S1

Synthesis and Structure Revision of Nakiterpiosin

Shuanhu Gao, Qiaoling Wang and Chuo Chen*

Supporting Information

Index S1

1H NMR spectrum of synthetic nakiterpiosin (1) S2

13C NMR spectrum of synthetic nakiterpiosin (1) S3

1H NMR spectrum of synthetic 1 overlaid with that of the natural sample S4

1H NMR spectrum of synthetic 6,20,25-epi-nakiterpiosin (2) at –10 °C S5

1H NMR spectrum of synthetic 6,20,25-epi-nakiterpiosin (2) at various temperatures S6

13C NMR spectrum of synthetic 6,20,25-epi-nakiterpiosin (2) at room temperatures S7

1H NMR spectrum of synthetic 2 overlaid with that of the natural sample S8

Comparison of the 1H NMR spectroscopic data of natural nakiterpiosin with 1 and 2 S9

Comparison of the 13

C NMR spectroscopic data of natural nakiterpiosin with 1 and 2 S10

CD spectrum of synthetic nakiterpiosin (1) S11

Synthesis of 2 S12

Experimental procedures S13

X-Ray crystallographic data of the key synthetic intermediates S24

1H NMR spectra of the synthetic intermediates S41

S2

S3

S4

S5

S6

S7

S8

S9

Table S1. 1H NMR chemical shifts and coupling constants of nakiterpiosin’s

natural sample* synthetic 1† synthetic 2‡ natural sample* synthetic 1† synthetic 2‡ 1a 2.05 (dd)

J = 12.3, 1.0 Hz 2.06 (dd) J = 12.4, 1.0 Hz

2.21 (d) J = 12.3 Hz

15 7.33 (d) J = 8.2 Hz

7.34 (d) J = 8.0 Hz

7.43 (d) J = 8.0 Hz

1b 2.60 (dd) J = 12.3, 7.8 Hz

2.61 (dd) J = 12.4, 7.8 Hz

2.67 (dd) J = 12.3, 7.4 Hz

16 7.89 (d) J = 8.2 Hz

7.90 (d) J = 8.0 Hz

7.86 (d) J = 8.0 Hz

2 4.23 (dd) J = 7.8, 1.0 Hz

4.25 (d) J = 7.8 Hz

4.27 (d) J = 7.4 Hz

18 2.70 (s) 2.72 (s) 2.68 (s)

3a 4.09 (d) J = 11.2 Hz

4.10 (d) J = 11.0 Hz

3.89 (d) J = 10.8 Hz

19 1.52 (s) 1.51 (s) 1.44 (s)

3b 3.11 (d) J = 11.2 Hz

3.12 (dd) J = 11.0, 1.0 Hz

3.57 (d) J = 10.8 Hz

20 3.89 (dd) J = 10.3, 3.8 Hz

3.89 (dd) J = 10.0, 3.2 Hz

3.78 (dd) J = 10.2, 3.6 Hz

4 5.28 (s) 5.29 (s) 5.37 (s) 21 6.32 (d) J = 10.3 Hz

6.32 (d) J = 10.0 Hz

6.66 (d) J = 3.6 Hz

6 4.70 (dd) J = 2.7, 1.4 Hz

4.71 (dd) J = 3.4, 2.5 Hz

4.74 (dd) J = 12.3, 5.1 Hz

22 4.39 (dd) J = 8.0, 3.8 Hz

4.41 (dd) J = 7.9, 3.2 Hz

4.52 (dd) J = 10.2, 2.3 Hz

7a 2.28 (m) 2.29 (ddd) J = 13.7, 12.7, 3.4 Hz

2.22 (ddd) J = 12.3, 12.0, 12.0 Hz

23 3.92 (ddd) J = 8.2, 8.0, 3.7 Hz

3.93 (ddd) J = 8.1, 7.9, 3.9 Hz

4.02 (ddd) J = 9.3, 6.8, 2.3 Hz

7b 2.74 (ddd) J = 13.4, 2.7, 1.4 Hz

2.75 (ddd) J = 13.7, 2.5, 2.3 Hz

2.94 (ddd) J = 12.0, 5.1, 2.7 Hz

24a 1.71 (ddd) J = 12.8, 8.4, 8.2 Hz

1.72 (ddd) J = 13.2, 8.2, 8.1 Hz

2.00 (m)

8 3.58 (m) 3.55 (ddd) J = 12.7, 9.4, 2.3 Hz

3.03 (ddd) J = 12.0, 9.1, 2.7 Hz

24b 2.28 (m) 2.29 (ddd) J = 13.2, 4.8, 3.9 Hz

2.00 (m)

9 2.69 (d) J = 9.3 Hz

2.70 (d) J = 9.4 Hz

2.75 (d) J = 9.1 Hz

25 2.69 (m) 2.71 (m) 2.61 (m)

26 1.13 (d) J = 7.3 Hz

1.15 (d) J = 7.3 Hz

1.19 (d) J = 7.1 Hz

* Recorded at 800 MHz as reported by Uemura et al. (Ref 1). † Recorded at 600 MHz.

‡ Recorded at 500 MHz.

Synthetic 1 vs the Natural Sample

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

H1a H1b H2 H3a H3b H4 H6 H7a H7b H8 H9 H15 H16 H18 H19 H20 H21 H22 H23 H24a H24b H25 H26

Synthetic 2 vs the Natural Sample

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

H1a H1b H2 H3a H3b H4 H6 H7a H7b H8 H9 H15 H16 H18 H19 H20 H21 H22 H23 H24a H24b H25 H26

S10

Table S2. 13

C NMR chemical shifts of nakiterpiosin’s

natural sample* synthetic 1† synthetic 2‡ natural sample* synthetic 1† synthetic 2‡ 1 41.7 43.5 44.5 14 152.3 154.2 154.0 2 75.1 76.9 76.4 15 120.5 122.4 122.6 3 63.7 65.6 72.2 16 134.1 135.9 136.1 4 91.1 93.0 100.2 17 134.9 136.7 134.6 5 83.4 85.2 86.1 18 12.4 14.3 14.7 6 51.8 53.7 51.8 19 14.3 16.2 15.86 7 34.9 36.8 39.35 20 51.5 53.3 50.7 8 35.1 36.9 41.4 21 75.2 77.4 77.0 9 63.5 65.3 65.5 22 71.2 73.0 72.9 10 44.8 46.6 39.36 23 78.7 80.5 80.6 11 204.6 206.4 206.1 24 31.1 33.0 30.2 12 138.6 140.5 140.4 25 33.3 35.1 36.9 13 135.7 137.5 136.5 26 14.8 16.6 15.88 27 180.6 182.4 182.3

* Recorded at 200 MHz as reported by Uemura et al. (Ref 1). † Recorded at 100 MHz.

‡ Recorded at 125 MHz.

Synthetic 1 vs Natural Sample

-8

-7

-6

-5

-4

-3

-2

-1

0

1

2

3

4

5

6

7

8

C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 C17 C18 C19 C20 C21 C22 C23 C24 C25 C26 C27

Synthetic 1 vs Natural Sample

-8

-7

-6

-5

-4

-3

-2

-1

0

1

2

3

4

5

6

7

8

C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 C17 C18 C19 C20 C21 C22 C23 C24 C25 C26 C27

Note: The 13C NMR spectrum of the natural product appears to be mis-referenced by ca. –2 ppm. We were

not able to obtain a copy of the 13C NMR spectrum of the natural sample. Nor could we get this

issued clarified with Prof. Uemura. The chemical shifts of the natural product were adjusted by

+2.0 ppm in these diagrams.

S11

CD Spectrum of Synthetic Nakieterpiosin (1)

S12

Scheme S1. The synthesis of 6-epi-6 (26)

Scheme S2. The synthesis of 20,25-epi-7 (33) and completion of the synthesis of 2

a

a Synthetic 2 existed as an equilibrium mixture of the C-4 hemiacetal and aldehyde forms favoring the hemiacetal form (3:1) at room

temperature. At –10 °C, only a small amount of the aldehyde form was detected.

Figure S1. Summary of the NOE and

3J data of 2 on the computed equilibrium geometry (MMFF/AM1).

S13

General Experimental Procedures. All reactions were performed in glassware under a positive

pressure of argon. Liquids and solvent were transferred via syringe. Organic solutions were

concentrated by rotary evaporator at ca. 30 mmHg. Flash column chromatography was performed as

described by Still (Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923–2925), employing

EMD silica gel 60 (230–400 mesh ASTM). TLC analyses were performed on EMD 250 m Silica Gel

60 F254 plates and visualized by quenching of UV fluorescence (λmax= 254 nm), or by staining ceric

ammonium molybdate. 1H and

13C NMR spectra were recorded on Varian Inova-600, Inova-500,

Inova-400 or Mercury-300 spectrometer. Chemical shifts for 1H and

13C NMR spectra are reported in

ppm (δ) relative to the 1H and

13C signals in the solvent (CDCl3: δ 7.26, 77.00 ppm; methanol-d4: δ

3.31, 49.50 ppm) and the multiplicities are presented as follows: s = singlet, d = doublet, t = triplet, m

= multiplet. Infrared spectra were recorded on a Perkin-Elmer 1000 series FTIR. Mass spectra were

acquired on a Shimadzu 2010 LC-MS or through the University of Illinois Urbana-Champaign Mass

Spectrometer Facility using the indicated ionization method.

Weinreb amide 8a. To a solution of 4-(furan-2-yl)-4-oxobutanoic acid 8 (12.0 g, 71.4

mmol, 1.0 equiv) in dry methylene chloride (240 mL) was added carbonyl diimidazole

(13.9 g, 85.6 mmol, 1.2 equiv) and N,O-dimethylhydroxylamine hydrochloride (8.3 g,

85.6 mmol, 1.2 equiv) at 23 °C. After stirring for 3 h at 23 °C, brine (100 mL) was added and the

biphasic mixture was extracted with ethyl acetate (300 mL), the organic phase was dried over

anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography

(gradient 30% → 50% ethyl acetate–hexanes) to give 8a as colorless oil (11.1 g, 74%): Rf = 0.25 (50%

ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3) δ 7.59–7.57 (m, 1H), 7.23–7.22 (m, 1H), 6.54–

6.52 (m, 1H), 3.75 (s, 3H), 3.22–3.16 (m, 2H), 3.18 (s, 3H), 2.91–2.83 (m, 2H); 13

C NMR (125 MHz,

CDCl3) δ 187.5, 172.4, 152.0, 145.9, 116.6, 111.7, 60.7, 32.1, 31.6, 25.2; MS(ES)+ calcd for

C10H13NNaO4 (M+Na)+

234.07, found 234.05.

Alcohol 9. To a solution of Di-μ-chlorobis[(p-cymene)chlororuthenium(II)] (0.61 g,

1.0 mmol, 0.022 equiv) in water (25 mL) was added (1S,2S)-(+)-N-p-Tosyl-1,2-

diphenylethylenediamine (0.85 g, 2.33 mmol, 0.024 equiv) at 23 °C. After stirring at

40 °C for 1 h, the mixture was cooled to 23 °C. Sodium formate (15.3 g, 226.0 mmol, 5.0 equiv) and

8a (9.0 g, 45.2 mmol, 1.0 equiv) were added to the solution at 23 °C. After degassing three times, the

solution was heated to 40 °C and reacted at this temperature for 2.5 h. After cooling to 23 °C, the

reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (100 mL×3), the

combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified

by silica gel column chromatography (50% ethyl acetate–hexanes) to give 9 as colorless oil (7.9 g,

87%, 91% ee as determined with the corresponding Mosher’s ester). Rf = 0.15 (50% ethyl acetate–

hexanes); 1H NMR (400 MHz, CDCl3) δ 7.33 (dd, J = 1.8, 0.7 Hz, 1H), 6.29 (dd, J = 3.2, 1.8 Hz, 1H),

6.23 (ddd, J = 3.2, 0.7, 0.7 Hz, 1H), 4.75 (dd, J = 7.2, 5.2 Hz, 2H), 3.64 (s, 3H), 3.57 (br, 1H, OH),

3.16 (s, 3H), 2.58 (t, J = 6.5 Hz, 2H), 2.22–2.11 (m, 2H);13

C NMR (125 MHz, CDCl3) δ 174.6, 156.6,

141.7, 110.0, 105.7, 67.3, 61.2, 32.2, 29.9, 28.0 (minor rotamer: 176.5, 150.8, 143.4, 110.4, 109.3, 74.3,

28.5, 26.5); MS(ES)+ calcd for C10H15NNaO4 (M+Na)

+ 236.09, found 236.05.

