Supporting Information

© Wiley-VCH 2008

69451 Weinheim, Germany

Regioselective Hydroxysulfenylation of α,β-Unsaturated Imines: Enhanced Stability of an Intermediate Radical

Masafumi Ueda,a Hideto Miyabe,b Hidenori Shimizu,a Hisako Sugino,a Okiko Miyata,a and Takeaki Naitoa* a Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan. b School of Pharmacy, Hyogo University of Health Sciences, Minatojima, Kobe 650-8530, Japan.

We investigated the hydroxysulfenylation of oxime ether 10 using several radical initiator (Table 1). Triethylborane was proved to be optimal radical initiator for this reaction (entry 1). No reaction was observed when Et2Zn[1] was employed as an initiator (entry 2). In the case of 9-BBN[2], β-hydroxysulfide 13a was obtained in 41% yield (entry 3). The use of Me3Al and Et2Zn[3] resulted in a deterioration in the yield of β-hydroxysulfide 13a (entries 4 and 5).

Table 1. Reaction of 10 using several radical initiator.

EtO2C NOBn

PhS

OHEtO2C NOBn

10 13a

Initiator

O2, CH2Cl2, RT, 15 h

PhSH (3.5 eq)

Entry Initiator (eq) Yield (%) 1 Et3B (0.5) 75 2 Et2Zn (0.5) Not detected 3 9-BBN (0.5) 41 4 Me3Al (0.5) 8 5 V-70 (1.2) 12

To study the reactivity of oxime ether 10, a competition experiment using aldehyde 9 and oxime ether 10 was

conducted under the hydroxysulfenylation reaction conditions (Scheme 1). After being stirred at the room temperature for 0.5 h, the Michael adduct 12 in 40% and β-hydroxysulfide 13a in 11%. This result suggests that α,β-unsaturated aldehyde has higher reactivity toward non-radical Michael addition and radical hydroxysulfenylation of α,β-unsaturated oxime ether is slow reaction. Thus, the suppression of competitive Michael addition was essential to achieve radical hydroxysulfenylation.

EtO2C NOBn EtO2C NOBn

PhS

OH

13a (11%)

12 (40%)

EtO2C O EtO2C O

PhS

O2, CH2Cl2, RT, 0.5 h

PhSH (3.5 eq)

10

+

Et3B (0.5 eq)

+9

Scheme 1. Crossover experiment using 9 and 10.

To a solution of triethylborane in CDCl3 was added thiophenol at the room temperature. Triethylborane immediately reacted with thiophenol to give PhSBEt2 via radical reaction pathway. We confirmed the formation of PhSBEt2 by 1H-NMR experiment (Scheme 2).

PhSH Et3B1H NMRPhSBEt2CDCl3

+ 0.98 (6H, br t)1.23-1.18 (4H, m)7.37-7.10 (5H, m)4

Et3BO2

EtPhSH

PhSEt3B

PhSBEt24

Scheme 2. 1H NMR of PhSBEt2 4.

1

It is assumed that PhSBEt2 4 acts as a promoter for the reduction of hydroperoxide with thiophenol. To gain further

insight into the reaction mechanism, we examined the effect of PhSBEt2 4 on the reduction of hydroperoxide by using t-butyl hydroperoxide (Table 2). Reactions were run in CH2Cl2 at the room temperature for 15 h. In the absence of triethylborane, the conversion of thiophenol to diphenyl disulfide 17 is 70% (entry 1). The reduction of t-butyl hydroperoxide was accelerated by using triethylborane (0.5 eq.) as an additive to give diphenyl disulfide 17 in 100% conversion (entry 2).

Table 2. Reactivity of PhSH toward reduction in the presence of Et3B.

PhSH PhSSPh+CH2Cl2, RT, 15 h

+ tBuOHtBuOOH

17(3.5 eq) (1 eq)

Entry Et3B (eq) PhSH : PhSSPh 17 Conversion to 17 (%) 1 none 3 : 1 70 2 0.5 1 : 1 100

The relative configuration of β-hydroxysulfides anti-13a and syn-13a was deduced from NOESY experiments of γ-

lactams cis-16 and trans-16, which were prepared from anti-13a and syn-13a (Figure 1).

NOBn

O

OTBSPhS

NOBn

O

OS H

SiMe

tBu

MeH

Ph

cis-16 trans-16

Figure 1. NOESY experiments of cis-16 and trans-16.

Diastereoselectivity and anti/syn-selectivity of oxime ether 28 were confirmed by reduction of oxime ether group, because oxime ether 28 was obtained as a 5:1 mixture of E- and Z-isomers (Scheme 3). Treatment of oxime ether 28 with NaBH3CN under acidic conditions gave amine 35 as a single isomer.

28Me Me

NSO2

NOBnO

PhS

OH

NaBH3CN, HCl

35Me Me

NSO2

NHOBnO

PhS

OH

Scheme 3. Reduction of oxime ether 28. The relative configuration of trans-31, cis-31, 32, 33, and 34 was deduced from NOESY experiments, coupling

constanct analysis, the reduction of cis-31 into cis-36 and the transformation of 33 into 34 under radical reaction conditions (Figure 2).

2

H

NOBnH

Me Me

HHSPh

HHO

HH

H

SPhMe

Me OH

NOBn

cis-31

EtOH, 90%

NaBH3CN, HCl NH

OBn

H H

Me Me

HH

H

H

SPhHOH

H

H

1

2 3

1

2 3

OH

NOBnH

H

H

MeH

H SPh

H

HO

MeMe

NOBn

PhS

MeOH

32

Me

MeHO

1

23

4

5 67

SPhMe

Me OH

NOBn

trans-311

2

3SPhMe

Me OH

NOBn

cis-31

Me Me

HH

H

H

SPhHH

HOH

H

NOBn

1

2 3

1

2

3 SPhMe

Me OH

NHOBn

cis-36

Me

OHH

H H

SPh

H

NOBnMe

H

H

H

H

NOBn

PhS

OHMe

Me

SPh

NOBn

PhS

OHMe

Me

33

34

1

23

4

56

78

NOBn

PhS

OHMe

Me

33

PhSH, AIBN

benzene, reflux

OH

NOBnH

H

H

MeH

H SPh

H

HO

MeMe

coupling constant analysis

J = 4.0 HzJ = 5.0 Hz 4

3

Figure 2. Determination of relative configuration, NOESY experiments and coupling constanct analysis. References [1] I. Ryu, F. Araki, S. Minakata, M. Komatsu, Tetrahedron Lett. 1998, 39, 6335. [2] V. T. Perchyonok, C. H. Schiesser, Tetrahedron Lett. 1998, 39, 5437. [3] a) Y. Kita, A. Sato, T. Yamaguchi, M. Oka, K. Gotanda, M. Matsugi, Tetrahedron Lett. 1997, 38, 3549; b) Y. Kita, K.

Gotanda, A. Sano, M. Oka, K. Murata, M. Suemura, M. Matsugi, Tetrahedron Lett. 1997, 38, 8345. General. Melting points are uncorrected. 1H and 13C NMR spectra were recorded at 300 or 500 MHz and at 75 or 125 MHz, respectively. IR spectra were recorded using FTIR apparatus. Mass spectra were obtained by EI or CI method. Medium-pressure column chromatography was performed using Lobar größe B (E. Merck 310-25, Lichroprep Si60).

3

General Procedure for Preparation of Oxime Ethers. To a solution of aldehyde or ketone (8.0 mmol) in pyridine (50 mL) were added BnONH3Cl (1.4 g, 8.8 mmol) under

N2 atmosphere at room temperature. After being stirred at the same temperature for 1 h, the reaction mixture was diluted with 10% HCl and extracted with Et2O. The organic phase was washed with saturated NaCl, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by medium-pressure column chromatography (hexane:AcOEt = 20:1–10:1) to afford the corresponding oxime ethers. Peaks of 13C NMR of E-20f, 14, 13b-d, 21a-c, 21f, and 28 could not be assigned due to overlap and isomers. The 13C NMR charts of these compounds were added at the end of supporting information. 2-Cyclohexenone (E)-O-(Phenylmethyl)oxime (7)

NOBn

7 According to general procedure, oxime ethers E-7 (55%) and Z-7 (37%) were prepared from 2-cyclohexenone.

E-7: a colorless oil. IR ν max cm-1: 3012, 2990, 2933, 2873, 1455. 1H-NMR δ: 7.38-7.28 (5H, m), 6.21 (1H, dt, J=10.0, 4.0 Hz), 6.12 (1H, dt, J=10.0, 2.0 Hz), 5.12 (2H, s), 2.61 (2H, t, J=6.5 Hz), 2.15 (2H, tdd, J=6.5, 4.0, 2.0 Hz), 1.72 (2H, quint, J=6.5 Hz). 13C-NMR δ: 155.9, 137.9, 136.1, 128.2, 127.8, 127.5, 124.3, 75.7, 24.9, 22.9, 20.7. HRMS m/z: Calcd for C13H15NO (M+) 201.1154, Found: 201.1149. Z-7: a colorless oil. IR ν max cm-1: 3012, 2988, 2933, 2872, 1455. 1H-NMR δ: 7.39-7.24 (5H, m), 6.79 (1H, dt, J=10.0, 2.0 Hz), 6.27 (1H, dt, J=10.0, 4.0 Hz), 5.09 (2H, s), 2.38 (2H, t, J=6.5 Hz), 2.20 (2H, tdd, J=6.5, 4.0, 2.0 Hz), 1.82 (2H, quint, J=6.5 Hz). 13C-NMR δ: 153.1, 139.5, 138.1, 128.2, 127.8, 127.5, 117.8, 75.4, 28.2, 26.2, 22.2. HRMS m/z: Calcd for C13H15NO (M+) 201.1154, Found: 201.1157. [4-(Phenylmethoxy)imino]-2-butenoic Acid Ethyl Ester (10). EtO2C NOBn

