Núria Llor, †Elies Molins, Joan Bosch* and Mercedes Amat*€¦ · S1 Enantioselective total synthesis of fluvirucinin B 1 Guillaume Guignard,† †Núria Llor, †Elies Molins,‡

S1

Enantioselective total synthesis of fluvirucinin B1

Guillaume Guignard,† Núria Llor,† Elies Molins,‡ Joan Bosch*†, and Mercedes Amat*†

† Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institute of Biomedicine (IBUB), University of

Barcelona, 08028-Barcelona, Spain ‡

Institut de Ciència de Materials (CSIC), Campus UAB, 08193-Cerdanyola, Spain

Supporting Information Available

I) Experimental procedures and spectroscopic data: pages S1-S17

II) Copies of 1H and

13C NMR spectra: pages S18-S48

III) X- ray crystallographic data for compound 18: pages S49-S59

Experimental procedures and spectroscopic data

General Procedures. All air sensitive reactions were performed under a dry argon or nitrogen

atmosphere with dry, freshly distilled solvents using standard procedures. Drying of organic

extracts during the work-up of reactions was performed over anhydrous Na2SO4 or MgSO4.

Evaporation of solvent was accomphished with a rotatory evaporator. Thin-layer chromatography

was done on SiO2 (silica gel 60 F254), and the spots were located by UV and either a 1% KMnO4

solution or hexachloroplatinate reagent. Chromatography refers to flash column chromatography

and was carried out on SiO2 (silica gel 60, 230-400 mesh). Melting points were determined in a

capillary tube and are uncorrected. NMR spectra were recorded at 400 MHz (1H) and 100.6 MHz

(13C), and chemical shifts are reported in values, in parts per million (ppm) relative to Me4Si (0

ppm) or relative to residual chloroform (7.26 ppm, 77.0 ppm) or benzene (7.15 ppm, 128.0 ppm)

as an internal standard. Data are reported in the following manner: chemical shift, multiplicity,

coupling constant (J) in hertz (Hz), integrated intensity, and assignment (when possible).

Assignments and stereochemical determinations are given only when they are derived from

definitive two-dimensional NMR experiments (HSQC-COSY). IR spectra were performed in a

spectrophotometer Nicolet Avatar 320 FT-IR and only noteworthy IR absorptions (cm-1) are listed.

Optical rotation were measured on Perlin-Elmer 241 polarimeter. []D values are given in 10-1 deg

cm2 g

-1. High resolution mass spectra (HMRS) were performed by Centres Científics i Tecnològics

de la Universitat de Barcelona.

S2

5-{[(1R)-2-Hydroxy-1-phenylethyl]amino}-1-pentanol (4e): n-BuLi (3.56

mL of a 2.5 M solution in hexanes, 8.9 mmol) was added to a solution of NH3.BH3 (275 mg, 8.9

mmol) in anhydrous THF (5 mL) at 0 ºC, and the resulting mixture was stirred at this temperature

for 10 min and at room temperature for 15 minutes. Then, the mixture was added to a solution of

3e1 (450 mg, 2.07 mmol) in anhydrous THF (10 mL), and the stirring was continued at 40 ºC for 1

h. The reaction mixture was quenched with H2O, and the resulting solution was extracted with

Et2O. The combined organic extracts were dried, filtered, and concentrated. Flash chromatography

(from 1:1 hexaneEtOAc to 8:2 EtOAcEtOH) of the residue gave aminodiol 4e (310 mg, 67%):

[]22

D 54.2 (c 1.25 in CHCl3); H (400 MHz; CDCl3; Me4Si) 1.37-1.43 (m, 2H, H-3), 1.47-1.58 (m,

4H, H-2, H-4), 2.46-2.60 (m, 2H, H-5), 3.45 (br.s, 3H, OH, NH), 3.55 (dd, J = 10.5, 8.5 Hz, 1H,

CH2O), 3.62 (t, J = 6.4 Hz, 2H, H-1), 3.71 (dd, J = 10.5, 4.4 Hz, 1H, CH2O), 3.76 (dd, J = 8.5, 4.4

Hz, 1H, CH), 7.26-7.30 (m, 3H, ArH), 7.33-7.37 (m, 2H, ArH); C (100.6 MHz; CDCl3; Me4Si)23.2

(C-3), 29.2 (C-4), 32.1 (C-2), 47.0 (C-5), 61.9 (C-1), 64.6 (CH), 66.4 (CH2O), 127.3 (C-o), 127.5

(C-p), 128.5 (C-m), 140.1 (C-i); HRMS (ESI-TOF) m/z [M + H]+ Calcd for C13H22NO2 224.1645,

found 224.1638.

(S)-5-[(tert-Butyldiphenylsilyl)oxy]-N-{(R)-2-[(tert-

butyldiphenylsilyl)oxy]-1-phenylethyl}-4-ethyl-1-pentanamine (5a): tert-Butyldiphenylsilyl

chloride (9.1 mL, 34.8 mmol) and imidazole (3.39 g, 34.8 mmol) were added to a solution of

aminodiol 4a2 (4.18 g, 16.6 mmol) in anhydrous CH2Cl2 (140 mL), and the mixture was heated at

reflux for 17 h. Saturated aqueous NH4Cl was added, and the mixture was extracted with CH2Cl2.

The combined organic extracts were dried, filtered, and concentrated. The resulting residue was

chromatographed (from hexane to 9:1 hexaneEt2O) to afford pure compound 5a (9.7 g, 81%) as

a colorless oil: []22

D 13.55 (c 1.0 in CHCl3); IR (film): = 3070, 2958, 2858, 1471, 1427, 1112 cm-

1; H (400 MHz; CDCl3; Me4Si) 0.82 (t, J = 7.2 Hz, 3H, CH3CH2), 1.05 [s, 18H, 2(CH3)3], 1.30-1.38

(m, 3H, H-2, CH3CH2), 1.38-1.48 (m, 4H, H-3, H-4, CH3CH2,), 1.90 (br.s, 1H, NH), 2.39-2.49 (m,

2H, H-1), 3.53 (dd, J = 4.5, 2.0 Hz, 2H, H-5), 3.63-3.70 (m, 2H, CH2O), 3.77 (dd, J = 8.1, 4.7 Hz,

1H, CHN), 7.19-7.26 (m, 5H, ArH), 7.32-7.44 (m, 12H, ArH), 7.60-7.67 (m, 8H, ArH); C (100.6

MHz; CDCl3; Me4Si) 11.2 (CH3CH2), 19.2 and 19.3 (CMe3), 23.5 (CH3CH2), 26.8 and 26.9 [(CH3)3],

27.7 (C-3), 28.8 (C-2), 42.0 (C-4), 48.2 (C-1), 65.1 (CHN), 65.8 (C-5), 69.0 (CH2O), 127.2 (CHAr),

S3

127.5 (CHAr), 127.6 (CHAr), 127.7 (CHAr), 128.2 (CHAr), 129.5 (CHAr), 129.6 (CHAr), 129.7

(CHAr), 133.3 (C-i), 133.5 (C-i), 134.1 (C-i), 134.1 (C-i), 135.6 (CHAr), 135.6 (CHAr), 141.1 (C-i);

HRMS (ESI-TOF) m/z [M + H] + Calcd for C47H62NO2Si2 728.4314, found 728.4314.

(S)-4-Benzyl-5-[(tert-butyldiphenylsilyl)oxy]-N-{(R)-2-

[(tert-butyldiphenylsilyl)oxy]-1-phenylethyl}-1-pentanamine (5b): Following the procedure

described for the preparation of 5a, from aminodiol 4b2 (510 mg, 1.63 mmol), tert-butyldiphenylsilyl

chloride (0.97 mL, 3.75 mmol), and imidazole (333 mg, 4.88 mmol) in anhydrous CH2Cl2 (15 mL),

amine 5b was obtained (990 mg, 77%) after column chromatography (96:4 hexaneEtOAc): []22

D

13.28 (c 1.0 in CHCl3); IR (film): = 2930, 2857, 1428, 1112 cm-1

; H (400 MHz; CDCl3; Me4Si)

0.96 [s, 9H, (CH3)3], 0.99 [s, 9H, (CH3)3], 1.25-1.34 (m, 4H, H-2, H-3), 1.58 (br.s, 1H, NH), 1.65-

1.72 (m, 1H, H-4), 2.29-2.33 (m, 2H, H-1), 2.48 (dd, J = 13.5, 6.8 Hz, 1H, CH2Ar), 2.73 (dd, J =

13.5, 7.1 Hz, 1H, CH2Ar), 3.41 (dd, J = 10.1, 5.4 Hz, 1H, H-5), 3.48 (dd, J = 10.1, 4.5 Hz, 1H, H-5),

3.53-3.61 (m, 2H, CH2O), 3.63-3.68 (m, 1H, CHN), 7.02-7.18 (m, 12H, ArH), 7.24-7.33 (m, 12H,

ArH), 7.51-7.57 (m, 6H, ArH); C (100.6 MHz; CDCl3; Me4Si)19.2 and 19.3 (CMe3), 26.8 and 27.0

[(CH3)3], 27.7 (C-3), 28.4 (C-2), 37.6 (CH2Ar), 42.6 (C-4), 48.0 (C-1), 64.9 (C-5), 65.0 (CHN), 68.9

(CH2O), 125.6 (CHAr), 127.2 (CHAr), 127.5 (CHAr), 127.6 (CHAr), 127.6 (CHAr), 127.6 (CHAr),

128.1 (CHAr), 128.2 (CHAr), 129.2 (CHAr), 129.5 (CHAr), 129.5 (CHAr), 129.6 (CHAr), 129.7

(CHAr), 133.3 (C-i), 133.4 (C-i), 133.8 (C-i), 133.9 (C-i), 134.8 (CHAr), 135.5 (CHAr), 135.5

(CHAr), 135.6 (CHAr), 140.9 (C-i), 141.0 (C-i); HRMS (ESI-TOF) m/z [M + H]+ Calcd for

C52H64NO2Si2 790.4470, found 790.4465.

