Enantioselective organocatalyzed functionalization of benzothiophene and thiophenecarbaldehyde derivatives

Article abstract of DOI:10.1016/j.tet.2012.04.008

Herein we report a study on the enantioselective organocatalyzed cross-aldol reaction of 1-benzothiophene and thiophenecarbaldehydes with different ketones. The reactions were conducted at 0 °C or room temperature to afford the corresponding adducts in high yields and good to excellent ee using different organocatalysts. Interestingly, using (S)-pyrrolidine tetrazole and acetoxyacetone an inversion of the aldol regiochemistry was observed.

Full text of DOI:10.1016/j.tet.2012.04.008

Tetrahedron 68 (2012) 4773e4781
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective organocatalyzed functionalization of benzothiophene and
thiophenecarbaldehyde derivatives
,
a
,
a
a
b
Francesco Secci a , Enzo Cadoni , Claudia Fattuoni , Angelo Frongia , Giuseppe Bruno ,
*
*
ꢀ b
Francesco Nicolo
a
ꢀ
Dipartimento di Scienze Chimiche e Geologiche, Universita degli Studi di Cagliari, Cittadella Universitaria di Monserrato, SS 554, Bivio per Sestu, Monserrato I-09042 (Ca), Italy
Dipartimento di Chimica Inorganica, Chimica Analitica e Chimica Fisica, Universita degli Studi di Messina, Salita Sperone 31, Villaggio S. Agata, I-98166 Messina, Italy
b
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Hereinwereport a studyon the enantioselective organocatalyzed cross-aldol reaction of 1-benzothiophene
and thiophenecarbaldehydes with different ketones. The reactions were conducted at 0 ꢀC or room tem-
perature to afford the corresponding adducts in high yields and good to excellent ee using different or-
ganocatalysts. Interestingly, using (S)-pyrrolidine tetrazole and acetoxyacetone an inversion of the aldol
regiochemistry was observed.
Received 17 October 2011
Received in revised form 12 March 2012
Accepted 2 April 2012
Available online 13 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
Enantioselectivity
Regiochemistry
Aldol reactions
Benzothiophene
1. Introduction
are valid therapeutic instruments for the treatment of depression
diseases4e (Fig. 1). Furthermore benzothiophene core-compounds
Organocatalyzed aldehydeealdehyde and aldehydeeketone
reactions have been performed on a wide variety of aromatic ac-
ceptors.1 However, since the development of this fundamental
carbonecarbon bond forming technology, few examples of sulfur
containing compounds have been reported or studied systemati-
cally.2 Due to our interest in organocatalyzed processes involving
sulfur containing compounds,3 we focused our attention on the
aldehydeeketone cross-aldol reaction of 2,3-disubstituted benzo-
thiophene derivatives. In fact, thiophene and benzothiophene de-
rivatives are useful building blocks in medicinal chemistry4 and
technological applications.5 Moreover benzothiophene poly-
alcohols have been reported to be able to interact as unnatural
nucleosides with DNA-chains making naturaleunnatural self
pairs.4a As a matter of fact once incorporated on DNA-fragments
they act as diagnostic probes, which modulate the formation of
intramolecular hydrogen bonds and the conformation of the DNA-
helix: a methodology able to generate this kind of scaffold might be
of multidisciplinary interest. Other benzothiophene derivatives,
such as NSC-380292, showed high HIV-1 RT inhibitor activity.4bed
DuloxetinÒ and benzothiopheneepiperazine antipsychotic drugs
exhibit interesting pharmacological properties, e.g., anti-inflam-
matory,4f antiallergic,4g antitrombotic-fibrillonitic4h and herpes
virus inhibitor.4i
OH
H
S
OH
S
H
N
H
N
H
N
O
S
O
O
OH
O
HO
N
H
Unnatural
Duloxetin
nucleosides
HIV-1 inhibitors
Fig. 1. Benzothiophene and thiophene containing drugs.
Recently we reported a highly efficient direct aldehydeeketone
aldol reaction of cyclopropyl-, cyclobutyl- and cyclopentylphenylthio
carbaldehydes using L-proline in acetone, which afforded the corre-
sponding cyclopropyl- and cyclobutylphenylthio carbinols in >99%
ee and 80e88% yield (Fig. 2).3a
Extending this investigation to linear non-enolizable a-phenyl-
thiocarbaldehydes6aec we could observe similar levels of reactivity
and enantioselection (98% ee)6a (Fig. 2). These compounds are
challenging aldol acceptors that were investigated by Governeur
etal. as potential biocatalytic targetsusing PBS (pH¼7.4) and ab84G3
antibodies for the construction of phenylthioaldol adducts6b and by
* Corresponding authors. Tel.: þ39 (0)70 6754445; fax: þ39 (0)70 6754388;
e-mail addresses: fsecci@unica.it (F. Secci), ecadoni@unica.it (E. Cadoni).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.008

4774
F. Secci et al. / Tetrahedron 68 (2012) 4773e4781
(
)
n
With this information in hand we submitted to aldol reaction
OH
OH
the aldehydes 1a, 1dem using catalyst II:9 we isolated the corre-
sponding aldol adducts in 69e94% yield and 49e92% ee (Table 2).
The aldehydes 1a, 1g and 1h afforded the aldol adducts 4a, 4g and
4h along with 10e15% of condensation products, which were easily
isolable by flash chromatography. The enantioselectivity and the
yield of the reactions between acetone and benzothiophene car-
baldehydes were good and practically independent of the sub-
stituent. 3-Thiophenecarbaldehyde (1l) and 2-benzothiazole
carbaldehyde (1m) aldol adducts were isolated in low ee (49% and
58%, respectively). The difference of ee between the reactions of 3-
thiophenecarbaldehyde (1l) and 3-benzothiophene carbaldehyde
(1i) is noteworthy.
O
O
S
S
ee 98, >99%
80-88% yield
ee 98%
80% yield
Fig. 2. Phenylthio carbinol derivatives.
Warren and co-workers as building blocks in the stereoselective
synthesis of tetrahydrofuran6c and oxetane6b heterocycles. This re-
sult encouraged us to study different aromatic sulfur containing
aldol acceptors focussing our attention on thiophene and benzo-
thiophene derivatives, with the aim of testing the effect of the sulfur
atom of the aromatic ring on the selectivity of organo-catalytic re-
actions. For this proposal, thiophene and 1-benzothiophene car-
baldehydes 1aem were prepared from commercially available 1-
benzothiophene and 3-methyl-1-benzothiophene or adapting
reported methodologies.7aeh
Table 2
Asymmetric aldol reaction of compounds 1aem with acetone
R
R
II
cat. 10%
OH
R
CHO
CHO
CHO
O
N
S
acetone
S
1
S
2
CHO
X
X
CHO
0 °C, 6-18h
CHO
R
S
S
1l
S
S
1a-f
1g-h
1i
1m
1a
1g
, R = H
, R = NO2
Entry
1
Acceptors 1aem
Products 2aem
Time (h) % Yielda % ee
1b, R = Me
1c, R = Cl
1h, R = H
1d
, R = Br
1e, R = Ph
1f
, R = CN
12
14
12
89
88
94
91
90b
90
1a
1b
1c
2. Results and discussion
2
3
We started our study on the organocatalyzed aldol reaction of
benzothiophene carbaldehydes using derivatives 1b and 1c in the
presence of acetone and catalysts IeIV, in different solvents. This
preliminary testshowedthatthecombinationofacetoneand catalyst
II provides the best yields and ee for different substrates. Other
typical solvents used in organocatalysis, such as DMF or DMSO,8 gave
lower yields and ee. We also observed that aldol reactions carried out
in water gave lower yields and racemic aldol adducts (Table 1).
Cl
OH
O
S
4
5
12
18
90
80
90c,d
1d
1e
Ph
Ph
OH
OH
Table 1
89e
Catalyst and solvent screeninga
O
O
CHO
S
S
H
Ph
N
N
COOH
S
CN
N
COOH
CN
O
N
H
N
H
N
H
O
O
HN
N
H2N
O
6
16
94
92
CHO
III
IV
S
I
II
S
1f
R
R
cat I-IV
OH
7
8
2
8
84
75
90
86
O
CHO
1g
acetone
S
S
solvent, 0 °C
1b-c
2b-c
OH
CHO
O
S
S
1h
Entry
R
Catalyst
Solvent
Time (h)
% Yield
% ee
1
2
3
4
5
6
7
8
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Me
Me
Me
Me
Me
Me
Me
Me
I
I
I
I
II
II
III
IV
I
DMSO
DMF
Acetone
H2O
DMSO
Acetone
Acetone
Acetone
DMSO
Dioxane
Acetone
Acetone
DMF
12
11
12
>72
10
10
12
15
14
48
10
15
10
48
15
21
59
47
55
45
72
84
80
75
60
24
88
90
58
27
81
60
78
80
84
rac
85
89
86
83
87
65
90
88
82
40
87
87
CHO
OH
9
10
69
88
O
S
S
1i
CHO
OH
O
10
12
10
77
92
49
58
S
S
1l
9
10
11
12
13
14
15
16
I
OH
N
S
N
II
III
III
III
IV
IV
O
CHO
11
S
1m
a
CH3CN
Acetone
DMSO
Yield after chromatography.
Using catalyst III ee 89%.
Using catalyst III ee 90%.
Using catalyst III ee 86%.
Using catalyst IV ee 47%.
b
c
d
e
a
Reactions were carried out using 20 equiv of acetone and 20 mol % of catalyst
IeIV. Analogous results were obtained using 10 mol % of catalyst.

F. Secci et al. / Tetrahedron 68 (2012) 4773e4781
4775
Table 3
We also used the other catalysts (I, III and IV) to verify if on
changing the substrate their performance increased. We observed
that -proline I gave poor results when the reactions were carried
out at room temperature due to the formation of the bicyclox-
azolidine derivatives 3 in 15e19% yield (entries 1, 3, 7, 8, Table
1)8e10 with concurrent catalyst depletion (Scheme 1).
