total synthesis of cis-reticulatacin10-ones a and b: absolute … · 2017. 4. 2. · si 1 total...

SI 1

Total Synthesis of cis-Reticulatacin-10-ones A and B: Absolute

Stereochemical Assignment

Sherif B. Abdel Ghani, Lynda J. Brown,

Bruno Figadère, and Richard C. D. Brown*

*Corresponding author [email protected]; FAX: +44 (0)23 80593781

Contents Page

1.0 General methods SI 2

2.0 Preparation of compounds SI 3

2.1 6-Bromo-N-methoxy-N-methyhexanamide (contains ~ 20% 6-chloro-N-methoxy-N-methyhexanamide) SI 3

2.2 1-Bromotridec-12-en-6-one (9) (contains ~ 20% 1-chlorotridec-12-en-6-one) SI 4

2.3 1-Bromotridec-12-en-6-ol (contains ~ 20% 1-chlorotridec-12-en-6-ol) SI 5

2.4 (±)-1-(Phenylsulfonyl)tridec-12-en-6-ol (6) SI 6

2.5 (1S,3R/S,8R/S)-1-[(2S,5R)-Tetrahydro-5-((1R)-1-hydroxytridecyl)furan-2-yl]-3-(phenylsulfonyl)pentadec-14-ene-1,8-

diolΨ SI 7

2.6 (1S,8R/S)-1-[(2S,5R)-Tetrahydro-5-((1R)1-hydroxytridecyl)furan-2-yl]pentadec-14-ene-1,8-diol (10B/A, ratio ~ 1:9) SI 8

2.7 (15S)-15-[(2S,5R)-Tetrahydro-5-((1R)1-hydroxytridecyl)furan-2-yl]-15-hydroxypentadec-1-en-8-oneΨ SI 9

2.8 (4E)-4,5-Didehydro-cis-reticulatacin-10-one B/A (11B/A, dr ~ 9:1) SI 10

2.9 cis-Reticulatacin-10-one B/A (4B/A, dr ~ 9:1) SI 12

3.0 NMR Spectra SI 3

3.1 1H NMR 6-Bromo-N-methoxy-N-methyhexanamide (contains ~ 20% 6-chloro-N-methoxy-N-methyhexanamide) SI 13

3.2 13C NMR 6-Bromo-N-methoxy-N-methyhexanamide (contains ~ 20% 6-chloro-N-methoxy-N-methyhexanamide) SI 14

3.3 1H NMR 1-Bromotridec-12-en-6-one (9) (contains ~ 20% 1-chlorotridec-12-en-6-one) SI 15

3.4 13C NMR 1-Bromotridec-12-en-6-one (9) (contains ~ 20% 1-chlorotridec-12-en-6-one) SI 16

3.5 1H NMR 1-Bromotridec-12-en-6-ol (contains ~ 20% 1-chlorotridec-12-en-6-ol) SI 17

3.6 13C NMR 1-Bromotridec-12-en-6-ol (contains ~ 20% 1-chlorotridec-12-en-6-ol) SI 18

3.7 1H NMR (±)-1-(Phenylsulfonyl)tridec-12-en-6-ol (6) SI 19

3.8 13C NMR (±)-1-(Phenylsulfonyl)tridec-12-en-6-ol (6) SI 20

3.9 1H NMR (1S,3R/S,8R/S)-1-[(2S,5R)-Tetrahydro-5-((1R)-1-hydroxytridecyl)furan-2-yl]-3-(phenylsulfonyl)pentadec-

14-ene-1,8-diolΨ SI 21

3.10 13C NMR (1S,3R/S,8R/S)-1-[(2S,5R)-Tetrahydro-5-((1R)-1-hydroxytridecyl)furan-2-yl]-3-(phenylsulfonyl)pentadec-

14-ene-1,8-diolΨ SI 22

3.11 1H NMR (1S,8R/S)-1-[(2S,5R)-Tetrahydro-5-((1R)1-hydroxytridecyl)furan-2-yl]pentadec-14-ene-1,8-diol (10A/B,

ratio ~ 1:9) SI 23

Ψ Mixture of A and B isomers in a ratio of 1:9

Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2010

SI 2

3.12 13C NMR (1S,8R/S)-1-[(2S,5R)-Tetrahydro-5-((1R)1-hydroxytridecyl)furan-2-yl]pentadec-14-ene-1,8-diol (10A/B,

ratio ~ 1:9) SI 24

3.13 1H NMR (15S)-15-[(2S,5R)-Tetrahydro-5-((1R)1-hydroxytridecyl)furan-2-yl]-15-hydroxypentadec-1-en-8-oneΨ SI 25

3.14 13C NMR (15S)-15-[(2S,5R)-Tetrahydro-5-((1R)1-hydroxytridecyl)furan-2-yl]-15-hydroxypentadec-1-en-8-oneΨ SI 26

3.15 1H NMR (4E)-4,5-Didehydro-cis-reticulatacin-10-one A/B (11A/B, dr ~ 1:9) SI 27

3.16 1H NMR (4E)-4,5-Didehydro-cis-reticulatacin-10-one A/B (11A/B, dr ~ 1:9) SI 28

3.17 13C NMR (4E)-4,5-Didehydro-cis-reticulatacin-10-one A/B (11A/B, dr ~ 1:9) SI 29

3.18 1H NMR (R,2Z,5E)-4-Nitrobenzyl 18-((2R,5S)-tetrahydro-5-((S)-1-hydroxyheptyl)furan-2-yl)-18-hydroxy-3-((S)-1-

hydroxyethyl)-11-oxooctadeca-2,5-dienoate (dr ~ 1:9) SI 30

3.19 13C NMR (R,2Z,5E)-4-Nitrobenzyl 18-((2R,5S)-tetrahydro-5-((S)-1-hydroxyheptyl)furan-2-yl)-18-hydroxy-3-((S)-1-

hydroxyethyl)-11-oxooctadeca-2,5-dienoate (dr ~ 1:9) SI 31

3.20 1H NMR cis-Reticulatacin-10-one A/B (4A/B, dr ~ 1:9) SI 32

3.21 1H NMR cis-Reticulatacin-10-one A/B (4A/B, dr ~ 1:9) SI 33

3.22 13C NMR cis-Reticulatacin-10-one A/B (4A/B, dr ~ 1:9) SI 34

3.23 1H NMR hydrazone byproduct SI 35

3.24 Mass spectrum of hydrazone byproduct SI 36

4.0 Chromatograms SI 36

4.1 Chiral HPLC chromatogram of synthetic cis-reticulatacin-10-one A/B (4A/B, dr ~ 1:9) SI 36

4.2 Chiral HPLC chromatogram of natural cis-reticulatacin-10-one A/B (4A/B) SI 37

4.3 Overlay of chiral HPLC chromatograms of natural cis-reticulatacin-10-one A/B (4A/B ) synthetic cis-reticulatacin-

10-one A/B (4A/B, dr ~ 1:9) SI 37

1.0 General methods

All reactions were carried out under an inert atmosphere in oven dried glassware. THF and Et2O were distilled

from sodium and benzophenone prior to use. Triethylamine and dichloromethane were dried by distillation from

CaH2. 1H NMR and

13C NMR spectra were recorded in CDCl3 solution using Bruker AC300, AV300 (300 and

75 MHz respectively) or Bruker DPX400 (400 and 100 MHz respectively) spectrometers. Chemical shifts are

reported in δ units using CHCl3 as an internal standard (δ 7.27 ppm 1H, δ 77.15 ppm

13C respectively). Infrared

spectra were recorded on a Nicolet 380 spectrometer fitted with a Diamond platform, as solids or neat liquids.

Melting points are uncorrected. Electron impact and chemical ionisation mass spectra were obtained using a

Fisons VG platform single quadropole mass spectrometer. Electrospray mass spectra were obtained using a

Micromass platform mass analyser with an electrospray ion source. Chiral HPLC separations were performed on

a Agilent 1120 Compact LC using a Chiral CD-Ph column (4.6 x 250 mm) eluting with isopropanol:hexane (1:4,

1 mL/min), monitored by UV detection at 210 nm.


