Novel Chiral Bifunctional L-Thiazoline-Thiourea Derivatives: Design and Application in Enantioselective Michael Reactions

Article abstract of DOI:10.1002/chir.22540

Several novel chiral bifunctional L-thiazoline-thiourea derivatives were easily synthesized from commercially available L-cysteine in high yield. These catalysts were subsequently applied to the enantioselective Michael addition of acetylacetone to β-nitr

Full text of DOI:10.1002/chir.22540

CHIRALITY 27:979–988 (2015)
Novel Chiral Bifunctional L-Thiazoline-Thiourea Derivatives: Design
and Application in Enantioselective Michael Reactions
*
QI LAI, YANG LI, ZHIYONG GONG, QINGWEN LIU, CHIYU WEI, AND ZHIGUANG SONG
Department of Organic Chemistry, College of Chemistry, Jilin University, Changchun, China
ABSTRACT
Several novel chiral bifunctional L-thiazoline-thiourea derivatives were easily
synthesized from commercially available L-cysteine in high yield. These catalysts were subse-
quently applied to the enantioselective Michael addition of acetylacetone to β-nitrostyrenes.
The products with S configuration were obtained in 98% enantiomeric excess (ee) when the
L-thiazoline-thiourea derivatives were used. A plausible transition state model is proposed to
explain the observed enantioselectivities. Chirality 27:979–988, 2015. © 2015 Wiley Periodicals, Inc.
KEY WORDS: chiral catalyst; asymmetric Michael addition; thiazoline; thiourea
Asymmetric organocatalytic reactions are extremely im-
portant in modern synthetic and pharmaceutical chemis-
try.1–5 In this field, catalytic asymmetric Michael addition
is widely regarded to be a fundamental C-C bond-forming
reaction utilized in organic synthesis.6,7 Furthermore, the
enantioselective addition of 1, 3-dicarbonyl compounds onto
β-nitrostyrenes is also regarded as one of the benchmark
reactions and an attractive strategy. The reaction has be-
come a standard for the evaluation of newly designed
organocatalysts. Therefore, considerable attention has been
focused on developing new effective chiral catalysts for
asymmetric Michael addition.8–14
Among various chiral catalysts, the H-bond donor catalysts
have been widely developed as a typical class of catalysts.15–18
Of the different H-bond donor catalysts reported to date,
those based on the thiourea core dominate the field. Thus,
new thioureas or other hydrogen bond donors from accessi-
ble members of the chiral pool are continuously being devel-
oped.19–29 Over the past few years, bifunctional tertiary
amine-thiourea organocatalysts have emerged as new and ef-
ficient organocatalysts for asymmetric reactions.30,31 It was
found that the cinchona alkaloid family and its derivatives as
the chiral amine parts of catalysts possessed high catalytic ac-
tivity resulting in a high ee value in the asymmetric Michael
addition.32–37 However, there are only a few examples that
chiral thiazoline-catalysts have been employed since they
were first investigated by Helmchen et al. in 1991.38–43 There
is no report about cinchonine- and quinine-derived chiral
thiazoline-containing catalysts, although the imino moiety-
containing thiazoline is an efficient surrogate for the func-
tional amino unit in some chiral catalysts. Therefore, the
development of efficient new catalysts containing thiazoline
for asymmetric transformations is challenging.
EXPERIMENTAL
Materials and Instruments
All analytical-grade reagents were purchased from Beijing Chemical
Reagent Co. (China) and used without further purification. The products
were purified by neutral column chromatography on silica gel (300–
400 mesh). The structures of chiral thiazoline ligands were identified by
1H NMR and 13C NMR (Varian Mercury 300 NMR spectrometer), using
tetramethylsilane (TMS) as an internal standard. Chemical shifts (δ) are
given in parts per million and coupling constants are given as absolute
values expressed in Hertz. Optical rotations were measured with a
WZZ-1S Digital Automatic Polarimeter from Shanghai Physical Optics
Instrument Factory (China). Concentration is given as absolute values
expressed in g/100 mL. High-performance liquid chromatography
(HPLC) analyses were performed using a Shimadzu (Kyoto, Japan)
LC-10A VP pump, SPD-10A VP UV detector, and Shimadzu CTO-10 AC
VP column oven with appropriate chiral columns. Mass spectra were
obtained using liquid chromatography / mass spectroscopy (LC/MS)
1100 from Agilent Technology (Palo Alto, CA) and Alltech (Deerfield,
IL) ELSD 2000 instrument. High-resolution mass spectroscopic analysis
(HRMS) data were measured on a Bruker (Billerica, MA) Apexll mass
spectrometer by means of the electrospray ionization (ESI) technique.
Melting points were determined by X-4 digital microscopy apparatus. C,
H, and N elemental analyses were taken on a Perkin–Elmer (Boston,
MA) 240C elemental analyzer.
Synthesis
(R)-tetrahydrothiazo-2-thione-4-carboxylic acid [(R)-TTCA] 2 was syn-
thesized by known methods,44 m.p. = 179–181 °C, [α]
= À86.3 (c 1.2,
20
D
0.5 N HCl).
General procedure for preparation of (3a-3c). To a solution of (R)-
TTCA (2) (2.0 g, 12.3 mmol) in acetonitrile (40 mL), the corresponding
halide (37.5 mmol) and anhydrous K2CO3 (3.4 g) were added at room
temperature. The solution was then stirred at 55 °C for 6 hours. Upon
cooling to room temperature, the precipitate was removed by filtration
and the filtrate was concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel (petroleum ether:
EtOAc).
We recently first reported the design, synthesis, and ap-
plication of a series of novel modular, thiazoline-containing
N-O ligands 6 derived from L-cysteine (Scheme 1) in asym-
metric addition of diethylzinc to aromatic aldehydes.44
Encouraged by these successful efforts and aiming to
demonstrate the generality of the new catalysts containing
thiazoline, we fixed our attention on employing these novel
catalysts 13 (Scheme 1) by tuning the thiourea moiety for
enantioselective addition of 1, 3-dicarbonyl compounds onto
β-nitrostyrenes.
*Correspondence to: Zhiguang Song, Department of Organic Chemistry, Col-
lege of Chemistry, Jilin University, Changchun 130021, China. E-mail: szg@jlu.
edu.cn
Received for publication 7 May 2015; Accepted 2 September 2015
DOI: 10.1002/chir.22540
Published online 1 October 2015 in Wiley Online Library
(wileyonlinelibrary.com).
© 2015 Wiley Periodicals, Inc.

980
LAI ET AL.
analysis calculated for C5H7NO2S2: C, 33.88; H, 3.98; N, 7.90. Found:
C, 34.69, H, 4.06, N, 7.80.
Procedure for preparation of (R)-2-((pyridin-2-ylmethyl)thio)-4-
methyloxycarbonyl À4, 5-dihydro-1, 3-thiazole (5). To a solution
of methyl-(R)-2-thioxothiazolidine-4-carboxylate (4) (1.35 g, 7.63 mmol)
in acetonitrile (20 mL), 2-(bromomethyl) pyridine hydrobromide (2.53 g,
10 mmol), anhydrous K2CO3 (2.8 g), and (0.1 g) KI were added at room
temperature. The solution was then stirred at 40 °C for 3 h. Upon cooling
to room temperature, the precipitate was removed by filtration and filtrate
was then concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel (petroleum ether: EtOAc = 1:1).
(R)-2-((pyridin-2-ylmethyl)thio)-4-methyloxycarbonyl À4, 5-dihydro-1,
3-thiazole 5 was obtained in 86% yield after purification by column chro-
= + 27 (c = 1.3, CHCl3), 1H NMR
Scheme 1. Chiral Bifunctional L-Thiazoline-Thiourea catalysts.
20
matography on silica gel, [α]
D
(300 MHz, CDCl3) δ(ppm) 3.60-3.74 (m, 2H), 3.80 (s, 3H), 4.55 (q, 2H,
J = 15 Hz), 5.08 (t, J = 7.5 Hz, 1H), 7.17-7.21 (m, 1H), 7.46-7.49 (m, 1H),
7.62-7.68 (m, 1 H), 8.54-8.56 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ(ppm) 37.58, 38.82, 52.69, 77.05, 122.35, 123.55, 136.67, 149.44, 156.62,
168.63 , 170.95. MS (ESI): m/z 269.2 [M + H+]; Elemental analysis calcu-
lated for C11H12N2O2S2: C, 49.23; H, 4.51; N, 10.44. Found: C, 49.20, H,
4.50, N, 10.48.
