Usa Tudo Seco

Supporting Information
Wiley-VCH 2014
69451 Weinheim, Germany
Direct Catalytic Asymmetric Vinylogous Conjugate Addition of

Unsaturated Butyrolactones to a,b-Unsaturated Thioamides**
Liang Yin, Hisashi Takada, Shaoquan Lin, Naoya Kumagai,* and Masakatsu Shibasaki*
anie_201402332_sm_miscellaneous_information.pdf
Direct Catalytic Asymmetric Vinylogous Conjugate Addition of Unsaturated Butyrolactones to ,-Unsaturated Thioamides
Direct Catalytic Asymmetric Vinylogous Conjugate Addition of

Unsaturated Butyrolactones to ,-Unsaturated Thioamides
Liang Yin, Hisashi Takada, Shaoquan Lin, Naoya Kumagai,*, and Masakatsu
Shibasaki*,,
Institute of Microbial Chemistry (BIKAKEN), Tokyo, Japan

JST, ACT-C
mshibasa@bikaken.or.jp, nkumagai@bikaken.or.jp
1. General
2. Instrumentation
3. Materials
4. General Procedures and Characterization of the Products
5. Transformation of the Products
6. Determination of Absolute Configuration
7. NMR Studies and HRMS Study of Cu(I) Complex
8. NMR Spectra of New Compounds
S1
1. General
Direct catalytic asymmetric vinylogous conjugate-addition of unsaturated butyrolactones to unsaturated thioamides
was performed in a flame-dried 20 mL glass test tube with a Teflon-coated magnetic stirring bar unless otherwise
noted. The flasks or test tubes were fitted with a 3-way glass stopcock and reactions were run under Ar atmosphere.
Air- and moisture-sensitive liquids were transferred via a gas-tight syringe and a stainless-steel needle. All work-up
and purification procedures were carried out with reagent-grade solvents under ambient atmosphere.
2. Instrumentation
Infrared (IR) spectra were recorded on a HORIBA FT210 Fourier transform infrared spectrophotometer. NMR was
recorded on JEOL ECS-400 or ECA-600. Chemical shifts for proton are reported in parts per million downfield from
tetramethylsilane and are referenced to residual protium in the NMR solvent (CDCl3: 7.24 ppm; CD OD: 3.34 ppm). 3
13
For C NMR, chemical shifts were reported in the scale relative to NMR solvent (CDCl3: 77.0 ppm; CD3OD: 49.0
ppm) as an internal reference. For F NMR, chemical shifts were reported in the scale relative to TFA ( 76.50 ppm) as
19
an external reference. NMR data are reported as follows: chemical shifts, multiplicity (s: singlet, d: doublet, dd: doublet
of doublets, t: triplet, q: quartet, m: multiplet, br: broad signal), coupling constant (Hz), and integration. Optical
rotation was measured using a 1 mL cell with a 1.0 dm path length on a JASCO polarimeter P-1030. High-resolution
mass spectra (ESI TOF (+)) were measured on Thermo Fisher Scientific LTQ Orbitrap XL. HPLC analysis was
conducted on a JASCO HPLC system equipped with Daicel chiral-stationary-phase columns ( 0.46 cm x 25 cm).
3. Materials
Unless otherwise noted, materials were purchased from commercial suppliers and were used without further
purification. THF were purified by passing through a solvent purification system (Glass Contour). [Cu(CH3CN)4]PF6,
(R,R)-Ph-BPE, (R)-BINAP, (R,R )-TANIAPHOS, (R)-DTBM-SEGPHOS, and (R)-SEGPHOS were purchased from
P
Aldrich or Strem Chemical Co. Ltd. and used as received (opened and handled in a dry box). Column chromatography
was performed with silica gel Merck 60 (230400 mesh ASTM) or silicagel 60 N (spherical, neutral, 4050 m) from
Kanto Chemical Co. Ltd. Preparative TLC plates (#1.05744.0001, PLC Silica gel 60 F254) were purchased from Merck.
,-Unsaturated thioamides were prepared by following the reported procedure. 1
4. General Procedure and Characterization of the Products

Preparation of Li(OC6H4-p-OMe) in THF
To a flame-dried 20 mL pear-shaped flask equipped with a magnetic stirring bar and a 3-way-stopcock was charged
with p-methoxyphenol (62.1 mg, 0.50 mmol) and dried under vacuum for 10 min. Ar was back-filled to the flask and
dry THF (4.8 mL) was added via a stainless steel needle and a syringe. To the solution was added nBuLi (189 L, 0.5
mmol, 2.65 M in n-hexane) at 78 C and stirred at the same temperature for 10 min and then at room temperature for
30 min to give colorless 0.1 M Li(OC6H4-p-OMe) solution in THF, which was stored at room temperature in dark and
used within one day.
General Procedure for Direct Catalytic Vinylogous Conjugate Addition of Unsaturated Butyrolactones 1 and 6 to
Unsaturated Thioamides (racemic synthesis)
A flame-dried 20 mL test tube equipped with a magnetic stirring bar and 3-way glass stopcock was charged with
[Cu(CH3CN)4]PF6 (7.4 mg, 0.02 mmol), rac-BINAP (12.5 mg, 0.02 mmol) and THF (0.8 mL). After the mixture was
stirred for 30 min at room temperature, Li(OC6H4-p-OMe) (0.2 mL, 0.1M) was added via a gas-tight syringe with a
stainless steel needle under an Ar atmosphere. Then the mixture was stirred for 5 min at room temperature and
,-unsaturated thioamide (0.2 mmol) and unsaturated butyrolactone 1 or 6 (0.6 mmol) were added. The resulting
(a) Yde, B.; Yousif, N. M.; Pedersen, U.; Thomsen, I.; Lawesson, S.-O. Tetrahedron 1984, 40, 2047. (b) Yazaki, R.; Kumagai, N.; Masakatsu, S. J. Am.
1
Chem. Soc. 2010, 132, 10275. (c) Yanagida, Y.; Yazaki, R.; Kumagai, N.; Masakatsu, S. Angew. Chem., Int. Ed. 2011, 50, 7910.
S2
reaction mixture was stirred at room temperature for 2472 h. Then, the reaction mixture was purified by preparative
TLC (n-hexane/ethyl acetate = 1/1) to give the pure products.
General Procedure for Direct Catalytic Asymmetric Vinylogous Conjugate Addition of -Crotonolactone 1a to
,-Unsaturated Thioamide 2a (Table 2, entry 1)
Preparation of catalyst solution
[Cu(CH3CN)4]PF6 (38.3 mg, 0.1 mmol), (R)-Segphos (61.1mg, 0.1 mmol) and THF (4.0 mL). The mixture was stirred for
30 min to form the complex. Then Cy2NMe (214 L, 1.0 mmol) was added via a gas-tight syringe with a stainless steel
needle under an Ar atmosphere. The mixture was stirred for 5 min to give colorless catalyst solution (for copper(I)
complex, 0.025 M; for Cy2NMe, 0.25 M), which was stored at room temperature and used within one day.
,-unsaturated thioamide 2a (38.3 mg, 0.2 mmol). The catalyst solution (0.025 M in Cu, 0.25 M in Cy2NMe, 0.4 mL)
containing copper (I) complex (0.01 mmol) and Cy2NMe (0.1 mmol) was added via a gas-tight syringe with a stainless
steel needle under an Ar atmosphere. Then -crotonolactone 1a (42.0 L, 0.6 mmol) was added via a gas-tight syringe
with a stainless steel needle under an Ar atmosphere. The resulting reaction mixture was stirred at room temperature
for 12 h. Then, the reaction mixture was purified by preparative TLC (n-hexane/ethyl acetate = 1/2) to give the
product (52.8 mg, 96% yield). Enantiomeric excess of the product was determined to be 98% ee by chiral stationary
phase HPLC analysis (CHIRALPAK IC ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/2, flow rate 1.0 mL/min,
detection at 254 nm, tR = 20.1 min (minor), 30.5 min (major)).
(R)-N,N-Dimethyl-3-((S)-5-oxo-2,5-dihydrofuran-2-yl)-3-phenylpropanethioamide (3a)
Amorphous white powder; IR (CHCl3): 1754, 1602, 1518 cm1; 1H NMR (400 MHz, CDCl3): 7.35
(d, J = 5.7 Hz, 1H), 7.277.17 (m, 5H), 5.81 (d, J = 5.7 Hz, 1H), 5.61 (s, 1H), 4.23 4.19 (m, 1H),
S
3.513.45 (m, 4H), 3.36 (s, 3H), 3.04 (dd, J = 5.5, 15.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): 200.5,
Me2N 173.0, 155.8, 137.0, 128.6, 128.5, 127.7, 121.8, 84.0, 48.2, 45.0, 43.1, 41.9; HRMS (ESI) Anal. calcd. for
O
C15H17O2NNaS m/z 298.0872 [M+Na]+, found 298.0873; []D23 150.4 (c 1.62, CHCl3); Enantiomeric
O
excess of the product was determined to be 98% ee by chiral stationary phase HPLC analysis
(CHIRALPAK IC ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/2, flow rate 1.0 mL/min, detection at 254 nm, tR = 20.1
min (minor), 30.5 min (major)).

