Enantioselective conjugate addition of aliphatic thiols to divergently activated electron poor alkenes and dienes

Article abstract of DOI:10.1016/j.tet.2014.06.035

Divergently activated double bonds in electron poor 4-oxo-butenoates and (2E,4E)-6-oxo-2,4-dienoates underwent stereoselective and regioselective addition of mercaptans catalyzed by simple Cinchona alkaloids. Application of quinine and quinidine afforded both enantiomers of the 1,4-adducts with respect to the ketone carbonyl group in ees of up to 80%. Single recrystallization of some adducts resulted in further enrichment of up to 99%ee.

Full text of DOI:10.1016/j.tet.2014.06.035

Tetrahedron 70 (2014) 5834e5842
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective conjugate addition of aliphatic thiols to divergently
activated electron poor alkenes and dienes
,
a
a
b
Rafa1 Kowalczyk a , Aleksandra J. Wierzba , Przemys1aw J. Boratynski , Julia Ba˛kowicz
*
ꢀ
a
ꢀ
Department of Organic Chemistry, Wrocław University of Technology, Wyspianskiego 27, Wrocław, Poland
Institute of Physical and Theoretical Chemistry, Wrocław University of Technology, Wyspianskiego 27, Wrocław, Poland
b
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Divergently activated double bonds in electron poor 4-oxo-butenoates and (2E,4E)-6-oxo-2,4-dienoates
underwent stereoselective and regioselective addition of mercaptans catalyzed by simple Cinchona al-
kaloids. Application of quinine and quinidine afforded both enantiomers of the 1,4-adducts with respect
to the ketone carbonyl group in ees of up to 80%. Single recrystallization of some adducts resulted in
further enrichment of up to 99%ee.
Received 31 March 2014
Received in revised form 28 May 2014
Accepted 10 June 2014
Available online 14 June 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Thia-Michael addition
Regioselectivity
Alkaloids
1. Introduction
Here we present the direct and enantioselective addition of
mercaptans to 4-oxo-butenoates and (2E,4E)-6-oxo-2,4-dienoates
Direct addition of sulfur-centered nucleophiles to Michael ac-
ceptors offers an access to products with new CeS bonds.1 Gener-
ally, thiols are recognized as good partners in additions to Michael
catalyzed by quinine and quinidine.
2. Results and discussion
acceptors. However, in the case of a,b-unsaturated carboxylic acid
esters the activation of the double bond is often insufficient.2 This
lack of reactivity can be overcome in substrates where an extra
electron withdrawing group is introduced. When such a group is at
Previous attempts to perform the addition of thiols to 4-oxo-
butenoates applying triethylamine revealed that the reaction oc-
curs regioselectively at the b
-position relative to the ketone group.8
the opposite end of the
functionality altering regioslectivity,3 and as a result the addition of
thiol may occur at the -carbon to the ester group. This formally
p-system it competes with the ester
With no precedent of a stereoselective variant of such addition,
search for the direct stereoselective thia-Michael addition to 4-oxo-
buteonates began with the application of chiral Michael acceptor 1.
In the reaction with benzyl mercaptan and DABCO the respective
adducts 2a,b were formed with only 55:45 dr (Scheme 1). There-
fore, the effect of the chiral auxiliary attached directly to the Mi-
chael acceptor is rather limited.
a
inverted reactivity pattern4 as compared to simple acrylates gives
access to products that are otherwise difficult to obtain. Conse-
quently, addition of various nucleophiles to modified acrylates
leads to multifunctional molecules, which are valuable synthetic
intermediates and are relevant to medicinal chemistry.5
Another challenge is associated with providing stereoselectivity
for the addition of thiols to such a system. Although 4-oxo-buteo-
noates received significant attention as electrophiles in metal- and
organocatalytic variants of asymmetric Michael addition and Frie-
deleCrafts reactions,6 no enantioselective addition of thiols was
reported.7
* Corresponding author. Tel.: þ48 713203302; fax: þ48 713202727; e-mail ad-
dress: rafal.kowalczyk@pwr.edu.pl (R. Kowalczyk).
URL: http://org.wch.pwr.edu.pl
Scheme 1.
http://dx.doi.org/10.1016/j.tet.2014.06.035
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

R. Kowalczyk et al. / Tetrahedron 70 (2014) 5834e5842
5835
stereoselectivity in catalytic asymmetric reactions,10 bifunctional
thiourea catalysts11 were applied (Fig. 1, C11e18). To our surprise,
all of the tested catalysts were inferior to simple alkaloids, while
thiourea C1712 and Takemoto catalyst (C16)13 provided less than
40%ee. Introduction of additional interacting sites in the catalyst, as
in cupreine (C8), also resulted in poor selectivity. Furthermore, an
approach involving stronger interactions with the catalyst, by the
expected14 formation of an iminium salt was tested. Although 9-
aminoalkaloids work perfectly in the thia-Michael reaction of al-
kyl thiols and enones,15 application of epi-9-amino-deoxyquinine
and 2-fluorobenzoic acid mixture led to nearly racemic products. It
must be emphasized that such a strategy in the case of ethyl (E)-4-
oxo-2-pentenoate was effective when a nitrogen-centered nucle-
ophile was applied.16 Moreover, only racemic products were ob-
served when thiophenol was applied. Thus, the aromatic nature of
the nucleophile is detrimental to the stereoselectivity in the tested
reaction.
In order to further investigate the impact of the structural ele-
ments in the most efficient catalyst on the chirality transfer, several
analogues of quinine were tested. These aminoalcohols were then
assayed in the reaction of bulky 4-tert-butylbenzylmercaptan with
acceptor 3 (Scheme 2). Modification of the vinyl group of quinine as
in C19 and dihydroquinine (C20) had a limited impact on the
stereoselectivity. However, the presence of a complete alkaloid
framework proved to be crucial, while application of aminoalcohol
C21 led to product with low ee.
However, an application of a chiral base (quinidine) led to dia-
stereomerically enriched product and 74:26 dr was achieved. With
quinine catalyst a different isomer of the adduct was obtained in
72:28 dr. The formation of antipodes of the product with the use of
catalysts of different configuration demonstrates that the chiral
catalyst, rather than the auxiliary, was able to control the stereo-
selectivity. The action of both these modalities is independent as
evidenced by the difference in diastereoselectivity for the pseu-
doenantiomeric catalysts being in qualitative agreement with the
value obtained in the reaction with achiral catalyst. Consequently,
simple Cinchona alkaloids were found to perform the addition of
benzyl thiol to acceptor 3 in an enantioselective manner (catalysts
C1eC5, Fig. 1). In each case the configuration at the 8-position in
the alkaloid determines the stereochemical result of the addition.
Hence, application of quinine (C1), cinchonidine (C3), as well as epi-
quinine (C5, all 8S) gave product of opposite configuration to the
one obtained when quinidine (C2) and cinchonine (C4) were ap-
plied. Modifications at the 9-position in parent alkaloid (C6e7)9 did
not provide higher level of stereoselectivity. Application of 9-O-
benzoyl quinine (C9) and (DHQ)2AQN (C10) gave products in 37 and
50%ee, respectively.
Scheme 2.
Therefore quinine (C1), a simple and readily available catalyst17
was chosen for further studies. This alkaloid is believed to act as
a bifunctional catalyst offering both a basic site to activate nucle-
ophile and a hydroxyl group to form hydrogen bond with re-
actants.18 The efficiency of such a system often relies on careful
solvent selection. The enantioselectivities increased gradually from
33 to 59%ee, as the solvent was changed from DME, xylenes, tolu-
ene, DCM, chlorobenzene to PhCF3. Even though in the last solvent
the reaction mixture remained inhomogeneous, lowering the
temperature to ꢀ25 ꢁC resulted in formation of the product with
69%ee. At this temperature, the reaction without the catalyst pro-
ceeds very slowly, and conversion was estimated at less than 0.1%
per hour. Homogenous reaction mixtures obtained with DCM as
a solvent, provided up to 62%ee at ꢀ30 ꢁC.
Having in hand the efficient catalytic system, we investigated
the scope of the reaction. Thus, different thiols (Table 1) and ac-
ceptors (Tables 2 and 3) were examined in reactions catalyzed by
quinine. The catalytic system was efficient in all the tested con-
centrations of quinine, which did not affect enantioselectivity giv-
ing products 4 in ee ranging from 67 to 71%, allowing catalyst
loading to be reduced to 0.5 mol %. Further decrease in the catalyst
loading to 0.2% resulted in only moderate deterioration of enan-
tioselectivity (Table 1). Nevertheless, such low catalyst loadings are
exceptional in organocatalysis. The reduction in catalyst amount
without compromising the reaction outcome could be performed
for other mercaptans with the exception of 4-tert-butylbenzyl thiol,
Fig. 1. Catalyst screening for asymmetric conjugate addition.
Based on the assumption that an increase in the subtle in-
teractions in hydrogen-bond donors leads to better control of

5836
R. Kowalczyk et al. / Tetrahedron 70 (2014) 5834e5842
Table 1
which gave slightly better outcome with 10 mol % C1. The selec-
tivity in this reaction was unchanged in an upscale procedure (1.5 g
of 3). The 4-tert-butylbenzyl thiol was chosen to study the effect of
Michael acceptor structure on enantioselectivity (Table 2).