10 According to general procedure, oxime ethers (2E, 4E)-10 (83%) and (2E, 4Z)-10 (3%) were prepared from

corresponding aldehyde. (2E, 4E)-10: a colorless oil. IR ν max (neat) cm-1: 3030, 1712. 1H-NMR δ: 7.86 (1H, dd, J=10.0, 0.5 Hz), 7.38-7.25 (5H, m), 7.22 (1H, dd, J=15.5, 10.0 Hz), 6.11 (1H, dd, J=15.5, 0.5 Hz), 5.17 (2H, s), 4.20 (2H, q, J=7.0 Hz), 1.29 (3H, t, J=7.0 Hz). 13C-NMR δ: 165.7, 148.3, 137.3, 136.7, 128.4, 128.3, 128.2, 127.0, 76.9, 60.7, 14.1. HRMS m/z: Calcd for C13H15NO3 (M+) 233.1052, Found: 233.1069. (2E, 4Z)-10: a colorless oil. IR ν max (neat) cm-1: 3020, 1715. 1H-NMR δ: 7.76 (1H, dd, J=16.0, 10.0 Hz), 7.38-7.30 (5H, m), 7.20 (1H, d, J=10.0 Hz), 6.12 (1H, d, J=16.0 Hz), 5.21 (2H, s), 4.24 (2H, q, J=7.0 Hz), 1.30 (3H, t, J=7.0 Hz). 13C-NMR δ: 165.9, 148.2, 145.5, 137.1, 129.7, 128.4, 128.2, 128.0, 76.8, 60.9, 14.1. HRMS m/z: Calcd for C13H15NO3 (M+) 233.1052, Found: 233.1061. (E)-2-Butenal O-(Phenylmethyl)oxime (20a) Me NOBn

20a According to general procedure, oxime ethers E-20a (59%) and Z-20a (26%) were prepared from crotonaldehyde.

E-20a: a colorless oil. IR ν max cm-1: 3014, 2939, 2917, 1651, 1455. 1H-NMR δ: 7.74 (1H, d, J=9.3 Hz), 7.37-7.27 (5H, m), 6.14 (1H, ddd, J=15.6, 9.3, 1.5 Hz), 5.98 (1H, dq, J=15.6, 6.6 Hz), 5.08 (2H, s), 1.81 (3H, dd, J=6.6, 1.5 Hz). 13C-NMR δ: 150.7, 137.5, 137.0, 128.2, 128.0, 127.7, 125.1, 75.7, 18.3. HRMS m/z: Calcd for C11H13NO (M+) 175.0997, Found: 175.0987. Z-20a: a colorless oil. IR ν max cm-1: 3010, 1647, 1455. 1H-NMR δ: 7.36-7.22 (5H, m), 6.99 (1H, d, J=9.5 Hz), 6.72 (1H, ddd, J=15.5, 9.5, 1.5 Hz), 6.08 (1H, dq, J=15.5, 7.0 Hz), 5.12 (2H, s), 1.83 (3H, dd, J=7.0, 1.5 Hz). 13C-NMR δ: 148.4, 139.1, 137.9, 128.3, 127.9, 127.7, 120.7, 75.9, 18.4. HRMS m/z: Calcd for C11H13NO (M+) 175.0997, Found: 175.1016. 3-Phenyl-2-propenal O-(Phenylmethyl)oxime (20b). Ph NOBn

20b According to general procedure, oxime ethers E-20b (50%) and Z-20b (15%) were prepared from trans-3-phenyl-2-

propenal. E-20b: a colorless crystal. mp 78-81 oC (hexane-AcOEt). IR ν max cm-1: 3011, 1451, 1160. 1H-NMR δ: 7.91 (1H, d, J=9.5 Hz), 7.38-7.22 (10H, m), 6.81 (1H, dd, J=16.0, 9.5 Hz), 6.69 (1H, d, J=16.0 Hz), 5.13 (2H, s). 13C-NMR δ: 150.9, 138.4, 137.4, 135.9, 128.7, 128.3, 128.2, 127.8, 126.8, 121.9, 76.1. One peak of 13C NMR was missing due to overlap. HRMS m/z: Calcd for C16H15NO (M+) 237.1154, Found: 237.1137. Anal. Calcd for C16H15NO: C, 80.98; H, 6.37; N, 5.90, Found: C, 80.84; H, 6.42; N, 5.88.

4

Z-20b: a colorless oil. IR ν max cm-1: 3060, 1451. 1H-NMR δ: 7.49 (1H, dd, J=8.0, 2.0 Hz), 7.42-7.20 (11H, m), 6.83 (1H, d, J=16.0 Hz), 5.20 (2H, s). 13C-NMR δ: 148.3, 139.8, 137.8, 135.7, 129.2, 128.7, 128.3, 128.0, 127.8, 127.4, 116.3, 76.2. HRMS m/z: Calcd for C16H15NO (M+) 237.1154, Found: 237.1161. 4-[(Phenylmethoxy)imino]-3-methyl-2-butenoic Acid Ethyl Ester (20d).

EtO2C NOBnMe

20d According to general procedure, oxime ether 20d (79%) was prepared from (2E)-4-oxo-3-methyl-2-butenoic acid

ethyl ester. a colorless oil. IR ν max cm-1: 2978, 2934, 1711, 1234. 1H-NMR δ: 7.73 (1H, s), 7.39-7.29 (5H, m), 5.87 (1H, s), 5.17 (2H, s), 4.18 (2H, q, J=7.0 Hz), 2.32 (3H, s), 1.28 (3H, t, J=7.0 Hz). 13C-NMR δ: 165.9, 151.8, 147.9, 136.9, 128.4, 128.3, 128.0, 123.7, 77.2, 76.8, 76.6, 60.0, 14.1, 13.0. HRMS m/z: Calcd for C14H17NO3 (M+) 247.1208, Found: 247.1182. (E)-3-Pentene-2-one O-(Phenylmethyl)oxime (20e) Me NOBn

Me20e According to general procedure, oxime ethers E-20e (57%) and Z-20e (31%) were prepared from 3-penten-2-one.

E-20e: a colorless oil. IR ν max cm-1: 3013, 2917, 1454, 1368. 1H-NMR δ: 7.37-7.16 (5H, m), 6.14 (1H, br d, J=15.8 Hz), 5.99 (1H, dq, J=15.8, 6.2 Hz), 5.11 (2H, s), 1.94 (3H, s), 1.78 (3H, d, J=6.2 Hz). 13C-NMR δ: 155.6, 138.0, 130.5, 128.8, 128.2, 127.8, 127.5, 75.6, 18.2, 10.2. HRMS m/z: Calcd for C12H15NO (M+) 189.1154, Found: 189.1180. Z-20e: a colorless oil. IR ν max cm-1: 3013, 2990, 2924, 1442. 1H-NMR δ: 7.37-7.18 (5H, m), 6.85 (1H, dq, J=16.0, 2.0 Hz), 6.12 (1H, dq, J=16.0, 6.5 Hz), 5.08 (2H, s), 1.93 (3H, s), 1.81 (3H, dd, J=6.5, 2.0 Hz). 13C-NMR δ: 152.6, 138.0, 134.8, 128.2, 127.8, 127.5, 121.6, 75.5, 18.6, 16.7. HRMS m/z: Calcd for C12H15NO (M+) 189.1154, Found: 189.1164. (E)-3-Phenylthio-2-propenal O-(Phenylmethyl)oxime (20f) PhS NOBn

20f According to general procedure, oxime ethers E-20f (24%, 2 steps) and Z-20f (16%, 2 steps) were prepared from 3-

phenylthio-2-propenal, which was synthesized from acrolein by the method described in literature.[5] Oxime ethers E-20f was obtained as a 4:1 mixture of olefinic E- and Z-isomers. E-20f: a colorless oil. IR ν max cm-1: 3062, 3032, 2929, 1557, 1479. 1H-NMR δ: 8.22 (1/5H, dd, J=10.0, 1.0 Hz), 7.79 (4/5H, dd, J=10.0, 1.5 Hz), 7.44-7.28 (10H, m), 6.71 (4/5H, dd, J=15.0, 1.5 Hz), 6.64 (1/5H, dd, J=10.0, 1.0 Hz), 6.28 (1/5H, br t, J=10.0 Hz), 6.15 (4/5H, dd, J=15.0, 10.0 Hz), 5.15 (2/5H, s), 5.06 (8/5H, s). HRMS m/z: Calcd for C16H15NOS (M+) 269.0874, Found: 269.0853. Z-20f: a colorless oil. IR ν max cm-1: 3061, 3031, 1606, 1477. 1H-NMR δ: 7.44-7.22 (10H, m), 7.01 (1H, d, J=8.5 Hz), 6.90-6.75 (2H, m), 5.10 (2H, s). 13C-NMR δ: 146.2, 139.6, 137.7, 132.4, 131.5, 129.3, 128.3, 128.2, 127.8, 127.7, 116.3, 75.1. HRMS m/z: Calcd for C16H15NOS (M+) 269.0874, Found: 269.0873. 2-Cyclopentenone O-(Phenylmethyl)oxime (23).