(S)-4-Benzyl-5-[(tert-butyldiphenylsilyl)oxy]-N-{(R)-2-[(tert-

butyldiphenylsilyl)oxy]-1-phenylethyl}-4-ethyl-1-pentanamine (5c): Following the procedure

described for the preparation of 5a, from aminodiol 4c2 (240 mg, 0.70 mmol), tert-butyldiphenylsilyl


amine 5c was obtained (414 mg, 72%) after column chromatography (from hexane to 95:5

hexaneEtOAc): []22

D 5.67 (c 1.15 in CHCl3); IR (film): = 3070, 2930, 2857, 1471, 1428, 1112

cm-1; H (400 MHz; CDCl3; Me4Si) 0.86 (t, J = 7.4 Hz, 3H, CH3CH2), 1.18 [s, 9H, (CH3)3], 1.19-1.26

S4

(m, 2H, H-3), 1.27 [s, 9H, (CH3)3], 1.31-1.38 (m, 1H, H-2), 1.39-1.48 (m, 2H, H-2, CH2CH3), 1.53-

1.64 (m, 1H, CH2CH3), 2.50-2.54 (m, 2H, H-1), 2.75 (d, J = 13.2 Hz, 1H, CH2Ar), 2.81 (d, J = 13.2

Hz, 1H, CH2Ar), 3.38 (d, J = 10.0 Hz, 1H, H-5), 3.42 (d, J = 10.0 Hz, 1H, H-5), 3.80-3.84 (m, 2H,

CH2O), 3.89 (dd, J = 8.0, 4.8 Hz, 1H, CHN), 7.34-7.40 (m, 10H, ArH), 7.44-7.56 (m, 12H, ArH),

7.72-7.76 (m, 4H, ArH), 7.78-7.81 (m, 4H, ArH); C (100.6 MHz; CDCl3; Me4Si)7.6 (CH3CH2), 19.2

and 19.4 (CMe3), 23.7 (CH3CH2), 25.4 (C-2), 26.9 and 27.1 [(CH3)3], 30.0 (C-3), 39.8 (CH2Ar), 41.8

(C-1), 48.5 (C-4), 65.0 (CHN), 66.1 (C-5), 68.9 (CH2O), 125.7 (CHAr), 127.2 (CHAr), 127.5

(CHAr), 127.6 (CHAr), 127.7 (CHAr), 128.2 (CHAr), 129.6 (CHAr), 129.6 (CHAr), 129.7 (CHAr),

130.5 (CHAr), 133.3 (C-i), 133.4 (C-i), 133.8 (C-i), 135.5 (CHAr), 135.5 (CHAr), 135.8 (CHAr),

135.9 (CHAr), 138.8 (C-i); HRMS (ESI-TOF) m/z [M + H] +

Calcd for C54H68NO2Si2 818.4783,

found 818.4773.

(3R,4S)-5-[(tert-Butyldiphenylsilyl)oxy]-N-

{(R)-2-[(tert-butyldiphenylsilyl)oxy]-1-phenylethyl}-3,4-(isopropylidenedioxy)-1-pentanamine

(5d): Following the procedure described for the preparation of 5a, from aminodiol 4d2 (95 mg, 0.32

mmol), tert-butyldiphenylsilyl chloride (0.17 mL, 0.64 mmol), and imidazole (22 mg, 0.97 mmol) in

anhydrous CH2Cl2 (3.5 mL), amine 5d was obtained (174 mg, 70%) after column chromatography

(from 95:5 hexaneEtOAc to EtOAc): []22

D 4.32 (c 1.35 in CHCl3); IR (film): = 2930, 2857,

1428, 1112 cm-1; H (400 MHz; CDCl3; Me4Si) 1.03 [s, 9H, (CH3)3], 1.04 [s, 9H, (CH3)3], 1.82 (br.s,

2H, H-2), 2.67 (br.s, 2H, H-1), 3.60 (dd, J = 10.5, 5.1 Hz, 1H, H-5), 3.65-3.73 (m, 3H, H-5, CH2O),

3.79 (br.s, 1H, CHN), 4.11-4.16 (m, 1H, H-4), 4.26-4.30 (m, 1H, H-3), 7.22-7.28 (m, 5H, ArH),

7.32-7.44 (m, 12H, ArH), 7.56-7.67 (m, 8H, ArH); C (100.6 MHz; CDCl3; Me4Si)19.1 and 19.2

(CMe3), 25.5 (CH3), 26.8 and 26.9 [(CH3)3], 28.0 (CH3), 29.6 (C-2), 45.2 (C-1), 62.5 (C-5), 64.5

(CHN), 67.8 (CH2O), 76.5 (C-3), 77.7 (C-4), 108.3 (CMe2), 127.6 (CHAr), 127.7 (CHAr), 127.7

(CHAr), 127.8 (CHAr), 128.4 (CHAr), 129.6 (CHAr), 129.7 (CHAr), 132.8 (C-i), 133.0 (C-i), 133.1

(C-i), 133.2 (C-i), 135.5 (CHAr); HRMS (ESI-TOF) m/z [M + H] +

Calcd for C48H62NO4Si2 772.4212,

found 772.4223.

S5

(R)-5-[(tert-Butyldiphenylsilyl)oxy]-N-

{2-[(tert-butyldiphenylsilyl)oxy]-1-phenylethyl}-1-pentanamine (5e): Following the procedure

described for the preparation of 5a, from aminodiol 4e (430 mg, 1.93 mmol), tert-butyldiphenylsilyl


amine 5e was obtained (890 mg, 72%) after column chromatography (from hexane to 8:2

hexaneEtOAc): []22

D 13.3 (c 1.3 in CHCl3); H (400 MHz; CDCl3; Me4Si) 1.10 [s, 9H, (CH3)3],

1.11 [s, 9H, (CH3)3], 1.46 (m, 2H, CH2), 1.53 (m, 2H, CH2), 1.63 (m, 2H, CH2), 2.52 (m, 2H, H-1),

3.71 (t, J = 6.5 Hz, 2H, H-5), 3.74 (m, 2H, CH2O), 3.83 (dd, J = 8.4, 4.0 Hz, 1H, CHN), 7.30-7.32

(m, 4H, ArH), 7.39-7.46 (m, 13H, ArH), 7.66-7.74 (m, 8H, ArH); C (100.6 MHz; CDCl3; Me4Si)19.2

(CMe3), 23.5 (C-3), 26.8 and 26.9 [(CH3)3], 30.0 (C-2), 32.5 (C-4), 47.6 (C-1), 63.9 and 65.1 (C-5,

CH2O), 68.9 (CH), 127.2 (CHAr), 127.5 (CHAr), 127.6 (CHAr), 128.2 (CHAr), 129.5 (CHAr), 129.6

(CHAr), 129.7 (CHAr), 133.3 (C-i), 133.5 (C-i), 134.1 (C-i), 134.9 (C-i), 135.5 (CHAr), 140.9 (C-i);

HRMS (ESI-TOF) m/z [M + H] + Calcd for C45H58NO2Si2 700.4001, found 700.3996.

(S)-5-[(tert-Butyldiphenylsilyl)oxy]-4-ethylpentanoic acid (6a): A solution

of amine 5a (2.15 g, 2.96 mmol) in CH2Cl2 (5 mL) was added to a solution of m-chloroperbenzoic

acid (70% of purity, 3.06 g, 12.4 mmol) in CH2Cl2 (28 mL) at reflux temperature, and the resulting

mixture was stirred at this temperature for 3 h. The reaction was quenched by addition of

saturated aqueous NaHCO3, and the mixture was extracted with CH2Cl2. The combined organic

extracts were dried, filtered, and concentrated, and the resulting residue (350 mg) was

chromatographed (from 1:1 hexaneCH2Cl2, CH2Cl2 to EtOAc) to afford the nitroso dimer 8 (420

mg) and carboxylic acid 6a (yellow oil; 930 mg, 82%). 8: IR (film): = 3070, 2857, 1589, 1495,

1471, 1427, 1211, 1104 cm-1; H (400 MHz; CDCl3; Me4Si) 1.00 [s, 9H, (CH3)3], 3.82 (dd, J = 10.8,

5.2 Hz, 1H, CH2O), 4.50 (dd, J = 10.8, 8.6 Hz, 1H, CH2O), 6.29 (dd, J = 8.6, 5.2 Hz, 1H, CHN),

7.00-7.02 (m, 2H, ArH), 7.11-7.14 (m, 2H, ArH), 7.18-7.23 (m, 1H, ArH), 7.30-7.41 (m, 6H, ArH),

7.54-7.57 (m, 2H, ArH), 7.67-7.69 (m, 2H, ArH); C (100.6 MHz; CDCl3; Me4Si)19.1 (CMe3), 26.7

[(CH3)3], 63.8 (CH2), 72.4 (CHN), 127.7 (CHAr), 127.7(CHAr), 127.8 (CHAr), 128.3 (CHAr), 128.5

(CHAr), 129.7 (CHAr), 129.7 (CHAr), 132.2 (C-i), 132.9 (C-i), 133.0 (C-i), 135.5 (CHAr), 135.6

(CHAr); HRMS (ESI-TOF) m/z [M + H]+ Calcd for C48H55N2O4Si2 779.3695, found 779.3683. 6a:

[]22

D 1.96 (c 1.36 in CHCl3); IR (film): = 2960, 2931, 1709 cm-1

; H (400 MHz; CDCl3; Me4Si)

S6

0.86 (t, J = 7.3 Hz, 3H, CH3CH2), 1.08 [s, 9H, (CH3)3], 1.32-1.45 (m, 2H, CH3CH2), 1.45-1.51 (m,

1H, H-4), 1.67-1.83 (m, 2H, H-3), 2.29-2.42 (m, 2H, H-2), 3.58 (dd, J = 10.2, 5.2 Hz, 1H, H-5),

3.59 (dd, J = 10.2, 5.2 Hz, 1H, H-5), 7.38-7.46 (m, 6H, ArH), 7.67-7.70 (m, 4H, ArH); C (100.6

MHz; CDCl3; Me4Si) 11.2 (CH3CH2), 19.3 (CMe3), 23.5 (CH3CH2), 25.9 (C-3), 26.9 [(CH3)3], 31.7

(C-2), 41.5 (C-4), 65.3 (C-5), 127.6 (C-o), 129.6 (C-p), 133.8 (C-i), 133.8 (C-i), 135.6 (C-m), 180.4

(CO); HRMS (ESI-TOF) m/z [M + H] + Calcd for C23H33O3Si 385.2193, found 385.2188.

(S)-4-Benzyl-5-[(tert-butyldiphenylsilyl)oxy]pentanoic acid (6b):

Operating as described in the preparation of 6a, from amine 5b (320 mg, 0.41 mmol) in CH2Cl2

(1.8 mL) and m-chloroperbenzoic acid (70% of purity, 420 mg, 1.70 mmol) in CH2Cl2 (4 mL), the

nitroso dimer 8 (55 mg) and carboxylic acid 6b (119 mg, 66%) were obtained after flash

chromatography (from 1:1 hexaneCH2Cl2, CH2Cl2 to EtOAc). 6b: []22

D 6.91 (c 1.0 in CHCl3); IR

(film): = 3069, 2930, 1708 cm-1; H (400 MHz; CDCl3; Me4Si) 1.01 [s, 9H, (CH3)3], 1.59-1.70 (m,

2H, H-3), 1.72-1.76 (m, 1H, H-4), 2.12-2.27 (m, 2H, H-2), 2.51 (dd, J = 13.6, 6.6 Hz, 1H, CH2Ar),

2.71 (dd, J = 13.6, 7.2 Hz, 1H, CH2Ar), 3.46 (dd, J = 4.5, 1.2 Hz, 2H, H-5), 7.04-7.18 (m, 5H, ArH),

7.26-7.37 (m, 6H, ArH), 7.54-7.57 (m, 4H, ArH); C (100.6 MHz; CDCl3; Me4Si)19.3 (CMe3), 25.9

(C-3), 26.9 [(CH3)3], 31.7 (C-2), 37.5 (CH2Ar), 41.9 (C-4), 64.6 (C-5), 125.8 (CHAr), 127.6 (CHAr),

127.7 (CHAr), 128.2 (CHAr), 129.1 (CHAr), 129.6 (CHAr), 129.6 (CHAr), 133.5 (C-i), 133.6

(CHAr), 135.6 (CHAr), 140.3 (C-i), 180.0 (CO); HRMS (ESI-TOF) m/z [M - H]- Calcd for C28H33O3Si

445.2204, found 445.2194.