Reaction of various thiols with (E)-4-oxo-4-phenylbut-2-enoatea
Reactions of various 4-aryl-4-oxo-butenoates 3, 5aeo afforded
thia-Michael adducts with good to excellent yields and ees ranging
from 50% for bulky mesityl substituent (Table 2, entry 4) up to 80%
for other butenoates. The influence of steric factor was also noted
for 4-alkyl-4-oxo-butenenoates. There, a gradual increase of ster-
eoselection was noted along with lowering of the steric demand of
the alkyl substituent. However, the configuration of the un-
saturated bond of the Michael acceptor turned out to be crucial for
enantioselection. Alkene of Z configuration 5l reacted with 4-tert-
butylbenzylmercaptan giving nearly racemic product, while the
application of E-isomer 5k led to a corresponding adduct with 50%
Entry
R1
Quinine, mol %
Product
Yield,b
%
ee,c
%
1
2
3
4
Bn
Bn
Bn
Bn
Bn
Bn
20
10
1
0.5
0.2
10
10
1
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
65
62
79
78
74
92
78
69
82
74
73
63
67
69
68
71
52
69
80
66
55
69
65
59
5
6d
7
4-t-BuC6H4CH2
PhCH2CH2
4-ClC6H4CH2
4-MeOC6H4CH2
Cyclohexyl
n-C12H25
8
9
10
11
12
10
10
1
ee. Also a complete lack of stereoselection was noted when a a-
1
4g
ketoester moiety was incorporated to the substrate instead of
simple ketone (Table 2, entry 16). On the other hand, replacing the
alkyl in the ester group had little impact on stereoselection (Table
3), although decreased stereoselectivity was noted for the benzyl
ester. Like in the initial screening, application of quinidine (Table 2,
entries 1, 5, 9, and 10) instead of quinine led to adducts with similar
ees and of opposite absolute configuration.
Several products obtained in the addition are crystalline and
their enantiomeric composition can be further enriched. Single
recrystallization of adducts 6d and 6i from ethanol resulted in ees
of 98 (6d) and 99% (6i). No measurable Self-Disproportionation of
Enantiomers (SDE)19 at the chromatographic separation stage
influenced the observed ees.
a
Reactions were performed on a 0.5-mmol scale of 3 and 1.5 equiv of thiol.
Isolated yield.
Determined using chiral HPLC.
b
c
d
Reaction performed in 7.5 mL of solvent.
Table 2
Reaction of various ethyl (E)-4-oxo-but-2-enoates with 4-tert-butylbenzyl thiol
(1.5 equiv)a
Entry
R2
Alkene
Product
Yield,b
78 (73)d
90
%
ee,c
%
A more profound derivation in the structure of the Michael ac-
1
2
3
4
5
6
7
8
Ph
3
4b
6a
6b
6c
6d
6e
6f
80 (ꢀ76)d
ceptor was made by extending the
p-system (Scheme 3). In com-
4-t-BuC6H4
4-i-PrC6H4
2,4,6-(CH3)3C6H2
2-Naphthyl
4-AcNHC6H4
4-OMeC6H4
4-BrC6H4
4-ClC6H4
4-FC6H4
4-NO2C6H4
t-Bu
5a
5b
5c
5d
5e
5f
75
76
50
parison to 4-oxo-butenoates, (2E,4E)-6-oxo-2,4-dienoates 9aec20
exhibited lower reactivity. Competitive experiments in which
equimolar amounts of ethyl 4-oxo-phenyl butenoate (3) and related
diene 9a were reacted with inexcess of benzyl thiol at 20 ꢁC
revealed that 3 was totally consumed within the first minutes of
reaction leaving 9a unreacted. Composition of the reaction mixture
was unchanged after 24 h, suggesting that the formed adduct was
stable under the tested conditions. Several dienes with flanking
ketone and ester functionalities were reacted with benzyl mer-
captan to give regioselectively only one product (Scheme 3).
95
94
97 (91)d
91
79 (ꢀ74)d
70
73
75
91
84
5g
5h
5i
6g
6h
6i
9
99 (99)d
96 (92)d
99
79 (ꢀ71)d
10e
11
12
13
14
15
16f
80 (ꢀ74)d
5j
6j
62
50
3
72
77
0
5k
5l
5m
5n
5o
6k
6k
6m
6n
6o
90
92
88
94
(Z)-t-Bu
i-Pr
Me
EtO2C
25
a
Unless indicated otherwise, reactions were performed on a 0.5-mmol scale and
1.5 equiv of thiol.
b
Isolated yield.
Determined using chiral HPLC.
In parentheses, reaction catalyzed by 10 mol % of quinidine.
Performed on a 2 mmol scale.
c
d
e
f
Performed at rt.
Scheme 3.
Table 3
Application of the conditions previously developed for 4-oxo-
butenoates resulted in heterogeneous mixtures due to limited
solubility of 9a in PhCF3. Therefore, various solvents were tested
and chlorobenzene turned out to be superior to both chloroalkanes
and comparable to PhCF3. As a result, the adduct was obtained with
moderate ee. Slightly better stereoselection was achieved when
(DHQ)2AQN was applied (Table 4, entry 4).
The effect of ester group in 4-oxo-4-phenylbut-2-enoates on reaction with 4-tert-
butylbenzyl thiola
Entry
R3
Alkene
Product
Yield,b
%
ee,c
%
A reaction performed on a 2-mmol scale gave a crystalline
product with nearly the same enantioselectivity (45%ee). Surpris-
ingly, a single recrystallization led to a solid product with only 35%
ee, whilst the filtrate turned out to be enantiomerically enriched
giving a waxy solid with 72%ee. Application of quinidine afforded
a different enantiomer with comparable ee and excellent yield.
Also, the outcome of the reaction was similar for other dienes, such
as naphthyl and chlorophenyl (Table 4).
1
2
3
4
5
6
Et
3
4b
8a
8b
8c
8d
8e
78
83
88
94
91
84
80
79
80
75
77
60
n-C6H13
n-C10H21
i-Pr
i-Bu
4-NO2C6H4CH2
7a
7b
7c
7d
7e
a
Reactions were performed on a 0.5-mmol scale and 1.5 equiv of thiol.
Isolated yield.
Determined using chiral HPLC.
b
c

R. Kowalczyk et al. / Tetrahedron 70 (2014) 5834e5842
5837
Table 4
The regiochemical outcome was unaltered under different ac-
tivating conditions. Bifunctional quinine catalyst can form hydro-
gen bond from its hydroxyl to the ketone group of the substrate,
which may lower the LUMO energy.18 In addition, basic quinucli-
dine nitrogen can activate a thiol group. This activation mode is the
only accessible for DABCO. When a system composed of a primary
amine and an acid is used, it may activate 4-oxo-butenoates via
formation of an iminium salt, thereby increasing the reactivity of
Reaction of dienes and benzyl thiol catalyzed by C1, C2, and C10a
Entry
R
Catalyst, solvent
Product
Yield,b
%
ee,c
47
%
1
Ph
Ph
Ph
Ph
C1, PhCF3
C1, PhCl
C2, PhCl
C10, PhCl
C1, PhCF3
C10, PhCl
C1, PhCF3
10a
10a
ent-10a
10a
10b
75
82
95
82
87
82
69
2d
3
45 (72)e
54
the resulting
a,b-unsaturated system and directing the nucleophile
to the
b
-position.15 Nevertheless, each approach afforded the same
4
5
6
7
56
51
57
44
4-ClC6H4
4-ClC6H4
2-Naphthyl
1,4-adducts indicating that all activation modes converge to the
same end product. Considering the factors, which might be re-
sponsible for the regioselectivity in the studied additions, it may be
assumed that increased electron density arising after nucleophilic
addition is better stabilized by the ketone group in comparison to
the ester moiety. Calculations at the DFT level of theory for sim-
plified anion structures indicate marked energy differences in favor
of additions directed by the ketone moiety (Section S2,
Supplementary data).
10b
10c
a
Unless indicated otherwise, reactions were performed on a 0.3-mmol scale of 9
and 1.5 equiv of benzyl mercaptan.
b
Isolated yield.
Determined using chiral HPLC.
Reaction performed on a 2-mmol scale.
Supernatant after single crystallization from EtOH.
c
d
e
In contrast to 4-oxo-butenoates having virtually two reactive
sites, dienes 9 offer multiple possible routes of addition21 (Scheme
3). However, in all the examined reactions the only products
However, for the extended p-systems of the dienes the observed
1,4-addition relative to the ketone group is better explained con-
sidering the electronic character of the double bonds. There, elec-
trostatic parameters, such as ChelpG charges indicate the most
electron-poor site (Fig. 4). Even though such approach relies only
on the acceptor structure giving no insight into the possible re-
action mechanism, the carbon of the most positive ChelpG charge
corresponds to the observed addition site.
formed resulted from b-addition with respect to ketone group.
The structures of the products were unambiguously proved
using 1H,13C HSQC and HMBC NMR experiments. Though, in case of
adducts of 4-oxo-butenoates such experiments turned out to bring
no clear answer. Therefore, adduct 4b was transformed to a cyclic
derivative. The ketone was first reduced by NaBH4 and spontaneous
intramolecular transesterification gave nearly equimolar ratio of
diastereomeric lactones 11 and 12. For the rigid compound 12, the
connectivity was unambiguously assigned using NOESY and HMBC
experiments. Thus, it was proven that 1,4-addition of the sulfur
nucleophile with respect to carbonyl group must have occurred
(Fig. 2).
Fig. 4. Calculated electrostatic charges (ChelpG, DFT/B3LYP/CC-pVDZ) for Michael
acceptors.
3. Conclusions
The unprecedented addition of mercaptans to 4-oxo-butenoates
and (2E,4E)-6-oxo-2,4-dienoates occurs with complete regiose-
lection in a 1,4-manner with respect to the ketone group. DFT cal-
culations of the Michael acceptors may indicate the reactive sites in
such divergently activated electron poor double bonds. Regiose-
lection in the tested reaction was controlled by the electronic
structure of the Michael acceptor and remained unchanged re-
gardless of the method of activation.
Stereoselectivity was secured by the catalyst. Among the tested
chiral bifunctional catalysts, easily available quinine afforded Mi-
chael adducts with good to excellent yields and ees of up to 80%.