(R)-2-ethylthio-4-ethyloxycarbonyl-4,5-dihydro-1,3-thiazole (3a) 3a
was obtained as a colorless oil, 88% yield after purification by column
20
chromatography on silica gel (petroleum ether: EtOAc = 3:1), [α]
D
= + 38.8 (c = 6.4, CHCl3), 1H NMR (300 MHz, CDCl3) δ(ppm) 1.29-
1.41 (m, 6H), 3.06-3.25 (m, 2H), 3.56-3.71 (m, 2H), 4.25 (q, J = 6 Hz,
2H), 5.06 (t, J = 7.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ(ppm)
14.08, 14.41, 27.34, 37.02, 61.58, 77.23, 170.50. MS (ESI): m/z 220.3
[M + H+]; Elemental analysis calculated for C8H13NO2S2: C, 43.81; H,
5.97; N, 6.39. Found: C, 43.83, H, 5.96, N, 6.36.
General procedure for preparation of (R)-2-substitutedthio-4-
hydroxymethyl-4, 5-dihydro-1, 3-thiazoles (6a-6d). To a solution
of 3 or 5 (5.0 mmol) in methanol (15 mL), NaBH4 (0.57 g, 15.0 mmol)
was added. The solution was then stirred at room temperature for 0.5 h
before water was added to quench the excessive NaBH4. The mixture
was then extracted twice with CH2Cl2. The combined organic phase were
washed twice with saturated brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The crude product was purified
by column chromatography on silica gel to give the alcohols 6a-6d.
(R)-2-ethylthio-4-hydroxymethyl-4,5-dihydro-1,3-thiazole (6a) 6a was ob-
(R)-2-butylthio-4-butyloxycarbonyl-4,5-dihydro-1,3-thiazole (3b) 3b
was obtained as a colorless oil, 72% yield after purification by column
chromatography on silica gel (petroleum ether: EtOAc = 5:1), [α] 2D0 = + 28.5
(c = 6.7, CHCl3), 1H NMR (300 MHz, CDCl3) δ(ppm) 0.92-0.95 (m, 6H),
1.39-1.44 (m, 4H), 1.64-1.69 (m, 4H), 3.08-3.23 (m, 2H), 3.59-3.66 (m,
2H, 4.19 (t, J = 6.6 Hz, 2H), 5.06 (t, J = 8.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ(ppm) 13.54 , 13.63, 19.01, 21.79, 30.50, 31.13, 32.75, 37.15,
65.47, 77.25, 170.65. MS (ESI): m/z 276.3 [M + H+]; Elemental analysis
calculated for C12H21NO2S2: C, 52.33; H, 7.68; N, 5.09. Found: C, 52.36,
H, 7.69, N, 5.06.
tained as a colorless oil, 99% yield after purification by column chromatogra-
20
phy on silica gel (petroleum ether: EtOAc = 1:2), [α]
= + 46.3 (c = 2.8,
D
CHCl3), 1H NMR (300 MHz, CDCl3) δ(ppm) 1.36 (t, J = 7.2 Hz, 3H), 2.06
(br, 1H), 3.07-3.14 (m, 2H), 3.27 (dd, J = 8.7 Hz, J = 10.8 Hz, 1H), 3.42 (dd,
J = 8.1 Hz, J = 10.8 Hz, 1H), 3.69 (dd, J = 5.7 Hz, J = 11.1 Hz, 1H), 3.88 (dd,
J = 4.8 Hz, J = 11.1 Hz, 1H), 4.54-4.63 (m, 1H, ); 13C NMR (75 MHz, CDCl3)
δ(ppm) 14.39, 27.13, 35.84, 63.76, 78.39. MS (ESI): m/z 179.0 [M + H+]; Ele-
mental analysis calculated for C6H11NOS2: C, 40.65; H, 6.25; N, 7.90. Found:
C, 40.67, H, 6.23, N, 7.93.
(R)-2-benzylthio-4-benzyloxycarbonyl-4,5-dihydro-1,3-thiazole (3c)
3c was obtained as a colorless oil, 56% yield after purification by
column chromatography on silica gel (petroleum ether: EtOAc = 5:1),
20
D
[α]
= + 17 (c = 3.1, CHCl3), 1H NMR (300 MHz, CDCl3) δ(ppm)
3.59-3.62 (m, 2H), 4.34-4.45 (m, 2H), 5.12 (m, 1 H), 5.25 (s, 2H),
7.26-7.39 (m, 10H); 13C NMR (75 MHz, CDCl3) δ(ppm) 37.19, 37.36,
67.20, 77.07, 127.49, 128.15, 128.36, 128.55, 129.04, 135.34, 136.28,
170.21. MS (ESI): m/z 344.2 [M + H+]; Elemental analysis calculated
for C18H17NO2S2: C, 62.94; H, 4.99; N, 4.08. Found: C, 62.97, H,
4.97, N, 4.07.
(R)-2-butylthio-4-hydroxymethyl-4,5-dihydro-1,3-thiazole (6b) 6b was ob-
tained as a colorless oil, 99% yield after purification by column chroma-
20
tography on silica gel (petroleum ether: EtOAc = 1:2), [α]
= + 28.4
D
(c = 3.9, CHCl3), 1H NMR (300 MHz, CDCl3) δ(ppm) 0.93 (t, J = 7.5 Hz,
3H), 1.37-1.49 (m, 2H), 1.63-1.73 (m, 2H), 1.94 (br, 1H), 3.12 (t,
J = 7.5 Hz, 2H), 3.27 (dd, J = 8.7 Hz, J = 10.8 Hz, 1H), 3.42 (dd, J = 8.4 Hz,
J = 10.8 Hz, 1H), 3.69 (dd, J = 5.7 Hz, J = 11.1 Hz, 1H), 3.89 (dd,
J = 4.8 Hz, J = 11.1 Hz, 1H), 4.54-4.63 (m,1H); 13C NMR (75 MHz, CDCl3)
δ(ppm) 13.47, 21.76, 31.24, 32.59, 35.90, 64.04, 78.46. MS (ESI): m/z
206.2 [M + H+]; Elemental analysis calculated for C8H15NOS2: C, 46.79;
H, 7.36; N, 6.82. Found: C, 46.75, H, 7.38, N, 6.86.
Procedure for preparation of methyl-(R)-2-thioxothiazolidine-4-car-
boxylate (4). To a solution of (R)-TTCA (2) (0.65 g, 4.0 mmol) in
methanol (10 mL), TiCl4 (0.1 mL, 1.0 mmol) was added at 0 °C. The solu-
tion was then stirred at room temperature for 12 h. Then the solution was
neutralized with 5% sodium bicarbonate solution to pH = 8 at 0 °C. The
mixture was then extracted twice with CH2Cl2. The combined organic
phase were washed with saturated brine twice, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The crude product
was purified by column chromatography on silica gel (petroleum ether:
EtOAc = 3:2) and then was obtained as a colorless oil, 99% yield.
(R)-2-benzylthio-4-hydroxymethyl-4,5-dihydro-1,3-thiazole (6c) 6c
was obtained as a light yellow oil, 98% yield after purification by column
20
D
chromatography on silica gel (petroleum ether: EtOAc = 1:2), [α] = + 21.6
(c = 2.2, CHCl3), 1H NMR (300 MHz, CDCl3) δ(ppm) 1.86 (s, 1H),
3.29 (dd, J = 8.4 Hz, J = 10.5 Hz, 1H), 3.44 (dd, J = 8.1 Hz, J = 10.5 Hz,
1H), 3.65 (dd, J = 5.7 Hz, J = 11.4 Hz, 1H), 3.88 (dd, J = 4.8 Hz,
J = 11.1 Hz, 1H), 4.35 (m, 2 H), 4.56-4.64 (m,1H), 7.28-7.38 (m, 5H);
13C NMR (75 MHz, CDCl3) δ(ppm) 36.26, 37.06, 64.09, 78.33, 127.48,
128.52, 128.89, 136.43. MS (ESI): m/z 240.1 [M + H+]; Elemental
(R)-methyl-2-thioxothiazolidine-4-carboxylate (4) 443 was obtained as
20
a colorless oil, 99% yield. [α]
= À 68 (c = 5.5, CHCl3), 1H NMR
D
(300 MHz, CDCl3) δ(ppm) 3.81 (d, J = 8 Hz, 2H), 3.86 (s, 3H), 4.83-4.88
(m, 1H), 8.21 (br, 1H). MS (ESI): m/z 177.1 [M + H+]; Elemental
Chirality DOI 10.1002/chir

NOVEL CHIRAL BIFUNCTIONAL L-THIAZOLINE-THIOUREA DERIVATIVES
981
analysis calculated for C11H13NOS2: C, 55.20; H, 5.47; N, 5.85. Found:
C, 55.26, H, 5.44, N, 5.88.
reduced pressure. The crude product 8 obtained was used directly in the next
step without purification.