NOBn

23 According to general procedure, oxime ethers E-23 (73%) and Z-23 (19%) were prepared from 2-cyclopentenone.

E-23: a colorless oil. IR ν max cm-1: 2912, 1361. 1H-NMR δ: 7.40-7.25 (5H, m), 6.58 (1H, dt, J=6.0, 3.0 Hz), 6.23 (1H, dt, J= 6.0, 2.5 Hz), 5.12 (2H, s), 2.68 (2H, m), 2.55 (2H, m). 13C-NMR δ: 168.3, 146.6, 138.3, 128.7, 128.3, 127.8, 127.6, 75.7, 30.9, 25.3. HRMS m/z: Calcd for C12H13NO (M+) 187.0997, Found: 187.0991. Z-23: a colorless oil. IR ν max cm-1: 2917, 1451, 1363. 1H-NMR δ: 7.38-7.22 (5H, m), 6.69 (1H, dt, J=6.0, 3.5 Hz), 6.60 (1H, dt, J= 6.0, 2.0 Hz), 5.08 (2H, s), 2.60-2.47 (4H, m). 13C-NMR δ: 165.4, 148.4, 138.3, 128.2, 127.8, 127.5, 124.3, 75.4, 29.9, 26.5. HRMS m/z: Calcd for C12H13NO (M+) 187.0997, Found: 187.0980. 3-Methylenebicyclo[2.2.1]heptan-2-one O-(Phenylmethyl)oxime (24).

N

E-24

OBn

HN

OBn

Z-24 According to general procedure, oxime ethers E-24 (75%) and Z-24 (21%) were prepared from 3-methylene-2-

norbornanone.

5

E-24: a colorless oil. IR ν max cm-1: 2967, 2874, 1453, 1365. 1H-NMR δ: 7.39-7.27 (5H, m), 5.43 (1H, s), 5.12 (2H, s), 4.90 (1H, s), 3.55 (1H, br s), 2.89 (1H, br s), 1.80-1.67 (2H, m), 1.52 (1H, m), 1.50-1.42 (2H, m), 1.39 (1H, dt, J=10.0, 1.5 Hz). 13C-NMR δ: 162.2, 148.4, 138.2, 128.3, 128.0, 127.6, 103.4, 75.9, 44.3, 39.1, 38.2, 28.2, 25.4. HRMS m/z: Calcd for C15H17NO (M+) 227.1310, Found: 227.1294. Z-24: a colorless oil. IR ν max cm-1: 2966, 2874, 1453, 1365. 1H-NMR δ: 7.38-7.27 (5H, m), 6.10 (1H, d, J=2.0 Hz), 5.38 (1H, d, J=2.0 Hz), 5.13 (2H, s), 2.91 (1H, br s), 2.84 (1H, br s), 1.81-1.73 (2H, m), 1.63 (1H, m), 1.55-1.43 (2H, m), 1.40 (1H, dt, J=10.0, 1.0 Hz). 13C-NMR δ: 159.8, 145.4, 137.9, 128.3, 127.7, 127.6, 116.1, 76.4, 46.2, 43.8, 39.4, 28.4, 26.6. HRMS m/z: Calcd for C15H17NO (M+) 227.1310, Found: 227.1320. 6,6-Dimetylbicyclo[3.1.1]hept-2-ene-2-carbaldehyde O-(Phenylmethyl)oxime (25).

25NOBn

Me

Me

According to general procedure, oxime ether 25 (98%) was prepared from (1R)-(-)-myrtenal.

a colorless oil. IR ν max cm-1: 2973, 2917, 2883, 1455, 1366. 1H-NMR δ: 7.74 (1H, s), 7.39-7.25 (5H, m), 5.83 (1H, m), 5.09 (2H, AB q, J=12.0 Hz), 2.85 (1H, t, J=6.0 Hz), 2.47-2.33 (3H, m), 2.14 (1H, m), 1.34 (3H, s), 1.16 (1H, d, J=9.0 Hz), 0.82 (3H, s). 13C-NMR δ: 150.4, 142.9, 137.5, 131.0, 128.3 (2C), 127.8, 76.0, 40.7, 40.3, 37.6, 32.3, 31.1, 26.0, 20.8. HRMS m/z: Calcd for C17H21NO (M+) 255.1623, Found: 255.1631. 5-(1-Hydroxy-1-methylethyl)-2-methyl-2-cyclohexenone O-(Phenylmethyl)oxime (26).

Me

NOBn26Me

MeHO

According to general procedure, oxime ether 26 (97%) was prepared from (S)-(+)-5-(1-hydroxy-1-methylethyl)-2-

methyl-2-cyclohexen-1-one. a colorless oil. IR ν max cm-1: 3408, 2973, 2925, 1453, 1366. 1H-NMR δ: 7.40-7.23 (5H, m), 5.97 (1H, m), 5.13 (2H, AB q, J=12.0 Hz), 3.27 (1H, ddd, J=16.0, 4.0, 1.5 Hz), 2.24 (1H, m), 1.96 (1H, m), 1.85 (1H, m), 1.83 (3H, s), 1.71 (1H, m), 1.61 (1H, br s), 1.21 (6H, s). 13C-NMR δ: 156.4, 138.2, 132.3, 130.5, 128.2 (2C), 127.6, 75.9, 72.1, 43.9, 27.0, 26.9, 26.2, 24.3, 17.5. HRMS m/z: Calcd for C17H23NO2 (M+) 273.1729, Found: 273.1732. 5-(1-Methylethenyl)-2-methyl-cyclohexenone O-(Phenylmethyl)oxime (27).

Me

NOBn27

Me

According to general procedure, oxime ether 27 (76%) was prepared from (R)-(-)-carvone.

a colorless oil. IR ν max cm-1: 2917, 1454. 1H-NMR δ: 7.41-7.26 (5H, m), 5.99 (1H, m), 5.13 (2H, s), 4.75 (2H, m), 3.20 (1H, ddd, J=17.0, 4.0, 1.5 Hz), 2.39-2.18 (2H, m), 2.12-2.01 (2H, m), 1.84 (3H, br t, J=1.5 Hz), 1.73 (3H, s). 13C-NMR δ: 156.1, 147.9, 138.1, 132.0, 130.6, 128.2, 128.1, 127.5, 109.8, 75.9, 40.3, 30.2, 27.9, 20.5, 17.6. HRMS m/z: Calcd for C17H21NO (M+) 255.1623, Found: 255.1632. (E)-4-[(Phenylmethoxy)imino]-2-butenoic Acid 1,1-Dimethylethyl Ester (20c). tBuO2C NOBn

20c

tBuO2C NOBn

O O OHO BnONH3ClBnON

CO2H

HCl HO2C NOBn Boc2O, DMAP

20c

O2, hνRose bengal

CHO

A solution of furfural (25.52 g, 0.27 mol) and rose bengal (160 mg, 0.16 mmol) in methanol (480 ml) was bubbled

by oxygen gas and the pink/orange solution irradiated by Hg lamp for 72 h.[1] The solution was concentrated under reduced pressure. To a solution of the crude product in water (85 mL) was added BnONH3Cl (1.12 g, 7.03 mmol) under N2 atmosphere at room temperature.[2] After being stirred at the same temperature for 1 h, the reaction mixture was diluted with AcOEt. The organic phase was washed with saturated NaCl, dried over MgSO4 and concentrated under reduced pressure to give orange tinged solid. After a solution of crude product in concentrated HCl were stirred under N2 atmosphere at room temperature for 4

6

h, the reaction mixture was neutralized with Na2CO3. The reaction mixture was diluted with AcOEt. The organic phase was washed with saturated NaCl, dried over MgSO4 and concentrated under reduced pressure. To a solution of crude product (0.1 g, 0.49 mmol) in t-BuOH (5 mL) were added Boc2O (0.23 mL, 0.98 mmol) and DMAP (30.5 mg, 0.25 mmol) under N2 atmosphere at room temperature.[3] After being stirred at the same temperature for 6 h, the reaction mixture was concentrated under reduced pressure. The crude product was purified by medium-pressure column chromatography (hexane:AcOEt = 10:1) to afford the corresponding oxime ether 20c (34%, 4 steps) as a colorless oil. IR ν max cm-1: 2978, 1709, 1303, 1259. 1H-NMR δ: 7.83 (1H, d, J=10.0 Hz), 7.36-7.30 (5H, m), 7.19 (1H, dd, J=16.0, 10.0 Hz), 6.02 (1H, d, J=16.0 Hz), 5.16 (2H, s), 1.48 (9H, s). 13C-NMR δ: 164.9, 148.5, 136.8, 136.2, 129.2, 128.4, 128.3, 128.1, 80.9, 76.8, 28.0. HRMS m/z: Calcd for C15H19NO3 (M+) 261.1365, Found: 261.1357. (E)-4-(Diphenylhydrazono)-2-butenoic Acid Ethyl Ester (11). EtO2C NNPh2