Further recrystallization of some enantiomerically enriched prod-
ucts led to ees reaching 99%. The use of quinidine led to another
enantiomer, and thus presented protocol offers the access to both
antipodes of sulfides. The reaction is easily scalable and can be
performed with exceptionally low catalyst loading (0.2 mol %)
without incurring substantial loss of enantioselectivity.
Fig. 2. Synthesis of lactones and crucial NOESY interactions.
Finally both the regiochemistry and absolute configuration of
the adducts of tert-butylbenzyl thiol to 4-oxo-butenoates was
assigned by X-ray crystallography (Fig. 3) with appropriate value of
Flack parameter (ꢀ0.06). Thus, for the quinine-catalyzed reaction S
configuration of the formed adducts was established. Tentatively
the same stereochemical course of the reaction may be expected in
the addition to extended p-systems.
4. Experimental section
4.1. General
Catalytic reactions were performed in reaction tubes with the
gas inlet. Tubes were heated to 550 ꢁC for 3e5 min under high
vacuum, cooled down, and then flushed with argon.
1H and 13C NMR (300, 600 MHz and 75.5, 151 MHz, respectively)
spectra were recorded in CDCl3 on Bruker Avance DRX 300 and
NMR Bruker Avance II 600 MHz. 1H NMR chemical shifts are
Fig. 3. ORTEP plot of (S)-6i, obtained in the quinine-catalyzed reaction. For clarity
disorder is not shown, and displacement ellipsoids are drawn at the 10% probability
level.22

5838
R. Kowalczyk et al. / Tetrahedron 70 (2014) 5834e5842
reported in parts per million (
d
) relative to tetramethylsilane (TMS)
(CDCl3, 300 MHz): d 7.86e7.91 (m, 2H), 7.52e7.59 (m, 1H),
and CDCl3
(d
7.26 ppm). 13C NMR chemical shifts are reported in
7.22e7.47 (m, 7H), 4.18e4.28 (m, 2H), 3.98 (d, J¼13.4 Hz, 1H), 3.89
ppm from tetramethylsilane (TMS) and CDCl3
(d 77.16 ppm). IR
(d, J¼13.4 Hz, 1H), 3.80 (dd, J¼10.7, 3.7 Hz, 1H), 3.67 (dd, J¼17.5,
spectra were recorded on System 2000 FT-IR PerkineElmer spec-
trometer. ESI HRMS spectra were recorded on Waters LCT Premier
XE apparatus. HPLC analysis was performed on Thermo Scientific
System using Chiralpak AD-H, Chiralcel OD-H columns
(4.6 mmꢂ25 cm) without guard columns. Each HPLC analysis has
been controlled by comparison with the pure sample and the ra-
cemate. Optical rotations were measured on anautomatic polar-
10.7 Hz, 1H), 3.16 (dd, J¼17.5, 3.7 Hz, 1H), 1.31 (t, J¼7.1 Hz, 3H). 13
C
NMR (CDCl3, 151 MHz):
d 196.9, 172.1, 137.6, 136.2, 133.5, 129.2,
128.72, 128.70, 128.1, 127.4, 61.4, 40.9, 40.7, 36.3, 14.3. IR (neat):
n
¼3062, 3029, 2981, 1731, 1686, 1450, 1213, 1158, 758, 703,
690 cmꢀ1. HPLC (Chiralcel OD-H, hexane/i-PrOH¼97:3, flow rate:
1.0 mL/min,
l¼220 nm): tR¼18.80 (major), 21.03 (minor). HRMS
(ESI): [C19H20O3SþH]þ requires: 329.1206; found: 329.1201.
imeter at
Flash chromatography was performed using silica gel
35e70 m.
Commercially available starting materials were used without
further purification. Chlorobenzene, xylenes, and -tri-
l¼589 nm (c g/100 mL).
4.4.2. Ethyl (S)-2-(4-tert-butylbenzylsulfanyl)-4-oxo-4-
20
m
phenylbutanoate (4b). Colorless oil; [
a]
ꢀ111 (c 1.1, CHCl3), 80%
D
ee. 1H NMR (CDCl3, 300 MHz):
d
7.88 (dd, J¼7.8, 1.4 Hz, 2H), 7.56 (tt,
a,
a,
a
J¼7.2, 1.4 Hz, 1H), 7.43 (dd, J¼7.8, 7.2 Hz, 2H), 7.35 (d, J¼8.6 Hz, 2H),
7.31 (d, J¼8.6 Hz, 2H), 4.22 (q, J¼7.2 Hz, 2H), 3.95 (d, J¼13.4 Hz, 1H),
3.86 (d, J¼13.4 Hz, 1H), 3.81 (dd, J¼10.8, 3.6 Hz, 1H), 3.67 (dd,
J¼17.6, 10.8 Hz, 1H), 3.15 (dd, J¼17.6, 3.6 Hz, 1H), 1.31 (t, J¼7.2 Hz,
flurotoluene were used as received. 1,2-Dichloroethane was dis-
tilled over P2O5 under argon. Dichloromethane and
dimethoxyethane were distilled with CaH2 under argon and further
stored over 3 A molecular sieves. Toluene was dried over sodium
3H), 1.31 (s, 9H). 13C NMR (CDCl3, 75.5 MHz):
d 196.9, 172.1, 150.3,
ꢁ
wire.
136.1, 134.6, 133.5, 128.8, 128.7, 128.1, 125.6, 61.4, 41.0, 40.7, 35.8,
34.6, 31.4, 14.3. IR (neat):
¼3059, 3027, 2963, 1732, 1687, 1449,
1364, 1328, 1261, 1213, 1158, 757, 690 cmꢀ1. HPLC (Chiralpak AD-H,
n
4.2. General procedure for reactions of 4-oxo-phenyl-bute-
noate with thiols (GP1, Fig. 1)
hexane/i-PrOH¼97:3, flow rate: 0.7 mL/min, ¼220 nm): tR¼18.57
l
(major), 21.85 (minor). HRMS (ESI): [C23H28O3SþH]þ requires:
Chiral base (10 mol %, 0.05 mmol) was added to a solution of
benzyl mercaptan (93 mg, 0.75 mmol, 1.5 equiv) in PhCF3 (2 mL) at
20 ꢁC and the resulted mixture was stirred for 15 min. Then 4-oxo-
phenyl-butenoate (3) (102 mg, 0.5 mmol, 1.0 equiv) in PhCF3
(0.5 mL) was added dropwise with a syringe. After 20 h at 20 ꢁC
reaction was quenched by AcOEt or chloroform/AcOEt mixture (1:1,
v/v) until become homogenous and filtered through a plug of silica
gel (5e10 g). Elution with a total volume of 100e150 mL of AcOEt or
chloroform/AcOEt mixture (1:1, v/v) afforded crude product, which
was further purified using column chromatography (silicagel,
hexanes/AcOEt, 10:1, v/v). Enantiomeric excess was determined
using HPLC on chiral stationary phases (OD-H, AD-H).
385.1832; found: 385.1839. For reaction catalyzed by quinidine (R)-
isomer was obtained, [
a
]
20 þ103 (c 1.3, CHCl3), 76%ee.
D
4.4.3. Ethyl (S)-4-oxo-2-(phenethylsulfanyl)-4-phenylbutanoate
20
(4c). Colorless oil; [
a
]
ꢀ55 (c 0.5, CHCl3), 66%ee. 1H NMR
D
(CDCl3, 300 MHz):
d
7.96 (dd, J¼7.8, 1.7 Hz, 2H), 7.58 (tt, J¼7.4,
1.7 Hz, 1H), 7.47 (dd, J¼7.8, 7.4 Hz, 2H), 7.28e7.34 (m, 2H), 7.19e7.26
(m, 3H), 4.24 (q, J¼7.1 Hz, 2H), 3.90 (dd, J¼10.5, 4.1 Hz,1H), 3.71 (dd,
J¼17.8, 10.5 Hz, 1H), 3.28 (dd, J¼17.8, 4.1 Hz, 1H), 2.86e3.09 (m, 4H),
1.30 (t, J¼7.1 Hz, 3H). 13C NMR (CDCl3, 75.5 MHz):
d 197.0, 172.2,
140.2, 136.2, 133.6, 128.8, 128.7, 128.6, 128.2, 126.6, 61.5, 41.11, 41.10,
36.0, 33.3, 14.3. IR (neat):
n
¼3063, 3028, 2981, 2933, 1731, 1686,
1449, 1328, 1213, 1157, 757, 690 cmꢀ1. HPLC (Chiralcel OD-H, hex-
4.3. General procedure for reactions of 4-oxo-phenyl-bute-
noate with thiols catalyzed by thioureas C11eC18 (GP2, Fig. 1)
ane/i-PrOH¼99:1, flow rate: 1.0 mL/min,
l
¼220 nm): tR¼26.99
(major), 32.82 (minor). HRMS (ESI): [C20H22O3SþNa]þ requires:
365.1182; found: 365.1192.
Chiral thiourea catalyst (10 mol %, 0.05 mmol) and 4-oxo-phe-
nyl-butenoate (102 mg, 0.5 mmol, 1.0 equiv) were treated with
PhCF3 (2.0 mL) and resulted mixture was stirred at 20 ꢁC for 20 min.
Then, a solution of thiol (0.75 mmol, 1.5 equiv) in PhCF3 (0.5 mL)
was added dropwise. Reaction was performed at 20 ꢁC for 20 h and
then filtered through a plug of silica, as described above in GP1.