Asymmetric aldol reaction with hydroxyacetone
R
R
L
cat. II 10%
OH
CHO
O
hydroxyacetone
0 °C, 6-18h
S
1
S
4
X
X
HO
Entry
Acceptors 1
Products 4
% dra
%
% ee
4-(syn/anti) Yieldb (syn/anti)
R
R
COOH
N
H
OH
S
H
N
O
O
1
2
28:72
36:64
93
71
90:90
CHO
S
acetone
r.t
S
S
HO
1a
O
H
H
Me
OH
Me
S
1a,c
R
3a,c (anti)
racemic
91:90c
CHO 1b
S
HO
Scheme 1.
Cl
OH
The stereochemistry of 3a,c was assigned by 1H NMR ROESY
analysis on 3a, (see Supplementary data). Moreover the coupling
constant values of the oxazolylic protons in 3a,c are analogous with
those obtained by Blackmond for similar compounds.10c (S)-Pyr-
rolidine-2-tetrazole III9 gave slightly lower ee. Interestingly, (S)-
tert-BuO-threonine IV gave results comparable to catalyst II (entries
4 and 15, Table 1). Also catalyst III gave for the aldehydes 1a, 1g and
1h condensation products (10e15%). These results showed that the
most general and efficient catalyst was II. Most of the aldol adducts,
namely compounds 2a, b, f, g, m, were isolated as crystalline solids.
Recrystallisation of these compounds (EtOAc/hexane) gave the
corresponding pure products in ee >99%. The absolute configura-
tion of compound 2f was established by X-ray crystallographic
analysis and is consistent with that predictable from previous
studies.3a The absolute configurations for 2aee and 2gei were
assigned by analogy.
3
4
O
45:55
26:74
87
92
89:90
S
1c
HO
Br
OH
81:87d
O
S
1d
HO
OH
O
5
32:68
39:61
90
91
76:86
67:82
S
O2N
1g
1h
HO
OH
O
6
S
HO
a
dr was determined by GCeMS or by 1H NMR.
Analogous results with catalyst III.
With cat. I dr 50:50, ee 86:77%.
b
c
d
With cat. I dr 60:40, ee 90:85%.
2.1. Synthesis of 3,4-dihydroxy-4-(1-benzothiophen-2-yl)-
butan-2-ones
carbonyl compound and the axial-H of the (E)-enamine.12 The
transition state B-(TS) becomes more important when the thio-
phene moiety can interact with the enamine OH-group.1,9,10 There
is some experimental evidence10b that supports this behaviour: (i)
stereochemical results obtained for reactions carried out in acetone
showed high aldehyde face discrimination and the stereochemical
induction is influenced only by the stereochemistry of the catalyst
Compound 1a was treated at 0 ꢀC with hydroxyacetone
(10 equiv) in DMSO in the presence of catalyst II. The aldol reaction
gave the corresponding diol 4a in 90% yield and good ee. Sub-
sequently we observed that the same reaction performed in neat
hydroxyacetone gave the same results in terms of yield (93%) and
ee. All further reactions were performed using this protocol. Car-
baldehydes 1bed, g, h reacted efficiently affording diols 4bed, g, h
in 71e92% and good ee. The results of these investigations are
shown in Table 3. The regioselectivity of the reaction was the same
as that reported by List10 for the reaction between hydroxyacetone
and several aromatic and aliphatic aldehydes under the same
conditions. Conversely, Gong et al.11 obtained reverse diaster-
eoselectivity for the reaction between hydroxyacetone and differ-
ent aldehydes using proline amide derivatives as catalysts and
a mixture of H2O/THF as solvent.
As shown, the diastereoselectivity was poor and all the 3,4-
dihydroxyketones were formed as (28:72e45:55) mixtures of
syn-/anti-adducts.1,10 The aldol reaction performed with catalysts I,
IV1,6a,b did not lead to better results. On the other hand, diols 4a, 4d
can be recrystallized from their diastereoisomeric mixture (AcOEt/
hexane) isolating the corresponding syn-diastereoisomers in ee
>99% as white needles. At this stage we were able to assign the
absolute configuration of the minor syn-diastereoisomer as (S,S)-4d
(Fig. 4). On the basis of the crystallographic results we observed
that the isolated minor syn-diastereoisomer showed (S) absolute
configuration at the b
-carbon.1,10,12 This result can be rationalized
with the sketched partial boat-like-ZimmermaneTraxler transition
state B with partially eclipsed disposition of the axial-H of the
Fig. 3. X-ray structure of the compound (R)-2f.

4776
F. Secci et al. / Tetrahedron 68 (2012) 4773e4781
(Table 2, Fig. 3) and the absolute configuration of the stereogenic
b
-
transition states respect to H, as previously reported in literature for
other donors.11,13e18 Furthermore the monoprotection on the ter-
minal hydroxyl group can be helpful for further transformations of
the chain extending the synthetic potential of these structures.18
carbon is predominantly -(R) when ( )-proline I or catalysts IIeIV
b
L
were used; (ii) the comparison of entries 1e6 (Table 3) with entries
1e4,7,10 (Table 2) clearly shows that the Si/Re face discrimination
on the aldehyde is remarkably reduced when we use hydrox-
yacetone instead of acetone.13
Table 4
Asymmetric aldol reaction with acetoxyacetatea
R
R
cat. III, 10% mol.
OH
O
CHO
acetoxyacetate
S
S
5-
iso
AcO
1
Entry
1
Acceptor 1
6 syn/anti 5 iso%
% Yield 5 iso
% ee iso
10:9:81
5:15:80
78
90b
1a
Me
2
3
78
90
CHO
S
1b
7:10:83
80
65
91
90
1d
1i
CHO
4
15:10:75
Fig. 4. Transition states A, B and X-ray structure of the (S,S)-syn-diol adduct 4d.
S
a
Experiments carried out with p-NO2-benzaldehyde, cat. III (10%) and acetox-
On the contrary, the face discrimination on the hydroxyl carbon
atom of hydroxyacetone was high, because the 4-anti (3R,4S) and 4-
syn (3R,4R) would be obtained by transition states where the
conformation of the enamine moiety is syn respect to the sulfon-
amide group: in fact, theoretical calculations on less hindered
catalysts showed these transition states as unfavourable.14
yacetone (4 equiv) gave the iso-adduct in 60% yield after chromatography. Cleavage
of the acetoxy protecting group lead us to compare the [
24
a
]
þ64.5 (c 43, EtOAc), ee
D
þ51.6 (c 31, EtOAc), and assign the absolute configuration as (R).11
25
90%, [a]
D
b
With catalyst II (10%) syn/anti/iso 21:15:64, yield iso 57%, ee 88%.
O
H
O
H
H
N
H
N
H
N
H
H
O
O
H
R
O
2.2. Synthesis of 4-(1-benzothiophen-2-yl)-4-hydroxy-2-
oxobutyl acetate
R
O
N
N
N
N
N
N
R
O
N
N
N
O
O
H
H
N
N
N
Compound 1a was reacted with acetoxyacetone (4 equiv) in the
presence of catalyst III. 1H NMR spectroscopic analysis un-
expectedly showed the predominant formation of the iso-
regioisomer15,17 5a along with the syn/anti diastereoisomers 6a-
syn, 6a-anti in 10:9 ratio (Scheme 2).
F
anti
G
syn
H
aldol
Fig. 5. Presumed transition states for compounds 5.
3. Conclusions
The organocatalyzed aldol reaction of thiophene- and benzo-
thiophene carboxyaldehyde derivatives has been studied using dif-
ferent catalysts and donors affording benzothiophene- and
thiophene-aldol derivatives in good to excellent yields and ee. The
scope and limitations of this reaction on aromatic sulfur containing
derivativesand somedifferent stereochemicalaspects of thisreaction
have been examined extending it to unconventional acceptors and
creating new chemical architectures. It was also showed that using
acetoxyacetone instead of hydroxyacetone it is possible to modulate
the regiochemistry of the reaction, when catalyst III is used, affording
predominantly the iso-linear adducts 5 in good ee and yields.
OH
OH
cat. III, 10% mol.
CHO
+
O
acetoxyacetone
S
S
S
O
AcO
1a
5-
iso
6 sy n/anti
AcO
Scheme 2.
The reaction was repeated several times confirming the same
result and subsequently we decided to test other benzothiophene
carbaldehydes to validate the result obtained with 1a. Reverse
regiochemistry was observed as predominant with benzothio-
phene carbaldehydes 1a, b, d, i (Table 4) with the iso-aldol adducts
obtained in 65e80% yield and excellent ee. The different result
obtained using acetoxyacetone and catalyst III, compared with the
aldol products isolated using hydroxyacetone as donor and catalyst
III, might be explained by a limited formation of the corresponding
acetyl-enamine in the transition state F or G (Fig. 5) due to the
4. Experimental section
4.1. General
reduced transfer of the oxygen lone pair to the
p
*
orbital of the C]C
NMR spectra were recorded on Varian 300, 400 and 500 spec-
trometers using the solvent peak as internal reference. MS analysis
double bond and not just by a lower steric hindrance in these

F. Secci et al. / Tetrahedron 68 (2012) 4773e4781
4777
was performed with an HP5989A MS spectrometer using direct in-
sertion probe (DIP) ethod. GCeMS analysis was performed with
Agilent 5973-N (cp sil 32 m), EI 70 eV. Infrared spectra were obtained
using a Bruker-FT-IR. HPLC analysis was performed with a Merck-
Hitachi L-7100 using the UV detector L-7400 and chiral columns
Chiralcel OD-H, AD-H, OJ and Chiralpak AS-H. Optical rotation values
were measured at 19e28 ꢀC using a PolAAr32. Microanalysis was
performed with a PerkineElmer 2400 series2. Melting points were
obtained on a Kofler hot stage microscope. THF was distilled from
sodium/benzophenone. Thiophene, 3-thiophenecarbaldehyde, 1-
benzothiophene-3-carbaldehyde, 5-nitro-2-thiophenecarbaldehyde,
1,3-benzothiazole-3-carbaldehyde, hydroxyacetone, acetone and
acetoxyacetate were used as purchased or distilled prior to use.