(R)-N,N-Dimethyl-3-((S)-5-oxo-2,5-dihydrofuran-2-yl)-3-(o-tolyl)propanethioamide (3b)
(dd, J = 1.4, 5.8 Hz, 1H), 7.197.17 (m, 1H), 7.107.07 (m, 3H), 5.83 (dd, J = 2.0, 5.7 Hz, 1H),
S
5.565.54 (m, 1H), 4.604.55 (m, 1H), 3.48 (s, 3H), 3.41 (dd, J = 8.5, 15.4 Hz, 1H), 3.34 (s, 3H), 3.00
Me2N (dd, J = 5.7, 15.4 Hz, 1H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3): 200.6, 172.9, 154.8, 135.9, 135.6,
O
130.6, 127.4, 127.2, 126.1, 122.2, 84.3, 44.9, 43.3, 42.5, 41.8, 20.3; HRMS (ESI) Anal. calcd. for
O
C16H19O2NNaS m/z 312.1029 [M+Na]+, found 312.1028; []D25 133.2 (c 3.51, CHCl3); Enantiomeric
excess of the product was determined to be 99% ee by chiral stationary phase HPLC analysis (CHIRALPAK IC ( 0.46
S3
cm x 25 cm), 2-propanol/n-hexane = 1/2, flow rate 1.0 mL/min, detection at 254 nm, tR = 17.6 min (minor), 24.3 min
(major)).
(R)-3-(4-Methoxyphenyl)-N,N-dimethyl-3-((S)-5-oxo-2,5-dihydrofuran-2-yl)propanethioamide (3c)
OMe White powder; M.p. 134135 C; IR (CHCl3): 1753, 1612, 1514 cm1; 1H NMR (400 MHz, CDCl3):
7.25 (d, J = 5.7 Hz, 1H), 7.01 (d, J = 8.0 Hz, 2H), 6.68 (d, J = 7.8 Hz, 2H ), 5.73 (d, J = 5.5 Hz, 1H), 5.47
(s, 1H), 4.084.04 (m, 1H), 3.66 (s, 3H), 3.403.26 (m, 7H), 2.94 (dd, J = 5.4, 15.1 Hz, 1H); 13C NMR
S
(100 MHz, CDCl3): 200.5, 173.0, 158.8, 155.9, 129.5, 128.9, 121.7, 113.7 84.2, 55.0, 47.4, 44.9, 43.4,
Me2N
41.9; HRMS (ESI) Anal. calcd. for C16H19O3NNaS m/z 328.0978 [M+Na]+, found 328.0977; []D25
O
197.0 (c 2.12, CHCl3); Enantiomeric excess of the product was determined to be 98% ee by chiral
O
stationary phase HPLC analysis (CHIRALPAK IC ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/2,
flow rate 1.0 mL/min, detection at 254 nm, tR = 25.5 min (minor), 37.5 min (major)).
(R)-3-(3-Methoxyphenyl)-N,N-dimethyl-3-((S)-5-oxo-2,5-dihydrofuran-2-yl)propanethioamide (3d)
7.31 (dd, J = 1.6, 5.8 Hz, 1H), 7.147.11 (m, 1H), 6.736.67 (m, 3H), 5.79 (dd, J = 2.0, 5.7 Hz, 1H),
S
5.575.56 (m, 1H), 4.154.11 (m, 1H), 3.72 (s, 3H), 3.473.37 (m, 4H), 3.32 (s, 3H), 2.99 (dd, J = 5.5,
Me2N 15.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): 200.3, 173.0, 159.5, 155.8, 138.6, 129.5, 121.7, 120.7,
O
114.1, 113.0, 83.9, 55.1, 48.1, 44.9, 43.1, 41.9; HRMS (ESI) Anal. calcd. for C16H19O3NNaS m/z
O
328.0978 [M+Na]+, found 328.0978; []D24 132.9 (c 3.19, CHCl3); Enantiomeric excess of the
product was determined to be 98% ee by chiral stationary phase HPLC analysis (CHIRALPAK IC ( 0.46 cm x 25 cm),
2-propanol/n-hexane = 1/2, flow rate 1.0 mL/min, detection at 254 nm, tR = 22.0 min (minor), 31.0 min (major)).
S4
(R)-N,N-Dibenzyl-3-(2-methoxyphenyl)-3-((S)-5-oxo-2,5-dihydrofuran-2-yl)propanethioamide (3e)
Colorless oil; IR (CHCl3): 1753, 1602, 1495 cm1; 1H NMR (400 MHz, CDCl3): 7.45 (dd, J = 1.4,
5.7 Hz, 1H), 7.397.30 (m, 3H), 7.257.24 (m, 3H), 7.207.16 (m, 1H), 7.117.03 (m, 5H), 6.836.80
S OMe
(m, 2H), 5.76 (dd, J = 2.1, 6.0 Hz, 1H), 5.595.58 (m, 1H), 5.34 (d, J = 4.2 Hz, 2H), 4.80 (s, 3H), 3.79
Bn2N
(s, 3H), 3.47 (dd, J = 8.0, 15.1 Hz, 1H), 3.24 (dd, J = 6.6, 15.1 Hz, 1H); 13C NMR (100 MHz, CDCl3):
O
O
203.5, 173.0, 156.7, 155.5, 135.2, 134.6, 129.2, 129.1, 128.6, 128.5, 128.0, 127.6, 127.5, 126.1, 124.7,
121.3, 120.5, 110.5, 84.2, 56.0, 55.5, 53.6, 42.5, 40.7; HRMS (ESI) Anal. calcd. for C28H27O3NNaS m/z
480.1604 [M+Na]+, found 480.1592; []D27 80.8 (c 3.87, CHCl3); Enantiomeric excess of the product was determined to
be 97% ee by chiral stationary phase HPLC analysis (CHIRALPAK IE ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/2,
flow rate 1.0 mL/min, detection at 254 nm, tR = 14.1 min (major), 15.7 min (minor)).
4-((R)-3-(Dimethylamino)-1-((S)-5-oxo-2,5-dihydrofuran-2-yl)-3-thioxopropyl)phenyl acetate (3f)

OAc Amorphous white powder; IR (CHCl3): 1754, 1604, 1508 cm1; 1H NMR (400 MHz, CDCl3): 7.31
(dd, J = 1.6, 6.0 Hz, 1H), 7.17 (d, J = 8.2 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 5.83 5.81 (m, 1H), 5.60
5.58 (m, 1H), 4.23 4.19 (m, 1H), 3.48 3.39 (m, 4H), 3.33 (s, 3H), 2.97 (dd, J = 5.5, 15.6 Hz, 1H),
S
2.25 (s, 3H); 13C NMR (100 MHz, CDCl3): 200.0, 172.8, 169.2 155.7, 149.9, 134.6, 129.5, 121.9, 121.5,
Me2N
83.8, 47.4, 44.9, 43.1, 41.8, 21.0; HRMS (ESI) Anal. calcd. for C17H19O4NNaS m/z 356.0927 [M+Na]+,
O
O
found 356.0925; []D27 139.3 (c 3.00, CHCl3); Enantiomeric excess of the product was determined
to be 94% ee by chiral stationary phase HPLC analysis (CHIRALPAK IA ( 0.46 cm x 25 cm),
2-propanol/n-hexane = 1/9, flow rate 1.0 mL/min, detection at 254 nm, tR = 28.7 min (minor), 37.7 min (major)).