4.4.4. Ethyl (S)-2-(4-chlorobenzylsulfanyl)-4-oxo-4-phenylbutanoate
20
(4d). Colorless oil; [
(CDCl3, 300 MHz):
a
]
ꢀ78 (c 0.5, CHCl3), 55%ee. 1H NMR
D
d
7.88 (dd, J¼8.4, 1.5 Hz, 2H), 7.56 (tt, J¼7.4,
1.5 Hz, 1H), 7.44 (dd, J¼8.4, 7.4 Hz, 2H), 7.32 (d, J¼8.8 Hz, 2H), 7.28
(d, J¼8.8 Hz, 2H), 4.22 (q, J¼7.1 Hz, 2H), 3.94 (d, J¼13.5 Hz, 1H), 3.83
(d, J¼13.5 Hz, 1H), 3.75 (dd, J¼10.6, 3.6 Hz, 1H), 3.65 (dd, J¼17.3,
4.4. General procedure for reactions of 4-oxo-butenoates and
(2E,4E)-6-oxo-2,4-dienoates with thiols at lower temperatures
(GP 3, Tables 1e4)
10.6 Hz, 1H), 3.16 (dd, J¼17.3, 3.6 Hz, 1H), 1.30 (t, J¼7.1 Hz, 3H). 13
C
NMR (CDCl3, 75.5 MHz):
d 196.7, 171.9, 136.1, 136.0, 133.6, 133.2,
130.5, 128.8, 128.7, 128.1, 61.5, 40.7, 40.5, 35.5, 14.3. IR (neat):
n
¼3063, 2981, 1731, 1686, 1491, 1449, 1329, 1262, 1214, 1158, 1093,
Quinine, quinidine or (DHQ)2AQN (10 mol %) was treated with
a solution of thiol (1.5 equiv) in PhCF3 (1.5 mL/0.5 mmol of accep-
tor) and the resulted mixture was stirred at 20 ꢁC for 15e20 min,
then cooled to ꢀ25 ꢁC, and stirred for next 10 min. Then, a solution
of Michael acceptor (1.0 equiv) in PhCF3 (1.0 mL/0.5 mmol of ac-
ceptor) was added slowly (0.75e1 h) via a syringe under positive
argon pressure. When addition was finished, reaction tube was
flushed with argon, sealed, and stirred for additional 20e21 h at
ꢀ25 ꢁC. Cold reaction mixtures were directly loaded on a plug of
silica gel analogously to procedure GP1. In cases when other solvent
than PhCF3 was used, this procedure was applied without further
modifications.
1016, 757, 690 cmꢀ1. HPLC (Chiralcel OD-H, hexane/i-PrOH¼97:3,
flow rate: 0.7 mL/min,
l¼220 nm): tR¼18.12 (major), 20.67 (minor).
HRMS (ESI): [C19H19Cl35O3SþNa]þ requires: 385.0636; found:
385.0637.
4.4.5. Ethyl (S)-2-(4-methoxybenzylsulfanyl)-4-oxo-4-
20
phenylbutanoate (4e). Colorless oil; [
a
]
ꢀ92 (c 0.5, CHCl3), 69%
D
ee. 1H NMR (CDCl3, 300 MHz):
d
7.88 (d, J¼7.7 Hz, 2H), 7.54 (t,
J¼7.2 Hz, 1H), 7.42 (dd, J¼7.7, 7.2 Hz, 2H), 7.30 (d, J¼8.7 Hz, 2H), 6.84
(d, J¼8.7 Hz, 2H), 4.17e4.29 (m, 2H), 3.93 (d, J¼13.3 Hz, 1H), 3.84 (d,
J¼13.3 Hz, 1H), 3.77 (dd, J¼10.7, 3.6 Hz, 1H), 3.77 (s, 3H), 3.66 (dd,
J¼17.3, 10.7 Hz, 1H), 3.15 (dd, J¼17.3, 3.6 Hz, 1H), 1.31 (t, J¼7.2 Hz,
3H). 13C NMR (CDCl3, 75.5 MHz):
d 196.8, 172.0, 158.9, 136.0, 133.4,
4.4.1. Ethyl (S)-2-(benzylsulfanyl)-4-oxo-4-phenylbutanoate
130.2, 129.3, 128.6, 128.0, 114.0, 61.3, 55.2, 40.8, 40.5, 35.6, 14.2. IR
(neat):
¼3062, 3032, 2980, 1730, 1686, 1610, 1512, 1249, 1213, 1175,
20
(4a). Colorless oil; [
a
]
D
ꢀ117 (c 0.73, CHCl3), 71%ee. 1H NMR
n

R. Kowalczyk et al. / Tetrahedron 70 (2014) 5834e5842
5839
1033, 758, 690 cmꢀ1. HPLC (Chiralcel OD-H, hexane/i-PrOH¼9:1,
J¼13.2 Hz, 1H), 3.76 (dd, J¼10.7, 3.8 Hz, 1H), 3.41 (dd, J¼19.0,
10.7 Hz, 1H), 2.92 (dd, J¼19.0, 3.8 Hz, 1H), 2.27 (s, 3H), 2.16 (s, 6H),
1.34 (t, J¼7.2 Hz, 3H), 1.32 (s, 9H). 13C NMR (CDCl3, 75.5 MHz):
flow rate: 1.0 mL/min,
l
¼220 nm): tR¼12.33 (major), 17.63 (minor).
HRMS (ESI): [C20H22O4SþH]þ requires: 359.1312; found: 359.1309.
d
207.1, 172.0, 150.3, 138.7, 138.2, 134.2, 132.9, 128.8, 128.5, 125.6,
4.4.6. Ethyl (S)-2-(cyclohexylsulfanyl)-4-oxo-4-phenylbutanoate
61.5, 46.9, 40.2, 36.0, 34.6, 31.4, 21.1, 19.0, 14.3. IR (neat):
n
¼2963,
20
(4f). Colorless oil; [
a
]
ꢀ64 (c 0.7, CHCl3), 65%ee; 1H NMR
1732, 1701, 1153, 851 cmꢀ1; HPLC (Chiralpak AD-H, hexane/i-
D
(CDCl3, 300 MHz):
d
7.93e7.97 (m, 2H), 7.57 (tt, J¼7.4, 1.7 Hz, 1H),
PrOH¼97:3, flow rate: 1.0 mL/min, ¼220 nm): tR¼7.32 (major),
l
7.42e7.48 (m, 2H), 4.12e4.29 (m, 2H), 3.93 (dd, J¼10.4, 4.4 Hz, 1H),
3.70 (dd, J¼17.9,10.4 Hz,1H), 3.27 (dd, J¼17.9, 4.4 Hz,1H), 2.91e3.01
(m, 1H), 2.07e2.16 (m, 1H), 1.90e2.01 (m, 1H), 1.70e1.81 (m, 2H),
1.56e1.65 (m, 1H), 1.24e1.42 (m, 5H), 1.28 (t, J¼7.2 Hz, 3H). 13C NMR
8.70 (minor). HRMS (ESI): [C26H34O3SþH]þ requires: 427.2301;
found: 427.2322.
4.4.11. Ethyl (S)-2-(4-tert-butylbenzylsulfanyl)-4-(naphtalen-2-yl)-
(CDCl3, 75.5 MHz):
d
197.2, 172.8, 136.3, 133.6, 128.8, 128.2, 61.3,
4-oxobutanoate (6d). Amorphous solid; 79%ee. 1H NMR (CDCl3,
44.5, 41.6, 39.9, 33.8, 33.6, 26.2, 26.0, 25.8, 14.2. IR (neat):
n
¼3062,
300 MHz): d 8.40 (s, 1H), 7.90e7.97 (m, 2H), 7.82e7.87 (m, 2H),
2931, 2853,1733,1686, 1449,1328,1259,1214,1158,1029,1001, 989,
7.50e7.61 (m, 2H), 7.35e7.41 (m, 4H), 4.27 (q, J¼7.1 Hz, 2H), 4.03 (d,
J¼13.3 Hz, 1H), 3.93 (d, J¼13.3 Hz, 1H), 3.78e3.93 (m, 2H),
3.24e3.38 (m, 1H), 1.34 (t, J¼7.1 Hz, 3H), 1.33 (s, 9H). 13C NMR
757, 690 cmꢀ1. HPLC (Chiralcel OD-H, hexane/i-PrOH¼98:2, flow
rate: 1.0 mL/min,
l
¼220 nm): tR¼8.78 (major), 9.94 (minor). HRMS
(ESI): [C18H24O3SþNa]þ requires: 343.1338; found: 343.1347.
(CDCl3, 75.5 MHz): d 196.7, 172.1, 150.2, 135.7, 134.5, 133.4, 132.4,
129.9, 129.6, 128.8, 128.6, 128.5, 127.8, 126.8, 125.6, 123.6, 61.4, 40.9,
40.8, 35.8, 34.5, 31.4, 14.3. IR (neat): 2959, 1728, 1677, 1175,
827 cmꢀ1. After recrystallization from ethanol (96%) of 211 mg of
solid, sample (61 mg) of colorless crystals was obtained,
4.4.7. Ethyl (S)-2-(dodecylsulfanyl)-4-oxo-4-phenylbutanoate
20
(4g). Colorless oil; [
a
]
ꢀ39 (c 0.5, CHCl3), 59%ee. 1H NMR
D
(CDCl3, 300 MHz):
d
7.94e7.98 (m, 2H), 7.58 (tt, J¼7.5, 1.5 Hz, 1H),
7.43e7.50 (m, 2H), 4.17e4.27 (m, 2H), 3.85 (dd, J¼10.4, 3.9 Hz, 1H),
3.72 (dd, J¼17.6, 10.4 Hz, 1H), 3.29 (dd, J¼17.6, 3.9 Hz, 1H),
2.63e2.81 (m, 2H), 1.54e1.71 (m, 2H), 1.22e1.42 (m, 18H), 1.29 (t,
J¼7.1 Hz, 3H), 0.88 (t, J¼6.7 Hz, 3H). 13C NMR (CDCl3, 75.5 MHz):
mp¼81.6e82.4 ꢁC; [
a
]
20 ꢀ97 (c 0.5, CHCl3), 98%ee. HPLC (Chiralpak
D
AD-H, hexane/i-PrOH¼95:5, flow rate: 1.0 mL/min, ¼220 nm):
l
tR¼18.32 (major), 21.13 (minor). HRMS (ESI): [C27H30O3SþNa]þ re-
quires: 457.1808; found: 457.1809. In a reaction catalyzed by
d
197.2, 172.4, 136.3, 133.6, 128.8, 128.3, 61.4, 41.25, 41.17, 32.1, 32.0,
quinidine, (R)-isomer was obtained [
a
]
20 þ73 (c 0.6, CHCl3), 74%ee.