Diol compounds were separated by chromatographic column
Method B. As a representative procedure, to an acetone (6.8 mL,
20 equiv) solution of benzo[b]thiophene-2-carbaldehyde 1a (1.0 g,
6.10 mmol) at 0 ꢀC, cat. III (154 mg, 0.61 mmol, 0.1 equiv) was
added in one portion. The mixture was stirred for 12 h at this
temperature, and the resulting solution was treated with a solution
of NH4Cl aq (15 mL) and extracted with EtOAc (20 mL). The organic
phase was dried with Na2SO4 and concentrated under reduced
pressure after filtration. The yellow crude solid was chromato-
graphed using petroleum ether/EtOAc 70:30 to afford the corre-
sponding aldol adduct 2a as a white solid (1.12 g, 84% yield).
4.2.1. (R)-4-(1-Benzothiophen-2-yl)-4-hydroxybutan-2-one
(2a). Following method A. Chromatography, petroleum ether/
23
EtOAc 70:30. White solid (1.2 g, yield 89%). Mp¼89e90 ꢀC. [
a]
D
(25 mmꢁ180 mm) filled with DAVISIL silica gel (40e63
m
), packed
þ69.8 (c 0.73, CHCl3). IR
n (neat) 3512, 3009, 2989, 2833, 1786, 1732,
with Buchi C-670 cartridger. 1-Benzothiophene-2-carbaldehydes
1aee were prepared as described in the literature and experimental
data are consistent with those reported.7
1160, 1062, 953, 632 cmꢂ1
.
1H NMR (300 MHz, CDCl3)
d
¼7.83 (d,
J¼7.5 Hz, 1H), 7.80 (d, J¼7.5 Hz, 1H), 7.34e7.26 (m, 2H), 7.20 (s, 1H),
5.45 (dd, J¼8.0, 3.9 Hz, 1H), 3.61 (br s, 1H), 3.03 (dd, J¼13.6, 8.0 Hz,
X-ray data collection and structure refinement. Colourless single
crystals of both compounds suitable for X-ray structural analysis
were selected from the crystals obtained from an ethylacetate/
hexane solution. Data were collected at room temperature with
2H), 2.20 (s, 3H). 13C NMR (75 MHz, CDCl3)
d
¼208.6, 147.6, 139.4,
130.9, 128.8, 124.3, 124.2, 122.4, 119.9, 66.6, 51.3, 30.7. MS-EI
(C12H12O2S) m/z: 220 (68, Mþ), 202 (18), 187 (23), 177 (19), 162
(80), 135 (77), 115 (29), 91 (64), 69 (32), 43 (100%). Anal. Calcd for
C12H12O2S: C, 65.43; H, 5.49; S, 14.55. Found: C, 65.51; H, 5.44; S,
14.59. HPLC: Diacel Chiralpak OJ. Hexane/i-PrOH, 88:12, 1.0 mL/
min, 254 nm: tR (minor)¼33.37 min; tR (major)¼40.10 min.
a Bruker APEX II CCD area-detector diffractometer and graphite-
ꢁ
monochromatized Mo K
a
radiation [
l
¼0.71073 A]. Data collec-
tion, cell refinement, data reduction and absorption correction by
multi-scan method were performed by the programs of the Bruker
software.19 The structure was solved by direct methods using XS97.
The non-hydrogen atoms were refined anisotropically by the full-
matrix least-squares method on F20 using SHELXL97.20 All the H
atoms were introduced in calculated positions and constrained to
ride on their parent atoms. The pictures are shown in Figs. 3 and 4.
CCDC 831213 and 831214 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
4.2.2. (R)-4-Hydroxy-4-(3-methyl-1-benzothiophen-2-yl)butan-2-
one (2b). Following method A. Chromatography, petroleum ether/
EtOAc 70:30. Pale yellow solid (1.2 g, yield 88%). Mp¼81e82 ꢀC.
[
a
]
25 þ78.2 (c 1.4, CHCl3). IR
n (neat) 3518, 3005, 2990, 2898, 1789,
D
1624, 1143, 1060, 786, 534 cmꢂ1. 1H NMR (300 MHz, CDCl3)
d¼7.79
(d, J¼7.2 Hz, 1H), 7.65 (d, J¼7.2 Hz, 1H), 7.38e7.28 (m, 1H), 5.64 (dd,
J¼9.3, 2.4 Hz, 1H), 3.35 (br s, 1H), 3.05 (dd, J¼17.1, 9.3 Hz, 1H), 2.88
(dd, J¼17.1, 2.4 Hz, 1H), 2.37 (s, 3H), 2.19 (s, 3H). 13C NMR (125 MHz,
CDCl3)
d
¼208.3, 140.4, 140.3, 138.3, 127.2, 124.3, 124.0, 122.5, 121.7,
Compound 1f has been prepared as follows:
64.8, 51.2, 30.3, 11.8. MS-EI (C13H14O2S) m/z: 234 (73, Mþ), 216 (38),
191 (72), 177 (81), 147 (36), 132 (21), 87 (20), 43 (100%). Anal. Calcd
for C13H14O2S: C, 66.64; H, 6.02; S, 13.68. Found: C, 66.55; H, 6.05; S,
13.73. HPLC: Diacel Chiralpak OJ. Hexane/i-PrOH, 91:9, 1.0 mL/min,
254 nm: tR (minor)¼23.71 min; tR (major)¼32.28 min.
2-Formyl-1-benzothiophene-3-carbonitrile (1f). To a solution of 1-
benzothiophene-3-carbonitrile (1.0 g, 6.28 mmol) in THF (50 mL) at
ꢂ78 ꢀC, n-BuLi (4.32 mL, 6.91 mmol,1.1 equiv) was added dropwise.
The reaction mixturewasstirredfor 1 hat thesame temperatureand
freshly distilled DMF (0.63 mL, 8.16 mmol,1.3 equiv) was added. The
resulting mixture was allowed to room temperature and treated
with an NH4Cl aq and extracted with EtOAc. The organic phase was
dried (Na2SO4) and concentrated. Chromatography, petroleum
4.2.3. (R)-4-(3-Chlorobenzo[b]thiophen-2-yl)-4-hydroxybutan-2-
one (2c). Following method A. Chromatography, petroleum ether/
EtOAc 70:30. Pale yellow solid (1.2 g, yield 94%). Mp¼118e119 ꢀC.
ether/EtOAc 90:10. White solid (1.1 g, 87% yield). Mp¼74e76 ꢀC. IR
n
[
a
]
24 þ44.4 (c 0.92, CHCl3). IR
n (neat) 3514, 3014, 2992, 2830, 1784,
D
(neat) 3470, 2349, 2316, 1712, 758 cmꢂ1. 1H NMR (500 MHz, CDCl3)
1620, 1156, 1062, 936, 545 cmꢂ1. 1H NMR (300 MHz, CDCl3)
d¼7.80
d
¼10.16 (s, 1H), 8.23 (dd, J¼6.9, 1.5 Hz, 1H), 8.23 (dd, J¼6.9, 2.4 Hz,
(d, J¼7.8 Hz, 1H), 7.67 (d, J¼7.8 Hz, 1H), 7.32e7.22 (m, 2H), 5.46 (dd,
1H), 7.64e7.56 (m, 2H). 13C NMR (125 MHz, CDCl3)
d
¼184.6, 143.0,
J¼7.8, 3.9 Hz,1H), 3.54 (br s, 1H), 3.08e2.94 (m, 2H), 2.22 (s, 3H). 13C
141.8,128.5,126.1,125.9,125.4,123.4123.3,109.9. MS-EI (C10H5NOS)
m/z: 187 (100, Mþ), 161 (73), 158 (89), 133 (47), 103 (29), 77 (28), 69
(20), 45 (18%). Anal. Calcd for C10H5NOS: C, 64.16; H, 2.69; N, 7.48; S,
17.12. Found: C, 63.96; H, 2.73; N, 7.57; S, 17.28.
NMR (75 MHz, CDCl3)
d¼208.3, 147.1, 139.4, 139.2, 124.3, 123.5,
122.4, 119.9, 66.7, 51.3, 30.8. MS-EI (C12H11ClO2S) m/z: 254, (48, Mþ),
236 (61), 211 (29), 197 (83), 167 (50), 133 (75), 108 (44), 87 (30), 43
(100%). Anal. Calcd for C12H11ClO2S: C, 56.58; H, 4.35; S, 12.59.
Found: C, 56.67; H, 4.38; S, 12.65. HPLC: Diacel Chiralpak OD-H.
Hexane/i-PrOH, 91:9, 1.0 mL/min, 254 nm: tR (minor)¼27.17 min;
tR (major)¼29.52 min.
4.2. General procedures for the synthesis of aldol adducts
2aem
Method A. As a representative procedure, to an acetone (3.6 mL,
20 equiv) solution of 1-benzothiophene-2-carbaldehyde 1a (0.5 g,
3.00 mmol) at 0 ꢀC, cat. II (41 mg, 0.30 mmol, 0.1 equiv) was added
in one portion. The mixture was stirred for 12 h at this temperature,
and the resulting solution was treated with a solution of NH4Cl aq
(15 mL) and extracted with EtOAc (20 mL). The organic phase was
dried with Na2SO4 and concentrated under reduced pressure after
filtration. The yellow crude solid was chromatographed using pe-
troleum ether/EtOAc 70:30 to afford the corresponding aldol ad-
duct 2a as a white solid (0.58 g, 89% yield).
4.2.4. (R)-4-(3-Bromo-1-benzothiophen-2-yl)-4-hydroxybutan-2-
one (2d). Following method A. Chromatography, petroleum ether/
EtOAc 70:30. Yellow oil (1.1 g, yield 90%). [
IR
732 cmꢂ1. 1H NMR (300 MHz, CDCl3)
a
]
26 þ30.5 (c 1.90, CHCl3).