(S)-4-Benzyl-5-[(tert-butyldiphenylsilyl)oxy]-4-ethylpentanoic acid (6c):

Operating as described in the preparation of 6a, from amine 5c (300 mg, 0.37 mmol) in CH2Cl2

(1.5 mL) and m-chloroperbenzoic acid (70% of purity, 380 mg, 1.54 mmol) in CH2Cl2 (3.5 mL), the

nitroso dimer 8 (57 mg) and carboxylic acid 6c (130 mg, 75%) were obtained after flash

chromatography (from 1:1 hexaneCH2Cl2, CH2Cl2 to EtOAc). 6c: []22

D +2.52 (c 0.65 in CHCl3); IR

(film): = 3074, 2933, 2861, 1707 cm-1; H (400 MHz; CDCl3; Me4Si) 0.83 (t, J = 7.4 Hz, 3H,

CH3CH2), 1.19 [s, 9H, (CH3)3], 1.22 (q, J = 7.4 Hz, 2H, CH3CH2), 1.54 (ddd, J = 14.0, 14.0, 5.0 Hz,

1H, H-3), 1.63 (ddd, J = 14.0, 14.0, 5.0 Hz, 1H, H-3), 2.06-2.14 (m, 1H, H-2), 2.18-2.27 (m, 1H, H-

S7

2), 2.66 (d, J = 13.0 Hz, 1H, CH2Ar), 2.72 (d, J = 13.0 Hz, 1H, CH2Ar), 3.29 (d, J = 10.3 Hz, 1H, H-

5), 3.34 (d, J = 10.3 Hz, 1H, H-5), 7.18-7.25 (m, 5H, ArH), 7.40-7.49 (m, 6H, ArH), 7.69-7.72 (m,

4H, ArH); C (100.6 MHz; CDCl3; Me4Si)7.4 (CH3CH2), 19.4 (CMe3), 24.7 (CH3CH2), 27.2 [(CH3)3],

27.8 (C-3), 28.4 (C-2), 39.6 (CH2Ar), 41.5 (C-4), 65.9 (C-5), 126.0 (C-p), 127.6 (CHAr), 127.7

(CHAr), 127.8 (CHAr), 129.7 (C-p), 129.7 (C-p), 130.5 (CHAr), 133.4 (C-i), 133.5 (C-i), 135.8

(CHAr), 135.9 (CHAr), 138.1 (C-i), 180.5 (CO); HRMS (ESI-TOF) m/z [M + H]+

Calcd for

C30H39O3Si 475.2663, found 475.2667.

(3R,4S)-5-[(tert-Butyldiphenylsilyl)oxy]3,4-(isopropylidenedioxy)pentanoic

acid (6d): Operating as described in the preparation of 6a, from amine 5d (70 mg, 0.09 mmol) in

CH2Cl2 (0.8 mL) and m-chloroperbenzoic acid (70% of purity, 94 mg, 0.38 mmol) in CH2Cl2 (1 mL),

the nitroso dimer 8 (8 mg) and carboxylic acid 6d (21 mg, 54%) were obtained after flash

chromatography (from 1:1 hexaneCH2Cl2, CH2Cl2 to EtOAc). 6d: []22

D +2.93 (c 0.6 in CHCl3); IR

(film): = 3071, 2931, 2858, 1714, 1112 cm-1; H (400 MHz; CDCl3; Me4Si) 0.98 [s, 9H, (CH3)3],

1.27 (s, 3H, CH3), 1.31 (s, 3H, CH3), 2.61 (dd, J = 16.1, 9.1 Hz, 1H, H-2), 2.79 (dd, J = 16.1, 4.5

Hz, 1H, H-2), 3.58-3.65 (m, 2H, H-5), 4.18 (m, 1H, H-4), 4.60 (m, 1H, H-3), 7.29-7.39 (m, 6H,

ArH), 7.57-7.60 (m, 4H, ArH); C (100.6 MHz; CDCl3; Me4Si)19.1 (CMe3), 25.4 (CH3), 26.8

[(CH3)3], 27.9 (CH3), 34.9 (C-2), 62.2 (C-5), 73.5 (C-3), 76.8 (C-4), 108.6 (CMe2), 127.8 (C-o),

129.9 (C-p), 133.0 (C-i), 135.5 (C-m), 176.1 (CO); HRMS (ESI-TOF) m/z [M - H]- Calcd for

C24H31O5Si 427.1946, found 427.1941.

5-[(tert-Butyldiphenylsilyl)oxy]pentanoic acid (6e). From

lactam 5e: Operating as described in the preparation of 6a, from amine 5e (285 mg, 0.41 mmol) in

CH2Cl2 (1.5 mL) and m-chloroperbenzoic acid (70% of purity, 422 mg, 1.71 mmol) in CH2Cl2 (4

mL), the nitroso dimer 8 (70 mg) and carboxylic acid 6e (103 mg, 71%) were obtained after flash

chromatography (from 1:1 hexaneCH2Cl2, CH2Cl2 to EtOAc). From nitrone 7e: UHP (202 mg,

2.09 mmol) and Na2WO4.2H2O (8.7 mg, 0.026 mmol) were added at room temperature to a

solution of amine 5e (365 mg, 0.52 mmol) in 1:1 CH2Cl2methanol (3.4 mL), and the mixture was

stirred at this temperature for 21 h. Solvents were removed under reduced pressure, and the

S8

crude residue was taken up with CH2Cl2. The resulting white solid was filtered, and the solvent was

removed under reduced pressure to afford nitrone 7e (320 mg), which was used without

purification in the next step: H (400 MHz; CDCl3; Me4Si) 0.79 (m, 2H, H-3), 0.93 [s, 9H, (CH3)3],

0.96 [s, 9H, (CH3)3], 1.50 (br.s, 2H, H-4), 2.40 (m, 1H, H-2), 2.47 (m, 1H, H-2), 3.58 (br.s, 2H, H-

5), 3.77 (dd, J = 10.0, 4.0 Hz, 1H, CHAr), 4.57 (t, J = 10.0 Hz, 1H, CH2O), 4.65 (dd, J = 10.0 , 4.0

Hz, 1H, CH2O), 6.75 (m. 1H, H-1), 7.20-7.40 (m, 17H, ArH), 7.55-7.65 (m, 8H, ArH); C (100.6

MHz; CDCl3; Me4Si)19.1 and 19.2 (CMe3), 22.1 (C-3), 26.5 (C-2), 26.7 and 26.8 [(CH3)3], 32.4 (C-

4), 63.4 (C-5), 63.7 (CH), 79.6 (CH2O), 127.6 (CHAr), 127.7 (CHAr), 127.8 (CHAr), 127.9 (CHAr),

128.4 (CHAr), 128.7 (CHAr),129.5 (CHAr), 129.7 (CHAr), 129.8 (CHAr), 132.8 (C-i), 133.4 (C-i),

133.8 (C-i), 133.9 (C-i), 134.6 (C-i), 135.4 (CHAr), 135.5 (CHAr), 135.6 (CHAr), 139.2 (C-1).

Operating as described in the preparation of 6a, from crude nitrone 7e (320 mg, 0.45 mmol) in

CH2Cl2 (1.5 mL) and m-chloroperbenzoic acid (70% of purity, 276 mg, 1.12 mmol) in CH2Cl2 (4

mL), the nitroso dimer 8 (41 mg) and carboxylic acid 6e (yellow oil; 84 mg, 45% from 5e) were

obtained after flash chromatography (from 1:1 hexaneCH2Cl2, CH2Cl2 to EtOAc). 6e: IR (film): =

3071, 2931, 2858, 1709 cm-1; H (400 MHz; CDCl3; Me4Si) 1.05 [s, 9H, (CH3)3], 1.57-1.64 (m, 2H,

H-4), 1.70-1.78 (m, 2H, H-3), 2.35 (t, J = 7.6 Hz, 2H, H-2), 3.67 (t, J = 5.6 Hz, 2H, H-5), 7.35-7.43

(m, 6H, ArH), 7.65-7.67 (m, 4H, ArH); C (100.6 MHz; CDCl3; Me4Si)19.2 (CMe3), 21.1 (C-3), 26.8

[(CH3)3], 31.8 (C-4), 33.7 (C-2), 63.3 (C-5), 127.6 (C-o), 129.6 (C-p), 133.8 (C-i),135.5 (C-m),

179.6 (CO); HRMS (ESI-TOF) m/z [M + H] + Calcd for C21H29O3Si 357.1880, found 357.1886.

(S)-5-[(tert-Butyldiphenylsilyl)oxy]-4-ethylpentanenitrile (9):

20% Aqueous solution of NH3 (6 mL) and iodine (228 mg, 0.90 mmol) were added to a solution of

amine 5a (70 mg, 0.01 mmol) in anhydrous THF (2 mL) at room temperature, and the resulting

mixture was stirred at 60 ºC for 21 h. The mixture was washed with saturated aqueous Na2SO3

and extracted with Et2O. The combined organic phases were dried, filtered, and concentrated to

give an oil. Flash chromatography (from hexane to 6:4 hexaneCH2Cl2) afforded pure nitrile 9 (25

mg, 71%) as a yellow oil: []22

D +3.75 (c 0.5 in CHCl3); IR (film): = 2960, 1471, 1427, 1112 cm-1;

H (400 MHz; CDCl3; Me4Si) 0.83 (t, J = 7.4 Hz, 3H, CH3), 1.06 [s, 9H, (CH3)3], 1.27-1.43 (m, 2H,

CH2CH3), 1.50-1.59 (m, 1H, H-4), 1.65-1.72 (m, 1H, H-3), 1.74-1.89 (m, 1H, H-3), 2.27-2.32 (m,

2H, H-2), 3.53 (dd, J = 10.4, 5.6 Hz, 1H, H-5), 3.59 (dd, J = 10.4, 4.4 Hz, 1H, H-5), 7.37-7.46 (m,

6H, ArH), 7.63-7.65 (m, 4H, ArH); C (100.6 MHz; CDCl3; Me4Si) 11.2 (CH3), 14.9 (C-2), 19.2

(CMe3), 23.3 (CH2), 26.9 [(CH3)3], 27.1 (C-3), 41.1 (C-4), 64.9 (C-5), 120.0 (CN), 127.7 (C-o),

S9

129.7 (C-p), 133.4 (C-i), 135.5 (C-m); HRMS (ESI-TOF) m/z [M + H] +

Calcd for C23H32NOSi

366.2248, found 366.2240.

Synthesis of fluvirucinin B1

(R)-5-{[(1S)-2-Hydroxy-1-phenylethyl]amino}-2-ethyl-1-pentanol (ent-4a

= 2) was prepared from lactam 13 by the same procedure as described for 4a.

2 Ent-4a: []

22D +64.5

(c 0.8 in MeOH).