SI 3

2.0 Preparation of Compounds

2.1 6-Bromo-N-methoxy-N-methyhexanamide (contains ~ 20% 6-chloro-N-methoxy-N-methy

hexanamide)

4

N

OBr/Cl

OMe

To a stirred suspension of O,N-dimethylhydroxylamine hydrochloride (2.73 g, 27.98 mmol) in anhydrous

CH2Cl2 (60 mL), 6-bromohexanoyl chloride (8, 5.00 g, 23.4 mmol) was added slowly, followed by dropwise

addition of i-Pr2NEt (9 mL, 51.6 mmol) at 0 °C. The solution was allowed to warm to rt, then stirred at rt for 4 h

before dilution with CH2Cl2. The reaction mixture was washed with 1 N HCl (3 x 50 mL), brine (25 mL) and

dried (MgSO4) followed by concentration in vacuo affording the title Weinreb amide as a mixture (~4:1) with

the corresponding alkyl chloride (5.30 g, 27.7 mmol, 99%).* IR νmax (neat)/cm–1

2937 (s), 2865 (s), 1658 (s),

1460 (s), 1415 (m), 997 (s); 1H-NMR (300 MHz, CDCl3) δ 3.66 (3H, s, NOCH3), 3.39 (2H, t, J = 6.7 Hz,

CH2Br), 3.15 (3H, s, NCH3), 2.41 (2H, t, J = 7.4 Hz, CH2CON-), 1.87 (2H, quintet, J = 7.0 Hz, CH2), 1.64 (2H,

quintet, J = 7.1 Hz, CH2), 1.51-1.42 (2H, m, CH2); [selected signals for the alkyl chloride: 3.52 (2H, t, J = 6.7

Hz, CH2Cl), 1.83-1.77 (m, CH2)]; 13

C-NMR (75 MHz, CDCl3) δ 174.4 (C=O), 61.3 (OCH3), 33.6 (CH2), 32.6

(CH2), 31.6 (CH2), 27.9 (CH2), 23.7 (NCH3); [selected signals for the alkyl chloride: 44.9 (CH2), 33.5 (CH2),

32.5 (CH2), 27.7 (CH2), 23.9 (NCH3)]; LRMS (EI+) m/z 238 ([M+H]

+), 158 ([M–halide]

+); HRMS (ES

+) m/z

C8H16BrNNaO2 Calcd. 260.026, found 260.028.

*Yield calculated based on a 4:1 mixture of bromide and chloride


SI 4

2.2 1-Bromotridec-12-en-6-one (9) (contains ~ 20% 1-chlorotridec-12-en-6-one)

4 4

9 (Br/Cl ~ 4:1)Br/Cl O

At –40 °C hept-7-enylmagnesium bromide in THF (30 mL of a 1.0 M solution, 30 mmol) was added dropwise to

a solution of 6-bromo-N-methoxy-N-methyhexanamide* (2.10 g, 9.17 mmol)* in THF (25 mL). The mixture

was left to stir at –35 ºC for 2 h. The reaction was quenched at –35 ºC by dropwise addition of cold water, then

allowed to warm to rt. The mixture was extracted with ether (3 x 30 mL). The combined organic extract was

washed with 1 N H2SO4 solution (20 mL) then water, brine, dried (MgSO4) and concentrated in vacuo to give a

colourless oil. Purification by silica gel column chromatography (Et2O/hexane, 1:19→1:9) gave the haloketones

as a colourless oil (1.452 g, 5.41 mmol, 59%).* IR νmax (neat)/cm–1

2931 (s), 2857 (s), 1712 (s), 1640 (s), 1460

(s), 1412 (m), 994 (s), 911 (s); 1H-NMR (300 MHz, CDCl3) δ 5.77 (1H, tdd, J = 6.8, 10.2, 17.0 Hz, CH=CH2),

5.02-4.87 (2H, m, CH=CH2), 3.38 (2H, t, J = 6.7 Hz, CH2Br), 2.39 (4H, q, J = 7.3 Hz, CH2C=OCH2), 2.03 (2H,

q, J = 6.8 Hz, CH2CH=CH2), 1.90-1.80 (2H, m, CH2CH2Br), 1.65-1.49 (4H, m, CH2), 1.41-1.20 (6H, m, CH2);

[selected signals for the alkyl chloride: 3.51 (2H, t, J = 6.6 Hz, CH2Cl), 1.81-1.75 (2H, m, CH2]; 13

C-NMR (75

MHz, CDCl3) δ 210.8 (C=O), 138.8 (CH=CH2), 114.4 (CH=CH2), 42.8 (CH2), 42.4 (CH2), 33.6 (CH2), 32.6

(CH2), 28.7 (CH2), 27.8 (CH2), 23.7 (CH2), 22.9 (CH2) [selected signals for the alkyl chloride: 44.8 (CH2Cl),

32.4 (CH2), 26.5 (CH2), 23.1 (CH2)]; LRMS (CI+) m/z 275 ([M+H]

+), 195 ([M–halide]

+); HRMS (ES

+) m/z

C13H23BrNaO Calcd. 297.083, found 297.083.

*Amounts and yields calculated based on a 4:1 mixture of bromide and chloride


SI 5

2.3 1-Bromotridec-12-en-6-ol (contains ~ 20% 1-chlorotridec-12-en-6-ol)

4 4

(Br/Cl ~ 4:1)Br/Cl OH

To a solution of the ketone (9, 30 mg, 0.112 mmol)* in EtOH (1 mL) was added NaBH4 (12 mg, 0.33 mmol) at 0

°C. The reaction was left to warm to rt. After 30 min 1 N HCl was added dropwise to the reaction mixture

[CAUTION: evolution of H2 gas]. The mixture was extracted with ether (2 x 10 mL). The combined organic

extract was washed with water, brine, then dried (MgSO4) and concentrated in vacuo. Purification by silica gel

column chromatography (EtOAc/hexane, 1:19→1:9) gave the title alcohol as a colourless oil (29.9 mg, 0.112

mmol, 100%).* IR νmax (neat)/cm–1

3347 (br), 2927 (s), 2855 (s), 1640 (s), 1460 (s), 994 (s), 909 (s); 1H-NMR

(400 MHz, CDCl3) δ 5.81 (1H, tdd, J = 6.5, 10.3, 17.1 Hz, CH=CH2), 5.00 (1H, d, J = 17.1 Hz, CH=CHH), 4.94

(1H, d, J = 10.3 Hz, CH=CHH), 3.59 (1H, m, CHOH), 3.41 (2H, t, J = 6.8 Hz, CH2Br), 2.10-2.00 (2H, m,

CH2CH=CH2), 1.90-1.80 (2H, m, CH2CH2Br), 1.55-1.25 (14H, m) [selected signals for the alkyl chloride: 3.56

(2H, t, J = 6.7 Hz, CH2Cl), 1.83-1.77 (2H, m, CH2)]; 13

C-NMR (100 MHz, CDCl3) δ 139.1 (CH=CH2), 114.3

(CH=CH2), 71.9 (CHOH), 37.6 (CH2), 37.3 (CH2), 33.8 (CH2), 32.8 (CH2), 29.2 (CH2), 28.9 (CH2), 28.3 (CH2),

25.6 (CH2), 24.9 (CH2) [selected signals for the alkyl chloride: 45.2 (CH2Br), 37.4 (CH2), 32.7 (CH2), 27.1

(CH2), 25.1 (CH2)]; LRMS (EI+) m/z 277 ([M+H]

+).

*Amounts and yields calculated based on a 4:1 mixture of bromide and chloride


SI 6

2.4 (±)-1-(Phenylsulfonyl)tridec-12-en-6-ol (6)

6

4 4PhO2S OH

To a stirred solution of the 1-bromotridec-12-en-6-ol (120 mg, 0.45 mmol)* in dry DMF (2 mL) at rt, was added

PhSO2Na (78 mg, 0.47 mmol). The reaction mixture was heated a 60 °C for 5 h. The cooled reaction mixture

was partitioned between ether and water. The combined ether extract was washed with 1 N HCl (aq), water,

brine, then dried (MgSO4) and concentrated in vacuo to give a cloudy oil. Purification by silica gel column

chromatography (EtOAc/hexane, 2:8→3:7) gave the title sulfone as a colourless oil (125 mg, 0.37 mmol, 82%).

IR νmax (neat)/cm–1

3526 (br), 2927 (s), 2855 (s), 1639 (s), 1447 (s), 1303 (s), 1144 (s), 1086 (s); 1H-NMR (400

MHz, CDCl3) δ 7.90 (2H, d, J = 7.8 Hz), 7.65 (1H, t, J = 7.5 Hz), 7.56 (2H, t, J = 7.5 Hz), 5.80 (1H, m, tdd, J =

6.8, 10.0, 17.1 Hz, CH=CH2), 4.98 (1H, d, J = 17.1 Hz, CH=CHH), 4.92 (1H, d, J = 10.0 Hz, CH=CHH), 3.53

(1H, m, CHOH), 3.07 (2H, m, CH2SO2), 2.03 (2H, q, J = 6.8 Hz, CH2CH=CH2), 1.77-1.67 (2H, m, CH2CH2S),

1.48-1.20 (14H, m); 13

C-NMR (100 MHz, CDCl3) δ 139.3 (CSO2), 139.1 (CH=CH2), 133.6 (CH), 129.3 (CH),

128.1 (CH), 114.3 (CH=CH2), 71.6 (CHOH), 56.2 (CH2), 37.5 (CH2), 37.0 (CH2), 33.7 (CH2), 29.1 (CH2), 28.9

(CH2), 28.3 (CH2), 25.5 (CH2), 25.1 (CH2), 22.7 (CH2); LRMS (CI+) m/z 361.2 ([M+Na]

+).