11 To a solution of (2E)-4-oxo-2-butenoic acid ethyl ester (1.0 g, 7.8 mmol) in EtOH (25 mL) were added Ph2NNH3Cl

(1.9 g, 8.6 mmol) and AcONa (0.7 g, 8.6 mmol) under N2 atmosphere at room temperature. After being stirred at the same temperature for 15 h, the reaction mixture was diluted with saturated NaHCO3 and extracted with CHCl3. The organic phase was washed with saturated NaCl, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by medium-pressure column chromatography (hexane:AcOEt = 10:1) to afford the corresponding oxime ether 11 (1.48 g, 65%) as a yellow crystal. mp 153-156 oC (hexane-AcOEt). IR ν max cm-1: 3016, 1698, 1492, 1259. 1H-NMR δ: 7.53 (1H, dd, J=16.0, 10.0 Hz), 7.46-7.38 (4H, m), 7.26-7.12 (6H, m), 6.90 (1H, d, J=10.0 Hz), 5.79 (1H, dd, J=16.0, 1.0 Hz), 4.20 (2H, q, J=7.0 Hz), 1.29 (3H, t, J=7.0 Hz). 13C-NMR δ: 166.7, 142.6, 142.1, 133.9, 129.8, 125.3, 122.4, 121.4, 60.2, 14.2. HRMS m/z: Calcd for C18H18N2O2 (M+) 294.1368, Found: 294.1350. Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52, Found: C, 73.20; H, 6.31; N, 9.56. General Procedure for Hydroxysulfenylation Reaction. To a solution of α,β-unsaturated oxime ether (0.5 mmol) in CH2Cl2 (6 mL) were added thiol (1.75 mmol) and Et3B (1.0 M in hexane, 0.25 mL, 0.25 mmol) under dry air atmosphere at room temperature. After being stirred at the same temperature for 15 h, the reaction mixture was concentrated under reduced pressure. Purification of the residue by medium-pressure column chromatography (hexane:AcOEt = 10:1–4:1) afforded the corresponding β-hydroxysulfide. 2-Hydroxy-2-methyl-3-phenylthiopropanoic Acid Ethyl Ester (2). EtO2C

SPhMe OH 2

According to general procedure for hydroxysulfenylation, hydroxysulfide 2 (46%) and sulfide 3 (33%) were obtained from α,β-unsaturated ethyl ester 1. a colorless oil. IR ν max cm-1: 3505, 2978, 1731. 1H-NMR δ: 7.44-7.39 (2H, m), 7.30-7.15 (3H, m), 4.12-4.00 (1H, m), 3.94-3.82 (1H, m), 3.57 (1H, s), 3.40 (1H, d, J=14.0 Hz), 3.20 (1H, d, J=14.0 Hz), 1.49 (3H, s), 1.15 (3H, t, J=7.0 Hz). 13C-NMR δ: 174.9, 135.8, 130.5, 128.8, 126.6, 74.5, 61.9, 44.9, 25.4, 13.9. HRMS m/z: Calcd for C12H16O3S (M+) 240.0820, Found: 240.0846. 2-Methyl-3-phenylthiopropanoic Acid Ethyl Ester (3). EtO2C

MeSPh

3 a colorless oil. IR ν max cm-1: 2978, 1731. 1H-NMR δ: 7.38-7.16 (5H, m), 4.12 (2H, q, J=7.0 Hz), 3.27 (1H, dd, J=13.0, 7.0 Hz), 2.92 (1H, dd, J=13.0, 7.0 Hz), 2.67 (1H, m), 1.26 (3H, d, J=7.0 Hz), 1.24 (3H, d, J=7.0 Hz). 13C-NMR δ: 174.7, 135.7, 129.9, 128.8, 126.3, 60.5, 39.6, 37.2, 16.6, 14.1. HRMS m/z: Calcd for C12H16O2S (M+) 224.0871, Found: 224.0878. 3-Phenylthiocyclohexanone (6).

O

PhS

6 Characterization data were reported.[4] 2-Hydroxy-3-phenylthiocyclohexanone O-(Phenylmethyl)oxime (8).

7

NOBn

PhS OH

8 According to general procedure for hydroxysulfenylation, trans-8 (74%) and cis-8 (11%) were obtained.

trans-8: a colorless oil. IR ν max cm-1: 3494. 1H-NMR δ: 7.52-7.50 (2H, m), 7.36-7.25 (8H, m), 5.11 (2H, s), 3.98 (1H, d, J=9.5 Hz), 3.63 (1H, br s), 3.16 (1H, m), 3.03 (1H, ddd, J=11.0, 9.5, 4.0 Hz), 2.10 (1H, m), 1.80 (2H, m), 1.53 (1H, m), 1.37 (1H, m). 13C-NMR δ: 158.0, 137.4, 133.9, 132.7, 128.8, 128.3, 128.2, 127.9, 127.6, 76.2, 72.7, 54.7, 30.7, 23.9, 23.7. HRMS m/z: Calcd for C19H21NO2S (M+) 327.1293, Found: 327.1289. cis-8: a white solid. IR ν max cm-1: 3500. 1H-NMR δ: 7.47-7.44 (2H, m), 7.35-7.23 (8H, m), 5.11 (1H, d, J=12.0 Hz), 5.08 (1H, d, J=12.0 Hz), 4.24 (1H, t, J=3.5 Hz), 3.52 (1H, dt, J=9.5, 3.5 Hz), 3.03 (1H, d, J=3.5 Hz), 2.66 (1H, dt, J=14.5, 5.5 Hz), 2.51 (1H, ddd, J=14.5, 10.0, 5.0 Hz), 1.97-1.83 (3H, m), 1.51 (1H, m). 13C-NMR δ: 158.3, 137.6, 133.6, 132.4, 129.1, 128.3, 128.0, 127.8, 127.5, 75.8, 70.1, 54.5, 27.0, 23.3, 21.7. HRMS m/z: Calcd for C19H21NO2S (M+) 327.1293, Found: 327.1301. 4-Oxo-2-phenylthiobutanoic Acid Ethyl Ester (12). EtO2C O

PhS 12 According to general procedure for hydroxysulfenylation, β-sulfide 12 (92%) was obtained from 9.

a colorless oil. IR ν max cm-1: 2984, 1728. 1H-NMR δ: 9.72 (1H, s), 7.51-7.45 (2H, m), 7.35-7.30 (3H, m), 4.13 (2H, q, J=7.0 Hz), 4.05 (1H, dd, J=9.5, 5.5 Hz), 3.11 (1H, dd, J=18.5, 9.5 Hz), 2.86 (1H, dd, J=18.5, 5.5 Hz), 1.19 (3H, t, J=7.0 Hz). 13C-NMR δ: 198.3, 170.9, 133.8, 131.7, 128.9, 128.6, 61.4, 45.3, 43.6, 13.7. HRMS m/z: Calcd for C12H14O3S (M+) 238.0664, Found: 238.0668. 3-Hydroxy-4-[(phenylmethoxy)imino]-2-phenylthiobutanoic Acid Ethyl Ester (13a).

EtO2C NOBn

PhS

OH

13a According to general procedure for hydroxysulfenylation, anti-13a (64%) and syn-13a (11%) were obtained.

anti-13a: a 3:1 mixture of E/Z isomers. a colorless oil. IR ν max cm-1: 3521, 2254, 1731. 1H-NMR δ: 7.62 (3/4H, d, J=4.5 Hz), 7.48-7.19 (10H, m), 6.93 (1/4H, d, J=5.5 Hz), 5.13-5.05 (2H, m), 4.95 (1/4H, t, J=5.5 Hz), 4.62 (3/4H, dd, J=7.0, 4.5 Hz), 4.19-4.06 (2H + 1/4H, m), 3.81 (3/4H, d, J=7.0 Hz), 3.56 (1/4H, br s), 3.47 (3/4H, br s), 1.21 (3/4H, t, J=7.0 Hz), 1.18 (9/4H, t, J=7.0 Hz). 13C-NMR δ: 170.8, 170.7, 151.2, 149.0, 137.1, 136.9, 133.4, 132.8, 132.4, 129.1, 129.0, 128.5, 128.4 (2C), 128.2 (2C), 128.1, 128.0, 76.7, 76.3, 69.7, 66.6, 61.8, 61.6, 54.2, 52.8, 13.9 (2C). Two peaks of 13C NMR were missing due to overlap. HRMS m/z: Calcd for C19H21NO4S (M+) 359.1191, Found: 359.1193. syn-13a: a 3:1 mixture of E/Z isomers. a colorless oil. IR ν max cm-1: 3533, 2253, 1730, 1370. 1H-NMR δ: 7.63 (3/4H, d, J=4.5 Hz), 7.50-7.43 (2H, m), 7.36-7.25 (8H, m), 6.99 (1/4H, d, J=4.5 Hz), 5.23 (1/4H, dd, J=4.5, 3.0 Hz), 5.08 (2H, s ), 4.63 (3/4H, dd, J=6.0, 4.5 Hz), 4.22-4.04 (2H + 1/4H, m), 3.86 (3/4H, d, J=6.0 Hz), 3.72 (1/4H, br s), 3.35 (3/4H, br s), 1.20 (3/4H, t, J=7.0 Hz), 1.71 (9/4H, t, J=7.0 Hz). 13C-NMR δ: 171.9, 170.2, 151.2, 148.6, 137.2, 137.1, 133.4, 133.1, 132.5, 129.1, 129.0, 128.4 (2C), 128.2 (2C), 128.1, 127.9, 76.6, 76.3, 68.9, 66.4, 61.8, 61.6, 55.8, 53.7, 13.9 (2C). Three peaks of 13C NMR were missing due to overlap. HRMS m/z: Calcd for C19H21NO4S (M+) 359.1191, Found: 359.1196. 2-[2-[(Phenylmethoxy)imino]ethyl]butanoic Acid Ethyl Ester (15). EtO2C NOBn