Enone 9a. To a solution of 9 (0.470 g, 2.21 mmol, 1.0 equiv) in dry tetrahydrofuran (20

mL) was added isopropenylmagnesium bromide solution (0.5 M in tetrahydrofuran, 9.72

mL, 4.86 mmol, 2.2 equiv) at 0 °C under argon. The reaction was slowly warmed to

23 °C and stirred for another 3 h before saturated aqueous ammonium chloride (15 mL) and ethyl

acetate (30 mL) were added. The layers were separated and the organic phase was washed with brine

(10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column

S14

chromatography (gradient 20% → 30% ethyl acetate–hexanes) to give 9a as colorless oil (0.360 g,

84%). Rf = 0.40 (50 % ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3) δ 7.33–7.32 (m, 1H), 6.29

(ddd, J = 3.2, 1.8, 1.8 Hz, 1H), 6.19–6.18 (m, 1H), 5.88 (s, 1H), 5.71 (s, 1H), 4.92 (dd, J = 6.0, 6.0 Hz,

1H), 2.81–2.72 (m, 1H), 2.69–2.61 (m, 1H), 2.22–2.06 (m, 2H), 1.84 (d, J = 0.6 Hz, 3H), 0.98 (d, J =

6.0 Hz, OH); 13

C NMR (100 MHz, CDCl3) δ 201.6, 156.70, 144.3, 141.2, 124.4, 109.9, 106.2, 67.7,

32.6, 31.7, 18.0; MS(ES)+ calcd for C11H14NaO3 (M+Na)

+ 217.08, found 217.05.

Ketone 9b. To a solution of the 9a (0.320 g, 1.63 mmol, 1.0 equiv) in dry methylene

chloride (20 mL) at -78 °C was slowly added a solution of dimethylaluminum chloride

solution (1.0 M in hexane, 4.07 mL, 4.07 mmol, 2.5 equiv) over 1 h. The reaction mixture

was slowly warmed up to -30 °C and stirred for an additional 5 h. Saturated sodium bicarbonate (15

mL) was added at -30 °C, the mixture was warmed to 23 °C. The layers were separated and the

aqueous phase was extracted with methylene chloride (10 mL×3). The combined organic phase was

washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified

by silica gel column chromatography (gradient 30% → 50% ethyl acetate–hexanes) to give 9b as

colorless oil (0.225 g, 71%). Rf = 0.16 (50% ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3) δ

6.54 (ddd, J = 5.7, 1.2, 1.2 Hz, 1H), 6.33 (d, J = 5.7 Hz, 1H), 4.90 (d, J = 4.9 Hz, 1H), 4.46 (dd, J =

11.8, 4.9 Hz, 1H), 2.85 (dd, J = 11.8, 4.9 Hz, 1H), 2.71 (ddd, J = 15.1, 14.8, 5.5 Hz, 1H), 2.44 (ddd, J

= 15.1, 3.4, 3.4 Hz, 1H), 2.24–2.18 (m, 1H), 2.02–1.91 (m, 1H), 1.94 (br, 1H, OH), 1.11 (s, 3H), 1.06

(d, J = 11.8 Hz, 1H);13

C NMR (100 MHz, CDCl3) δ 211.6, 139.6, 133.4, 94.3, 78.5, 67.0, 54.4, 38.4,

36.6, 29.6, 22.3; MS(ES)+ calcd for C11H14NaO3 (M+Na)

+ 217.08, found 217.15.

Sulfonate 10. To a solution of 9b (0.213 g, 1.10 mmol, 1.0 equiv) in dry methylene

chloride (10 mL) was added 4-(dimethylamino)pyridine (161.0 mg, 1.32 mmol, 1.2

equiv) at 0 °C. A solution of methyl 2-(chlorosulfonyl)benzoate (0.27 g, 1.16 mmol, 1.05

equiv) in dry methylene chloride (2 mL) was slowly added. After stirring at 0 °C for 1 h,

saturated aqueous sodium bicarbonate (10 mL) was added. The biphasic mixture was

extracted with ethyl acetate (10 mL×3). The combined organic extracts were washed with saturated

aqueous sodium bicarbonate (15 mL) dried over anhydrous sodium sulfate, filtered, concentrated, and

purified by silica gel column chromatography (40% ethyl acetate–hexanes) to give 10 as colorless oil

(0.431 g, 100%). Rf = 0.3 (50% ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3) δ 8.10–8.07 (m,

1H), 7.73–7.61 (m, 3H), 6.48 (dd, J = 5.8, 1.5 Hz, 1H), 6.14 (d, J = 5.8 Hz, 1H), 5.72 (dd, J = 12.2, 4.9

Hz, 1H), 4.90 (d, J = 5.1 Hz, 1H), 3.98 (s, 3H), 2.82 (dd, J = 11.8, 5.1 Hz, 1H), 2.76 (dd, J = 15.4, 6.0

Hz, 1H), 2.47 (ddd, J = 15.4, 3.5, 3.5 Hz, 1H), 2.36–2.25 (m, 1H), 2.21–2.15 (m, 1H), 1.15 (s, 3H),

1.04 (d, J = 11.8 Hz, 1H); 13

C NMR (75 MHz, CDCl3) δ 210.2, 167.5, 139.4, 134.9, 133.6, 132.9,

132.0, 130.9, 130.0, 128.9, 92.2, 78.5, 77.0, 56.3, 53.4, 38.4, 36.4, 26.3, 22.0; MS(ES)+ calcd for

C19H20NaO7S (M+Na)+

415.08, found 415.05.

Diol 10a. To a solution of 10 (0.408 g, 1.04 mmol, 1.0 equiv) in a 9:1 mixture of

acetone/water (10 mL) was added osmium tetroxide solution (0.4 M in water, 0.52 mL,

0.21 mmol, 0.2 equiv,) and N-methylmorpholine N-oxide (184.1 mg, 1.56 mmol, 1.5

equiv) at 23 °C. After stirring for 12 h at 23 °C, saturated aqueous sodium sulfite (10 mL)

was added and stirred for 30 min. The solvent was evaporated in vacuo, the residue was

diluted with water (10 mL) and extracted with ethyl acetate (20 mL×3).The combined organic extracts

were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column

chromatography (gradient 50% ethyl acetate–hexanes→ 100% ethyl acetate) to give 10a as colorless

oil (0.395 g, 89%). Rf = 0.11 (70% ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3) δ 8.11–8.07

(m, 1H), 7.72–7.63 (m, 3H), 5.49 (dd, J = 10.3, 4.9 Hz, 1H), 4.31 (d, J = 6.7 Hz, 1H), 4.16 (d, J = 5.8

Hz, 1H), 3.99 (s, 3H), 3.82 (d, J = 5.8 Hz, 1H), 3.35 (br, 1H, OH), 2.85 (dd, J = 13.1, 6.7 Hz, 1H), 2.71

S15

(ddd, J = 14.6, 4.6, 4.6 Hz,1H), 2.58–2.33 (m, 3H), 2.38 (br, 1H, OH), 1.23 (s, 3H), 0.93 (d, J = 13.1

Hz, 1H); 13

C NMR (100 MHz, CDCl3) δ 208.6, 168.3, 135.9, 133.5, 132.2, 131.1, 129.5, 129.3, 88.6,

79.8, 76.9, 75.0, 72.1, 56.3, 53.8, 35.4, 34.9, 28.8, 20.0; MS(ES)+ calcd for C19H22NaO9S (M+Na)

+

449.09, found 449.00.

Bromide 11. To a solution of 10a (0.386 g, 0.91 mmol, 1.0 equiv) in acetone (10 mL)

was added lithium bromide (313.0 mg, 3.64 mmol, 4.0 equiv) at 23 °C. The mixture was

heated to 70 °C and reacted for 24 h. After cooling the solution to 23 °C, the solvent

was evaporated in vacuo and water (10 mL) was added to dissolve all the salts. The aqueous layer was

extracted with ethyl acetate (10 mL×2). The combined extracts were washed with brine (10 mL), dried

over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column

chromatography (20% ethyl acetate–hexanes) to give 11 as colorless solid (0.186 g, 62%).

Recrystallization from diethyl ether gave single crystals suitable for X-ray analysis. Rf = 0.70 (50%

ethyl acetate–hexanes); 1H NMR (600 MHz, CDCl3) δ 4.78 (ddd, J = 3.5, 2.4, 1.2 Hz, 1H), 4.72 (d, J =

5.5 Hz, 1H), 4.30 (d, J = 5.5 Hz, 1H), 4.27 (d, J = 6.8 Hz, 1H), 3.16 (ddd, J = 14.7, 14.5, 5.4 Hz, 1H),

2.89 (dd, J = 13.2, 6.8 Hz, 1H), 2.54 (dddd, J = 14.7, 14.5, 3.6, 3.5 Hz, 1H), 2.38 (dddd, J = 14.7, 3.6,

2.6, 1.2 Hz, 1H), 2.32 (dddd, J = 14.7, 5.4, 2.6, 2.4 Hz, 1H), 1.56 (s, 3H), 1.44 (s, 3H), 1.35 (s, 3H),

1.02 (d, J = 13.2 Hz, 1H); 13

C NMR (125 MHz, CDCl3) δ 211.1, 112.0, 90.0, 83.2, 80.0, 78.9, 54.2,

45.4, 37.3, 34.0, 30.6, 25.9, 25.3, 21.7; MS(ES)+ calcd for C14H20BrO4 (M+H)

+ 331.0, found 331.1.

Triflate 6. To a solution of 11 (0.175 g, 0.53 mmol, 1.0 equiv) in dry tetrahydrofuran

(5 mL) was added potassium bis(trimethylsilyl)amide (0.5 M in toluene,1.91 mL, 0.95

mmol, 1.8 equiv) at − 78 °C under argon. The mixture was stirred at same temperature

for 30 min before a solution of N-phenyltrifluoromethanesulfonimide (0.246 g, 0.69 mmol, 1.3 equiv)

in dry tetrahydrofuran (2 mL) was added at −78 °C. After stirring for another 30 min at same

temperature, a solution of aqueous saturated ammonium chloride (6 mL) was added and the mixture

was warmed to 23 °C. The biphasic mixture was extracted with ethyl acetate (10 mL×2), and the

organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered,

concentrated, and purified by silica gel column chromatography (gradient 5% → 10% ethyl acetate–

hexanes) to give 6 as colorless oil (0.236 g, 96%): Rf = 0.70 (30% ethyl acetate–hexanes); 1H NMR

(400 MHz, CDCl3) δ 5.65 (dd, J = 6.1, 2.1, 0.8 Hz, 1H), 4.78 (d, J = 5.4 Hz, 1H), 4.62 (d, J = 4.9 Hz,

1H), 4.37 (d, J = 5.4 Hz, 1H), 4.33 (d, J = 6.3 Hz, 1H), 3.10 (ddd, J = 18.8, 4.9, 2.1 Hz, 1H), 2.74 (dd,

J = 18.8, 6.1 Hz, 1H), 2.15 (dd, J = 12.8, 6.3 Hz, 1H), 1.50 (s, 3H), 1.47 (s, 3H), 1.33 (s, 3H), 1.28 (d, J

= 12.8 Hz, 1H); 13

C NMR (100 MHz, CDCl3) δ 151.7, 118.3 (q, J = 319 Hz), 112.2, 110.8, 88.9, 82.8,

79.6, 79.5, 44.4, 39.8, 39.5, 31.4, 25.9, 25.3, 20.9; MS(ES)+ calcd for C15H19BrF3O6S (M+1)

+ 463.0,

found 462.9.

Alcohol 27a. To a solution of 3-bromo-2-methylbenzenecarboxylic acid (16.0 g, 74.8

mmol, 1.0 equiv) in dry tetrahydrofuran (300 mL) was slowly added a solution of borane-

tetrahydrofuran complex (1.0 M in tetrahydrofuran, 97.2 mL, 97.2 mmol, 1.3 equiv) at

S16

0 °C. After stirring at 23 °C for 12 h, a mixture of tetrahydrofuran and water (1:1 v/v, 150 mL) was

added slowly. The resulting biphasic mixture was extracted with ethyl acetate (150 mL×3), and the

organic phase was washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered,

concentrated to give 27a as yellow solid which was directly used in the next step without purification.

Rf = 0.60 (50% ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 7.8 Hz, 1H), 7.32 (d,

J = 7.6 Hz, 1H), 7.06 (dd, J = 7.8, 7.6 Hz, 1H), 4.73 (d, J = 3.6 Hz, 2H), 2.43 (s, 3H), 1.61 (t, J = 3.6

Hz, 1H, OH); 13

C NMR (125 MHz, CDCl3) δ 140.4, 135.6, 131.9, 127.0, 126.4, 126.0, 63.8, 18.3;

MS(EI)+ calcd for C8H9BrO (M)

+ 200.0, found 200.1.

Aldehyde 27b. To a suspension of pyridinium chlorochromate (29.0 g, 134.6 mmol, 1.8

equiv) and silicon gel (30 g) in dry methylene chloride (500 mL) was slowly added a

solution of crude 27a obtained above in methylene chloride (20 mL) at 23 °C. After

stirring at 23 °C for 12 h, ether (300 mL) was added and the mixture was stirred for 1h. Filtered the

mixture with neutral aluminum oxide, the filtrates was concentrated to give crude 27b as yellow oil

which was directly used in the next step without purification. Rf = 0.61 (30% ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3) δ 10.25 (s, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.24

(dd, J = 9.0, 7.9 Hz, 1H), 2.75 (s, 3H); 13

C NMR (100 MHz, CDCl3) δ 191.6, 139.8, 137.5, 135.7,

130.8, 127.5, 127.2, 18.0; MS(EI)+ calcd for C8H7BrO (M)

+ 198.0, found (M+15)

+, 213.1.