*Amounts calculated based on a 4:1 mixture of bromide and chloride


SI 7

2.5 (1S,3R/S,8R/S)-1-[(2S,5R)-Tetrahydro-5-((1R)-1-hydroxytridecyl)furan-2-yl]-3-

(phenylsulfonyl)pentadec-14-ene-1,8-diol (mixture of B/A isomers ~1:9)

44

C11H23

HO

O

OHHH OH

SO2Ph

44

C11H23

HO

O

OHHH OH

SO2Ph

Ratio ~ 9:1

To a solution of the sulfone 6 (300 mg, 0.891 mmol) in dry THF (10 mL) at –78 °C, was added n-BuLi (730 µL

of 2.45 M in hexane, 1.76 mmol) dropwise. The reaction mixture left to stir at –78 °C for 30 min before adding

BF3•Et2O (225 µL, 1.76 mmol). The mixture was left to stir at –78 °C for 30 min, then a solution of enantiomeric

epoxides (5 B/A, er ~ 9:1, 138.6 mg, 0.444 mmol) in THF (1 mL) was added dropwise. The mixture was left to

stir at –78 °C for 1 h, then the cooling bath was removed and the reaction was allowed to warm to rt. Aqueous 1

N HCl (10 mL) was added dropwise, and the mixture was extracted with EtOAc (3 x 20 mL). The combined

organic extract was washed with water, brine, then dried (MgSO4) and concentrated in vacuo. Purification by

silica gel column chromatography (EtOAc/hexane, 2:8→3:7) gave a mixture of diastereoisomeric sulfones as a

colourless oil (160 mg, 0.246 mmol, 55%). ΙR νmax (neat)/cm–1

3381 (br), 2923 (s), 2853 (s), 1464 (s), 1447 (s),

1301 (s), 1143 (s), 1084 (s); 1Η-ΝΜR (300 ΜΗz, CDCl3) δ 7.89 (2Η, d, J = 7.7 Ηz), 7.64 (1Η, t, J = 6.9 Ηz),

7.55 (2Η, t, J = 7.4 Ηz), 5.80 (1Η, m, CΗ=CΗ2), 5.02-4.91 (2Η, m, CΗ=CΗ2), 3.90-3.70 (2Η, m, CΗΟ x 2),

3.60-3.48 (2Η, m, CΗΟΗ x 2), 3.47-3.30 (2Η, m), 2.10-1.70 (10Η, m), 1.55-1.20 (39Η, m), 0.92 (3H, t, J = 6.4

Hz, CH3); 13

C-NMR (75 MHz, CDCl3) [multiple signals observed due to the presence of diastereoisomers] δ

139.1 (C), 138.0 (CH), 133.6 (CH), 129.2 (2CH), 128.9 (2CH), 114.3 (CH2), 82.6 (CH), 82.4 (CH), 82.3 (CH),

74.1 (CHOH), 72.0 (CHOH), 71.8 (CHOH), 71.6 (CHOH), 71.2 (CHOH), 60.9 (CHSO2), 37.7 (CH2), 37.6

(CH2), 34.7 (CH2), 33.8 (CH2), 32.7 (CH2), 32.0 (CH2), 29.7 (CH2), 29.4 (CH2), 29.2 (CH2), 28.9 (CH2), 28.9

(CH2), 28.1 (CH2), 26.6 (CH2), 25.4 (CH2), 25.3 (CH2), 22.7 (CH2), 14.2 (CH3); LRMS (ES+) m/z 651.5

([M+H]+), 673.5 ([M+Na]

+).


SI 8

2.6 (1S,8R/S)-1-[(2S,5R)-Tetrahydro-5-((1R)1-hydroxytridecyl)furan-2-yl]pentadec-14-ene-

1,8-diol (10B) (+ 10A, ratio ~ 9:1)

10B

4 4

C11H23

HO

O

OHHH

OH

10A

4 4

C11H23

HO

O

OHHH

OH

Ratio 10B/10A ~ 9:1

Τo a solution of 1-tetrahydro-5-(1-hydroxytridecyl)furan-2-yl)-3-(phenylsulfonyl)pentadec-14-ene-1,8-diol (A/B

isomers, ratio ~ 1:9) (130 mg, 0.200 mmol) in dry MeOH (5 mL) at 0 °C, was added Na2HPO4 (80 mg, 0.56

mmol) and stirred for 2 min before the addition of Na/Hg amalgam 10% (600 mg). The reaction was allowed to

warm to rt, left to stir for 3 h, then diluted with ether and dropwise addition of saturated NH4Cl (aq). The mixture

was extracted with EtOAc (4 x 10 mL) and the combined organic solution washed with water, brine, dried

(MgSO4) and concentrated in vacuo. Purification by silica gel column chromatography (EtOAc-hexane,

1:4→1:1) gave the title isomeric triols as a white solid (83 mg, 0.162 mmol, 81%). [α]27

D –0.07 (CHCl3, c 1.00);

Mp 55-58 °C; IR νmax (neat)/cm–1

3381 (br), 2917(s), 2849 (s), 1466 (s), 1308 (s), 1086 (s), 1026 (s); 1H-NMR

(400 MHz, CDCl3) δ 5.81 (1H, tdd, J = 6.8, 10.0, 17.1 Hz, CH=CH2), 4.99 (1H, qd, J = 1.8, 17.1 Hz, CH=CHH),

4.93 (1H, tdd, J = 1.3, 1.8, 10.0, CH=CHH), 3.85-3.78 (2H, m, CHO x 2), 3.62-3.54 (1H, m, CHOH), 3.45-3.38

(2H, m, CHOH x 2), 2.42 (3H, br, OH), 2.05 (2H, tq, J = 1.3, 6.8, CH2CH=CH2), 1.98-1.88 (2H, m, CH2 THF),

1.80-1.71 (2H, m, CH2 THF) 1.56-1.2 (42H, m), 0.88 (3H, t, J = 6.9 Hz, CH3); 13

C-NMR (100 MHz, CDCl3) δ

139.2 (CH), 114.3 (CH2), 82.8 (2 x CH), 74.5 (CH), 74.4 (CH), 72.1 (CH), 37.5 (CH), 34.2 (CH2), 34.1 (CH2),

33.8 (CH2), 32.0 (CH2), 29.8 (CH2), 29.8 (CH2), 29.7 (CH2), 29.4 (CH2), 29.3 (CH2), 29.0 (CH2), 28.3 (CH2),

25.8 (CH2), 25.7 (CH2), 25.7 (CH2), 25.6 (CH2), 22.8 (CH2), 14.2 (CH3); LRMS (ES+) m/z 511.5 ([M+H]

+),

533.5 ([M+Na]+); HRMS (ES

+) m/z C32H62NaO4 Calcd. 533.455, found 533.453.


SI 9

2.7 (15S)-15-[(2S,5R)-Tetrahydro-5-((1R)1-hydroxytridecyl)furan-2-yl]-15-hydroxypentadec-

1-en-8-one (+ A isomer, dr ~ 9:1)

4 4

C11H23

HO

O

OHHH

O4 4

C11H23

HO

O

OHHH

O

Ratio ~ 9:1

At 0 °C, Dess-Martin periodinane (51.1 mg, 0.117 mmol) was added in two batches to a solution of the triols

(10B/A ratio ~ 9:1, 60 mg, 0.117 mmol) in dry CH2Cl2 (2 mL). After 5 h, the mixture was diluted with ether and

filtered through a plug of silica eluting with 30% EtOAc in hexane and then concentrated in vacuo. Purification

by silica gel column chromatography (EtOAc-hexane, 1:4→1:1) gave the title ketones as a white solid (33 mg,

0.064 mmol, 56%). The starting triols (10B/A ratio ~9:1, 20mg, 0.039mmol, 33%) were also recovered. [α]27

D –

0.06 (CHCl3, c 1.00); Mp 54-57 °C; IR νmax (neat)/cm–1

3441 (br), 2918 (s), 2849 (s), 1708 (s), 1640 (s), 1467 (s),

1414 (s), 1310 (s), 1079 (s), 1027 (s); 1H-NMR (400 MHz, CDCl3) δ 5.80 (1H, tdd, J = 6.5, 10.3, 16.8 Hz,

CH=CH2), 4.99 (1H, d, J = 16.8 Hz, CH=CHH), 4.94 (1H, d, J = 10.3, CH=CHH), 3.85-3.75 (2H, m, CHO x 2),

3.45-3.35 (2H, m, CHOH x 2), 2.43 (2H, br, OH), 2.38 (4H, t, J = 7.4 Hz, CH2C=OCH2), 2.08-2.01 (2H, m,

CH2CH=CH2), 1.98-1.88 (2H, m, CH2 THF), 1.80-1.71 (2H, m, CH2 THF) 1.56-1.2 (40H, m), 0.88 (3H, t, J =

6.7 Hz, CH3); 13

C-NMR (100 MHz, CDCl3) δ 211.6 (C=O), 139.0 (CH), 114.4 (CH2), 82.8 (CH x 2), 74.5 (CH),

74.4 (CH), 42.9 (CH2), 42.9 (CH2), 34.2 (CH2), 34.1 (CH2), 33.7 (CH2), 32.0 (CH2), 29.8 (CH2), 29.8 (CH2), 29.8


(CH2), 23.8 (CH2), 22.8 (CH2), 14.2 (CH3); LRMS (ES+) m/z 531.5 ([M+Na]

+); HRMS (ES

+) m/z C32H60NaO4

Calcd. 531.439, found 531.438.