(R)-2-((pyridin-2-ylmethyl)thio)-4-hydroxymethyl-4,5-dihydro-1,3-thiazole
(6d) 6d was obtained as a light yellow solid, 88% yield after purification by
To a solution of the crude product 8 (2 mmol) in THF (20 mL),
triphenylphosphine (1.05 g, 4 mmol) and water (0.08 mL, 4 mmol) were
added at room temperature. The reaction mixture was stirred at room
temperature for 24 h. Then the reaction was quenched by addition of
water, neutralized with 1 M hydrochloric acid to pH = 2 at 0 °C, and ex-
tracted with ethyl acetate. Then the aqueous phase was neutralized to
pH = 12 with sodium hydroxide solution at 0 °C, and then extracted with
ethyl acetate (20 mL × 3). The combined organic phase was washed with
brine, dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The crude product 9 obtained and purified by column chroma-
tography on silica gel.
column chromatography on silica gel (CH3OH: CH2Cl2 = 1:20), m. p. = 60 °C,
20
D
[α]
= + 62 (c = 2.0, CHCl3), 1H NMR (300 MHz, CDCl3) δ(ppm) 3.31
(dd, J = 7.5 Hz, J = 10.8 Hz, 1H), 3.45 (dd, J = 8.4 Hz, J = 10.8 Hz, 1H), 3.62
(dd, J = 5.4 Hz, J = 11.1 Hz, 1H), 3.86 (dd, J = 4.5 Hz, J = 11.1 Hz, 1H), 4.32
(d, J = 13.8 Hz, 1H), 4.65 (d, J = 13.8 Hz, 1H), 4.59-4.68 (m,1H), 7.16-7.20
(m, 1H), 7.35-7.38 (m, 1H), 7.62-7.67 (m, 1H), 8.51-8.54 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ(ppm) 36.72, 38.4, 64.36, 77.15, 122.45, 123.31,
136.91, 149.43, 157.07, 165.95. HRMS (ESI) m/z calcd for C10H13N2OS2
[M + H+]: 241.0464, found 241.0463.
(R)-(2-(ethylthio)-4,5-dihydrothiazol-4-yl)methanamine (9a) 9a was ob-
tained as a yellow oil, 90% yield after purification by column chromatogra-
phy on silica gel (CH2Cl2: CH3OH = 9:1), 1H NMR (400 MHz, CDCl3)
δ(ppm) 1.36 (t, J = 7.2 Hz, 3H), 2.88 (q, J = 6.4 Hz, 1H), 2.97 (dd,
J = 5.2 Hz, J = 12.8 Hz, 1H), 3.08-3.11 (m, 1H), 3.18 (dd, J = 8.0 Hz,
J = 14.4 Hz, 1H), 3.42-3.47 (m, 2H), 4.44-4.51 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ(ppm) 9.42, 21.94, 31.89, 40.61, 74.14, 159.96; MS
(ESI): m/z 177.0 [M + H+].
(R)-(2-(butylthio)-4,5-dihydrothiazol-4-yl)methanamine (9b) 9b was ob-
tained as a colorless oil, 89% yield after purification by column chromatog-
raphy on silica gel (CH2Cl2: CH3OH = 9:1), 1H NMR (300 MHz, CDCl3)
δ(ppm) 0.93 (t, J = 7.5 Hz, 3H), 1.39-1.47 (m, 2H), 1.63-1.73 (m, 2H), 1.91
(br, 2H), 2.85-2.96 (m, 2H), 3.07-3.13 (m, 2H), 3.17 (dd, J = 8.4 Hz,
J = 10.8 Hz, 1H), 3.43 (dd, J = 8.4 Hz, J = 10.8 Hz, 1H), 4.54-4.63 (m,1H);
13C NMR (75 MHz, CDCl3) δ(ppm) 13.61, 21.86, 31.39, 32.56, 37.17,
45.94, 79.46, 165.52; MS (ESI): m/z 205.2 [M + H+].
(R)-(2-(benzylthio)-4,5-dihydrothiazol-4-yl)methanamine (9c) 9c was ob-
tained as a light yellow oil, 86% yield after purification by column chroma-
tography on silica gel (CH2Cl2: CH3OH = 9:1), 1H NMR (300 MHz,
DMSO) δ(ppm) 2.64-2.78 (m, 2 H), 3.33 (dd, J = 7.5 Hz, J = 11.8 Hz, 1H),
3.49 (dd, J = 8.1 Hz, J = 11.8 Hz, 1H), 4.35 (d, J = 3 Hz, 2H), 4.38-4.46
(m,1H), 7.26-7.37 (m, 5H); 13C NMR (75 MHz, DMSO) δ(ppm) 35.86,
37.17, 44.90, 79.32, 127.27, 128.40, 128.94, 129.36, 137.28, 162.15; MS
(ESI): m/z 239.1 [M + H+].
(R)-(2-((pyridin-2-ylmethyl)thio)-4,5-dihydrothiazol-4-yl)metha-namine
(9d) 9d was obtained as a light yellow oil, 88% yield after purification by
column chromatography on silica gel (CH2Cl2: CH3OH = 9:1), 1H NMR
(300 MHz, DMSO) δ(ppm) 2.63-2.75 (m, 1H), 3.33 (dd, J = 7.5 Hz,
J = 10.8 Hz, 1H), 3.86 (dd, J = 4.5 Hz, J = 11.1 Hz, 1H), 4.35-4.42 (m, 1H),
4.46 (d, J = 5.1 Hz, 2H), 7.26-7.30 (m, 1H), 7.35-7.46 (d, J = 7.8 Hz, 1H),
7.72-7.78 (m, 1H), 8.50-8.51 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ(ppm) 32.43, 33.35, 40.76, 74.04, 117.02, 117.99, 131.36, 144.23,
151.72, 159.22; MS (ESI): m/z 241.1 [M + H+].
General procedure for preparation of (7a-7d). To a solution of 6
(3 mmol) in dry CHCl3 (10 mL), triethylamine (0.83 mL, 6 mmol) and
p-toluenesulfonyl chloride (0.86 g, 4.5 mmol) were added at 0 °C. The
reaction mixture was stirred at room temperature for 60 h. Then the
reaction was quenched by addition of 5% sodium bicarbonate solution
and extracted with CHCl3 (20 mL × 3). The combined organic phase was
washed with brine and dried over anhydrous Na2SO4. The solvent was
then removed under reduced pressure. The crude product was purified
by column chromatography on silica gel.
(R)-(2-(ethylthio)-4,5-dihydrothiazol-4-yl)methyl-4-methylbenzenesulfo-
nate (7a) 7a43 was obtained as a light yellow oil, 82% yield after purifica-
tion by column chromatography on silica gel (petroleum ether:
EtOAc = 5:1), 1H NMR (300 MHz, CDCl3) δ(ppm) 1.31 (t, J = 7.5 Hz,
3H), 2.46 (s, 3 H), 3.04 (q, J = 7.5 Hz, 2H), 3.27 (dd, J = 6.3 Hz,
J = 11.1 Hz, 1H), 3.46 (dd, J = 8.1 Hz, J = 11.1 Hz, 1H), 3.99 (dd,
J = 8.1 Hz, J = 9.9 Hz, 1H), 4.21 (dd, J = 4.2 Hz, J = 9.9 Hz, 1H), 4.64-4.73
(m, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.80 (d, J = 8.1 Hz, 2H).