(R)-N,N-Dibenzyl-3-(4-fluorophenyl)-3-((S)-5-oxo-2,5-dihydrofuran-2-yl)propanethioamide (3g)
F Colorless oil; IR (CHCl3): 1755, 1605, 1510 cm1; 1H NMR (400 MHz, CDCl3): 7.417.30 (m, 4H),
7.257.24 (m, 3H), 7.117.05 (m, 4H), 6.986.89 (m, 4H), 5.83 (dd, J = 2.1, 5.7 Hz, 1H), 5.515.49 (m,
1H), 5.40 (d, J = 14.6 Hz, 1H), 5.22 (d, J = 14.6 Hz, 1H), 4.804.69 (m, 2H), 4.384.33 (m, 1H),
S
3.343.32 (m, 2H); 13C NMR (100 MHz, CDCl3): 202.6, 172.6, 162.1 (d, J 1C-F = 245 Hz), 155.3, 134.9,
Bn2N
134.4, 132.1(d, J4C-F = 2.9 Hz), 130.4 (d, J3C-F = 8.6 Hz), 129.2, 128.7, 128.1, 127.7, 127.4, 126.0, 122.1,
O
115.4 (d, J2C-F = 21 Hz), 84.4, 56.2, 53.6, 48.1, 43.6; 19F NMR (375 MHz, CDCl3): 14.1; HRMS (ESI)
O
Anal. calcd. for C27H24O2NFNaS m/z 468.1404 [M+Na]+, found 468.1390; []D25 70.7 (c 4.50, CHCl3);
Enantiomeric excess of the product was determined to be 98% ee by chiral stationary phase HPLC analysis
(CHIRALPAK IF ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/2, flow rate 1.0 mL/min, detection at 254 nm, tR = 8.5 min
S5
(minor), 11.5 min (major)).
(R)-N,N-Dibenzyl-3-(4-bromophenyl)-3-((S)-5-oxo-2,5-dihydrofuran-2-yl)propanethioamide (3h)
Br Colorless oil; IR (CHCl3): 1756, 1604, 1489 cm1; 1H NMR (400 MHz, CDCl3): 7.387.24 (m, 9H),
7.066.93 (m, 6H), 5.85 (d, J = 5.5 Hz, 1H), 5.49 (s, 1H), 5.42 (d, J = 14.6 Hz, 1H), 5.19 (d, J = 14.7 Hz,
1H), 4.72 (t, J = 17.0 Hz, 2H), 4.364.32 (m, 1H), 3.343.31 (m, 2H); 13C NMR (100 MHz, CDCl3):
S
202.5, 172.6, 155.1, 135.3, 134.9, 134.4, 131.7, 130.6, 129.3, 128.8, 128.2, 127.8, 127.4, 126.1, 122.3,
Bn2N
121.8, 84.3, 56.3, 53.7, 48.4, 43.4; HRMS (ESI) Anal. calcd. for C27H24O2NBrNaS m/z 528.0603
O
[M+Na]+, found 528.0593; []D25 67.4 (c 2.57, CHCl3); Enantiomeric excess of the product was
O
determined to be 98% ee by chiral stationary phase HPLC analysis (CHIRALPAK AD-H ( 0.46
cm x 25 cm), 2-propanol/n-hexane = 1/9, flow rate 1.0 mL/min, detection at 254 nm, tR = 15.9 min (minor), 32.5 min
(major)).
(R)-N,N-Dibenzyl-3-((S)-5-oxo-2,5-dihydrofuran-2-yl)-3-(pyridin-3-yl)propanethioamide (3i)
N Colorless oil; IR (CHCl3): 1758, 1604, 1496 cm1; 1H NMR (400 MHz, CDCl3): 8.47 (brs, 2H), 7.41
7.04 (m, 13H), 5.82 (dd, J = 1.6, 5.5 Hz, 1H), 5.54 (s, 1H), 5.41 (d, J = 14.7 Hz, 1H), 5.22 (d, J = 14.9
S
Hz, 1H), 4.78 (t, J = 17.0 Hz, 2H), 4.444.40 (m, 1H), 3.433.38 (m, 1H), 3.253.20 (m, 1H); 13C NMR
Bn2N
(100 MHz, CDCl3): 201.9, 172.3, 155.1, 135.8, 135.0, 134.3, 129.3, 128.8, 128.2, 127.8, 127.6, 126.0,
O
O
122.6, 83.9, 56.4, 53.6, 46.0, 42.8; HRMS (ESI) Anal. calcd. for C26H25O2N2S m/z 429.1631 [M+H]+,
found 429.1628; []D25 66.7 (c 1.66, CHCl3); Enantiomeric excess of the product was determined to
be 98% ee by chiral stationary phase HPLC analysis (CHIRALPAK IA ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/2,

S6
(S)-N,N-Dimethyl-3-((S)-5-oxo-2,5-dihydrofuran-2-yl)-3-(thiophen-2-yl)propanethioamide (3j)
White powder; M.p. 139140 C; IR (CHCl3): 1756, 1602, 1519 cm1; 1H NMR (400 MHz, CDCl3):
S
S 7.32 (dd, J = 1.4, 5.7 Hz, 1H), 7.12 (d, J = 5.3, 1H), 6.896.84 (m, 2H), 5.88 (dd, J = 2.0, 6.0 Hz, 1H),
5.575.55 (m, 1H), 4.634.58 (m, 1H), 3.48 (s, 3H), 3.423.32 (m, 4H), 3.24 (dd, J = 5.7, 15.3 Hz, 1H);
Me2N
O
13C NMR (100 MHz, CDCl3): 199.6, 172.8, 155.2, 138.6, 126.6, 126.1, 124.7, 122.1, 83.4, 44.9, 44.6,
O 43.4, 41.8; HRMS (ESI) Anal. calcd. for C13H15O2NNaS2 m/z 304.0436 [M+Na]+, found 304.0434;
[]D25 146.2 (c 2.53, CHCl3); Enantiomeric excess of the product was determined to be 98% ee by chiral stationary
phase HPLC analysis (CHIRALPAK IC ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/2, flow rate 1.0 mL/min, detection
at 254 nm, tR = 20.8 min (minor), 35.8 min (major)).
(R)-N-Methoxy-N-methyl-3-((S)-5-oxo-2,5-dihydrofuran-2-yl)-3-phenylpropanethioamide (3k)
S
(d, J = 5.7 Hz, 1H), 7.287.18 (m, 5H), 5.82 (dd, J = 1.8, 5.7 Hz, 1H), 5.55 (s, 1H), 4.194.15 (m, 1H),
3.79 (s, 3H), 3.66 (s, 3H), 3.52 (dd, J = 8.7, 15.8 Hz, 1H), 3.21 (dd, J = 6.2, 15.8 Hz, 1H); 13C NMR (100
N
OMe O
MHz, CDCl3): 196.6, 173.0, 155.5, 136.7, 128.7, 128.4, 127.5, 121.9, 84.2, 61.6, 47.1, 39.9, 38.8; HRMS
O (ESI) Anal. calcd. for C15H17O3NNaS m/z 314.0821 [M+Na]+, found 314.0819; []D23 149.4 (c 2.10,
CHCl3); Enantiomeric excess of the product was determined to be 98% ee by chiral stationary
phase HPLC analysis (CHIRALPAK IA ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/9, flow rate 1.0 mL/min, detection
at 254 nm, tR = 11.5 min (minor), 13.2 min (major)).
(S)-N,N-Dimethyl-3-((R)-5-oxo-2,5-dihydrofuran-2-yl)butanethioamide (3l)
S Colorless oil; IR (CHCl3): 1756, 1601, 1519 cm1; 1H NMR (400 MHz, CDCl3): 7.43 (dd, J = 1.6, 5.7
Hz, 1H), 6.13 (dd, J = 2.3, 5.7 Hz, 1H), 5.285.26 (m, 1H), 3.51 (s, 3H), 3.37 (s, 3H), 3.012.93 (m, 2H),
Me2N
O 2.672.60 (m, 1H), 0.83 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): 201.2, 173.3, 155.9, 121.9,
O 84.8, 44.9, 44.6, 41.9, 36.2, 12.6; HRMS (ESI) Anal. calcd. for C10H16O2NS m/z 214.0896 [M+H]+,
found 214.0897; []D22 49.9 (c 0.76, CHCl3); Enantiomeric excess of the product was determined to
be 96% ee by chiral stationary phase HPLC analysis (CHIRALPAK IC ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/2,
S7
(R)-N,N-Dibenzyl-3-cyclohexyl-3-((S)-5-oxo-2,5-dihydrofuran-2-yl)propanethioamide (3m)
Colorless oil; IR (CHCl3): 1752, 1603, 1496 cm1; 1H NMR (400 MHz, CDCl3): 7.47 (dd, J = 1.1, 5.7
Hz, 1H), 7.377.21 (m, 8H), 7.09 (d, J = 7.3 Hz, 2H), 6.06 (dd, J = 2.1, 5.7 Hz, 1H), 5.80 (d, J = 14.4 Hz,
S
1H), 5.285.26 (m, 1H), 4.94 (q, J = 16.2 Hz, 2H), 4.66 (d, J = 16.7 Hz, 1H), 2.972.86 (m, 2H),
Bn2N
2.732.68 (m, 1H), 1.651.42 (m, 5H), 1.140.90 (m, 5H); 13C NMR (100 MHz, CDCl3): 204.6, 172.9,
O
156.5, 135.5, 134.8, 129.2, 128.8, 128.0, 127.8, 126.1, 121.7, 84.8, 56.5, 53.7, 46.9, 39.2, 37.9, 31.4, 30.2,
O
26.6, 26.5, 26.1; HRMS (ESI) Anal. calcd. for C27H31O2NNaS m/z 456.1968 [M+Na]+, found 456.1956;
[]D24 28.0 (c 3.29, CHCl3); Enantiomeric excess of the product was determined to be 97% ee by chiral stationary phase
HPLC analysis (CHIRALPAK IC ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/9, flow rate 1.0 mL/min, detection at 254
nm, tR = 35.9 min (minor), 53.8 min (major)).