SI 10

2.8 (4E)-4,5-Didehydro-cis-reticulatacin-10-one B/A (11B/A, dr ~ 9:1)

6 4

C11H23

HO

O

OHHH

O

O

O6 4

C11H23

HO

O

OHHH

O

O

O

11B 11A

Ratio 11B/11A ~ 9:1

To a stirred solution of (15S)-15-[(2S,5R)-tetrahydro-5-((1R)1-hydroxytridecyl)furan-2-yl]-15-hydroxypentadec-

1-en-8-one (+ A isomer, dr ~ 9:1) (26 mg, 0.051 mmol) and alkyne (7, 14.0 mg, 0.056 mmol) in DMF (3 mL)

was added CpRu(MeCN)3PF6 (2.2 mg, 0.005 mmol, 10 mol %). The reaction was stirred at rt for 1 h, then

diluted with ether and filtered through a plug of silica eluting with 40 % EtOAc in hexane. The solvents were

removed in vacuo. Purification by silica gel column chromatography (EtOAc/hexane, 1:4→3:2) gave the title

butenolide (21.8 mg, 0.036 mmol, 71 %) as a white solid, and the uncyclised nitrobenzyl ester byproduct (3 mg,

0.004 mmol, 8 %). Data for 11B/A: [α]26

D +10.4 (CHCl3, c 1.0); Mp 63-66 °C; IR νmax (neat)/cm–1

3431 (w),

3321 (s), 2918 (s), 2849 (s), 1737 (s), 1703 (s), 1469 (s), 1409 (s), 1377 (s), 1323 (s), 1086 (s); 1H-NMR (400

MHz, CDCl3) δ 7.00 (1H, q, J = 1.5 Hz, CH=C), 5.59-5.43 (2H, m, CH=CHCH2C), 5.00 (1H, dq, J = 1.5, 6.9

Hz, CHCH3), 3.85-3.77 (2H, m, CHO x 2), 3.45-3.34 (2H, m, CHOH x 2), 2.95 (2H, d, J = 6.5 Hz, =CHCH2C),

2.44 (2H, br s, OH x 2), 2.40 (2H, t, J = 7.5 Hz, CH2C=OCH2), 2.38 (2H, t, J = 7.5 Hz, CH2C=OCH2), 2.07-1.99

(2H, m, CH2CH=CH),1.98-1.89 (2H, m, CH2 THF), 1.81-1.71 (2H, m, CH2 THF), 1.54-1.20 (34H, m), 1.41 (3H,

d, J = 6.9 Hz, CH3CH), 0.89 (3H, t, J = 6.8 Hz, CH3CH2); 13

C-NMR (100 MHz, CDCl3) δ 211.4 (C), 173.6 (C),

149.6 (CH=C), 134.3 (CH=CH), 133.7 (CH=C), 124.4 (CH=CH), 82.8 (CH), 82.7 (CH), 77.7 (CH), 74.5 (CH),

74.4 (CH), 42.9 (CH2C=OCH2), 42.6 (CH), 34.2 (CH2), 34.1 (CH2), 32.3 (CH2), 32.0 (CH2), 30.5 (CH2), 29.8


(CH2), 28.2 (CH2), 25.8 (CH2), 25.6 (CH2), 23.9 (CH2), 23.4 (CH2), 22.8 (CH2), 19.2 (CH3), 14.2 (CH3); LRMS

(ES+) m/z 628 ([M + Na]

+).


SI 11

Data for (R,2Z,5E)-4-nitrobenzyl 18-((2R,5S)-tetrahydro-5-((S)-1-hydroxyheptyl)furan-2-yl)-18-

hydroxy-3-((S)-1-hydroxyethyl)-11-oxooctadeca-2,5-dienoate (+ A isomer, dr ~ 9:1)

6 4

C11H23

HO

O

OHHH

ORatio ~ 9:1

OH

O

O

NO2 6 4

C11H23

HO

O

OHHH

O OH

O

O

NO2

IR νmax (neat)/cm–1

3384 (br), 2922 (s), 2852 (s), 1738 (s), 1719 (s), 1457 (s), 1346 (s), 1148 (s), 1071 (s); 1H-

NMR (300 MHz, CDCl3) δ 8.23 (2H, d, J = 8.7 Hz ArH), 7.54 (2H, d, J = 8.7 Hz ArH), 6.14 (1H, s, CH=C),

5.57-5.36 (2H, m, CH=CHCH2C), 5.25 (2H, s, OCH2Ar), 4.37 (1H, m, CHOHCH3), 3.86-3.75 (2H, m, CHO x

2), 3.63 (1H, dd, J = 5.4, 13.4 Hz, =CHCHHC=), 3.45-3.35 (2H, m, CHOH x 2), 3.07 (1H, dd, J = 6.2, 13.4 Hz,

=CHCHHC=), 2.46 (2H, br s, OH), 2.42-2.37 (4H, m, CH2C=OCH2), 2.02-1.88 (4H, m, CH2), 1.82-1.65 (2H, m,

CH2), 1.52-1.17 (40H, m, CH2), 1.34 (3H, d, J = 6.4 Hz, CH3CHOH), 0.88 (3H, t, J = 6.6 Hz, CH3CH2); 13

C-

NMR (75 MHz, CDCl3) δ 211.8 (C=O), 166.0 (C), 143.7 (CH), 132.5 (CH), 128.4 (CH), 126.9 (CH), 123.9

(CH), 112.9 (CH), 82.8 (CH), 82.7 (CH), 74.5 (CH), 74.4 (CH), 70.5 (CH), 64.3 (CH2), 42.9 (CH2C=OCH2),

42.5 (CH2C=OCH2), 34.2 (CH2), 34.1 (CH2), 33.0 (CH2), 32.1 (CH2), 32.0 (CH2), 28.2 (CH2), 25.8 (CH2), 25.5

(CH2), 23.8 (CH2), 23.1 (CH2), 22.8 (CH2), 22.4 (CH2), 14.2 (CH3); LRMS (ES+) m/z 780 ([M+Na]

+).


SI 12

2.9 cis-Reticulatacin-10-one B/A (4B/A, dr ~ 9:1)

6 4

C11H23

HO

O

OHHH

O

O

O6 4

C11H23

HO

O

OHHH

O

O

O

4B 4A

Ratio 4B/4A ~ 9:1

To a solution of (4E)-4,5-didehydro-cis-reticulatacin-10-one B/A (11B/A, dr ~ 9:1, 10 mg, 0.0165 mmol) and

NsNHNH2 (30.4 mg, 0.14 mmol) in THF (3 mL) was added a solution of NaOAc (11.5 mg, 0.14 mmol) in H2O

(1 mL). The mixture was stirred at rt for 36 h before EtOAc (10 mL) and brine (3 mL) were added. The organic

phase was separated, re-extracting the aqueous solution with EtOAc (2 x 10 mL) and the combined organics was

dried (MgSO4), and concentrated in vacuo. 1H NMR analysis of the crude product indicated that the reduction

had not proceeded to completion, so the crude material was heated in THF (1 mL) containing TsNHNH2 (6.0

mg, 0.032 mmol) and NaOAc (6.0 mg, 0.032 mmol) for 24 h. Following the same work-up procedure described

above, the obtained residue was dissolved in ether and washed with 1 M HCl (aq), brine, saturated KHCO3 (aq),

then dried (MgSO4). Purification by preparative normal phase HPLC (EtOAc/hexane, 35:65) gave cis-

reticulatacin-10-ones B/A (4B/A, dr ~ 9:1) (7 mg, 0.0115 mmol, 69 %) as a white solid along with the hydrazone

byproduct* (3.5 mg, 0.004 mmol, 25%). [α]26

D +13.7 (CHCl3, c 0.5); Mp 68-72 °C; IR νmax (neat)/cm–1

3449

(br), 2918 (s), 2849 (s), 1743 (s), 1703 (s), 1470 (s), 1458 (s), 1412 (s), 1321 (s); 1H-NMR (400 MHz, CDCl3) δ

6.98 (1H, q, J = 1.5 Hz, CH=C), 4.99 (1H, dq, J = 1.5, 6.8 Hz, CHCH3), 3.85-3.77 (2H, m, CHO x 2), 3.45-3.38

(2H, m, CHOH x 2), 2.43 (2H, br, s, OH), 2.26 (4H, t, J = 7.4 Hz, CH2C=OCH2), 2.26 (2H, t, J = 7.8 Hz,

CH2C=), 1.98-1.89 (2H, m, CH2 THF), 1.80-1.69 (2H, m, CH2 THF), 1.62-1.20 (48H, m), 1.41 (3H, d, J = 6.8

Hz, CH3CH), 0.87 (3H, t, J = 6.7 Hz, CH3CH2); 13

C-NMR (100 MHz, CDCl3) δ 211.6 (C), 174.0 (C) 149.0

(CH), 134.3 (C), 82.8 (CH), 82.7 (CH), 77.5 (CH), 74.5 (CH), 74.4 (CH), 42.9 (CH2C=OCH2), 42.8

(CH2C=OCH2), 34.2 (CH2), 34.1 (CH2), 32.0 (CH2), 29.8 (CH2), 29.8 (CH2), 29.5 (CH2), 29.4 (CH2), 29.3 (CH2),

29.2 (CH2), 29.1 (CH2), 28.2 (2CH2), 27.4 (CH2), 25.8 (CH2), 25.6 (CH2), 25.2 (CH2), 23.9 (CH2), 23.8 (CH2),

22.8 (CH2), 19.3 (CH3), 14.2 (CH3); LRMS (ES+) m/z 630 ([M+Na]

+); HRMS (ES

+) m/z C37H66Na O6 Calcd.