(R)-(2-(butylthio)-4,5-dihydrothiazol-4-yl)methyl-4-methylbenzenesulfo-
nate (7b) 7b43 was obtained as a light yellow oil, 80% yield after purifica-
tion by column chromatography on silica gel (petroleum ether:
EtOAc = 5:1), 1H NMR (300 MHz, CDCl3) δ(ppm) 0.91 (t, J = 7.2 Hz, 3H),
1.33-1.43 (m, 2H), 1.56-1.68 (m, 2H), 2.46 (s, 3H), 3.04 (t, J = 7.2 Hz, 2H),
3.27 (dd, J = 6.3 Hz, J = 11.1 Hz, 1H), 3.46 (dd, J = 8.1 Hz, J = 11.1 Hz, 1H),
3.98 (dd, J = 8.4 Hz, J = 9.6 Hz, 1H), 4.21 (dd, J = 4.2 Hz, J = 9.9 Hz, 1H),
4.66-4.72 (m, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.80 (d, J = 8.1 Hz, 2H).
(R)-(2-(benzylthio)-4,5-dihydrothiazol-4-yl)methyl-4-methylbenzenesul-
fonate (7c) 7c was obtained as a yellow oil, 84% yield after purification by
column chromatography on silica gel (petroleum ether: EtOAc = 5:1), 1H
NMR (300 MHz, CDCl3) δ(ppm) 2.45 (s, 3H), 3.28 (dd, J = 6.3 Hz,
J = 11.1 Hz, 1H), 3.47 (dd, J = 8.1 Hz, J = 11.1 Hz, 1H), 3.98 (dd, J = 8.1 Hz,
J = 9.9 Hz, 1H), 4.20 (dd, J = 4.2 Hz, J = 9.9 Hz, 1H), 4.27 (s, 2H), 4.65-4.74
(m, 1H), 7.27-7.32 (m, 5H), 7.36 (d, J = 8.1 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H).
(R)-(2-((pyridin-2-ylmethyl)thio)-4,5-dihydrothiazol-4-yl)methyl-
4-methylbenzenesulfonate (7d) 7d was obtained as a yellow oil, 90%
yield after purification by column chromatography on silica gel (petro-
leum ether: EtOAc = 1:1), 1H NMR (300 MHz, CDCl3) δ(ppm) 2.45 (s,
3H), 3.27 (dd, J = 6.6 Hz, J = 11.1 Hz, 1H), 3.47 (dd, J = 8.1 Hz,
J = 11.1 Hz, 1H), 3.97 (dd, J = 8.1 Hz, J = 9.9 Hz, 1H), 4.17 (dd, J = 4.5 Hz,
J = 9.9 Hz, 1H), 4.42 (s, 2H), 4.64-4.73 (m, 1H), 7.16-7.21 (m, 1H), 7.35-
7.38 (m, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.62-7.68 (m, 1H), 7.80 (d,
J = 8.4 Hz, 2H), 8.53-8.55 (m, 1H).
General procedure for preparation of (11a-11b). A cinchona alka-
loid (2.5 mmol) and triphenylphosphine (0.8 g, 3 mmol) were dissolved
in THF (25 mL) and the solution was cooled to 0 °C. Diethy-
lazodicarboxylate (3 mmol, 0.6 mL) was subsequently added. To the
resulting solution was added dropwise the solution of diphenyl phospho-
ryl azide (0.65 mL, 3 mmol) in THF (10 mL) at 0 °C. The mixture was
allowed to warm to room temperature. After being stirred for 24 h, it
was heated to 50 °C and stirred for 3 h. Triphenylphosphine (0.85 g,
3.3 mmol) was added again, and the mixture was stirred at 50 °C for an
additional 3 h. After the solution was cooled to room temperature, H2O
(3 mL) was added, and the solution was stirred for 12 h. Then the reaction
was quenched by addition of water, neutralized with 1 M hydrochloric
acid to pH = 2 at 0 °C, and extracted with ethyl acetate. Then the aqueous
phase was neutralized to pH = 12 with sodium hydroxide solution at 0 °C,
and then extracted with ethyl acetate (20 mL × 3). The combined organic
phase was washed with brine, dried over anhydrous Na2SO4, and
Chirality DOI 10.1002/chir
General procedure for preparation of (8, 9). To a solution of 7
(3 mmol) in dry DMSO (20 mL), sodium azide (1.95 g, 30 mmol) was added
at room temperature The reaction mixture was stirred at room temperature
for 24 h. Then the reaction was quenched by addition of water and extracted
with CHCl3 (20 mL × 3). The combined organic phase was washed with brine
and dried over anhydrous Na2SO4. The solvent was then removed under

982
LAI ET AL.
concentrated in vacuo. Purification by silica gel column chromatography
using EtOAc: CH3OH: (Et)3N =100:100:1) as an eluent gave the corre-
sponding amine.
13b was obtained as a white solid, 80% yield after purification by
column chromatography on silica gel (CH2Cl2: CH3OH = 9:1), [α] 2D0 = À67
(c = 1.0, CHCl3), m.p. = 120–122 °C 1H NMR (300 MHz, CDCl3) δ(ppm)
0.91 (t, J = 7.2 Hz, 3H), 1.02-1.08 (m, 1H), 1.21-1.67 (m, 6H, thiazoline),
1.82 (brs, 3H), 2.45 (brs, 1H), 2.91-3.05 (m, 4H), 3.07-3.13 (m, 1H),
3.31-3.43 (m, 2H), 3.55-3.68 (m, 3H), 3.83-3.90 (m, 1H), 4.00 (s, 3H),
4.52-4.59 (m, 1H), 5.02-5.08 (m, 2H), 5.63-5.74 (m, 1H), 7.37-7.41 (m,
1H), 7.50-7.52 (m, 1H), 7.84 (brs, 1H), 8.02 (d, J = 9.0 Hz, 1H), 8.75-8.76
(m, 1H); 13C NMR (75 MHz, CDCl3) δ(ppm) 14.01, 22.27, 25.32, 26.60,
27.55, 31.76, 33.23, 37.47 (ÀSCH2CHN=), 38.48, 41.86, 48.51, 55.12,
56.41 , 60.80, 76.34, 102.68, 116.66, 121.19, 122.71 , 128.19, 132.34,
139.19, 145.51, 148.10, 158.73, 167.80, 183.40. HRMS (ESI) m/z calcd for
11a was obtained as a light yellow oil, 76% yield after purification by
20
D
column chromatography on silica gel, [α]
= +110 (c = 1.0, CHCl3), 1H
NMR (300 MHz, CDCl3) δ(ppm) 0.94-1.05 (m, 1H), 1.43-1.48 (m, 3H),
2.18-2.26 (m, 2H), 2.88-2.96 (m, 5H), 4.71 (d, J = 10.2 Hz, 1H), 5.04-5.13
(m, 2H), 5.84-5.95 (m, 1H), 7.60-7.68 (m, 2H), 7.72-7.77 (m, 1H), 8.03 (d,
J = 5.4 Hz, 1H), 8.50-8.52 (m, 1H), 8.86 (d, J = 4.2 Hz, 1H).
11b was obtained as a light yellow oil, 80% yield after purification by
20
D
column chromatography on silica gel, [α]
= + 80 (c 1.0, CHCl3), 1H
NMR (300 MHz, CDCl3) δ(ppm) 0.65-0.72 (m, 1H), 1.16-1.25 (m, 1H),
1.52 (m, 3H), 2.24 (m, 2H), 2.64-2.69 (m, 2H), 2.91-2.99 (m, 1H), 3.141-
3.22 (m, 1H), 3.93 (s, 3H), 4.62 (d, J = 10.2 Hz, 1H, 4.91-5.02 (m, 2H),
5.77-5.88 (m, 1H), 7.40 (dd, J = 2.7 Hz, J = 8.7 Hz, 1H), 7.59 (d, J = 5.4 Hz,
1 H), 7.92 (d, J = 9.3 Hz, 1H), 8.33 (m, 1H), 8.70 (d, J = 4.5 Hz, 1H).
C
29H40N5OS3 [M + H+]: 570.2389, found 570.2387.