Et 15 A 3:2 mixture of E/Z isomers was obtained. a colorless oil. IR ν max cm-1: 2970, 2937, 1732, 1456. 1H-NMR δ: 7.44 (3/5H, dd, J=6.5, 5.0 Hz), 7.37-7.26 (5H, m), 6.71 (2/5H, t, J=5.5 Hz), 5.10 (4/5H, s), 5.04 (6/5H, s), 4.112 (6/5H, q, J=7.0 Hz), 4.107 (4/5H, q, J=7.0 Hz), 2.64-2.58 (4/5H, m), 2.56-2.45 (6/5H + 3/5H, m), 2.41-2.29 (2/5H, m), 1.74-1.48 (2H, m), 1.24 (6/5H, t, J=7.0 Hz), 1.23 (9/5H, t, J=7.0 Hz), 0.912 (6/5H, t, J=7.0 Hz), 0.906 (9/5H, t, J=7.0 Hz). 13C-NMR δ: 174.7, 174.6, 149.3, 148.8, 137.8, 137.5, 128.2 (2C), 128.1, 127.8, 127.7, 127.6, 75.7, 75.5, 60.4, 60.3, 44.3, 43.9, 31.2, 27.6, 25.0, 24.9, 14.1 (2C), 11.3, 11.2. HRMS m/z: Calcd for C15H21NO3 (M+) 263.1521, Found: 263.1518. (Z)-4-(Diphenylhydrazono)-3-hydroxy-2-phenylthiobutanoic Acid Ethyl Ester (14)

EtO2C NNPh2

PhS

OH

14

8

According to general procedure for hydroxysulfenylation, β-Hydroxysulfide 14 (71%) was obtained as a 4:1 mixture of anti- and syn- isomers. a colorless oil. IR ν max cm-1: 3478, 1731. 1H-NMR δ: 7.50-7.04 (15H, m), 6.67 (4/5H, d, J=3.0 Hz), 6.61 (1/5H, d, J=3.0 Hz), 4.70 (1H, m), 4.24-4.08 (2H, m), 3.95 (1/5H, d, J=6.0 Hz), 3.93 (4/5H, d, J=6.0 Hz), 3.79 (4/5H, d, J=8.0 Hz), 3.59 (1/5H, d, J=4.0 Hz), 1.19 (3H, t, J=7.0 Hz). HRMS m/z: Calcd for C24H24N2O3S (M+) 420.1508, Found: 420.1500. 2-[(4-Chlorophenyl)thio]-3-hydroxy-4-[(phenylmethoxy)imino]butanoic Acid Ethyl Ester (13b)

EtO2C NOBn

S

OH

Cl

13b

According to general procedure for hydroxysulfenylation, a 6:1 mixture of anti-13b (E:Z = 7:1) and syn-13b (E:Z =

7:1) were obtained in 78% yield. a colorless oil. IR ν max cm-1: 3467, 2983, 1731. 1H-NMR for anti,E-13b δ: 7.60 (1H, d, J=4.5 Hz), 7.42-7.10 (9H, m), 5.08 (2H, s), 4.60 (1H, m), 4.20-4.02 (2H, m), 3.77 (1H, d, J=7.0 Hz), 3.47 (1H, br d, J=7.0 Hz), 1.20 (3H, t, J=7.0 Hz). HRMS m/z: Calcd for C19H20ClNO4S (M+) 393.0802, Found: 393.0796. 3-Hydroxy-2-[(4-hydroxyphenyl)thio]-4-[(phenylmethoxy)imino]butanoic Acid Ethyl Ester (13c)

EtO2C NOBn

S

OH

HO

13c

According to general procedure for hydroxysulfenylation, a 6:1 mixture of anti-13c (E:Z = 2:1) and syn-13c (E:Z =

2:1) were obtained in 64% yield. a colorless oil. IR ν max cm-1: 3396, 2983, 1717. 1H-NMR for anti,E-13c δ: 7.65 (1H, d, J=5.0 Hz), 7.44-7.18 (7H, m), 6.76-6.61 (2H, m), 5.67 (1H, br m), 5.10 (2H, s), 4.55 (1H, m), 4.11 (2H, m), 3.64 (1H, d, J=7.5 Hz), 3.43 (1H, br m), 1.22 (3H, t, J=7.0 Hz). HRMS m/z: Calcd for C19H21NO5S (M+) 375.1140, Found: 375.1129. 2-(Dodecylthio)-3-hydroxy-4-[(phenylmethoxy)imino]butanoic Acid Ethyl Ester (13d)

EtO2C NOBn

H3C(CH2)11S

OH

13d According to general procedure for hydroxysulfenylation, anti-13d (38%) as a 3:1 mixture of E/Z isomers and syn-

13d (6%) as a 11:1 mixture of E/Z isomers were obtained. anti-13d: a colorless oil. IR ν max cm-1: 3451, 2923, 1728. 1H-NMR δ: 7.63 (3/4H, d, J=5.0 Hz), 7.42-7.25 (5H, m), 6.92 (1/4H, d, J=5.0 Hz), 5.13 (2/4H, s), 5.09 (6/4H, s), 4.95 (1/4H, br m), 4.58 (3/4H, br m), 4.30-4.12 (2H, m), 3.62 (1/4H, d, J=6.0 Hz) 3.61 (1/4H, br m), 3.46 (3/4H, br d, J=6.0 Hz), 3.41 (3/4H, d, J=7.0 Hz), 2.62 (6/4H, t, J=7.5 Hz), 2.60 (2/4H, t, J=7.0 Hz), 1.60-1.21 (23H, m), 0.89 (3H, br t, J=7.0 Hz). HRMS m/z: Calcd for C25H41NO4S (M+) 451.2756, Found: 451.2764. syn-13d: a colorless oil. IR ν max cm-1: 3527, 2929, 1726. 1H-NMR δ: 7.64 (11/12H, d, J=5.0 Hz), 7.37-7.28 (5H, m), 6.93 (1/12H, d, J=5.0 Hz), 5.12 (2/12H, s), 5.10 (22/12H, s), 4.95 (1/12H, m), 4.60 (11/12H, m), 4.23-4.11 (2H, m), 3.63 (1/12H, d, J=6.0 Hz), 3.53 (1/12H, d, J=7.5 Hz), 3.42 (11/12H, d, J=7.0 Hz), 3.33 (11/12H, d, J=7.0 Hz), 2.63 (2H, t, J=7.5 Hz), 1.66-1.22 (23H, m), 0.88 (3H, br t, J=6.0 Hz). HRMS m/z: Calcd for C25H41NO4S (M+) 451.2756, Found: 451.2772. 3-Hydroxy-3-phenylthiobutyraldehyde O-(Phenylmethyl)oxime (21a).

Me NOBn

PhS

OH

21a According to general procedure for hydroxysulfenylation, a 5:6 mixture of anti-21a (E:Z = 4:1) and syn-21a (E:Z =

>20:1) were obtained in 61% yield. a colorless oil. IR ν max cm-1: 3429, 2972. 1H-NMR for two major isomers δ: 7.55 (1/2H, d, J=5.0 Hz), 7.52 (1/2H, d, J=5.0 Hz), 7.44-7.06 (10H, m), 5.12 (1/2H, d, J=12.0 Hz), 5.08 (1H, s), 5.04 (1/2H, d, J=12.0 Hz), 4.29 (1/2H, dd, J=10.0, 5.0 Hz), 4.20 (1/2H, dd, J=10.0, 5.0 Hz), 3.44-3.30 (1H, m), 3.15 (1/2H, d, J=5.0 Hz), 2.82 (1/2H, d, J=5.0 Hz), 1.31 (3/2H, d, J=7.0 Hz), 1.26 (3/2H, d, J=7.0 Hz). HRMS m/z: Calcd for C17H19NO2S (M+) 301.1136, Found: 301.1158. 2-Hydroxy-3-phenyl-3-phenylthiopropenal O-(Phenylmethyl)oxime (21b).

9

Ph NOBn

PhS

OH

21b According to general procedure for hydroxysulfenylation, a 3:1 mixture of anti-21b (E:Z = 8:1) and syn-21b (E:Z =

2:1) were obtained in 69% yield. a colorless oil. IR ν max cm-1: 3423, 3027, 1454. 1H-NMR for anti,E-21b δ: 7.42 (1H, d, J=5.5 Hz), 7.37-7.15 (15H, m), 5.06 (2H, s), 4.60 (1H, m), 4.34 (1H, d, J=6.0 Hz), 2.81 (1H, d, J=5.0 Hz). HRMS m/z: Calcd for C22H22NO2S (M+H+) 364.1370, Found: 364.1359. 3-Hydroxy-4-[(phenylmethoxy)imino]-2-phenylthiobutanoic Acid 1,1-Dimethylethyl Ester (21c).

tBuO2C NOBn

PhS

OH

21c According to general procedure for hydroxysulfenylation, a 10:1 mixture of anti-21c (E:Z = 2:1) and syn-21c (E:Z =

2:1) were obtained in 70% yield. a colorless crystal. mp 65-68 oC (hexane-AcOEt). IR ν max cm-1: 3352, 1726. 1H-NMR for anti-21c δ: 7.61 (2/3H, d, J=5.0 Hz), 7.52-7.16 (10H, m), 6.92 (1/3H, d, J=5.0 Hz), 5.10 (2/3H, s), 5.08 (4/3H, s), 4.93 (1/3H, m), 4.58 (2/3H, m), 4.08 (1/3H, d, J=5.0 Hz), 3.76 (2/3H, d, J=7.0 Hz), 3.71 (1/3H, d, J=8.0 Hz), 3.62 (2/3H, d, J=7.0 Hz), 1.382 (9/3H, s), 1.375 (18/3H, s). HRMS m/z: Calcd for C21H25NO4S (M+) 387.1503, Found: 387.1511. Anal. Calcd for C21H25NO4S: C, 65.09; H, 6.50; N, 3.61, Found: C, 65.11; H, 6.38; N, 3.64. (E)-3-Hydroxy-3-methyl-4-[(phenylmethoxy)imino]-2-phenylthiobutanoic Acid Ethyl Ester (21d).