629.476, found 629.476.

*The hydrazone byproduct (12 mg, 0.014 mmol) was converted to the mixture of cis-reticulaticin-10-ones B/A

(dr ~ 9:1) by dissolving in THF (1 mL), water (0.2 mL) and AcOH (0.2 mL). The reaction mixture was left to

stir at rt for 3 days. The mixture was neutralised with saturated NaHCO3 (aq) and extracted with EtOAc (3 x 10

mL), dried (MgSO4) and purified by silica gel column chromatography (20 % to 50 % EtOAc/hexane, 1:41:1) to

give the diastereomeric mixture of acetogenins 4B/A (7 mg, 0.011 mmol, 78%).


SI 13

3.0 NMR Spectra

3.1 1H NMR 6-Bromo-N-methoxy-N-methyhexanamide (contains ~ 20% 6-chloro-N-methoxy-N-methyhexanamide)

4

N

OBr/Cl

OMe

1.4

95

5

0.1

97

1

0.8

51

3

1.4

85

8

1.0

00

0

1.0

84

9

1.0

61

9

1.0

21

6

Inte

gra

l

7.2

70

0

3.6

63

03

.54

23

3.5

20

43

.49

78

3.4

17

33

.39

42

3.3

71

6

3.1

55

2

2.4

41

42

.41

70

2.3

92

01

.92

02

1.8

97

01

.87

32

1.8

48

21

.82

57

1.8

11

61

.78

79

1.7

62

91

.74

03

1.6

95

81

.67

20

1.6

45

21

.61

96

1.5

95

81

.51

96

1.5

02

61

.49

40

1.4

82

51

.47

09

1.4

53

21

.44

16

1.4

22

1

(ppm)

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5

shbf4719/2 big scale crude amide

3.4

17

3

3.3

94

2

3.3

71

6

(ppm)

3.5

42

3

3.5

20

4

3.4

97

8

(ppm)

3.503.55

2.4

41

4

2.4

17

0

2.3

92

0

(ppm)

2.32.4

1.9

20

21

.89

70

1.8

73

21

.84

82

1.8

25

71

.81

16

1.7

87

9

1.7

62

91

.74

03

1.6

95

8

1.6

72

0

1.6

45

2

1.6

19

6

1.5

95

8

1.5

19

61

.50

26

1.4

94

01

.48

25

1.4

70

91

.45

32

1.4

41

61

.42

21

(ppm)

1.401.501.601.701.801.90


SI 14

3.2 13

C NMR 6-Bromo-N-methoxy-N-methyhexanamide (contains ~ 20% 6-chloro-N-methoxy-N-methyhexanamide) 4

N

OBr/Cl

OMe

17

4.3

91

5

77

.57

49

77

.15

00

76

.72

51

61

.28

25

44

.91

69

33

.67

19

33

.50

34

32

.63

90

32

.47

05

32

.32

40

31

.67

93

27

.99

45

27

.70

88

26

.71

25

23

.89

21

23

.76

76

(ppm)

102030405060708090100110120130140150160170

shbf4719/2 crude amide


SI 15

3.3 1H NMR 1-Bromotridec-12-en-6-one (9) (contains ~ 20% 1-chlorotridec-12-en-6-one)

1.0

000

2.0

768

0.4

012

1.7

668

4.4

415

2.2

146

1.9

764

4.5

745

6.8

063

Inte

gra

l

7.2

700

5.8

466

5.8

240

5.8

124

5.8

021

5.7

899

5.7

673

5.7

558

5.7

448

5.7

332

5.7

113

5.0

059

5.0

005

4.9

425

4.9

383

4.9

041

3.5

356

3.5

136

3.4

917

3.4

094

3.3

869

3.3

649

2.4

231

2.4

005

2.3

761

2.3

518

2.0

652

2.0

427

2.0

189

1.9

951

1.8

982

1.8

750

1.8

513

1.8

263

1.8

037

1.7

897

1.7

659

1.7

409

1.7

184

1.6

885

1.6

343

1.6

111

1.5

867

1.5

611

1.5

367

1.5

129

1.4

642

1.4

386

1.4

148

1.3

849

1.3

599

1.3

313

1.3

246

1.3

002

1.2

776

1.2

618

1.2

484

(ppm)

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5

shbf4719/9 Ketone

5.8

240

5.8

124

5.8

021

5.7

899

5.7

673

5.7

558

5.7

448

5.7

332

5.7

113

(ppm)

5.7

5.0

059

5.0

005

4.9

425

4.9

383

4.9

041

(ppm)

4.95.0

3.5

356

3.5

136

3.4

917

3.4

094

3.3

869

3.3

649

(ppm)

3.43.5

2.4

231

2.4

005

2.3

761

2.3

518

(ppm)

2.4

2.0

652

2.0

427

2.0

189

1.9

951

(ppm)

2.00

4 4



SI 16

3.4 13C NMR 1-Bromotridec-12-en-6-one (9) (contains ~ 20% 1-chlorotridec-12-en-6-one)

210.8

735

138.8

837

114.4

525

77.5

749

77.1

500

76.7

251

44.8

583

42.8

584

42.4

774

33.6

206

32.6

463

28.7

637

28.7

344

27.8

333

26.5

660

23.7

529

22.9

324

(ppm)

102030405060708090100110120130140150160170180190200210

shbf4719/9 Ketone

4 4



SI 17

1.0

00

0

2.1

21

8

1.5

97

3

1.8

49

9

2.3

12

2

2.3

74

2

0.0

32

4

18

.24

1

Inte

gra

l

7.2

70

0

5.8

63

2

5.8

46

9

5.8

38

1

5.8

29

9

5.8

21

1

5.8

04

2

5.7

95

4

5.7

87

3

5.7

78

5

5.7

62

2

5.0

18

9

4.9

76

3

4.9

52

4

4.9

26

7

3.5

95

8

3.5

60

0

3.5

43

1

3.5

26

8

3.4

35

2

3.4

18

3

3.4

01

3

2.0

81

1

2.0

64

1

2.0

46

6

2.0

29

6

1.8

96

0

1.8

79

1

1.8

62

2

1.8

45

2

1.8

10

7

1.7

93

2

1.7

76

2

1.6

32

6

1.4

71

4

1.4

62

6

1.4

54

5

1.4

41

9

1.4

23

1

1.4

06

8

1.3

89

9

1.3

72

3

1.3

39

1

1.2

61

3

(ppm)

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5

4921/21 Br-6-OH-13-tri5

.86

32

5.8

46

9

5.8

38

1

5.8

29

9

5.8

21

1

5.8

04

2

5.7

95

4

5.7

87

3

5.7

78

5

5.7

62

2

(ppm)

5.85

5.0

18

9

4.9

76

3

4.9

52

4

4.9

26

7

(ppm)

4.95.0

3.5

95

8

3.5

60

0

3.5

43

1

3.5

26

8

(ppm)

3.60

3.4

35

2

3.4

18

3

3.4

01

3

(ppm)

3.40

2.0

46

6

2.0

29

6

1.8

96

0

1.8

79

1

1.8

62

2

1.8

45

2

1.8

10

7

1.7

93

2

1.7

76

2

(ppm)

1.82.0

3.5 1H NMR 1-Bromotridec-12-en-6-ol (contains ~ 20% 1-chlorotridec-12-en-6-ol)

4 4



SI 18

3.6 13

C NMR 1-Bromotridec-12-en-6-ol (contains ~ 20% 1-chlorotridec-12-en-6-ol)

13

9.1

56

1

11

4.3

78

8

77

.45

91

77

.15

00

76

.83

12

71

.90

47

45

.15

68

37

.62

22

37

.37

10

37

.34

20

33

.97

08

33

.82

59

32

.86

95

32

.69

57

29

.25

68

28

.98

63

28

.32

94

27

.05

44

25

.60

54

25

.07

41

24

.94

85

(ppm)

102030405060708090100110120130140

4921/21 Br-6-OH-13-tri

4 4



SI 19

3.7 1

H NMR (±)-1-(Phenylsulfonyl)tridec-12-en-6-ol (6)

6

4 4PhO2S OH

2.0

00

0

1.0

37

7

2.1

78

4

0.8

17

4

1.9

07

7

1.4

34

2

3.0

70

0

2.6

57

0

3.2

75

3

23

.67

8

Inte

gra

l7

.90

91

7.8

89

17

.66

89

7.6

50

17

.63

19

7.5

81

17

.56

23

7.5

43

5

7.2

70

0

5.8

46

25

.82

93

5.8

20

55

.80

36

5.7

86

65

.77

79

5.7

70

35

.76

16

5.7

44

6

5.0

03

34

.96

06

4.9

36

84

.91

17

3.5

31

8

3.0

99

03

.07

90

3.0

58

9

2.0

60

42

.04

41

2.0

26

52

.00

96

1.7

39

91

.72

17

1.7

03

51

.39

61

1.3

65

41

.30

58

1.2

92

7

(ppm)

