Methyl 6-hydroxyhexa-2E,4E-dienoate (435)

O O

Br O

O HO

429 435

Impure methyl 6-bromohexa-2E,4E-dienoate 429 12 (0.92 g) was dissolved in acetone (12 mL) and a saturated solution of NaHCO3 (8 mL) was added. A yellowish slurry was formed. The reaction flask was equipped with a reflux condenser and a magnetic stirring bar. The reaction mixture was refluxed until TLC (30 % MTBE/hexane) showed the absence of the starting material. Refluxing was continued for 3 hours and 3 drops of 5 w-

% HCl solution was added to neutralize the mixture. Acetone was evaporated and 20 mL of EtOAc was added. The layers didn’t separate and thus H2O (5 mL) was added. The layers were separated and the water layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 15 mL), dried overnight with Na2SO4, filtered and concentrated to give 0.45 g of yellow oil. The crude product was purified by a flash chromatography (25% EtOAc/hexane) to yield a white solid (0.27 g, 42 %). Mp. = 56-58 °C. Rf (50% EtOAc/hexane) = 0.20. ¹H NMR (CDCl3/TMS, 400.13 MHz) δ 7.34-7.27 (m, 1 H), 6.46-6.39 (m, 1 H), 6.27-6.21 (m, 1 H), 5.90 (d, 1 H, J = 16.0 Hz), 4.31 (d, 2 H, J = 4.0 Hz), 3.77 (s, 3 H), 1.7 (br s, 1H). ¹³C NMR (CDCl3, 100.62 MHz) 168.1, 144.6, 141.8, 128.4, 121.6, 63.3, 52.3. LRMS (EI) 142, 113, 98, 81(100), 55. Ref: (108) mp. = 52-54 °C.

6.1.6 6-Benzyloxy-hexa-2E,4E-dienoic acid methyl ester (437)

O O

HO O

O BnO

435 437

165

Benzyl alcohol (0.649 g, 6.00 mmol, 536 mol-%) was dissolved in dry CH2Cl2 (5 mL) in a dry argon flushed flask and 2,6-dimethylpyridine (0.643 g, 6.00 mmol, 536 mol-%) was added. A second dry argon flushed flask was charged with methyl 6-hydroxyhexa-2E,4E- dienoate 435 (0.160 g, 1.12 mmol, 100 mol-%), dry CH2Cl2 (9 mL) and 2,6-di- methylpyridine (0.484 g, 4.52 mmol, 404 mol-%). A third dry argon flushed flask was charged with dry CH2Cl2 (15 mL) and trifluoromethanesulfonic anhydride (1.693 g, 6.00 mmol, 536 mol-%). The third flask was cooled to –78 °C with a cooling bath (acetone/CO2(s)). After this, the contents of the first flask were transferred into the cooled flask dropwise. The addition took 10 minutes and the reaction was followed by TLC (50

% EtOAc/hexane). Stirring was continued for 25 minutes and the reagents from the second flask were transferred dropwise into the reaction mixture. The addition took 15 minutes. Stirring was continued for 40 minutes at -78 °C and then the reaction mixture was immersed into a cooling bath at – 25 °C (ethylene glycol/CO2). After stirring for 1.5 hours, pyridine (2 mL) was added followed by H2O (10 mL). The organic layer was washed with H2O (2 x 10 mL). The organic phase was stored in a refrigerator over weekend. The organic phase was dried with Na2SO4, filtered and concentrated to give 2.62 g of yellow oil. The crude product was purified by flash chromatography (5 % EtOAc/hexane) to give 437 (0.244 g, 93%) as a clear oil. Rf (25% EtOAc/hexane) = 0.35.

1H NMR (CDCl3/TMS, 400.13 MHz) δ 7.36 (m, 6 H), 6.46-6.39 (m, 1 H), 6.22-6.15 (m, 1 H), 5.89 (dt, 1 H, J = 15.4, 0.7 Hz), 4.55 (s, 2 H), 4.14 (dd, 2 H, J = 5.2, 1.6 Hz), 3.75 (s, 3 H). ¹³C NMR (CDCl3, 100.62 MHz) 168.1, 144.7, 139.4, 138.5, 129.8, 129.1, 128.5, 128.4, 121.7, 73.3, 70.3, 52.2. Ref: (108).