D
n
(neat) 3499, 3008, 2996, 2841, 1787, 1630, 1160, 1120, 968,
d
¼7.76 (t, J¼8.7 Hz, 1H), 7.42
(dt, J¼7.2, 1.0 Hz, 1H), 7.34 (dt, J¼7.2, 1.2 Hz, 1H), 5.66 (dd, J¼9.0,
3.3 Hz, 1H), 3.86 (br s, 1H), 3.02 (dd, J¼17.7, 3.3 Hz, 1H), 2.92 (dd,
J¼17.7, 9.3 Hz 1H), 2.22 (s, 3H). 13C NMR (75 MHz, CDCl3)
¼208.4,
d
141.9, 137.9, 137.1, 125.2, 125.0, 122.6, 122.5, 103.5, 66.5, 49.8, 30.6.
MS-EI (C12H11BrO2S) m/z: 298 (100, Mþ), 297 (80), 255 (40), 241

4778
F. Secci et al. / Tetrahedron 68 (2012) 4773e4781
(65), 219 (18), 213 (22), 132 (42), 89 (34), 57 (36), 43 (41%). Anal.
Calcd for C12H11BrO2S: C, 48.18; H, 3.71; S, 10.72. Found: C, 48.28; H,
3.75; S, 10.67. HPLC: Diacel Chiralpak OJ. Hexane/i-PrOH, 91:9,
1.0 mL/min, 254 nm: tR (minor)¼28.52 min; tR (major)¼40.25 min.
CHCl3). IR
(300 MHz, CDCl3)
n .
(neat) 3437, 3002, 2989, 1721, 1065 cmꢂ1 1H NMR
d
¼7.85e7.79 (m, 2H), 7.38e7.33 (m, 2H), 7.32 (s,
1H), 5.52 (dd, J¼8.4, 4.0 Hz, 1H), 3.52 (br s, 1H), 3.03 (dd, J¼17.7,
8.4 Hz, 1H), 2.95 (dd, J¼17.7, 4.0 Hz, 1H), 2.19 (s, 3H). 13C NMR
(75 MHz, CDCl3)
d
¼208.8, 140.8, 137.5, 136.8, 124.2, 123.0, 122.7,
4.2.5. (R)-4-Hydroxy-4-(3-phenyl-1-benzothiophen-2-yl)butan-2-
one (2e). Following method A. Chromatography, petroleum ether/
122.2, 121.7, 67.6, 52.0, 32.7. MS-EI (C12H12O2S) m/z: 220 (40, Mþ),
202 (19), 187 (21), 163 (50), 162 (100), 135 (64), 115 (20), 91 (24),
89 (28), 63 (15), 43 (84%). Anal. Calcd for C12H12O2S: C. 65.43; H.
5.49; S. 14.55. Found: C. 65.32; H. 5.42; S. 14.50. HPLC: Diacel
Chiralpak OJ. Hexane/i-PrOH, 91:9, 1.0 mL/min, 254 nm: tR (minor)¼
35.83 min; tR (major)¼44.60 min.
26
EtOAc 60:40. White solid (1.1 g, yield 89%). Mp¼95e97 ꢀC. [
a]
D
þ78.8 (c 1.12, CHCl3). IR
n (neat) 3509, 3005, 2987, 2887, 1784, 1646,
1171, 1010, 847 cmꢂ1. 1H NMR (300 MHz, CDCl3)
d
¼7.85 (d, J¼8.1 Hz,
1H), 7.58e7.48 (m, 4H), 7.45e7.33 (m, 4H), 5.50 (dd, J¼9.6, 2.7 Hz,
1H), 3.58 (br s, 1H), 3.04 (dd, J¼17.7, 9.6 Hz, 1H), 2.84 (dd, J¼17.7,
2.7 Hz, 1H), 2.16 (s, 3H). 13C NMR (75 MHz, CDCl3)
d
¼208.4, 142.3,
4.2.10. (R)-4-Hydroxy-4-(thiophen-3-yl)butan-2-one (2l). Following
method A. Chromatography, petroleum ether/EtOAc 70:30. Colour-
139.8, 138.4, 134.5, 133.9, 129.9, 129.6, 128.9, 128.6, 127.7, 124.5,
122.6, 122.5, 65.2, 51.2, 30.6. MS-EI (C18H16O2S) m/z: 296 (18, Mþ),
253 (31), 239 (100), 221 (11), 208 (24), 177 (18), 165 (30), 133 (75),
119 (6), 104 (7), 86 (21), 76 (30), 43 (42%). Anal. Calcd for C18H16O2S:
C, 72.45; H, 5.44; S, 10.82. Found: C, 72.36; H, 5.47; S, 10.77. HPLC:
Diacel Chiralpak OD-H. Hexane/i-PrOH, 90:10, 1.0 mL/min, 254 nm:
tR (minor)¼39.90 min; tR (major)¼44.18 min.
26
less oil (1.2 g, yield 77%). [
a]
þ13.71 (c 1.75, CHCl3). IR
n
(neat)
1H NMR (300 MHz, CDCl3)
¼7.28e7.26 (m, 1H), 7.18e7.17 (m, 1H), 7.02 (dd, J¼3.9, 1.2 Hz, 1H),
D
3453, 3003, 2987, 2893, 1719 cmꢂ1
d
.
5.20 (dd, J¼7.8, 4.2 Hz,1H), 3.37 (br s,1H), 2.91e2.79 (m, 2H), 2.16 (s,
1H). MS-EI (C8H10O2S) m/z: 170 (13, Mþ), 152 (71), 137 (92), 111
(100),109 (80), 85 (31), 65 (27), 43 (30%). Anal. Calcd for C8H10O2S: C,
56.45; H, 5.92; S, 18.83. Found: C, 56.52; H, 5.90; S, 18.77. HPLC:
Diacel Chiralpak OD-H. Hexane/i-PrOH, 91:9, 0.5 mL/min, 254 nm:
tR (minor)¼26.83 min; tR (major)¼30.33 min.
4.2.6. 2-((R)-1-Hydroxy-3-oxobutyl)-1-benzothiophene-3-carbonitrile
(2f). Following method A. Chromatography, petroleum ether/EtOAc
25
70:30. White solid (1.2 g, yield 94%). Mp¼90e91 ꢀC. [
a]
D
þ59.5 (c
0.37, CHCl3). IR
n
(neat) 3470, 2349, 2316, 1712, 758 cmꢂ1. 1H NMR
4.2.11. (R)-4-(1,3-Benzothiazol-2-yl)-4-hydroxybutan-2-one
(300 MHz, CDCl3)
d
¼7.87 (d, J¼7.2 Hz, 1H), 7.84 (d, J¼7.4 Hz, 1H),
(2m). Following method A. Chromatography, petroleum ether/
26
7.49e7.42 (m, 2H), 5.70 (dd, J¼8.7, 3.9 Hz,1H), 4.44 (br s,1H), 3.16 (dd,
EtOAc 70:30. White solid (1.2 g, yield 92%). Mp¼94e95 ꢀC. [
a]
D
J¼18.0, 3.0 Hz,1H), 3.02 (dd, J¼18.0, 9.2 Hz,1H), 2.25 (s, 3H).13C NMR
þ26.3 (c 0.68, CHCl3). IR
n .
(neat) 3427, 1718 cmꢂ1 1H NMR
¼7.95 (d, J¼8.0 Hz, 1H), 7.88 (d, J¼5.4 Hz, 1H),
(75 MHz, CDCl3)
d
¼208.7,160.4,137.7,137.2,126.0,125.9,122.7,122.2,
(300 MHz, CDCl3)
d
113.6, 101.7, 66.3, 50.2, 30.5. MS-EI (C13H11NO2S) m/z: 245 (30, Mþ),
228 (15), 212 (%), 202 (100), 186 (21), 160 (18), 133 (8), 114 (7), 43
(37%). Anal. Calcd for C13H11NO2S: C, 63.65; H, 4.52; N, 5.71 S. 10.82.
Found: C, 63.57; H, 4.48; N, 5.77 S. 13.12. HPLC: Diacel Chiralpak OD-
H. Hexane/i-PrOH, 95:5, 0.5 mL/min, 254 nm: tR (minor)¼35.34 min;
tR (major)¼38.58 min.
7.42 (dt, J¼1.2, 8.0 Hz, 1H), 7.36 (dt, J¼1.2, 8.0 Hz, 1H), 5.46e5.41 (m,
1H), 4.32 (d, J¼5.4 Hz, 1H D2Oexc), 3.31 (dd, J¼18.0, 3.2 Hz, 1H), 3.16
(dd, J¼18.0, 8.0 Hz, 1H), 2.23 (s, 3H). 13C NMR (125 MHz, CDCl3)
d¼208.8,174.6,153.1,135.1,126.0,124.9,122.8, 121.8, 68.8, 49.0, 30.7.
MS-EI (C11H11NO2S) m/z: 222 (100, MþH), 204 (8), 178 (44), 162
(21), 136 (33), 108 (16), 82 (6), 59 (12), 43 (82%). Anal. Calcd for
C11H11NO2S: C, 59.71; H, 5.01; N, 6.33; S, 14.49. Found: C, 59.80; H,
4.95; N, 6.28; S, 14.53. HPLC: Diacel Chiralpak OD-H. Hexane/i-
PrOH, 95:5, 0.5 mL/min, 254 nm: tR (minor)¼27.63 min; tR
(major)¼36.02 min.
4.2.7. (R)-4-Hydroxy-4-(thiophen-2-yl)butan-2-one (2g). Following
method A. Chromatography, petroleum ether/EtOAc 70:30. Col-
22
ourless oil (1.1 g, yield 84%). [
a
]
þ12.4 (c 2.0, CHCl3). IR
n
(neat)
1H NMR (300 MHz, CDCl3)
¼7.55 (d, J¼15.9 Hz, 1H), 7.32 (d, J¼4.5 Hz, 1H), 7.20 (m, 1H), 5.32
(dd, J¼9.0, 3.6 Hz, 1H), 2.96 (dd, J¼17.1, 8.1 Hz, 1H), 2.85 (dd, J¼17.1,
3.6 Hz, 1H), 2.24 (s, 3H). 13C NMR (75 MHz, CDCl3)
D
3419, 3002, 2986, 2833, 1710 cmꢂ1
.
d
4.2.12. 2,3-Di(1-benzothiophen-2-yl)-hexahydropyrrolo[2,1-b][1,3]-
oxazole (3a-anti). Chromatography, petroleum ether/Et2O 70:30.
d¼207.5, 146.5,
White solid (0.3 g, yield 15%). Mp¼115e117 ꢀC. IR
n
(neat) 3060,
.