D
29.79, 29.76, 29.73, 29.65, 29.5, 29.4, 29.3, 29.0, 22.8, 14.3, 14.3. IR
(neat):
n
¼3063, 2926, 2854, 1733, 1688, 1449, 1212, 1157, 756,
4.4.12. Ethyl (S)-4-(4-acetamidophenyl)-2-(4-tert-butylbenzylsulfanyl)-
690 cmꢀ1. HPLC (Chiralcel OD-H, hexane/i-PrOH¼99:1, flow rate:
4-oxobutanoate (6e). Colorless foam; [
a
]
20 ꢀ68 (c 0.5, CHCl3), 70%ee.
D
1.0 mL/min,
l¼220 nm): tR¼9.11 (major), 10.21 (minor). HRMS
1H NMR (CDCl3, 300 MHz):
d
8.1 (br,1H), 7.78 (d, J¼8.8 Hz, 2H), 7.56 (d,
(ESI): [C24H38O3SþH]þ requires: 407.2614; found: 407.2619.
J¼8.8 Hz, 2H), 7.34 (d, J¼8.6 Hz, 2H), 7.29 (d, J¼8.6 Hz, 2H), 4.16e4.26
(m, 2H), 3.94 (d, J¼13.5 Hz, 1H), 3.85 (d, J¼13.5 Hz, 1H), 3.78 (dd,
J¼10.9, 3.8 Hz, 1H), 3.59 (dd, J¼17.8, 10.9 Hz, 1H), 3.12 (dd, J¼17.8,
3.8 Hz, 1H), 2.16 (s, 3H), 1.30 (s, 9H), 1.30 (t, J¼7.1 Hz, 3H). 13C NMR
4.4.8. Ethyl
phenyl)-4-oxobutanoate (6a). Colorless oil; [
75%ee. 1H NMR (CDCl3, 300 MHz):
(S)-2-(4-tert-butylbenzylsulfanyl)-4-(4-tert-butyl-
a
]
20 ꢀ56 (c 3.2, CHCl3),
D
d
7.84 (d, J¼8.7 Hz, 2H), 7.46 (d,
(CDCl3, 151 MHz): d 195.7, 172.6, 169.0, 150.4, 143.0, 134.4, 131.5, 129.5,
J¼8.7 Hz, 2H), 7.36 (d, J¼8.6 Hz, 2H), 7.33 (d, J¼8.6 Hz, 2H), 4.23 (q,
J¼7.1 Hz, 2H), 3.97 (d, J¼13.4 Hz, 1H), 3.88 (d, J¼13.4 Hz, 1H), 3.83
(dd, J¼10.9, 3.9 Hz, 1H), 3.66 (dd, J¼17.7, 10.9 Hz, 1H), 3.15 (dd,
128.8, 125.6, 118.9, 61.5, 40.8, 40.7, 35.9, 34.6, 31.4, 24.8, 14.3. IR (neat):
¼3347, 2963, 1730, 1705, 1678, 1595, 1528, 1409, 1369, 1322, 1262,
1217, 1176, 1023, 991, 835 cmꢀ1. HPLC (Chiralpak AD-H, hexane/i-
n
J¼17.7, 3.9 Hz, 1H), 1.34 (s, 9H), 1.32 (s, 9H), 1.31 (t, J¼7.1 Hz, 3H). 13
C
PrOH¼90:10, flow rate: 1.0 mL/min, ¼220 nm): tR¼22.16 (major),
l
NMR (CDCl3, 75.5 MHz):
d
196.5, 172.1, 157.2, 150.2, 134.6, 133.6,
26.69 (minor). HRMS (ESI): [C25H31NO4SþNa]þ requires: 464.1866;
128.8, 128.1, 125.60, 125.58, 61.3, 40.9, 35.9, 35.2, 34.6, 31.4, 31.1 (2C
overlapped), 14.3. IR (neat):
¼2964, 1732, 1683, 1607, 1406, 1365,
1268, 1217, 1157, 1108, 1025, 991, 830 cmꢀ1. HPLC (Chiralpak AD-H,
found: 464.1866.
n
4.4.13. Ethyl (S)-2-(4-tert-butylbenzylsulfanyl)-4-(4-
20
hexane/i-PrOH¼97:3, flow rate: 1.0 mL/min,
l¼220 nm): tR¼17.94
methoxyphenyl)-4-oxobutanoate (6f). Colorless oil; [
a]
ꢀ52 (c
D
(major), 24.41 (minor). HRMS (ESI): [C27H36O3SþH]þ requires:
0.7, CHCl3), 73%ee. 1H NMR (CDCl3, 600 MHz):
d
7.86 (d, J¼8.8 Hz,
441.2458; found: 441.2451.
2H), 7.35 (d, J¼8.4 Hz, 2H), 7.31 (d, J¼8.4 Hz, 2H), 6.90 (d, J¼8.8 Hz,
2H), 4.18e4.26 (m, 2H), 3.94 (d, J¼13.4 Hz, 1H), 3.86 (d, J¼13.4 Hz,
1H), 3.84 (s, 3H), 3.80 (dd, J¼10.9, 4.0 Hz, 1H), 3.62 (dd, J¼17.7,
10.9 Hz, 1H), 3.12 (dd, J¼17.7, 4.0 Hz, 1H), 1.31 (s, 9H), 1.30 (t,
4. 4 . 9. Ethyl (S) -2-(4-tert-butylbenzylsu lfanyl)-4-(4-
20
isopropylphenyl)-4-oxobutanoate (6b). Colorless oil; [
a
]
ꢀ84 (c
D
1.7, CHCl3), 76%ee. 1H NMR (CDCl3, 300 MHz):
d
7.83 (d, J¼8.3 Hz,
J¼7.1 Hz, 3H). 13C NMR (CDCl3,151 MHz):
d 195.4,172.2,163.8,150.3,
2H), 7.37 (d, J¼8.7 Hz, 2H), 7.33 (d, J¼8.7 Hz, 2H), 7.29 (d, J¼8.3 Hz,
2H), 4.23 (q, J¼7.1 Hz, 2H), 3.97 (d, J¼13.5 Hz, 1H), 3.88 (d,
J¼13.5 Hz, 1H), 3.83 (dd, J¼10.9, 3.8 Hz, 1H), 3.67 (dd, J¼17.7,
10.9 Hz, 1H), 3.15 (dd, J¼17.7, 3.8 Hz, 1H), 2.96 (sept, J¼6.9 Hz, 1H),
1.33 (s, 9H), 1.32 (t, J¼7.1 Hz, 3H), 1.27 (d, J¼6.9 Hz, 6H). 13C NMR
134.6, 130.4, 129.3, 128.8, 125.6, 113.8, 61.3, 55.5, 40.9, 40.6, 35.8,
34.6, 31.4, 14.3. IR (neat):
n
¼3056, 2954, 2908, 2870, 1732, 1679,
1600, 1576, 1512, 1464, 1420, 1357, 1261, 1216, 1166, 1031, 989, 911,
832, 733, 559 cmꢀ1. HPLC (Chiralpak AD-H, hexane/i-PrOH¼95:5,
flow rate: 1.0 mL/min,
l
¼220 nm): tR¼23.11 (major), 29.03 (minor).
(CDCl3, 75.5 MHz):
d
196.5, 172.1, 155.0, 150.2, 134.6, 134.0, 128.8,
HRMS (ESI): [C24H30O4SþNa]þ requires: 437.1757; found: 437.1765.
128.4, 126.7, 125.6, 61.3, 40.8 (2C overlapped), 35.8, 34.6, 34.3, 31.4,
23.7 (2C overlapped), 14.3. IR (neat): 2963, 1732, 1684, 1607, 1216,
828 cmꢀ1. HPLC (Chiralpak AD-H, hexane/i-PrOH¼97:3, flow rate:
4.4.14. Ethyl (S)-2-(4-tert-butylbenzylsulfanyl)-4-(4-bromophenyl)-
20
4-oxobutanoate (6g). Waxy yellowish solid; [
a
]
ꢀ75 (c 0.5,
D
1.0 mL/min,
l¼220 nm): tR¼13.83 (major), 18.78 (minor). HRMS
CHCl3), 75%ee. 1H NMR (CDCl3, 300 MHz):
d
7.73 (d, J¼8.8 Hz, 2H),
(ESI): [C26H34O3SþH]þ requires: 427.2301; found: 427.2298.
7.56 (d, J¼8.8 Hz, 2H), 7.35 (d, J¼8.6 Hz, 2H), 7.31 (d, J¼8.6 Hz, 2H),
4.18e4.26 (m, 2H), 3.95 (d, J¼13.5 Hz, 1H), 3.86 (d, J¼13.5 Hz, 1H),
3.80 (dd, J¼10.7, 3.8 Hz, 1H), 3.62 (dd, J¼17.7, 10.7 Hz, 1H), 3.10 (dd,
J¼17.7, 3.8 Hz,1H),1.31 (s, 9H),1.31 (t, J¼7.1 Hz, 3H). 13C NMR (CDCl3,
4.4.10. Ethyl (S)-2-(4-tert-butylbenzylsulfanyl)-4-mesityl-4-
20
oxobutanoate (6c). Colorless oil; [
1H NMR (CDCl3, 600 MHz):
2H), 6.82 (s, 2H), 4.22e4.29 (m, 2H), 3.93 (d, J¼13.2 Hz, 1H), 3.86 (d,
a
]
ꢀ33 (c 0.5, CHCl3), 50%ee.