6.1.7 1-Benzyloxy-6-hydroxyhexa-2E,4E-diene (438)

O O

BnO BnO OH

437 438

166

Methyl 6-benzyloxyhexa-2E,4E-dienoate 437 (8.15 g, 35.1 mmol, 100 mol-%) was dissolved in dry toluene (250 mL) and the resulting mixture was cooled to –75 °C (ethyl acetate/N2). A 1 M solution of diisobutylaluminum hydride in toluene (110 mL, 110 mmol, 314 mol-%) was added dropwise in portions (30 mL) to keep the inside temperature between –70 – 75 ^oC. After stirring for 10 minutes, acetone (6 mL) and MeOH (2 mL) were added to quench the reaction. The reaction mixture was poured into a beaker, which contained 1 M solution of HCl (300 mL) The mixture was stirred for 15 minutes. The layers were separated and the water layer was extracted with ether (3 x 200 mL). The combined organic layers were washed twice with brine (150, 100 mL), dried with Na2SO4 and filtered. The solvents were evaporated to give 7.7 g of clear oil. The crude product was purified by flash chromatography (20% EtOAc/hexane) to yield 438 (0.80 g, 80%) as a clear oil. Rf (25% EtOAc/hexane) = 0.11. ¹H NMR (CDCl3/TMS, 400.13 MHz) δ 7.35 – 7.26 (m, 5 H), 6.32-6.23 (m, 2 H), 5.87-5.78 (m, 2 H), 4.52 (s, 2 H), 4.18 (t, 2 H, J = 5.5 Hz), 4.06 (d, 2 H, J = 5.4 Hz). ¹³C NMR (CDCl3, 100.62 MHz) 138.9, 133.1, 132.6, 131.2, 130.6, 129.1, 128.4, 128.3, 72.8, 70.9, 63.9. LRMS (EI) 204, 186, 169, 160, 130, 107, 97, 83(100), 69, 55. HRMS (EI) calculated for C13H16O2: 204.1150, found 204.1166.

6.1.8 1-Acetoxy-6-benzyloxyhexa-2E,4E-diene (439)

BnO OH

BnO OAc

438 439

1-Benzyloxy-6-hydroxyhexa-2E,4E-diene 438 (0.71 g, 3.5 mmol, 100 mol-%) was dissolved in pyridine (2.75 g, 34.7 mmol, 1000 mol-%) and acetic anhydride (3.54 g, 34.7 mmol, 1000 mol-%) was added. The orange reaction mixture was followed by TLC (50

% EtOAc/hexane) and stirred for 2 hours. Excess pyridine and acetic anhydride was

167

distilled from the reaction mixture (24-40 °C/9-10 mmHg). The distillation residue was diluted with ether (30 mL) and washed with a 0.5 M solution of H3PO4 (15 mL). The layers were separated and the water layer was extracted with ether (10 mL). The combined organic layers were washed with brine (10 mL), dried with Na2SO4 and filtered. The evaporation of the solvents gave 1.0 g of yellow oil. The crude product was purified by flash chromatography (10% EtOAc/hexane) to give 439 (0.78 g, 91%) as a clear oil. Rf (50% EtOAc/hexane) = 0.57. ¹H NMR (CDCl3/TMS, 400.13 MHz) δ 7.28- 7.26 (m, 5 H), 6.34-6.24 (m, 2 H), 5.88-5.73 (m, 2 H), 4.60 (d, 2 H, J = 6.2 Hz), 4.52 (s, 2 H), 4.07 (d, 2 H, J = 5.5 Hz), 2.07 (s, 3 H). ¹³C NMR (CDCl3, 100.62 MHz) 171.4, 138.9, 134.2, 132.0, 131.9, 129.1, 128.4, 128.3, 127.5, 72.9, 70.8, 65.3, 21.6. LRMS (EI) 246, 235, 220, 202, 168, 155, 142, 130, 108, 91, 79, 67(100), 51. HRMS (EI) calculated for C15H18O3: 246.1256, found 246.1258.

6.1.9 2-(8-Benzyloxyocta-4E,6E-diene)-1,3-dioxolane (440)

BnO OAc

BnO

BrMg O

28 O

439

440

BnO

O O O

O

+

441

Grignard reagent 28 was prepared as follows. 2-(2-Bromoethyl)-1,3-dioxolane 28 (1.12 g, 6.19 mmol, 205 mol-%) was diluted with dry THF (9 mL). This mixture was added into a flask equipped with a reflux condenser, which contained magnesium chips (0.24 g, 9.97 mmol, 330 mol-%). The addition was done in portions to avoid over boiling of THF.

Stirring was continued for 60 minutes. 1-Acetoxy-6-benzyloxyhexa-2E,4E-diene 439 (0.74 g, 3.02 mmol, 100 mol-%) was dissolved in dry THF (4 mL) and a 0.1 M solution of Li2CuCl4 (1.4 mL, 0.14 mmol, 4.5 mol-%) in THF was added. This resulted formation of orange mixture. The Grignard reagent was added in portions into the reaction flask.