126.7, 124.7, 123.5, 66.1, 51.7, 30.7. MS-EI (C8H10O2S) m/z: 170 (75,
Mþ), 152 (30), 137 (35), 113 (100), 99 (8), 85 (84), 58 (26), 43 (94%).
Anal. Calcd for C8H10O2S: C, 56.45; H, 5.92; S,18.83. Found: C, 56.50;
H, 5.97; S, 18.76. HPLC: Diacel Chiralpak OJ. Hexane/i-PrOH, 92:8,
0.5 mL/min, 254 nm: tR (minor)¼27.12 min; tR (major)¼30.41 min.
2915, 2880, 2356, 2345, 1484, 1393, 1238, 1147 cmꢂ1 1H NMR
(500 MHz, CDCl3)
d
¼7.87e7.82 (m, 2H), 7.74e7.72 (m, 1H), 7.67 (d,
J¼8.0 Hz, 1H), 7.37e7.27 (m, 4H), 7.25 (s, 1H), 7.08 (s, 1H), 5.34 (d,
J¼3.0 Hz, 1H), 5.20 (d, J¼7.5 Hz, 1H), 4.42(d, J¼7.5 Hz, 1H),
3.32e3.27 (m, 1H), 3.07e3.03 (m, 1H), 2.23e2.13 (m, 3H), 1.94e1.89
(m, 1H). 13C NMR (125 MHz, CDCl3)
d¼147.0, 142.9, 140.2, 139.6,
4.2.8. (R)-4-Hydroxy-4-(5-nitrothiophen-2-yl)butan-2-one
(2h). Following method A. Chromatography, petroleum ether/
139.6, 139.5, 139.4, 124.5, 124.3, 124.2, 123.9, 123.63, 123.2, 122.5,
122.4, 122.2, 120.3, 98.8, 84.2, 74.4, 31.5, 23.8, MS-EI (C22H19NOS2)
m/z: 292 (2), 291 (2), 290 (3), 216 (41), 215 (100), 214 (32), 198 (14),
186 (27), 162 (39), 161 (46), 160 (183), 147 (27), 115 (10), 89 (17).
24
EtOAc 60:40. Orange oil (1.1 g, yield 75%). [
CHCl3). IR
a
]
¼ꢂ16.5 (c 1.91,
D
n
(neat) 3431, 1722, 1730 cmꢂ1. 1H NMR (300 MHz, CDCl3)
d
¼7.71 (d, J¼5.4 Hz, 1H), 6.80 (d, J¼5.4 Hz, 1H), 5.32 (dd, J¼5.1,
12.0 Hz,1H), 3.94 (s,1H), 2.96 (dd, J¼6.9, 2.1 Hz,1H), 2.23 (s, 3H). 13C
4.2.13. 2,3-Di(3-chloro-1-benzothiophen-2-yl)-hexahydropyrrolo
[2,1-b][1,3]-oxazole (3c-anti). Chromatography, petroleum ether/
NMR (75 MHz, CDCl3)
d¼207.7, 155.6, 130.8, 128.4, 121.9, 66.1, 50.8,
30.5. MS-EI (C8H9NO4S) m/z: 215 (18, Mþ), 197 (65), 172 (34), 158
(100), 141 (50), 128 (71), 108 (44), 83 (44%), 57 (20), 43 (57%). Anal.
Calcd for C8H9NO4S: C, 44.65; H, 4.21; N, 6.51; S. 14.90. Found: C,
44.56; H, 4.28; N, 6.66; S, 17.85. HPLC: Diacel Chiralpak OJ. Hexane/
i-PrOH, 91:9, 1.0 mL/min, 254 nm: tR (minor)¼33.16 min; tR
(major)¼39.67 min.
EtOAc 60:40. White solid (0.4 g, yield 19%). Mp¼127e130 ꢀC. IR
n
(neat) 3021, 3007, 2997, 2881, 1815, 1612, 1437, 1226, 1124,
728 cmꢂ1. 1H NMR (500 MHz, CDCl3)
d
¼7.86e7.83 (m, 2H), 7.75 (d,
J¼7.5 Hz, 1H), 7.70 (d, J¼5.5 Hz, 1H), 7.62e7.37 (m, 4H), 5.54 (d,
J¼7.5 Hz, 1H), 5.43e5.42 (m, 1H), 4.74 (d, J¼7.5 Hz, 1H),
7.62e3.30e3.25 (m, 1H), 3.13e3.07 (m, 1H), 2.27e2.13 (m, 3H),
1.94e1.91 (m, 1H). 13C NMR (125 MHz, CDCl3)
d
¼141.4, 138.6, 138.1,
4.2.9. (R)-4-(1-Benzothiophen-3-yl)-4-hydroxybutan-2-one
137.6, 137.5 137.4, 125.4, 125.2, 125.0, 124.9, 123.4, 123.3, 123.0,
122.9, 122.7, 122.6, 99.1, 82.4, 73.7, 55.7, 32.7, 23.7. MS-EI
(C22H17Cl2NOS2) m/z: 328 (6), 293 (89), 264 (10), 215 (31), 212
(2i). Following method A. Chromatography, petroleum ether/
27
EtOAc 70:30. Colourless oil (0.9 g, yield 69%). [
a
]
þ37.4 (c 0.85,
D

F. Secci et al. / Tetrahedron 68 (2012) 4773e4781
4779
(30), 197 (100), 196 (63), 195 (79), 169 (18), 168 (26), 147 (14), 134
(48), 131 (48), 112 (39), 111 (39), 89 (35).
138.9,137.1,129.2,124.7,124.1,122.5,121.29, 80.4, 69.4, 26.6,12.1. MS-
EI(C13H14O3S) m/z: 250(13, Mþ), 232(15), 207 (23),177(32),161 (64),
147 (44), 102 (30), 89 (15%), 75 (41), 43 (100%). Anal. Calcd for
C13H14O3S:C. 62.38; H. 5.64;S.12.81. Found:C. 62.46;H. 5.61;S.12.77.
HPLC: Diacel Chiralpak OD-H. Hexane/i-PrOH, 95:5, 1.0 mL/min,
254 nm: tR (major)¼20.41 min; tR (minor)¼19.18 min.
4.3. General procedure for the synthesis of the diol-adducts
4aed, g, h
To a hydroxyacetone (4.4 mL, 60 mmol, 20 equiv) solution of
1-benzothiophene-2-carbaldehyde 1a (0.5 g, 3.00 mmol) at 0 ꢀC,
cat. II (18 mg, 0.070 mmol, 0.1 equiv) was added in one portion. The
mixture was stirred for 78 h at this temperature, and the resulting
solution was treated with a solution of NH4Cl aq (15 mL) and
extracted with EtOAc (20 mL). The organic phase was dried with
Na2SO4 and concentrated under reduced pressure after filtration.
The yellow crude solid was chromatographed using petroleum
ether/DCM/EtOAc 35:35:20 to afford the corresponding aldol ad-
ducts 4a-anti and 4a-syn.
4.3.5. (3S,4R)-4-(3-Chloro-1-benzothiophen-2-yl)-3,4-dihydroxybu-
tan-2-one (4c-anti). Chromatography, petroleum ether/DCM/
EtOAc 35:35:20. Colourless oil (0.6 g, yield 48%). [
a
]
27 þ18.9 (c 0.56,
D
CHCl3). IR
n
(neat) 3443, 1730 cmꢂ1
.
1H NMR (500 MHz, CDCl3)
d
¼7.82e7.78 (m, 2H), 7.47e7.41 (m, 2H), 5.66 (s, 1H), 4.75 (s, 1H),
3.86 (br s, 1H D2Oexc), 2.98 (br s, 2H D2Oexc), 2.20 (s, 3H). 13C NMR
(125 MHz, CDCl3)
d
¼206.2, 137.5, 135.9, 135.2, 125.8, 125.0, 122.7,
121.9, 118.6, 79.3, 69.3, 26.8. MS-EI (C12H11ClO3S) m/z: 270 (5, Mþ),
212 (21), 197 (100), 168 (30), 132 (27), 113 (15), 89 (29), 74 (65%).
Anal. Calcd for C12H11ClO3S: C. 53.24; H. 4.10; S. 11.84. Found: C.
53.32; H. 4.13; S. 11.89. HPLC: Diacel Chiralpak AD-H. Hexane/i-
PrOH, 15:85, 1.0 mL/min, 254 nm: tR (major)¼26.23 min; tR
(minor)¼28.53 min.
4.3.1. (3S,4R)-4-(1-Benzothiophen-2-yl)-3,4-dihydroxybutan-2-one
(4a-anti). Chromatography, petroleum ether/DCM/EtOAc 35:35:20.
26
White solid (0.9 g, yield 67%). Mp¼82e84 ꢀC. [
a]
D
þ20.5 (c 0.54,
CHCl3). IR
n .
(neat) 3455, 1728 cmꢂ1 1H NMR (500 MHz, CDCl3)
d
¼7.79 (d, J¼7.5 Hz, 1H), 7.71 (d, J¼7.0 Hz, 1H), 7.34e7.31 (m, 2H),
5.30 (s, 1H), 4.55 (s, 1H), 3.80 (br s, 1H D2Oexc), 3.20 (br s, 1H D2Oexc),
2.13 (s, 3H). 13C NMR (125 MHz, CDCl3)
4.3.6. (3S,4S)-4-(3-Chloro-1-benzothiophen-2-yl)-3,4-dihydroxybu-
tan-2-one (4c-syn). Chromatography, petroleum ether/DCM/EtOAc
d¼206.9, 142.6, 139.6, 139.0,
35:35:20. White solid (0.5 g, yield 39%). Mp¼98e100 ꢀC. [
a]
22 þ33.4
D
124.6, 124.5, 123.7, 122.3, 121.9 80.5, 72.0, 27.1. MS-EI (C12H12O3S)
m/z: 236 (11, Mþ), 218 (17), 187 (7), 178 (25), 161 (70), 147 (67), 134
(23), 115 (35), 89 (40), 57 (61), 43 (100%). Anal. Calcd for C12H12O3S:
C, 61.00; H, 5.12; S, 13.57. Found: C, 60.93; H, 5.15; S, 13.62. HPLC:
Diacel Chiralpak AD-H. Hexane/i-PrOH, 90:10, 1.0 mL/min, 254 nm:
tR (major)¼29.63 min; tR (minor)¼28.33 min.