EtO2C NOBn

PhS

OHMe

21d According to general procedure for hydroxysulfenylation, 21d (71%) as a 3:2 mixture of stereoisomers was obtained.

a colorless oil. IR ν max cm-1: 3478, 1734. 1H-NMR δ: 7.69 (2/5H, s), 7.61 (3/5H, s), 7.54-7.26 (10H, m), 5.08 (4/5H, s), 5.04 (3/5H, d, J=11.5 Hz), 5.02 (3/5H, d, J=11.5 Hz), 4.44 (3/5H, s), 4.20-3.85 (2H, m), 3.85 (3/5H, s), 3.82 (2/5H, s), 3.79 (2/5H, s), 1.56 (9/5H, s), 1.52 (6/5H, s), 1.17 (6/5H, t, J=7.0 Hz), 1.11 (9/5H, t, J=7.0 Hz). 13C-NMR δ: 172.6, 171.2, 153.5, 152.4, 137.2, 134.0, 133.9, 132.9, 132.5, 129.0, 128.9, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 76.1, 76.0, 73.4, 72.8, 61.4, 61.2, 60.6, 58.8, 25.6, 24.3, 13.9, 13.8. Three peaks of 13C NMR were missing due to overlap. HRMS m/z: Calcd for C20H24NO4S (M+H+) 374.1424, Found: 374.1398. 3-Hydroxy-4-phenylthio-2-pentanone O-(Phenylmethyl)oxime (21e).

Me NOBn

PhS

OH

21eMe According to general procedure for hydroxysulfenylation, anti-21e (60%) and syn-21e (3%) were obtained.

anti-21e: a colorless oil. IR ν max cm-1: 3516. 1H-NMR δ: 7.46-7.24 (10H, m), 5.11 (2H, s), 4.24 (1H, d, J=4.0 Hz), 3.43 (1H, qd, J=7.0, 4.0 Hz), 3.11 (1H, br s), 1.81 (3H, s), 1.20 (3H, d, J=7.0 Hz). 13C-NMR δ: 156.3, 137.7, 134.3, 132.5, 129.0, 128.3, 128.0, 127.8, 127.3, 76.0, 74.2, 47.0, 14.5, 12.0. HRMS m/z: Calcd for C18H21NO2S (M+) 315.1292, Found: 315.1308. syn-21e: a white solid. IR ν max cm-1: 3516. 1H-NMR δ: 7.39-7.25 (7H, m), 7.15 (1H, m), 7.03 (2H, m), 5.05 (1H, d, J=11.0 Hz), 4.95 (1H, d, J=11.0 Hz), 4.76 (1H, m), 4.04 (1H, qd, J=7.0, 3.0 Hz), 2.62 (1H, d, J=2.5 Hz), 1.95 (3H, s), 1.26 (3H, d, J=7.0 Hz). 13C-NMR δ: 159.4, 137.2, 133.4, 130.7, 128.9, 128.51, 128.48, 128.0, 126.8, 76.3, 68.2, 45.1, 17.3, 13.9. HRMS m/z: Calcd for C18H21NO2S (M+) 315.1293, Found: 315.1320. 2-Hydroxy-3,3-diphenylthiopropenal O-(Phenylmethyl)-oxime (21f).

PhS NOBn

PhS

OH

21f According to general procedure for hydroxysulfenylation, E-21f (39%) and Z-21f (33%) were obtained.

a colorless oil. IR ν max cm-1: 3450, 3060, 1476, 1437. 1H-NMR δ: 7.66 (6/11H, d, J=4.5 Hz), 7.46-7.07 (15H, m), 6.99 (5/11H, d, J=4.0 Hz), 5.10 (12/11H, s), 5.04 (5/11H, d, J=12.0 Hz), 4.98 (5/11H, d, J=12.0 Hz), 4.95 (1H, br m), 4.53 (1H, m), 3.29 (6/11H, br d, J=4.5 Hz), 3.06 (5/11H, br s). HRMS m/z: Calcd for C22H21NO2S2 (M+) 395.1013, Found: 395.1032. Hexahydro-8,8-dimethyl-1-[(4E/Z)-3-hydroxy-2-phenylthio-4-[(phenylmethoxy)imino]butyl]- 3H-3a,6-methano-2,1-benzisothiazole 2,2-Dioxide (28)

10

28Me Me

NSO2

NOBnO

PhS

OH

According to general procedure for hydroxysulfenylation, 28 (70%) was obtained as a 5:1 mixture of E- and Z-

isomers. a colorless oil. IR ν max cm-1: 3494, 2961, 1687, 1333, 1210. 1H-NMR δ: 7.62 (5/6H, d, J=5.0 Hz), 7.50-7.10 (10H, m), 6.97 (1/6H, d, J=5.0 Hz), 5.11 (1/6H, d, J=12.0 Hz), 5.10 (10/6H, s), 5.07 (1/6H, d, J=12.0 Hz), 4.92 (1/6H, m), 4.79 (1/6H, br s), 4.64 (5/6H, m), 4.45 (5/6H, br s), 3.93 (1/6H, br s), 3.89 (1H, br t), 3.47 (1H, d, J=14.0 Hz), 3.43 (1H, d, J=14.0 Hz), 3.23 (5/6H, br s), 2.05 (2H, m), 1.94-1.84 (3H, m), 1.40-1.31 (2H, m), 1.11 (3/6H, s), 1.09 (15/6, s), 0.96 (3H, s). Anal. Calcd for C27H32N2O5S2: C, 59.32; H, 6.27; N, 5.12, Found: C, 59.75; H, 5.93; N, 5.14. 2-Hydroxy-3-phenylthiocyclopentanone O-(Phenylmethyl)oxime (29)

NOBn

PhSOH

29 According to general procedure for hydroxysulfenylation, trans-29 (71%) and cis-29 (7%) were obtained.

trans-29: a colorless oil. IR ν max cm-1: 3396. 1H-NMR δ: 7.45-7.42 (2H, m), 7.34-7.21 (8H, m), 5.10 (2H, s), 4.31 (1H, d, J=6.0 Hz), 3.44 (1H, dd, J=13.5, 6.0 Hz), 3.03 (1H, br s), 2.56 (2H, m), 2.28 (1H, m), 1.71 (1H, m). 13C-NMR δ: 163.7, 137.6, 133.6, 132.1, 128.9, 128.3, 128.0, 127.8, 127.3, 76.15, 76.07, 52.2, 27.1, 24.9. HRMS m/z: Calcd for C18H19NO2S (M+) 313.1136, Found: 313.1165. cis-29: a colorless oil. IR ν max cm-1: 3577. 1H-NMR δ: 7.47-7.43 (2H, m), 7.37-7.23 (8H, m), 5.11 (1H, d, J=12.5 Hz), 5.08 (1H, d, J=12.5 Hz), 4.66 (1H, br d, J=5.5 Hz), 3.57 (1H, m), 3.30 (1H, br s), 2.61-2.48 (2H, m), 2.31 (1H, m), 1.74 (1H, dq, J=13.0, 8.0 Hz). 13C-NMR δ: 164.4, 137.1, 134.2, 132.4, 131.6, 129.0, 128.6, 128.2, 127.1, 76.4, 75.0, 51.6, 28.8, 28.3. HRMS m/z: Calcd for C18H19NO2S (M+) 313.1136, Found: 313.1154. Hydroxysulfenylation reaction of oxime ether E-24.

To a solution of oxime ether E-24 (113 mg, 0.5 mmol) in CH2Cl2 (6 mL) were added thiophenol (193 mg, 1.75 mmol) and Et3B (1.0 M in hexane, 0.25 mL, 0.25 mmol) under air at room temperature. After being stirred at the same temperature for 1 h, the reaction mixture was concentrated under reduced pressure. Purification of the residue by medium-pressure column chromatography (hexane:AcOEt = 10:1) afforded the corresponding hydroxysulfide 30a (26.6 mg, 15%), more polar sulfide 30b (114 mg, 67%) and less polar sulfide 30b (4 mg, 3%).

2-Hydroxy-3-phenylthiobicyclo[2.2.1]heptane (E)-O-(Phenylmethyl)oxime (30a).

