enantiomer, tR = 10.6
S-Phenyl 3-Hydroxy-2-phenyl-3-(3-methylphenyl)propanethioate
min; anti-enantiomer, t = 11.1 min.
R
(
8e)
Thioester 5 (91 mg, 0.4 mmol, 2 equiv), catalyst 2 (12 mg, 0.02 mmol,
.1 equiv), 3-methylbenzaldehyde (24 mg, 0.2 mmol, 1 equiv), i-
Pr NEt (517 mg, 4 mmol, 10 equiv), SiCl (102 mg, 0.6 mmol, 3 equiv),
1
H NMR (300 MHz, CDCl ): δ = 7.52 (d, J = 7.7 Hz, 2 H), 7.45–7.19 (m, 7
3
H), 7.10 (d, J = 7.4 Hz, 2 H), 6.62 (dd, J = 8.4, 2.6 Hz, 1 H), 5.90 (d, J = 7.9
Hz, 1 H), 4.56 (d, J = 8.2 Hz, 1 H), 3.83 (d, J = 2.4 Hz, 1 H), 2.07 (d,
J = 2.3 Hz, 1 H).
0
2
4
and anhydrous CH Cl (1.3 mL) were used. After workup, the product
2
2
13
was purified by flash chromatography on silica gel with hexane–
EtOAc (9:1) as eluent. This purification furnished a mixture of syn-
and anti-diastereoisomers; yield: 56.0 mg (80%); pale-yellow solid;
C NMR (75 MHz, CDCl ): δ =195.2, 158.2, 136.0, 134.4, 129.6, 129.4,
3
129.1, 128.9, 128.4, 127.6, 116.8, 104.4, 103.9, 69.3, 65.5, 55.9.
MS (ESI+): m/z = 417.1 [M + Na]+.
mp 33–35 °C; R = 0.13 (hexane–EtOAc, 9:1, stained with phosphomo-
f
lybdic acid).
S-Phenyl 3-Hydroxy-3-(4-fluorophenyl)-2-phenylpropanethioate
HPLC: Phenomenex Lux-3u cellulose-2; eluent: hexane–i-PrOH
(
8h)
Thioester 5 (91 mg, 0.4 mmol, 2 equiv), catalyst 2 (12 mg, 0.02 mmol,
.1 equiv), 4-fluorobenzaldehyde (25 mg, 0.2 mmol, 1 equiv), i-Pr NEt
(95:5); flux: 0.8 mL/min; detection: 210 nm; syn-enantiomer, t = 3.7
R
min; syn-enantiomer, tR = 5.5 min; anti-enantiomer, tR = 7.1 min;
anti-enantiomer, t = 8.5 min.
0
2
R
(517 mg, 4 mmol, 10 equiv), SiCl4 (102 mg, 0.6 mmol, 3 equiv), and
1
H NMR (300 MHz, CDCl ): δ = 7.50–6.88 (m, 15 H, syn + anti), 5.34 (d,
anhydrous CH Cl (1.3 mL) were used. After workup, the product was
3
2
2
J = 7.6 Hz, 1 H, syn), 5.26 (d, J = 9.0 Hz, 1 H, anti), 4.21 (d, J = 9.0 Hz, 1
H, syn), 4.16 (d, J = 7.6 Hz, 1 H, anti), 2.38 (s, 3 H, syn), 2.27 (s, 3 H,
anti).
purified by flash chromatography on silica gel with hexane–EtOAc
(9:1) as eluent. This purification furnished a mixture of syn- and anti-
diastereoisomers; yield: 41.5 mg (59%); white solid; mp 92–95 °C;
Rf = 0.11 (hexane–EtOAc, 9:1, stained with phosphomolybdic acid).
13
C NMR (75 MHz, CDCl ): δ = 199.0 (anti), 197.5 (syn), 140.5, 140.4,
3
1
1
2
37.9, 137.7, 134.5, 134.4, 134.2, 129.5, 129.4, 129.2, 129.1, 128.9,
28.8, 128.6, 128.2, 127.9, 127.8, 127.5, 127.2, 123.9, 123.7, 75.5, 67.7,
1.4.