(c 0.70, CHCl3). IR
n
(neat) 3447, 1727 cmꢂ1
.
1H NMR (500 MHz,
CDCl3)
d
¼7.80(t, J¼6.5 Hz, 2H), 7.48e7.41 (m, 2H), 5.64 (s, 1H), 4.50
(s, 1H), 2.36 (s, 3H). 13C NMR (125 MHz, CDCl3)
d
¼206.4, 137.4, 137.2,
136.1, 125.6, 125.0, 122.7, 121.7, 117.5, 79.3, 68.7, 25.7. MS-EI
(C12H11ClO3S) m/z: 270 (18, Mþ), 212 (30), 197 (100), 168 (34), 132
(41),113 (19), 89 (24), 74 (87%). Anal. Calcd for C12H11ClO3S: C, 53.24;
H, 4.10; S, 11.84. Found: C, 53.31; H, 4.07; S, 11.91. HPLC: Diacel
Chiralpak AD-H. Hexane/i-PrOH, 85:15, 1.0 mL/min, 254 nm: tR
(major)¼35.95 min; tR (minor)¼41.78 min.
4.3.2. (3S,4S)-4-(1-Benzothiophen-2-yl)-3,4-dihydroxybutan-2-one
(4a-syn). Chromatography, petroleum ether/DCM/EtOAc 35:35:20.
24
White solid (0.4 g, yield 26%). Mp¼87e89 ꢀC. [
a]
þ13.8 (c 0.46,
D
CHCl3). IR
n
(neat) 3460, 1730 cmꢂ1
.
1H NMR (500 MHz, CDCl3)
4.3.7. (3S,4R)-4-(3-Bromo-1-benzothiophen-2-yl)-3,4-dihydroxybu-
d
¼7.81 (d, J¼7.5 Hz, 1H), 7.73 (d, J¼7.0 Hz, 1H), 7.40e7.32 (m, 2H),
5.34 (s, 1H), 4.49 (s, 1H), 3.88 (br s,1H D2Oexc), 2.98 (br s,1H D2Oexc),
2.32 (s, 3H). 13C NMR (125 MHz, CDCl3)
tan-2-one (4d-anti). Chromatography, petroleum ether/DCM/
EtOAc 35:35:20. White solid (0.9 g, yield 68%). Mp¼112e114 ꢀC.
24
d¼206.8, 143.9, 139.7, 139.1
[
a
]
þ71.4 (c 0.392, CHCl3). IR
n
(neat) 3438, 3002, 1731 cmꢂ1. 1H
¼7.81 (t, J¼8.0 Hz, 2H), 7.46 (t, J¼8.0 Hz,
D
124.5, 124.4, 122.7, 122.6, 80.0, 70.9, 26.1. MS-EI (C12H12O3S) m/z:
236 (7, Mþ), 218 (10), 187 (12), 178 (21), 161 (70), 147 (62), 134 (31),
115 (21), 89 (47), 57 (35), 43 (100%). Anal. Calcd for C12H12O3S: C,
61.00; H, 5.12; S, 13.57. Found: C, 61.09; H, 5.08; S, 13.51. HPLC:
Diacel Chiralpak AD-H. Hexane/i-PrOH, 90:10, 1.0 mL/min, 254 nm:
tR (major)¼36.50 min; tR (minor)¼34.55 min.
NMR (500 MHz, CDCl3)
d
1H), 7.42 (t, J¼8.0 Hz, 1H), 5.64 (t, J¼4.5 Hz, 1H), 4.76 (t, J¼4.5 Hz,
1H), 3.86 (d, J¼5.0 Hz,1H D2Oexc), 3.01 (d, J¼6.5 Hz,1H D2Oexc), 2.19
(s, 3H). 13C NMR (125 MHz, CDCl3)
d
¼206.1, 138.0, 137.6, 137.0,
125.9, 125.3, 123.3, 122.6, 107.1, 79.2, 70.7, 27.0. MS-EI
(C12H11BrO3S) m/z: 314 (6, Mþ), 296 (5), 241 (18), 223 (20), 205
(8), 185 (15), 173 (19), 159 (21), 149 (67), 141 (50), 112 (85), 99 (42),
85 (90), 69 (63), 57 (62), 43 (100%). Anal. Calcd for C12H11BrO3S: C.
45.73; H. 3.52; S. 10.17. Found: C. 45.63; H. 3.57; S. 10.11. HPLC:
Diacel Chiralpak AD-H. Hexane/i-PrOH, 89:11, 1.0 mL/min, 254 nm:
tR (major)¼15.47 min; tR (minor)¼16.59 min.
4.3.3. (3S,4R)-3,4-Dihydroxy-4-(3-methyl-1-benzothiophen-2-yl)bu-
tan-2-one (4b-anti). Chromatography, petroleum ether/DCM/EtOAc
35:35:20. White solid (0.6 g, yield 45%). Mp¼97e99 ꢀC.
23.5
[a
]
¼ꢂ125 (c 0.112, CHCl3). IR
n
(neat) 3447, 1729 cmꢂ1. 1H NMR
¼7.80 (d, J¼7.5 Hz, 1H), 7.68 (d, J¼7.5 Hz, 1H),
D
(500 MHz, CDCl3)
7.39e7.33 (m, 2H), 5.41 (d, J¼5.5 Hz, 1H), 4.53 (d, J¼5.5 Hz, 1H), 2.42
(s, 3H), 2.18 (s, 3H). 13C NMR (125 MHz, CDCl3)
136.3, 129.7, 124.8, 124.1, 122.5, 121.9, 79.8, 69.8, 27.2, 12.3. MS-EI
(C13H14O3S) m/z: 250 (15, Mþ), 232 (21), 207 (30), 177 (37), 161
(53), 147 (40), 102 (75), 89 (23), 75 (33), 43 (100%). Anal. Calcd for
C13H14O3S: C, 62.38; H, 5.64; S, 12.81. Found: C, 62.30; H, 5.69; S,
12.72. HPLC: Diacel Chiralpak OD-H. Hexane/i-PrOH, 95:5,
1.0 mL/min, 254 nm: tR (major)¼17.78 min; tR (minor)¼14.85 min.
d
4.3.8. (3S,4S)-4-(3-Bromo-1-benzothiophen-2-yl)-3,4-dihydroxybu-
d¼207.7, 139.9, 139.1,
tan-2-one (4d-syn). Chromatography, petroleum ether/DCM/EtOAc
25
35:35:20. White solid (0.4 g, yield 33%). Mp¼93e95 ꢀC. [
a]
D
¼ꢂ45.4
(c 0.08, CHCl3). IR n
(neat) 3430, 3002,1727 cmꢂ1. 1H NMR (500 MHz,
CDCl3)
1H), 4.54 (s, 1H), 3.87(d, J¼4.5, 1H D2Oexc), 2.93 (d, J¼7.0, 1H D2Oexc),
2.39 (s, 3H). 13C NMR (125 MHz, CDCl3)
d¼7.82e7.81 (m, 2H), 7.47e7.39 (m, 2H), 5.63 (d, J¼3.5, Hz,
d¼206.3, 139.4, 137.7, 137.6,
125.7, 125.2, 122.9, 122.6, 105.4, 79.3, 70.1, 25.7. MS-EI (C12H11BrO3S)
m/z: 314 (11, Mþ), 296 (8), 242 (16), 223 (23), 185 (19), 173 (21), 159
(27), 142 (44), 112 (80), 99 (40), 85 (91), 69 (60), 57 (64), 43 (100%).
Anal. Calcd for C12H11BrO3S: C. 45.73; H. 3.52; S. 10.17. Found: C.
45.65; H. 3.50; S.10.19. HPLC: Diacel Chiralpak AD-H. Hexane/i-PrOH,
89:11,1.0 mL/min, 254 nm: tR (major)¼21.35 min; tR (minor)¼24.11 min.
4.3.4. (3S,4S)-3,4-Dihydroxy-4-(3-methyl-1–benzothiophen-2-yl)bu-
tan-2-one (4b-syn). Chromatography, petroleum ether/DCM/EtOAc
35:35:20. Viscous yellow oil (0.4 g, yield 26%). [
CHCl3). IR
28
a]
D
þ83.2 (c 0.81,
n
(neat) 3451,1730 cmꢂ1.1H NMR (500 MHz, CDCl3)
d
¼7.81
(d, J¼7.5 Hz, 1H), 7.67 (d, J¼7.5 Hz, 1H), 7.40e7.30 (m, 2H), 5.37 (d,
J¼3.5 Hz,1H), 4.41 (s,1H), 3.81 (br s,1H D2Oexc), 3.03 (br s,1H D2Oexc),
4.3.9. (3S,4R)-3,4-Dihydroxy-4-(5-nitrothiophen-2-yl)butan-2-one
(4g-anti). Chromatography, petroleum ether/DCM/EtOAc 35:35:20.