NOBn

OHSPh30a

a colorless oil. IR ν max cm-1: 3450, 2961, 1473. 1H-NMR δ: 7.43-7.18 (10H, m), 5.08 (1H, d, J=12.0 Hz), 5.05 (1H, d, J=12.0 Hz), 3.40 (1H, br d, J=3.5 Hz), 3.32 (1H, d, J=14.0 Hz), 3.28 (1H, d, J=14.0 Hz), 2.72 (1H, br s), 2.52 (1H, br m), 2.06 (1H, m), 1.71 (1H, tt, J=12.0, 4.5 Hz), 1.56-1.51 (2H, m), 1.47 (1H, m), 1.37 (1H, dt, J=10.5, 1.0 Hz). 13C-NMR δ: 167.5, 137.9, 136.7, 129.8, 129.0, 128.3, 128.1, 127.8, 126.4, 79.0, 76.0, 44.5, 43.3, 39.3, 35.2, 26.6, 21.1. HRMS m/z: Calcd for C21H23NO2S (M+) 353.1449, Found: 353.1451. 3-Phenylthiobicyclo[2.2.1]heptane (E)-O-(Phenylmethyl)oxime (30b).

NOBn

SPh30b more polar sulfide 30b: a colorless oil. IR ν max cm-1: 2963, 1479. 1H-NMR δ: 7.37-7.09 (10H, m), 5.05 (1H, d, J=12.0 Hz), 5.02 (1H, d, J=12.0 Hz), 4.10 (1H, dd, J=14.0, 4.0 Hz), 2.86 (1H, br m), 2.83 (1H, m), 2.66 (1H, br m), 2.59 (1H, dd, J=14.0, 12.0 Hz), 1.77 (1H, tt, J=12.0, 4.5 Hz), 1.64 (1H, m), 1.53 (1H, m), 1.48-1.39 (3H, m). 13C-NMR δ: 166.8, 137.8, 136.2, 128.8, 128.4 (2C), 128.2, 127.8, 125.5, 75.8, 43.8, 43.7, 38.5, 38.2, 30.2, 26.3, 22.0. HRMS m/z: Calcd for C21H23NOS (M+) 337.1500, Found: 337.1505. less polar sulfide 30b: a colorless oil. IR ν max cm-1: 2956, 1478. 1H-NMR δ: 7.37-7.15 (10H, m), 5.05 (1H, d, J=12.0 Hz), 5.02 (1H, d, J=12.0 Hz), 3.44-3.40 (2H, m), 2.76 (1H, dd, J=12.5, 11.5 Hz), 2.68 (1H, dt, J=11.5, 4.0 Hz), 2.61 (1H, br m), 1.66 (1H,

11

m), 1.51-1.48 (2H, m), 1.43-1.38 (2H, m), 1.30 (1H, m). 13C-NMR δ: 168.0, 138.3, 136.3, 129.2, 128.9, 128.2, 128.0, 127.6, 125.9, 75.5, 46.1, 40.2, 38.3, 37.6, 33.0, 26.6, 20.9. HRMS m/z: Calcd for C21H23NOS (M+) 337.1500, Found: 337.1496. Hydroxysulfenylation reaction of oxime ether 25.

To a solution of oxime ether 25 (128 mg, 0.5 mmol) in CH2Cl2 (6 mL) were added thiophenol (220 mg, 2.0 mmol) and Et3B (1.0 M in hexane, 0.5 mL, 0.5 mmol) under dry O2 at room temperature. After being stirred at the same temperature for 15 h, the reaction mixture was concentrated under reduced pressure. Purification of the residue by medium-pressure column chromatography (hexane:AcOEt = 10:1) afforded the corresponding hydroxysulfides trans-31 (58.5 mg, 31%) and cis-31 (39 mg, 20%). 6,6-Dimetyl-2-hydroxy-3-phenylthiobicyclo[3.1.1]heptane-2-carbaldehyde (E)-O-(Phenylmethyl)oxime (31).

trans-31 cis-31

SPhMe

Me OH

NOBnSPhMe

Me OH

NOBn

trans-31: a colorless oil. IR ν max cm-1: 3489, 2920, 1481. 1H-NMR δ: 8.17 (1H, s), 7.50-7.47 (2H, m), 7.34-7.16 (8H, m), 4.96 (1H, d, J=11.0 Hz), 4.92 (1H, d, J=11.0 Hz), 3.97 (1H, dd, J=10.0, 9.0 Hz), 3.36 (1H, br s), 2.49 (1H, ddd, J=14.0, 10.0, 5.0 Hz), 2.23 (1H, m), 2.05 (1H, br t, J=5.5 Hz), 1.98 (1H, m), 1.84 (1H, m), 1.73 (1H, d, J=10.0 Hz), 1.21 (3H, s), 0.92 (3H, s). 13C-NMR δ: 154.3, 137.1, 135.8, 130.9, 128.7, 128.4, 128.3, 128.0, 126.5, 79.1, 76.2, 55.2, 48.4, 40.3, 39.5, 33.3, 26.9, 24.6, 24.0. HRMS m/z: Calcd for C23H27NO2S (M+) 381.1762, Found: 381.1776. cis-31: a colorless oil. IR ν max cm-1: 3431, 2922, 1454. 1H-NMR δ: 7.50-7.47 (2H, m), 7.34-7.23 (9H, m), 4.87 (2H, s), 4.27 (1H, dd, J=10.0, 7.0 Hz), 3.78 (1H, br s), 2.56 (1H, m), 2.27 (1H, m), 2.23 (1H, br t, J=7.0 Hz), 2.03 (1H, ddd, J=14.0, 7.0, 2.5 Hz), 1.95 (1H, m), 1.56 (1H, d, J=10.0 Hz), 1.23 (3H, s), 0.87 (3H, s). 13C-NMR δ: 153.2, 137.3, 134.9, 132.8, 128.9, 128.5, 128.3, 127.9, 127.4, 76.0, 75.3, 51.5, 47.7, 41.1, 38.3, 37.0, 27.7, 27.6, 23.2. HRMS m/z: Calcd for C23H27NO2S (M+) 381.1762, Found: 381.1781. Hydroxysulfenylation reaction of oxime ether 26.

To a solution of oxime ether 26 (82 mg, 0.3 mmol) in CH2Cl2 (6 mL) were added thiophenol (123 mg, 4.0 mmol) and Et3B (1.0 M in hexane, 0.3 mL, 0.3 mmol) under dry O2 at room temperature. After being stirred at the same temperature for 15 h, the reaction mixture was concentrated under reduced pressure. Purification of the residue by medium-pressure column chromatography (hexane:AcOEt = 10:1–4:1) afforded the corresponding hydroxysulfide 32 (69 mg, 58%). 5-(1-Hydroxy-1-methylethyl)-2-hydroxy-2-methyl-3-phenylthiocyclohexenone (E)-O-(Phenylmethyl)oxime (32).

NOBn

PhS

MeOH

32

Me

MeHO

a colorless oil. IR ν max cm-1: 3401, 2972, 1366. 1H-NMR δ: 7.44-7.19 (10H, m), 5.14 (2H, s), 3.63 (1H, dd, J=5.0, 4.0 Hz), 3.07 (1H, ddd, J=14.0, 5.0, 1.5 Hz), 2.43 (1H, br s), 2.29 (1H, dd, J=14.0, 11.0 Hz), 2.19 (1H, ddd, J=14.0, 11.0, 4.0 Hz), 1.95 (1H, tt, J=11.0, 5.0 Hz), 1.75 (1H, ddd, J=14.0, 5.0, 1.5 Hz), 1.65 (1H, br s), 1.55 (3H, s), 1.14 (3H, s), 1.11 (3H, s). 13C-NMR δ: 160.4, 138.0, 135.3, 132.1, 129.0, 128.3, 128.2, 127.8, 127.0, 76.0, 74.1, 72.6, 57.2, 42.2, 28.0, 27.9, 27.2, 24.4, 22.3. HRMS m/z: Calcd for C23H29NO3S (M+) 399.1868, Found: 399.1866. Hydroxysulfenylation reaction of oxime ether 27.

To a solution of oxime ether 27 (128 mg, 0.5 mmol) in CH2Cl2 (6 mL) were added thiophenol (248 mg, 2.25 mmol) and Et3B (1.0 M in hexane, 0.5 mL, 0.5 mmol) under dry O2 at room temperature. After being stirred at the same temperature for 15 h, the reaction mixture was concentrated under reduced pressure. Purification of the residue by medium-pressure column chromatography (hexane:AcOEt = 10:1–4:1) afforded the corresponding hydroxysulfide 34 (121 mg, 50%). 2-Hydroxy-2-metyl-5-[1-methyl-2-phenylthioethyl]-3-phenylthiocyclohexanone (E)-O-(Phenylmethyl)oxime (34).