13c was obtained as a white solid, 85% yield after purification by column
chromatography on silica gel (CH2Cl2: CH3OH = 9:1), [α] 2D0 = À92.9 (c = 1.0,
1
CHCl3), m.p. = 98–100 °C, H NMR (300 MHz, CDCl3) δ(ppm) 0.88-0.97
(m, 1H), 1.30-1.41 (m, 1H), 1.62-1.69 (m, 3H), 2.31 (brs, 1H), 2.71-2.88
(m, 3H), 3.02-3.30 (m, 5H,), 3.54-3.68 (m, 1H), 3.78-3.90 (m, 1H), 3.97
(s, 3 H), 4.19 (d, J = 6.9 Hz, 2H), 4.38-4.53 (m, 1H), 4.93-5.00 (m, 2H),
5.61-5.73 (m, 1H), 7.26-7.39 (m, 7H), 7.74 (brs, 1H), 8.00 (d,
J = 9.3 Hz, 1H), 8.70-8.72 (m, 1H); 13C NMR (75 MHz, CDCl3) δ(ppm)
26.07, 27.64, 27.83, 37.38, 37.48, 39.54 , 41.56 , 48.55, 55.77, 56.26,
60.91, 76.19, 102.60, 115.43, 120.55, 122.48, 127.99, 129.01, 129.40,
129.47 , 132.12, 136.76, 140.99, 145.17,148.03, 158.38, 167.40, 183.30.
HRMS (ESI) m/z calcd for C32H38N5OS3 [M + H+]: 604.2233, found
604.2231.
General procedure for preparation of (12a-12b). To a solution of
the corresponding primary amine 11 (1.55 mmol) in dry THF (10 mL)
at À10 °C were added CS2 (9.3 mmol, 0.56 mL) and DCC (1.55 mmol,
0.32 g). The reaction mixture was warmed slowly to room temperature
over a period of 3 h and then stirred 48 h at room temperature. The sol-
vent was subsequently removed under vacuum. The residue was purified
by chromatography on silica gel.
12a45 was obtained as a white solid, 80% yield after purification by
20
D
column chromatography on silica gel (EtOAc: CH3OH = 10:1), [α]
=
+117.6 (c = 1.0, CHCl3), m.p. = 176–180 °C. 1H NMR (CDCl3, 300 MHz)
δ(ppm) 1.86-1.96 (m, 4H), 2.07 (brs, 1H), 2.62-2.70 (m, 1H), 3.14-3.33
(m, 3H), 3.52-3.56 (m, 1H), 3.81-3.88 (m, 1H), 5.19-5.32 (m, 2H), 5.51 (d,
J = 10.2 Hz, 1H), 5.84-5.95 (m, 1H), 7.56 (d, J = 4.5 Hz, 1H), 7.62 (d,
J = 7.5 Hz, 1H), 7.75 (t, J = 7.5 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.16 (d,
J = 8.4 Hz, 1H), 8.90 (dd, J = 4.2 Hz, J = 11.7 Hz, 1H). HRMS (ESI) m/z
calcd for C20H22N3S [M + H+]: 336.1529, found 336.1521.
13d was obtained as a white solid, 87% yield after purification by column
chromatography on silica gel (CH2Cl2: CH3OH = 9:1), [α] 2D0 = À69 (c = 1.0,
CHCl3), m.p. = 104–106 °C, 1H NMR (300 MHz, CDCl3) δ(ppm) 0.95-1.00
(m, 1H), 1.36-1.45 (m, 1H), 1.73 (brs, 3H), 2.36 (brs, 1H), 2.73-2.88 (m,
3H), 3.09-3.36 (m, 5H), 3.54-3.68 (m, 1 H), 3.80-3.95 (m, 1H), 3.99 (s,
3H), 4.31-4.55 (m, 3H), 4.96-5.02 (m, 2H), 5.61-5.73 (m, 1H), 7.13-7.19
(m, 1H), 7.32-7.37 (m, 2H), 7.39-7.45 (m, 1H), 7.59-7.64 (m, 1H), 7.84
(brs, 1H), 7.99-8.03 (m, 1H), 8.51-8.54 (m, 1H), 8.72 (t, J = 4.8 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ(ppm) 25.48, 27.03, 27.21, 37.27, 38.26,
38.86, 41.11, 47.78, 55.19, 55.64, 60.49, 75.47, 102.31, 114.70, 119.91 ,
121.82, 122.21, 123.16, 127.93, 131.25, 136.68 , 140.41, 144.44, 147.30,
149.00, 156.38, 157.68, 165.68, 182.85. HRMS (ESI) m/z calcd for
12b46 was obtained as a white solid, 84% yield after purification by
20
column chromatography on silica gel (EtOAc: CH3OH = 10:1), [α]
=
D
+15 (c = 1.0, CHCl3), m.p. = 86–88 °C. 1H NMR (CDCl3, 300 MHz)
δ(ppm) 1.52-1.59 (m, 1H), 1.84-1.92 (m, 3H), 2.07 (brs, 1H), 2.65 (m,
1H), 3.10-3.17 (m, 1H), 3.22-3.31 (m, 2H), 3.49-3.52 (m, 1H), 3.70-3.72
(m, 1H), 3.93 (s, 3H), 5.04-5.12 (m, 2H), 5.38 (d, J = 10.2 Hz, 1H), 5.63-
5.74 (m, 1H), 7.28 (d, J = 2.7 Hz, 1H), 7.34 (dd, J = 2.7 Hz, J = 9.0 Hz, 1H),
7.38 (d, J = 4.5 Hz, 1H), 7.99 (d, J = 9.3 Hz, 1H), 8.70 (d, J = 4.5 Hz, 1H).
HRMS (ESI) m/z calcd for C21H24N3OS [M + H+]: 366.1635, found
366.1636.
C
31H37N6OS3 [M + H+]: 605.2185, found 605.2182.
13e was obtained as a white solid, 60% yield after purification by column
chromatography on silica gel (CH2Cl2: CH3OH = 9:1), [α] 2D0 = +116 (c = 1.0,
CHCl3), m.p. = 58–60 °C, 1H NMR (400 MHz, CDCl3) δ(ppm) 1.00-1.03
(m, 1H), 1.14-1.40 (m, 2H), 1.60-1.76 (m, 3H), 2.32-2.46 (m, 2H), 2.58-
2.67 (m, 2H), 3.01-3.21 (m, 4H), 3.35-3.41 (m, 1H), 3.68-3.78 (m, 1H),
3.87-3.91 (m, 1H), 4.37-4.41 (m, 1H), 4.48-4.60 (m, 1H), 4.79-4.82 (m,
1H), 5.09-5.14 (m, 1H), 5.20-5.27 (m, 1H), 5.87-5.95 (m, 1H), 7.21-7.22
(m, 1 H), 7.41-7.42 (m, 1H), 7.51 (m, 1H), 7.58-7.67 (m, 2H), 7.73-7.77
(m, 1H), 8.15-8.17 (m, 1H), 8.35-8.45 (m, 1H), 8.59 (m, 1H), 8.93 (m,
1H); 13C NMR (100 MHz, CDCl3) δ(ppm) 24.92, 25.68, 26.44, 27.21,
29.68 , 37.56 , 38.57, 39.37, 47.33, 48.08, 53.51, 58.04, 75.70, 100.00,
114.81, 119.91, 122.42, 123.47, 126.68, 130.39, 136.92, 140.24, 148.55,
147.30, 150.24, 156.67, 156.81, 166.09, 183.29. HRMS (ESI) m/z calcd
for C30H35N6S3 [M + H+]: 575.2080, found 575.2087.
General procedure for preparation of (13a-13e). To a solution of
chiral amine 9 (2.7 mmol) in anhydrous CH2Cl2 (20 mL) was added iso-
thiocyanate 12 (2.7 mmol) at room temperature. The solution was stirred
overnight. Thin-layer chromatography (TLC) indicated completion of
the reaction. The reaction mixture was concentrated under vacuum.
The residue was purified by silica gel chromatography to afford the pure
product 13.
