stereocontrolled synthesis of the oxathiabicylo[3.3.1 ... · stereocontrolled synthesis of the...

S1

Stereocontrolled Synthesis of the Oxathiabicylo[3.3.1]nonane Core Structure of Tagetitoxin

Hitomi Yamada, Masaatsu Adachi, and Toshio Nishikawa*

Laboratory of Organic Chemistry, Graduate School of Bioagricultural Sciences,

Nagoya University, Chikusa, Nagoya 464-8601, Japan

Supplementary Information

Index

General Experimental………………………………………...…S1-S2

The proposed reaction mechanism for formation of 23…….......S2

Experimental Procedures and Characterization Data………..….S3-S19

Crystal Data and Structure Refinement for 15………………….S20-S21

Spectra………………………………………….…………….....S22-S58

General Experimental

Melting points (mp) were recorded on a Yanaco MP-S3 melting point apparatus and

are not corrected. Optical rotations were measured on a JASCO DIP-370 digital

polarimeter. Infrared spectra (IR) were recorded on a JASCO FT/IR-8300

spectrophotometer and are reported in wave number (cm-1). Proton nuclear magnetic

resonance (1H NMR) spectra were recorded on a Bruker AVANCE-400 (400 MHz) or a

Varian Gemini-2000 (300 MHz) spectrometer. NMR samples were dissolved in CDCl3,

and chemical shifts are reported in ppm relative to the residual undeuterated solvent

(CDCl3 as ! = 7.26 ppm). 1H NMR data are reported as follows; chemical shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broadened,

m = multiplet), coupling constant, and assignment. Carbon nuclear magnetic resonance

(13C NMR) spectra were recorded on a Bruker AVANCE-400 (100 MHz) or a Varian

Gemini-2000 (75 MHz) spectrometer. The samples were dissolved in CDCl3, and

chemical shifts are reported in ppm relative to the solvent (CDCl3 as ! = 77.0 ppm). 1H

Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is © The Royal Society of Chemistry 2013

S2

NMR and 13C NMR spectra were measured at 300 K unless otherwise noted. Elemental

analyses were performed at the Analytical Laboratory of the Graduate School of

Bioagricultural Sciences, Nagoya University. High resolution mass spectra (HRMS)

were recorded on an Applied Biosystems Mariner Biospectrometry Workstation and are

reported in m/z. Reactions were monitored by thin-layer chromatography (TLC) on 0.25

mm silica gel coated glass plate 60 F254 (Merck, #1.05715). Silica gel 60 (particle size

63-200 µm, 70-230 mesh ASTM, Merck Ltd.) and silica gel 60 N (spherical, neutral,

particle size 63-210 µm, Kanto Chemical Co., Inc.) were used for open-column

chromatography. Silica gel 60 (spherical, particle size 40-50 µm, Kanto Chemical Co.,

Inc.) was used for flash column chromatography. Preparative thin-layer

chromatographic separations were carried out on 0.5 mm silica gel coated glass plate 60

F254 (Merck, #1.05744). Unless otherwise noted, non-aqueous reactions were carried out

in oven-dried (120 oC) or flame-dried glassware under nitrogen or argon. Dry CH3CN

was distilled from CaH2. Dry toluene was distilled from sodium. Dry THF, CH2Cl2 and

Et2O were purchased from Kanto Chemical Co., Inc. All other commercially available

reagents were used as received.

The proposed reaction mechanism for formation of 23

The reaction mechanism for the facile formation of the thioacetal 23 is proposed as

described below. First, the aldehyde 21 reacted with benzylamine followed by the

oxidation of a resulting hemiaminal with I2 to give an amide E. The sulfide was then

activated with I2 to generate the sulfonium ion F, which was captured by methanol from

the less-hindered convex face, yielding the observed thioacetal 23.

21

BnNH2I2

MeOH

OMeOOC

OR

H

ONBn

O

S CONHBnH

E (R = Ac or H)

OMeOOC

OR

H

ONBn

O

S CONHBn

F

23

I2

OS

MeOOC

ONBn

O

OR

NHBnO

H

HOMe


S3

Experimental Procedures and Characterization Data

Diol 6: Tri-O-Ac-D-galactal (3) (38.1 g, 140 mmol) was dissolved in CH2Cl2 (466 mL),

and it was cooled to 0 oC under nitrogen. To the solution were added tri-n-butylstannyl

(trimethylsilyl)acetylene (53.5 mL, 146 mmol) and TMSOTf (30.5 mL, 169 mmol).

After being stirred for 0.5 h, the reaction mixture was poured into an ice-cooled

saturated aqueous NaHCO3 (600 mL). The aqueous layer was separated and extracted

with CH2Cl2 (200 mL x 2). The combined extracts were washed with brine, and then

dried over Na2SO4. The solution was concentrated to dryness in vacuo. The residue was

passed through a column packed with silica gel, and then concentrated to dryness in

vacuo. The residue was used for the next reaction without further purification.

"-Glycoside 5: Rf = 0.69 (hexane/EtOAc 2:3); 1H NMR (300 MHz, CDCl3) ! 0.16 (9H,

s, SiMe3), 2.06 (3H, s, COCH3), 2.07 (3H, s, COCH3), 4.13 (1H, dd, J = 11.4, 7.2 Hz,

H-2a), 4.28 (1H, dd, J = 11.4, 4.8 Hz, H-2b), 4.33 (1H, ddd, J = 7.2, 4.8, 2.4 Hz, H-1),

5.01 (1H, dd, J = 3.0, 1.2 Hz, H-5), 5.06 (1H, dd, J = 4.8, 2.4 Hz, H-8), 5.98 (1H, ddd, J

= 10.2, 4.8, 1.2 Hz, H-7), 6.04 (1H, dd, J = 10.2, 3.0 Hz, H-6); 13C NMR (75 MHz,

CDCl3) ! -0.4, 20.7, 20.7, 62.7, 63.3, 64.3, 69.6, 92.1, 100.2, 122.4, 132.0, 170.5, 170.8.

The residue was dissolved in MeOH (280 mL), and it was cooled to 0 oC under nitrogen.

To the solution was added NaOMe (3.78 g, 70.0 mmol). After being stirred for 3 h, the

reaction mixture was adjusted to pH 7 with DOWEX® (50Wx8-200, 8.46 g). The

resultant solution was filtered through a paper filter. The filtrate was concentrated to

dryness in vacuo. The residue was washed with pentane (40 mL x 6) to give diol 6 (20.5

g, 133 mmol, 95% in 2 steps) as a white solid.