NOBn

PhS

OHMe

34

Me

SPh

The hydroxysulfide 34 was obtained as a 1:1 mixture of diastereoisomers concerning stereocenter on the side chain. a colorless oil. IR ν max cm-1: 3434, 2928, 1369. 1H-NMR (500 MHz) δ: 7.49-7.11 (15H, m), 5.14-5.08 (2H, m), 3.34 (1H, ddd, J=9.0, 4.0, 2.5 Hz), 3.14 (1/2H, br s), 3.07 (1/2H, br s), 2.99 (1/2H, dd, J=12.0, 4.0 Hz), 2.86 (1/2H, dd, J=12.0, 4.0 Hz), 2.78

12

(1/2H, dd, J=12.0, 8.0 Hz), 2.77 (1/2H, dd, J=15.0, 5.0 Hz), 2.71 (1/2H, m), 2.53 (1/2H, dd, J=12.0, 8.0 Hz), 2.53 (1/2H, dd, J=14.0, 5.0 Hz), 2.45 (1/2H, dd, J=14.0, 5.0 Hz), 2.13 (1H, m), 2.02 (1H, m), 1.71-1.56 (2H, m), 1.51 (3H, s), 1.02 (3/2H, d, J=7.0 Hz), 0.85 (3/2H, d, J=7.0 Hz). 13C-NMR (125 MHz) δ: 160.0, 160.0, 137.6, 137.4, 137.3, 136.9, 135.1, 135.0, 132.8, 132.7, 129.2, 129.0, 128.9 (2C), 128.8, 128.4 (2C), 128.3, 127.9 (2C), 127.3, 125.8, 125.6, 76.3, 76.2, 74.4, 74.3, 57.5, 57.4, 39.2, 38.8, 37.2, 36.9, 34.4, 34.2, 31.7, 30.9, 25.4, 24.5, 23.8, 23.7, 17.1, 16.2. Three peaks of 13C NMR were missing due to overlap. HRMS m/z: Calcd for C29H33NO2S2 (M+) 491.1953, Found: 491.1956. 2-Hydroxy-2-methyl-5-(1-methylethenyl)-3-phenylthiocyclohexanone (E)-O-(Phenylmethyl)oxime (33).

NOBn

PhS

OHMe

33

Me

a colorless oil. IR ν max cm-1: 3437, 2931. 1H-NMR (500 MHz) δ: 7.46-7.21 (10H, m), 5.14 (1H, d, J=12.0 Hz), 5.12 (1H, d, J=12.0 Hz), 4.73 (2H, br s), 3.41 (1H, br s), 3.38 (1H, dd, J=10.0, 3.0 Hz), 3.05 (1H, ddd, J=15.0, 5.0, 1.5 Hz), 2.55 (1H, br quint, J=5.0 Hz), 2.44 (1H, dd, J=15.0, 5.0 Hz), 2.20 (1H, m), 1.82 (1H, ddd, J=14.0, 10.0, 5.0 Hz), 1.55 (3H, s), 1.51 (3H, s). 13C-NMR (125 MHz) δ: 160.4, 145.7, 137.4, 135.2, 132.2, 128.9, 128.4 (2C), 127.9, 127.0, 111.1, 76.2, 74.3, 55.9, 39.4, 32.4, 25.6, 23.9, 21.6. HRMS m/z: Calcd for C23H27NO2S (M+) 381.1762, Found: 381.1771. Transformation of anti-13a into lactam cis-16. To a solution of β-hydroxysulfide anti-13a (500 mg, 1.39 mmol) in ethanolic HCl (0.1 M, 50 mL) was added NaBH3CN (175 mg, 2.78 mmol) at room temperature. After the reaction mixture was stirred at the same temperature for 5 h, additionally NaBH3CN (175 mg, 2.78 mmol) was added. After being stirred at the same temperature for 24 h, the reaction mixture was neutralized with saturated aqueous NaHCO3 and then extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. Purification of the residue by medium-pressure column chromatography (hexane:AcOEt = 4:1–2:1) afforded the desired amine (366 mg, 73%) as a colorless oil. To a solution of the amine (50 mg, 0.14 mmol) in CH2Cl2 (5 mL) were added TBDMSOTf (0.06 mL, 0.35 mmol) and 2,6-lutidine (0.04 mL, 0.35 mmol) under N2 atmosphere at room temperature. After the reaction mixture was stirred at the same temperature for 24 h, TBDMSOTf (0.06 mL, 0.35 mmol) and 2,6-lutidine (0.04 mL, 0.35 mmol) were additionally added to complete the reaction. After being stirred at the same temperature for 12 h, the reaction mixture was diluted with H2O and then extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. Purification of the residue by medium-pressure column chromatography (hexane:AcOEt = 10:1–4:1) afforded the silyl ether (46 mg, 75%) as a colorless oil.

To a solution of the silyl ether (207 mg, 0.43 mmol) in toluene (14 mL) was added p-TsOH (7.0 mg, 0.04 mmol) at room temperature. After being stirred at reflux under N2 atmosphere for 7 h, the reaction mixture was diluted with H2O and then extracted with CHCl3. The organic phase was dried over MgSO4 and concentrated under reduced pressure. Purification of the residue by medium-pressure column chromatography (hexane:AcOEt = 4:1–2:1) afforded cis-16 (111 mg, 60%) as a colorless oil.

According to similar procedure for transformation of anti-13a into cis-16, trans-16 was obtained from syn-13a. 4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-1-phenylmethoxy-3-phenylthio-2-pyrrolidinone (16).

NOBn

O

OTBSPhS

NOBn

O

OTBSPhS

cis-16 trans-16 cis-16: a colorless oil. IR ν max cm-1: 1715. 1H-NMR (300 MHz) δ: 7.64-7.59 (2H, m), 7.44-7.33 (5H, m), 7.31-7.19 (3H, m), 5.01 (1H, d, J=11.0 Hz), 4.89 (1H, d, J=11.0 Hz), 4.46 (1H, dq, J=5.0, 3.0 Hz), 3.75 (1H, d, J=6.0 Hz), 3.42 (1H, dd, J=9.0, 5.0 Hz), 3.17 (1H, dd, J=9.0, 3.0 Hz), 0.90 (9H, s), 0.11 (3H, s), 0.03 (3H, s). 13C-NMR (75 MHz) δ: 167.2, 134.9, 134.7, 131.8, 129.3, 128.7, 128.6, 128.4, 127.0, 76.7, 65.8, 54.5, 53.5, 25.6, 18.0, -5.1, -5.2. HRMS m/z: Calcd for C23H31NO3SSi (M+) 429.1794, Found: 429.1818. trans-16: a colorless oil. IR ν max cm-1: 2928, 1720. 1H-NMR (500 MHz) δ: 7.81-7.30 (10H, m), 4.95, 4.88 (2H, AB q, J=11.0 Hz), 4.15 (1H, dt, J=6.0, 4.0 Hz), 3.51 (1H, d, J=4.0 Hz), 3.19 (1H, dd, J=9.0, 6.0 Hz), 3.05 (1H, dd, J=9.0, 4.0 Hz), 0.82 (9H, s), 0.07 (3H, s), 0.04 (3H, s). 13C-NMR (75 MHz) δ: 166.4, 134.9, 133.8, 132.1, 129.7, 129.2, 128.9, 128.6, 128.5, 76.9, 69.3, 54.8, 54.7, 25.6, 17.8, -4.8, -5.0. HRMS m/z: Calcd for C23H31NO3SSi (M+) 429.1794, Found: 429.1820. Reaction of PhSBEt2 with TEMPO. To a hexane solution of Et3B (1.0 M in hexane, 0.5 mL, 0.5 mmol) was added thiophenol (55 mg, 0.5 mmol) to generate PhSBEt2 at room temperature. To the resulting solution was added TEMPO (155 mg, 1.0 mmol) and then the reaction mixture was stirred at the same temperature for 15 h. After evaporation of solvent, the residue was purified by medium-pressure column chromatography (hexane:AcOEt = 10:1) to form (PhS)2 (20.4 mg, 38%) and 18 (25.5 mg, 20%).

13

2,2,6,6-Tetramethyl-1-(phenylthiooxy)piperidine (18).

NO

SPh 18 a colorless oil. IR ν max cm-1: 2934, 1472, 1442. 1H-NMR δ: 7.70-7.67 (2H, m), 7.46-7.42 (2H, m), 7.38 (1H, tt, J=7.5, 1.5 Hz), 1.90-1.32 (6H, br m), 1.67 (3H, br s), 1.57 (3H, br s), 1.51 (3H, br s), 0.91 (3H, br s). 13C-NMR δ: 150.3, 129.3, 128.5, 126.0, 61.3, 58.8, 43.5, 41.4, 35.4, 32.6, 28.8, 28.0, 17.3. HRMS m/z: Calcd for C15H23NOS (M+) 265.1500, Found: 265.1512. Crossover reaction of 10 and 20a. To a solution of oxime ethers 10 (57.6 mg, 0.3 mmol) and 20a (70 mg, 0.3 mmol) in CH2Cl2 (8 mL) were added thiophenol (116 mg, 3.5 mmol) and Et3B (1.0 M in hexane, 0.15 mL, 0.15 mmol) under dry air atmosphere at room temperature. After being stirred at the same temperature for 15 h, the reaction mixture was concentrated under reduced pressure. Purification of the residue by medium-pressure column chromatography (hexane:AcOEt = 10:1–4:1) afforded the corresponding β-hydroxysulfide 13a (80.7 mg, 38%) and β-hydroxysulfide 21a (29.8 mg, 17%). 13C NMR charts of E-20f, 14, 13b-d, 21a-c, 21f, and 28 .

14

15

16

17

18

References [1] K. Gollnick, A. Griesbeck, Tetrahedron 1985, 41, 2057. [2] B. M. Trost, F. D. Toste, J. Am. Chem. Soc. 2003, 125, 3090. [3] J. F. Paquin, C. R. J. Stephenson, C. Defieber, E. M. Carreira, Org. Lett. 2005, 7, 3821. [4] F. Chen, B. Mudryk, T. Cohen, Tetrahedron 1999, 55, 3291. [5] H. Danda, M. M. Hansen, C. H. Heathcock, J. Org. Chem. 1990, 55, 173.

19