Ester 27c. To a suspension of sodium hydrogen (3.59 g, 60% dispersion in mineral oil,

89.7 mmol, 1.2 equiv) in dry tetrahydrofuran (400 mL) was added triethyl

phosphonoacetate (16.3 mL, 82.3 mmol, 1.1 equiv) at 0 °C under argon. After stirring

at 0 °C for 30 min, a solution of crude aldehyde 27b obtained above in dry tetrahydrofuran (20 mL)

was slowly added. The mixture was stirred for 1 h at 0 °C, a solution of aqueous saturated ammonium

chloride (150 mL) was then added and the mixture was warmed to 23 °C. The biphasic mixture was

extracted with ethyl acetate (100 mL×2), and the organic phase was washed with brine (200 mL), dried

over anhydrous sodium sulfate, filtered, concentrated to give crude 27c as yellow oil which was

directly used in the next step without purification. Rf = 0.72 (30% ethyl acetate–hexanes); 1H NMR

(500 MHz, CDCl3) δ 7.97 (d, J = 15.8 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 7.7 Hz, 1H), 7.06

(dd, J = 7.9, 7.7 Hz, 1H), 6.29 (d, J = 15.8 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 2.50 (s, 3H), 1.34 (t, J =

7.2 Hz, 3H); 13

C NMR (125 MHz, CDCl3) δ 166.6, 142.5, 136.8, 135.8, 133.9, 127.3, 126.4, 125.8,

121.2, 60. 7, 19.5, 14.3; MS(ES)+ calcd for C12H14BrO2 (M+H)

+ 269.0, found 269.1.

Alcohol 12. To a solution of crude ester 27c obtained above in dry methylene chloride

(350 mL) was added a solution of diisobutylaluminium hydride (1.0 M in toluene,

157.1 mL, 157.1 mmol, 2.1 equiv) at 0 °C under argon. After stirring at 0 °C for 1 h,

water (100 mL) was slowly added. The residue suspension was added a solution of aqueous

hydrochloric acid (1N, 100 mL) and extracted with ethyl acetate (100 mL×3), and the organic phase

was washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated and

purified by silica gel column chromatography (25% ethyl acetate–hexanes) to give 12 as colorless oil

(15.0 g, 89% over four steps). Rf = 0.50 (50 % ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3) δ

7.46 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.01 (dd, J = 7.9, 7.7 Hz, 1H), 6.85 (d, J = 15.7 Hz,

1H), 6.18 (dtd, J = 15.7, 5.5, 1.0 Hz, 1H), 4.35 (d, J = 5.5 Hz, 2H), 2.43 (s, 3H); 13

C NMR (100 MHz,

CDCl3) δ 138.0, 134.7, 131.42, 131.38, 128.6, 126.8, 125.7, 125.2, 63.0, 19.2; MS(EI)+ calcd for

C10H11BrO (M)+ 226.0, found 226.1.

Epoxide 12a. To a solution of diethyl-D-tartrate (0.24 mL, 1.14 mmol, 0.18 equiv) and

powdered 4Å molecular sieves (0.190 g) in dry methylene chloride (20 mL) was added

a solution of titanium(IV) isopropoxide (0.28 mL, 0.95 mmol, 0.15 equiv) in dry

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methylene chloride (1 mL) at -20 °C under argon. Then, an anhydrous solution of tert-butyl

hydroperoxide (5.5 M in decane, 2.30 mL, 12.64 mmol, 2.0 equiv) was slowly added. After stirring at

same temperature for 30 min, a solution of allylic alcohol 12 (1.44 g, 6.32 mmol, 1.0 equiv) in dry

methylene chloride (2 mL) was added. The mixture was stirred at -20 °C for 5 h, aqueous sodium

hydroxide solution (10%, 10 mL) and brine (10 mL) was then added. The biphasic mixture was

extracted with ethyl acetate (20 mL×3) and the organic phase was washed with brine (20 mL), dried

over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column

chromatography (30% ethyl acetate–hexanes) to give 12a as colorless oil (1.50 g, 98%, 92 % ee as

determined by HPLC: chiralcel OD-H column, 12% iso-propanol–hexane, 1 mL/min, tR(major) = 7.8 min,

tR(minor) = 11.8 min). Rf = 0.23 (30% ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J =

8.0 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 7.05 (dd, J = 8.0, 7.7 Hz, 1H), 4.10–4.08 (m, 1H), 4.07–4.05 (m,

1H), 3.87 (dddd, J = 10.0, 6.5, 3.3, 0.9 Hz, 1H), 3.07–3.05 (m, 1H), 2.46 (s, 3H), 1.81 (ddd, J = 6.5,

5.2, 1.1 Hz, 1H, OH); 13

C NMR (100 MHz, CDCl3) δ 137.4, 135.4, 132.0, 127.3, 125.5, 123.8, 61.34,

61.28, 54.3, 18.4; MS(ES)+ calcd for C10H11BrNaO2 (M+Na)

+ 264.98, found 265.45.

TBS Ether 12b. To a solution of the alcohol 12a (1.40 g, 5.79 mmol, 1.0 equiv) in

dimethylformamide (3 mL) were successively added imidazole (0.945 g, 13.90 mmol,

2.4 equiv) and t-butyldimethylsilyl chloride (1.05 g, 6.95 mmol, 1.2 equiv) at 23 °C.

After stirring at same temperature for 2 h, the mixture was diluted with ethyl acetate (100 mL) and

washed with brine (15 mL×5), dried over anhydrous sodium sulfate, filtered, concentrated, and

purified by silica gel column chromatography (gradient 2% → 5% ethyl acetate–hexanes) to give 12b

as colorless oil (2.0 g, 97%): Rf = 0.50 (10% ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3) δ

7.48 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.04 (d, J = 7.9, 7.5 Hz, 1H), 3.94 (d, J = 2.1 Hz,

1H), 3.91 (d, J = 3.9 Hz, 2H), 2.97 (td, J = 3.9, 2.1 Hz, 1H), 2.46 (s, 3H), 0.92 (s, 9H), 0.11 (s, 3H),

0.10 (s, 3H); 13

C NMR (100 MHz, CDCl3) δ 137.8, 135.2, 131.7, 127.2, 125.4, 123.8, 62.8, 61.5, 54.6,

25.8, 18.4, 18.3, –5.37, –5.40; MS(ES)+ calcd for C16H25BrNaO2Si (M+Na)

+ 379.07, found 379.20.

Aldehyde 13. A solution of 4-bromo-2,6-di-tert-butylphenol (6.08 g, 21.32 mmol, 4.0

equiv) in dry methylene chloride (105 mL) was degassed using freeze-pump-thaw. A

solution of trimethylaluminium (2.0 M in hexane, 5.33 mL, 10.66 mmol, 2.0 equiv) was

then added at 23 °C. After stirring at same temperature for 1 h, the solution was cooled to –78 °C and a

solution of 12b (1.90 g, 5.33 mmol, 1.0 equiv) in dry methylene chloride (5 mL) was slowly added.

The mixture was stirred at –78 °C for 10 min before addition of sodium fluoride (1.34 g, 31.98 mmol,

6.0 equiv) and water (0.767 mL, 42.64 mmol, 8.0 equiv). The mixture was allowed to warm to 23 °C

and stirred for 10 min. Filtered the resulted suspension and washed with methylene chloride (50 mL),

the combined filtrates was concentrated, and purified by silica gel column chromatography (2% ethyl

acetate–hexanes) to give 13 as yellow oil (1.50 g, 79%, 71% ee as determined by the corresponding

benzoyl ester with HPLC: chiralpak AD-H, 0.2% iso-propanol–hexanes, 0.8 mL/min, tR(minor) = 15.3

min, tR(major) = 16.0 min). Rf = 0.47 (10% ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3) δ 9.76 (d,

J = 1.4 Hz, 1H), 7.51 (dd, J = 6.6, 2.7 Hz, 1H), 7.05 (dd, J = 7.8, 6.6 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H),

4.24 (dd, J = 10.1, 6.9 Hz, 1H), 4.08 (ddd, J = 6.9, 5.9, 1.4 Hz, 1H), 3.91 (dd, J = 10.1, 5.8 Hz, 1H),

2.47 (s, 3H), 0.83 (s, 9H), –0.01 (s, 3H), –0.03 (s, 3H); 13

C NMR (100 MHz, CDCl3) δ 199.9, 137.0,

135.1, 132.1, 127.6, 127.2, 126.5, 62.9, 57.9, 25.7, 19.7, 18.1, –5.6, –5.7; MS(ES)+ calcd for

C16H25BrNaO2Si (M+Na)+

379.07, found 379.10.

Furanone 14. To a solution of aldehyde 13 (1.45 g, 4.08 mmol, 1.0 equiv) and 2-

(trisopropylsiloxy)-3-metyl-furan (1.55 g, 6.12 mmol, 1.5 equiv) in dry ether (15

mL) was added bismuth triflate (26.9 mg, 0.041 mmol, 0.10 equiv) at –78 °C under

argon. The mixture was allowed to warm to –40 °C and reacted for 5 h. Water (10 mL) was then added

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and warmed to 23 °C. The biphasic mixture was extracted with ethyl acetate (15 mL×3), and the

organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered,

concentrated, and purified by silica gel column chromatography (gradient 10% → 20% ethyl acetate–

hexanes) to give 14 as colorless oil (0.550 g, 69%, 60% ee as determined by HPLC: chiralcel OD-H,

1.5% iso-propanol–hexane, 1.1 mL/min, tR(minor) = 12.1 min tR(major) = 15.4 min ) and recover aldehyde

13 (0.827 g, 57%) : Rf = 0.33 (30% ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3) δ 7.48 (dd, J

= 7.7, 1.4 Hz, 1H), 7.07 (dd, J = 7.7, 1.4 Hz, 1H), 7.02 (dd, J = 7.7, 7.7 Hz, 1H), 6.91 (dq, J = 1.7, 1.6

Hz, 1H), 4.49 (qdd, J = 1.8, 1.7, 1.7 Hz, 1H), 4.31 (br, 1H, OH), 4.30–4.26 (m, 1H), 4.01 (dd, J = 10.0,

9.6 Hz, 1H), 3.82 (dd, J = 10.0, 4.0 Hz, 1H), 3.58 (ddd, J = 9.6, 9.4, 4.0 Hz, 1H), 2.58 (s, 3H), 1.90 (dd,

J = 1.8, 1.6 Hz, 3H), 0.89 (s, 9H), 0.073 (s, 3H), 0.067 (s, 3H); 13

C NMR (100 MHz, CDCl3) δ 174.2,

145.9, 138.6, 136.7, 131.7, 130.9, 127.1, 126.7, 125.8, 81.2, 75.3, 67.4, 45.5, 25.7, 19.5, 18.0, 10.8, –

5.67, –5.75; MS(ES)+ calcd for C21H31BrNaO4Si (M+Na)

+ 477.11, found 477.05.

Lactone 15. A dried vial (40 mL) with 14 (0.534 g, 1.17 mmol, 1.0 equiv) was

evacuated and refilled with hydrogen three times. To this vial was added dry

methylene chloride (10 mL). A solution of crabtree’s catalyst (97 mg, 0.12 mmol,

0.1 equiv) in dry methylene chloride (2.0 mL) was added in five portions every 30 min. After stirring

at 23 °C for another 2 h, the solvent was evaporated under vacuo and the residue was purified by silica

gel column chromatography (20% ethyl acetate–hexanes) to give 15 as colorless oil (0.520 g, 97%): Rf

= 0.41 (30% ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3) δ 7.44 (dd, J = 5.0, 4.1 Hz, 1H),

7.04–6.96 (m, 2H), 4.64–4.62 (m, 1H), 4.09 (d, J = 10.2 Hz, 1H), 4.01–3.93 (m, 2H), 3.78 (dd, J =

10.2, 3.8 Hz, 1H), 3.50 (ddd, J = 10.0, 9.7, 3.8 Hz, 1H), 2.95 (ddq, J = 9.2, 8.9, 7.4 Hz, 1H), 2.55 (s,

3H), 2.43 (ddd, J = 12.5, 9.2, 2.3 Hz, 1H), 1.78 (ddd, J = 12.5, 9.4, 8.9 Hz, 1H), 1.16 (d, J = 7.4 Hz,

3H), 0.88 (s, 9H), 0.07 (s, 6H); 13

C NMR (100 MHz, CDCl3) δ 181.0, 138.7, 136.7, 131.5, 127.0, 126.7,

125.7, 79.1, 77.0, 68.0, 44.5, 34.0, 32.7, 25.7, 19.4, 18.0, 16.3, –5.7, –5.8; MS(ES)+ calcd for

C21H33BrNaO4Si (M+Na)+ 479.12, found 479.15.