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0

4719/66.1-sulphone-6-OH-tride-

13-ene

7.9

09

1

7.8

89

1

(ppm)

7.6

68

97

.65

01

7.6

31

9

7.5

81

17

.56

23

7.5

43

5

(ppm)

7.6

5.8

46

25

.82

93

5.8

20

55

.80

36

5.7

86

65

.77

79

5.7

70

35

.76

16

5.7

44

6

(ppm)

5.80

5.0

03

3

4.9

60

6

4.9

36

8

4.9

11

7

(ppm)

4.95.0

3.0

99

03

.07

90

3.0

58

9

(ppm)

2.0

60

42

.04

41

2.0

26

52

.00

96

(ppm)

2.00

1.7

39

91

.72

17

1.7

03

5

(ppm)

1.71.8


SI 20

3.8 13

C NMR (±)-1-(Phenylsulfonyl)tridec-12-en-6-ol (6)

6

4 4PhO2S OH

139.3

494

139.0

982

133.6

984

129.3

418

128.1

150

114.3

402

77.4

688

77.1

500

76.8

312

71.6

826

56.2

849

37.5

835

37.0

329

33.7

679

29.1

892

28.9

284

28.3

778

25.5

378

25.1

417

22.7

075

(ppm)

102030405060708090100110120130140150160170

4719/66


SI 21

3.9 1

H NMR (1S,3R/S,8R/S)-1-[(2S,5R)-Tetrahydro-5-((1R)-1-hydroxytridecyl)furan-2-yl]-3-(phenylsulfonyl)pentadec-14-ene-1,8-diol (mixture of

A and B isomers in a ratio of 1:9)

2.2

55

5

3.5

54

8

1.0

00

0

2.1

90

7

3.2

09

4

5.4

00

4

11

.98

3

50

.93

4

4.2

92

0

Inte

gra

l

7.9

07

67

.88

20

7.6

43

17

.62

05

7.5

82

17

.55

65

7.5

32

7

7.2

70

0

5.8

71

05

.84

96

5.8

16

15

.79

29

5.7

60

05

.73

75

5.0

18

14

.95

29

4.9

15

1

3.8

15

43

.74

65

3.7

11

23

.52

52

3.4

13

7

3.0

84

5

2.0

54

32

.03

23

2.0

09

81

.89

88

1.8

35

41

.81

35

1.6

34

31

.38

31

1.2

60

6

0.8

99

70

.87

96

0.8

57

0

(ppm)

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5

shbf4719/100 pure reticulata thf sulfon 6OL 13 ene

7.9

07

6

7.8

82

0

(ppm)

7.6

43

17

.62

05

7.5

82

17

.55

65

7.5

32

7

(ppm)

5.8

71

05

.84

96

5.8

16

15

.79

29

5.7

60

05

.73

75

(ppm)

5.75.8

5.0

18

1

4.9

52

94

.91

51

(ppm)

3.8

15

43

.74

65

3.7

11

2

3.5

25

2

3.4

13

7

(ppm)

3.6

0.8

99

7

0.8

79

6

0.8

57

0

(ppm)

0.90

2.0

54

32

.03

23

2.0

09

8

1.8

98

81

.83

54

1.8

13

5

(ppm)

2.0

44

C11H23

HO

O

OHHH OH

SO2Ph

44

C11H23

HO

O

OHHH OH

SO2Ph

Ratio ~ 9:1


SI 22

3.10 13

C NMR (1S,3R/S,8R/S)-1-[(2S,5R)-Tetrahydro-5-((1R)-1-hydroxytridecyl)furan-2-yl]-3-(phenylsulfonyl)pentadec-14-ene-1,8-diol (mixture

of A and B isomers in a ratio of 1:9)

139.1

328

138.0

413

133.6

971

133.6

385

129.2

065

128.9

794

114.3

646

82.6

296

82.3

952

82.2

707

77.5

749

77.1

500

76.7

251

74.0

805

72.0

806

71.9

707

71.7

876

71.6

191

71.2

308

71.1

429

71.0

550

60.9

602

37.7

743

37.6

937

37.5

619

37.1

443

36.9

758

36.9

172

34.7

195

34.5

290

33.8

258

32.7

562

32.0

310

29.7

673

29.4

596

29.2

765

28.9

981

28.2

802

28.1

117

26.7

858

26.6

612

25.9

067

25.6

356

25.4

671

25.3

060

22.7

932

14.2

148

(ppm)

102030405060708090100110120130140

shbf4719/100 pure reticulata thf sulfon 6OL 13 ene

44

C11H23

HO

O

OHHH OH

SO2Ph

44

C11H23

HO

O

OHHH OH

SO2Ph

Ratio ~ 9:1


SI 23

10B

4 4

C11H23

HO

O

OHHH

OH

10A

4 4

C11H23

HO

O

OHHH

OH

Ratio 10B/10A ~ 9:1

3.11 1

H NMR (1S,8R/S)-1-[(2S,5R)-Tetrahydro-5-((1R)1-hydroxytridecyl)furan-2-yl]pentadec-14-ene-1,8-diol (10A/B, ratio ~ 1:9)

1.0

00

0

2.3

43

8

2.5

39

5

1.2

61

3

2.6

61

3

1.5

87

8

2.8

87

3

2.9

31

2

3.3

36

6

62

.96

0

4.4

99

1

Inte

gra

l5

.77

72

5.7

60

35

.02

46

5.0

20

25

.01

52

5.0

11

44

.98

13

4.9

77

54

.97

25

4.9

68

84

.95

31

4.9

50

64

.94

74

4.9

44

94

.94

18

4.9

28

04

.92

48

4.9

22

34

.91

98

4.9

16

73

.83

79

3.8

26

03

.81

22

3.8

00

33

.58

07

3.5

73

23

.56

25

3.4

40

93

.42

89

3.4

14

53

.39

88

2.5

69

72

.07

86

2.0

61

62

.04

53

2.0

42

82

.02

90

2.0

25

92

.02

27

1.9

68

21

.96

38

1.9

51

91

.93

99

1.9

33

71

.92

68

1.9

22

41

.90

86

1.9

04

21

.89

54

1.7

93

21

.78

19

1.7

76

91

.76

49

1.7

60

61

.75

30

1.7

46

81

.73

55

1.7

24

81

.71

92

1.7

08

51

.47

96

1.4

67

61

.45

13

1.4

35

71

.40

30

1.3

87

41

.36

92

1.3

21

51

.31

34

1.2

60

70

.90

00

0.8

83

10

.86

55

(ppm)

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5

4921/ HPLC F-2

5.8

61

9

5.8

45

05

.83

62

5.8

28

75

.81

99

5.8

02

35

.79

35

5.7

86

05

.77

72

5.7

60

3

(ppm)

5.765.805.84

5.0

24

65

.02

02

5.0

15

25

.01

14

4.9

81

34

.97

75

4.9

72

54

.96

88

4.9

53

14

.95

06

4.9

47

44

.94

49

4.9

41

84

.92

80

4.9

24

84

.92

23

4.9

19

84

.91

67

(ppm)

4.924.965.00

3.8

37

93

.82

60

3.8

12

23

.80

03

(ppm)

3.5

80

73

.57

32

3.5

62

5

3.4

40

93

.42

89

3.4

14

53

.39

88

(ppm)

3.43.53.6

0.9

00

0

0.8

83

1

0.8

65

5

(ppm)

0.90


SI 24

3.12 13

C NMR (1S,8R/S)-1-[(2S,5R)-Tetrahydro-5-((1R)1-hydroxytridecyl)furan-2-yl]pentadec-14-ene-1,8-diol (10A/B, ratio ~ 1:9)

10B

4 4

C11H23

HO

O

OHHH

OH

10A

4 4

C11H23

HO

O

OHHH

OH

Ratio 10B/10A ~ 9:1

139.2

045

114.3

498

82.8

493

77.4

688

77.1

500

76.8

312

74.4

742

74.4

453

72.0

593

37.5

835

34.2

509

34.1

736

33.8

549

32.0

485

29.7

977

29.7

784

29.7

494

29.4

886

29.3

051

29.0

153

28.2

522

25.8

469

25.7

406

25.6

923

25.6

344

22.8

137

14.2

455

(ppm)

102030405060708090100110120130140

4921/6

desulphonated-6-OH-13ene


SI 25

3.13 1

H NMR (15S)-15-[(2S,5R)-Tetrahydro-5-((1R)1-hydroxytridecyl)furan-2-yl]-15-hydroxypentadec-1-en-8-one (mixture of A and B isomers in

a ratio of 1:9)