Rf = 0.10 (hexane/EtOAc 2:3); mp 103-105 oC; [#]D27 -500 (c 0.23, CHCl3); IR (film)

$max 3283, 2942, 2884, 1472, 1457, 1079, 1050, 913, 703 cm-1; 1H NMR (400 MHz,

CDCl3) ! 1.80-2.35 (2H, br s, OH), 2.51 (1H, d, J = 2.4 Hz, C!CH), 3.86 (1H, dd, J =

OHOH

HO6


S4

12.0, 4.8 Hz, H-2a), 3.95 (1H, dd, J = 12.0, 6.4 Hz, H-2b), 3.96 (1H, dd, J = 5.6, 2.0 Hz,

H-8), 4.07 (1H, ddd, J = 6.4, 4.8, 2.0 Hz, H-1), 5.01 (1H, ddd, J = 4.0, 2.4, 2.0 Hz, H-5),

5.95 (1H, dd, J = 10.0, 4.0 Hz, H-6), 6.07 (1H, ddd, J = 10.0, 5.6, 2.0 Hz, H-7); 13C

NMR (100 MHz, CDCl3) ! 62.7, 62.8, 63.9, 73.5, 74.8, 79.5, 126.9, 129.7; Anal. Calcd

for C8H10O3: C, 62.33; H, 6.54. Found: C, 62.33; H, 6.56.

TBS ether 7: Diol 6 (20.5 g, 133 mmol) was dissolved in CH2Cl2 (1.33 L), and it was

cooled to 0 oC under nitrogen. To the solution were added TBSCl (20.0 g, 133 mmol),

triethylamine (28 mL, 200 mmol) and N,N-dimethyl-4-aminopyridine (487 mg, 3.99

mmol). After being stirred for 0.5 h, the reaction mixture was allowed to warm to room

temperature. After being stirred for 14 h, the reaction mixture was cooled to 0 oC. To

the reaction mixture were added TBSCl (6.00 g, 39.8 mmol) and triethylamine (8.4 mL,

60.3 mmol) twice every 7 h. After being stirred at room temperature for 3.5 h, the

reaction mixture was poured into a water-cooled saturated aqueous NH4Cl (1.5 L). The

aqueous layer was separated and extracted with CH2Cl2 (200 mL x 3). The combined

extracts were washed with brine, and then dried over Na2SO4. The solution was

concentrated to dryness in vacuo. The residue was purified by column chromatography

(silica gel, hexane/EtOAc 4:1) to give TBS ether 7 (30.3 g, 113 mmol, 85%) as a

colorless oil.

Rf = 0.63 (hexane/EtOAc 2:3); [#]D27 -262 (c 1.11, CHCl3); IR (film) $max 3447, 3309,

2954, 2929, 2885, 2857, 1472, 1255, 1109, 1097, 836 cm-1; 1H NMR (400 MHz,

CDCl3) ! 0.08 (6H, s, SiMe2CMe3), 0.89 (9H, s, SiMe2CMe3), 2.23 (1H, br d, J = 8.0

Hz, OH), 2.47 (1H, d, J = 2.4 Hz, C!CH), 3.83 (1H, dd, J = 10.4, 6.0 Hz, H-2a), 3.87

(1H, dd, J = 10.4, 6.0 Hz, H-2b), 3.92-3.97 (1H, m, H-8), 4.00 (1H, ddd, J = 6.0, 6.0,

2.0 Hz, H-1), 4.95 (1H, ddd, J = 3.6, 2.4, 2.0 Hz, H-5), 5.90 (1H, dd, J = 10.0, 3.6 Hz,

H-6), 6.06 (1H, ddd, J = 10.0, 5.2, 2.0 Hz, H-7); 13C NMR (100 MHz, CDCl3) ! -5.5,

OTBSOH

HO7


S5

-5.4, 18.2, 25.8, 61.8, 62.5, 63.8, 73.5, 74.3, 79.9, 127.1, 129.4; HRMS (ESI) for

C14H25O3Si (M+H), calcd 269.1573, found 269.1588.

Carbamate 8: TBS ether 7 (30.3 g, 113 mmol) was dissolved in CH2Cl2 (565 mL), and

it was cooled to 0 oC under nitrogen. To the solution was added trichloroacetyl

isocyanate (14.8 mL, 124 mmol) over 3 min. After being stirred for 0.5 h, the reaction

mixture was concentrated to dryness in vacuo at 5 oC. The residue was dissolved in

MeOH (452 mL), and it was cooled to 0 oC under nitrogen. To the solution were added

water (113 mL) and potassium carbonate (46.8 g, 339 mmol). After being stirred for 5 h,

the reaction mixture was concentrated to dryness in vacuo. The residue was dissolved in

CH2Cl2 and washed with brine, and then dried over Na2SO4. The solution was


(silica gel, hexane/EtOAc 4:1) to give carbamate 8 (25.6 g, 82.2 mmol, 73%) as a white

solid.

Rf = 0.54 (hexane/EtOAc 3:2); mp 116-117 oC; [#]D26 -308 (c 1.00, CHCl3); IR (film)

$max 3461, 3330, 3304, 3272, 3192, 2952, 2928, 2884, 2857, 1728, 1599, 1386, 1314,

1111, 1022, 837 cm-1; 1H NMR (400 MHz, CDCl3) ! 0.05 (3H, s, SiMe2CMe3), 0.06

(3H, s, SiMe2CMe3), 0.87 (9H, s, SiMe2CMe3), 2.49 (1H, d, J = 2.4 Hz, C!CH), 3.72

(1H, dd, J = 10.8, 6.4 Hz, H-2a), 3.77 (1H, dd, J = 10.8, 6.4 Hz, H-2b), 4.14 (1H, ddd, J

= 6.4, 6.4, 2.0 Hz, H-1), 4.96-5.02 (4H, m, H-5, H-8, NH2), 5.99 (1H, dd, J = 10.0, 4.0

Hz, H-6), 6.09 (1H, ddd, J = 10.0, 5.6, 2.0 Hz, H-7); 13C NMR (100 MHz, CDCl3) !

-5.6, -5.4, 18.1, 25.8, 61.5, 63.5, 63.7, 72.6, 74.7, 79.5, 123.7, 131.2, 156.3; Anal. Calcd

for C15H25NO4Si: C, 57.85; H, 8.09; N, 4.50. Found: C, 57.75; H, 8.04; N, 4.47.

OTBSOH

O

NH2O8


S6

Aziridine 9: Carbamate 8 (12.4 g, 39.8 mmol), iodosobenzene (26.1 g, 119 mmol) and

activated MS-4Å (24.8 g) were dissolved in CH2Cl2 (398 mL) under nitrogen. To the

solution was added rhodium(II) diacetate dimer (702 mg, 1.59 mmol). After being

stirred for 22 h, to the reaction mixture was added rhodium(II) diacetate dimer (70.2 mg,

0.159 mmol). After being stirred for 11 h, to the reaction mixture was added

iodosobenzene (0.60 g, 2.73 mmol). After being stirred for 37 h, the reaction mixture

was filtered through a paper filter. The filtrate was concentrated to dryness in vacuo.

The residue was purified by column chromatography (silica gel, hexane/EtOAc 4:1) to

give aziridine 9 (8.66 g, 28.0 mmol, 70%) as a colorless oil.