Ketone 15a. To a solution of 15 (0.508 g, 1.1 mmol, 1.0 equiv) in dry methylene

chloride (15 mL) was added Dess-Martin periodinane (729.3 mg, 1.6 mmol, 1.5

equiv) at 23 °C. After stirring for 5 min, a solution of water (29 μL, 1.6 mmol, 1.5

equiv) in methylene chloride (1 mL) was added. The white suspension was stirred for another 30 min,

an aqueous solution of 10% sodium bisulfate/saturated sodium bicarbonate (1:1 v/v, 10 mL) was then

added. After stirring for another 10 min, the biphasic mixture was extracted with ethyl acetate (3×15

mL), and the organic phase was washed with saturated sodium bicarbonate (15 mL), dried over

anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography

(10% ethyl acetate–hexanes) to give 15a as colorless oil (0.496 g, 98%): Rf = 0.60 (30% ethyl acetate–

hexanes); 1H NMR (500 MHz, CDCl3) δ 7.48 (d, J = 7.8 Hz, 1H), 7.05 (d, J = 7.4 Hz, 1H), 6.98 (dd, J

= 7.8, 7.4 Hz, 1H), 4.69 (dd, J = 8.9, 2.9 Hz, 1H), 4.62 (dd, J = 9.0, 5.4 Hz, 1H), 4.15 (dd, J = 9.5, 9.0

Hz, 1H), 3.62 (dd, J = 9.5, 5.4 Hz, 1H), 2.60 (s, 3H), 2.58–2.53 (m, 2H), 2.05–2.00 (m, 1H), 1.24 (d, J

= 6.7 Hz, 3H), 0.81 (s, 9H), –0.01 (s, 3H), –0.04 (s, 3H); 13

C NMR (126 MHz, CDCl3) δ 206.8, 178.6,

137.0, 134.3, 132.3, 127.2, 126.6, 126.3, 79.2, 64.4, 52.8, 33.2, 32.5, 25.7, 19.6, 18.1, 15.3, –5.68, –

5.71; MS(ES)+ calcd for C21H31BrNaO4Si (M+Na)

+ 477.11, found 477.05.

Alcohol 15b. To a solution of 15a (0.482 g, 1.1 mmol, 1.0 equiv) in a 10:3

tetrahydrofuran:ethanol (10 mL) was added sodium borohydride (54.3 mg, 1.4

mmol, 1.3 equiv) at –78 °C. The solution was stirred at this temperature for 15 min

before addition of acetone (3 mL). The mixture was allowed to warm to 23 °C and evaporated the

solvent under vacuo. The residue was diluted with ethyl acetate (30 mL) and saturated ammonium

chloride (10 mL), and the organic phase was collected and dried over anhydrous sodium sulfate,

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filtered, concentrated, and purified by silica gel column chromatography (20% ethyl acetate–hexanes)

to give 15b as colorless oil (0.450 g, 93%). Rf = 0.41 (30% ethyl acetate–hexanes); 1H NMR (500 MHz,

CDCl3) δ 7.49 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.03 (dd, J = 7.9, 7.8 Hz, 1H), 4.51 (ddd, J

= 8.1, 5.5, 4.4 Hz, 1H), 4.27 (dd, J = 5.9, 5.5, 3.8 Hz, 1H), 3.88 (dd, J = 10.4, 6.6 Hz, 1H), 3.81 (dd, J

= 10.4, 4.3 Hz, 1H), 3.35 (ddd, J = 6.6, 5.9, 4.3 Hz, 1H), 2.75 (ddq, J = 7.8, 7.6, 7.4 Hz, 1H), 2.60 (br,

1H, OH), 2.52–2.46 (m, 1H), 2.48 (s, 3H), 1.83 (ddd, J = 13.0, 8.1, 7.8 Hz, 1H), 1.25 (d, J = 7.4 Hz,

3H), 0.88 (s, 9H), 0.01 (s, 3H), –0.01 (s, 3H); 13

C NMR (125 MHz, CDCl3) δ 180.4, 139.3, 136.5,

131.3, 127.1, 126.8, 126.2, 78.6, 74.0, 65.3, 45.0, 34.0, 30.5, 25.7, 19.6, 18.1, 16.2, –5.67, –5.69;

MS(ES)+ calcd for C21H33BrNaO4Si (M+Na)

+ 479.12, found 479.25.

TBS Ether 16. To a solution of 15b (0.433 g, 0.95 mmol, 1.0 equiv) in dry

methylene chloride (10 mL) was added 2,6-lutidine (0.33 mL, 2.85 mmol, 3.0 equiv)

at 23 °C. The mixture was heated to 40 °C and added tert-butyldimethylsilyl

trifluoromethanesulfonate (0.37 mL, 1.62 mmol, 1.7 equiv). After stirring at this temperature for 30

min, the mixture was cooled down to 23 °C and water (10 mL) was added. The biphasic mixture was

extracted with ethyl acetate (20 mL), and the organic phase was washed with brine (15 mL), dried over

anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography

(gradient 3% → 8% ethyl acetate–hexanes) to give 16 as colorless oil (0.505 g, 93%): Rf = 0.70 (30%

ethyl acetate–hexanes); 1H NMR (500 MHz, CDCl3) δ 7.45 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 7.7 Hz,

1H), 6.99 (dd, J = 7.9, 7.7 Hz, 1H), 4.63 (ddd, J = 7.5, 7.4, 3.1 Hz, 1H), 4.43 (dd, J = 6.1, 3.1 Hz, 1H),

3.82 (dd, J = 10.5, 8.4 Hz, 1H), 3.57 (dd, J = 10.5, 4.8 Hz, 1H), 3.21 (ddd, J = 8.4, 6.1, 4.8 Hz, 1H),

2.61 (dqd, J = 9.7, 7.5, 4.6 Hz, 1H), 2.46 (s, 3H), 2.45 (ddd, J = 12.8, 9.7, 7.4 Hz, 1H), 1.52 (ddd, J =

12.8, 7.5, 4.6 Hz, 1H), 1.24 (d, J = 7.5 Hz, 3H), 0.87 (s, 9H), 0.79 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H),

0.00 (s, 3H), –0.23 (s, 3H); 13

C NMR (125 MHz, CDCl3) δ 178.0, 140.5, 136.4, 131.2, 127.1, 126.8,

126.1, 80.1, 73.7, 64.4, 46.9, 34.7, 29.3, 26.0, 25.8, 19.8, 18.2, 18.1, 16.8, –4.58, –5.0, –5.43, –5.45;

MS(ES)+ calcd for C27H47BrNaO4Si2 (M+Na)

+ 593.21, found 593.30.

Alcohol 16a. A solution of l6 (0.495 g, 0.86 mmol, 1.0 equiv) in a 3:2:2 mixture of

acetic acid:tetrahydrofuran:water (5 mL) was stirred at 60 °C for 4 h. Then, solvent

was evaporated under vacuo and the residue was diluted with ethyl acetate (50 mL)

and washed with a saturated solution of sodium bicarbonate (15 mL) and dried over anhydrous sodium

sulfate, filtered, concentrated, and purified by silica gel column chromatography (25% ethyl acetate–

hexanes) to give 16a as colorless oil (0.300 g, 76%): Rf = 0.20 (30% ethyl acetate–hexanes); 1H NMR

(500 MHz, CDCl3) δ 7.47 (dd, J = 7.9, 0.9 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.03 (dd, J = 7.9, 7.8 Hz,

1H), 4.55 (ddd, J = 7.5, 7.2, 3.0 Hz, 1H), 4.38 (dd, J = 6.1, 3.0 Hz, 1H), 3.90 (dd, J = 10.8, 7.6 Hz, 1H),

3.76 (dd, J = 10.8, 6.3 Hz, 1H), 3.38 (ddd, J = 7.6, 6.3, 6.1 Hz, 1H), 2.62 (dqd, J = 9.7, 7.5, 4.8 Hz,

1H), 2.48 (s, 3H), 2.41 (ddd, J = 12.8, 9.7, 7.2 Hz, 1H), 1.54 (ddd, J = 12.8, 7.5, 4.8 Hz, 1H), 1.24 (d, J

= 7.5 Hz, 3H), 0.81 (s, 9H), 0.04 (s, 3H), –0.18 (s, 3H); 13

C NMR (100 MHz, CDCl3) δ 179.8, 139.9,

136.8, 131.4, 126.9, 126.9, 126.4, 79.8, 73.8, 63.6, 47.1, 34.7, 29.3, 25.9, 19.6, 18.1, 16.6, –4.4, –5.0;

MS(ES)+ calcd for C21H33BrNaO4Si (M+Na)

+ 479.12, found 479.05.

Aldehyde 17. To a solution of 16a (0.279 g, 0.61 mmol, 1.0 equiv) in dry

methylene chloride (5 mL) was added Dess-Martin periodinane (404.4 mg, 0.92

mmol, 1.5 equiv) at 23 °C. After stirring for 5 min, a solution of water (0.0166 mL,

0.92 mmol, 1.5 equiv) in methylene chloride (0.2 mL) was added. The suspension was stirred for

another 30 min, an aqueous solution of 10% sodium bisulfate/saturated sodium bicarbonate (1:1 v/v, 5

mL) was then added. After stirring for another 10 min, the biphasic mixture was extracted with ethyl

acetate (10 mL×3), the organic phase was washed with saturated sodium bicarbonate (10 mL), dried

over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column

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chromatography (15% ethyl acetate–hexanes) to give 17 as colorless oil (0.253 g, 91%): Rf = 0.43

(30% ethyl acetate–hexanes); 1H NMR (500 MHz, CDCl3) δ 9.65 (s, 1H), 7.56 (d, J = 7.7 Hz, 1H),

7.13 (d, J = 7.7 Hz, 1H), 7.09 (dd, J = 7.7, 7.7 Hz, 1H), 4.64 (dd, J = 7.4, 3.7 Hz, 1H), 4.58 (ddd, J =

7.4, 7.2, 3.7 Hz, 1H), 4.06 (d, J = 7.4 Hz, 1H), 2.74–2.66 (m, 1H), 2.55–2.46, (m, 1H), 2.50 (s, 3H),

1.74 (ddd, J = 12.8, 7.4, 5.2 Hz, 1H), 1.29 (d, J = 7.4 Hz, 3H), 0.72 (s, 9H), 0.04 (s, 3H), –0.40 (s, 3H); 13

C NMR (125 MHz, CDCl3) δ 198.5, 179.3, 138.0, 133.2, 132.4, 128.8, 127.2, 126.7, 78.6, 72.2, 57.7,

34.3, 29.0, 25.6, 19.9, 17.8, 16.5, –4.7, –5.3; MS(ES)+ calcd for C21H31BrNaO4Si (M+Na)

+ 477.11,

found 477.15.

Bromide 18. To a solution of triphenyl phosphite (0.027 mL, 0.1 mmol, 2.0 equiv)

in dry methylene chloride (2.5 mL) was induced chlorine at –78 °C until the

solution became yellow. The color was discharged by argon bubbling (1 min). Then,

freshly distilled triethylamine (0.028 mL, 0.2 mmol, 4.0 equiv) and a solution of 17 (0.0237 g, 0.052

mmol, 1.0 equiv) in dry methylene chloride (0.5 mL) was added at same temperature. The mixture was

allowed to warm to 23 °C and stirred for 30 min. Then, heated the solution to 40 °C and stirred for 10

min. The solvent was evaporated in vacuo and the residue was purified by silica gel column

chromatography (10% ethyl acetate–hexanes) to give 18 as colorless oil (0.0220 g, 83%). Rf = 0.62

(30 % ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.9

Hz, 1H), 7.02 (dd, J = 7.9, 7.9 Hz, 1H), 5.89 (d, J = 10.1 Hz, 1H), 4.71 (dd, J = 4.9, 2.3 Hz, 1H), 4.12

(ddd, J = 7.2, 5.3, 4.9 Hz, 1H), 3.83 (dd, J = 10.1, 2.3 Hz, 1H), 2.55 (s, 3H), 2.54–2.47 (m, 1H), 2.09

(ddd, J = 13.2, 9.4, 7.2 Hz, 1H), 1.18 (d, J = 7.5 Hz, 3H), 1.12 (ddd, J = 13.2, 7.4, 5.3 Hz, 1H), 0.93 (s,

9H), 0.26 (s, 3H), 0.14 (s, 3H); 13

C NMR (125 MHz, CDCl3) δ 178.9, 137.5, 136.6, 132.4, 127.8, 126.6,

126.2, 79.2, 74.8, 73.0, 54.0, 34.0, 30.2, 26.0, 20.0, 18.4, 16.4, –4.2, –4.7; MS(ES)+ calcd for

C21H31BrCl2NaO3Si (M+Na)+ 531.05, found 531.15. Deprotection of the TBS ether followed by

recrystallization from 10% ethyl acetate–hexanes gave single crystals suitable for X-ray analysis.