(R)-5-[(tert-Butyldiphenylsilyl)oxy]-N-{(S)-2-[(tert-

butyldiphenylsilyl)oxy]-1-phenylethyl}-4-ethyl-1-pentanamine (ent-5a) was prepared from

aminodiol ent-4a operating as in the above preparation of 5a. Ent-5a: []22

D +13.7 (c 1.0 in CHCl3).

(R)-5-[(tert-Butyldiphenylsilyl)oxy]-4-ethylpentanoic acid (ent-6a)

was prepared from amine ent-5a operating as in the above preparation of carboxylic acid 6a. Ent-

6a: []22

D +2.23 (c 1.38 in CHCl3).

(R)-5-[(tert-Butyldiphenylsilyl)oxy]-4-ethyl-1-pentanol: BH3-THF (3.83 mL of

a 1.0 M solution in THF, 3.83 mmol) was added to a cooled (0 ºC) solution of ent-6a (490 mg, 1.28

mmol) in anhydrous THF (15 mL), and the mixture was stirred at room temperature for 4 h. The

reaction was quenched with 8 mL of a 1:1 H2OEt2O mixture, poured into saturated aqueous

K2CO3, and extracted with Et2O. The combined organic extracts were dried, filtered, and

concentrated. The resulting residue was purified by flash chromatography (85:15 hexaneEtOAc)

S10

to gave the title alcohol (423 mg, 90%) as a colorless oil: []22

D +2.12 (c 3.9 in CHCl3) {Lit4

[]23

D

+2.7 (c 0.05 in CHCl3); Lit5 (for the enantiomer) []

22D 2.00 (c 3.9 in CHCl3)}; IR (film): = 3400,

2930, 1427, 1112 cm-1

; H (400 MHz; CDCl3; Me4Si) 0.83 (t, J = 7.3 Hz, 3H, CH3), 1.05 [s, 9H,

(CH3)3], 1.30-1.37 (m, 2H, H-3, CH2CH3), 1.40-1.45 (m, 3H, H-3, H-4, CH2CH3), 1.46-1.51 (m, 2H,

H-2), 1.55 (br.s, 1H, OH), 3.56 (d, J = 4.5 Hz, 2H, H-5), 3.59 (t, J = 6.5 Hz, 2H, H-1), 7.35-7.44 (m,

6H, ArH), 7.65-7.68 (m, 4H, ArH); C (100.6 MHz; CDCl3; Me4Si) 11.2 (CH3), 19.3 (CMe3), 23.6

(CH2), 26.6 [(CH3)3], 26.9 (C-3), 30.1 (C-2), 41.8 (C-4), 63.3 (C-1), 64.3 (C-5), 127.5 (C-o), 129.5

(C-p), 133.9 (C-i), 135.6 (C-m); HRMS (ESI-TOF) m/z [M + H]+

Calcd for C23H35O2Si 371.2401,

found 371.2416.

(R)-1-[(tert-Butyldiphenylsilyl)oxy]-2-ethyl-5-iodopentane (10):

Triphenylphosphine (300 mg, 1.13 mmol) and imidazole (80 mg, 1.13 mmol) were added to a

solution of the above alcohol (200 mg, 0.54 mmol) in CH2Cl2 (7 mL) at room temperature. Then,

iodine (290 mg, 1.13 mmol) was added at 0 °C, and the mixture was stirred at room temperature

for 15 h. The solvent was evaporated under reduced pressure to afford a brown residue. Flash

chromatography (from hexane to 95:5 hexaneCH2Cl2) of the residue gave iodide 10 (232 mg,

90%) as a colorless oil: []22

D +1.47 (c 0.75 in CHCl3); IR (film): = 2929, 1111 cm-1; H (400 MHz;

CDCl3; Me4Si) 0.83 (t, J = 7.4 Hz, 3H, CH3), 1.06 [s, 9H, (CH3)3], 1.30-1.51 (m, 5H, H-2, H-3,

CH2CH3), 1.73-1.80 (quint, J = 7.5 Hz, 2H, H-4), 3.13 (t, J = 7.5 Hz, 2H, H-5), 3.51 (dd, J = 10.1,

4.5 Hz, 1H, H-1), 3.55 (dd, J = 10.1, 4.8 Hz, 1H, H-1), 7.36-7.45 (m, 6H, ArH), 7.64-7.67 (m, 4H,

ArH); C (100.6 MHz; CDCl3; Me4Si) 7.5 (C-5), 11.3 (CH3), 19.3 (CMe3), 23.6 (CH2), 26.6 [(CH3)3],

31.1 (C-4), 31.8 (C-3), 41.3 (C-2), 65.6 (C-1), 127.6 (C-o), 129.5 (C-p), 133.9 (C-i), 135.6 (C-m);

HRMS (ESI-TOF) m/z [M + H]+ Calcd for C23H34IOSi 481.1418, found 481.1425.

(R)-7-[(tert-Butyldiphenylsilyl)oxy]-6-ethyl-2-methyl-1-heptene (11):

Isopropenylmagnesium bromide (3.62 mL of a 0.5 M solution in THF, 1.81 mmol) was added at 0

ºC to a suspension of iodide 10 (290 mg, 0.60 mmol) and CuI (12.6 mg, 0.066 mmol) in anhydrous

THF (3.5 mL), and the resulting mixture was stirred at room temperature for 2 h. Then, saturated

aqueous NH4Cl was added, and the mixture was extracted with EtOAc. The combined organic

extracts were dried, filtered, and evaporated. The resulting residue was chromatographed

(hexane) to afford alkene 11 (211 mg, 89%) as a colorless oil: []22

D +0.66 (c 1.05 in CHCl3); IR

S11

(film): = 2927, 1425, 1113 cm-1; H (400 MHz; CDCl3; Me4Si) 0.82 (t, J = 7.3 Hz, 3H, CH3CH2),

1.05 [s, 9H, (CH3)3], 1.25-1.33 (m, 1H, H-5), 1.35-1.47 (m, 6H, H-4, H-5, H-6, CH3CH2), 1.69 (s,

3H, CH3), 1.95-1.98 (brt, J = 7.0 Hz, 2H, H-3), 3.54 (d, J = 4.9 Hz, 2H, H-7), 4.64-4.68 (m, 2H, H-

1), 7.35-7.44 (m, 6H, ArH), 7.65-7.68 (m, 4H, ArH); C (100.6 MHz; CDCl3; Me4Si) 11.3 (CH3CH2),

19.3 (CMe3), 22.4 (CH3), 23.6 (CH3CH2), 24.9 (C-4), 26.9 [(CH3)3], 30.3 (C-5), 38.2 (C-3), 42.0 (C-

6), 65.8 (C-7), 109.6 (C-1), 127.5 (C-o), 129.5 (C-p), 134.1 (C-i), 135.6 (C-m), 146.2 (C-2); HRMS

(ESI-TOF) m/z [M + H]+ Calcd for C26H39OSi 395.2765, found 395.2762.

(R)-2-Ethyl-6-methyl-6-hepten-1-ol: Tetrabutylammonium fluoride (3.83

mL of a 1.0 M solution in THF, 3.83 mmol) was added to a solution of 11 (378 mg, 0.96 mmol) in

anhydrous THF (6 mL) at 0 ºC, and the mixture was stirred at room temperature for 17 h. The

solvent was eliminated under reduced pressure and the crude residue was purified by flash

chromatography (from hexane to 8:2 hexaneEtOAc) to give the title alcohol (187 mg, 80%) as a

colorless liquid: []22

D 1.41 (c 0.7 in CHCl3); IR (film): = 3336, 1649, 1460 cm-1; H (400 MHz;

CDCl3; Me4Si) 0.90 (t, J = 7.3 Hz, 3H, CH2CH3), 1.26-1.32 (m, 2H, CH3CH2), 1.32-1.49 (m, 5H, H-

2, H-3, H-4), 1.71 (s, 3H, CH3), 2.01 (t, J = 7.5 Hz, 2H, H-5), 3.55 (d, J = 5.2 Hz, 2H, H-1), 4.67-

4.70 (m, 2H, H-7); C (100.6 MHz; CDCl3; Me4Si) 11.1 (CH3CH2), 22.3 (CH3), 23.3 (CH3CH2), 24.8

(C-4), 30.0 (C-3), 38.1 (C-5), 41.9 (C-2), 65.2 (C-1), 109.8 (C-7), 146.0 (C-6).

(R) 2-Ethyl-6-methyl-6-heptenoic acid (12): DMSO (0.46 mL, 6.47 mmol) was

added to a cooled (–78 ºC) solution of oxalyl chloride (0.27 mL, 3.23 mmol) in CH2Cl2 (16 mL), and

the mixture was stirred at this temperature for 10 min. Then, a solution of the above alcohol (459

mg, 2.94 mmol) in CH2Cl2 (16 mL) was added, and the mixture was stirred at –78 ºC for 30 min.

Triethylamine (2.05 mL, 14.7 mmol) was added and, after 40 min, the mixture was allowed to

warm to room temperature and was washed with saturated NaHCO3. The organic extract was

dried, filtered, and concentrated, to give the corresponding aldehyde (460 mg) as a yellow oil,

which was used without further purification: H (400 MHz; CDCl3; Me4Si) 0.92 (t, J = 7.5 Hz, 3H,

CH3CH2), 1.42-1.49 (m, 3H), 1.51-1.58 (m, 1H), 1.60-1.69 (m, 2H), 1.70 (s, 3H, CH3), 2.02 (t, J =

7.0 Hz, 2H, H-5), 2.15-2.23 (m, 1H), 4.66-4.67 (m, 1H, H-7), 4.70-4.71 (m, 1H, H-7), 9.58 (d, J =

3.0 Hz, 1H, CHO). A solution of NaClO2 (3.19 g, 35.28 mmol) and NaH2PO4 (3.24 g, 27.0 mmol) in

water (14 mL) was added to a solution of the above crude aldehyde (460 mg) and 2-methyl-2-

butene (14.7 mL of a 2.0 M solution in THF, 29.4 mmol) in t-BuOH (28 mL), and the mixture was

S12

stirred at room temperature for 3 h. The reaction was quenched by addition of H2O, and the

aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried, filtered, and

concentrated. Flash chromatography (from 8:2 hexane–CH2Cl2 to CH2Cl2) of the residue gave

carboxylic acid 12 (370 mg, 74%) as a colorless liquid: []22

D –6.87 (c 1.2 in CHCl3); IR (film): =

3074, 2938, 1707 cm-1

; H (400 MHz; CDCl3; Me4Si) 0.94 (t, J = 7.4 Hz, 3H, CH3CH2), 1.43-1.68

(m, 6H, CH3CH2, H-3, H-4), 1.70 (s, 3H, CH3), 2.02 (brt, J = 7.0 Hz, 2H, H-5), 2.30 (m, 1H, H-2),

4.67 (br.s, 1H, H-7), 4.70 (br.s, 1H, H-7); C (100.6 MHz; CDCl3; Me4Si) 11.7 (CH3CH2), 22.2

(CH3), 25.2 (CH3CH2, C-4), 31.2 (C-3), 37.6 (C-5), 47.0 (C-2), 110.1 (C-7), 145.4 (C-6), 182.8

(CO); HRMS (ESI-TOF) m/z [M - H]- Calcd for C10H17O2 169.1234, found 169.1228.