Rf = 0.29 (hexane/EtOAc 1:1); [#]D26 -99.0 (c 0.690, CHCl3); IR (film) $max 3269, 2954,

2930, 2886, 2857, 1777, 1335, 1259, 1104, 1006, 839, 780 cm-1; 1H NMR (400 MHz,

CDCl3) ! 0.05 (6H, s, SiMe2CMe3), 0.87 (9H, s, SiMe2CMe3), 2.65 (1H, d, J = 2.0 Hz,

C!CH), 2.97 (1H, d, J = 4.8 Hz, H-6), 3.52-3.57 (2H, m, H-2a, H-7), 3.63 (1H, dd, J =

10.0, 5.6 Hz, H-2b), 3.82 (1H, dd, J = 8.8, 6.0 Hz, H-1), 4.86 (1H, d, J = 6.0 Hz, H-8),

5.17 (1H, br s, H-5); 13C NMR (100 MHz, CDCl3) ! -5.6, -5.5, 18.1, 25.7, 40.4, 45.2,

60.6, 61.8, 68.8, 69.6, 76.6, 78.2, 163.6; Anal. Calcd for C15H23NO4Si: C, 58.22; H,

7.49; N, 4.53. Found: C, 58.23; H, 7.37; N, 4.48.

Acetate 10: Aziridine 9 (4.22 g, 13.6 mmol) was dissolved in acetic acid (136 mL), and

it was allowed to warm to 80 oC under nitrogen. After being stirred at the same

temperature for 9.5 h, to the reaction mixture was added water (130 mL) at 0 oC. The

OTBSOH

ON

O9

OTBSOH

ONH

O10

OAc


S7

resultant solution was extracted with CH2Cl2 (50 mL x 3). The combined extracts were

poured into an ice-cooled saturated aqueous NaHCO3 (500 mL). The aqueous layer was

separated and extracted with CH2Cl2 (50 mL x 3). The combined extracts were washed

with brine, and then dried over Na2SO4. The solution was concentrated to dryness in

vacuo. The residue was purified by column chromatography (silica gel, hexane/EtOAc

7:3 " 1:1) to give acetate 10 (3.69 g, 9.99 mmol, 73%) as an amorphous solid.

Rf = 0.56 (hexane/EtOAc 1:1); [#]D29 +30.8 (c 1.20, CHCl3); IR (film) $max 3275, 2954,

2930, 2886, 2857, 1767, 1374, 1254, 1229, 1213, 1104, 1061, 839, 780 cm-1; 1H NMR

(400 MHz, CDCl3) ! 0.07 (6H, s, SiMe2CMe3), 0.88 (9H, s, SiMe2CMe3), 2.13 (3H, s,

COCH3), 2.55 (1H, d, J = 2.4 Hz, C!CH), 3.81 (1H, dd, J = 10.0, 6.4 Hz, H-2a), 3.87

(1H, dd, J = 10.0, 7.2 Hz, H-2b), 3.92 (1H, dd, J = 7.6, 6.8 Hz, H-7), 4.25 (1H, ddd, J =

7.2, 6.4, 2.4 Hz, H-1), 4.69 (1H, dd, J = 6.8, 2.4 Hz, H-8), 4.84 (1H, dd, J = 7.6, 5.6 Hz,

H-6), 4.92 (1H, dd, J = 5.6, 2.4 Hz, H-5), 6.63 (1H, s, NH); 13C NMR (100 MHz,

CDCl3) ! -5.5, -5.4, 18.2, 20.7, 25.8, 52.6, 61.5, 63.5, 70.6, 71.7, 74.4, 76.6, 77.8, 159.4,

170.2; HRMS (ESI) for C17H28NO6Si (M+H), calcd 370.1686, found 370.1684.

[11194]

Alcohol 11: Acetate 10 (4.57 g, 12.4 mmol), benzyl bromide (2.4 mL, 19.8 mmol) and

tetrabutylammonium iodide (458 mg, 1.24 mmol) were dissolved in DMF (124 mL),

and it was cooled to 0 oC under nitrogen. To the solution was added sodium hydride

(495 mg, 12.6 mmol). After being stirred for 1 h, the reaction mixture was poured into a

water-cooled saturated aqueous NH4Cl (200 mL). The aqueous layer was separated and

extracted with EtOAc (50 mL x 3). The combined extracts were washed with brine, and

then dried over Na2SO4. The solution was concentrated to dryness in vacuo. The residue

was purified by column chromatography (silica gel, hexane/EtOAc 4:1) to give benzyl

OHOH

ONBn

O11

OAc


S8

carbamate S1 (5.16 g, 11.2 mmol, 90%) as a white solid.

Rf = 0.56 (hexane/EtOAc 3:2); mp 107-108 oC; [#]D26 +17.2 (c 1.01, CHCl3); IR (film)

$max 3267, 2954, 2930, 2886, 2857, 1758, 1416, 1218, 1095, 839 cm-1; 1H NMR (400

MHz, CDCl3) ! 0.08 (6H, s, SiMe2CMe3), 0.89 (9H, s, SiMe2CMe3), 2.06 (3H, s,

COCH3), 2.48 (1H, d, J = 2.0 Hz, C!CH), 3.80 (1H, dd, J = 10.0, 6.0 Hz, H-2a), 3.83

(1H, dd, J = 7.6, 6.4 Hz, H-7), 3.87 (1H, dd, J = 10.0, 7.2 Hz, H-2b), 4.19 (1H, ddd, J

= 7.2, 6.8, 2.4 Hz, H-1), 4.19 (1H, d, J = 15.2 Hz, PhCH2), 4.56 (1H, dd, J = 7.6, 2.4 Hz,

H-8), 4.77 (1H, d, J = 15.2 Hz, PhCH2), 4.88 (1H, dd, J = 5.2, 2.0 Hz, H-5), 4.99 (1H,

dd, J = 6.4, 5.2 Hz, H-6), 7.27-7.40 (5H, m, aromatic); 13C NMR (100 MHz, CDCl3) !

-5.5, -5.4, 18.2, 20.7, 25.8, 47.3, 54.0, 61.5, 63.3, 69.9, 70.7, 71.7, 76.8, 77.4, 127.9,

128.1, 128.9, 135.9, 157.4, 169.4; Anal. Calcd for C24H33NO6Si: C, 62.72; H, 7.24; N,

3.05. Found: C, 62.70; H, 6.96; N, 3.08.

Benzyl carbamate S1 (5.16 g, 11.2 mmol) was dissolved in THF (75 mL), and it was

cooled to 0 oC under nitrogen. To the solution were added acetic acid (765 µL, 13.4

mmol) and TBAF (1.0 M solution in THF; 12.3 mL, 12.3 mmol). After being stirred at

room temperature for 20 h, the reaction mixture was poured into an ice-cooled water

(100 mL). The aqueous layer was separated and extracted with EtOAc (30 mL x 3). The

combined extracts were washed with brine, and then dried over Na2SO4. The solution

was concentrated to dryness in vacuo. The residue was purified by column

chromatography (silica gel, hexane/EtOAc 2:3) to give alcohol 11 (3.00 g, 8.69 mmol,

78%) as a colorless oil.