Stannane 7. A solution of 18 (0.0314 mg, 0.062 mmol, 1.0 equiv) in dry 1,4-

dioxane (0.5 mL) was degassed using freeze-pump-thaw. A solution of

tetrakis[triphenylphosphine]palladium (0.0107 mg, 0.0093 mmol, 0.15 equiv) in

degassed 1,4-dioxane (0.2 mL) was then added at 23 °C. After stirring at same temperature for 5 min, a

solution of hexamethylditin (0.013 mL, 0.062 mmol, 1.0 equiv) in degassed 1,4-dioxane (0.2 mL) was

added and the mixture was heated to 100 °C. The additions of solutions of

tetrakis[triphenylphosphine]palladium (0.15 equiv) and hexamethylditin (1.0 equiv) were repeated two

more times every 2 hours at 100 °C. Then, the solution was cooled to 23 °C, filtered with a celite

column and washed with ethyl acetate (10 mL). The combined filtrates were evaporated in vacuo and

purified by silica gel column chromatography (gradient 3% → 8% ethyl acetate–hexanes) to give 7 as

S21

colorless oil (0.0185 g, 50%): Rf = 0.71 (30% ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3) δ

7.44 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.14 (dd, J = 7.8, 7.2 Hz, 1H), 5.97 (d, J = 10.0 Hz,

1H), 4.82 (dd, J = 3.5, 3.0 Hz, 1H), 4.26 (ddd, J = 8.1, 7.2, 3.0 Hz, 1H), 3.75 (dd, J = 10.0, 3.0 Hz, 1H),

2.49 (s, 3H), 2.45–2.41 (m, 1H), 2.03 (ddd, J = 13.3, 8.8, 8.1 Hz, 1H), 1.14 (d, J = 7.5 Hz, 3H), 0.93 (s,

9H), 0.82 (ddd, J = 13.3, 7.2, 3.9 Hz, 1H), 0.32 (s, 9H), 0.25 (s, 3H), 0.12 (s, 3H); 13

C NMR (100 MHz,

CDCl3) δ 179.3, 143.8, 143.4, 135.6, 134.4, 129.2, 125.2, 80.2, 75.2, 72.7, 53.9, 34.3, 29.5, 26.1, 23.2,

18.5, 16.4, –4.4, –4.5, –8.3; MS(ES)+ calcd for C24H40Cl2NaO3SiSn (M+Na)

+ 617.10, found 617.05.

Enone 19. A dried vial (4 mL) with 6 (0.0139 g, 0.031 mmol, 1.0 equiv),

tetrakis[triphenylphosphine]palladium (0.0537 g, 0.046 mmol, 1.5 equiv)

and copper(I) chloride (0.0045 mg, 0.046 mmol, 1.5 equiv) was

evacuated and refilled with carbon monoxide three times. To this vial was

added degassed dimethyl sulfoxide (0.4 mL), and the mixture was heated to 55 °C. A solution of 7

(0.0185 mg, 0.031 mmol, 1.0 equiv) in degassed dimethyl sulfoxide (0.2 mL) was added at same

temperature. The suspension was stirred at 55 °C for 30 min. The mixture was then cooled to 23 °C

and water (3 mL) was added. The mixture was extracted with ethyl acetate (5 mL×3), and the organic

phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel

column chromatography (25% ethyl acetate–hexanes) to give an inseparable 4:1 mixture of 19 and it’s

diastereomer as colorless oil (0.0150 g, 62%): Rf = 0.21 (30% ethyl acetate–hexanes); MS(ES)+ calcd

for C36H49BrCl2NaO7Si (M+Na)+ 793.17, found 793.30.

Ketone 20. A solution of 19 (0.0120 g, 0.016 mmol, 1.0 equiv) in dry

acetonitrile (6 mL) was degassed by bubbling argon through the solution

for 30 min. The solution was then photolyzed at 23 °C in a Rayonet

chamber reactor at 350 nm for 4 h. The solution was then poured into a

saturated aqueous solution of ammonium chloride (5 mL) and extracted

with ethyl acetate (8 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered,

concentrated. The residue was then dissolved in a mixture of 0.2% diisopropylamine in dry methanol

(3 mL). The solution was heated to 50 °C and reacted for 2 h. The solvent was then evaporated in

vacuo and the residue was purified by silica gel column chromatography (30% ethyl acetate–hexanes)

to give 20 as colorless oil (0.0072 g, 60% over two steps): Rf = 0.17 (30% ethyl acetate–hexanes); 1H

NMR (500 MHz, CDCl3) δ 7.71 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 5.89 (d, J = 10.3 Hz, 1H),

4.87 (dd, J = 3.0, 2.4 Hz, 1H), 4.77 (d, J = 5.5 Hz, 1H), 4.75 (dd, J = 5.6, 2.4 Hz, 1H), 4.37 (d, J = 6.4

Hz, 1H), 4.29 (d, J = 5.5 Hz, 1H), 4.11 (ddd, J = 7.3, 6.8, 5.6 Hz, 1H), 3.84 (dd, J = 10.3, 2.4 Hz, 1H),

3.62 (dd, J = 9.5, 9.3 Hz, 1H), 2.82 (d, J = 9.3 Hz, 1H), 2.80 (dd, 13.7, 2.4 Hz, 1H), 2.72 (s, 3H), 2.53

(dqd, J = 9.2, 7.4, 4.9 Hz, 1H), 2.35 (dd, 13.3, 6.4 Hz, 1H), 2.34 (ddd, J = 13.7, 9.3, 3.0 Hz, 1H), 2.08

(ddd, J = 13.1, 9.2, 6.8 Hz, 1H), 1.51 (s, 3H), 1.44 (s, 3H), 1.37 (d, J =13.3 Hz, 1H), 1.36 (s, 3H), 1.16

(d, J = 7.4 Hz, 3H), 1.12 (ddd, 13.1, 7.3, 4.9Hz, 1H), 0.95 (s, 9H), 0.29 (s, 3H), 0.15 (s, 3H); 13

C NMR

(125 MHz, CDCl3) δ 204.3, 179.0, 152.4, 138.7, 135.1, 135.0, 133.8, 120.6, 111.2, 88.6, 83.0, 81.4,

80.3, 79.4, 75.0, 73.0, 63.0, 51.9, 47.8, 42.0, 35.7, 35.1, 34.1, 30.5, 29.7, 26.1, 26.0, 25.2, 18.6, 17.2,

16.5, 13.6, –4.0, –4.6; MS(ES)+ calcd for C36H49BrCl2NaO7Si (M+Na)

+ 793.17, found 793.40.

Diol 20a. A solution of 20 (0.0072 g, 0.0094 mmol, 1.0 equiv) in

trifluoroacetic acid/methylene chloride/water (9:1:1 v/v/v) was stirred at

23 °C for 30 min. The solvent was then evaporated under vacuo and the

residue was dried using high vacuum for 2 h to give the crude 20a which

was directly used in the next step without purification. Rf = 0.27 (50% ethyl

acetate–hexanes); 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H),

5.88 (d, J = 10.3 Hz, 1H), 4.88 (dd, J = 3.1, 2.7 Hz, 1H), 4.74 (dd, J = 5.0, 2.4 Hz, 1H), 4.45 (dd, J =

S22

5.9, 5.8 Hz, 1H), 4.31 (d, J = 6.4 Hz, 1H), 4.10 (ddd, J = 7.3, 7.2, 5.0 Hz, 1H), 3.99 (dd, J = 6.0, 5.9 Hz,

1H), 3.83 (dd, J = 10.3, 2.4 Hz, 1H), 3.59 (ddd, J = 11.9, 9.2, 2.5 Hz, 1H), 2.97 (d, J = 6.0 Hz, 1H,

OH), 2.89 (d, J = 5.8 Hz, 1H, OH), 2.83 (d, J = 9.2 Hz, 1H), 2.82 (ddd, 14.1, 2.7, 2.5 Hz, 1H), 2.70 (s,

3H), 2.52 (dqd, J = 9.3, 7.4, 4.5 Hz, 1H), 2.37 (dd, 13.2, 6.4 Hz, 1H), 2.39–2.31 (m, 1H), 2.07 (ddd, J

= 13.1, 9.3, 7.3 Hz, 1H), 1.44 (s, 3H), 1.42 (d, J =13.2 Hz, 1H), 1.15 (d, J = 7.4 Hz, 3H), 1.12 (ddd,

13.1, 7.2, 4.5Hz, 1H), 0.94 (s, 9H), 0.28 (s, 3H), 0.15 (s, 3H); MS(ES)+ calcd for C33H45BrCl2NaO7Si

(M+Na)+ 753.14, found 753.20.

Bisacetal 20b. To a solution of crude 20a obtained above in acetone/pH7.4

buffer (2:1 v/v, 0.2 mL) was added a solution of sodium periodate (4.0 mg,

0.019 mmol, 2.0 equiv) in buffer (0.1 mL) at 23 °C. After stirring for 30

min, the suspension was diluted with water (2 mL) and extracted with ethyl

acetate (3×3 mL), and the organic phase was dried over anhydrous sodium

sulfate, filtered, concentrated to give crude 20b which was directly used in the next step without

purification. Rf = 0.32 (50% ethyl acetate–hexanes); 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.0 Hz,

1H), 7.26 (d, J = 8.0 Hz, 1H), 5.90 (d, J = 10.3 Hz, 1H), 5.39 (d, J = 6.5 Hz, 1H), 4.82 (dd, J = 3.2, 2.4

Hz, 1H), 4.74 (dd, J = 6.1, 2.5 Hz, 1H), 4.61 (d, J = 9.4 Hz, 1H), 4.21 (d, J = 7.9 Hz, 1H), 4.11 (d, J =

13.8, 6.1, 1.6 Hz, 1H), 3.95 (d, J = 9.4 Hz, 1H, OH), 3.86 (dd, J = 10.3, 2.5 Hz, 1H), 3.60 (ddd, J =

12.1, 9.3, 2.4 Hz, 1H), 3.56 (d, J = 6.5 Hz, 1H, OH), 2.74 (s, 3H), 2.75–2.73 (m, 1H), 2.64 (dd, J =

12.9, 7.9 Hz, 1H), 2.54 (m, 1H), 2.39 (ddd, J = 13.6, 12.1, 3.2 Hz, 1H), 2.09 (ddd, J = 13.6, 9.3, 7.3 Hz,

1H), 2.01 (dd, J = 13.0, 1.6 Hz, 1H), 1.56 (s, 3H), 1.30–1.25 (m, 1H), 1.19–1.11 (m, 1H), 1.17 (d, J =

7.5 Hz, 3H), 1.12 (ddd, J = 13.3, 7.4, 4.7 Hz, 1H), 0.95 (s, 9H), 0.30 (s, 3H), 0.16 (s, 3H); MS(ES)+

calcd for C33H45BrCl2NaO8Si (M+Na)+ 769.13, found 769.05.

Acetal 20c. To a solution of crude 20b obtained above in methylene chloride

(0.2 mL) was added triethylsilane (0.0018 mL, 0.011 mmol, 1.2 equiv) and

borontrifluoride diethyl etherate (0.0035 mL in 0.15 mL anhydrous methylene

chloride, 0.0028 mmol, 3.0 equiv) at 0 °C. After stirring at same temperature

for 2 h, a saturated aqueous solution of sodium bicarbonate (1.5 mL) was

added. The biphasic mixture was extracted with ethyl acetate (3 mL×3), and the organic phase was

dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column

chromatography (20% ethyl acetate–hexanes) to give 20c as colorless oil (0.0030 g, 44% over three

steps). Rf = 0.44 (50% ethyl acetate–hexanes); 1H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 7.9 Hz, 1H),

7.25 (d, J = 7.9 Hz, 1H), 5.89 (d, J = 10.3 Hz, 1H), 5.40 (d, J = 6.7 Hz, 1H), 4.76 (dd, J = 4.9, 2.3 Hz,

1H), 4.71 (dd, J = 2.5, 2.5 Hz, 1H), 4.27 (d, J = 7.9 Hz, 1H), 4.12 (d, J = 11.4 Hz, 1H), 4.14–4.10 (m,

1H), 3.85 (dd, J = 10.3, 2.3 Hz, 1H), 3.58 (ddd, J = 12.0, 9.3, 2.5 Hz, 1H), 3.21 (d, J = 11.4 Hz, 1H),

3.05 (d, J = 6.7 Hz, 1H, OH), 2.73 (s, 3H), 2.71 (d, J = 9.3 Hz, 1H), 2.64 (dd, J = 13.0, 7.9 Hz, 1H),

2.53 (dqd, J = 9.3, 7.4, 4.7 Hz, 1H), 2.34 (ddd, J = 13.2, 12.0, 2.5 Hz, 1H), 2.15 (d, J = 13.2 Hz, 1H),

2.08 (ddd, J = 13.3, 9.3, 7.5 Hz, 1H), 1.56 (s, 3H), 1.26 (m, 1H), 1.17 (d, J = 7.4 Hz, 3H), 1.12 (ddd, J

= 13.3, 7.4, 4.7 Hz, 1H), 0.95 (s, 9H), 0.30 (s, 3H), 0.16 (s, 3H); 13

C NMR (125 MHz, CDCl3) δ 203.9,

179.0, 152.2, 138.7, 135.2, 135.0, 133.8, 120.6, 104.7, 91.7, 83.4, 79.4, 75.0, 73.0, 64.3, 63.3, 51.9,

51.5, 51.4, 44.9, 41.5, 35.0, 34.1, 30.4, 26.1, 18.6, 16.5, 15.2, 13.6, –4.0, –4.6; MS(ES)+ calcd for

C33H45BrCl2NaO7Si (M+Na)+ 753.14, found 753.30.