4 4

C11H23

HO

O

OHHH

O4 4

C11H23

HO

O

OHHH

O

Ratio ~ 9:1

1.0

00

0

2.1

77

7

2.1

45

4

2.3

93

6

6.7

11

0

2.4

88

9

2.4

98

0

2.4

51

6

49

.98

5

3.7

44

0

Inte

gra

l

7.2

70

0

5.8

50

0

5.8

33

7

5.8

24

9

5.8

17

4

5.8

08

0

5.7

91

0

5.7

82

2

5.7

74

7

5.7

65

3

5.7

49

0

5.0

15

2

4.9

72

5

4.9

51

2

4.9

26

1

3.8

23

5

3.8

14

7

3.4

35

8

3.4

23

3

3.4

08

9

3.3

95

7

2.4

34

2

2.4

05

3

2.3

86

5

2.3

68

3

2.0

74

8

2.0

57

2

2.0

39

7

2.0

22

1

1.9

70

0

1.9

38

7

1.9

27

4

1.7

66

8

1.7

55

5

1.7

39

2

1.6

48

9

1.6

11

9

1.5

93

1

1.5

74

3

1.5

55

5

1.4

70

2

1.4

56

4

1.4

36

3

1.4

16

2

1.3

96

8

1.3

79

2

1.3

61

0

1.2

63

2

0.9

01

9

0.8

85

6

0.8

68

7

(ppm)

0.51.01.52.02.53.03.54.04.55.05.56.06.57.0

shbf/4921/8

5.8

33

7

5.8

24

9

5.8

17

4

5.8

08

0

5.7

91

0

5.7

82

2

5.7

74

7

5.7

65

3

5.7

49

0

(ppm)

5.85

5.0

15

2

4.9

72

5

4.9

51

2

4.9

26

1

(ppm)

4.905.00

2.4

34

2

2.4

05

3

2.3

86

5

2.3

68

3

(ppm)

2.40

2.0

74

8

2.0

57

2

2.0

39

7

2.0

22

1

1.9

70

0

1.9

38

7

1.9

27

4

1.7

66

8

1.7

55

5

1.7

39

2

(ppm)

1.71.81.92.0

0.9

01

9

0.8

85

6

0.8

68

7

(ppm)

0.850.90


SI 26

21

1.6

23

8

13

8.9

91

9

11

4.4

94

7

82

.79

13

77

.46

88

77

.15

00

76

.83

12

74

.48

39

74

.42

59

42

.89

64

42

.85

78

34

.25

09

34

.14

47

33

.70

03

32

.04

85

29

.83

64

29

.80

74

29

.75

91

29

.55

63

29

.48

86

29

.31

48

28

.84

14

28

.80

28

28

.25

22

25

.84

69

25

.64

40

23

.91

49

23

.81

83

22

.81

37

14

.24

55

(ppm)

102030405060708090100110120130140150160170180190200210

shbf/4921/83

4.2

50

9

34

.14

47

33

.70

03

32

.04

85

29

.83

64

29

.80

74

29

.75

91

29

.55

63

29

.48

86

29

.31

48

28

.84

14

28

.80

28

28

.25

22

25

.84

69

25

.64

40

23

.91

49

23

.81

83

22

.81

37

(ppm)

222324252627282930313233343536

3.14 13

C NMR (15S)-15-[(2S,5R)-Tetrahydro-5-((1R)1-hydroxytridecyl)furan-2-yl]-15-hydroxypentadec-1-en-8-one (mixture of A and B isomers

in a ratio of 1:9

4 4

C11H23

HO

O

OHHH

O4 4

C11H23

HO

O

OHHH

O

Ratio ~ 9:1


SI 27

3.15 1

H NMR (4E)-4,5-Didehydro-cis-reticulatacin-10-one A/B (11A/B, dr ~ 1:9)

6 4

C11H23

HO

O

OHHH

O

O

O6 4

C11H23

HO

O

OHHH

O

O

O

11B 11A

Ratio 11B/11A ~ 9:1

1.0

054

2.1

163

1.0

000

2.1

890

2.2

532

2.2

325

6.6

710

2.4

611

2.5

298

2.5

432

6.7

038

6.1

027

4.9

483

33.1

85

3.9

973

Inte

gra

l

7.2

700

7.0

097

7.0

066

5.5

909

5.5

753

5.5

527

5.5

364

5.5

213

5.5

094

5.4

937

5.4

774

5.4

555

5.4

392

5.0

164

5.0

127

4.9

995

4.9

957

3.8

210

3.8

147

3.4

478

3.4

352

3.4

227

3.4

064

3.3

938

2.9

636

2.9

485

2.4

448

2.4

141

2.4

028

2.3

959

2.3

846

2.3

777

2.3

664

2.0

717

2.0

541

2.0

365

2.0

196

1.9

700

1.9

550

1.9

381

1.9

268

1.9

105

1.7

675

1.7

555

1.7

392

1.6

508

1.6

125

1.5

937

1.5

749

1.5

561

1.5

373

1.4

702

1.4

551

1.4

231

1.4

056

1.3

855

1.3

673

1.3

479

1.2

613

0.9

000

0.8

837

0.8

662

(ppm)

0.51.01.52.02.53.03.54.04.55.05.56.06.57.0

4921/10 (F-1)didehydro reticulatacin-10-one

7.0

097

7.0

066

(ppm)

7.00

5.5

909

5.5

753

5.5

527

5.5

364

5.5

213

5.5

094

5.4

937

5.4

774

5.4

555

5.4

392

(ppm)

5.505.60

5.0

164

5.0

127

4.9

995

4.9

957

(ppm)

5.00

3.8

210

3.8

147

(ppm)

3.80

3.4

478

3.4

352

3.4

227

3.4

064

3.3

938

(ppm)

3.45

2.4

448

2.4

141

2.4

028

2.3

959

2.3

846

2.3

777

2.3

664

(ppm)

2.42.5

0.9

000

0.8

837

0.8

662

(ppm)

0.9

1.4

231

1.4

056

(ppm)


SI 28

3.16 1

H NMR (4E)-4,5-Didehydro-cis-reticulatacin-10-one A/B (11A/B, dr ~ 1:9)

6 4

C11H23

HO

O

OHHH

O

O

O6 4

C11H23

HO

O

OHHH

O

O

O

11B 11A

Ratio 11B/11A ~ 9:1

5.4

94

45

.49

12

5.4

80

65

.47

81

5.4

74

95

.47

18

5.4

56

15

.45

36

5.4

39

85

.43

73

5.0

39

05

.03

46

5.0

29

65

.02

21

5.0

17

05

.01

27

5.0

07

65

.00

51

5.0

00

14

.99

57

4.9

90

74

.98

76

4.9

83

24

.97

88

4.9

73

8

3.8

39

13

.83

35

3.8

28

53

.82

22

3.8

15

33

.80

90

3.8

04

03

.79

77

3.7

92

13

.44

90

3.4

36

53

.42

39

3.4

19

53

.41

20

3.4

06

43

.39

32

2.9

69

82

.96

54

2.9

62

92

.95

85

2.9

49

12

.44

55

2.4

14

72

.40

41

2.3

96

62

.38

53

2.3

77

72

.36

64

2.0

72

92

.05

47

2.0

36

52

.02

09

2.0

18

31

.42

31

1.4

06

20

.90

06

0.8

84

30

.86

68

(ppm)

0.51.01.52.02.53.03.54.04.55.05.56.06.57.0

4921/10 (F-1)

28

06

.80

28

05

.30

28

03

.54

28

02

.03

(ppm)

7.00

15

36

.16

15

33

.90

15

31

.89

15

29

.38

15

26

.62

15

24

.11

15

22

.10

15

19

.59

15

17

.33

(ppm)

3.803.85

11

88

.32

11

86

.56

11

85

.56

11

83

.80

11

80

.03

(ppm)

2.922.96

97

8.5

1

96

6.2

19

61

.94

95

8.9

39

54

.41

95

1.4

09

46

.89

(ppm)

2.40


SI 29

3.17 13

C NMR (4E)-4,5-Didehydro-cis-reticulatacin-10-one A/B (11A/B, dr ~ 1:9)

6 4

C11H23

HO

O

OHHH

O

O

O6 4

C11H23

HO

O

OHHH

O

O

O

11B 11A

Ratio 11B/11A ~ 9:1

21

1.4

78

9

17

3.6

22

3

14

9.6

66

0

13

3.5

63

1

13

3.4

95

5

12

4.9

75

6

82

.82

03

82

.78

17

77

.75

86

77

.46

88

77

.35

29

77

.15

00

76

.83

12

74

.48

39

74

.42

59

42

.95

44

42

.65

49

34

.26

06

34

.15

43

32

.33

83

32

.04

85

29

.82

67

29

.80

74

29

.78

81

29

.76

88

29

.74

94

29

.55

63

29

.47

90

29

.31

48

28

.93

80

28

.55

16

28

.25

22

25

.84

69

25

.65

37

23

.91

49

23

.39

33

22

.81

37

19

.26

86

14

.24

55

(ppm)

102030405060708090100110120130140150160170180190200210

4921/10 (F-1)

29

.82

67

29

.80

74

29

.78

81

29

.76

88

29

.74

94

29

.55

63

29

.47

90

29

.31

48

28

.93

80

28

.55

16

28

.25

22

25

.84

69

25

.65

37

23

.91

49

23

.39

33

22

.81

37

(ppm)