HPLC: Chiralcel OD-H; eluent: hexane–i-PrOH (9:1); flux: 0.8
mL/min; detection: 210 nm; anti-enantiomer, tR = 14.0 min; syn-en-
antiomer, t = 16.5 min; anti-enantiomer, t = 17.9 min; syn-enantio-
R
R
mer, t = 21.3 min.
R
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1
H NMR (300 MHz, CDCl ): δ = 7.48–7.15 (m, 10 H), 7.15–7.03 (m, 2
S-Phenyl 3-Hydroxy-3-(naphthalen-1-yl)-2-phenylpropanethio-
3
H), 6.89 (t, J = 8.6 Hz, 1 H), 5.37 (d, J = 7.3 Hz, 1 H, syn), 5.29 (d, J = 9.2
Hz, 1 H, anti), 4.15 (d, J = 9.2 Hz, 1 H, anti), 4.11 (d, J = 7.3 Hz, 1 H,
syn), 3.01 (br, 1 H, anti), 2.52 (br, 1 H, syn).
ate (8m)
Thioester 5 (91 mg, 0.4 mmol, 2 equiv), catalyst 2 (12 mg, 0.02 mmol,
0.1 equiv), 1-naphthylaldehyde (0.2 mmol, 1 equiv), i-Pr NEt (517 mg,
2
13
C NMR (75 MHz, CDCl ): δ = 199.1 (anti), 197.7 (syn), 162.7 (d,
4 mmol, 10 equiv), SiCl
(102 mg, 0.6 mmol, 3 equiv), and anhydrous
4
3
J = 228 Hz), 136.5, 136.3, 134.5, 134.4, 133.9, 129.7, 129.4, 129.2,
CH Cl (1.3 mL) were used. After workup, the product was purified by
2
2
1
1
28.9, 128.8, 128.6, 128.5, 128.4, 128.3, 128.2, 128.0, 127.0, 115.3,
15.1, 115.0, 114.8, 76.1, 74.7, 67.9, 67.7.
flash chromatography on silica gel with hexane–EtOAc (9:1) as elu-
ent. This purification furnished a mixture of syn- and anti-diastereo-
isomers; yield: 33.6 mg (44%); pale-yellow solid; mp 40–42 °C;
Rf = 0.11 (hexane–EtOAc, 9:1, stained with phosphomolybdic acid).
19
F NMR (282 MHz, CDCl ): δ = –114.5 (syn), –114.7 (anti).
3
MS (ESI+): m/z = 375.0 [M + Na]+.
HPLC: Phenomenex Lux-3u cellulose-1 equipped with securityguard
filter; eluent: hexane–EtOH (98:2); flux: 0.8 mL/min; detection: 210
nm; syn-enantiomer, tR = 18.1 min; syn-enantiomer, tR = 23.3 min;
anti-enantiomer, t = 27.1 min; anti-enantiomer, t = 34.8 min.
S-Phenyl 3-Hydroxy-2-phenyl-3-[4-(trifluoromethyl)phenyl]pro-
panethioate (8i)
R
R
Thioester 5 (91 mg, 0.4 mmol, 2 equiv), catalyst 2 (12 mg, 0.02 mmol,
1
H NMR (300 MHz, CDCl ): δ = 8.24 (d, J = 8.4 Hz, 1 H, syn), 8.18 (m, 1
3
0.1 equiv), 4-(trifluoromethyl)benzaldehyde (35 mg, 0.2 mmol, 1
H, anti), 7.94 (d, J = 7.7 Hz, 1 H, syn), 7.83–7.80 (m, 1 H, syn + anti),
.76 (d, J = 7.7 Hz, 1 H), 7.68–7.20 (m, 12 H), 7.16–7.10 (m, 3 H), 6.23
d, J = 5.6 Hz, 1 H, syn), 5.98 (d, J = 8.3 Hz, 1 H, anti), 4.68 (d, J = 8.3 Hz,
H, anti), 4.51 (d, J = 5.6 Hz, 1 H, syn), 3.31 (br, 1 H, anti), 2.91 (br, 1 H,
syn).