Nakiterpiosin (1). To a solution of 20c (0.0030 g, 0.0041 mmol, 1.0 equiv) in

anhydrous tetrahydrofuran (0.2 mL) was added a solution of

tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 0.0045 mL, 1.1 equiv)

at 23 °C. After stirring at 23 °C for 15 min, calcium carbonate (0.005 g),

Dowex 50WX8-400 (0.007 g) and methanol (0.15 mL) were added. The

S23

mixture was stirred at same temperature for 15 min and filtered through a pad of Celite and washed

with methanol (5 mL). The combined filtrates was concentrated, and purified by silica gel column

chromatography (50% ethyl acetate–hexanes) to give 1 as colorless oil (0.002 g, 79%). Rf = 0.19 (50 %

ethyl acetate–hexanes); FTIR (neat, cm-1

) 3422, 2924, 2852, 1770, 1033; 1H NMR (600 MHz, CD3OD)

δ 7.90 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 6.32 (d, J = 10.0 Hz, 1H), 5.29 (s, 1H), 4.71 (dd, J

= 3.4, 2.5 Hz, 1H), 4.41 (dd, J = 7.9, 3.2 Hz, 1H), 4.25 (d, J = 7.8 Hz, 1H), 4.10 (d, J = 11.0 Hz, 1H),

3.93 (ddd, J = 8.1, 7.9, 3.9 Hz, 1H), 3.89 (dd, J = 10.0, 3.2 Hz, 1H), 3.55 (ddd, J = 12.7, 9.4, 2.3 Hz,

1H), 3.12 (dd, J = 11.0, 1.0 Hz, 1H), 2.75 (ddd, J = 13.7, 2.5, 2.3 Hz, 1H), 2.72 (s, 3H), 2.73–2.69 (m,

1H), 2.70 (d, J = 9.4 Hz, 1H), 2.61 (dd, J = 12.4, 7.8 Hz, 1H), 2.29 (ddd, J = 13.7, 12.7, 3.4 Hz, 1H),

2.06 (dd, J = 12.4, 1.0 Hz, 1H), 1.72 (ddd, J = 13..2, 8.2, 8.1 Hz, 1H), 1.51 (s, 3H), 1.15 (d, J = 7.3 Hz,

3H); 13

C NMR (100 MHz, CD3OD) δ 206.4, 182.4, 154.2, 140.5, 137.5, 136.7, 135.9, 122.4, 93.0, 85.2,

80.5, 77.4, 76.9, 73.0, 65.6, 65.3, 53.7, 53.3, 46.6, 43.5, 36.9, 36.8, 35.1, 33.0, 16.6, 16.2, 14.3;

MS(ES)+ calcd for C27H32BrCl2O7 (M+H)

+ 617.0708, found 617.0682. The Mosher ester analysis

S1

was carried out as described by Uemura and co-workers (Ref. 1). The ΔδSR

value for H-4 in the 4-

Mosher ester of 1 is +0.03 ppm (6.53–6.50 = 0.03). The ΔδSR

value for H-4 in the 4,22-di-Mosher ester

of the natural product is +0.04 ppm.

Bromide 25a. 1H NMR (400 MHz, CDCl3) δ 4.74 (dd, J = 8.4, 4.4 Hz, 1H), 4.62 (d, J =

5.6 Hz, 1H), 4.39 (d, J = 6.6 Hz, 1H), 4.34 (d, J = 5.6 Hz, 1H), 2.85 (dd, J = 13.1, 6.6

Hz, 1H), 2.64–2.54 (m. 3H), 2.52–2.41 (m, 1H), 1.56 (s, 3H), 1.31 (s, 3H), 1.24 (s, 3H),

1.08 (d, J = 13.1 Hz, 1H); 13

C NMR (100 MHz, CDCl3) δ 209.8, 112.7, 87.8, 83.2, 80.5, 77.9, 54.5,

42.9, 37.5, 36.7, 33.4, 25.6, 25.1, 21.2.

Bromide 32. 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J = 8.0, 0.9 Hz, 1H), 7.48 (dd,

J = 7.9, 0.9 Hz, 1H), 7.12 (dd, J = 8.0, 7.9 Hz, 1H), 6.41 (d, J = 3.1 Hz, 1H), 4.62

(dd, J = 10.1, 1.8 Hz, 1H), 3.95 (ddd, J = 10.7, 5.8, 1.8 Hz, 1H), 3.67 (dd, J = 10.1,

3.1 Hz, 1H), 2.51 (s, 3H), 2.54–2.46 (m, 1H), 2.00 (ddd, J = 12.0, 12.0, 10.7 Hz, 1H), 1.86 (ddd, J =

12.0, 8.8, 5.8 Hz, 1H), 1.22 (d, J = 7.1 Hz, 3H), 0.95 (s, 9H), 0.27 (s, 3H), 0.15 (s, 3H); 13

C NMR (100

MHz, CDCl3) δ 178.4, 137.6, 133.6, 132.9, 128.4, 126.9, 126.9, 78.0, 74.4, 72.2, 52.2, 35.3, 28.6, 26.3,

20.5, 18.5, 14.8, –3.6, –4.9.

epi-Nakiterpiosin (2). 1H NMR (500 MHz, CD3OD) δ 7.86 (d, J = 8.0 Hz,

1H), 7.43 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 3.6 Hz, 1H), 5.37 (s, 1H), 4.74 (dd,

J = 12.3, 5.1 Hz, 1H), 4.52 (dd, J = 10.2, 2.3 Hz, 1H), 4.27 (d, J = 7.4 Hz, 1H),

4.02 (ddd, J = 9.3, 6.8, 2.3 Hz, 1H), 3.89 (d, J = 10.8 Hz, 1H), 3.78 (dd, J =

10.2, 3.6 Hz, 1H), 3.57 (d, J = 10.8 Hz, 1H), 3.03 (ddd, J = 12.0, 9.1, 2.7 Hz,

1H), 2.94 (ddd, J = 12.0, 5.1, 2.7 Hz, 1H), 2.75 (d, J = 9.1 Hz, 1H), 2.68 (s, 3H), 2.67 (dd, J = 12.3, 7.4

Hz, 1H), 2.66–2.58 (m, 1H), 2.22 (ddd, J = 12.3, 12.0, 12.0 Hz, 1H), 2.21 (d, J = 12.3 Hz, 1H), 2.03–

1.97 (m, 2H), 1.44 (s, 3H), 1.19 (d, J = 7.1 Hz, 3H); 13

C NMR (125 MHz, CD3OD) δ 206.1, 182.2,

154.0, 140.5, 136.9, 136.1, 134.6, 122.6, 100.2, 86.1, 80.6, 76.7, 76.4, 72.9, 72.2, 65.5, 51.8, 50.8, 44.5,

41.4, 39.39, 39.37, 36.9, 30.3, 15.87, 15.85, 14.7.

S1. Hoye, T. R.; Jeffrey, C. S.; Shao, F. Nat. Protoc. 2007, 2, 2451–2458.

S24

11

18a

25a

32a

Figure S2. The ORTEP representation of the key synthetic intermediates with the thermal ellipsoids drawn at 50%

probability level.

S25

X-ray Experimental for 11 (C14H19BrO4): Crystals grew as colorless prisms by slow evaporation from

diethyl ether. The data crystal was cut from a large prisms and had approximate dimensions;

0.24×0.14×0.06 mm. The data were collected on a Nonius Kappa CCD diffractometer using a graphite

monochromator with MoKα radiation (λ = 0.71073Å). A total of 246 frames of data were collected

using ω-scans with a scan range of 2° and a counting time of 214 seconds per frame. The data were

collected at 153 K using an Oxford Cryostream low temperature device. Details of crystal data, data

collection and structure refinement are listed in Table S3. Data reduction were performed using

DENZO-SMN.S2

The structure was solved by direct methods using SIR97S3

and refined by full-matrix

least-squares on F2 with anisotropic displacement parameters for the non-H atoms using SHELXL-

97.S4

The hydrogen atoms on carbon were observed in a ΔF map and refined with isotropic

displacement parameters. The function, Σw(|Fo|2 – |Fc|

2)2, was minimized, where w = 1 / [(σ(Fo))

2 +

(0.0222*P)2 + (0.0475*P)] and P = (|Fo|

2 + 2|Fc|

2) / 3. Rw(F

2) refined to 0.0616, with R(F) equal to

0.0286 and a goodness of fit, S, = 1.05. Definitions used for calculating R(F), Rw(F2) and the goodness

of fit, S, are given below.S5

The data were corrected for secondary extinction effects. The correction

takes the form: Fcorr = kFc / [1 + (1.67(16)×10–5

)* Fc2 λ

3/(sin2θ)]

0.25 where k is the overall scale factor.

Neutral atom scattering factors and values used to calculate the linear absorption coefficient are from

the International Tables for X-ray Crystallography (1992).S6

All figures were generated using ORTEP-

3.S7

Tables of positional and thermal parameters, bond lengths and angles, torsion angles, figures and

lists of observed and calculated structure factors are located in Tables S3 through S8.

S2. DENZO-SMN. (1997). Z. Otwinowski and W. Minor, Methods in Enzymology, 276: Macromolecular

Crystallography, part A, 307–326, C. W. Carter, Jr. and R. M. Sweets, Editors, Academic Press.

S3. SIR97. (1999). A program for crystal structure solution. Altomare A., Burla M.C., Camalli M., Cascarano G.L.,

Giacovazzo C. , Guagliardi A., Moliterni A.G.G., Polidori G.,Spagna R. J. Appl. Cryst. 32, 115–119.

S4. Sheldrick, G. M. (1994). SHELXL97. Program for the Refinement of Crystal Structures. University of Gottingen,

Germany.

S5. Rw(F2) = {Σw(|Fo|

2 – |Fc|

2)

2 / Σw(|Fo|)

4}

½ where w is the weight given each reflection.

R(F) = Σ(|Fo| – |Fc|)/Σ|Fo|} for reflections with Fo > 4(σ(Fo))

S = [Σw(|Fo|2 – |Fc|

2)

2/(n – p)]

½, where n is the number of reflections and p is the number of refined parameters.

S6. International Tables for X-ray Crystallography (1992). Vol. C, Tables 4.2.6.8 and 6.1.1.4, A. J. C. Wilson, editor,

Boston: Kluwer Academic Press.

S7. L. J. Farrugia, J. Appl. Cryst (1997), 30, 565.

S26

Table S3. Crystal data and structure refinement for 11.

Empirical formula C14 H19 Br O4

Formula weight 331.20

Temperature 153(2) K

Wavelength 0.71070 Å

Crystal system Monoclinic

Space group P21

Unit cell dimensions a = 7.2459(4) Å = 90°.

b = 8.6833(4) Å = 104.730(3)°.

c = 11.2308(5) Å = 90°.

Volume 683.40(6) Å3

Z 2

Density (calculated) 1.610 Mg/m3

Absorption coefficient 3.015 mm-1

F(000) 340

Crystal size 0.24 x 0.14 x 0.06 mm

Theta range for data collection 1.87 to 32.47°.

Index ranges -10<=h<=10, -11<=k<=13, -16<=l<=16

Reflections collected 11272

Independent reflections 4235 [R(int) = 0.0366]

Completeness to theta = 32.47° 99.3 %

Absorption correction Analytical

Max. and min. transmission 0.828 and 0.579

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 4235 / 1 / 249

Goodness-of-fit on F2 1.048

Final R indices [I>2sigma(I)] R1 = 0.0286, wR2 = 0.0577

R indices (all data) R1 = 0.0388, wR2 = 0.0616

Absolute structure parameter -0.015(6)

Extinction coefficient 1.67(16)x10-5

Largest diff. peak and hole 0.345 and -0.425 e.Å-3

S27

Table S4. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 11. U(eq) is

defined as one third of the trace of the orthogonalized Uij tensor.