(R,E)-N,N-Dimethyl-3-((S)-5-oxo-2,5-dihydrofuran-2-yl)hex-4-enethioamide (3n)
Colorless oil; IR (CHCl3): 1753, 1601, 1519 cm1; 1H NMR (400 MHz, CDCl3): 7.367.35 (m, 1H),
S 6.066.04 (m, 1H), 5.595.50 (m, 1H), 5.285.26 (m, 1H), 5.135.06 (m, 1H), 3.463.41 (m, 4H), 3.33 (s,
Me2N
3H), 3.05 (dd, J = 8.2, 14.9 Hz, 1H), 2.76 (dd, J = 6.2, 14.6 Hz, 1H), 1.56 (dd, J = 1.4, 6.4 Hz, 3H); 13C
O NMR (100 MHz, CDCl3): 200.8, 173.3, 156.3, 130.3, 125.1, 121.7, 84.3, 45.2, 44.8, 43.4, 42.0, 17.9;
O HRMS (ESI) Anal. calcd. for C12H17O2NNaS m/z 262.0872 [M+Na]+, found 262.0870; []D24 147.0 (c
1.68, CHCl3); Enantiomeric excess of the product was determined to be 97% ee by chiral stationary phase HPLC
analysis (CHIRALPAK IC ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/2, flow rate 1.0 mL/min, detection at 254 nm, tR
= 16.8 min (minor), 27.9 min (major)).
S8
(R)-N,N-Dimethyl-3-((R)-3-methyl-5-oxo-2,5-dihydrofuran-2-yl)-3-phenylpropanethioamide (3o)
Amorphous white powder; IR (CHCl3): 1755, 1644, 1518 cm1; 1H NMR (400 MHz, CDCl3):
7.297.21 (m, 5H), 5.555.53 (m, 1H), 5.39 (s, 1H), 4.254.21 (m, 1H), 3.513.44 (m, 4H), 3.35 (s, 3H),
S
3.02 (dd, J = 5.2, 15.3 Hz, 1H), 2.06 (s, 3H); 13C NMR (100 MHz, CDCl3): 200.5, 173.1, 168.0, 136.7,
Me2N
128.54, 128.47, 127.6, 117.6, 85.3, 47.0, 44.9, 43.7, 41.8, 14.0; HRMS (ESI) Anal. calcd. for
O
O C16H19O2NNaS m/z 312.1029 [M+Na]+, found 312.1030; []D24 94.7 (c 2.49, CHCl3); Enantiomeric
(CHIRALPAK IA ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/9, flow rate 1.0 mL/min, detection at 254 nm, tR = 11.6
General Procedure for Direct Catalytic Asymmetric Vinylogous Conjugate Addition of -Angilica Lactone 6a to
,-Unsaturated Thioamide 2a (Table 3, entry 1)
[Cu(CH3CN)4]PF6 (7.4 mg, 0.02 mmol), (R)-Segphos (12.2 mg, 0.02 mmol) and THF (4.0 mL). The mixture was stirred
for 30 min to form the complex. Then Et3N (139 L, 1.0 mmol) was added via a gas-tight syringe with a stainless steel
needle under an Ar atmosphere. The mixture was stirred for 5 min to give colorless catalyst solution (for copper(I)
complex, 0.005 M; for Et3N, 0.25 M), which was stored at room temperature and used within one day.
,-unsaturated thioamide 2a (38.3 mg, 0.2 mmol). The catalyst solution (0.005 M in Cu, 0.25 M in Et N, 0.4 mL) 3
containing copper (I) complex (0.002 mmol) and Et N (0.1 mmol) was added via a gas-tight syringe with a stainless
3
steel needle under an Ar atmosphere. Then -angelica lactone 6a (53.6 L, 0.6 mmol) was added via a gas-tight syringe
with a stainless steel needle under an Ar atmosphere. The resulting reaction mixture was stirred at room temperature
for 24 h. Then, the reaction mixture was purified by preparative TLC (n-hexane/ethyl acetate = 1/1) to give the
product (53.6 mg, 93% yield). Enantiomeric excess of the product was determined to be 98% ee by chiral stationary
phase HPLC analysis (CHIRALPAK IE ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/2, flow rate 1.0 mL/min,
detection at 254 nm, tR = 14.7 min (minor), 16.7 min (major)).
(R)-N,N-Dimethyl-3-((S)-2-methyl-5-oxo-2,5-dihydrofuran-2-yl)-3-phenylpropanethioamide (7a)
7.257.12 (m, 6H), 5.72 (d, J = 5.7 Hz, 1H), 4.11 (dd, J = 3.4, 9.8 Hz, 1H), 3.373.30 (m, 4H),
S
3.153.11 (m, 4H), 1.57 (s, 3H); 13C NMR (100 MHz, CDCl3): 201.2, 172.5, 160.2, 138.2, 128.6, 128.4,
Me2N 127.5, 120.2, 90.3, 52.8, 44.8, 41.9, 41.8, 23.5; HRMS (ESI) Anal. calcd. for C16H19O2NNaS m/z
O
312.1029 [M+Na]+, found 312.1025; []D25 291.8 (c 0.11, CHCl3); Enantiomeric excess of the
O
product was determined to be 98% ee by chiral stationary phase HPLC analysis (CHIRALPAK IE
( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/2, flow rate 1.0 mL/min, detection at 254 nm, tR = 14.7 min (major), 16.7
min (minor)).

S9

(R)-N,N-Dimethyl-3-((S)-2-methyl-5-oxo-2,5-dihydrofuran-2-yl)-3-(o-tolyl)propanethioamide (7b)
7.24 (d, J = 5.5 Hz, 1H), 7.137.05 (m, 4H), 5.69 (d, J = 5.7 Hz, 1H), 4.51 (dd, J = 3.7, 9.6 Hz, 1H),
S
3.433.32 (m, 4H), 3.203.15 (m, 4H), 2.42 (s, 3H), 1.59 (s, 3H); 13C NMR (100 MHz, CDCl3): 201.6,
Me2N 172.5, 159.4, 137.1, 136.7, 130.8, 127.1, 126.5, 126.0, 120.6, 90.8, 46.7, 45.0, 42.4, 41.9, 23.5, 20.9;
O
HRMS (ESI) Anal. calcd. for C17H21O2NNaS m/z 326.1185 [M+Na]+, found 326.1182; []D25 265.7 (c
O
0.37, CHCl3) Enantiomeric excess of the product was determined to be 99% ee by chiral
stationary phase HPLC analysis (CHIRALPAK IE ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/2, flow rate 1.0 mL/min,
detection at 254 nm, tR = 12.5 min (major), 14.0 min (minor)).

(R)-3-(4-Methoxyphenyl)-N,N-dimethyl-3-((S)-2-methyl-5-oxo-2,5-dihydrofuran-2-yl)propanethioamide (7c)
7.257.22 (m, 1H), 7.067.04 (m, 2H), 6.756.72 (m, 2H), 5.73 (dd, J = 2.1, 5.7 Hz, 1H), 4.064.02 (m,
1H), 3.72 (d, J = 1.8 Hz, 3H), 3.353.28 (m, 4H), 3.143.08 (m, 4H), 1.56 (d, J = 1.6 Hz, 3H); 13C NMR
S
(100 MHz, CDCl3): 201.4, 172.6, 160.4, 158.8, 130.1, 129.6, 120.2, 113.7, 90.6, 55.1, 52.1, 44.9, 42.1,
Me2N
41.9, 23.5; HRMS (ESI) Anal. calcd. for C17H21O3NNaS m/z 342.1134 [M+Na]+, found 342.1132; []D25
O
O
stationary phase HPLC analysis (CHIRALPAK IE ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/2,

S10
(R)-3-(3-Methoxyphenyl)-N,N-dimethyl-3-((S)-2-methyl-5-oxo-2,5-dihydrofuran-2-yl)propanethioamide (7d)
7.257.24 (m, 1H), 7.157.11 (m, 1H), 6.736.68 (m, 3H), 5.73 (d, J = 5.8 Hz, 1H), 4.09 (dd, J = 3.4, 9.6
S
Hz, 1H), 3.73 (s, 3H), 3.363.30 (m, 4H), 3.153.10 (m, 4H), 1.57 (s, 3H); 13C NMR (100 MHz,
Me2N CDCl3): 201.2, 172.6, 160.2, 159.5, 139.9, 129.5, 120.9, 120.2, 114.3, 112.9, 90.3, 55.2, 52.8, 45.0, 42.0,
O
41.9, 23.6; HRMS (ESI) Anal. calcd. for C17H21O3NNaS m/z 342.1134 [M+Na]+, found 342.1131;
O
[]D25 269.8 (c 0.57, CHCl3); Enantiomeric excess of the product was determined to be 99% ee by
chiral stationary phase HPLC analysis (CHIRALPAK IE ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/2, flow rate 1.0
mL/min, detection at 254 nm, tR = 18.8 min (major),29.8 min (minor)).
4-((R)-3-(Dimethylamino)-1-((S)-2-methyl-5-oxo-2,5-dihydrofuran-2-yl)-3-thioxopropyl)phenyl acetate (7e)