equiv), i-Pr NEt (517 mg, 4 mmol, 10 equiv), SiCl (102 mg, 0.6 mmol,
3
product was purified by flash chromatography on silica gel with hex-
ane–EtOAc (9:1) as eluent. This purification furnished a mixture of
syn- and anti-diastereoisomers; yield: 60.9 mg (76%); white solid; mp
2
4
7
(
1
equiv), and anhydrous CH Cl (1.3 mL) were used. After workup, the
2 2
13
C NMR (75 MHz, CDCl ): δ = 199.4, 198.6, 135.6, 134.9, 134.5, 134.4,
110–112 °C; R = 0.11 (hexane–EtOAc, 9:1, stained with phosphomo-
3
f
1
1
7
33.8, 133.6, 129.8, 129.6, 129.2, 129.1, 128.8, 128.6, 128.5, 128.4,
28.1, 127.8, 126.3, 126.0, 125.5, 125.3, 125.2, 125.0, 123.5, 122.9,
5.0, 71.7, 65.8, 65.4.
lybdic acid).
HPLC: Phenomenex Lux-3u cellulose-1 equipped with securityguard
filter; eluent: hexane–i-PrOH (95:5); flux: 0.8 mL/min; detection:
MS (ESI+): m/z = 407.1 [M + Na]+.
210 nm; anti-enantiomer, tR = 9.4 min; anti-enantiomer, tR = 12.1
min; syn-enantiomer, t = 14.8 min; syn-enantiomer, t = 27.8 min.
R
R
1
S-Phenyl 3-(Furan-2-yl)-3-hydroxy-2-phenylpropanethioate (8n)
Thioester 5 (91 mg, 0.4 mmol, 2 equiv), catalyst 2 (12 mg, 0.02 mmol,
H NMR (300 MHz, CDCl ): δ = 7.62 (d, J = 8.0 Hz, 2 H), 7.50–7.34 (m, 8
3
H), 7.22–7.13 (m, 3 H) 7.13–7.08 (m, 1 H), 5.46 (d, J = 6.8 Hz, 1 H, syn),
.36 (d, J = 9.1 Hz, 1 H, anti), 4.13 (d, J = 9.1 Hz, 1 H, anti), 4.14 (d,
J = 6.7 Hz, 1 H, syn), 3.17 (s, 1 H, anti), 2.68 (br, 1 H, syn).
5
0.1 equiv), furan-2-carbaldehyde (19 mg, 0.2 mmol, 1 equiv), i-Pr
(517 mg, 4 mmol, 10 equiv), SiCl (102 mg, 0.6 mmol, 3 equiv), and
anhydrous CH Cl (1.3 mL) were used. After workup, the product was
purified by flash chromatography on silica gel with hexane–EtOAc
9:1) as eluent. This purification furnished a mixture of syn- and anti-
2
NEt
4
13
2
2
C NMR (75 MHz, CDCl ): δ = 199.1 (anti), 197.9 (syn), 144.4, 134.5,
3
1
1
34.4, 134.1, 133.4, 130.4, 129.7, 129.5, 129.3, 128.9, 128.5, 128.2,
27.2, 126.9, 125.9, 125.0, 124 (q, J = 270 Hz), 76.1, 74.6, 67.5, 67.2.
(
diastereoisomers; yield: 49.1 mg (76%); pale-yellow solid; mp 77–79
19
F NMR (282 MHz, CDCl ): δ = –62.96 (syn), –62.98 (anti).
3
°C; R = 0.10 (hexane–EtOAc, 9:1, stained with phosphomolybdic
f
MS (ESI+): m/z = 425.1 [M + Na]+.
acid).
HPLC: Phenomenex Lux-3u cellulose-1 equipped with securityguard
filter; eluent: hexane–i-PrOH (95:5); flux: 0.8 mL/min; detection:
210 nm; anti-enantiomer, t = 7.0 min; syn-enantiomer, t = 8.7 min;
S-Phenyl 3-Hydroxy-3-(2-nitrophenyl)-2-phenylpropanethioate
(
8l)
Thioester 5 (91 mg, 0.4 mmol, 2 equiv), catalyst 2 (12 mg, 0.02 mmol,
.1 equiv), 2-nitrobenzaldehyde (30 mg, 0.2 mmol, 1 equiv), i-Pr NEt
R
R
anti-enantiomer; t
= 11.3 min; syn-enantiomer, t
= 14.2 min.