D
d
7.35 (d, J¼8.2 Hz, 2H), 7.30 (d, J¼8.2 Hz,
75.5 MHz): d 195.9, 172.0, 150.3, 134.8, 134.5, 132.0, 129.6, 128.8,
128.7, 125.6, 61.5, 40.9, 40.6, 35.9, 34.6, 31.4, 14.3. IR (neat):
n
¼3057,

5840
R. Kowalczyk et al. / Tetrahedron 70 (2014) 5834e5842
2964, 2907, 1732, 1681, 1585, 1398, 1357, 1260, 1211, 1165, 1070,
(neat):
n
¼2965, 1733, 1707 cmꢀ1. HPLC (Chiralpak AD-H, hexane/i-
1010, 987, 818, 555 cmꢀ1. HPLC (Chiralpak AD-H, hexane/i-
PrOH¼99:1, flow rate: 1.0 mL/min, ¼254 nm): tR¼7.48 (major),
l
PrOH¼95:5, flow rate: 1.0 mL/min,
l
¼220 nm): tR¼14.47 (major),
11.98 (minor). HRMS (ESI): [C21H32O3SþH]þ requires: 365.2145;
19.13 (minor). HRMS (ESI): [C23H27Br79O3SþNa]þ requires:
485.0756; found: 485.0790; [C23H27Br81O3SþNa]þ requires:
487.0736; found: 485.0747.
found: 365.2146.
4.4.19. Ethyl (S)-2-(4-tert-butylbenzylsulfanyl)-5-methyl-4-
20
oxohexanoate (6m). Colorless oil; [
a]
ꢀ121 (c 0.5, CHCl3), 72%ee.
D
4.4.15. Ethyl (S)-2-(4-tert-butylbenzylsulfanyl)-4-(4-chlorophenyl)-
1H NMR (CDCl3, 300 MHz):
d
7.34 (d, J¼8.5 Hz, 2H), 7.27 (d, J¼8.5 Hz,
20
4-oxobutanoate (6h). Waxy solid; [
a
]
ꢀ92 (c 0.5, CHCl3), 79%ee.
2H), 4.12e4.23 (m, 2H), 3.89 (d, J¼13.4 Hz, 1H), 3.81 (d, J¼13.4 Hz,
1H), 3.63 (dd, J¼10.7, 4.4 Hz, 1H), 3.13 (dd, J¼18.0, 10.7 Hz, 1H), 2.63
(dd, J¼18.0, 4.4 Hz, 1H), 2.53 (sept, J¼6.9 Hz, 1H), 1.31 (s, 9H), 1.29 (t,
J¼7.1 Hz, 3H), 1.07 (d, J¼6.9 Hz, 3H), 1.06 (d, J¼6.9 Hz, 3H). 13C NMR
D
1H NMR (CDCl3, 300 MHz):
d
7.81 (d, J¼8.7 Hz, 2H), 7.39 (d,
J¼8.7 Hz, 2H), 7.36 (d, J¼8.7 Hz, 2H), 7.32 (d, J¼8.7 Hz, 2H),
4.18e4.28 (m, 2H), 3.96 (d, J¼13.5 Hz, 1H), 3.87 (d, J¼13.5 Hz, 1H),
3.81 (dd, J¼10.8, 3.8 Hz, 1H), 3.64 (dd, J¼17.7, 10.8 Hz, 1H), 3.11 (dd,
J¼17.7, 3.8 Hz, 1H), 1.32 (s, 9H), 1.31 (t, J¼7.1 Hz, 3H). 13C NMR
(CDCl3, 151 MHz): d: 211.4, 172.1, 150.3, 134.4, 128.8, 125.6, 61.3, 42.1,
40.7, 40.4, 35.9, 34.6, 31.4, 18.15, 18.06, 14.2. IR (neat):
n
¼2967, 1732,
(CDCl3, 151 MHz): d: 195.8, 172.0, 150.4, 140.0, 134.49, 134.47, 129.5,
1715, 1466, 1367, 1268, 1227, 1157, 758 cmꢀ1. HPLC (Chiralpak AD-H,
129.0, 128.8, 125.6, 61.5, 40.9, 40.6, 35.9, 34.6, 31.4, 14.3. IR (neat):
hexane/i-PrOH¼97:3, flow rate: 0.7 mL/min, ¼220 nm): tR¼9.90
l
n
¼2963, 1731, 1688, 1590, 1401, 1261, 1212, 1167, 1092, 989,
(major), 12.18 (minor). HRMS (ESI): [C20H30O3SþH]þ requires:
822 cmꢀ1. HPLC (Chiralpak AD-H, hexane/i-PrOH¼97:3, flow rate:
351.1988; found: 351.2000.
1.0 mL/min,
l¼220 nm): tR¼22.55 (major), 28.59 (minor). HRMS
(ESI): [C23H27Cl35O3SþH]þ requires: 419.1442; found: 419.1457;
4.4.20. Ethyl (S)-2-(4-tert-butylbenzylsulfanyl)-4-oxopentanoate
20
[C23H27Cl37O3SþH]þ requires: 421.1413; found: 421.1400. In a re-
(6n). Colorless oil; [
a
]
ꢀ163 (c 2.1, CHCl3), 77%ee. 1H NMR
D
action catalyzed by quinidine (R)-isomer was obtained, [
a
]
20 þ87 (c
(CDCl3, 300 MHz):
d
7.34 (d, J¼8.3 Hz, 2H), 7.27 (d, J¼8.3 Hz, 2H),
D
0.5, CHCl3), 71%ee.
4.18 (q, J¼7.1 Hz, 2H), 3.89 (d, J¼13.3 Hz,1H), 3.80 (d, J¼13.3 Hz,1H),
3.60 (dd, J¼10.5, 4.4 Hz, 1H), 3.11 (dd, J¼17.9, 10.5 Hz, 1H), 2.64 (dd,
4.4.16. Ethyl (S)-2-(4-tert-butylbenzylsulfanyl)-4-(4-fluorophenyl)-
4-oxobutanoate (6i). Reaction was performed in a 2 mmol scale;
J¼17.9, 4.5 Hz, 1H), 2.10 (s, 3H), 1.32 (s, 9H), 1.30 (t, J¼7.1 Hz, 3H). 13
C
NMR (CDCl3, 75.5 MHz):
d 205.2, 172.0, 150.2, 134.2, 128.8, 125.5,
colorless crystals, [
300 MHz):
a
]
20 ꢀ106 (c 0.5, CHCl3), 80%ee. 1H NMR (CDCl3,
61.3, 45.1, 40.1, 35.7, 34.5, 31.4, 29.7, 14.2. IR (neat): 3055, 2963,
2908, 1725, 1515, 1400, 1364, 1321, 1264, 1232, 1161, 1042, 1021, 837,
560 cmꢀ1. HPLC (Chiralpak AD-H, hexane/i-PrOH¼97:3, flow rate:
D
d
7.90 (dd, J¼8.8, 5.4 Hz, 2H), 7.35 (d, J¼8.7 Hz, 2H), 7.32
(d, J¼8.7 Hz, 2H), 7.10 (t, J¼8.6 Hz, 2H), 4.19e4.27 (m, 2H), 3.95 (d,
J¼13.4 Hz, 1H), 3.87 (d, J¼13.4 Hz, 1H), 3.80 (dd, J¼10.9, 3.8 Hz, 1H),
3.64 (dd, J¼17.7, 10.9 Hz, 1H), 3.11 (dd, J¼17.7, 3.8 Hz, 1H), 1.32 (s,
0.7 mL/min,
l
¼220 nm): tR¼11.30 (major), 12.44 (minor). HRMS
(ESI): [C18H26O3SþH]þ requires: 323.1675; found: 323.1696.
9H),1.32 (t, J¼7.1 Hz, 3H). 13C NMR (CDCl3, 75.5 MHz):
d 195.3,172.0,
165.9 (d, JCF¼255 Hz), 150.3, 134.5, 132.6, 130.8 (d, JCF¼9.5 Hz),
4. 4. 21. Diethyl rac-2-(4-tert-butylbenzylsulfanyl)-4-
128.8, 125.6, 115.8 (d, JCF¼22 Hz), 61.4, 40.9, 40.7, 35.8, 34.6, 31.4,
oxopentadienoate (6o). Colorless oil; 1H NMR (CDCl3, 300 MHz):
14.3. IR (KBr):
n
¼3057, 2964, 2909, 1731, 1683, 1598, 1508, 1411,
d
7.34 (d, J¼8.5 Hz, 2H), 7.27 (d, J¼8.5 Hz, 2H), 4.30 (q, J¼7.2 Hz, 2H),
1359, 1299, 1158, 1099, 1023, 992, 911, 836, 734, 557 cmꢀ1. After
4.13e4.23 (m, 2H), 3.91 (d, J¼13.2 Hz, 1H), 3.82 (d, J¼13.2 Hz, 1H),
3.63 (dd, J¼10.3, 4.2 Hz, 1H), 3.52 (dd, J¼18.6, 10.3 Hz, 1H), 3.10 (dd,
J¼18.6, 4.2 Hz, 1H), 1.35 (t, J¼7.2 Hz, 3H), 1.31 (s, 9H), 1.30 (t,
recrystallization from ethanol (96%) of 502 mg of solid, 208 mg of
20
colorless crystals was obtained: mp¼61e62 ꢁC; [
a
]
ꢀ136 (c 0.5,
D
CHCl3), 99%ee, HPLC (Chiralpak AD-H, hexane/i-PrOH¼95:5, flow
J¼7.2 Hz, 3H). 13C NMR (CDCl3, 75.5 MHz):
d 191.2, 171.5, 160.1,
rate: 1.0 mL/min,
l
¼254 nm): tR¼12.35 (major), 14.19 (minor).