OAc Colorless crystal; M.p. 8587 C; IR (CHCl3): 1756, 1605, 1508 cm1; 1H NMR (400 MHz, CDCl3):
7.23 (d, J = 5.7 Hz, 1H), 7.177.14 (m, 2H), 6.976.94 (m, 2H), 5.75 (d, J = 5.5 Hz, 1H), 4.17 (dd, J =
3.6, 9.8 Hz, 1H), 3.323.27 (m, 4H), 3.163.11 (m, 4H), 2.24 (s, 3H), 1.58 (s, 3H); 13C NMR (100 MHz,
S
CDCl3): 200.9, 172.5, 169.2, 160.2, 149.9, 135.9, 129.6, 121.6, 120.4, 90.2, 52.1, 45.0, 42.1, 41.8, 23.6,
Me2N
21.1; HRMS (ESI) Anal. calcd. for C18H21O4NNaS m/z 370.1084 [M+Na]+, found 370.1077; []D25
O
O
stationary phase HPLC analysis (CHIRALPAK IE ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/2,

4-((R)-3-(Dimethylamino)-1-((S)-2-methyl-5-oxo-2,5-dihydrofuran-2-yl)-3-thioxopropyl)phenyl acetate (7f)
F White powder; M.p. 185186 C; IR (CHCl3): 1755, 1605, 1510 cm1; 1H NMR (400 MHz, CDCl3):
7.407.34 (m, 3H), 7.277.17 (m, 4H), 7.147.11 (m, 2H), 7.046.94 (m, 4H), 6.72 (d, J = 7.4 Hz, 2H),
5.775.73 (m, 2H), 4.854.75 (m, 2H), 4.454.29 (m, 2H), 3.53 (dd, J = 11.0, 14.6 Hz, 1H), 3.19 (dd, J =
S
3.2, 14.7 Hz, 1H), 1.62 (s, 3H); 13C NMR (100 MHz, CDCl3): 203.4, 172.4, 162.2 (d, J1C-F = 245 Hz),
Bn2N
160.2, 134.8, 134.5, 133.5, 130.6 (d, J3C-F = 8.6 Hz), 129.2, 128.6, 128.1, 127.6, 127.1, 126.1, 120.4, 115.5
O
(d, J2C-F = 21 Hz), 89.9, 56.2, 53.6, 52.6, 41.5, 23.3; 19F NMR (375 MHz, CDCl3): 114.1; HRMS (ESI)
O
Anal. calcd. for C28H26O2NFNaS m/z 482.1560 [M+Na]+, found 482.1545; []D25 121.6 (c 0.20,
CHCl3); Enantiomeric excess of the product was determined to be 97% ee by chiral stationary phase HPLC analysis
(CHIRALPAK IE ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/2, flow rate 1.0 mL/min, detection at 254 nm, tR = 8.7 min
(major), 10.9 min (minor)).
S11
(R)-N,N-Dibenzyl-3-(4-bromophenyl)-3-((S)-2-methyl-5-oxo-2,5-dihydrofuran-2-yl)propanethioamide (7g)
Br Amorphous white powder; IR (CHCl3): 1753, 1604, 1496 cm1; 1H NMR (400 MHz, CDCl3):
7.387.32 (m, 5H), 7.227.19 (m, 4H), 7.006.98 (m, 4H), 6.686.66 (m, 2H), 5.735.70 (m, 2H),
4.834.71 (m, 2H), 4.424.38 (m, 1H), 4.26 (dd, J = 3.4, 11.0 Hz, 1H), 3.50 (dd, J = 11.0, 14.9 Hz, 1H),
S
3.14 (dd, J = 3.4, 14.9 Hz, 1H), 1.58 (s, 3H); 13C NMR (100 MHz, CDCl3): 203.2, 172.3, 160.0, 136.7,
Bn2N
134.7, 134.5, 131.7, 130.8, 129.2, 128.7, 128.1, 127.6, 127.1, 126.1, 121.8, 120.6, 89.6, 56.2, 53.7, 52.9,
O
41.2, 23.3; HRMS (ESI) Anal. calcd. for C28H26O2NBrNaS m/z 542.0760 [M+Na]+, found 542.0749;
O
[]D25 99.6 (c 0.13, CHCl3); Enantiomeric excess of the product was determined to be 96% ee by
chiral stationary phase HPLC analysis (CHIRALPAK IE ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/2, flow rate 1.0
mL/min, detection at 254 nm, tR = 9.2 min (major), 11.1 min (minor)).
(R)-N,N-Dibenzyl-3-((S)-2-methyl-5-oxo-2,5-dihydrofuran-2-yl)-3-(pyridin-3-yl)propanethioamide (7h)
N White powder; M.p. 181182 C; IR (CHCl3): 1751, 1604, 1496 cm1; 1H NMR (400 MHz, CDCl3):
7.407.20 (m, 9H), 6.99 (d, J = 6.4 Hz, 2H), 6.84 (d, J = 6.0 Hz, 2H), 5.735.72 (m, 1H), 5.455.41 (m,
S
1H), 5.045.01 (m, 1H), 4.794.74 (m, 1H), 4.564.52 (m, 1H), 4.404.38 (m, 1H), 3.493.43 (m, 1H),
Bn2N
3.223.18 (m, 1H), 1.58 (d, J = 2.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): 202.5, 171.9, 159.8, 134.9,
O
O
134.4, 129.3, 128.7, 128.2, 127.7, 127.4, 126.0, 120.9, 89.6, 56.4, 53.6, 40.9, 23.3; HRMS (ESI) Anal.
calcd. for C27H27O2N2S m/z 443.1788 [M+H]+, found 443.1772; []D25 101.9 (c 0.79, CHCl3);
Enantiomeric excess of the product was determined to be 98% ee by chiral stationary phase HPLC analysis
(CHIRALPAK IE ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/2, flow rate 1.0 mL/min, detection at 254 nm, tR = 32.2
S12
(S)-N,N-Dimethyl-3-((S)-2-methyl-5-oxo-2,5-dihydrofuran-2-yl)-3-(thiophen-2-yl)propanethioamide (7i)
S
S 7.31 (d, J = 5.7 Hz, 1H), 7.117.09 (m, 1H), 6.866.82 (m, 2H), 5.81 (d, J = 5.8 Hz, 1H), 4.49 (dd, J =
3.2, 10.1 Hz, 1H), 3.353.25 (m, 4H), 3.163.07 (m, 4H), 1.60 (s, 3H); 13C NMR (100 MHz, CDCl3):
Me2N
O 200.6, 172.5, 159.6, 140.4, 126.7, 126.6, 124.7, 120.6, 89.8, 48.3, 45.0, 43.3, 41.9, 23.3; HRMS (ESI)
O Anal. calcd. for C14H17O2NNaS2 m/z 318.0593 [M+Na]+, found 318.0589; []D25 269.7 (c 0.50,
CHCl3); Enantiomeric excess of the product was determined to be 99% ee by chiral stationary phase HPLC analysis
(CHIRALPAK IA ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/9, flow rate 1.0 mL/min, detection at 254 nm, tR = 18.5
(R)-N-Methoxy-N-methyl-3-((S)-2-methyl-5-oxo-2,5-dihydrofuran-2-yl)-3-phenylpropanethioamide (7j)
Colorless crystal; M.p. 109111 C; IR (CHCl3): 1753, 1604, 1520 cm1; 1H NMR (400 MHz, CDCl3):
S
7.277.14 (m, 6H), 5.75 (d, J = 5.7 Hz, 1H), 4.09 (dd, J = 3.9, 10.3 Hz, 1H), 3.65 3.53 (m, 4H), 3.49
(s, 3H), 3.05 (dd, J = 3.7, 15.1 Hz, 1H), 1.54 (s, 3H); 13C NMR (100 MHz, CDCl3): 197.3, 172.5, 160.0,
N
OMe O
138.1, 129.0, 128.4, 127.5, 120.5, 90.3, 61.5, 51.9, 38.8, 23.5; HRMS (ESI) Anal. calcd. for
min (major), 65.1 min (minor)).
(R)-N,N-Dibenzyl-3-cyclohexyl-3-((S)-2-methyl-5-oxo-2,5-dihydrofuran-2-yl)propanethioamide (7k)
Colorless crystal; M. p. 119 122 C; IR (CHCl3): 1749, 1604, 1521 cm1; 1H NMR (400 MHz,
CDCl3): 7.51 (d, J = 5.7 Hz, 1H), 7.40 7.28 (m, 8H), 7.13 7.12 (m, 2H), 5.95 (d, J = 5.5 Hz, 1H),
S
5.79 (d, J = 14.7 Hz, 1H), 5.11 (d, J = 14.6 Hz, 1H), 4.95 4.91 (m, 1H), 4.77 4.73 (m, 1H), 3.33 3.30
Bn2N
(m, 1H), 2.88 (dd, J = 5.2, 16.9 Hz, 1H), 2.72 (dd, J = 5.0, 17.0 Hz, 1H), 1.65 1.33 (m, 9H), 1.16 0.74
O
(m, 5H); 13C NMR (100 MHz, CDCl3): 206.3, 172.6, 161.3, 135.6, 134.9, 129.2, 128.8, 128.1, 128.0,
O
127.9, 126.2, 119.7, 92.6, 57.1, 53.5, 49.9, 40.4, 38.2, 31.7, 29.3, 26.8, 26.5, 26.1, 25.0; HRMS (ESI) Anal.
calcd. for C28H33O2NNaS m/z 470.2124 [M+Na]+, found 470.2110; []D25 27.0 (c 0.39, CHCl3); Enantiomeric excess of the
product was determined to be 98% ee by chiral stationary phase HPLC analysis (CHIRALPAK IE ( 0.46 cm x 25 cm),
2-propanol/n-hexane = 1/2, flow rate 1.0 mL/min, detection at 254 nm, tR = 8.8 min (major), 10.3 min (minor)).