R
R
0
1
2
H NMR (300 MHz, CDCl ): δ = 7.48–7.33 (m, 9 H), 7.28 (s, 2 H), 6.35
3
(517 mg, 4 mmol, 10 equiv), SiCl4 (102 mg, 0.6 mmol, 3 equiv), and
(d, J = 15.0 Hz, 2 H), 6.14 (d, J = 40.6 Hz, 2 H, overlapping signals), 5.41
(d, J = 8.0 Hz, 1 H, syn), 5.32 (d, J = 8.8 Hz, 1 H, anti), 4.53 (d, J = 9.0 Hz,
anhydrous CH Cl (1.3 mL) were used. After workup, the product was
2
2
purified by flash chromatography on silica gel with hexane–EtOAc
9:1) as eluent. This purification furnished a mixture of syn- and anti-
diastereoisomers; yield: 51.2 mg (67%); pale-yellow solid; mp 63–65
C; R = 0.11 (hexane–EtOAc, 9:1, stained with phosphomolybdic ac-
1
H, anti), 4.46 (d, J = 8.1 Hz, 1 H, syn), 3.00 (br, 1 H), 2.34 (br, 1 H).
(
13
C NMR (75 MHz, CDCl ): δ = 197.0, 153.0, 142.4, 134.4, 134.1, 129.6,
3
1
1
29.3, 129.2, 129.0, 128.8, 128.6, 128.4, 128.0, 127.2, 110.4, 110.1,
08.1, 70.2, 69.1, 64.5.
°
f
id).
MS (ESI+): m/z = 347.1 [M + Na]+.
HPLC: Chiralcel OD-H; eluent: hexane–i-PrOH (9:1); flux: 0.8
mL/min; detection: 210 nm; minor enantiomer, t = 12.7 min; major
R
S-Phenyl 2-(4-Fluorophenyl)-3-hydroxy-3-phenylpropanethioate
enantiomer, t = 15.4 min.
R
(10a)
1
H NMR (300 MHz, CDCl ): δ (syn) = 8.00 (dd, J = 6.0 Hz, 3.5 Hz, 1 H),
3
Thioester 9a (148 mg, 0.6 mmol, 2 equiv), catalyst 1 (18 mg, 0.03
7.51–7.22 (m, 10 H), 7.10–7.13 (m, 3 H), 6.06 (d, J = 3.4 Hz, 1 H), 4.55
mmol, 0.1 equiv), benzaldehyde (32 mg, 0.3 mmol, 1 equiv), i-Pr NEt
2
(d, J = 3.4 Hz, 1 H), 3.60 (br, 1 H).
(775 mg, 6 mmol, 10 equiv), SiCl4 (153 mg, 0.9 mmol, 3 equiv), and
13
C NMR (75 MHz, CDCl ): δ (syn) = 200.3, 147.4, 135.5, 134.6, 132.9,
3
anhydrous CH Cl (2 mL) were used. After workup, the product was
2
2
132.5, 130.3, 129.8, 129.3, 128.4, 128.4, 128.2, 126.9, 124.3, 69.7, 63.5.
purified by flash chromatography on silica gel with hexane–EtOAc
(9:1) as eluent. This purification furnished a mixture of syn- and anti-
diastereoisomers; yield: 46.5 mg (44%); white solid; mp 106–108 °C;
Rf = 0.13 (hexane–EtOAc, 9:1, stained with phosphomolybdic acid).
MS (ESI+): m/z = 402.1 [M + Na]+.
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1
HPLC: Phenomenex Lux-3u cellulose 4; eluent: hexane–EtOH (98:2);
flux: 0.8 mL/min; detection: 210 nm; syn-enantiomer, tR = 3.6 min;
syn-enantiomer, t = 4.6 min; anti-enantiomer, t = 5.4 min; anti-en-
H NMR (300 MHz, CDCl ): δ = 7.27–7.38 (m, 7 H), 7.28–7.18 (m, 4 H),
3
6.90 (d, J = 8.7 Hz, 2 H, syn), 6.71 (d, J = 8.7 Hz, 2 H, anti), 5.30 (d,
J = 7.8 Hz, 1 H, syn), 5.23 (d, J = 9.1 Hz, 1 H, anti), 4.12 (d, J = 9.1 Hz, 1
H, anti), 4.10 (d, J = 7.8 Hz, 1 H, syn), 3.84 (s, 3 H, syn), 2.50 (d, J = 7.8
Hz, 2H, syn), 2.40 (d, J = 7.8 Hz, 2 H, anti), 1.97–1.78 (m, 1 H), 0.94 (d,
J = 6.60 Hz, 3 H, syn + anti), 0.93 (d, J = 6.60 Hz, 3 H, syn + anti), 0.88
R
R
antiomer, t = 7.0 min.