(R)-4-(Hydroxymethyl)hexanenitrile: 20% Aqueous solution of NH3 (196 mL)

and iodine (11.59 g, 45.7 mol) were added to a solution of amine ent-5a (4.11 g, 5.65 mol) in

anhydrous THF (10 mL) at room temperature, and the resulting mixture was stirred at 60 ºC for 21

h. The mixture was washed with a saturated aqueous Na2SO3 and extracted with Et2O. The

combined organic phases were dried, filtered, and concentrated to give crude ent-9 as an oil,

which was used without purification in the next step. An aliquot was chromatographed (from

hexane to 6:4 hexane–CH2Cl2) to give pure ent-9 {[]22

D –4.00 (c 0.5 in CHCl3)}.

Tetrabutylammonium fluoride (17.6 mL of a 1.0 M solution in THF, 17.6 mmol) was added to a

solution of the above crude ent-9 (2.06 g) in anhydrous THF (36 mL) at 0 ºC, and the mixture was

stirred at room temperature for 3.5 h. The solvent was eliminated under reduced pressure and the

crude residue was purified by flash chromatography (from 9:1 to 1:1 hexaneEtOAc) to give (R)-4-

(hydroxymethyl)hexanenitrile (540 mg, 75% from ent-5a) as a yellow oil: []22

D –5.26 (c 1.25 in

CHCl3) {Lit6

[]22

D –7.1 (c 0.97 in CHCl3)}; IR (film): = 3440, 2247 cm-1; H (400 MHz; CDCl3;

Me4Si) 0.93 (t, J = 7.5 Hz, 3H, H-6), 1.32-1.45 (m, 2H, H-5), 1.52-1.62 (m, 1H, H-4), 1.65-1.83 (m,

2H, H-3), 2.05 (br.s, 1H, OH), 2.38-2.50 (m, 2H, H-2), 3.54 (dd, J = 10.9, 6.1 Hz, 1H, CH2O), 3.65

(dd, J = 10.9, 4.6 Hz, 1H, CH2O); C (100.6 MHz; CDCl3; Me4Si) 11.0 (C-6), 15.0 (C-2), 23.1 (C-5),

26.8 (C-3), 40.8 (C-4), 64.1 (CH2O), 120.1 (CN); HRMS (ESI-TOF) m/z [M + NH4]+ Calcd for

C7H17N2O 145.1335, found 145.1337.

(R)-4-Formylhexanenitrile (13): DMSO (0.25 mL, 3.55 mmol) was added to a

cooled (–78 ºC) solution of oxalyl chloride (0.15 mL, 1.77 mmol) in CH2Cl2 (7 mL), and the mixture

S13

was stirred at this temperature for 10 min. Then, a solution of (R)-4-(hydroxymethyl)hexanenitrile

(205 mg, 1.61 mmol) in CH2Cl2 (7 mL) was slowly added, and the yellow mixture was stirred at –78

ºC for 30 min. Triethylamine (1.12 mL, 8.06 mmol) was added and, after 1 h, the mixture was

allowed to warm to room temperature and washed with saturated NaHCO3. The organic layer was

dried, filtered, and concentrated, and the resulting residue was chromatographed (9:1 hexane–

EtOAc) to afford aldehyde 13 (152 mg, 75%): []22

D +9.1 (c 0.35 in CHCl3); H (400 MHz; CDCl3;

Me4Si) 0.99 (t, J = 7.5 Hz, 3H, CH3), 1.58-1.68 (m, 1H), 1.70-1.84 (m, 2H), 1.99-2.11 (m, 1H),

2.35-2.50 (m, 3H, H-4, H-2), 9.67 (s, 1H, CHO); HRMS (ESI-TOF) m/z [M + NH4]+ Calcd for

C7H15N2O 143.1179, found 143.1181.

(4R,5R)-4-Ethyl-5-hydroxy-7-octenenitrile (14): (S,S)-2-Allyl-1,3-bis-(4-

bromobenzyl)-2-chlorooctahydro-2-1H-1,3,2-benzodiazasilole (Leighton reagent; 1.30 g, 2.30

mmol) and scandium triflate (49 mg, 0.096 mmol) were added to a solution of aldehyde 13 (240

mg, 1.92 mmol) in anhydrous CH2Cl2 (19 mL), and the resulting mixture was stirred at 0 ºC for 5 h,

and at room temperature for 12 h. Then, a solution of tetrabutylammonium fluoride (1.9 mL, 1.9

mmol) was added, and the mixture was stirred at room temperature for 30 min. The solvent was

evaporated, and the resulting residue was chromatographed (from 8:2 hexaneCH2Cl2 to CH2Cl2)

to give alcohol 14 together with minor amounts of 5-epi-14 (dr 9:1, 284 mg, 85% yield): IR (film):

= 3468, 2247 cm-1; H (400 MHz; CDCl3; Me4Si, from the mixture) 0.95 (t, J = 7.5 Hz, 3H, CH3CH2),

1.31-1.40 (m, 1H), 1.40-1.49 (m, 1H), 1.54-1.62 (m, 3H, 2H, OH), 1.62-1.71 (m, 1H), 2.09-2.18 (m,

1H), 2.25-2.31 (m, 1H), 2.45 (m, 2H, CH2CN), 3.67-3.73 (m, 1H, H-5), 5.14-5.21 (m, 2H, H-8),

5.77-5.87 (m, 1H, H-7); C (100.6 MHz; CDCl3; Me4Si, from the mixture) 14: 11.6 (CH3CH2), 15.4

(CH2CN), 21.4 (CH2), 25.5 (CH2), 37.9 (CH2CH=CH2), 43.3 (CH), 71.3 (CHOH), 118.3 (CH2=CH),

120.0 (CN), 134.9 (CH2=CH); 5-epi-14: 11.0 (CH3CH2), 15.2 (CH2CN), 22.4 (CH2), 24.9 (CH2),

39.5 (CH2CH=CH2), 43.2 (CH), 71.4 (CHOH), 118.5 (CH2=CH), 120.1 (CN), 134.6 (CH2=CH);

HRMS (ESI-TOF) m/z [M + NH4]+ Calcd for C10H21N2O 185.1648, found 185.1643.

(4R,5R)-5-[(tert-Butyldimethylsilyl)oxy]-4-ethyl-7-

octenenitrile: tert-Butyldimethylsilyl chloride (760 mg, 5.04 mmol) and imidazole (458 mg, 6.73

mmol) were added to a solution of the above mixture of epimeric alcohols 14 (281 mg, 1.68 mmol)

in CH2Cl2 (5 mL). The solution was stirred at reflux temperature for 15 h. Then, saturated aqueous

S14

NH4Cl was added, and the mixture was extracted with CH2Cl2. The combined organic extracts

were dried, filtered, and concentrated. Flash chromatography (from 9:1 to 8:2 hexane-CH2Cl2) of

the residue afforded the protected alcohol (9:1 mixture of C-5 epimers; 365 mg, 77% yield) as a

colorless oil: IR (film): = 2959, 2246 cm-1; H (400 MHz; CDCl3; Me4Si, from the mixture) 0.05 (s,

3H, CH3Si), 0.06 (s, 3H, CH3Si), 0.89 [s, 9H, (CH3)3], 0.94 (t, J = 7.4 Hz, 3H, CH3CH2), 1.29-1.36

(m, 2H, CH2), 1.48-1.60 (m, 2H, H-4, CH2), 1.82-1.90 (m, 1H, CH2), 2.09-2.23 (m, 2H, H-6), 2.41

(t, J = 7.5 Hz, 2H, H-2), 3.72-3.77 (m, 1H, H-5), 5.02-5.08 (m, 2H, H-8), 5.73-5.83 (m, 1H, H-7); C

(100.6 MHz; CDCl3; Me4Si, from the mixture) 5R (major epimer): 4.5 (CH3Si), 4.4 (CH3Si), 12.0

(CH3CH2), 15.8 (C-2), 18.0 (CMe3), 22.7 (CH2), 25.6 (CH2), 25.8 [(CH3)3], 37.3 (C-6), 44.4 (C-4),

73.4 (C-5), 116.9 (C-8), 119.9 (C-1), 135.6 (C-7); 5S (minor epimer): 4.8 (CH3Si), 4 .2 (CH3Si),

11.6 (CH3CH2), 15.3 (C-2), 18.0 (CMe3), 22.6 (CH2), 24.8 (CH2), 25.8 [(CH3)3], 39.5 (C-6), 42.6 (C-

4), 72.8 (C-5), 117.2 (C-8), 120.2 (C-1), 134.6 (C-7); HRMS (ESI-TOF) m/z [M + H]+

Calcd for

C16H32NOSi 282.2248, found 282.2245.

(4R,5R)-5-[(tert-Butyldimethylsilyl)oxy]-4-ethyl-7-octenamine (15): A

solution of the above mixture of epimeric nitriles (345 mg, 1.23 mmol) in anhydrous Et2O (1.0 mL)

was slowly added to a cooled (0 ºC) solution of LiAlH4 (2.1 mL of a 1.0 M solution in THF, 2.09

mmol) in anhydrous Et2O (1.0 mL), and the resulting mixture was stirred at room temperature for 2

h. After cooling to 0 ºC, H2O (132 L), 10% aqueous NaOH (250 L), and H2O (573 L) were

successively added. The insoluble white precipitate was removed by filtration and washed with

Et2O. The filtrate was dried, filtered, and concentrated to give pure amine 15 (305 mg, 87%) as a

colorless oil: []22

D +7.23 (c 1.0 in MeOH); IR (film): = 2957, 2930, 2858 cm-1; H (400 MHz;

CDCl3; Me4Si) 0.03 (s, 3H, CH3Si), 0.04 (s, 3H, CH3Si), 0.86-0.91 (m, 3H, CH3CH2), 0.88 [s, 9H,

(CH3)3], 1.25-1.54 (m, 7H, H-2, H-3, H-4, CH3CH2), 2.11-2.22 (m, 2H, H-6), 2.67 (t, J = 7.0 Hz, 2H,

H-1), 3.70-3.74 (m, 1H, H-5), 4.98-5.05 (m, 2H, H-8), 5.75-5.85 (dddd, J = 14.2, 10.3, 7.2, 7.2 Hz,

1H, H-7); C (100.6 MHz; CDCl3; Me4Si) 4.7 (CH3Si), 4.4 (CH3Si), 12.1 (CH3CH2), 17.9 (CMe3),

22.3 (CH2), 25.7 [(CH3)3], 26.3 (CH2), 31.9 (CH2), 37.8 (C-6), 42.5 (C-1), 44.7 (C-4), 73.4 (C-5),

116.1 (C-8), 136.1 (C-7); HRMS (ESI-TOF) m/z [M + H]+

Calcd for C16H36NOSi 286.2561, found

286.2554.