S13

(R)-3-((S)-2-Ethyl-5-oxo-2,5-dihydrofuran-2-yl)-N,N-dimethyl-3-phenylpropanethioamide (7l)
7.247.13 (m, 6H), 5.79 (d, J = 5.7 Hz, 1H), 4.17 (dd, J = 3.2, 9.8 Hz, 1H), 3.373.30 (m, 4H), 3.123.08
S
(m, 4H), 2.071.89 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): 201.3, 172.8, 158.6,
Me2N
138.3, 128.8, 128.5, 127.5, 121.5, 93.2, 51.8, 44.9, 42.0, 41.8, 28.8, 7.9; HRMS (ESI) Anal. calcd. for
O
min (major), 15.1 min (minor)).

(R)-3-((S)-2-Allyl-5-oxo-2,5-dihydrofuran-2-yl)-N,N-dimethyl-3-phenylpropanethioamide (7m)
7.227.13 (m, 6H), 5.77 (d, J = 5.7 Hz, 1H), 5.725.62 (m, 1H), 5.175.10 (m, 2H), 4.20 (dd, J = 3.4,
S
10.1 Hz, 1H), 3.413.30 (m, 4H), 3.173.13 (m, 4H), 2.732.64 (m, 2H); 13C NMR (100 MHz, CDCl3):
Me2N
201.1, 172.5, 158.7, 138.0, 130.3, 128.8, 128.5, 127.6, 121.5, 120.7, 92.0, 51.6, 44.9, 42.0, 41.8, 40.4;
O
O
HRMS (ESI) Anal. calcd. for C18H21O2NNaS m/z 338.1185 [M+Na]+, found 338.1180; []D25 198.3 (c
0.23, CHCl3); Enantiomeric excess of the product was determined to be 98% ee by chiral stationary
phase HPLC analysis (CHIRALPAK IE ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/2, flow rate 1.0 mL/min, detection
at 254 nm, tR = 12.5 min (major), 14.8 min (minor)).
S14
(R,E)-N,N-Dimethyl-3-((S)-2-methyl-5-oxo-2,5-dihydrofuran-2-yl)hex-4-enethioamide (7n)
Colorless oil; IR (CHCl3): 1756, 1604, 1522 cm1; 1H NMR (400 MHz, CDCl3): 7.33 (d, J = 5.8 Hz,
S 1H), 6.00 (d, J = 5.7 Hz, 1H), 5.585.50 (m, 1H), 5.125.07 (m, 1H), 3.42 (s, 3H), 3.283.16 (m, 4H),
Me2N
2.952.84 (m, 2H), 1.59 (dd, J = 1.6, 6.4 Hz, 3H), 1.49 (s, 3H); 13C NMR (100 MHz, CDCl3): 201.5,
O 172.5, 160.2, 130.5, 126.6, 120.6, 90.2, 50.2, 44.8, 42.6, 42.1, 23.1, 17.9; HRMS (ESI) Anal. calcd. for
excess of the product was determined to be 98% ee by chiral stationary phase HPLC analysis (CHIRALPAK OD-H
( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/20, flow rate 1.0 mL/min, detection at 254 nm, tR = 17.9 min (minor), 21.6
min (major)).
(S)-Ethyl 4-(dimethylamino)-2-((S)-2-methyl-5-oxo-2,5-dihydrofuran-2-yl)-4-thioxobutanoate (7o)

O OEt Colorless crystal; M.p. 8081 C; IR (CHCl3): 1760, 1731, 1604, 1520 cm1; 1H NMR (400 MHz,
S
CDCl3): 7.55 (d, J = 5.8 Hz, 1H), 6.03 (d, J = 5.5 Hz, 1H), 4.184.10 (m, 2H), 3.76 (dd, J = 2.7, 11.2
Me2N
Hz, 1H), 3.43 (s, 3H), 3.29 (s, 3H), 3.08 (dd, J = 11.2, 15.6 Hz, 1H), 2.63 (dd, J = 2.3, 15.6 Hz, 1H), 1.54
O
(s, 3H), 1.24 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): 199.5, 171.5, 171.1, 159.1, 120.6, 87.4,
O
61.3, 52.8, 44.7, 41.6, 38.7, 23.8, 14.1; HRMS (ESI) Anal. calcd. for C13H19O4NNaS m/z 308.0927
[M+Na]+, found 308.0924; []D25 95.5 (c 0.31, CHCl3); Enantiomeric excess of the product was determined to be 96% ee
by chiral stationary phase HPLC analysis (CHIRALPAK IC ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/2, flow rate
1.0 mL/min, detection at 254 nm, tR = 31.3 min (major), 42.5 min (minor)).
Gram-Scale Reaction for Direct Catalytic Asymmetric Addition of -Angilica lactone 6a to ,-Unsaturated
Thioamide 2c (Table 3, entry 3)
A flame-dried 50 mL round-bottom flask equipped with a magnetic stirring bar and 3-way glass stopcock was charged
with [Cu(CH3CN)4]PF6 (74.5 mg, 0.2 mmol), (R)-Segphos (122.1 mg, 0.2 mmol) and THF (20 mL). The mixture was
stirred for 30 min to form the complex. Then Et3N (697 L, 5.0 mmol) was added via a gas-tight syringe with a stainless
steel needle under an Ar atmosphere. The mixture was stirred for 5 min to give colorless catalyst solution (for copper(I)
complex, 0.01 M; for Et3N, 0.25 M), which was stored at room temperature and used within one day.
A flame-dried 50 mL round-bottom flask equipped with a magnetic stirring bar and 3-way glass stopcock was charged
with ,-unsaturated thioamide 2c (1.33 g, 6.0 mmol). The catalyst solution (12 mL) containing copper (I) complex (0.12
S15
mmol) and Et N (3.0 mmol) was added via a gas-tight syringe with a stainless steel needle under an Ar atmosphere.
3
Then -angelicalactone (1.6 mL, 18 mmol) was added via a gas-tight syringe with a stainless steel needle under an Ar
atmosphere. The resulting reaction mixture was stirred at room temperature for 24 h. Then, the reaction mixture was
purified by silica gel column (eluent: n-hexane/ethyl acetate from 9/1 to 4/1, finally to 1/1) to give the product (1.78
mg, 93% yield). Enantiomeric excess of the product was determined to be 99% ee by chiral stationary phase HPLC
analysis (CHIRALPAK IE ( 0.46 cm x 25 cm), 2-propanol/n-hexane = 1/2, flow rate 1.0 mL/min, detection at 254 nm,
t = 22.3 min (minor), 24.4 min (major)).
R
5. Transformation of the Products

(R)-3-(4-Methoxyphenyl)-N,N-dimethyl-3-((S)-2-methyl-5-oxo-2,5-dihydrofuran-2-yl)propanamide (8)
OMe OMe
S TFAA, CH2Cl2, rt, 3 h; O
Me2N then H2O Me2N