2938, 1751, 1419, 1219, 1052, 704 cm-1; 1H NMR (400 MHz, CDCl3) ! 2.04 (3H, s,

COCH3), 2.54 (1H, d, J = 2.0 Hz, C!CH), 2.69 (1H, br s, OH), 3.81-3.92 (3H, m, H-2,

H-7), 4.21 (1H, d, J = 15.2 Hz, PhCH2), 4.29 (1H, ddd, J = 7.6, 5.6, 2.4 Hz, H-1), 4.59

(1H, dd, J = 7.2, 2.4 Hz, H-8), 4.74 (1H, d, J = 15.2 Hz, PhCH2), 4.93 (1H, dd, J = 5.6,

2.0 Hz, H-5), 4.98 (1H, dd, J = 6.4, 5.6 Hz, H-6), 7.26-7.39 (5H, m, aromatic); 13C

NMR (100 MHz, CDCl3) ! 20.6, 47.3, 54.1, 61.2, 63.3, 70.1, 70.4, 72.1, 76.4, 78.0,


S9

127.7, 128.0, 128.9, 135.8, 157.3, 169.4; Anal. Calcd for C18H19NO6: C, 62.60; H, 5.55;

N, 4.06. Found: C, 62.57; H, 5.45; N, 3.90.

Selenide 12: Alcohol 11 (3.00 g, 8.69 mmol) was dissolved in CH3CN (43 mL), and it

was cooled to -20 oC under nitrogen. To the solution were added 2,6-lutidine (3.3 mL,

28.7 mmol) and trifluoromethanesulfonic anhydride (1.6 mL, 9.56 mmol). After being

stirred for 0.5 h, the reaction mixture was diluted with Et2O (30 mL) and poured into an

ice-cooled saturated aqueous NaHCO3 (80 mL). The aqueous layer was separated and

extracted with Et2O (30 mL x 3). The combined extracts were washed with brine, and


was purified by column chromatography (silica gel, hexane/Et2O 1:1 " 3:7) to give

triflate S2 (3.86 g, 8.09 mmol, 93%) as a colorless oil.


3033, 2979, 2931, 1761, 1417, 1372, 1246, 1215, 1145, 963, 704 cm-1; 1H NMR (400

MHz, CDCl3) ! 2.08 (3H, s, COCH3), 2.56 (1H, d, J = 2.4 Hz, C!CH), 3.91 (1H, dd, J

= 7.6, 6.8 Hz, H-7), 4.22 (1H, d, J = 15.2 Hz, PhCH2), 4.49-4.53 (1H, m, H-1), 4.55 (1H,

dd, J = 7.6, 2.4 Hz, H-8), 4.66-4.70 (2H, m, H-2), 4.75 (1H, d, J = 15.2 Hz, PhCH2),

4.93 (1H, dd, J = 5.2, 2.4 Hz, H-5), 5.03 (1H, dd, J = 6.8, 5.2 Hz, H-6), 7.27-7.40 (5H,

m, aromatic); 13C NMR (100 MHz, CDCl3) ! 20.7, 47.5, 53.9, 63.7, 68.1, 69.0, 70.7,

73.2, 75.7, 78.6, 118.5 (q, JC-F = 317 Hz), 127.9, 128.4, 129.1, 135.4, 156.5, 169.2;

HRMS (ESI) for C19H19F3NO8S (M+H), calcd 478.0783, found 478.0778.

Diphenyldiselenide (2.78 g, 8.90 mmol) was dissolved in THF (45 mL), and it was

cooled to -20 oC under argon. To the solution was added n-butyllithium (1.64 M

solution in hexane; 5.7 mL, 9.30 mmol). In another flask, triflate S2 (3.86 g, 8.09

mmol) was dissolved in THF (40 mL), and it was cooled to -20 oC under argon. To the

OPhSeH

ONBn

O12

OAc


S10

solution was added the solution of lithium selenide over 40 min. After being stirred for

2 h, the reaction mixture was poured into a water-cooled saturated aqueous NH4Cl (100

mL). The aqueous layer was separated and extracted with EtOAc (20 mL x 3). The

combined extracts were washed with brine, and then dried over Na2SO4. The solution

was concentrated to dryness in vacuo. The residue was purified by column

chromatography (silica gel, hexane/EtOAc 4:1) to give selenide 12 (3.38 g, 6.98 mmol,

86%) as a colorless oil.

Rf = 0.56 (hexane/EtOAc 1:1); [#]D27 -22.6 (c 1.08, CHCl3); IR (film) $max 3281, 3060,

3032, 2940, 1758, 1438, 1416, 1219, 1203, 1071, 1051, 739 cm-1; 1H NMR (400 MHz,

CDCl3) ! 2.02 (3H, s, COCH3), 2.42 (1H, d, J = 2.4 Hz, C!CH), 3.15 (1H, dd, J = 12.8,

8.0 Hz, H-2a), 3.21 (1H, dd, J = 12.8, 6.8 Hz, H-2b), 3.81 (1H, dd, J = 7.2, 7.2 Hz, H-7),

4.17 (1H, d, J = 15.2 Hz, PhCH2), 4.23 (1H, ddd, J = 8.0, 6.8, 2.0 Hz, H-1), 4.66 (1H,

dd, J = 7.2, 2.0 Hz, H-8), 4.76 (1H, d, J = 15.2 Hz, PhCH2), 4.89 (1H, dd, J = 5.6, 2.4

Hz, H-5), 4.96 (1H, dd, J = 7.2, 5.6 Hz, H-6), 7.22-7.38 (8H, m, aromatic), 7.49-7.54

(2H, m, aromatic); 13C NMR (100 MHz, CDCl3) ! 20.7, 26.5, 47.3, 54.2, 63.7, 69.5,

69.9, 72.5, 76.4, 77.8, 127.3, 127.8, 128.1, 128.9, 129.1, 129.1, 132.9, 135.8, 157.0,

169.2; Anal. Calcd for C24H23NO5Se: C, 59.51; H, 4.79; N, 2.89. Found: C, 59.51; H,

4.77; N, 2.76.

Exo-glycal 13: Selenide 12 (3.38 g, 6.35 mmol) was dissolved in CH2Cl2 (64 mL), it

was cooled to -78 oC under nitrogen. To the solution was added MCPBA (1.21 g, 6.99

mmol), and it was allowed to warm to -40 oC over 0.6 h. After being stirred for 2 h, to

the reaction mixture was added MCPBA (0.440 g, 2.55 mmol). After being stirred for 1

h, the reaction mixture was poured into an ice-cooled mixture of saturated aqueous

NaHCO3 (60 mL) and saturated aqueous Na2CO3 (30 mL). The aqueous layer was

O

ONBn

O13

OAc


S11

separated and extracted with CH2Cl2 (30 mL x 3). The combined extracts were washed



The residue was dissolved in THF (64 mL), and it was cooled to 0 oC under nitrogen.