R
1
H NMR (300 MHz, CDCl ): δ = 7.40–7.00 (m, 14 H), 5.35 (dd, J = 1.8,
3
6.7 Hz, 1 H, syn), 5.23 (dd, J = 2.3, 9.2 Hz, 1 H, anti), 4.17 (d, J = 9.2 Hz,
(d, J = 6.60 Hz, 3 H, syn + anti).
1
H, anti), 4.13 (d, J = 6.7 Hz, 1 H, syn), 2.89 (br, 1 H, anti), 2.51 (br, 1 H,
13
syn).
C NMR (75 MHz, CDCl ): δ = 197.6, 159.4, 141.8, 134.4, 132.8, 131.5,
3
1
3
129.6, 129.4, 129.1, 129.0, 128.1, 127.3, 113.7, 75.1, 67.6, 55.3, 45.1,
0.1, 22.4.
MS (ESI+): m/z = 443.2 [M + Na]+.
C NMR (75 MHz, CDCl ): δ = 198.89 (anti), 198.0 (syn), 162.7 (d,
3
3
J = 247.2 Hz), 140.4, 134.5, 134.4, 131.2, 131.1, 130.5, 129.8, 129.7,
1
7
29.2, 128.3, 128.2, 128.1, 127.3, 127.0, 126.7, 126.6, 115.8, 115.5,
5.2, 66.5.
19
F NMR (282 MHz, CDCl ): δ = –114.37 (syn), –114.49 (anti).
S-Phenyl 3-Hydroxy-2-(4-isobutylphenyl)-3-(4-chlorophenyl)pro-
3
MS (ESI+): m/z = 375.1 [M + Na]+.
panethioate (10d)
Thioester 9b (1.70 g, 0.6 mmol, 2 equiv), catalyst 2 (19 mg, 0.03
mmol, 0.1 equiv), 4-chlorobenzaldehyde (42 mg, 0.3 mmol, 1 equiv),
i-Pr NEt (775 mg, 6 mmol, 10 equiv), SiCl (153 mg, 0.9 mmol, 3
S-Phenyl 3-Hydroxy-2-(4-isobutylphenyl)-3-phenylpropanethio-
ate (10b)
2
4
equiv), and anhydrous CH Cl (2 mL) were used. After workup, the
2
2
Thioester 9b (1.70 g, 0.6 mmol, 2 equiv), catalyst 2 (19 mg, 0.03
product was purified by flash chromatography on silica gel with hex-
ane–EtOAc (97:3) as eluent. This purification furnished isolated syn-
and anti-diastereoisomers; yield: 75.2 mg (59%); white solid; mp
mmol, 0.1 equiv), benzaldehyde (32 mg, 0.3 mmol, 1 equiv), i-Pr NEt
2
(775 mg, 6 mmol, 10 equiv), SiCl4 (153 mg, 0.9 mmol, 3 equiv), and
anhydrous CH Cl (2 mL) were used. After workup, the product was
2
2
1
03–105 °C; R = 0.22 (syn), R = 0.14 (anti) (hexane–EtOAc, 97:3,
f
f
purified by flash chromatography on silica gel with hexane–EtOAc
95:5) as eluent. This purification furnished a mixture of syn- and
anti-diastereoisomers; yield: 55.0 mg (47%); white solid; mp 88–90
C; R = 0.31 (syn), R = 0.23 (anti) (hexane–EtOAc, 9:1, stained with
stained with phosphomolybdic acid).
(
HPLC: Chiralcel OD-H; eluent: hexane–i-PrOH (9:1); flux: 0.8
mL/min; detection: 210 nm; syn-enantiomer, tR = 10.0 min; syn-en-
antiomer, t = 12.4 min; anti-enantiomer, t = 14.2 min; anti-enantio-
°
f
f
phosphomolybdic acid).
R
R
mer, t = 15.4 min.