________________________________________________________________________________

x y z U(eq)

________________________________________________________________________________

Br1 2361(1) -2424(1) 2286(1) 31(1)

O1 1523(2) 2297(1) 2193(1) 24(1)

O2 2676(2) 2961(2) 4828(2) 36(1)

O3 2184(2) 385(2) 4412(2) 34(1)

O4 3758(3) 1938(2) -473(2) 49(1)

C1 1149(3) -400(2) 1855(2) 22(1)

C2 322(3) -299(3) 472(2) 30(1)

C3 1897(3) -236(3) -216(2) 31(1)

C4 3262(3) 1079(3) 230(2) 29(1)

C5 4118(3) 1236(2) 1628(2) 22(1)

C6 4548(3) 2946(2) 1993(2) 28(1)

C7 3116(3) 3284(2) 2752(2) 27(1)

C8 3840(2) 2592(3) 4029(2) 26(1)

C9 1662(3) 1644(2) 5083(2) 24(1)

C10 3501(3) 848(2) 3744(2) 23(1)

C11 2582(2) 860(2) 2340(2) 19(1)

C12 5920(3) 226(3) 1913(2) 28(1)

C13 -450(3) 1920(3) 4653(3) 40(1)

C14 2290(4) 1276(3) 6441(2) 37(1)

________________________________________________________________________________

S28

Table S5. Bond lengths [Å] and angles [°] for 11.

__________________________________________________________________________________________

Br1-C1 1.9697(19)

O1-C7 1.447(2)

O1-C11 1.452(2)

O2-C8 1.416(2)

O2-C9 1.427(2)

O3-C10 1.414(2)

O3-C9 1.432(2)

O4-C4 1.206(3)

C1-C11 1.511(3)

C1-C2 1.518(3)

C1-H1A 0.93(2)

C2-C3 1.533(3)

C2-H2A 0.97(2)

C2-H2B 0.95(3)

C3-C4 1.510(3)

C3-H3A 1.00(3)

C3-H3B 0.94(3)

C4-C5 1.540(3)

C5-C12 1.537(3)

C5-C6 1.551(3)

C5-C11 1.561(3)

C6-C7 1.529(3)

C6-H6A 0.91(3)

C6-H6B 0.97(2)

C7-C8 1.520(3)

C7-H7A 0.94(3)

C8-C10 1.554(3)

C8-H8A 0.96(2)

C9-C13 1.502(3)

C9-C14 1.511(3)

C10-C11 1.548(3)

C10-H10A 1.01(2)

C12-H12A 0.92(3)

C12-H12B 0.90(3)

C12-H12C 1.00(3)

C13-H13A 1.05(3)

C13-H13B 0.95(4)

C13-H13C 0.99(3)

C14-H14A 0.85(3)

C14-H14B 1.05(3)

C14-H14C 0.96(3)

C7-O1-C11 96.84(13)

C8-O2-C9 111.44(17)

C10-O3-C9 111.44(15)

C11-C1-C2 112.52(18)

C11-C1-Br1 109.59(13)

C2-C1-Br1 109.78(14)

C11-C1-H1A 109.5(14)

C2-C1-H1A 112.2(13)

Br1-C1-H1A 102.9(15)

C1-C2-C3 111.52(17)

C1-C2-H2A 109.3(14)

C3-C2-H2A 109.5(14)

C1-C2-H2B 107(2)

C3-C2-H2B 109.1(18)

H2A-C2-H2B 110(2)

C4-C3-C2 111.63(19)

C4-C3-H3A 105.6(15)

C2-C3-H3A 112.7(16)

C4-C3-H3B 104.5(14)

C2-C3-H3B 112.2(13)

H3A-C3-H3B 110(2)

O4-C4-C3 122.0(2)

O4-C4-C5 120.2(2)

C3-C4-C5 117.70(18)

C12-C5-C4 105.21(17)

C12-C5-C6 112.85(17)

S29

C4-C5-C6 110.85(18)

C12-C5-C11 116.90(18)

C4-C5-C11 110.40(16)

C6-C5-C11 100.74(16)

C7-C6-C5 102.24(15)

C7-C6-H6A 111.5(16)

C5-C6-H6A 108.8(15)

C7-C6-H6B 111.5(15)

C5-C6-H6B 113.4(14)

H6A-C6-H6B 109(2)

O1-C7-C8 102.78(16)

O1-C7-C6 102.93(15)

C8-C7-C6 109.24(17)

O1-C7-H7A 111.1(12)

C8-C7-H7A 114.2(12)

C6-C7-H7A 115.3(13)

O2-C8-C7 112.98(18)

O2-C8-C10 105.21(17)

C7-C8-C10 101.12(16)

O2-C8-H8A 109.9(14)

C7-C8-H8A 113.4(14)

C10-C8-H8A 113.8(17)

O2-C9-O3 106.76(15)

O2-C9-C13 110.00(18)

O3-C9-C13 109.66(18)

O2-C9-C14 109.47(18)

O3-C9-C14 108.53(18)

C13-C9-C14 112.3(2)

O3-C10-C11 111.66(16)

O3-C10-C8 105.15(15)

C11-C10-C8 101.97(16)

O3-C10-H10A 109.7(15)

C11-C10-H10A 111.7(15)

C8-C10-H10A 116.4(14)

O1-C11-C1 106.65(14)

O1-C11-C10 101.51(16)

C1-C11-C10 116.11(18)

O1-C11-C5 100.79(15)

C1-C11-C5 118.75(18)

C10-C11-C5 110.19(15)

C5-C12-H12A 106.2(16)

C5-C12-H12B 111.1(15)

H12A-C12-H12B 109(2)

C5-C12-H12C 109.9(15)

H12A-C12-H12C 110(2)

H12B-C12-H12C 111(2)

C9-C13-H13A 107.3(14)

C9-C13-H13B 108.6(16)

H13A-C13-H13B 108(2)

C9-C13-H13C 107.3(15)

H13A-C13-H13C 116(2)

H13B-C13-H13C 110(2)

C9-C14-H14A 109(2)

C9-C14-H14B 112.7(16)

H14A-C14-H14B 113(3)

C9-C14-H14C 108.9(19)

H14A-C14-H14C 107(3)

H14B-C14-H14C 106(2)

__________________________________________________________________________________________

S30

Table S6. Anisotropic displacement parameters (Å2x 103) for 11. The anisotropic displacement factor exponent takes the

form: -2π2[ h2 a*2U11 + ... + 2 h k a* b* U12 ]

______________________________________________________________________________

U11 U22 U33 U23 U13 U12

______________________________________________________________________________

Br1 41(1) 16(1) 38(1) 0(1) 12(1) 1(1)

O1 26(1) 16(1) 32(1) 3(1) 10(1) 5(1)

O2 56(1) 20(1) 41(1) -8(1) 28(1) -6(1)

O3 56(1) 18(1) 36(1) -4(1) 30(1) -4(1)

O4 68(1) 50(1) 32(1) 9(1) 17(1) -17(1)

C1 22(1) 17(1) 28(1) 1(1) 9(1) 1(1)

C2 25(1) 31(1) 31(1) 0(1) 3(1) -3(1)

C3 35(1) 37(1) 20(1) 0(1) 4(1) -3(1)

C4 31(1) 32(1) 26(1) 5(1) 11(1) 1(1)

C5 23(1) 20(1) 25(1) 0(1) 9(1) -4(1)

C6 32(1) 24(1) 32(1) 0(1) 14(1) -6(1)

C7 34(1) 13(1) 34(1) 2(1) 11(1) -1(1)

C8 33(1) 19(1) 30(1) -3(1) 12(1) 1(1)

C9 32(1) 21(1) 21(1) -3(1) 10(1) -1(1)

C10 30(1) 17(1) 24(1) 1(1) 11(1) 2(1)

C11 21(1) 14(1) 23(1) 2(1) 8(1) 3(1)

C12 22(1) 32(1) 32(1) -4(1) 10(1) 2(1)

C13 33(1) 34(1) 47(2) -5(1) 1(1) 7(1)

C14 43(1) 38(1) 26(1) -1(1) 1(1) -3(1)

______________________________________________________________________________

S31

Table S7. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2 x 10 3) for 11.

________________________________________________________________________________

x y z U(eq)

________________________________________________________________________________

H1A 200(30) -390(30) 2290(20) 23(5)

H2A -490(30) -1190(30) 200(20) 27(6)

H2B -410(40) 630(40) 320(30) 49(8)

H3A 2700(40) -1190(30) -100(30) 42(7)

H3B 1410(30) -50(30) -1060(20) 29(6)

H6A 4310(30) 3530(30) 1300(20) 26(6)

H6B 5850(30) 3120(30) 2470(20) 36(7)

H7A 2730(30) 4320(40) 2752(18) 14(7)

H8A 5140(30) 2850(30) 4410(20) 35(6)

H10A 4660(30) 170(30) 3960(20) 29(6)

H12A 6720(30) 650(30) 1480(30) 34(7)

H12B 5640(30) -750(30) 1660(20) 28(6)

H12C 6550(30) 250(30) 2820(30) 35(7)

H13A -750(30) 2210(40) 3720(30) 53(8)

H13B -770(40) 2780(50) 5080(30) 60(9)

H13C -1090(40) 990(30) 4860(30) 41(7)

H14A 3490(50) 1180(40) 6650(30) 54(9)

H14B 1570(40) 320(30) 6680(30) 41(7)

H14C 1980(30) 2130(40) 6890(30) 53(8)

________________________________________________________________________________

S32

Table S8. Torsion angles [°] for 11.

_________________________________________________________________________________________

C11-C1-C2-C3 53.1(2)

Br1-C1-C2-C3 -69.2(2)

C1-C2-C3-C4 -55.8(3)

C2-C3-C4-O4 -133.3(2)

C2-C3-C4-C5 50.5(3)

O4-C4-C5-C12 -88.5(3)

C3-C4-C5-C12 87.7(2)

O4-C4-C5-C6 33.8(3)

C3-C4-C5-C6 -150.02(19)

O4-C4-C5-C11 144.5(2)

C3-C4-C5-C11 -39.3(2)

C12-C5-C6-C7 -129.41(19)

C4-C5-C6-C7 112.88(18)

C11-C5-C6-C7 -4.0(2)

C11-O1-C7-C8 -57.57(18)

C11-O1-C7-C6 55.94(17)

C5-C6-C7-O1 -31.30(19)

C5-C6-C7-C8 77.4(2)

C9-O2-C8-C7 109.9(2)

C9-O2-C8-C10 0.5(2)

O1-C7-C8-O2 -76.1(2)

C6-C7-C8-O2 175.05(18)

O1-C7-C8-C10 35.81(18)

C6-C7-C8-C10 -73.00(18)

C8-O2-C9-O3 -0.5(2)

C8-O2-C9-C13 -119.41(19)

C8-O2-C9-C14 116.8(2)

C10-O3-C9-O2 0.3(2)

C10-O3-C9-C13 119.4(2)

C10-O3-C9-C14 -117.6(2)

C9-O3-C10-C11 -109.80(19)

C9-O3-C10-C8 0.0(2)

O2-C8-C10-O3 -0.3(2)

C7-C8-C10-O3 -118.05(16)

O2-C8-C10-C11 116.34(16)

C7-C8-C10-C11 -1.42(17)

C7-O1-C11-C1 177.47(17)

C7-O1-C11-C10 55.48(16)

C7-O1-C11-C5 -57.92(17)

C2-C1-C11-O1 67.7(2)

Br1-C1-C11-O1 -169.83(12)

C2-C1-C11-C10 179.97(16)

Br1-C1-C11-C10 -57.59(19)

C2-C1-C11-C5 -45.0(2)

Br1-C1-C11-C5 77.4(2)

O3-C10-C11-O1 78.80(18)

C8-C10-C11-O1 -33.01(16)

O3-C10-C11-C1 -36.4(2)

C8-C10-C11-C1 -148.19(16)

O3-C10-C11-C5 -175.04(15)

C8-C10-C11-C5 73.15(18)

C12-C5-C11-O1 160.44(17)

C4-C5-C11-O1 -79.39(19)

C6-C5-C11-O1 37.80(19)

C12-C5-C11-C1 -83.6(2)

C4-C5-C11-C1 36.5(2)

C6-C5-C11-C1 153.72(18)

C12-C5-C11-C10 53.8(2)

C4-C5-C11-C10 173.96(17)

C6-C5-C11-C10 -68.85(19)

_________________________________________________________________________________________

S33

X-ray Experimental for 18a (C15H17O3Cl2Br): Crystals grew as colorless needles by slow

evaporation from 10% ethyl acetate–hexanes. The data crystal was a needle that had

approximate dimensions; 0.24×0.06×0.05 mm. The data were collected on a Nonius Kappa

CCD diffractometer using a graphite monochromator with MoKα radiation (λ = 0.71073Å). A

total of 322 frames of data were collected using ω-scans with a scan range of 1.1° and a counting

time of 197 seconds per frame. The data were collected at 153 K using an Oxford Cryostream

low temperature device. Details of crystal data, data collection and structure refinement are

listed in Table S9. Data reduction were performed using DENZO-SMN.S2

The structure was

solved by direct methods using SIR97S3

and refined by full-matrix least-squares on F2 with

anisotropic displacement parameters for the non-H atoms using SHELXL-97.S4

The hydrogen

atoms on carbon were calculated in ideal positions with isotropic displacement parameters set to

1.2×Ueq of the attached atom (1.5×Ueq for methyl hydrogen atoms). The hydrogen atom on the

hydroxyl oxygen atom, O16, was observed in a ΔF map and refined with an isotropic

displacement parameter. The function, Σw(|Fo|2 – |Fc|

2)2, was minimized, where w = 1 / [(σ(Fo))

2

+ (0.0248*P)2 + (0.574*P)] and P = (|Fo|

2 + 2|Fc|

2) / 3. Rw(F

2) refined to 0.0846, with R(F) equal

to 0.0440 and a goodness of fit, S, = 1.02. Definitions used for calculating R(F), Rw(F2) and the

goodness of fit, S, are given below.S5

The data were checked for secondary extinction but no

correction was necessary. Neutral atom scattering factors and values used to calculate the linear

absorption coefficient are from the International Tables for X-ray Crystallography (1992).S6

All

figures were generated using ORTEP-3.S7

Tables of positional and thermal parameters, bond

lengths and angles, torsion angles, figures and lists of observed and calculated structure factors

are located in Tables S9 through S14.