To the solution was added NaHCO3 (2.67 g, 31.8 mmol), and the reaction mixture was

allowed to warm to 65 oC. After being stirred for 2 h, the reaction mixture was poured

into an ice-cooled saturated aqueous NaHCO3 (80 mL). The aqueous layer was

separated and extracted with Et2O (30 mL x 3). The combined extracts were washed


vacuo. The residue was purified by column chromatography (silica gel, hexane/Et2O 7:3

" 1:1) to give exo-glycal 13 (2.09 g, 5.57 mmol, 88% in 2 steps) as an amorphous

solid.

Rf = 0.61 (Et2O); [#]D28 -18.2 (c 1.23, CHCl3); IR (film) $max 3284, 3064, 3033, 2960,

2938, 1759, 1657, 1456, 1438, 1417, 1376, 1227, 1084, 1061, 757, 704 cm-1; 1H NMR

(400 MHz, CDCl3) ! 2.08 (3H, s, COCH3), 2.54 (1H, d, J = 1.6 Hz, C!CH), 3.83 (1H,

br dd, J = 8.4, 2.0 Hz, H-7), 4.25 (1H, d, J = 15.2 Hz, PhCH2), 4.56 (1H, d, J = 1.6 Hz,

H-2a), 4.77 (1H, d, J = 15.2 Hz, PhCH2), 4.81 (1H, d, J = 1.6 Hz, H-2b), 4.87 (1H, d, J

= 8.4 Hz, H-8), 4.95-4.99 (2H, m, H-5, H-6), 7.27-7.37 (5H, m, aromatic); 13C NMR

(100 MHz, CDCl3) ! 20.6, 46.5, 54.6, 63.3, 68.4, 70.9, 76.1, 76.9, 98.6, 128.2, 128.2,

128.9, 135.5, 148.8, 156.4, 169.7; HRMS (ESI) for C18H18NO5 (M+H), calcd 328.1185,

found 328.1199.

Spiro-epoxyacetal 14: Exo-glycal 13 (622 mg, 1.66 mmol) and NaHCO3 (837 mg, 9.96

mmol) were dissolved in CH2Cl2 (20 mL), and it was cooled to 0 oC under nitrogen. To

O

ONBn

O14

OAc

O


S12

the solution was added MCPBA (573 mg, 3.32 mmol). After being stirred at room

temperature for 5 h, the reaction mixture was poured into an ice-cooled mixture of

saturated aqueous NaHCO3 (10 mL) and saturated aqueous Na2SO3 (10 mL). The

aqueous layer was separated and extracted with CH2Cl2 (10 mL x 3). The combined

extracts were washed with brine, and then dried over Na2SO4. The solution was


(neutral silica gel, hexane/Et2O 2:3 " 1:4) to give spiro-epoxyacetal 14 (640 mg, 1.64

mmol, 98%, ca. 3:2 diastereomeric mixture) as an amorphous solid.

Rf = 0.46 (Et2O); [#]D27 +8.6 (c 0.28, CHCl3); IR (film) $max 3376, 1768, 1417, 1224,

1059, 1034, 704 cm-1; 1H NMR (400 MHz, CDCl3) ! 2.10 (1.2H, s, COCH3), 2.12

(1.8H, s, COCH3), 2.47 (0.4H, d, J = 2.4 Hz, C!CH), 2.54 (0.6H, d, J = 2.0 Hz, C!CH),

2.92 (0.6H, d, J = 4.0 Hz, H-2a), 3.00 (0.4H, d, J = 4.0 Hz, H-2a), 3.10 (0.6H, d, J = 4.0

Hz, H-2b), 3.11 (0.4H, d, J = 4.0 Hz, H-2b), 4.03 (0.4H, dd, J = 7.6, 4.0 Hz, H-7), 4.08

(0.6H, dd, J = 8.0, 5.2 Hz, H-7), 4.30 (0.6H, d, J = 15.2 Hz, PhCH2), 4.34 (0.6H, d, J =

8.0 Hz, H-8), 4.49 (0.4H, d, J = 15.6 Hz, PhCH2), 4.56 (0.4H, d, J = 15.6 Hz, PhCH2),

4.73-4.75 (0.4H, m, H-5), 4.76 (0.6H, d, J = 15.6 Hz, PhCH2), 4.89 (0.6H, dd, J = 4.0,

2.0 Hz, H-5), 4.95 (0.4H, d, J = 7.6 Hz, H-8), 5.15 (0.6H, dd, J = 5.2, 4.0 Hz, H-6), 5.32

(0.4H, dd, J = 4.0, 3.2 Hz, H-6), 7.29-7.42 (5H, m, aromatic); 13C NMR (100 MHz,

CDCl3) ! 20.5, 20.6, 47.5, 47.8, 49.5, 49.8, 54.2, 56.7, 63.2, 63.3, 65.0, 66.8, 67.9, 73.2,

76.2, 76.8, 77.1, 79.4, 80.4, 128.1, 128.2, 128.3, 128.5, 129.0, 129.1, 135.2, 135.3,

156.6, 157.7, 169.2, 169.6 (one peak missing or overlap); HRMS (ESI) for C18H17NO6

(M+H), calcd 344.1134, found 344.1127.

Nitrile 15: Spiro-epoxyacetal 14 (640 mg, 1.86 mmol) was dissolved in a mixture of

O

ONBn

O15

OAc

HONC


S13

toluene (20 mL) and hexane (10 mL), and it was cooled to 0 oC under argon. To the

solution were added TMSCN (1.15 mL, 9.30 mmol) and iodide (944 mg, 3.72 mmol).

After being stirred for 11 h, the reaction mixture was poured into an ice-cooled

saturated aqueous Na2SO3 (30 mL). The aqueous layer was separated and extracted with

EtOAc (10 mL x 3). The combined extracts were poured into aqueous 1N HCl (50 mL).

After being stirred at room temperature for 10 h, the reaction mixture was poured into

an ice-cooled saturated aqueous NaHCO3 (100 mL). The aqueous layer was separated

and extracted with EtOAc (10 mL x 3). The combined extracts were washed with

saturated aqueous NaHCO3 and brine, and then dried over Na2SO4. The solution was


(silica gel, hexane/EtOAc 7:3 " 9:11) to give nitrile 15 (300 mg, 0.810 mmol, 44%) as

a white solid.