2.40 (s, 3H), 2.21 (s, 3H). 13C NMR (125 MHz, CDCl3)
d¼207.3, 140.0,

4780
F. Secci et al. / Tetrahedron 68 (2012) 4773e4781
23
Colourless oil (0.9 g, yield 61%). [
a
]
þ28.5 (c 0.63, CHCl3). IR
n
4.4.1. (R)-4-(1-Benzothiophen-2-yl)-4-hydroxy-2-oxobutyl acetate
(5a). Chromatography, petroleum ether/EtOAc 70:30. Colourless
D
(neat) 3215, 3000, 2989, 1780, 1624, 1347 cmꢂ1. 1H NMR (500 MHz,
CDCl3) ¼7.80 (d, J¼4.5 Hz, 1H), 6.98 (d, J¼4.0 Hz, 1H), 5.20 (d,
J¼4.0 Hz, 1H), 4.48 (d, J¼4.0 Hz, 1H), 3.76 (br s, 1H D2Oexc), 3.20 (s,
1H D2Oexc), 2.19 (s, 3H). 13C NMR (125 MHz, CDCl3)
128.2, 124.2, 110.0, 79.9, 71.5, 27.3. MS-EI (C8H9NO3S) m/z: 231 (8,
Mþ), 213 (23), 188 (61), 158 (95), 128 (34), 74 (51), 43 (100%). Anal.
Calcd for C8H9NO5S: C, 41.56; H, 3.92; N, 6.06; S, 13.87. Found: C,
41.65; H, 3.94; N, 6.12; S, 13.81. HPLC: Diacel Chiralpak AD-H.
Hexane/i-PrOH, 85:15, 1.0 mL/min, 254 nm: tR (major)¼26.35
min; tR (minor)¼24.10 min.
28
d
oil (1.3 g, yield 78%). [
a
]
þ17.45 (c 1.05, CHCl3). IR
n
(neat) 3129,
D
3009, 2989, 2833, 1724, 1732 cmꢂ1
.
1H NMR (300 MHz, CDCl3)
d
¼206.3, 150.6,
d
¼7.81 (d, J¼7.2 Hz, 1H), 7.78 (d, J¼7.2 Hz, 1H), 7.37e7.28 (m, 2H),
7.21 (s, 1H), 5.45 (dd, J¼8.1, 3.5 Hz, 1H), 4.65 (s, 2H), 3.57 (br s, 1H),
3.07 (dd, J¼13.0, 8.1 Hz, 2H), 2.15 (s, 3H). 13C NMR (125 MHz, CDCl3)
d
¼208.1, 170.4, 145.0, 139.4, 134.9, 128.8, 124.3, 124.2, 123.5, 120.9,
69.7, 56.2, 44.0, 21.9. MS-EI (C14H14O4S) m/z: 278 (15, Mþ), 260 (27),
235 (60), 219 (35), 190 (74), 177 (83), 160 (89), 74 (26), 43 (95%).
Anal. Calcd for C14H14O4S: C, 60.42; H, 5.07; S, 11.52. Found: C,
60.53; H, 5.12; S, 11.44. HPLC: Diacel Chiralcel OJ. Hexane/i-PrOH,
92:8, 0.5 mL/min, 254 nm: tR (minor)¼21.12 min; tR (major)¼27.35 min.
4.3.10. (3S,4S)-3,4-Dihydroxy-4-(5-nitrothiophen-2-yl)butan-2-one
(4g-syn). Chromatography, petroleum ether/DCM/EtOAc 35:35:20.
24
Colourless oil (0.4 g, yield 29%). [
a
]
þ45.3 (c 0.82, CHCl3). IR
n
4.4.2. (R)-4-Hydroxy-4-(3-methyl-1-benzothiophen-2-yl)-2-oxobutyl
acetate (5b). Chromatography, petroleum ether/EtOAc 70:30. Col-
D
(neat) 3201, 3003, 2989, 1727, 1620, 1350 cmꢂ1. 1H NMR (500 MHz,
CDCl3)
¼7.82 (d, J¼4.0 Hz, 1H), 7.04 (d, J¼4.0 Hz, 1H), 5.31 (s, 1H),
4.37 (s, 1H), 3.91 (br s, 1H D2Oexc), 2.97 (br s, 1H D2Oexc), 2.37 (s, 3H).
13C NMR (125 MHz, CDCl3)
26
d
ourless oil (1.3 g, yield 78%). [
a
]
þ6.06 (c 1.65, CHCl3). IR
n
(neat)
D
3427, 1735, 1719 cmꢂ1
.
1H NMR (300 MHz, CDCl3)
d
¼7.78 (d,
d
¼206.3, 151.8, 128.2, 124.1, 110.0, 79.2,
J¼7.2 Hz, 1H), 7.63 (d, J¼7.8 Hz, 1H), 7.37e7.29 (m, 2H), 5.65 (dd,
J¼9.3, 2.4 Hz, 1H), 4.66 (s, 2H), 3.09 (br s, 1H), 3.04 (dd, J¼16.8,
9.3 Hz,1H), 2.79 (dd, J¼16.8, 3.3 Hz,1H), 2.34 (s, 3H), 2.14 (s, 3H). 13C
70.2, 25.9. MS-EI (C8H9NO3S) m/z: 231 (12, Mþ), 213 (15), 188 (54),
158 (100), 128 (29), 72 (44), 43 (92%). Anal. Calcd for C8H9NO5S: C,
41.56; H, 3.92; N, 6.06; S, 13.87. Found: C, 41.61; H, 3.89; N, 5.99; S,
13.95. HPLC: Diacel Chiralpak AD-H. Hexane/i-PrOH, 85:15, 1.0 mL/
min, 254 nm: tR (major)¼38.58 min; tR (minor)¼40.84 min.
NMR (75 MHz, CDCl3)
d
¼203.0, 170.2, 140.3, 140.0, 138.3, 127.4,
124.4, 124.0, 122.5, 121.7, 68.4, 64.7, 47.1, 20.4, 11.8. MS-EI
(C15H16O4S) m/z: 292 (20, Mþ), 274 (31), 249 (45), 233 (90), 190
(31), 176 (84), 162 (100), 158 (27), 74 (85), 43 (94%). Anal. Calcd for
C15H16O4S: C, 61.63; H, 5.52; S, 10.97. Found: C, 61.53; H, 5.56; S,
11.02. HPLC: Diacel Chiralpak OJ. Hexane/i-PrOH, 90:10, 1.0 mL/min,
254 nm: tR (minor)¼27.12 min; tR (major)¼30.31 min.
4.3.11. (3S,4R)-3,4-Dihydroxy-4-(thiophen-2-yl)butan-2-one (4h-
anti). Chromatography, petroleum ether/DCM/EtOAc 35:35:20.
25
Colourless oil (1.0 g, yield 61%). [
a
]
þ44.2 (c 0.65, CHCl3). IR
n
D
(neat) 3502, 3003, 2989, 2889, 1780, 1166, 1060 cmꢂ1
.
1H NMR
(500 MHz, CDCl3)
d
¼7.28(d, J¼5.0 Hz, 1H), 7.03 (d, J¼3.5 Hz, 1H),
4.4.3. (R)-4-(3-Bromo-1-benzothiophen-2-yl)-4-hydroxy-2-oxobutyl
acetate (5d). Chromatography, petroleum ether/EtOAc 80:20. Col-
6.99e6.98 (m, 1H), 5.25 (d, J¼4.0 Hz, 1H), 4.51 (d, J¼4.0 Hz, 1H),
3.74 (br s, 1H D2Oexc), 2.11 (s, 3H). 13C NMR (125 MHz, CDCl3)
ourless oil (1.2 g, yield 80%). [
a
]
27 þ94.11ꢀ (c 1.01, CHCl3). IR
n
(neat)
D
d
¼206.9 141.8, 126.7, 125.8, 125.2, 80.6, 71.3, 26.9. MS-EI
3450, 1732, 1722 cmꢂ1
.
1H NMR (300 MHz, CDCl3)
d
¼7.78 (t,
(C8H10O3S) m/z: 186 (5, Mþ), 168 (12), 131 (81), 113 (95), 97
(29), 85 (77), 74 (40), 58 (100%). Anal. Calcd for C8H10O3S: C. 51.60;
H. 5.41; S. 17.22. Found: C. 51.62; H. 5.37; S. 17.26. HPLC: Diacel
Chiralpak AD-H. Hexane/i-PrOH, 85:15, 1.0 mL/min, 254 nm: tR
(major)¼34.57 min; tR (minor)¼29.63 min.
J¼8.4 Hz, 1H), 7.76 (t, J¼9.3 Hz, 1H), 7.45e7.34 (m, 2H), 5.70 (dd,
J¼7.5, 4.8 Hz, 1H), 4.71 (s, 2H), 3.55 (br s, 1H), 2.97 (dd, J¼4.8, 3.0 Hz,
2H), 2.16 (s, 3H). 13C NMR (75 MHz, CDCl3)
d
¼203.1, 170.3, 141.7,
137.9, 137.1, 125.4, 125.1, 123.1, 122.7, 103.8, 68.3, 66.3, 45.8, 22.3.
MS-EI (C14H13BrO4S) m/z: 356 (34, Mþ), 338 (75), 313 (34), 297 (50),
254 (68), 240 (87), 132 (26), 58 (28), 43 (100%). Anal. Calcd for
C14H13BrO4S: C, 47.07; H, 3.67; S, 8.97. Found: C, 47.16; H, 3.52; S,
8.91. HPLC: Diacel Chiralpak OJ. Hexane/i-PrOH, 92:8, 1.0 mL/min,
254 nm: tR (minor)¼29.11 min; tR (major)¼32.40 min.
4.3.12. (3S,4S)-3,4-Dihydroxy-4-(thiophen-2-yl)butan-2-one (4h-
syn). Chromatography, petroleum ether/DCM/EtOAc 35:35:20.
25
Colourless oil (0.5 g, yield 29%). [
a
]
þ19.8 (c 0.58, CHCl3). IR
n
D
(neat) 3507, 3004, 2989, 2890, 1787, 1201, 1064 cmꢂ1
.
1H NMR
(500 MHz, CDCl3)
d
¼7.30(d, J¼4.0 Hz, 1H), 7.10 (d, J¼3.5 Hz, 1H),
4.4.4. (R)-4-(1-Benzothiophen-3-yl)-4-hydroxy-2-oxobutyl acetate
6.99 (dd, J¼3.5, 3.5 Hz, 1H), 5.24 (s, 1H), 4.40 (s, 1H), 3.83 (d,
J¼4.0 Hz, 1H D2Oexc), 2.85 (d, J¼5.5 Hz, 1H D2Oexc), 2.27 (s, 3H).