S34

Table S9. Crystal data and structure refinement for 18a.

Empirical formula C15 H17 Br Cl2 O3

Formula weight 396.10

Temperature 153(2) K

Wavelength 0.71070 Å

Crystal system Orthorhombic

Space group P212121

Unit cell dimensions a = 7.1360(2) Å = 90°.

b = 14.0600(4) Å = 90°.

c = 16.6160(5) Å = 90°.

Volume 1667.12(8) Å3

Z 4

Density (calculated) 1.578 Mg/m3

Absorption coefficient 2.792 mm-1

F(000) 800

Crystal size 0.24 x 0.06 x 0.05 mm3

Theta range for data collection 1.90 to 29.99°.

Index ranges -9<=h<=9, -19<=k<=19, -23<=l<=23

Reflections collected 16966

Independent reflections 4671 [R(int) = 0.0555]

Completeness to theta = 29.99° 99.6 %

Absorption correction Analytical

Max. and min. transmission 0.880 and 0.650

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 4671 / 0 / 196

Goodness-of-fit on F2 1.022

Final R indices [I>2sigma(I)] R1 = 0.0440, wR2 = 0.0725

R indices (all data) R1 = 0.0902, wR2 = 0.0846

Absolute structure parameter -0.017(8)

Largest diff. peak and hole 0.315 and -0.444 e.Å-3

S35

Table S10. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 18a. U(eq)

is defined as one third of the trace of the orthogonalized Uij tensor.

________________________________________________________________________________

x y z U(eq)

________________________________________________________________________________

Br1 11234(1) 841(1) 6397(1) 55(1)

Cl1 4461(1) 4522(1) 8245(1) 53(1)

Cl2 5819(1) 2575(1) 8221(1) 47(1)

O1 9189(3) 4877(1) 6059(1) 32(1)

C2 9864(4) 5775(2) 6091(2) 35(1)

C3 8345(4) 6484(2) 5913(2) 35(1)

C4 6944(4) 5873(2) 5437(2) 33(1)

C5 7236(4) 4885(2) 5791(2) 30(1)

C6 5943(4) 4678(2) 6498(2) 31(1)

C7 6582(4) 3807(2) 6997(2) 28(1)

C8 7066(4) 2930(2) 6502(2) 28(1)

C9 8786(4) 2446(2) 6628(2) 29(1)

C10 9042(4) 1602(2) 6208(2) 36(1)

C11 7785(5) 1251(2) 5653(2) 40(1)

C12 6155(5) 1753(2) 5518(2) 40(1)

C13 5771(4) 2574(2) 5952(2) 33(1)

C15 9054(5) 7378(2) 5507(2) 41(1)

C17 5076(4) 3544(2) 7606(2) 35(1)

C18 10247(4) 2837(2) 7189(2) 43(1)

O14 11476(3) 5924(2) 6271(2) 48(1)

O16 4124(3) 4507(2) 6178(1) 40(1)

________________________________________________________________________________

S36

Table S11. Bond lengths [Å] and angles [°] for 18a.

_________________________________________________________________________________________

Br1-C10 1.921(3)

Cl1-C17 1.792(3)

Cl2-C17 1.783(3)

O1-C2 1.352(4)

O1-C5 1.463(4)

C2-O14 1.207(3)

C2-C3 1.502(4)

C3-C15 1.513(4)

C3-C4 1.538(4)

C3-H3 1.00

C4-C5 1.523(4)

C4-H4A 0.9900

C4-H4B 0.9900

C5-C6 1.522(4)

C5-H5 1.00

C6-O16 1.423(3)

C6-C7 1.547(4)

C6-H6 1.00

C7-C17 1.522(4)

C7-C8 1.522(4)

C7-H7 1.00

C8-C13 1.392(4)

C8-C9 1.419(4)

C9-C10 1.390(4)

C9-C18 1.502(4)

C10-C11 1.378(4)

C11-C12 1.379(5)

C11-H11 0.95

C12-C13 1.389(4)

C12-H12 0.95

C13-H13 0.95

C15-H15A 0.98

C15-H15B 0.98

C15-H15C 0.98

C17-H17 1.00

C18-H18A 0.98

C18-H18B 0.98

C18-H18C 0.98

O16-H16 0.74(3)

C2-O1-C5 110.2(2)

O14-C2-O1 120.7(3)

O14-C2-C3 128.4(3)

O1-C2-C3 110.8(2)

C2-C3-C15 113.4(3)

C2-C3-C4 101.5(2)

C15-C3-C4 116.8(3)

C2-C3-H3 108.2

C15-C3-H3 108.2

C4-C3-H3 108.2

C5-C4-C3 102.8(2)

C5-C4-H4A 111.2

C3-C4-H4A 111.2

C5-C4-H4B 111.2

C3-C4-H4B 111.2

H4A-C4-H4B 109.1

O1-C5-C6 110.0(2)

O1-C5-C4 104.7(2)

C6-C5-C4 112.9(2)

O1-C5-H5 109.7

C6-C5-H5 109.7

C4-C5-H5 109.7

O16-C6-C5 107.3(2)

O16-C6-C7 109.6(2)

C5-C6-C7 112.7(2)

O16-C6-H6 109.1

S37

C5-C6-H6 109.1

C7-C6-H6 109.1

C17-C7-C8 108.8(2)

C17-C7-C6 109.9(2)

C8-C7-C6 114.7(2)

C17-C7-H7 107.7

C8-C7-H7 107.7

C6-C7-H7 107.7

C13-C8-C9 120.0(3)

C13-C8-C7 119.7(3)

C9-C8-C7 120.3(2)

C10-C9-C8 116.7(3)

C10-C9-C18 122.2(3)

C8-C9-C18 121.1(3)

C11-C10-C9 123.8(3)

C11-C10-Br1 116.1(2)

C9-C10-Br1 120.0(2)

C10-C11-C12 118.4(3)

C10-C11-H11 120.8

C12-C11-H11 120.8

C11-C12-C13 120.5(3)

C11-C12-H12 119.8

C13-C12-H12 119.8

C12-C13-C8 120.6(3)

C12-C13-H13 119.7

C8-C13-H13 119.7

C3-C15-H15A 109.5

C3-C15-H15B 109.5

H15A-C15-H15B 109.5

C3-C15-H15C 109.5

H15A-C15-H15C 109.5

H15B-C15-H15C 109.5

C7-C17-Cl2 110.9(2)

C7-C17-Cl1 112.4(2)

Cl2-C17-Cl1 108.64(17)

C7-C17-H17 108.3

Cl2-C17-H17 108.3

Cl1-C17-H17 108.3

C9-C18-H18A 109.5

C9-C18-H18B 109.5

H18A-C18-H18B 109.5

C9-C18-H18C 109.5

H18A-C18-H18C 109.5

H18B-C18-H18C 109.5

C6-O16-H16 117(2)

_________________________________________________________________________________________

S38

Table S12. Anisotropic displacement parameters (Å2x 103) for 18a. The anisotropic displacement factor exponent

takes the form: -2π2[ h2 a*2U11 + ... + 2 h k a* b* U12 ]

______________________________________________________________________________

U11 U22 U33 U23 U13 U12

______________________________________________________________________________

Br1 56(1) 57(1) 53(1) 2(1) 9(1) 27(1)

Cl1 54(1) 54(1) 52(1) -12(1) 20(1) 0(1)

Cl2 49(1) 51(1) 40(1) 13(1) 7(1) -4(1)

O1 27(1) 28(1) 40(1) 3(1) 2(1) 4(1)

C2 34(2) 30(2) 40(2) 1(2) 1(1) 2(1)

C3 33(2) 32(2) 40(2) 3(2) 0(2) 2(1)

C4 34(2) 31(2) 35(2) 2(2) -3(1) -1(1)

C5 33(2) 28(2) 29(2) 0(1) -5(1) 0(1)

C6 29(2) 25(1) 39(2) -7(1) 0(2) 1(1)

C7 24(2) 29(2) 30(2) -1(1) -2(1) -1(1)

C8 31(2) 27(2) 25(2) 3(1) 2(1) -3(1)

C9 27(1) 31(2) 28(2) 8(1) 2(1) -4(1)

C10 33(2) 38(2) 37(2) 10(1) 9(2) 7(1)

C11 54(2) 33(2) 32(2) -2(1) 9(2) -1(2)

C12 50(2) 37(2) 33(2) -2(1) -2(2) -9(2)

C13 32(2) 31(2) 36(2) 1(1) -7(1) -4(1)

C15 42(2) 34(2) 47(2) 8(2) -3(2) 0(2)

C17 33(2) 38(2) 35(2) -5(1) 2(1) 2(2)

C18 32(2) 48(2) 49(2) 3(2) -6(2) 8(2)

O14 25(1) 39(1) 79(2) -1(1) -8(1) 3(1)

O16 25(1) 39(1) 54(2) -5(1) -11(1) 5(1)

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S39

Table S13. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for 18a.

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x y z U(eq)

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H3 7744 6670 6434 42

H4A 5642 6095 5520 40

H4B 7232 5882 4854 40

H5 7051 4393 5363 36

H6 5895 5249 6856 37

H7 7730 3996 7303 33

H11 8035 678 5370 48

H12 5288 1535 5125 48

H13 4614 2896 5874 40

H15A 10081 7649 5824 61

H15B 8032 7842 5468 61

H15C 9506 7222 4966 61

H17 3930 3342 7305 42

H18A 11391 2455 7146 64

H18B 9778 2814 7743 64

H18C 10524 3498 7043 64

H16 3410(40) 4880(20) 6249(18) 23(9)

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S40

Table S14. Torsion angles [°] for 18a.

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C5-O1-C2-O14 -177.4(3)

C5-O1-C2-C3 5.0(3)

O14-C2-C3-C15 33.7(5)

O1-C2-C3-C15 -149.0(3)

O14-C2-C3-C4 159.8(3)

O1-C2-C3-C4 -22.9(3)

C2-C3-C4-C5 30.4(3)

C15-C3-C4-C5 154.3(3)

C2-O1-C5-C6 -106.2(3)

C2-O1-C5-C4 15.4(3)

C3-C4-C5-O1 -28.6(3)

C3-C4-C5-C6 91.1(3)

O1-C5-C6-O16 -168.6(2)

C4-C5-C6-O16 74.7(3)

O1-C5-C6-C7 -47.9(3)

C4-C5-C6-C7 -164.5(2)

O16-C6-C7-C17 -51.5(3)

C5-C6-C7-C17 -170.9(2)

O16-C6-C7-C8 71.5(3)

C5-C6-C7-C8 -48.0(3)

C17-C7-C8-C13 70.1(3)

C6-C7-C8-C13 -53.5(3)

C17-C7-C8-C9 -106.5(3)

C6-C7-C8-C9 129.9(3)

C13-C8-C9-C10 -2.6(4)

C7-C8-C9-C10 174.0(3)

C13-C8-C9-C18 177.2(3)

C7-C8-C9-C18 -6.2(4)

C8-C9-C10-C11 3.9(4)

C18-C9-C10-C11 -175.9(3)

C8-C9-C10-Br1 -175.25(19)

C18-C9-C10-Br1 5.0(4)

C9-C10-C11-C12 -1.6(5)

Br1-C10-C11-C12 177.6(2)

C10-C11-C12-C13 -2.1(5)

C11-C12-C13-C8 3.2(5)

C9-C8-C13-C12 -0.8(4)

C7-C8-C13-C12 -177.4(3)

C8-C7-C17-Cl2 56.2(3)

C6-C7-C17-Cl2 -177.4(2)

C8-C7-C17-Cl1 178.0(2)

C6-C7-C17-Cl1 -55.6(3)

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S41

S42

S43

S44

S45

S46

S47

S48

S49

S50

S51

S52

S53

S54

S55

S56