S15

(R)-N-{(4R,5R)-5-[(tert-Butyldimethylsilyl)oxy]-4-ethyl-7-octen-1-yl}-2-ethyl-

6-methyl-6-heptenamide (16): N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride

(189 mg, 0.99 mmol) was added to a cooled solution (0 ºC) of amine 15 (268 mg, 0.94 mmol) and

1-hydroxybenzotriazole (159 mg, 1.17 mmol) in anhydrous DMF (5.5 mL), and the resulting

mixture was stirred at 0 ºC for 10 min. Then, a solution of carboxylic acid 12 (176 mg, 10.3 mmol)

in anhydrous DMF (1.5 mL) was added, and the stirring was continued at room temperature for 15

h. The solvent was evaporated, the resulting residue was dissolved in Et2O, and the solution was

washed with H2O. The organic layer was dried, filtered, and concentrated to give an oil. Flash

chromatography (8:2 hexaneEtOAc) afforded amide 16 (325 mg, 79%) as a colorless oil: []22

D

+3.69 (c 2.05 in CHCl3); IR (film): = 3297, 2963, 1641, 1549, 1462 cm-1; H (400 MHz; CDCl3;

Me4Si) 0.01 (s, 3H, CH3Si), 0.01 (s, 3H, CH3Si), 0.84-0.88 (m, 15H, 2CH3CH2, (CH3)3), 1.12-1.18

(m, 1H), 1.25-1.32 (m, 3H), 1.35-1.49 (m, 7H), 1.49-1.54 (m, 2H), 1.66 (s, 3H, CH3), 1.88 (m, 1H),

1.96 (t, J = 7.0 Hz, 2H, CH2CH2=CH), 2.06-2.19 (m, 2H, CH2CH2=CH), 3.15-3.27 (m, 2H, CH2N),

3.66-3.70 (m, 1H, CHO), 4.63 (br.d, J = 14.0 Hz, 2H, CH2=CMe), 4.95-5.03 (m, 2H, CH2=CH), 5.57

(br.t, J = 5.3 Hz, 1H, NH), 5.71-5.81 (m, 1H, CH2=CH); C (100.6 MHz; CDCl3; Me4Si) 4.5

(CH3Si), 4.3 (CH3Si), 12.1 (CH3CH2), 12.1 (CH3CH2), 18.0 (CMe3), 22.2 (CH3), 22.5 (CH2), 25.6

(CH2), 25.8 [(CH3)3], 26.0 (CH2), 26.6 (CH2), 28.1 (CH2), 32.3 (CH2), 37.7 (CH2CH=CH2), 37.8

(CH2CH=CH2), 39.7 (CH2NH), 44.7 (CH), 49.7 (CH), 73.5 (CHO), 109.9 (CH2=CH), 116.3

(CH2=CH), 136.1 (CH2=CH), 145.5 (CH2=CMe), 175.5 (CO); HRMS (ESI-TOF) m/z [M + H]+

Calcd

for C26H52NO2Si 438.3762, found 438.3772.

O-[(tert-Butyldimethylsilyl)oxy]-6,7-didehydrofluvirucinin B1 (17): A solution

of second-generation Hoveyda-Grubbs catalyst (40 mg, 0.063 mmol) in anhydrous toluene (32

mL) was added to a solution of 16 (138 mg, 0.32 mmol) and 1,4-benzoquinone (3.5 mg, 0.032

mmol) in anhydrous toluene (160 mL) at room temperature, and the resulting mixture was heated

at 80 ºC for 17 h. The solvent was evaporated, and the resulting residue was chromatographed

(from CH2Cl2 to 99:1 CH2Cl2Et2O) to yield lactam 17Z (56 mg, 43%) as a brown foam and its

diastereoisomer 17E (45 mg, 35%) as a brown oil. 17Z: IR (film): = 3292, 2959, 1641, 1549,

1462 cm-1; H (400 MHz; CDCl3; Me4Si) 0.03 [s, 6H, Si(CH3)2], 0.82 (t, J = 7.1 Hz, 3H, CH3CH2),

S16

0.88-0.92 [m, 12H, CH3CH2, (CH3)3], 1.15-1.65 (m, 12H), 1.68 (s, 3H, CH3), 1.69-1.90 (m, 2H),

1.95-2.08 (m, 2H), 2.20 (m, 2H), 2.98 (dm, J = 6.6 Hz, 1H, H-13), 3.58-3.68 (m, 2H, H-9, H-13),

5.19 (brt, J = 7.0 Hz, 1H, H-7), 5.62 (dd, J = 8.1, 3.7 Hz, 1H, NH); C (100.6 MHz; CDCl3; Me4Si)

4.6 (CH3Si), 4.2 (CH3Si), 10.5 (CH3CH2), 12.3 (CH3CH2), 18.2 (CMe3), 21.9 (CH2), 24.0 (CH3),

25.7 (CH2), 26.0 [(CH3)3], 26.7 (CH2), 26.9 (CH2), 27.5 (CH2), 32.4 (C-5), 32.8 (C-8), 33.6 (CH2),

39.1 (C-13), 43.9 (C-10), 49.7 (C-2), 74.0 (C-9), 120.6 (C-7), 136.3 (C-6), 175.5 (C-1); HRMS

(ESI-TOF) m/z [M + H]+ Calcd for C24H48NO2Si 410.3449, found 410.3461. 17E: IR (film): = 3292,

2959, 1641, 1549, 1462 cm-1; H (400 MHz; CDCl3; Me4Si) 0.04 (s, 3H, CH3Si), 0.06 (s, 3H,

CH3Si), 0.87-0.93 [m, 15H, 2CH3CH2, (CH3)3], 1.20-1.24 (m, 1H), 1.30-1.50 (m, 8H), 1.52-1.58 (m,

3H), 1.60 (s, 3H, CH3), 1.62-1.66 (m, 1H), 1.90-2.09 (m, 3H, H-2, H-5), 2.17-2.24 (m, 1H, H-8),

2.26-2.33 (m, 1H, H-8), 3.01 (m, 1H, H-13), 3.57-3.65 (m, 1H, H-13), 3.70 (ddd, J = 7.4, 4.3, 3.2

Hz, 1H, H-9), 5.27 (br.t, J = 7.0 Hz, 1H, H-7), 5.32 (br.s, 1H, NH); C (100.6 MHz; CDCl3; Me4Si)

4.8 (CH3Si), 4.4 (CH3Si), 11.4 (CH3CH2), 12.4 (CH3CH2), 16.9 (CH3), 18.1 (CMe)3, 22.1 (CH2),

24.8 (CH2), 25.0 (CH2), 25.9 [(CH3)3], 26.3 (CH2), 27.4 (CH2), 31.3 (CH2), 33.2 (C-8), 37.4 (C-5),

39.7 (C-13), 43.6 (C-10), 48.3 (C-2), 73.3 (C-9), 121.1 (C-7), 135.7 (C-6), 175.6 (C-1); HRMS

(ESI-TOF) m/z [M + H]+ Calcd for C24H48NO2Si 410.3449, found 410.3464.

O-[(tert-Butyldimethylsilyl)oxy]fluvirucinin B1 (18): From 17Z: A solution of

17Z (30 mg, 0.073 mmol) in toluene (3 mL) containing Pd/C (26 mg) was hydrogenated at room

temperature and atmospheric pressure for 17 h. The catalyst was removed by filtration over

Celite®. The organic solution was concentrated, and the resulting oil was chromatographed (from

CH2Cl2 to 98:2 CH2Cl2Et2O) and then crystallized (9:1 hexaneEtOAc) to give pure 18 (27 mg,

90%) as white solid. From a mixture of diastereoisomers E-Z: Operating as above, from a 1.2:1

mixture of macrocycles 17Z-17E (47 mg, 0.11 mmol) and Pd/C (41 mg) in anhydrous toluene (4.7

mL), compound 18 (43 mg, 91%) was obtained after flash chromatography (from CH2Cl2 to 98:2

CH2Cl2Et2O) and crystallization (9:1 hexaneEtOAc): mp 185-187 ºC [Lit7 mp 187-188ºC]; []

22D

+17.0 (c 0.02, CH2Cl2) {Lit7 []

22D +12.0 (c 0.02, CH2Cl2)}; IR (film): = 3297, 2928, 1642, 1552

cm-1; H (400 MHz; C6D6; Me4Si) 0.11 (s, 3H, CH3Si), 0.12 (s, 3H, CH3Si), 0.82 (t, J = 7.4 Hz, 3H,

CH3CH2), 0.89 (t, J = 7.4 Hz, 3H, CH3CH2), 0.97 (d, J = 7.0 Hz, 3H, CH3CH), 1.04 [s, (CH3)3, 9H],

1.19-1.41 (m, 9H), 1.43-1.56 (m, 6H), 1.58-1.73 (m, 4H), 1.77-1.88 (m, 2H), 2.47 (dm, J = 13.7 Hz,

1H, H-13), 3.52 (dt, J = 9.1, 3.4 Hz, 1H, H-9), 3.77 (m, 1H, H-13), 4.53 (dd, J = 9.0, 3.0 Hz, 1H,

NH); C (100.6 MHz; C6D6; Me4Si)7,8

4.7 (CH3Si), 3.7 (CH3Si), 9.2 (CH3CH2), 12.5 (CH3CH2),

S17

18.4 (CMe3), 20.9 (CH3), 21.1 (CH2), 24.4 (CH2), 25.2 (CH2), 25.9 (CH2), 26.2 [(CH3)3], 26.3 (CH2),

27.0 (CH2), 28.5 (CH2), 31.5 (C-6), 34.1 (CH2), 34.8 (CH2), 38.7 (CH2), 42.9 (C-10), 50.9 (C-2),

73.1 (C-9), 174.8 (C-1); HRMS (ESI-TOF) m/z [M + H]+

Calcd for C24H50NO2Si 412.3605, found

412.3611.

Fluvirucinin B1: A solution of 18 (9 mg, 0.022 mmol) in 1% HCl-EtOH (2 mL) was

stirred at room temperature for 2 h. Then, the solution was concentrated to give fluvirucinin B1 (6

mg, 92%) as a white solid: mp 236-238 ºC [Lit9 mp 235-245 ºC]; []

22D +14.3 (c 0.175 in 1:1

CHCl3-CH3OH); IR (film): = 3308, 2953, 2926, 2872, 2855, 1635 cm-1; H (400 MHz; 1:1

CD3ODCDCl3; Me4Si) 0.88 (t, J = 7.4 Hz, 3H, CH3CH2), 0.89 (t, J = 7.3 Hz, 3H, CH3CH2), 0.91 (d,

J = 6.9 Hz, 3H, CH3), 1.02-1.18 (m, 3H, CH2, OH), 1.27-1.44 (m, 11H, 5CH2, H-10), 1.52-1.73 (m,

7H, 3CH2, H-6), 2.09-2.16 (m, 1H, H-2), 2.69 (m, 1H), 3.29-3.34 (masked, 1H, H-9), 3.75 (m, 1H),

7.88 (dd, J = 8.5, 4.1 Hz, 1H, NH); C (100.6 MHz; CD3ODCDCl3; Me4Si) 11.7 (CH3CH2), 13.2

(CH3CH2), 22.2 (CH3), 22.8 (CH2), 23.8 (CH2), 26.7 (CH2), 26.8 (CH2), 30.1 (CH2), 31.1 (CH2), 31.3

(CH2), 32.9 (C-6), 34.5 (CH2), 35.0 (CH2), 40.4 (CH2), 45.5 (C-10), 49.9 (masked, C-2), 75.0 (C-9),

178.9 (C-1); HRMS (ESI-TOF) m/z [M + H]+ Calcd for C18H36NO2 298.2741, found 298.274.