R
HPLC: (syn-isomer) Chiralcel OD-H; eluent: hexane–i-PrOH (8:2);
1
H NMR (300 MHz, CDCl ): δ (syn) = 7.43–6.99 (m, 13 H), 5.31 (d,
flux: 0.8 mL/min; detection: 210 nm; minor enantiomer, t = 9.7; ma-
3
R
J = 7.2 Hz, 1 H), 4.03 (d, J = 7.2 Hz, 1 H), 2.48 (d, J = 7.1 Hz, 2 H), 1.88
jor enantiomer, tR = 11.5 min; (anti-isomer) Chiralcel OD-H; eluent:
hexane–i-PrOH (8:2); flux: 0.8 mL/min; detection: 210 nm; major en-
antiomer, t = 11.8 min; minor enantiomer, t = 13.8 min.
(m, 1 H), 0.92 (d, J = 6.6 Hz, 6 H); δ (anti) = 7.45–7.34 (m, 4 H), 7.13 (d,
J = 8.3 Hz, 2 H), 7.01–6.95 (m, 7 H), 5.23 (d, J = 9.1 Hz, 1 H), 4.06 (d,
J = 9.1 Hz, 1 H), 3.03 (br, 1 H), 2.41 (d, J = 7.2 Hz, 2 H), 1.88–1.69 (m, 1
H), 8.86 (d, J = 6.6 Hz, 6 H).
R
R
1
H NMR (300 MHz, CDCl ): δ (syn) = 7.40–7.30 (m, 10 H), 7.28–7.15
3
(m, 4 H), 5.35 (d, J = 7.5 Hz, 1 H), 4.12 (d, J = 7.6 Hz, 1 H), 2.44 (d,
13
C NMR (75 MHz, CDCl ): δ = 197.6, 141.8, 138.8, 134.4, 134.1, 133.4,
J = 7.2 Hz, 2 H), 1.97–1.81 (m, 1 H), 0.94 (d, J = 6.6 Hz, 3 H), 0.93 (d,
J = 6.6 Hz, 3 H); δ (anti) = 7.42–7.38 (m, 5 H), 7.28–7.18 (m, 3 H),
3
130.5, 129.3, 128.9, 128.1, 128.0, 126.8, 74.3, 66.9, 44.8, 29.8, 22.1.
7.15–7.08 (m, 2 H), 7.00 (s, 4 H) 5.28 (d, J = 7.5 Hz, 1 H), 4.15 (d, J = 7.5
MS (ESI+): m/z = 447.3 [M + Na]+.
Hz, 1 H), 2.42 (d, J = 7.2 Hz, 2 H), 1.97–1.81 (m, 1 H), 0.88 (d, J = 6.6 Hz,
3
H), 0.85 (d, J = 6.6 Hz, 3 H).
S-Benzyl 3-Hydroxy-2,3-diphenylpropanethioate (12)
13
C NMR (75 MHz, CDCl ): δ (syn) = 199.3, 141.4, 140.8, 134.5, 131.9,
Thioester 11 (145 mg, 2 equiv, 0.6 mmol), catalyst 2 (19 mg, 0.1 equiv,
3
1
3
29.5, 129.4, 129.2, 128.6, 128.0, 127.7, 127.6, 126.5, 76.8, 67.5, 45.0,
0.1, 22.3.
0.03 mmol), benzaldehyde (32 mg, 0.3 mmol, 1 equiv), i-Pr NEt (775
2
mg, 6 mmol, 10 equiv), SiCl (153 mg, 0.9 mmol, 3 equiv), and anhy-
4
MS (ESI+): m/z = 413.2 [M + Na]+.
drous CH Cl (2 mL) were used. After workup, the product was puri-
2 2
fied by flash chromatography on silica gel with hexane–EtOAc–CH Cl2
2
(
9:0.5:0.5) as eluent. This purification furnished a mixture of syn- and
anti-diastereoisomers; yield: 30.3 mg (29%); white solid; mp 81–83
C; R = 0.18 (hexane–EtOAc, 9:1, stained with phosphomolybdic
S-Phenyl 3-Hydroxy-2-(4-isobutylphenyl)-3-(4-methoxyphe-
nyl)propanethioate (10c)
°
f
Thioester 9b (1.70 g, 0.6 mmol, 2 equiv), catalyst 2 (19 mg, 0.03
mmol, 0.1 equiv), 4-methoxybenzaldehyde (41 mg, 0.3 mmol, 1
equiv), i-Pr NEt (775 mg, 6 mmol, 10 equiv), SiCl (153 mg, 0.9 mmol,
acid).