168

The color of the reaction mixture changed in the following order: orange-brown-green- yellow-brown-purple. The addition took 35 minutes. The reaction was followed by TLC (50 % EtOAc/hexane). The reaction mixture was immersed in an ice bath. Stirring was continued for 1.5 hours and after this, the reaction mixture was allowed to warm to r.t.

Stirring was continued for 14 hours and the reaction mixture was diluted with ether (25 mL). The mixture was washed with a saturated solution of NH4Cl (2 x 10 mL), which was made basic (pH ≈ 8) with NH4OH before use. The combined water layers were extracted once with ether (20 mL). The combined organic layers were washed with brine (15 mL), dried with Na2SO4 and filtered to give 1.0 g of yellowish oil. The crude product was purified by flash chromatography (10 % MTBE/hexane) to yield 440/441 (0.57 g, 65%) as a clear oil. The ratio of 440/441 was (84:16). The products 440/441 were inseparable by flash chromatography. Rf 440/441 (20% MTBE/hexane) = 0.25. ¹H NMR 440 (CDCl3/TMS, 400.13 MHz) δ 7.35-7.26 (m, 6 H), 6.23 (dd, 1 H, J = 14.8, 10.4 Hz), 6.07 (dd, 1 H, J = 14.7, 10.2 Hz), 5.69 (dt, 2 H, J = 14.7, 7.0 Hz), 4.86 (t, 1 H, J = 4.6 Hz), 4.51 (s, 2 H), 4.04 (d, 2 H, J = 6.6 Hz), 3.96-3.94 (m, 2 H), 3.86-3.83 (m, 2 H), 2.14 (q, 2 H, J = 7.5 Hz), 1.70-1.64 (m, 2 H), 1.57-1.49 (m, 3 H). ¹³C NMR (CDCl3, 100.62 MHz) 139.1, 135.5, 134.0, 130.7, 129.0, 128.5, 128.2, 127.9, 105.1, 72.6, 71.2, 65.5, 34.0, 33.1, 24.2. LRMS (EI) 287, 197, 181, 153, 99, 91(100), 73, 65, 51. HMRS (EI+) calculated for C18 H24O3Na: 311.1628, found 311.1623.

6.1.10 9-Benzyloxynona-5E,7E-dien-1-al (442)

BnO O

O

BnO O

440 442

2-(8-Benzyloxyocta-4E,6E-diene)-1,3-dioxolane mixture 440/441 (2.49 g, 8.64 mmol, 100 mol-%) was dissolved in acetone (150 mL) and a 0.5 M solution of HCl (150 mL) was added. The reaction mixture was stirred for 17 hours at r.t. The reaction was followed by TLC (40 % MTBE/hexane, ninhydrin) and a small samples were worked up

169

and analyzed by ¹H NMR during the reaction. The mixture was diluted with ether (200 mL) and the layers were separated. The water phase was extracted with ether (100, 50 mL). The combined organic phases were washed with brine (150 mL), dried with MgSO4, filtered and concentrated to give 2.7 g of the product as an oil. The crude product was purified by flash chromatography (13 % MTBE/hexane) to yield 442 (1.84 g, 87 %) as a clear oil. Rf (40 % MTBE/hexane) = 0.34. ¹H NMR (CDCl3/TMS, 400.13 MHz) δ 9.78 (s, 1 H), 7.35-7.33 (m, 5 H), 7.29-7.25 (m, 1 H), 6.95 (dt, 1 H, J = 15.7, 7.0 Hz), 6.23 (dd, 1 H, J = 15.2, 10.4 Hz), 6.06 (dd, 1H, J = 15.0, 10.4 Hz), 5.82 (dt, 1 H, J = 15.5, 1.6 Hz), 5.72-5.62 (m, 2 H), 4.51 (s, 2 H), 4.04 (d, 2 H, J = 6.3 Hz), 3.72 (s, 3 H), 2.20 (qd, 2 H, J = 7.2, 1.5 Hz), 2.11 (q, 2 H, J = 7.0 Hz), 1.56 (q, 2 H, J = 7.4 Hz). ¹³C NMR (CDCl3, 100.62 MHz) 203.0, 139.0, 134.3, 133.5, 131.4, 129.1, 128.5, 128.4, 128.3, 72.7, 71.1, 43.8, 32.5, 22.2. LRMS (EI+) 244, 200, 181, 170, 153, 135, 107, 91, 81(100), 65. HRMS (EI+) calculated for C16H20O2: 244.1463, found 244.1468.