(5i). Chromatography, petroleum ether/EtOAc 70:30. White solid
26
(1.1 g, yield 65%). Mp¼79e80 ꢀC. [
a
]
D
þ26.54 (c 1.12, CHCl3). IR
n
13C NMR (125 MHz, CDCl3)
d
¼207.1, 143.2, 126.7, 125.8, 125.4,
(neat) 3431, 1727, 1720 cmꢂ1 1H NMR (300 MHz, CDCl3)
.
80.2, 70.4, 26.1. MS-EI (C8H10O3S) m/z: 186 (7, Mþ), 168 (10), 126
(7), 113 (100), 111 (31), 97 (28), 85 (46), 74 (34%). Anal. Calcd for
C8H10O3S: C, 51.60; H, 5.41; S, 17.22. Found: C, 51.69; H, 5.38; S,
17.15. HPLC: Diacel Chiralpak AD-H. Hexane/i-PrOH, 85:15,
1.0 mL/min, 254 nm: tR (major)¼38.42 min; tR (minor)¼36.15 min.
d
¼7.91e7.81 (m, 2H), 7.42e7.32 (m, 2H), 5.59 (dd, J¼9.0, 3.0 Hz, 1H),
4.70 (s, 2H), 3.04 (dd, J¼16.8, 9.0 Hz, 1H), 3.01 (s, 1H), 2.94 (dd,
J¼16.8, 3.0 Hz, 1H), 2.16 (s, 3H). 13C NMR (75 MHz, CDCl3)
¼203.8,
d
170.3, 137.3, 136.6, 124.5, 124.2, 123.0, 122.7, 121.8, 110.5, 68.4, 65.6,
45.9, 20.4. MS-EI (C14H14O4S) m/z: 278 (18, Mþ), 218 (10), 205 (28),
163 (91), 147 (19), 135 (48), 116 (21), 91 (30), 74 (55), 43 (100%).
Anal. Calcd for C14H14O4S: C, 60.42; H, 5.07; S, 11.52. Found: C,
60.51; H, 5.06; S. 11.59. HPLC: Diacel Chiralpak OJ. Hexane/i-PrOH,
91:9, 0.5 mL/min, 254 nm: tR (minor)¼39.25 min; tR (major)¼44.37 min.
4.4. General procedure for the synthesis of the aldol adducts
5a, b, d, i
To an acetoxyacetate (2.85 g, 24.6 mmol, 20 equiv) solution of
1-benzothiophene-2-carbaldehyde 1a (0.2 g, 1.23 mmol) at 0 ꢀC,
cat. III (19 mg, 0.123 mmol, 0.1 equiv) was added in one portion. The
mixture was stirred for 12 h at this temperature, and the resulting
solution was treated with a solution of NH4Cl aq (15 mL) and
extracted with EtOAc (20 mL). The organic phase was dried with
Na2SO4 and concentrated under reduced pressure after filtration.
The yellow crude solid was chromatographed using petroleum
ether/EtOAc 70:30 to afford the corresponding aldol adduct as
a white solid (0.26 g, 78% yield).
4.5. Synthesis of (R)-4-hydroxy-5-methyl-5-(phenylthio)
hexan-2-one
Acetone (5.0 mL, 20 equiv) and 1-(phenylthio)cyclopropane
carbaldehyde (0.8 g, 4.40 mmol) were dissolved in dry DMSO at
0 ꢀC, cat. I (10 mg, 0.88 mmol, 0.2 equiv) was added in one portion.
The mixture was stirred for 48 h at this temperature, and the
resulting solution was treated with a solution of NH4Cl aq (15 mL)
and extracted with EtOAc (20 mL). The organic phase was dried

F. Secci et al. / Tetrahedron 68 (2012) 4773e4781
4781
3034e3038; (d) Hsiao, C. N.; Kolasa, T. Tetrahedron Lett. 1992, 33, 2629e2632;
with Na2SO4 and concentrated under reduced pressure after fil-
tration. The yellow crude solid was chromatographed using pe-
troleum ether/EtOAc 80:20 to afford the corresponding aldol
ꢂ
ꢀ
(e) Martinez, J.; Perez, S.; Oficialdegui, A. M.; Heras, B.; Orus, L.; Villanueva, H.;
Palop, J. A.; Roca, J.; Mourelle, M.; Bosch, A.; Del Castillo, J.-C.; Lasheras, B.;
Tordera, R.; del Rio, J.; Monge, A. Eur. J. Med. Chem. 2001, 36, 55e61; (f) Bo-
schelli, D. H.; Kramer, J. B.; Khatana, S. S.; Sorenson, R. J.; Connor, D. T.; Ferin, M.
A.; Wright, C. D.; Lesch, M. E.; Imre, K.; Okonkwo, G. C.; Schrier, D. J.; Conroy, M.
C.; Ferguson, E.; Woelle, J.; Saxena, U. J. Med. Chem. 1995, 38, 4597e4614; (g)
Connor, D. T.; Cetenko, W. A.; Mullican, M. D.; Sorenson, R. J.; Weikert, R. J.;
Adolphson, R. L.; Kennedy, J. A.; Thueson, D. O.; Wright, C. D.; Conroy, M. C. J.
Med. Chem. 1992, 35, 958e965; (h) De Nanteuil, G.; Lila-Ambroise, C.; Vallez,
M.-O.; Verbeuren, T. J. Bioorg. Med. Chem. Lett. 2003, 13, 1705e1708; (i) Boul-
ware, S. L.; Bronstein, J. C.; Nordby, E. C.; Weber, P. C. Antiviral Res. 2001, 51,
111e125.
26
adduct as a white solid (0.23 g, 69% yield). Mp¼69e71 ꢀC. [
a]
D
þ20.85 (c 2.11, CHCl3). IR
n (neat) 3479, 3000, 2989, 1723, 1630,
1154 cmꢂ1
.
1H NMR (300 MHz, CDCl3)
d
¼7.53e7.49 (m, 2H),
7.38e7.33 (m, 3H), 3.91 (dt, J¼10.2, 2.4 Hz, 1H), 3.16 (m, 1H), 2.79
(dd, J¼16.8, 2.4 Hz, 1H), 2.64 (J¼16.8, 10.2 Hz, 1H), 2.22 (s, 3H), 1.26
(s, 3H), 1.20 (s, 3H). 13C NMR (75 MHz, CDCl3)
d
¼208.8, 137.4, 130.4,
129.1, 128.7, 72.1, 53.1, 44.8, 30.9, 24.6, 23.9. MS-EI (C13H18O2S) m/z:
238 (7, Mþ), 220 (45), 205 (24), 195 (16), 180 (89), 111 (77), 109
(100), 58 (64), 43 (40%). Anal. Calcd for C13H18O2S: C, 48.18; H, 3.71;
S,10.72. Found: C, 48.28; H, 3.75; S,10.67. HPLC: Diacel Chiralpak OJ.
Hexane/i-PrOH, 98:2, 1.0 mL/min, 254 nm: tR (minor)¼16.14 min; tR
(major)¼23.46 min (ee 98%).
5. (a) Irie, M. Chem. Rev. 2000, 100, 1685e1716; (b) Irie, M. Photo-reactive Materials
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Full characterization of syn/anti diastereoisomers 6 was limited
by the purification step: they were identified through 1H NMR
analysis of the coupling constants of the carbinolic protons. Com-
pound 6a-anti: 5.28 (d, J¼4.2 Hz, 1H), 4.57 (dd, J¼4.2, 6.9 Hz, 1H),
4.06 (d, J¼6.9 Hz, 1H). Compound 6a-syn: 5.35 (d, J¼1.8 Hz, 1H),
4.48 (dd, J¼1.8, 2.7 Hz, 1H), 4.20 (br s, 1H). Compound 6b-anti: 5.44
(dd, J¼3.0, 6.6 Hz,1H), 5.23 (d, J¼6.6 Hz,1H), 3.70 (d, J¼3.0 Hz), 2.35
(s, 3H). Compound 6b-syn: 5.53 (dd, J¼7.2, 2.4 Hz, 1H), 5.28 (d,
J¼7.2 Hz, 1H), 3.63 (d, J¼2.4 Hz, 1H). Compound 6d-anti: 5.63 (dd,
J¼3.0, 6.6 Hz, 1H), 5.39 (d, J¼6.6 Hz, 1H), 3.49 (d, J¼3.0 Hz, 1H).
Compound 6d-syn: 5.80 (dd, J¼2.2, 5.1 Hz, 1H), 5.61 (d, J¼5.1 Hz,
1H), 3.31 (m, 1H). Compound 6i-anti: 5.46 (dd, J¼3.6, 6.0 Hz, 1H),
5.40 (d, J¼6.0 Hz 1H), 2.91 (d, J¼3.6 Hz, 1H). Compound 6i-syn: 5.60
(dd, J¼1.5, 5.7 Hz, 1H), 4.89 (d, J¼5.7 Hz, 1H), 4.40 (d, J¼1.5 Hz, 1H).
Acknowledgements
11. Chen, X.-H.; Luo, S.-W.; Tang, Z.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z.
Chem.dEur. J. 2007, 13, 689e701.
Financial support from the MIUR, Rome, from the University of
Cagliari (National Project ‘Stereoselezione in Sintesi Organica
Metodologie ed Applicazioni’) and from CINMPIS and FIRB is
gratefully acknowledged.
12. (a) Bonini, C.; Chiumiento, L.; De Bonis, M.; Funicello, M.; Lupattelli, P.; Pan-
dolfo, R. Tetrahedron: Asymmetry 2006, 17, 2919e2924; (b) Bonini, C.; Chiu-
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Supplementary data
13. Primary amines, such as catalyst IV and its derivatives have recently emerged as
potential syn- or anti-selective organocatalysts using substituted benzaldehyde
derivatives. See: (a) Utsumi, N.; Imai, M.; Tanaka, F.; Ramasastry, S. S. V.; Barbas,
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omol. Chem. 2011, 9, 2731e2742; (e) Wu, C.; Fu, X.; Ma, X.; Li, S.; Li, C. Tetra-
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Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.04.008.
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