HPLC: Chiralcel OD-H; eluent: hexane–i-PrOH (9:1); flux: 0.8
mL/min; detection: 230 nm; anti-enantiomer, tR = 14.4 min; syn-en-
antiomer, t = 16.6 min; syn-enantiomer, t = 20.4 min; anti-enantio-
mer, t = 30.8 min.
1
2
4
3
equiv), and anhydrous CH Cl (2 mL) were used. After workup, the
2 2
product was purified by flash chromatography on silica gel with hex-
ane–EtOAc (85:15) as eluent. This purification furnished a mixture of
syn- and anti-diastereoisomers; yield: 54.3 mg (43%); white solid; mp
R
R
R
H NMR (300 MHz, CDCl ): δ = 7.39–7.06 (m, 15 H), 5.38 (d, J = 6.0 Hz,
3
8
1–83 °C; R = 0.10 (hexane–EtOAc, 97:3, stained with phosphomo-
1 H, syn), 5.30 (d, J = 6.0 Hz, 1 H, anti), 4.22 (d, J = 13.8 Hz, 1 H, anti),
4.13 (d, J = 13.8 Hz, 1 H, syn), 4.13–4.02 (m, 3 H), 3.87 (d, J = 14.0 Hz, 1
H, anti).
f
lybdic acid).
HPLC: Chiralcel OD-H; eluent: hexane–i-PrOH (9:1); flux: 0.8
mL/min; detection: 210 nm; syn-enantiomer, tR = 12.6 min; syn-en-
antiomer, t = 14.3 min; anti-enantiomer, t = 16.2 min; anti-enantio-
13
C NMR (75 MHz, CDCl ): δ = 200.1 (anti), 198.5 (syn), 140.5 (syn),
3
140.7 (syn), 140.5 (anti), 136.8, 134.9 (anti), 134.4 (syn), 129.3, 128.8,
R
R
mer, t = 18.5 min.
128.7, 128.6, 128.5, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.3,
R
127.2, 126.8, 126.6, 75.2, 67.9 (syn), 67.8 (anti), 33.7 (anti), 33.3 (syn).
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MS (ESI+): m/z = 371.2 [M + Na]+.
(8) (a) Rossi, S.; Benaglia, M.; Cozzi, F.; Genoni, A.; Benincori, T. Adv.
Synth. Catal. 2011, 353, 848. (b) Bonsignore, M.; Benaglia, M.;
Cozzi, F.; Genoni, A.; Rossi, S.; Raimondi, L. Tetrahedron 2012, 68,
8251.
Acknowledgment
(
9) For examples of thioesters in Mannich reactions, see: (a) Ricci,
A.; Pettersen, D.; Bernardi, L.; Fini, F.; Fochi, M.; Herrera, R. P.;
Sgarzani, V. Adv. Synth. Catal. 2007, 349, 1037. (b) Utsumi, N.;
Kitagaki, S.; Barbas, C. F. III Org. Lett. 2008, 10, 3405.
S.R. thanks Università degli Studi di Milano for a postdoctoral fellow-
ship.
(c) Bahlinger, A.; Fritz, S. P.; Wennemers, H. Angew. Chem. Int.
Supporting Information
Ed. 2014, 53, 8779. For examples of thioesters in Michael reac-
tions, see: (d) Alonso, D. A.; Kitagaki, S.; Utsumi, N.; Barbas, C. F.
III Angew. Chem. Int. Ed. 2008, 47, 4588.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379914.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
(
10) For examples of malonic acid half thioesters in Mannich reac-
tions, see: (a) Pan, Y.; Kee, C. W.; Jiang, Z.; Ma, T.; Zhao, Y.; Yang,
Y.; Xue, H.; Tan, C.-H. Chem. Eur. J. 2011, 17, 8363. (b) Zhong, F.;
Jiang, C.; Yao, W.; Xu, L.-W.; Lu, Y. Tetrahedron Lett. 2013, 54,
References
4
333. For examples of malonic acid half thioesters in Michael
(
1) (a) Denmark, S. E.; Beutner, G. L. Angew. Chem. Int. Ed. 2008, 47,
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