2122232425262728293031


SI 30

3.18 1

H NMR (R,2Z,5E)-4-Nitrobenzyl 18-((2R,5S)-tetrahydro-5-((S)-1-hydroxyheptyl)furan-2-yl)-18-hydroxy-3-((S)-1-hydroxyethyl)-11-oxoocta

deca-2,5-dienoate (dr ~ 1:9)

6 4

C11H23

HO

O

OHHH

ORatio ~ 9:1

OH

O

O

NO2 6 4

C11H23

HO

O

OHHH

O OH

O

O

NO2

1.9

989

2.0

000

0.9

702

2.5

025

2.0

119

1.0

310

2.3

838

1.2

158

2.6

241

1.3

403

7.1

095

1.1

072

5.5

797

2.5

960

58.9

40

5.1

570

Inte

gra

l

8.2

466

8.2

179

7.5

602

7.5

309

7.2

700

6.1

404

5.5

521

5.5

320

5.5

009

5.4

808

5.4

625

5.4

436

5.4

241

5.3

924

5.3

723

5.2

571

4.3

890

4.3

683

3.8

270

3.8

105

3.6

593

3.6

404

3.6

136

3.5

972

3.5

124

3.4

929

3.4

246

3.0

272

3.0

046

2.9

815

2.9

614

2.3

963

2.3

731

2.3

542

2.1

890

2.0

049

1.9

829

1.9

433

1.9

281

1.7

696

1.7

537

1.5

946

1.5

605

1.5

361

1.5

099

1.4

709

1.4

495

1.4

294

1.4

075

1.3

514

1.3

301

1.2

630

0.9

076

0.8

869

0.8

637

(ppm)

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5

shbf4921/10 F2 the opend product8.2

466

8.2

179

(ppm)

8.20

7.5

602

7.5

309

(ppm)

5.5

521

5.5

320

5.5

009

5.4

808

5.4

625

5.4

436

5.4

241

5.3

924

5.3

723

(ppm)

5.45.5

4.3

890

4.3

683

(ppm)

4.35

0.9

076

0.8

869

0.8

637

(ppm)

1.3

514

1.3

301

(ppm)

3.8

270

3.8

105

3.6

593

3.6

404

3.6

136

3.5

972

3.5

124

3.4

929

3.4

246

(ppm)

3.43.63.8


SI 31

3.19 13

C NMR (R,2Z,5E)-4-Nitrobenzyl 18-((2R,5S)-tetrahydro-5-((S)-1-hydroxyheptyl)furan-2-yl)-18-hydroxy-3-((S)-1-hydroxyethyl)-11-oxoocta

deca-2,5-dienoate (dr ~ 1:9)

211.8

258

166.0

255

143.8

066

132.5

983

128.4

226

126.9

062

123.9

027

112.9

507

82.7

981

82.7

468

74.5

054

74.4

395

70.4

983

64.3

227

42.9

682

42.5

214

34.2

726

34.1

261

33.0

639

32.1

775

32.0

603

28.2

509

25.8

334

25.5

770

23.8

188

23.1

302

22.8

225

22.4

563

(ppm)

020406080100120140160180200220

shbf4921/10 F2 the opend product

211.8

258

166.0

255

143.8

066

132.5

983

128.4

226

126.9

062

123.9

027

112.9

507

82.7

981

82.7

468

(ppm)

90100110120130140150160170180190200210

74.4

395

70.4

983

64.3

227

42.9

682

42.5

214

34.2

726

34.1

261

33.0

639

32.1

775

32.0

603

28.2

509

25.8

334

25.5

770

23.8

188

23.1

302

22.8

225

22.4

563

(ppm)

203040506070

6 4

C11H23

HO

O

OHHH

ORatio ~ 9:1

OH

O

O

NO2 6 4

C11H23

HO

O

OHHH

O OH

O

O

NO2


SI 32

3.20 1

H NMR cis-Reticulatacin-10-one A/B (4A/B, dr ~ 1:9)

6 4

C11H23

HO

O

OHHH

O

O

O6 4

C11H23

HO

O

OHHH

O

O

O

4B 4A

Ratio 4B/4A ~ 9:1

1.0

42

9

1.0

00

0

2.0

98

7

2.2

24

7

6.3

34

4

2.5

72

4

2.4

32

2

2.4

51

7

16

.90

9

4.6

85

7

38

.74

5

4.6

28

0

Inte

gra

l

7.2

70

0

6.9

89

6

5.0

22

1

5.0

05

1

4.9

92

6

4.9

88

2

4.9

75

7

3.8

25

3

3.8

17

2

3.4

39

0

3.4

25

8

3.4

10

8

3.3

98

2

2.4

05

3

2.3

87

1

2.3

68

3

2.2

85

5

2.2

66

1

2.2

46

6

1.9

73

8

1.9

58

8

1.9

41

2

1.9

30

5

1.9

13

6

1.7

70

6

1.7

58

7

1.7

42

4

1.5

62

4

1.5

51

7

1.4

72

0

1.4

58

9

1.4

43

2

1.4

20

0

1.4

03

0

1.3

15

9

1.2

63

8

0.9

02

5

0.8

86

8

0.8

69

3

(ppm)

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5

4921/18Reticulatacin-10-one6

.98

96

(ppm)

7.00

5.0

22

1

5.0

05

1

4.9

92

6

4.9

88

2

4.9

75

7

(ppm)

5.00

3.8

25

3

3.8

17

2

3.4

39

0

3.4

25

8

3.4

10

8

3.3

98

2(ppm)

3.43.63.8

2.4

05

3

2.3

87

1

2.3

68

3

(ppm)

2.40

2.2

85

5

2.2

66

1

2.2

46

6

(ppm)

2.25

1.4

20

0

1.4

03

0

(ppm)

1.40

0.9

02

5

0.8

86

8

0.8

69

3

(ppm)

0.90


SI 33

3.21 1

H NMR cis-Reticulatacin-10-one A/B (4A/B, dr ~ 1:9)

6 4

C11H23

HO

O

OHHH

O

O

O6 4

C11H23

HO

O

OHHH

O

O

O

4B 4A

Ratio 4B/4A ~ 9:1

6.9

97

26

.99

34

6.9

89

66

.98

59

2.4

06

02

.38

71

2.3

69

0

1.4

20

61

.40

30

(ppm)

0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5

4921/18

27

99

.77

27

98

.27

27

96

.76

27

95

.26

(ppm)

6.99


SI 34

3.22 13

C NMR cis-Reticulatacin-10-one A/B (4A/B, dr ~ 1:9)

6 4

C11H23

HO

O

OHHH

O

O

O6 4

C11H23

HO

O

OHHH

O

O

O

4B 4A

Ratio 4B/4A ~ 9:1

211.6

818

174.0

183

149.0

671

134.3

842

82.8

203

82.7

816

77.5

557

77.4

688

77.1

500

76.8

312

74.5

032

74.4

452

42.9

254

42.8

578

34.2

702

34.1

640

32.0

581

29.8

364

29.8

170

29.5

659

29.4

983

29.3

244

29.2

278

29.2

085

29.1

119

28.2

618

27.4

890

25.8

565

25.6

537

25.2

866

23.9

246

23.8

956

22.8

234

19.3

555

14.2

551

(ppm)

102030405060708090100110120130140150160170180190200210

4921/18

211.6

818

174.0

183

149.0

671

134.3

842

82.8

203

82.7

816

(ppm)

90100110120130140150160170180190200210

34.2

702

34.1

640

32.0

581

29.8

364

29.8

170

29.5

659

29.4

983

29.3

244

29.2

278

29.2

085

29.1

119

28.2

618

27.4

890

25.8

565

25.6

537

25.2

866

23.9

246

23.8

956

22.8

234

(ppm)

242628303234


SI 35

3.23 1H NMR Hydrazone byproduct

11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0

Chemical Shift (ppm)

6.94

42.87

18.60

14.62

4.30

2.41

2.04

1.00

1.14

4.33

2.22

7.84

7.81

7.38

7.35

7.31

7.29

7.28

7.27

7.01

7.01

5.02

5.01

5.00

4.99

3.82

3.50

3.43

2.43

2.41

2.39

2.29

2.26

2.24

2.17

2.07

1.95

1.53

1.43

1.41

1.40

1.26

0.91

0.89

0.86

0.08


SI 36

3.24 Mass spectrum Hydrazone byproduct

4.0 Chromatograms

4.1 Chiral HPLC chromatogram of synthetic cis-reticulatacin-10-one A/B (4A/B, dr ~ 1:9)


SI 37

4.2 Chiral HPLC chromatogram of natural cis-reticulatacin-10-one A/B (4A/B)

4.3 Overlay of chiral HPLC chromatograms of ── natural cis-reticulatacin-10-one A/B (4A/B )

── synthetic cis-reticulatacin-10-one A/B (4A/B, dr ~ 1:9)


total synthesis of cis-reticulatacin10-ones a and b: absolute … · 2017. 4. 2. · si 1 total...

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