6.1.11 11-Benzyloxyundeca-2E,7E,9E-triene methyl ester (443)

BnO O BnO OMe

O

442 443

9-Benzyloxynona-5E,7E-dien-1-al 442 (133 mg, 0.55 mmol, 100 mol-%) was dissolved in dry CH2Cl2 (2 mL) and methyl (tri-phenyl-phosphoranylidene) (195 mg, 0.58 mmol, 105 mol-%) was added The reaction was followed by TLC (40 % MTBE/hexane, PMA).

The reaction mixture was stirred for 21 hours at r.t. At this point, a second portion of methyl (tri-phenyl-phosphoranylidene) (18 mg, 0.055 mmol, 10 mol-%) was added.

Stirring was continued for 2 hours and the mixture was diluted with CH2Cl2 (10 mL). The mixture was washed with brine (5 mL) and the layers were separated. The water layer was extracted once with EtOAc (5 mL) and the combined organics were dried with Na2SO4, filtered and the solvents were evaporated to give 161 mg of yellow oil. Hexane

170

(5 mL) was added and the mixture was stirred vigorously for 30 minutes. The white precipitate was filtered and washed with hexane (2 x 5 mL). The solvents were evaporated to give 161 mg of clear oil. The crude product was purified by flash chromatography (7 % MTBE/hexane) to yield 443 (33 mg, 80 %) as a clear oil. Rf (50 % MTBE/hexane) = 0.51. ¹H NMR (CDCl3/TMS, 400.13 MHz) δ 7.34-7.26 (m, 5 H), 6.23 (dd, 1 H, J = 15.2, 10.6 Hz), 6.07 (dd, 1 H, J = 15.0, 10.6 Hz), 5.66 (m, 2 H), 4.51 (s, 2 H), 4.04 (d, 2 H, J = 6.2 Hz), 2.44 (td, 2 H, J = 7.4, 1.7 Hz), 2.14 (q, 2 H, J = 7.2 Hz), 1.74 (q, 2 H, J = 7.3 Hz). ¹³C NMR (CDCl3, 100.62 MHz) 167.5, 149.5, 138.8, 134.5, 133.4, 130.7, 128.8, 128.2, 121.6, 72.6, 71.0, 51.8, 32.3, 32.0, 28.3, 27.3, 23.1. LRMS (EI+) 299 (M-1), 209, 181, 165, 136, 105, 91(100), 81, 67, 55. HRMS (EI+) calculated for C19H24O3: 300.1726, found (M-1) 299.1733. The yield of 2Z,7E,9E-isomer of the product was 11 mg (6%).

6.1.12 11-Benzyloxyundeca-2E,7E,9E-triene acid (444)

BnO OMe

O

BnO OH

O

443 444

11-Benzyloxyundeca-2E,7E,9E-triene methyl ester 443 (133 mg, 0.44 mmol, 100 mol-%) was dissolved in THF (2 mL) and a 1 M solution of NaOH (7 mL) was added. The reaction was followed by TLC (40% MTBE/hexane, PMA). The reaction mixture was stirred for 16 hours at r.t. After this, the reaction mixture was immersed in an oil bath to 60-70 ^oC. Stirring was continued for 3 hours and the mixture was diluted with ether (10 mL). The layers were separated and the water layer was extracted with ether (20 mL).

The aqueous layer was acidified with 5 M HCl until the pH was 1-2. The aqueous was extracted with CH2Cl2 (2 x 10 mL). The combined organics were dried with Na2SO4. Na2SO4 was filtered and the solvents were evaporated to give 444 (97 mg, 77%) as a yellow oil. Rf (50% EtOAc/hexane) = 0.18. ¹H NMR (CDCl3/TMS, 400.13 MHz) δ 7.35-

171

7.26 (m, 5 H), 7.06 (dt, 1 H, J = 15.7, 6.8 Hz), 6.23 (dd, 1 H, J = 14.7, 10.4 Hz), 6.07 (dd, 1 H, J = 15.0, 10.8 Hz), 5.83 (dt, 1 H, J = 15.7, 1.5 Hz), 5.74-5.62 (m, 2 H), 4.51 (s, 2 H), 4.05 (dd, 2 H, J = 6.2, 0.9 Hz), 2.25 (qd, 2 H, J = 7.2, 1.6 Hz), 2.13 (q, 2 H, J = 7.2 Hz), 1.58 (q, 2 H, J = 7.5 Hz). ¹³C NMR (CDCl3, 100.62 MHz) 172.4, 152.4, 134.7, 133.7, 131.1, 129.0, 128.3, 121.6, 72.8, 71.1, 32.6, 32.3, 28.0. LRMS (EI+) 285 (M-1), 195, 181, 165, 141, 119, 105, 91(100), 79, 67, 55. HRMS (EI+) calculated for C18H22O3: 286.1569, found 286.1572.