13a was obtained as a white solid, 83% yield after purification by column
chromatography on silica gel (CH2Cl2: CH3OH = 9:1), [α] 2D0 = À90.9 (c = 1.0,
CHCl3), m.p. = 100–102 °C . 1H NMR (300 MHz, CDCl3) δ(ppm) 0.88-0.99
(m, 1H), 1.28 (t, J = 7.2 Hz, 3H), 1.34-1.45 (m, 1H), 1.64-1.74 (m, 3H),
2.33 (brs, 1H), 2.72-2.88 (m, 2H), 2.91-3.05 (m, 3H), 3.22-3.32 (m, 4H),
3.52-3.56 (m, 1H), 3.80-3.84 (m, 2H), 4.00 (s, 3H), 4.42-4.52 (m, 1H),
4.95-5.02 (m, 2H), 5.64-5.75 (m, 1H), 7.37-7.47 (m, 2H), 7.87 (brs, 1H),
8.02 (d, J = 9.3 Hz, 1H), 8.72-8.75 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ(ppm) 14.71, 25.53, 26.88, 27.22 , 27.46, 37.03, 38.76, 41.86, 47.98, 55.16,
56.14 , 60.78, 75.93, 102.76, 115.63, 120.36, 122.41, 128.39, 131.47, 140.06,
144.73, 147.72 , 158.20, 167.53, 182.92. HRMS (ESI) m/z calcd for
General procedure for the Michael addition. 1, 3-dicarbonyl com-
pound (1 mmol) was added to a mixture of catalyst 13 (5 mol%) and the
corresponding nitroolefin (0.20 mmol) in toluene (2 mL). The reaction
mixture was stirred at room temperature for 48 h. The mixture was
concentrated in vacuum. The residue was purified by chromatography
on silica gel using ethyl acetate / hexanes (1:5) as the eluent to give
the adduct. The enantiomeric excess (ee) of the products was determined
by chiral HPLC analysis using chiral columns.
C
27H36N5OS3 [M + H+]: 542.2076, found 542.2073.
Chirality DOI 10.1002/chir

NOVEL CHIRAL BIFUNCTIONAL L-THIAZOLINE-THIOUREA DERIVATIVES
983
(S)-3-(2-nitro-1-phenylethyl)-pentane-2, 4-dione (14a) 99% yield, 97% ee,
by HPLC analysis (Daicel Chiralcel AD column, hexane: 2-
propanol = 90:10, 0.7 mL/min, 254 nm UV detector), tR = 16.5 min for
(major) and tR = 22.2 min for (minor). 1H NMR (300 MHz, CDCl3) δ
(ppm) 1.94 (s, 3H), 2.30 (s, 3H), 4.21-4.28 (m, 1H), 4.38 (d, J = 10.8 Hz,
1H), 4.62-4.68 (m, 2H), 7.17-7.20 (m, 2H), 7.29-7.37 (m, 3H); 13C NMR
(75 MHz, CDCl3) δ (ppm) 29.62, 30.47, 42.82, 70.70, 78.19, 127.97,
128.56, 129.35, 136.03, 201.03, 201.77.
(S)-3-[1-(4-chlorophenyl)-2-nitroethyl]-pentane-2, 4-dione (14b) 85% yield,
>99% ee, by HPLC analysis (Daicel Chiralcel AD column, hexane: 2-
propanol = 80:20, 1.0 mL/min, 215 nm UV detector), tR = 12.68 min for (major)
and tR = 30.0 min for (minor). 1H NMR (300 MHz, CDCl3) δ (ppm) 2.00 (s,
3H), 2.32 (s, 3H), 4.28-4.30 (m, 1H), 4.34 (d, J = 10.8 Hz, 1H), 4.63-4.64 (m,
2H), 7.16 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H).
(S)-3-[1-(4-fluorophenyl)-2-nitroethyl]-pentane-2, 4-dione (14c) 90% yield,
84% ee, by HPLC analysis (Daicel Chiralcel AD column, hexane: 2-
propanol = 90:10, 0.7 mL/min, 210 nm UV detector), tR = 20.95 min for
(major) and tR = 41.1 min for (minor). 1H NMR (300 MHz, CDCl3) δ
(ppm) 1.97 (s, 3H), 2.30 (s, 3H), 4.23-4.27 (m, 1H), 4.33 (d, J = 10.8 Hz,
1H), 4.61 (d, J = 6.0 Hz, 2H), 7.01-7.05 (m, 2H), 7.16-7.19 (m, 2H).
(S)-3-[1-(4-bromophenyl)-2-nitroethyl]-pentane-2, 4-dione (14d) 99% yield,
98% ee, by HPLC analysis (Daicel Chiralcel OD column, hexane: 2-
propanol = 90:10, 0.8 mL/min, 230 nm UV detector), tR = 36.85 min for
(major) and tR = 40.88 min for (minor). 1H NMR (300 MHz, CDCl3) δ
(ppm) 1.99 (s, 3H), 2.30 (s, 3H), 4.22-4.26 (m, 1H), 4.34 (d, J = 10.8 Hz,
1H), 4.62 (d, J = 6.0 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H).
(S)-3-[1-(3-bromophenyl)-2-nitroethyl]-pentane-2, 4-dione (14e) 97% yield,
98% ee, by HPLC analysis (Daicel Chiralcel AD column, hexane: 2-
propanol = 95:5, 1.0 mL/min, 230 nm UV detector), tR = 18.32 min for
(major) and tR = 19.55 min for (minor). 1H NMR (300 MHz, CDCl3) δ
(ppm) 2.02 (s, 3H), 2.31 (s, 3H), 4.23-4.24 (m, 1H), 4.36 (d, J = 10.8 Hz,
1H), 4.64 (d, J = 6.0 Hz, 2H), 7.14 (d, J = 8.4 Hz, 1H), 7.22 (t, J = 8.4 Hz,
1H), 7.38 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H).
(major) and tR = 15.92 min for (minor). 1H NMR (300 MHz, CDCl3) δ
(ppm) 1.95 (s, 3H), 2.29 (s, 3H), 3.90 (s, 3H), 4.98-4.52 (m, 1H), 4.60 (t,
J = 6.0, 1H), 4.80 (t, J = 10.8 Hz, 2H), 6.90 (d, J = 7.2 Hz, 2H), 7.09 (d,
J = 7.2 Hz, 1H), 7.27 (d, J = 8.4 Hz, 2H).
(S)-3-[1-(furan-2-yl)-2-nitroethyl]-pentane-2, 4-dione (14 k) 95% yield,
88% ee, by HPLC analysis (Daicel Chiralcel AD column, hexane: 2-
propanol = 90:10, 1.0 mL/min, 220 nm UV detector), tR = 11.92 min for
(major) and tR = 14.03 min for (minor). 1H NMR (300 MHz, CDCl3) δ
(ppm) 2.10 (s, 3H), 2.30 (s, 3H), 4.37-4.42 (m, 2H), 4.68 (d, J = 4.8 Hz,
2H), 6.19 (s, 1H), 6.32 (s, 1H), 7.38 (s, 1H).
(S)-3-[1-(naphthalen-2-yl)-2-nitroethyl]-pentane-2, 4-dione (14 l) 99%
yield, 86% ee, by HPLC analysis (Daicel Chiralcel AD column, hexane:
2-propanol = 90:10, 0.7 mL/min, 210 nm UV detector), tR = 25.27 min for
(major) and tR = 32.78 min for (minor). 1H NMR (300 MHz, CDCl3) δ
(ppm) 1.94 (s, 3H), 2.32 (s, 3H), 4.41-4.49 (m, 1H), 4.50 (d, J = 10.8 Hz,
1H), 4.67-4.77 (m, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.48-7.51 (m, 1H), 7.65
(s, 1H), 7.78-7.84 (m, 3H).
(3S)-ethyl-2-acetyl-4-nitro-3-phenylbutyrate (14 m) 99% yield, HPLC
analysis (Daicel Chiralcel AD column, hexane: 2-propanol = 95:5,
0.8 mL/min, 220 nm UV detector), dr = 80:20, major diastereomer:
tR = 15.23 min for (major) and tR = 23.23 min for (minor), 89% ee; minor di-
astereomer: tR = 49.05 min for (major) and tR = 25.58 min for (minor), 43%
ee. 1H NMR (300 MHz, CDCl3) δ (ppm) 1.00-1.28 (t, J = 7.2 Hz, 3H), 2.05-
2.30 (t, J = 7.2 Hz, 3H), 3.96 (q, J = 7.2 Hz, 1H), 4.03-4.12 (d, J = 9.9 Hz, 1H),
4.17-4.27 (m, 2H), 4.75 (d, J = 6.6 Hz, 1H), 4.82-4.85 (m, 1H), 7.19-7.22 (m,
2H), 7.27-7.31 (m, 3H).