Rf = 0.35 (Et2O); mp 190-191 oC; [#]D27 +21.8 (c 0.945, CHCl3); IR (film) $max 3447,

3288, 3065, 3033, 2929, 1774, 1753, 1399, 1372, 1223, 1084, 1061, 704 cm-1; 1H NMR

(400 MHz, CDCl3) ! 2.11 (3H, s, COCH3), 2.30 (1H, dd, J = 9.6, 5.2 Hz, OH), 2.50 (1H,

d, J = 2.4 Hz, C!CH), 3.86-3.94 (2H, m, H-2a, H-7), 4.06 (1H, dd, J = 12.0, 5.2 Hz,

H-2b), 4.50 (1H, d, J = 15.2 Hz, PhCH2), 4.65 (1H, d, J = 15.2 Hz, PhCH2), 4.72 (1H,

dd, J = 2.4, 2.0 Hz, H-5), 4.78 (1H, d, J = 7.6 Hz, H-8), 5.29 (1H, dd, J = 2.0, 2.0 Hz,

H-6), 7.31-7.45 (5H, m, aromatic); 13C NMR (100 MHz, CDCl3) ! 20.4, 48.3, 56.5, 63.4,

64.5, 65.1, 75.7, 76.5, 76.8, 114.8, 128.5, 128.6, 129.2, 134.9, 156.8, 169.3; HRMS

(ESI) for C19H19N2O6 (M+H), calcd 371.1243, found 371.1237.

Thioacetate 16: Nitrile 15 (268 mg, 0.724 mmol) and 2,6-lutidine (380 µL, 3.26 mmol)

were dissolved in CH3CN (14 mL), and it was cooled to -20 oC under nitrogen. To the

O

ONBn

O16

OAc

NCAcS


S14

solution was added trifluoromethenesulfonic anhydride (180 µL, 1.09 mmol). After

being stirred for 0.2 h, the reaction mixture was poured into an ice-cooled saturated

aqueous NaHCO3 (70 mL). The aqueous layer was separated and extracted with Et2O

(15 mL x 3). The combined extracts were washed with aqueous 1N HCl (x 3), saturated

aqueous NaHCO3 and brine, and then dried over Na2SO4. The solution was concentrated

to dryness in vacuo. The residue was used for the next reaction without further

purification.

The residue was dissolved in DMF (14 mL), and it was cooled to 0 oC under nitrogen.

To the solution were added thioacetic acid (260 µL, 3.62 mmol) and sodium hydride

(85.0 mg, 2.17 mmol). After being stirred at room temperature for 9 h, the reaction

mixture was poured into an ice-cooled saturated aqueous NaHCO3 (100 mL). The

aqueous layer was separated and extracted with EtOAc (5 mL x 3). The resultant

solution was filtered through a paper filter. The filtrate was washed with brine, and then

dried over Na2SO4. The solution was concentrated to dryness in vacuo. The residue was

purified by column chromatography (silica gel, hexane/EtOAc 3:2) to give thioacetate

16 (275 mg, 0.642 mmol, 89% in 2 steps) as an amorphous solid.

Rf = 0.57 (Et2Ox2); [#]D26 -17.4 (c 0.735, CHCl3); IR (film) $max 3284, 1780, 1751,

1701, 1397, 1362, 1221, 1125, 1065, 1047, 704 cm-1; 1H NMR (400 MHz, CDCl3) !

2.12 (3H, s, COCH3), 2.41 (3H, s, SCOCH3), 2.48 (1H, d, J = 2.4 Hz, C!CH), 3.40 (1H,

d, J = 14.0 Hz, H-2a), 3.73 (1H, d, J = 14.0 Hz, H-2b), 3.85 (1H, dd, J = 7.6, 2.4 Hz,

H-7), 4.45 (1H, d, J = 7.6 Hz, H-8), 4.50 (1H, d, J = 15.2 Hz, PhCH2), 4.60 (1H, d, J =

15.2 Hz, PhCH2), 4.66 (1H, dd, J = 2.4, 2.4 Hz, H-5), 5.27 (1H, dd, J = 2.4, 2.4 Hz,

H-6), 7.29-7.43 (5H, m, aromatic); 13C NMR (100 MHz, CDCl3) ! 20.4, 30.3, 36.3, 48.2,

56.7, 63.6, 64.2, 68.6, 75.5, 76.4, 76.7, 114.9, 128.5, 128.6, 129.1, 134.8, 156.6, 169.3,

192.9; HRMS (ESI) for C21H21N2O6S (M+H), calcd 429.1120, found 429.1119.


S15

Vinyl sulfoxide 17: Thioacetate 16 (275 mg, 0.642 mmol), thiophenol (660 µL, 6.42

mmol) and AIBN (53.0 mg, 0.324 mmol) were dissolved in t-BuOH (64 mL) under

argon. The solution was degassed by freeze-thaw cycles and allowed to warm to 100 oC.

After being stirred for 2 h, the reaction mixture was concentrated to dryness in vacuo.

The residue was passed through a column packed with silica gel, and then concentrated

to dryness in vacuo. The residue was used for the next reaction without further

purification.

The residue was dissolved in CH2Cl2 (10 mL), and it was cooled to -78 oC under

nitrogen. To the solution was added MCPBA (99.0 mg, 0.574 mmol), and it was

allowed to warm to -40 oC. After being stirred for 6 h, the reaction mixture was poured

into an ice-cooled mixture of saturated aqueous NaHCO3 (10 mL) and saturated

aqueous Na2SO3 (10 mL). The aqueous layer was separated and extracted with CH2Cl2

(5 mL x 3). The combined extracts were washed with saturated aqueous NaHCO3 and

brine, and then dried over Na2SO4. The solution was concentrated to dryness in vacuo.

The residue was purified by column chromatography (silica gel, hexane/EtOAc 3:2 "

1:4) to give vinyl sulfoxide 17 (221 mg, 0.398 mmol, 62% in 2 steps, ca.

0.42:0.36:0.13:0.09 diastereomeric mixture) as an amorphous solid.

Rf = 0.63 (EtOAc); [#]D26 -21.6 (c 0.960, CHCl3); IR (film) $max 3056, 3033, 2987,

2926, 1779, 1751, 1701, 1396, 1371, 1221, 1117, 1085, 1048, 704 cm-1; 1H NMR (400

MHz, CDCl3) ! 1.85 (1.27H, s, COCH3), 1.99 (1.09H, s, COCH3), 2.03 (0.26H, s,

COCH3), 2.13 (0.38H, s, COCH3), 2.33 (1.09H, s, SCOCH3), 2.35 (1.27H, s, SCOCH3),

2.38 (0.38H, s, SCOCH3), 2.40 (0.26H, s, SCOCH3), 3.39 (0.36H, d, J = 14.0 Hz, H-2a),

3.43 (0.42H, d, J = 14.0 Hz, H-2a), 3.44 (0.09H, d, J = 14.0 Hz, H-2a), 3.50 (0.13H, d, J

ONC

OAc

AcSSPh

H

O

ONBn

O17


S16

= 14.0 Hz, H-2a), 3.63 (0.36H, d, J = 14.0 Hz, H-2b), 3.68 (0.42H, d, J = 14.0 Hz,