6.1.13 11-Benzyloxy-undeca-2E,7E,9E-trien-1-ol (469)

BnO OH

BnO OMe

443 O 469

11-Benzyloxy-undeca-2,7,9-trienoic acid methyl ester 443 (0.352 g, 1.17 mmol, 100 mol-

%) was dissolved in dry CH2Cl2 (10 mL) and cooled to – 78 °C. DIBAL-H (3.6 mL, 3.60 mmol, 308 mol-%) was added dropwise. Stirring was continued for 70 minutes and MeOH (1 mL) was added to quench the reaction. The mixture was allowed to warm to 0

°C. After 10 minutes of stirring, a 1 M solution of HCl (10 mL) was added and stirring was continued at room temperature for 30 minutes. The layers were separated and the water layer was extracted with ether (3 x 10 mL). The combined organics were washed with brine (10 mL), dried with Na2SO4, filtered and concentrated to give 0.332 g of 469 as a clear oil. The product was was pure enough for the next reaction. Rf (40 % MTBE in hexanes) = 0.16. ¹H NMR (CDCl3, 400.132 MHz) δ 7.34 – 7.26 (m, 7 H), 6.23 (dd, 1 H, J

= 15.0, 10.5 Hz), 6.06 (dd, 1 H, J = 15.1, 11.0 Hz), 5.72 – 5.65 (m, 4 H), 4.51 (s, 2 H), 4.09 (br s, 2 H), 4.04 (d, 2 H, J = 6.3 Hz), 2.13 – 2.03 (m, 4 H), 1.52 – 1.45 (m, 2 H). ¹³C NMR (CDCl3, 100.62 MHz) δ 139.0, 135.6, 134.0, 133.5, 130.6, 130.0, 129.0, 128.4, 128.2, 127.8, 72.7, 71.2, 64.4, 32.7, 32.3, 29.3. LRMS (EI+) 271 (M-1), 197, 181, 165,

172

129, 119, 105, 91(100), 79, 67, 55. HRMS (EI+) calculated for C18H24O2: 272.1776, found 272.1786.

6.1.14 11-Benzyloxy-undeca-2E,7E,9E-trienal (470)

BnO O

BnO OH

469 470

Crude 11-Benzyloxy-undeca-2,7,9-trien-1-ol 469 (0.313 g, 1.15 mmol, 100 mol-%) was dissolved in CH2Cl2 (20 mL) and MnO2 (0.600 g, 6.9 mmol, 600 mol-%) was added.

Stirring was continued for 15 hours and a second portion of MnO2 (0.102 g, 1.17 mmol, 102 mol-%) was added. Stirring was continued for 3.5 hours and a third portion of MnO2

(0.298 g, 3.43 mmol, 298 mol-%) was added. Stirring was continued for 5 hours and the reaction mixture was filtered through a thin pad of Celite. The product was concentrated to give 0.461 g of yellowish oil. The crude product was purified by flash chromatography (14 % MTBE/hexane) to yield 470 (0.264 g, 89 % over 2 steps) as a clear oil. Rf (40 % MTBE in hexanes) = 0.22. ¹H NMR (CDCl3, 400.132 MHz) δ) 9.51 (d, 1 H, J = 7.8 Hz), 7.35 – 7.26 (m, 5 H), 6.83 (dt, 1 H, J = 15.6, 6.8 Hz), 6.24 (dd, 1 H, J = 14.8, 10.8 Hz), 6.15 – 6.04 (m, 2 H), 5.75 – 5.61 (m, 2 H), 4.51 (s, 2 H), 4.05 (d, 2 H, J = 6.0 Hz), 2.34 (qd, 2 H, J = 7.3, 1.4 Hz), 2.15 (q, 2 H, J = 7.3 Hz), 1.62 (q, 2 H, J = 7.3 Hz). ¹³C NMR (CDCl3, 100.62 MHz) δ 194.7, 158.9, 140.8, 139.0, 136.0, 134.4, 133.8, 133.5, 131.2, 129.0, 128.3, 72.7, 71.1, 32.7, 32.6, 28.0. LRMS (EI+) 270, 180, 105, 91(100), 79, 65.

HRMS (EI+) calculated for [M-43] 227.1435, found 227.1491.

173

6.2 Chiral auxiliary induced preparation of bicyclo[4.3.0]nonene