REFERENCES

1. Amat, M.; Bosch, J.; Hidalgo, J.; Cantó, M.; Pérez, M.; Llor, N.; Molins, E.; Miravitlles, C.;

Orozco, M.; Luque, J. J. Org. Chem. 2000, 65, 3074-3084.

2. Guignard, G.; Llor, N.; Urbina, A.; Bosch, J.; Amat, M. Eur. J. Org. Chem. 2016, 693-703.

3. Amat, M.; Escolano, C.; Llor, N.; Lozano, O.; Gómez-Esqué, A.; Griera, R.; Bosch, J.

Arkivoc 2005, ix, 115-123.

4. Panek, J. S.; Jain, N. F. J. Org. Chem. 2001, 66, 2747-2756.

5. Paquette, L. A.; Duan, M.; Konetzki, I.; Kempmann, C. J. Am. Chem. Soc. 2002, 124,

4257-4270.

6. White, J. D.; Hanselmann, R.; Jackson, R. W.; Porter, W. J.; Ohba, Y.; Tiller, T.; Wang, S.

J. Org. Chem. 2001, 66, 5217-5231.

7. Trost, B. M.; Ceschi, M. A.; König, B. Angew. Chem. Int. Ed. 1997, 36, 1486-1489.

8. Xu, Z.; Johannes, C. W.; Houri, A. F.; La, D. S.; Cogan, D. A.; Hofilena, G. E.; Hoveyda, A.

H. J. Am. Chem. Soc. 1997, 119, 10302-10316.

9. Naruse, N.; Tsuno, T.; Sawqada, Y.; Konishi, M.; Oki, T. J. Antibiotics 1991, 44, 741-755.

S18

1H NMR (400 MHz; CDCl3; Me4Si)

13C NMR (100.6 MHz; CDCl3; Me4Si)

S19



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S26



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S32


13C NMR (100.6 MHz, CDCl3; Me4Si)

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S47

1H NMR (400 MHz; C6D6; Me4Si)

13C NMR (100.6 MHz; C6D6; Me4Si)

S48

1H NMR (400 MHz; 1:1 CD3OD-CDCl3; Me4Si)

13C NMR (100.6 MHz; 1:1 CD3OD-CDCl3; Me4Si)

S49

Table 1. Crystal data and structure refinement for 18.

Identification code Jb118

Empirical formula C48 H98 N2 O4 Si2

Formula weight 823.46

Temperature 293(2) K

Wavelength 1.54184 Å

Crystal system Monoclinic

Space group P 21

Unit cell dimensions a = 9.6625(2) Å = 90°.

b = 21.1407(6) Å = 95.786(2)°.

c = 13.3829(3) Å = 90°.

Volume 2719.82(11) Å3

Z 2

Density (calculated) 1.005 Mg/m3

Absorption coefficient 0.874 mm-1

F(000) 920

Theta range for data collection 3.319 to 70.406°.

Index ranges -10<=h<=11, -25<=k<=25, -16<=l<=13

Reflections collected 18365

Independent reflections 9939 [R(int) = 0.0624]

Completeness to theta = 67.684° 98.9 %

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 9939 / 58 / 580

Goodness-of-fit on F2 1.153

Final R indices [I>2sigma(I)] R1 = 0.0666, wR2 = 0.1759

R indices (all data) R1 = 0.0878, wR2 = 0.1855

Absolute structure parameter 0.02(4)

Largest diff. peak and hole 0.265 and -0.265 e.Å-3

S50

Table 2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103)

for jb118. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

________________________________________________________________________________

x y z U(eq)

________________________________________________________________________________

Si(2) -710(2) 5453(1) 2042(2) 70(1)

O(1) 3295(4) 3332(3) 7669(5) 82(2)

O(9) 4788(5) 2287(3) 2857(3) 79(2)

O(21) -1802(4) 3400(3) 7072(3) 64(1)

O(29) 83(5) 5023(2) 2942(3) 61(1)

N(14) 5517(5) 3044(2) 7622(4) 49(1)

N(34) 427(5) 3173(2) 6911(4) 50(1)

C(1) 4509(6) 3474(3) 7669(5) 52(2)

C(2) 4968(7) 4161(3) 7714(6) 62(2)

C(3) 4465(8) 4481(4) 6719(6) 75(2)

C(4) 5241(8) 4274(4) 5848(6) 66(2)

C(5) 4563(7) 4479(4) 4832(6) 73(2)

C(6) 5301(8) 4258(5) 3933(6) 80(2)

C(7) 5466(7) 3540(4) 3893(5) 69(2)

C(8) 4100(6) 3175(4) 3836(5) 63(2)

C(9) 4229(7) 2458(4) 3769(5) 62(2)

C(10) 5117(7) 2138(3) 4645(5) 56(2)

C(11) 4679(6) 2344(3) 5657(4) 51(1)

C(12) 5599(7) 2088(3) 6558(5) 56(2)

C(13) 5255(8) 2367(3) 7546(5) 58(2)

Si(1)* 3750(8) 2341(5) 1733(4) 64(2)

C(15)* 3280(30) 3133(12) 1189(15) 96(8)

C(16)* 2060(20) 1912(14) 1869(16) 104(8)

C(17)* 4870(30) 1941(11) 901(15) 94(12)

C(18)* 4050(30) 1752(17) -99(17) 127(11)

C(19)* 5450(40) 1343(12) 1410(20) 138(12)

Si(1A)** 4061(4) 1944(4) 1821(3) 72(2)

C(15A)** 2840(20) 2551(13) 1229(16) 143(9)

C(16A)** 3090(20) 1190(10) 2032(13) 127(8)

C(17A)** 5450(20) 1774(7) 1023(11) 65(4)

C(18A)** 4870(20) 1392(8) 94(10) 84(5)

C(19A)** 6620(20) 1418(9) 1615(12) 102(6)

C(20) 6068(12) 2366(5) 644(8) 111(4)

C(21)* -585(5) 3455(3) 7367(4) 46(1)

S51

C(21A)** 4421(10) 4483(4) 8621(7) 87(3)

C(22)* -104(6) 3859(3) 8279(5) 52(1)

C(22A)** 4954(11) 4213(6) 9615(7) 113(4)

C(23) -432(8) 4552(3) 8037(5) 60(2)

C(24) 426(7) 4824(3) 7252(5) 57(2)

C(25) 44(7) 5476(3) 6872(5) 60(2)

C(26) 926(7) 5719(3) 6054(5) 59(2)

C(27) 882(7) 5269(3) 5145(5) 55(2)

C(28) -555(6) 5101(3) 4646(5) 54(2)

C(29) -539(7) 4684(3) 3712(5) 54(2)

C(30) 221(6) 4053(3) 3894(5) 50(1)

C(31) -307(6) 3673(3) 4748(5) 52(1)

C(32) 567(7) 3101(3) 5070(5) 57(2)

C(33) 165(7) 2783(3) 6018(5) 57(2)

C(35) -1664(16) 6134(6) 2550(8) 144(5)

C(36) -1990(9) 4971(5) 1246(7) 96(3)

C(37) 742(11) 5720(5) 1309(7) 96(3)

C(38) 1496(11) 5139(6) 938(8) 109(4)

C(39) 1725(15) 6130(6) 1988(10) 152(6)

C(40) 131(13) 6110(6) 383(7) 117(4)

C(61) 4586(11) 4529(6) 2957(8) 118(4)

C(101) 5131(8) 1418(4) 4526(6) 74(2)

C(102) 3758(9) 1095(4) 4678(9) 99(3)

C(221) -801(8) 3614(4) 9180(5) 70(2)

C(222) -486(11) 2930(5) 9430(7) 91(3)

C(261) 527(10) 6387(4) 5738(7) 79(2)

C(301) 233(7) 3661(4) 2926(5) 60(2)

C(302) -1135(8) 3362(4) 2531(6) 79(2) ________________________________________________________________________________

Partial occupation factors of 0.415(12)* and 0.585(12)**

S52

Table 3. Bond lengths [Å] and angles [°] for jb118.

_____________________________________________________

Si(2)-O(29) 1.636(5)

Si(2)-C(36) 1.852(9)

Si(2)-C(35) 1.875(11)

Si(2)-C(37) 1.878(11)

O(1)-C(1) 1.211(7)

O(9)-C(9) 1.430(8)

O(9)-Si(1A) 1.657(7)

O(9)-Si(1) 1.726(9)

O(21)-C(21) 1.208(7)

O(29)-C(29) 1.435(8)

N(14)-C(1) 1.339(8)

N(14)-C(13) 1.456(8)

N(34)-C(21) 1.343(7)

N(34)-C(33) 1.453(8)

C(1)-C(2) 1.516(10)

C(2)-C(3) 1.528(11)

C(2)-C(21A) 1.533(11)

C(3)-C(4) 1.514(11)

C(4)-C(5) 1.512(11)

C(5)-C(6) 1.531(12)

C(6)-C(61) 1.526(12)

C(6)-C(7) 1.528(13)

C(7)-C(8) 1.524(9)

C(8)-C(9) 1.524(11)

C(9)-C(10) 1.537(9)

C(10)-C(11) 1.523(8)

C(10)-C(101) 1.530(11)

C(11)-C(12) 1.523(8)

C(12)-C(13) 1.514(9)

Si(1)-C(17) 1.84(2)

Si(1)-C(15) 1.86(2)

Si(1)-C(16) 1.894(17)

C(17)-C(19) 1.52(3)

C(17)-C(20) 1.53(2)

C(17)-C(18) 1.54(2)

Si(1A)-C(17A) 1.835(17)

Si(1A)-C(15A) 1.86(2)

S53

Si(1A)-C(16A) 1.887(17)

C(17A)-C(20) 1.496(16)

C(17A)-C(19A) 1.51(2)

C(17A)-C(18A) 1.541(18)

C(21)-C(22) 1.522(9)

C(21A)-C(22A) 1.491(13)

C(22)-C(23) 1.527(10)

C(22)-C(221) 1.529(9)

C(23)-C(24) 1.516(9)

C(24)-C(25) 1.502(9)

C(25)-C(26) 1.541(10)

C(26)-C(261) 1.514(10)

C(26)-C(27) 1.541(9)

C(27)-C(28) 1.520(9)

C(28)-C(29) 1.532(9)

C(29)-C(30) 1.530(9)

C(30)-C(31) 1.526(9)

C(30)-C(301) 1.538(9)

C(31)-C(32) 1.513(9)

C(32)-C(33) 1.521(9)

C(37)-C(39) 1.519(13)

C(37)-C(38) 1.535(16)

C(37)-C(40) 1.554(12)

C(101)-C(102) 1.524(12)

C(221)-C(222) 1.508(12)

C(301)-C(302) 1.512(10)

O(29)-Si(2)-C(36) 110.8(4)

O(29)-Si(2)-C(35) 111.7(4)

C(36)-Si(2)-C(35) 107.8(6)

O(29)-Si(2)-C(37) 103.5(4)