O yield, 90% O
7c O 8 O
To a stirred CH2Cl2 (dry solvent, 2.0 mL) solution of 7c (63.9 mg, 0.2 mmol, 99% ee) in a 20 mL test tube equipped with
a magnetic stirring bar was added TFAA (62.5 L, 0.45 mmol) dropwise at 0 C under an Ar atmosphere. After stirring
the resulting mixture at room temperature for 3 h, saturated NaHCO3 aq. was added. The resulting biphasic mixtue
was extracted three times with ethyl acetate. The combined organic layer was washed with bring and then dried with
Na2SO4. Volatiles were removed under reduced pressure and the residue was purified by silica gel column
chromatography (eluent: n-hexane/ethyl acetate from 2/1 to 1/1) to give the title compound 8 as a viscous colorless oil
(54.5mg, 0.18 mmol, 90% yield). Colorless oil; IR (CHCl3): 1753, 1639, 1612, 1514 cm1; 1H NMR (400 MHz, CDCl3):
7.25 (d, J = 5.5 Hz, 1H), 7.03 (d, J = 7.8 Hz, 2H), 6.72 (d, J = 7.6 Hz, 2H), 5.73 (d, J = 5.0 Hz, 1H), 3.743.69 (m, 4H), 2.90 (s,
3H), 2.802.74 (m, 5H), 1.42 (s, 3H); 13C NMR (100 MHz, CDCl3): 172.7, 170.7, 160.3, 158.5, 131.1, 129.3, 120.3, 113.8,
90.6, 55.0, 47.5, 37.2, 35.6, 33.7, 23.3; HRMS (ESI) Anal. calcd. for C17H21O4NNa m/z 326.1363 [M+Na]+, found 326.1360;
[]D21 136.1 (c 2.18, CHCl3).
(R)-S-Methyl 3-(4-methoxyphenyl)-3-((S)-2-methyl-5-oxo-2,5-dihydrofuran-2-yl)propanethioate (9)

OMe OMe
S MeI, THF/H2O, rt, 12 h O
Me2N yield, 88% S

O O
7c O 9 O
To a stirred solution of 7c (0.64 g, 2.0 mmol, 99% ee) in THF/H2O (5.0 mL/0.25 mL) in a 20 mL test tube equipped with
a magnetic stirring bar was added MeI (3.0 mL) at room temperature. After stirring the mixture at room temperature
for 5 min, TFA (0.5 mL) was added dropwise. The resulting mixture was stirred for overnight at room temperature.
Then volatiles were removed under reduced pressure and the residue was purified by silica gel column
chromatography (eluent: n-hexane/ethyl acetate from 9/1 to 4/1) to give the title compound 9 as a pale yellow solid
(0.52 g, 1.76 mmol, 88% yield). Pale yellow solid; M.p. 141142 oC; IR (CHCl3): 1755, 1685, 1513 cm1; 1H NMR (400
MHz, CDCl3): 7.25 (d, J = 3.0 Hz, 1H), 7.04 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 5.85 (d, J = 5.5 Hz, 1H), 3.75 (s,
3H), 3.65 (dd, J = 4.8, 9.9 Hz, 1H), 3.082.93 (m, 2H), 2.16 (s, 3H), 1.42 (s, 3H); 13C NMR (100 MHz, CDCl3): 197.5, 172.1,
158.94, 158.87, 129.5, 129.4, 121.1, 113.9, 89.9, 55.1, 47.9, 43.9, 23.4, 11.7; HRMS (ESI) Anal. calcd. for C16H18O4NaS m/z
329.0818 [M+Na]+, found 329.0815; []D23 240.3 (c 1.30, CHCl3).
S16
(S)-5-((R)-1-(4-Methoxyphenyl)-3-oxobutyl)-5-methylfuran-2(5H)-one (11)
OMe OMe
S MeOTf, THF/Et2O, 10 min; O
Me2N LiMe, 78 C, 30 min

O yield, 79% O
7c O 11 O
To a stirred solution of 7c (63.9 mg, 0.2 mmol, 99% ee) in THF/ether (2.0 mL/20 mL) in a 20 mL test tube equipped
with a magnetic stirring bar was added MeOTf (26.2L, 0.24 mmol) at room temperature under an Ar atmosphere.
After stirring the mixture at room temperature for 10 min, the reaction mixture was cooled to 78 C. To the mixture
was added MeLi (21.6 L, 1.11M in THF, 0.24 mmol) and the resulting mixture was stirred at 78 C for 30 min. The
reaction was quenched with silica gel (acidic, 1 g) and dried under reduced pressure. The residue was loaded on a
silcal gel column and purified (eluent: n-hexane/ethyl acetate from 4/1 to 1/1) to give 11 as a viscous colorless oil (43.3
mg, 0.158 mmol, 79% yield). Colorless oil; IR (CHCl3): 1754, 1718, 1611, 1514 cm1; 1H NMR (400 MHz, CDCl3): 7.24
(d, J = 5.7 Hz, 1H), 7.067.02 (m, 2H), 6.806.76 (m, 2H), 5.84 (d, J = 5.7 Hz, 1H), 3.74 (s, 3H), 3.63 (dd, J = 5.3, 8.7 Hz, 1H),
2.922.80 (m, 2H), 2.03 (s, 3H), 1.40 (s, 3H); 13C NMR (100 MHz, CDCl3): 206.1, 172.3, 159.3, 158.8, 130.6, 129.5, 114.0,
90.1, 55.1, 46.6, 43.9, 30.5, 23.5; HRMS (ESI) Anal. calcd. for C16H18O4Na m/z 297.1097 [M+Na]+, found 297.1100; []D20
182.0 (c 0.66, CHCl3).
(R)-3-(4-Methoxyphenyl)-3-((S)-2-methyl-5-oxo-2,5-dihydrofuran-2-yl)propanal (12)
OMe OMe
S MeOTf, THF/Et2O, 10 min; O
Me2N LiAlH(OtBu)3, 78 C, 12 h H
O yield, 85% O
7c O 12 O
To a stirred solution of 7c (63.9 mg, 0.2 mmol, 99% ee) in THF/ether (2.0 mL/2.0 mL) in a 20 mL test tube equipped
with a magnetic stirring bar was added MeOTf (43.7L, 0.4 mmol) at room temperature under an Ar atmosphere. After
stirring the mixture at room temperature for 10 min, the reaction mixture was cooled to 78 C. To the mixture was
added LiAlH(OtBu)3 (0.40 mL, 1M in THF, 0.40 mmol) and the resulting mixture was stirred at 78 C for 12 h. The
reaction was quenched with silica gel (acidic, 1 g) and dried under reduced pressure. The residue was loaded on a
silcal gel column and purified (eluent: n-hexane/ethyl acetate from 4/1 to 1/1) to give 12 as a viscous colorless oil (44.2
mg, 0.170 mmol, 85% yield). Colorless oil; IR (CHCl3): 1758, 1726, 1612, 1514 cm1; 1H NMR (400 MHz, CDCl3): 9.58
(t, J = 1.1 Hz, 1H), 7.24 (d, J = 10.3 Hz, 1H), 7.057.03 (m, 2H), 6.806.78 (m, 2H), 5.88 (d, J = 5.7 Hz, 1H), 3.74 (s, 3H), 3.64
(dd, J = 5.3, 9.2 Hz, 1H), 2.912.78 (m, 2H), 1.41 (s, 3H); 13C NMR (100 MHz, CDCl3): 199.8, 171.9, 159.0, 158.8, 129.7,
129.6, 121.4, 114.2, 89.9, 55.2, 45.7, 44.1, 23.5; HRMS (ESI) Anal. calcd. for C15H16O4Na m/z 283.0941 [M+Na]+, found
283.0943; []D19 185.6 (c 0.66, CHCl3).
(S)-5-((R)-3-Hydroxy-1-(4-methoxyphenyl)propyl)-5-methylfuran-2(5H)-one (13)
OMe OMe
O CeCl3, NaBH4
H MeOH, 0 C, 30 min HO
O yield, 81% O
O O
12 13
CeCl3 (98.6 mg, 0.4 mmol) was added to a solution of compound 12 (52.1 mg, 0.2 mmol) in MeOH (4.0 mL). The
reaction mixture was cooled to 0 C and NaBH4 (15.1 mg, 0.4 mmol) was added in three equal portions. The reaction
mixture was stirred at 0 C for 30 min. After completion of the reaction (monitored by TLC), 1 M HCl (aq. 0.5 mL) was
added dropwise until effervescence ceased. The reaction mixture was concentrated under reduced pressure and the
residue was purified by flash chromatography (eluent: n-hexane/ethyl acetate from 4/1 to 1/1) to afford the title
S17
compound 13 as a colorless oil (42.5 mg, 0.162 mmol, 81% yield). Colorless oil; IR (CHCl3): 1751, 1514 cm1; 1H NMR
(400 MHz, CDCl3): 7.29 (d, J = 5.7 Hz, 1H), 7.067.04 (m, 2H), 6.836.80 (m, 2H), 5.87 (d, J = 5.8 Hz, 1H), 3.77 (s, 3H),
3.563.50 (m, 1H), 3.343.27 (m, 1H), 3.15 (dd, J = 3.4, 11.9 Hz, 1H ), 2.102.02 (m, 1H), 1.89 1.80 (m, 1H), 1.41 (s, 3H);
13 C NMR (100 MHz, CDCl3): 172.6, 159.7, 158.7, 130.1, 129.7, 120.7, 114.0, 90.7, 60.3, 55.1, 48.4, 31.8, 23.3; HRMS (ESI)
Anal. calcd. for C15H18O4Na m/z 285.1097 [M+Na]+, found 285.1097; []D22 152.0 (c 0.50, CHCl3).
(3aR,7R,7aR)-7-(4-Methoxyphenyl)-7a-methylhexahydro-2H-furo[3,2-b]pyran-2-one (14)
OMe
O H
NaHMDS, THF, C, 1 h O O
HO yield, 72%
O
O MeO
13 14
To a stirred solution of compound 13 (26.2 mg, 0.1 mmol) in THF (5.0 mL) at 0 C was added NaHMDS (0.11 mL, 1 M
in THF, 0.11 mmol). The mixture was stirred for 1 h at 0 C. Then the reaction was quenched by 1 M HCl (aq. 0.1 mL).
The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography
(eluent: n-hexane/ethyl acetate from 9/1 to 4/1) to afford the title compound 14 as a colorless oil (18.8 mg, 0.072 mmol,
72% yield). Colorless oil; IR (CHCl3): 1769, 1515 cm1; 1H NMR (400 MHz, CDCl3): 7.17 (d, J = 8.5 Hz, 2H), 6.85 (d, J =
8.5 Hz, 2H), 3.963.91 (m, 3H), 3.78 (s, 3H), 3.25 (dd, J = 6.0, 10.5 Hz, 1H), 2.84 (dd, J = 6.6, 18.3 Hz, 1H), 2.67 (dd, J = 2.0,
18.1 Hz, 1H), 1.981.91 (m, 2H), 0.95 (s, 3H); 13C NMR (100 MHz, CDCl3): 174.6, 158.6, 130.7, 129.4, 113.6, 88.3, 76.9,
63.2, 55.2, 42.9, 34.7, 24.8, 19.3; HRMS (ESI) Anal. calcd. for C15H18O4Na m/z 285.1097 [M+Na]+, found 285.1099; []D18
24.5 (c 0.36, CHCl3). Stereochemistry of configuration newly generated stereogenic center was determined by NOE
analysis shown below.
0.9%
O H
O O
H 2.0%
MeO
6. Determination of the Relative and Absolute Configuration