H-2b), 3.72 (0.13H, d, J = 14.0 Hz, H-2b), 3.73 (0.09H, d, J = 14.0 Hz, H-2b),

3.76-3.85 (0.22H, m, H-7), 3.86 (0.42H, dd, J = 7.2, 2.0 Hz, H-7), 3.89 (0.36H, dd, J =

7.2, 2.0 Hz, H-7), 4.23 (0.36H, d, J = 15.0 Hz, PhCH2), 4.28 (0.42H, d, J = 15.0 Hz,

PhCH2), 4.32-4.48 (1.78H, m, H-5, H-8), 4.58 (0.13H, d, J = 15.0 Hz, PhCH2), 4.68

(0.09H, d, J = 15.0 Hz, PhCH2), 4.72 (0.09H, d, J = 15.0 Hz, PhCH2), 4.74 (0.13H, d, J

= 15.0 Hz, PhCH2), 4.82 (0.42H, d, J = 15.0 Hz, PhCH2), 4.85 (0.36H, d, J = 15.0 Hz,

PhCH2), 5.05 (0.36H, br s, H-6), 5.09 (0.42H, br s, H-6), 5.29 (0.13H, br d, J = 5.6 Hz,

H-5), 5.42 (0.09H, br d, J = 6.8 Hz, H-5), 5.48 (0.13H, br s, H-6), 5.57 (0.09H, br s,

H-6), 5.72 (0.13H, dd, J = 11.0, 5.6 Hz, CH=CHSOPh), 5.84 (0.09H, dd, J = 11.0, 6.8

Hz, CH=CHSOPh), 6.04 (0.42H, dd, J = 15.0, 4.0 Hz, CH=CHSOPh), 6.07 (0.36H, dd,

J = 15.0, 4.0 Hz, CH=CHSOPh), 6.13 (0.42H, br d, J = 15.0 Hz, CH=CHSOPh), 6.20

(0.36H, dd, J = 15.0, 1.6 Hz, CH=CHSOPh), 6.15-6.25 (0.22H, m, CH=CHSOPh),

7.16-7.70 (5H, m, aromatic); 13C NMR (100 MHz, CDCl3) ! 20.2, 20.4, 20.5, 20.6, 30.3,

30.3, 30.3, 36.3, 36.3, 36.4, 36.5, 47.6, 48.0, 48.6, 48.6, 56.6, 57.1, 57.8, 58.0, 63.9,

64.1, 64.3, 65.9, 68.5, 68.6, 68.6, 69.0, 69.7, 70.9, 71.0, 76.5, 76.7, 76.8, 115.0, 115.1,

115.1, 124.3, 124.3, 124.6, 125.3, 128.5, 128.5, 128.6, 128.6, 128.6, 128.7, 128.8, 129.0,

129.1, 129.5, 129.5, 129.6, 129.7, 131.0, 131.1, 131.3, 131.4, 131.6, 134.8, 135.0, 135.5,

135.7, 138.5, 138.9, 139.5, 140.4, 142.9, 143.1, 143.1, 156.6, 156.7, 169.1, 169.3, 169.4,

169.5, 192.8, 192.8, 192.9; HRMS (ESI) for C27H27N2O7S2 (M+H), calcd 555.1260,

found 555.1272.

Acetate 20: Vinyl sulfoxide 17 (202 mg, 0.364 mmol) was dissolved in MeOH (12 mL),

and it was cooled to 0 oC under nitrogen. To the solution was added lithium hydride (3.2

OMeOOC

OAc

H

ONBn

O

S SPhOH

20


S17

mg, 0.40 mmol). After being stirred for 1 h, the reaction mixture was allowed to warm

to room temperature. After being stirred for 2.5 h, to the reaction mixture were added an

ice-cooled aqueous 1N HCl (8 mL) at 0 oC. After being stirred for 28 h, to the reaction

mixture was added ice (20 mL). The aqueous layer was separated and extracted with

EtOAc (5 mL x 3). The combined extracts were washed with saturated aqueous

NaHCO3 and brine, and then dried over Na2SO4. The solution was concentrated to

dryness in vacuo. The residue was used for the next reaction without further

purification.

The residue was dissolved in CH2Cl2 (7.3 mL), and it was cooled to 0 oC under nitrogen.

To the solution were added pyridine (1.8 mL, 22.3 mmol) and acetic anhydride (1.8 mL,

19.0 mmol), and the reaction mixture was allowed to warm to room temperature. After

being stirred for 1.5 h, the solution was concentrated to dryness in vacuo. The residue

was purified by column chromatography (silica gel, hexane/EtOAc 3:2 " 1:4) to give

acetate 20 (138 mg, 0.253 mmol, 71% in 2 steps, ca. 1:1 diastereomeric mixture) as an

amorphous solid.

Rf = 0.70 (EtOAc); [#]D28 -82.1 (c 1.02, CHCl3); IR (film) $max 3060, 3033, 2953, 2928,

1763, 1218, 1058, 734 cm-1; 1H NMR (400 MHz, CDCl3) ! 2.06 (1.5H, s, COCH3),

2.09 (1.5H, s, COCH3), 2.70 (0.5H, d, J = 14.0 Hz, H-2a), 2.78 (0.5H, d, J = 14.4 Hz,

H-2a), 2.99-3.22 (3H, m, H-2b, H-4, CH2SOPh), 3.39 (0.5H, dd, J = 13.2, 10.8 Hz,

CH2SOPh), 3.54 (0.5H, dd, J = 12.4, 10.8 Hz, CH2SOPh), 3.84 (1.5H, s, COOCH3),

3.85 (1.5H, s, COOCH3), 4.09 (0.5H, d, J = 15.6 Hz, PhCH2), 4.12 (0.5H, d, J = 15.6

Hz, PhCH2), 4.36 (0.5H, br d, J = 7.2 Hz, H-5), 4.62 (0.5H, dd, J = 7.6, 7.6 Hz, H-7),

4.67 (0.5H, dd, J = 7.2, 7.2 Hz, H-7), 4.71 (0.5H, d, J = 7.6 Hz, H-8), 4.73 (0.5H, d, J =

7.2 Hz, H-8), 4.80 (0.5H, d, J = 15.6 Hz, PhCH2), 4.82 (0.5H, d, J = 15.6 Hz, PhCH2),

4.92 (0.5H, br d, J = 7.2 Hz, H-5), 5.20 (0.5H, dd, J = 7.2, 7.2 Hz, H-6), 5.26 (0.5H, dd,

J = 7.6, 7.2 Hz, H-6), 7.18-7.41 (5H, m, aromatic), 7.48-7.62 (5H, m, aromatic); 13C

NMR (100 MHz, CDCl3) ! 20.7, 20.9, 26.7, 26.8, 27.2, 28.3, 47.1, 47.1, 53.4x2, 55.7,

55.8, 59.9, 60.0, 69.2, 71.8, 72.0, 73.3, 73.4, 75.7, 75.8, 123.8, 123.8, 127.5, 127.6,


S18

128.1, 128.2, 129.0, 129.0, 129.5, 131.5, 131.5, 135.6, 135.7, 143.1, 155.6, 155.7, 167.8,

167.8, 169.1, 169.1; HRMS (ESI) for C26H27NO8S2 (M+H), calcd 546.1256, found

546.1299.