150.5, 133.9, 128.9, 125.7, 62.9, 61.7, 41.4, 39.9, 35.8, 34.6, 31.4, 14.3,
HRMS (ESI): [C23H27FO3SþNa]þ requires: 425.1557; found:
14.1. IR (neat):
n
¼2964, 1732, 1366, 1268, 1155, 1109 cmꢀ1. HPLC
425.1555. In a reaction catalyzed by quinidine, (R)-isomer was ob-
(Chiralcel OD-H, hexane/i-PrOH¼97:3, flow rate: 0.7 mL/min,
tained, [
a
]
20 þ102 (c 0.6, CHCl3), 74%ee.
l
¼220 nm): tR¼14.68, 18.33, racemate. HRMS (ESI):
D
[C20H28O5SþH]þ requires: 381.1730; found: 381.1748.
4.4.17. Ethyl (S)-2-(4-tert-butylbenzylsulfanyl)-4-(4-nitrophenyl)-4-
20
oxobutanoate (6j). Waxy yellow solid; [
a]
ꢀ63 (c 3.5, CHCl3),
4.4.22. Hexyl (S)-2-(4-tert-butylbenzylsulfanyl)-4-oxo-4-
D
62%ee. 1H NMR (CDCl3, 600 MHz):
d
8.28 (d, J¼9.0 Hz, 2H), 8.02 (d,
phenylbutanoate (8a). Colorless oil; [
a
]
ꢀ92 (c 1.5, CHCl3), 79%
20
D
J¼9.0 Hz, 2H), 7.35 (d, J¼8.4 Hz, 2H), 7.31 (d, J¼8.4 Hz, 2H),
4.19e4.26 (m, 2H), 3.95 (d, J¼13.5 Hz, 1H), 3.87 (d, J¼13.5 Hz, 1H),
3.81 (dd, J¼10.6, 3.9 Hz, 1H), 3.68 (dd, J¼18.0, 10.6 Hz, 1H), 3.16 (dd,
J¼18.0, 3.9 Hz, 1H), 1.32 (t, J¼7.1 Hz, 3H), 1.30 (s, 9H). 13C NMR
ee. 1H NMR (CDCl3, 600 MHz):
d
7.88 (d, J¼8.0 Hz, 2H), 7.55 (t,
J¼7.3 Hz, 1H), 7.43 (t, J¼7.8 Hz, 2H), 7.36 (d, J¼8.3 Hz, 2H), 7.33 (d,
J¼8.3 Hz, 2H), 4.13e4.22 (m, 2H), 3.96 (d, J¼13.5 Hz, 1H), 3.88 (d,
J¼13.5 Hz, 1H), 3.83 (dd, J¼10.9, 3.8 Hz, 1H), 3.68 (dd, J¼17.9,
10.9 Hz, 1H), 3.15 (dd, J¼17.9, 3.8 Hz, 1H), 1.65e1.72 (m, 2H),
1.35e1.42 (m, 2H), 1.32 (s, 9H), 1.28e1.34 (m, 4H), 0.89 (t, J¼7.0 Hz,
(CDCl3, 151 MHz):
d 195.6, 171.9, 150.6, 150.5, 140.5, 134.4, 129.2,
128.9, 125.7, 124.0, 61.7, 41.5, 40.5, 36.0, 34.6, 31.4, 14.3. IR (neat):
n
¼2964,1728,1695,1603,1526,1345,1211,1172, 995, 852, 749 cmꢀ1
.
3H). 13C NMR (CDCl3, 75.5 MHz):
d 196.9, 172.2, 150.3, 136.2, 134.6,
HPLC (Chiralcel OD-H, hexane/i-PrOH¼95:5, flow rate: 1.0 mL/min,
133.5, 128.9, 128.7, 128.1, 125.6, 65.6, 41.0, 40.8, 35.9, 34.6, 31.5, 31.4,
28.7, 25.7, 22.6, 14.1. IR (neat):
¼3059, 3028, 2959, 2932, 2870,
1732, 1688, 1450, 1362, 1329, 1268, 1214, 1160, 757, 690, 558 cmꢀ1
HPLC (Chiralpak AD-H, hexane/i-PrOH¼97:3, flow rate: 1.0 mL/min,
l
¼220 nm): tR¼31.00 (minor), 42.42 (major). HRMS (ESI):
n
[C23H27NO5SþNa]þ requires: 452.1502; found: 452.1491.
;
4.4.18. Ethyl (S)-2-(4-tert-butylbenzylsulfanyl)-5,5-dimethyl-4-
l
¼220 nm): tR¼9.27 (major), 11.06 (minor). HRMS (ESI):
oxohexanoate (6k). Colorless oil; [
a]
ꢀ70 (c 0.8, CHCl3), 50%ee.
[C27H36O3SþNa]þ requires: 463.2277; found: 463.2301.
20
D
1H NMR (CDCl3, 300 MHz):
d
7.34 (d, J¼8.5 Hz, 2H), 7.28 (d,
J¼8.5 Hz, 2H), 4.12e4.23 (m, 2H), 3.89 (d, J¼13.5 Hz, 1H), 3.80 (d,
J¼13.5 Hz,1H), 3.62 (dd, J¼10.9, 4.0 Hz,1H), 3.18 (dd, J¼18.1,10.9 Hz,
1H), 2.63 (dd, J¼18.1, 4.0 Hz, 1H), 1.30 (s, 9H), 1.29 (t, J¼7.1 Hz, 3H),
4.4.23. Decyl (S)-2-(4-tert-butylbenzylsulfanyl)-4-oxo-4-
20
phenylbutanoate (8b). Colorless oil; [
a
]
D
ꢀ91 (c 1.6, CHCl3), 80%
ee. 1H NMR (CDCl3, 300 MHz):
d
7.87e7.91 (m, 2H), 7.52e7.58 (m,
1.09 (s, 9H). 13C NMR (CDCl3, 75.5 MHz):
d
212.9, 172.0, 150.2, 134.6,
1H), 7.41e7.46 (m, 2H), 7.37 (d, J¼8.7 Hz, 2H), 7.33 (d, J¼8.7 Hz, 2H),
128.8, 125.6, 61.2, 43.8, 40.7, 39.3, 35.9, 34.6, 31.4, 26.4, 14.2. IR
4.12e4.25 (m, 2H), 3.98 (d, J¼13.4 Hz, 1H), 3.88 (d, J¼13.4 Hz, 1H),

R. Kowalczyk et al. / Tetrahedron 70 (2014) 5834e5842
5841
3.84 (dd, J¼11.0, 3.8 Hz, 1H), 3.69 (dd, J¼17.8, 11.0 Hz, 1H), 3.15 (dd,
J¼17.8, 3.8 Hz, 1H), 1.64e1.75 (m, 2H), 1.25e1.44 (m, 14H), 1.33 (s,
(d, J¼13.5 Hz,1H), 3.66 (d, J¼13.5 Hz,1H), 3.27 (d, J¼6.9 Hz, 2H),1.30
(t, J¼7.1 Hz, 3H). 13C NMR (CDCl3, 75.5 MHz):
d 196.0, 166.2, 146.5,
9H), 0.90 (t, J¼6.8 Hz, 3H). 13C NMR (CDCl3, 75.5 MHz):
d
196.8,
137.5, 136.4, 133.5, 129.1, 128.8, 128.7, 128.1, 127.3, 121.9, 60.6, 42.4,
172.1, 150.2, 136.1, 134.5, 133.4, 128.8, 128.7, 128.1, 125.6, 65.5, 40.9,
40.8, 35.8, 34.6, 32.0, 31.4, 29.6 (2C overlapped), 29.4, 29.3, 28.7,
40.9, 35.6, 14.3. IR (neat):
n
¼3063, 3031, 2986, 1705, 1677, 1645,
1447, 1370, 1264, 1250, 1234, 1167, 759, 713, 689 cmꢀ1. HPLC
26.0, 22.8, 14.2. IR (neat):
n
¼3060, 2958, 2926, 2856, 1732, 1689,
(Chiralpak AD-H, hexane/i-PrOH¼97:3, flow rate: 0.7 mL/min,
1470, 1362, 1329, 1267, 1213, 1159, 991, 757, 690 cmꢀ1. HPLC (Chir-
l
¼220 nm): tR¼39.11 (major), 40.75 (minor). HRMS (ESI):
alpak AD-H, hexane/i-PrOH¼99:1, flow rate: 1.0 mL/min,
[C21H22O3SþNa]þ requires: 377.1182; found: 377.1181. Reaction
l
¼220 nm): tR¼18.51 (major), 30.28 (minor). HRMS (ESI):
catalyzed by quinidine afforded opposite enantiomer: [
0.9, CHCl3), 54%ee.
a
]
20 þ84 (c
D
[C31H44O3SþH]þ requires: 497.3084; found: 497.3091.