C(36)-Si(2)-C(37) 110.8(4)

C(35)-Si(2)-C(37) 112.2(6)

C(9)-O(9)-Si(1A) 131.3(5)

C(9)-O(9)-Si(1) 119.5(5)

C(29)-O(29)-Si(2) 127.4(4)

C(1)-N(14)-C(13) 123.3(5)

C(21)-N(34)-C(33) 123.4(5)

O(1)-C(1)-N(14) 122.7(6)

S54

O(1)-C(1)-C(2) 121.1(6)

N(14)-C(1)-C(2) 116.2(5)

C(1)-C(2)-C(3) 108.9(6)

C(1)-C(2)-C(21A) 109.5(7)

C(3)-C(2)-C(21A) 112.8(6)

C(4)-C(3)-C(2) 113.8(6)

C(5)-C(4)-C(3) 113.9(7)

C(4)-C(5)-C(6) 115.1(6)

C(61)-C(6)-C(7) 112.5(9)

C(61)-C(6)-C(5) 110.6(8)

C(7)-C(6)-C(5) 112.9(6)

C(8)-C(7)-C(6) 114.4(6)

C(7)-C(8)-C(9) 115.5(6)

O(9)-C(9)-C(8) 110.0(6)

O(9)-C(9)-C(10) 108.0(6)

C(8)-C(9)-C(10) 115.9(6)

C(11)-C(10)-C(101) 112.5(6)

C(11)-C(10)-C(9) 111.6(5)

C(101)-C(10)-C(9) 111.7(6)

C(10)-C(11)-C(12) 114.3(5)

C(13)-C(12)-C(11) 113.1(5)

N(14)-C(13)-C(12) 113.0(5)

O(9)-Si(1)-C(17) 99.8(9)

O(9)-Si(1)-C(15) 119.9(8)

C(17)-Si(1)-C(15) 108.3(10)

O(9)-Si(1)-C(16) 108.4(8)

C(17)-Si(1)-C(16) 114.0(10)

C(15)-Si(1)-C(16) 106.7(13)

C(19)-C(17)-C(20) 110(2)

C(19)-C(17)-C(18) 108(2)

C(20)-C(17)-C(18) 107.1(16)

C(19)-C(17)-Si(1) 108.8(14)

C(20)-C(17)-Si(1) 111.7(13)

C(18)-C(17)-Si(1) 111.1(18)

O(9)-Si(1A)-C(17A) 107.4(6)

O(9)-Si(1A)-C(15A) 104.6(8)

C(17A)-Si(1A)-C(15A) 110.9(9)

O(9)-Si(1A)-C(16A) 114.8(7)

C(17A)-Si(1A)-C(16A) 109.1(9)

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C(15A)-Si(1A)-C(16A) 109.9(11)

C(20)-C(17A)-C(19A) 106.9(15)

C(20)-C(17A)-C(18A) 106.9(11)

C(19A)-C(17A)-C(18A) 110.9(14)

C(20)-C(17A)-Si(1A) 111.9(10)

C(19A)-C(17A)-Si(1A) 110.3(10)

C(18A)-C(17A)-Si(1A) 109.9(12)

O(21)-C(21)-N(34) 122.6(6)

O(21)-C(21)-C(22) 121.6(5)

N(34)-C(21)-C(22) 115.8(5)

C(22A)-C(21A)-C(2) 114.9(8)

C(21)-C(22)-C(23) 109.1(5)

C(21)-C(22)-C(221) 108.7(5)

C(23)-C(22)-C(221) 113.1(6)

C(24)-C(23)-C(22) 113.3(6)

C(25)-C(24)-C(23) 116.8(6)

C(24)-C(25)-C(26) 114.3(6)

C(261)-C(26)-C(27) 111.6(6)

C(261)-C(26)-C(25) 111.4(6)

C(27)-C(26)-C(25) 112.4(5)

C(28)-C(27)-C(26) 116.2(6)

C(27)-C(28)-C(29) 114.1(5)

O(29)-C(29)-C(30) 108.7(5)

O(29)-C(29)-C(28) 109.7(5)

C(30)-C(29)-C(28) 114.6(5)

C(31)-C(30)-C(29) 112.7(5)

C(31)-C(30)-C(301) 112.2(5)

C(29)-C(30)-C(301) 112.3(5)

C(32)-C(31)-C(30) 114.5(5)

C(31)-C(32)-C(33) 114.2(5)

N(34)-C(33)-C(32) 113.4(5)

C(39)-C(37)-C(38) 111.2(10)

C(39)-C(37)-C(40) 109.8(9)

C(38)-C(37)-C(40) 108.7(9)

C(39)-C(37)-Si(2) 108.3(8)

C(38)-C(37)-Si(2) 109.3(6)

C(40)-C(37)-Si(2) 109.4(8)

C(102)-C(101)-C(10) 114.5(6)

C(222)-C(221)-C(22) 113.9(7)

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C(302)-C(301)-C(30) 116.0(5)

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Table 4. Anisotropic displacement parameters (Å2x 103)for jb118. The anisotropic

displacement factor exponent takes the form: -22[ h2a*2U11 + ... + 2 h k a* b* U12 ]

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U11 U22 U33 U23 U13 U12

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Si(2) 84(1) 71(1) 50(1) -5(1) -12(1) 6(1)

O(1) 31(2) 95(4) 118(4) -19(3) 4(2) -1(2)

O(9) 66(3) 126(5) 46(2) -15(3) 15(2) -16(3)

O(21) 27(2) 100(4) 64(3) -15(3) 7(2) -2(2)

O(29) 59(3) 74(3) 47(2) 1(2) 1(2) -5(2)

N(14) 36(2) 62(3) 47(3) -3(2) -1(2) 0(2)

N(34) 36(3) 55(3) 60(3) -5(2) 5(2) 0(2)

C(1) 30(3) 73(4) 53(3) -7(3) -1(2) 7(3)

C(2) 43(3) 65(4) 78(5) -15(4) 4(3) 5(3)

C(3) 68(5) 67(5) 91(6) 2(4) 9(4) 15(4)

C(4) 59(4) 64(4) 75(5) 6(4) 2(3) 1(3)

C(5) 51(4) 76(5) 89(6) 19(4) 1(4) 0(3)

C(6) 52(4) 106(6) 82(5) 37(5) 5(4) -13(4)

C(7) 40(3) 109(6) 59(4) 15(4) 10(3) -4(4)

C(8) 38(3) 104(6) 46(3) 13(4) 1(2) 0(3)

C(9) 44(3) 102(6) 39(3) -4(3) 6(2) -11(3)

C(10) 44(3) 79(4) 46(3) -9(3) 3(2) -4(3)

C(11) 48(3) 60(4) 45(3) -2(3) 3(2) 1(3)

C(12) 64(4) 53(3) 49(3) 0(3) -1(3) 6(3)

C(13) 69(4) 59(4) 45(3) 5(3) 2(3) 1(3)

Si(1) 70(4) 81(5) 42(3) -6(3) 11(2) -13(4)

C(15) 115(18) 130(20) 42(10) 6(12) 4(10) 0(16)

C(16) 101(15) 152(19) 61(11) -20(12) 15(10) -55(14)

C(17) 190(40) 56(13) 36(10) 4(9) 18(15) 11(18)

C(18) 150(20) 150(20) 84(15) -33(16) 38(15) -34(18)

C(19) 180(20) 120(20) 120(20) -34(17) 58(19) 28(19)

Si(1A) 54(2) 113(5) 50(2) -13(2) -2(2) 3(2)

C(15A) 116(14) 190(20) 110(14) -53(14) -33(12) 64(15)

C(16A) 121(14) 184(19) 76(10) -12(11) 14(9) -79(13)

C(17A) 99(11) 48(9) 47(8) 8(6) 2(7) -2(8)

C(18A) 103(12) 92(11) 55(8) -11(8) 6(8) -13(9)

C(19A) 103(13) 134(15) 68(10) -11(10) 0(9) 33(12)

C(20) 127(9) 116(8) 96(7) -17(7) 35(6) -23(7)

C(21) 29(3) 59(3) 50(3) 2(3) 11(2) 4(2)

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C(21A) 87(6) 81(6) 91(6) -30(5) 0(5) 8(5)

C(22) 45(3) 64(4) 46(3) -5(3) 0(2) 0(3)

C(22A) 102(7) 153(11) 79(6) -37(7) -12(5) 29(7)

C(23) 67(4) 64(4) 48(3) -10(3) 5(3) 2(3)

C(24) 50(4) 62(4) 58(4) 1(3) 3(3) 4(3)

C(25) 69(4) 55(3) 53(3) -10(3) -2(3) 4(3)

C(26) 61(4) 51(3) 62(4) -3(3) -4(3) -2(3)

C(27) 50(4) 60(4) 54(3) 0(3) 0(3) -2(3)

C(28) 48(4) 58(4) 55(4) -3(3) 1(3) 8(3)

C(29) 46(3) 65(4) 50(3) -5(3) 0(3) 0(3)

C(30) 39(3) 62(4) 50(3) -8(3) 5(2) -6(3)

C(31) 45(3) 62(4) 51(3) -11(3) 8(3) -4(3)

C(32) 62(4) 54(4) 58(4) -9(3) 15(3) -2(3)

C(33) 52(4) 51(3) 69(4) -10(3) 13(3) -1(3)

C(35) 220(13) 126(9) 82(7) -4(7) -3(8) 84(9)

C(36) 76(6) 130(8) 77(6) 10(6) -17(4) -6(5)

C(37) 115(8) 95(6) 71(5) 22(5) -22(5) -36(6)

C(38) 91(7) 159(11) 79(6) 31(7) 13(5) -4(7)

C(39) 171(11) 152(11) 118(9) 33(8) -49(8) -90(9)

C(40) 151(10) 120(8) 74(6) 32(6) -21(6) -21(8)

C(61) 107(8) 149(10) 97(7) 64(8) 3(6) -13(7)

C(101) 65(5) 87(5) 71(5) -22(4) 4(4) 13(4)

C(102) 83(6) 73(5) 139(9) -25(6) 0(6) -4(5)

C(221) 79(5) 85(5) 47(4) -6(4) 11(3) -8(4)

C(222) 110(7) 97(7) 68(5) 18(5) 15(5) -12(5)

C(261) 100(6) 53(4) 82(5) -2(4) 4(4) -2(4)

C(301) 51(4) 72(4) 58(4) -13(3) 13(3) -2(3)

C(302) 72(5) 94(6) 71(5) -35(4) 7(4) -16(4)

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Table 5. Hydrogen bonds for jb118 [Å and °].

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D-H...A d(D-H) d(H...A) d(D...A) <(DHA)

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N(14)-H(14)...O(21)#1 0.86 2.05 2.864(6) 156.7

N(34)-H(34)...O(1) 0.86 2.01 2.873(7) 176.7

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Symmetry transformations used to generate equivalent atoms:

#1 x+1,y,z

Documents

Núria Llor, †Elies Molins, Joan Bosch* and Mercedes Amat*€¦ · S1 Enantioselective total synthesis of fluvirucinin B 1 Guillaume Guignard,† †Núria Llor, †Elies Molins,‡