(3S)-ethyl-2-benzoyl-4-nitro-3-phenylbutanoate (14n) 99% yield, HPLC
analysis (Daicel Chiralcel AD column, hexane: 2-propanol = 95:5,
1.0 mL/min, 245 nm UV detector), dr = 94:6, major diastereomer:
tR = 17.53 min for (major) and tR = 40.05 min for (minor), 83% ee; minor
diastereomer: tR = 33.17 min for (major) and tR = 16.02 min for (minor),
67% ee. 1H NMR (300 MHz, CDCl3) δ (ppm) 0.90 (t, J = 7.2 Hz, 3 H,
ÀCH2CH3), 3.87 (q, J = 7.2 Hz, 1H), 4.47-4.50 (m, 1H), 4.79-4.80 (m, 1H),
4.94-4.97 (m, 2H), 7.21 (m, 3H), 7.31 (m, 2H), 7.49 (t, J = 7.2 Hz, 2H),
7.60-7.62 (m, 1H), 8.05 (d, J = 8.4 Hz, 2H).
(S)-diethyl-2-(2-nitro-1-phenylethyl)malonate (14o) 99% yield, 46 ee, by
HPLC analysis (Daicel Chiralcel AD column, hexane:ethanol = 90:10,
1.0 mL/min, 254 nm UV detector), tR = 10.13 min for (major) and
tR = 14.83 min for (minor). 1H NMR (300 MHz, CDCl3) δ (ppm) 1.05 (t,
J = 7.2, 3H), 1.26 (t, J = 7.2 Hz, 3H), 3.82 (d, J = 9.3 Hz, 1H), 4.01 (q,
J = 7.2 Hz, 2H), 4.17-4.28 (m, 3H), 4.82-4.96 (m, 2H), 7.23-7.34 (m, 5H).
(S)-3-[1-(4-nitrophenyl)-2-nitroethyl]-pentane-2, 4-dione (14f) 80% yield, 86%
ee, by HPLC analysis (Daicel Chiralcel AD column, hexane: etha-
nol = 80:20, 1.0 mL/min, 254 nm UV detector), tR = 17.53 min for (major)
and tR = 20.32 min for (minor). 1H NMR (300 MHz, CDCl3) δ (ppm) 2.04
(s, 3H), 2.33 (s, 3H), 4.40 (m, 2H), 4.69 (m, 2H), 7.42 (d, J = 8.4 Hz, 2H),
8.21 (d, J = 8.4 Hz, 2H).
(S)-3-[1-(3-nitrophenyl)-2-nitroethyl]-pentane-2, 4-dione (14 g) 85% yield,
>99% ee, by HPLC analysis (Daicel Chiralcel AS column, hexane: 2-
propanol = 80:20, 0.8 mL/min, 215 nm UV detector), tR = 34.52 min for
(major) and tR = 50.32 min for (minor). 1H NMR (300 MHz, CDCl3) δ
(ppm) 2.06 (s, 3H), 2.34 (s, 3H), 4.43 (m, 2H), 4.70 (m, 2H), 7.55 (d,
J = 8.4 Hz, 2H), 8.12 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H).
RESULTS AND DISCUSSION
Synthesis of Catalysts
(S)-3-[1-(2-nitrophenyl)-2-nitroethyl]-pentane-2, 4-dione (14 h) 84% yield,
96% ee, by HPLC analysis (Daicel Chiralcel AS column, hexane: 2-
propanol = 80:20, 0.8 mL/min, 215 nm UV detector), tR = 29.85 min for
(major) and tR = 32.35 min for (minor). 1H NMR (300 MHz, CDCl3) δ
(ppm) 2.14 (s, 3H), 2.31 (s, 3H), 4.67 (d, J = 8.4 Hz, 2H), 4.72-4.77 (m,
1H), 4.84 (dd, J = 3.6 Hz, J = 13.2 Hz, 1H), 4.98 (dd, J = 7.2 Hz,
J = 13.2 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.49 (t, J = 8.4 Hz, 1H), 7.59 (t,
J = 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H).
(S)-3-[1-(4-methoxyphenyl)-2-nitroethyl]-pentane-2, 4-dione (14i) 94%
yield, 74% ee, by HPLC analysis (Daicel Chiralcel AD column, hexane:
2-propanol = 85:15, 0.65 mL/min, 210 nm UV detector), tR = 18.15 min for
(major) and tR = 27.65 min for (minor). 1H NMR (300 MHz, CDCl3) δ
(ppm) 1.94 (s, 3H), 2.29 (s, 3H), 3.77 (s, 3H), 4.16-4.22 (m, 1H), 4.33 (d,
J = 10.8 Hz, 1H), 4.59 (d, J = 6.0 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 7.10 (d,
J = 8.4 Hz, 2H).
We synthesized a series of novel chiral thiazoline-
containing catalysts 13 in high yield (Scheme 2). First,
(R)-tetrahydrothiazo-2-thione-4-carboxylic acid [(R)-TTCA]
2 was obtained by cyclization between L-cysteine and car-
bon disulfide under basic condition. Then alkyl bromide
was added in situ to facilitate a tandem alkylation of 2 to af-
ford 3 in moderate yield. Finally, thioether derivatives 3 and
5 were converted to chiral β-imino primary alcohols (6a-6d)
upon NaBH4 treatment. Conventionally, the reduction of es-
ter to primary alcohol with lithium aluminum hydride re-
quires a relatively longer time, as well as moisture-free and
low-temperature conditions.47,48 Nevertheless, in this study
the use of sodium borohydride/MeOH system at room tem-
perature provided a straightforward and more efficient
method for synthesizing the chiral imino primary alcohols
6a-6d. This method also successfully suppressed the race-
mization and maintained the optical purity of the resulting
alcohols.
(S)-3-[1-(2-methoxyphenyl)-2-nitroethyl]-pentane-2, 4-dione (14j) 90%
yield, 80% ee, by HPLC analysis (Daicel Chiralcel AS column, hexane: 2-
propanol = 80:20, 0.8 mL/min, 215 nm UV detector), tR = 14.10 min for
Chirality DOI 10.1002/chir

984
LAI ET AL.
Scheme 2. The synthesis strategy for 13a-13e.
Furthermore, we have documented a new protocol for the
in Scheme 1. With this consideration in mind, we designed
and synthesized chiral bifunctional L-thiazoline-thiourea
catalysts 13, which consist of these functional groups. The
catalyst structure was slightly changed to investigate the
strength of H-bondings, catalytic activity, and selectivity.
direct esterification of 2 to afford compound 4 at room
temperature using catalytic TiCl4. Compared with the conven-
tional method using other Lewis acids, this new modification
significantly improved the chemoselectivity and overall effi-
ciency with complete retention of the original (R) configura-
tion of 2.49 Then the thiazoline primary alcohols 6a-6d
were converted to the thiazoline primary amines 9a-9d in
moderate yield. For preliminary investigations, we selected
cinchonine and quinine as representatives of the cinchona al-
kaloid family. After the cinchonine and quinine were reacted
in THF in the presence of triphenylphosphine, diphenyl
azidophosphate, and diisopropyl azodicarboxylate (DIAD),
the cinchonine and quinine primary amines 11a-11b were
obtained. Then the cinchonine and quinine primary amines
11a-11b were converted to isothiocyanate 12a-12b. Lastly,
the chiral bifunctional L-thiazoline-thiourea catalysts 13
could be easily synthesized from these chiral thiazoline pri-
mary amines and the isothiocyanates in high yield. So there
are three chiral building blocks in these catalysts as shown
Chirality DOI 10.1002/chir
Observation of Catalytic Activity
In order to detect the catalytic activity of L-thiazoline-
thiourea catalysts derivatives, the asymmetric Michael reac-
tion of β-nitrostyrene and acetylacetone was chosen as the
model reaction (Table 1). First, the solvents, catalyst loading
and temperature were screened. We found that the solvent
employed significantly affected the conversion and
enantioselectivity. Among the solvents tested, CH2Cl2 was
identified to lead to the corresponding product (S-14a) in
96% yield, 86% ee in the presence of 10 mol% 13d. Further
studies showed that the optimal solvent for this reaction
was toluene, which could provide a relatively higher yield
and ee (98% and 90%, respectively) of the product S-14a in
the presence of 10 mol% 13d. We also found that the catalyst

NOVEL CHIRAL BIFUNCTIONAL L-THIAZOLINE-THIOUREA DERIVATIVES
985
TABLE 1. Effect of the amount of catalyst 13 and solvent on asymmetric Michael reactiona
Entry
Solvent
Temperature (°C)
13 (mol%)
13d (10)
Yield (%)b
ee (%)c
Configurationd
1
n-hexane
CH2Cl2
brine
25
25
25
80
96
85
98
83
99
94
99
99
99
96
82
86
70
90
85
97
80
84
87
95
77
S
S
S
S
S
S
S
S
S
R
S
2
13d (10)
13d (10)
13d (10)
13d (5)
3
4
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
25
5
À20
6
25
13d (5)
7
25
25
25
25
13a (5)
8
13b (5)
9
13c (5)
10
11
13e (5)
25
13d (5) + AcOH
aThe reactions were conducted with β-nitrostyrene (0.2 mmol) and acetylacetone (1 mmol) in 2 mL solvent for 48 h.