4.4.24. Isopropyl (S)-2-(4-tert-butylbenzylsulfanyl)-4-oxo-4-
4.4.28. Ethyl
hex-2-enoate (10b). Light yellow oil; [
ee. 1H NMR (CDCl3, 300 MHz):
(S)-(E)-4-(benzylsulfanyl)-6-oxo-6-(4-chlorophenyl)
20
phenylbutanoate (8c). Colorless oil; [
a
]
ꢀ104 (c 0.4, CHCl3), 75%
a
]
D
20 ꢀ66.8 (c 1.6, CHCl3), 57%
D
ee. 1H NMR (CDCl3, 300 MHz):
d
7.86e7.90 (m, 2H), 7.52e7.58 (m,
d
7.79 (d, J¼8.7 Hz, 2H), 7.40 (d,
1H), 7.39e7.46 (m, 2H), 7.37 (d, J¼8.9 Hz, 2H), 7.33 (d, J¼8.9 Hz, 2H),
5.11 (sept, J¼6.3 Hz, 1H), 3.98 (d, J¼13.3 Hz, 1H), 3.88 (d, J¼13.3 Hz,
1H), 3.79 (dd, J¼10.8, 3.4 Hz, 1H), 3.69 (dd, J¼17.5, 10.8 Hz, 1H), 3.14
(dd, J¼17.5, 3.4 Hz, 1H), 1.34 (d, J¼6.3 Hz, 3H), 1.33 (s, 9H), 1.30 (d,
J¼8.7 Hz, 2H), 7.20e7.31 (m, 5H), 6.78 (dd, J¼15.5, 9.2 Hz, 1H), 5.84
(d, J¼15.5 Hz, 1H), 4.20 (q, J¼7.1 Hz, 2H), 3.90 (ddd, J¼9.2, 7.5,
6.3 Hz, 1H), 3.74 (d, J¼13.6 Hz, 1H), 3.65 (d, J¼13.6 Hz, 1H), 3.22 (d,
J¼6.3 Hz, 1H), 3.22 (d, J¼7.5 Hz, 1H), 1.29 (t, J¼7.1 Hz, 3H). 13C NMR
J¼6.3 Hz, 3H). 13C NMR (CDCl3, 75.5 MHz):
d
196.9, 171.5, 150.2,
(CDCl3, 75.5 MHz): d 194.8, 166.2, 146.3, 140.0, 137.5, 134.8, 129.5,
136.2, 134.6, 133.4, 128.8, 128.6, 128.1, 125.6, 68.8, 40.9, 40.8, 35.7,
129.12, 129.05, 128.7, 127.4, 122.0, 60.7, 42.5, 40.9, 35.6, 14.3. IR
34.6, 31.4, 21.82, 21.79. IR (neat):
n
¼3060, 3028, 2964, 2871, 1732,
(neat):
n
¼3062, 3030, 2982, 1716, 1689, 1590, 1271, 1218, 1157, 1093,
1683, 1598, 1516, 1464, 1449, 1396, 1365, 1323, 1267, 1214, 1165,
979, 820, 705 cmꢀ1. HPLC (Chiralpak AD-H, hexane/i-PrOH¼9:1,
1108, 991, 932, 920, 827, 759, 690, 558 cmꢀ1. HPLC (Chiralpak AD-H,
flow rate: 1.0 mL/min,
l¼220 nm): tR¼21.04 (major), 25.07 (minor).
hexane/i-PrOH¼95:5, flow rate: 1.0 mL/min,
l¼220 nm): tR¼8.72
HRMS (ESI): [C21H21ClO3SþH]þ requires: 389.0973; found:
(major), 11.09 (minor). HRMS (ESI): [C24H30O3SþH]þ requires:
389.0984.
399.1988; found: 399.1990.
4.4.29. Ethyl (S)-(E)-4-(benzylsulfanyl)-6-oxo-6-(naphtalene-2-yl)
4.4.25. Isobutyl (S)-2-(4-tert-butylbenzylsulfanyl)-4-oxo-4-
hex-2-enoate (10c). Light yellow oil; [
a
]
20 ꢀ51.3 (c 1.0, CHCl3), 44%
D
20
phenylbutanoate (8d). Colorless oil; [
a
]
ꢀ89 (c 0.4, CHCl3), 77%
ee. 1H NMR (CDCl3, 300 MHz):
d
8.34 (s, 1H), 7.89e7.96 (m, 2H), 7.85
D
ee. 1H NMR (CDCl3, 600 MHz):
d
7.89 (d, J¼7.9 Hz, 2H), 7.55 (t,
(d, J¼8.5 Hz, 2H), 7.51e7.62 (m, 2H), 7.19e7.35 (m, 5H), 6.88 (dd,
J¼15.5, 9.1 Hz, 1H), 5.90 (d, J¼15.5 Hz, 1H), 4.21 (q, J¼7.1 Hz, 2H),
4.01 (dt, J¼9.1, 6.9 Hz, 1H), 3.77 (d, J¼13.5 Hz, 1H), 3.69 (d,
J¼13.5 Hz, 1H), 3.39 (d, J¼6.9 Hz, 2H), 1.30 (t, J¼7.1 Hz, 3H). 13C NMR
J¼7.4 Hz, 1H), 7.43 (t, J¼7.7 Hz, 2H), 7.36 (d, J¼8.1 Hz, 2H), 7.33 (d,
J¼8.1 Hz, 2H), 3.94e3.99 (m, 3H), 3.89 (d, J¼13.4 Hz, 1H), 3.85 (dd,
J¼10.8, 3.8 Hz, 1H), 3.69 (dd, J¼17.7, 10.8 Hz, 1H), 3.17 (dd, J¼17.7,
3.8 Hz,1H), 2.00 (nonet, J¼6.7 Hz,1H),1.32 (s, 9H), 0.98 (d, J¼6.7 Hz,
(CDCl3, 75.5 MHz):
d 195.8, 166.2, 146.5, 137.5, 135.7, 133.7, 132.4,
6H). 13C NMR (CDCl3, 75.5 MHz):
d
196.9, 172.1, 150.3, 136.2, 134.5,
129.9, 129.6, 129.0, 128.70, 128.65, 128.58, 127.8, 127.3, 126.9, 123.6,
133.5, 128.8, 128.7, 128.1, 125.6, 71.4, 41.0, 40.8, 35.9, 34.6, 31.4, 27.9,
19.23, 19.20. IR (neat):
¼3059, 2963, 2909, 2874, 1732, 1449, 1361,
1328, 1268, 1214, 1157, 1001, 757, 690 cmꢀ1. HPLC (Chiralpak AD-H,
121.8, 60.5, 42.4, 41.0, 35.6,14.3. IR (neat):
n
¼3062, 2978,1710,1673,
n
1643, 1369, 1264, 1228, 1166, 1034, 862, 822, 714, 698 cmꢀ1. HPLC
(Chiralcel OD-H, hexane/i-PrOH¼9:1, flow rate: 1.0 mL/min,
hexane/i-PrOH¼97:3, flow rate: 1.0 mL/min,
l
¼220 nm): tR¼10.72
l
¼220 nm): tR¼29.1 (minor), 37.34 (major). HRMS (ESI):
(major), 12.69 (minor). HRMS (ESI): [C25H32O3SþH]þ requires:
[C25H24O3SþH]þ requires: 405.1519; found: 405.1507.
413.2145; found: 413.2164.
Acknowledgements
4.4.26. 4-Nitrobenzyl (S)-2-(4-tert-butylbenzylsulfanyl)-4-oxo-4-
20
phenylbutanoate (8e). White solid, mp¼128e132 ꢁC; [
a
]
ꢀ75 (c
D
The authors are grateful to National Science Centre, Poland for
funding (Grant No. 03/D/ST5/05766).
0.5, CHCl3), 60%ee. 1H NMR (CDCl3, 600 MHz):
d
8.21 (d, J¼8.8 Hz,
2H), 7.87 (d, J¼8.0 Hz, 2H), 7.57 (t, J¼7.5 Hz, 1H), 7.55 (d, J¼8.8 Hz,
2H), 7.44 (t, J¼7.8 Hz, 2H), 7.34 (d, J¼8.3 Hz, 2H), 7.26 (d, J¼8.3 Hz,
2H), 5.29 (d, J¼13.6 Hz, 1H), 5.27 (d, J¼13.6 Hz, 1H), 3.89 (d,
J¼13.4 Hz, 1H), 3.89 (dd, J¼11.3, 3.8 Hz 1H), 3.85 (d, J¼13.4 Hz, 1H),
3.70 (dd, J¼18.0, 11.3 Hz, 1H), 3.22 (dd, J¼18.0, 3.8 Hz, 1H), 1.31 (s,
Supplementary data
Supplementary data contains additional experimental and
computational details, copies of NMR spectra and HPLC chro-
matograms. Supplementary data related to this article can be found
at http://dx.doi.org/10.1016/j.tet.2014.06.035.
9H). 13C NMR (CDCl3, 151 MHz):
d 196.9, 171.6, 150.5, 147.7, 143.3,
135.9, 134.2, 133.7, 128.80, 128.78, 128.3, 128.1, 125.7, 123.8, 65.4,
41.1, 40.8, 35.8, 34.6, 31.4. IR (neat):
¼3115, 3086, 1723, 1676, 1521,
1349, 1331, 1208, 1143, 754, 685 cmꢀ1. HPLC (Chiralpak AD-H,
n
References and notes
hexane/i-PrOH¼9:1, flow rate: 0.75 mL/min,
l
¼220 nm):
tR¼44.25 (minor), 48.83 (major). HRMS (ESI): [C28H29O5NSþH]þ
1. (a) Koval’, I. V. Russ. J. Org. Chem. 2007, 43, 319e346; (b) Enders, D.; Luttgen, K.;
Narine, A. A. Synthesis 2007, 959e980; (c) Liu, W.; Zhao, X. Synthesis 2013, 45,
2051e2069.
requires: 492.1839; found: 492.1845.
2. (a) Kobayashi, Y.; Taniguchi, Y.; Hayama, N.; Inokuma, T.; Takemoto, Y. Angew.
Chem., Int. Ed. 2013, 52, 11114e11118; (b) Fang, X.; Li, J.; Wang, C.-J. Org. Lett.
2013, 15, 3448e3451; (c) Dong, X.-Q.; Fang, X.; Tao, H.-Y.; Zhou, X.; Wang, C.-J.
Adv. Synth. Catal. 2012, 354, 1141e1147.
4.4.27. Ethyl (S)-(E)-4-(benzylsulfanyl)-6-oxo-6-phenylhex-2-enoate
(10a). After chromatography, obtained product was recrystallized
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20
[
d
a
]
ꢀ86.1 (c 0.9, CHCl3), 72%ee. 1H NMR (CDCl3, 300 MHz):
D
7.84e7.88 (m, 2H), 7.53e7.59 (m,1H), 7.41e7.47 (m, 2H), 7.29e7.32
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5842
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