Determination of absolute and relative configuration of the products in Table 2
3a was converted to the corresponding phenyl ketone S1 by following the procedure below. 2
O Ph
S MeOTf, THF;
4S
Ph 3R
Me2N then PhLi, HMPA
O
O 78 C, 30 min
O
3a O S1
1
H NMR and HPLC analysis of thus obtained S1 matched the reported data for (3R,4S)-S1, revealing the
stereochemistry of 3a as designated above.
The absolute and relative configuration of other products 3 from 1a and 1b was deduced by analogy.
Determination of absolute and relative configuration of the products in Table 3

n-Hexane/ethyl acetate solution of 7m prepared from (R)-catalyst was left stand at room temperature to grow a single
crystal. Single-crystal X-ray data were collected on a Rigaku R-AXIS RAPID II imaging plate area detector with
graphite-monochromated Cu-K radiation. Data collection was conducted at 93 K. All structures were solved by direct
methods and refined by full matrix least-squares against F2 with all reflections. All non-hydrogen atoms were refined
2
Zhang, Y.; Yu, C.; Ji, Y.; Wang, W. Chem. Asian J. 2010, 5, 1303.
S18
anisotropically. All hydrogen atoms were placed in standard calculated positions, and were refined using the riding
model. Refined crystallographic parameters are summarized in Table S1. The absolute and relative configuration of 7m
was determined to be as depicted below by Flack parameter.3 The absolute and relative configuration of other
products 7 from 6a and 6b was deduced by analogy. CCDC987259 contains the supplementary crystallographic data.
Table S1. Selected Crystallographic Data of 7m
7m
molecular formula C18H21NO2S
formula weight 315.43
crystal color, habit colorless, needle
crystal system orthorhombic
space group P212121
cell constants
a () 10.7955 (2)
b () 23.6764(4)
c () 6.58041(12)
V ( ) 3
1681.94(5)
Z 4
calcd (g cm3) 1.246
S R1 0.0465
Me2N wR2 0.1116

O F(000) 672.00
O
7m Flack parameter 0.01(2)
7. NMR Studies and HRMS Study of Cu(I) Complex

Following samples were prepared to compare the chemical shift of ,-unsaturated 2a in the absence and presence of
Cu(I)/(R)-Segphos complex.
Sample A: 2a in CD2Cl2
Sample B: Cu(I)/(R)-Segphos in CD2Cl2
Sample C: Cu(I)/(R)-Segphos : 2a = 1:0.8 in CD Cl 2 2
Procedure for preparation of sample AC

A Thioamide 2a (3.8 mg, 0.02 mmol) in CD2Cl2 (0.5 mL).
B [Cu(CH3CN)4]PF6 (7.4 mg, 0.02 mmol) and (R)-Segphos (12.2 mg, 0.02 mmol) in CD2Cl2 (0.5 mL) was stirred at room
temperature for 30 min. Then H NMR was scanned and recorded.
C [Cu(CH3CN)4]PF6 (7.4 mg, 0.02 mmol) and (R)-Segphos (12.2 mg, 0.02 mmol) in CD2Cl2 (0.5 mL) was stirred at room
temperature for 30 min. Then Thioamide 2a (3.1 mg, 0.016 mmol) was added to the mixture. After stirred at room
temperature for 30 min, the resulting mixture was subjected to 1H NMR.
As shown in Figure S1, in the presence of Cu(I)/(R)-Segphos, chemical shift of 2a was significantly changed (olefinic
protons ,, and Me protons a,b), suggesting that complexation of Cu(I)/(R)-Segphos and 2a. This was further
supported by the detection of the peak corresponds to Cu(I)/(R)-Segphos/2a [anal. calcd. for C49H41NO4CuP2S m/z
864.1522 [M]+, found 864.1506] in ESI-TOF HRMS analysis of sample C (Figure S2). Positive enhancement of the
protons at aromatic region by the irradiation of Me protons of 2a in NOE experiment of sample C would be indicative
that 2a was in close proximity of Cu(I) surrounded by peripheral phenyl groups of (R)-Segphos.
3
Flack, H. D. Acta Cryst. 1983, A39, 876.
S19
Figure S1. H NMR analysis of samples AC.

1
S20
Figure S2. HRMS analysis of sample C.
Figure S3. NOE experiment of sample C.
S21
8. NMR Spectra of New Compounds
S22
S23
S24
S25
S26
S27
S28
S29
S30
S31
S32
S33
S34
S35
S36
S37
S38
S39
S40
S41
S42
S43
S44
S45
S46
S47
S48
S49
S50
S51
S52
S53
S54
S55
S56
S57
S58
S59
S60
S61
S62
S63
S64
S65
S66
S67
S68
S69
S70
S71
S72
S73
S74
S75
S76
S77
S78
S79
S80
S81
S82
S83
S84
S85
S86
S87
S88
S89
S90
S91
S92
S93
S94

Usa Tudo Seco

Transféré par

Informations du document

Copyright

Formats disponibles

Partager ce document

Partager ou intégrer le document

Options de partage

Avez-vous trouvé ce document utile ?

Ce contenu est-il inapproprié ?

Droits d'auteur :

Formats disponibles

Usa Tudo Seco

Transféré par

Droits d'auteur :

Formats disponibles

Supporting Information

Direct Catalytic Asymmetric Vinylogous Conjugate Addition of

Direct Catalytic Asymmetric Vinylogous Conjugate Addition of

Institute of Microbial Chemistry (BIKAKEN), Tokyo, Japan

4. General Procedure and Characterization of the Products

4-((R)-3-(Dimethylamino)-1-((S)-5-oxo-2,5-dihydrofuran-2-yl)-3-thioxopropyl)phenyl acetate (3f)

4-((R)-3-(Dimethylamino)-1-((S)-2-methyl-5-oxo-2,5-dihydrofuran-2-yl)-3-thioxopropyl)phenyl acetate (7e)

(S)-Ethyl 4-(dimethylamino)-2-((S)-2-methyl-5-oxo-2,5-dihydrofuran-2-yl)-4-thioxobutanoate (7o)

5. Transformation of the Products

S TFAA, CH2Cl2, rt, 3 h; O

Me2N then H2O Me2N

(R)-S-Methyl 3-(4-methoxyphenyl)-3-((S)-2-methyl-5-oxo-2,5-dihydrofuran-2-yl)propanethioate (9)

S MeI, THF/H2O, rt, 12 h O

Me2N yield, 88% S

S MeOTf, THF/Et2O, 10 min; O

Me2N LiMe, 78 C, 30 min

S MeOTf, THF/Et2O, 10 min; O

6. Determination of the Relative and Absolute Configuration

Determination of absolute and relative configuration of the products in Table 3

Me2N wR2 0.1116

7. NMR Studies and HRMS Study of Cu(I) Complex

Procedure for preparation of sample AC

Figure S1. H NMR analysis of samples AC.

Figure S2. HRMS analysis of sample C.

Figure S3. NOE experiment of sample C.

Vous aimerez peut-être aussi