bYields after silica gel column chromatography.
cee was determined by HPLC using a Daicel Chiral AD column.
dThe absolute configurations of the products were assigned by comparing the retention times in HPLC with those reported in the literature.50
13d loading had a significant influence on stereoselectivity
but a slight influence on yield of the model reaction. Decreas-
ing the 13d loading from 10 mol% to 5 mol% relative to
β-nitrostyrene could enhance the ee of the product (S-14a)
from 90% to 97%. Higher catalyst loading resulted in a slight
decrease of the ee of the product. Temperature also signifi-
cantly affected the yield, but only slightly influenced the
stereoselectivity of the reaction (Table 1, entries 5 and 6).
At À20 °C and 5 mol% of 13d in toluene, the product (S-14a)
was obtained with only 83% yield and 85% ee. However,
when the temperature was elevated to 25 °C the product
was isolated in 99% yield and a higher 97% ee.
onto β-nitrostyrenes, a series of aryl β-nitrostyrenes were tested
under optimized conditions with catalyst 13d (Table 2). A
general trend was observed in the reaction between
acetylacetone and substituted β-nitrostyrenes with respect
TABLE 2. Asymmetric Michael reaction of various substrates
catalyzed by 13a
We then explored the influence of thio-alkyl moiety of the
catalysts on enantioselectivity. The catalysts 13a–13e were
screened with the model reaction under optimized condi-
tions using 5 mol% catalysts loading in toluene at 25 °C
(Table 1, entries 6–10). The catalyst 13d exhibited the
best catalytic efficiency, resulting in 99% yield and good
stereoselectivity (97% ee) of S-14a (Table 1, entry 6).
The catalyst 13b (R1 = n-butyl, Table 1, entry 8) exhibited
84% ee of S-14a, whereas the least hindered 13a exhib-
ited a lower ee. The ee increased as the function of the
bulk of the thio-substituents. Similarly with catalyst 13d,
thio-2-pyridylmethyl substitution on catalyst based cincho-
nine 13e (Table 1, entry 10) exhibited an effect on the
enantioselectivity of the reaction (95% ee of R-14a). The
best amine part for the catalyst was based on quinine.
We also found that carboxylic acid additives could not en-
hance the catalytic activity and stereoselectivity with 13d.
Addition of AcOH and 13d in a 1:1 ratio decreased
enantioselectivity but only slightly affected yield (Table 1,
entry 6 vs. entry 11). Therefore, catalyst 13d was used for
further study on the enantioselective Michael reaction.
To explore the influence of the electronic and steric effects of
the substrate in the asymmetric Michael addition of acetylacetone
Yield
(%)b
ee
Entry
Product
14a (R = Ph)
14b (R = 4-ClC6H4)
14c (R = 4-FC6H4)
14d (R = 4-BrC6H4)
14e (R = 3-BrC6H4)
14f (R = 4-NO2C6H4)
14 g (R = 3-NO2C6H4)
14 h (R = 2-NO2C6H4)
14i (R = 4-OCH3C6H4)
14j (R = 2-OCH3C6H4)
14 k (R = furan-2-yl)
14 l (R = naphthalen-2-yl)
(%)c
Configurationd
1
99
85
90
99
97
80
85
84
94
90
95
99
97
>99
84
98
98
86
>99
96
74
80
S
S
S
S
S
S
S
S
S
S
S
S
2
3
4
5
6
7
8
9
10
11
12
88
86
aThe reactions were conducted with β-nitrostyrene (0.2 mmol) and acetylacetone
(1 mmol) in 2 mL toluene at 25 °C for 48 h.
bYields after silica gel column chromatography.
cee was determined by HPLC using a Daicel Chiral column.
dThe absolute configurations of the products were assigned by comparing re-
tention times in HPLC with those reported in the literature.50
Chirality DOI 10.1002/chir

986
LAI ET AL.
to the enantioselectivities of the adduct as a function of the
electron-withdrawing abilities of the substituents. The
substrates with electron-withdrawing groups on the β-
nitrostyrene aromatic ring (entries 2–8) exhibited higher
enantioselectivity than those with electron-donating groups
(entries 9 and 10). Furthermore, the enantioselectivity was
significantly affected by the nature of the electron-
withdrawing group (entries 3 and 6) and, in some cases, by
the substituent position (entries 6 vs. 7, 8). The other aro-
matic styrenes, such as furan-2-yl- and naphthalen-2-yl-β-
nitrostyrene underwent the asymmetric Michael addition
with acetylacetone, generating the corresponding adducts
in 95% and 99% yield and 88% and 86% ee (Table 2, entries 11
and 12).
The asymmetric Michael addition of other nucleophiles to
β-nitrostyrene as catalyzed by 13d was also investigated to
determine the scope of nucleophile donors. As shown in
Scheme 3, the 1, 3-dicarbonyl compound ethyl acetoacetate
generated the desired product 14 m in high yield and with
good diastereoselectivity (80:20) and enantioselectivity (89%
and 43% ee for the major and minor diastereomers, respec-
tively). Significantly, the reaction generated 14n as the major
product with remarkably high diastereoselectivity (94:6) and
enantioselectivity (83% and 67% ee for the major and minor di-
astereomers, respectively). However, in the case of diethyl
malonate the reaction produced the adduct 14o with S con-
figuration in high yield but poor enantioselectivity (46% ee).
Finally, based on experimental observations and related
mechanistic studies by Takemoto and colleagues,26,51 we pro-
posed a transition state model for the asymmetric Michael ad-
dition of acetylacetone onto β-nitrostyrenes as catalyzed by
chiral bifunctional L-thiazoline-thiourea catalysts 13 (Fig. 1).
The thiourea moiety of catalyst 13d interacts through
H-bonding with the β-nitro group of the nitroalkene and en-
hances the electrophilicity of the α-alkene carbon, while the
tertiary amine deprotonates an acidic proton of the 2, 4-
pentandione, generating a ternary complex. The synergistic
steric hindrance from the chiral moiety of the bifunctional
Fig. 1. A possible transition state for asymmetric Michael addition reaction.
catalyst 13d may be responsible for the increased
stereocontrol of the Michael addition reaction.
CONCLUSION
In summary, a series of novel chiral bifunctional L-
thiazoline-thiourea catalysts were facilely synthesized from
L-cysteine in high yield. These compounds were found to
efficiently catalyze enantioselective Michael reactions of 1,
3-dicarbonyl compounds onto β-nitrostyrenes in excellent
enantioselectivity. This result represented a significant im-
provement on this type reaction mediated by quinine deriva-
tives. Furthermore, a plausible transition state model was
proposed to elucidate the observed diverse stereoselectivity.
The thiazoline-thiourea scaffold studied may provide a
promising route for designing new chiral catalysts for this
type of reaction. The catalytic activities of the synthesized
thiazoline-thiourea in other asymmetric reactions are under
study and will be disclosed in due course.
ACKNOWLEDGMENTS
This work was supported by grants from the National Nature
Science Foundation of China (Projects 90813003) and Foun-
dation of State Key Laboratory of Theoretical and Computa-
tional Chemistry.
Scheme 3. Michael addition reaction of various carbonyl compounds onto β-nitrostyrenes.
Chirality DOI 10.1002/chir

NOVEL CHIRAL BIFUNCTIONAL L-THIAZOLINE-THIOUREA DERIVATIVES
987
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