Aldehyde 21: Acetate 20 (118 mg, 0.216 mmol) was dissolved in CH2Cl2 (4.3 mL), and

it was cooled to 0 oC under nitrogen. To the solution were added triethylamine (900 µL,

6.48 mmol) and TMSOTf (390 µL, 2.16 mmol). After being stirred for 8 min, the

reaction mixture was poured into an ice-cooled saturated aqueous NaHCO3 (10 mL).

The aqueous layer was separated and extracted with CH2Cl2 (5 mL x 3). The combined

extracts were washed with aqueous 1N HCl, saturated aqueous NaHCO3 and brine, and


was purified by column chromatography (silica gel, hexane/EtOAc 7:3 " 2:3) to give

aldehyde 21 (59.1 mg, 0.136 mmol, 63%) as an amorphous solid.

Rf = 0.60 (EtOAc); [#]D29 -10.7 (c 0.625, CHCl3); IR (film) $max 3062, 3032, 3007,

2954, 2929, 1762, 1437, 1415, 1218, 1089, 1062, 735, 704 cm-1; 1H NMR (400 MHz,

CDCl3) ! 2.03 (3H, s, COCH3), 2.77 (1H, d, J = 14.0 Hz, H-2a), 2.94 (1H, d, J = 14.0

Hz, H-2b), 2.97 (1H, br s, H-4), 3.83 (3H, s, COOCH3), 4.11 (1H, d, J = 15.6 Hz,

PhCH2), 4.62 (1H, dd, J = 7.2, 7.2 Hz, H-7), 4.75 (1H, d, J = 7.2 Hz, H-8), 4.84 (1H, d,

J = 15.6 Hz, PhCH2), 5.10 (1H, br d, J = 7.2 Hz, H-5), 5.33 (1H, dd, J = 7.2, 7.2 Hz,

H-6), 7.22-7.42 (5H, m, aromatic), 9.65 (1H, s, CHO); 13C NMR (100 MHz, CDCl3) !

20.8, 28.1, 42.0, 47.2, 53.4, 56.1, 66.1, 71.4, 73.3, 75.7, 127.4, 128.2, 129.0, 135.7,

155.7, 167.5, 168.7, 193.5; HRMS (ESI) for C20H22NO8S (M+H), calcd 436.1066,

found 436.1055.

OMeOOC

OAc

H

ONBn

O

S CHOH

21


S19

Acetate 24: To a solution of aldehyde 21 (59.1 mg, 0.136 mmol) in MeOH (6.8 mL)

were added benzyl amine (300 µL, 2.72 mmol) and iodine (138 mg, 0.544 mmol) at

room temperature under nitrogen. After being stirred for 8 h, the reaction mixture was

poured into an ice-cooled saturated aqueous Na2SO3 (10 mL). The aqueous layer was

separated and extracted with EtOAc (5 mL x 3). The combined extracts were washed



The residue was dissolved in pyridine (2.0 mL) and acetic anhydride (2.0 mL), and the

reaction mixture was allowed to warm to room temperature. After being stirred for 1.5 h,

the solution was concentrated to dryness in vacuo. The residue was purified by

preparative thin-layer chromatography (hexane/EtOAc 1:3) to give acetate 24 (23.1 mg,

40.5 µmol, 30% in 2 steps) as a white solid.

Rf = 0.19 (hexane/EtOAc 1:3); mp 150-155 oC; [#]D27 -53.8 (c 1.16, CHCl3); IR (film)

$max 3323, 3063, 3032, 2953, 2933, 1764, 1673, 1217, 1067, 702 cm-1; 1H NMR (400

MHz, CDCl3) ! 1.82 (3H, s, COCH3), 2.78 (1H, d, J = 14.0 Hz, H-2a), 3.02 (1H, d, J =

14.0 Hz, H-2b), 3.10 (3H, s, OCH3), 3.84 (3H, s, COOCH3), 3.98 (1H, dd, J = 14.4, 4.0

Hz, CONHCH2Ph), 4.23 (1H, d, J = 15.6 Hz, CH2Ph), 4.63 (1H, d, J = 6.8 Hz, H-5),

4.67 (1H, d, J = 15.6 Hz, CH2Ph), 4.73 (1H, dd, J = 14.4, 8.0 Hz, CONHCH2Ph), 4.80

(1H, d, J = 7.6 Hz, H-8), 4.86 (1H, dd, J = 8.4, 7.6 Hz, H-7), 5.24 (1H, dd, J = 8.4, 6.8

Hz, H-6), 6.28-6.36 (1H, m, NH), 7.20-7.38 (10H, m, aromatic); 13C NMR (100 MHz,

CDCl3) ! 20.5, 29.1, 44.2, 47.6, 51.2, 53.4, 56.2, 72.7, 73.7, 74.0, 76.5, 87.8, 127.1,

128.0, 128.0, 128.2, 129.0, 136.1, 136.8, 156.0, 167.0, 167.7, 169.7; HRMS (ESI) for

C28H31N2O9S (M+H), calcd 571.1750, found 571.1801.

OMeOOC

OAc

H

ONBn

O

S CONHBnMeO

24


S20

Table S1. Crystal Data and Structure Refinement for 15

Identification code 15

Empirical formula C19 H18 N2 O6

Formula weight 370.35

Temperature 93 K

Wavelength 0.71073 Å

Crystal system Orthorhombic

Space group P2(1)2(1)2(1)

Unit cell dimensions a = 10.4965(6) Å a= 90°.

b = 11.6262(7) Å b= 90°.

c = 14.6325(9) Å g = 90°.

Volume 1785.67(18) Å3 Z 4

Density (calculated) 1.378 Mg/m3

Absorption coefficient 0.104 mm-1 F(000) 776

Crystal size 0.19 x 0.16 x 0.16 mm3 Theta range for data collection 2.24 to 25.17°.

Index ranges -12<=h<=11, -9<=k<=13, -17<=l<=16

Reflections collected 8700

Independent reflections 3208 [R(int) = 0.0272]

Completeness to theta = 25.17° 99.9 %

Absorption correction Semi-empirical from equivalents

Max. and min. transmission 0.9836 and 0.9805

Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 3208 / 71 / 254

Goodness-of-fit on F2 1.040 Final R indices [I>2sigma(I)] R1 = 0.0299, wR2 = 0.0710

R indices (all data) R1 = 0.0317, wR2 = 0.0720

Absolute structure parameter -0.9(8)

Extinction coefficient 0.0094(10)

Largest diff. peak and hole 0.270 and -0.173 e.Å-3


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Figure S1. Perspective ORTEP Drawing for 15


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stereocontrolled synthesis of the oxathiabicylo[3.3.1 ... · stereocontrolled synthesis of the...

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