Whitby group

To a solution of Cp₂ZrCl₂ (0.293 g, 1.0 mmol) in dry THF (5 mL) cooled to –78 °C was added n-BuLi (0.80 mL of a 2.5 M solution in hexanes, 2.0 mmol) dropwise over 3 minutes. After 25 min at the same temperature, a solution of bis(methoxymethyl)hepta-1,6-diene (0.184 g, 1.0 mmol) in dry THF (3 mL) was added dropwise. After 30 min at –78 °C the reaction mixture was allowed to warm to room temperature and stirred for 12 h. After cooling the reaction to –78 °C, 1,1-dichloromethane (0.064 mL, 1.0 mmol) was added followed by dropwise addition of freshly prepared LiTMP, [prepared from freshly distilled 2,2,6,6-tetramethylpiperidine (0.20 mL, 1.2 mmol) in dry THF (2 mL) and n-BuLi (0.48 mL of a 2.5 M solution in hexanes, 1.15 mmol) at 0 °C over 20 min]. The reaction mixture was stirred for 1 h during which was allowed to warm to –65 °C before re-cooling to –78 °C and dropwise addition of lithium phenyl acetylide, [prepared from phenylacetylene (0.33 mL, 3.0 mmol) in dry THF (3 mL) and n-BuLi (1.2 mL of a 2.5 M solution in hexanes, 3.0 mmol) at 0 ^oC over 15 min]. The stirring was continued for 3 h during which time the reaction mixture was allowed to warm to –35 °C before addition of MeOH (5 mL) and a saturated aqueous solution of NaHCO₃ (6 mL). The whole mixture was allowed to warm to room temperature and left stirring for 18 h. The mixture then was poured onto H₂O (100 mL), the products were extracted with Et₂O (3 × 50 mL). The combined organic phases were washed with H₂O (3 × 100 mL) and brine (100 mL), dried over MgSO₄, filtered and concentrated in vacuo to give the crude product as a brown oil.

Purification of the crude material by column chromatography on SiO₂ (230 – 400 mesh) with 5% of Et₂O in hexanes gave the title compounds as an inseparable mixture of compounds in the following ratio: 3.80a/b : 3.80b/a, 1 : 1.8 and 3.80 : 3.81, 1 : 2, as a pale yellow oil in combined yield of 0.033 g (10%).

Further acetylide insertion allows for incorporation of the alkynyl moiety into the molecule to provide intermediate 3.79, which after protonolysis gives three products: 3.80a, b and 3.81 as an inseparable mixture of compounds in 10% combined yield and following ratio: 3.80a/b : 3.80b/a, 1.8 : 1 and 3.80 : 3.81, 1 : 2 by NMR. Despite considerable optimization undertaken, the reaction proved to be low yielding and the purification of the final product difficult due to many unidentifiable products. 

¹H NMR (400 MHz, CDCl₃): δ (ppm) = 7.393 – 7.145 (15H, m, H^Ar), 6.162 (1H, dd, J = 6.3, 3.0 Hz, H^17a/b), 6.160 (1H, dd, J = 6.3, 2.9 Hz, H^17a/b), 5.685 (2H, td, J = 6.5, 3.5 Hz, H¹⁵), 3.334 – 3.218 (30H, m), 2.723 – 2.650 (2H, m, H¹⁴), 2.433 (2H, d, J = 7.0 Hz, H¹⁰), 1.989 – 1.348 (27H, m), 1.319 – 0.841 (14H, m).

¹³C NMR (100.5 MHz, CDCl₃): δ (ppm) = 203.46 (C^16a/b), 203.40 (C^16a/b), 135.18 (2C^{i-Ph B}), 131.54 (2CH^{o-Ph A}), 128.53 (4CH^{m-Ph B}), 128.14 (2CH^{m-Ph A}), 127.40 (CH^{p-Ph A}), 126.59 (2CH^{o-Ph B}), 126.54 (2CH^{p-Ph B}), 126.49 (2CH^{o-Ph B}), 124.15 (C^{i-Ph A}), 101.81  (CH^17a/b), 101.76 (CH^17a/b), 95.73 (2CH^{15a + b}), 89.90 (C¹²), 80.45 (C¹³), 78.17 (2CH₂²), 78.10 (4CH₂²), 59.20 (6CH₃¹), 54.42 (2C³), 54.34 (C³), 52.33 (3CH^6/7), 50.90 (2CH^6/7), 50.76 (CH^6/7), 43.33 (CH ¹⁰), 42.92 (2CH ¹⁴), 34.72 (2CH₂), 34.40 (CH₂), 34.33 (2CH₂), 34.25 (2CH₂), 34.20 (2CH₂), 33.61 (2CH₂), 32.51 (CH₂), 26.99 (CH₂).

LRMS (CI): m/z: 313 ([M + H]^+·, 9%), 268 ([M – MeOH + H]^+·, 6%), 267 ([M – Et₂O + H]^+·, 4%), 249 ([M – 2MeOH + H]^+·, 9%), 235 ([M – Ph]^+·, 7%), 115 ([C₉H₇]^+·, 34%).

To a solution of Cp₂ZrCl₂ (0.293 g, 1.0 mmol) in dry THF (5 mL) cooled to –78 °C was added n-BuLi (0.80 mL of a 2.5 M solution in hexanes, 2.0 mmol) dropwise over 3 minutes. After 25 min at the same temperature, a solution of 3-(1-methoxy-2-(methoxymethyl)pent-4-en-2-yl)cyclohex-1-ene (0.224 g, 1.0 mmol) in dry THF (3 mL) was added dropwise. After 30 min at –78 °C the reaction mixture was allowed to warm to room temperature and stirred for 2 h. After cooling the reaction mixture to –90 °C, a solution of 1,1-dibromoheptane (0.284 g, 1.1 mmol) in dry THF (1 mL) was added followed by dropwise addition of freshly prepared LiTMP, [prepared from freshly distilled 2,2,6,6-tetramethylpiperidine (0.196 mL, 1.15 mmol) in dry THF (2 mL) and n-BuLi (0.46 mL of a 2.5 M solution in hexanes, 1.15 mmol) at 0 °C over 20 min]. The reaction mixture was stirred for 20 min during which was allowed to warm to –78 °C before dropwise addition of lithium phenyl acetylide. [prepared from phenylacetylene (0.33 mL, 3.0 mmol) in dry THF (3 mL) and n-BuLi (1.2 mL of a 2.5 M solution in hexanes, 3.0 mmol) at 0 ^oC over 15 min]. The stirring was continued for 2 h during which time the reaction mixture was allowed to warm to RT before addition of MeOH (5 mL) and a saturated aqueous solution of NaHCO₃ (6 mL). The whole mixture was allowed to warm to room temperature and left stirring overnight. The mixture was poured onto H₂O (100 mL), the products extracted with Et₂O (3 × 50 mL). The combined organic phases were washed with H₂O (3 × 100 mL) and brine (100 mL), dried over MgSO₄, filtered and concentrated in vacuo to give the crude product as a yellow oil.

Purification of the crude material by column chromatography on SiO₂ (230 – 400 mesh) with 5% of Et₂O in hexanes and Kugelrohr distillation (200 °C, 1.0 mmHg) gave the title compounds as an inseparable mixture 3 : 1 of E : Z isomers as a pale yellow oil in yield of 0.029 g (9%).

To a solution of Cp₂ZrCl₂ (0.293 g, 1.0 mmol) in dry THF (5 mL) cooled to –78 °C was added n-BuLi (0.80 mL of a 2.5 M solution in hexanes, 2.0 mmol) dropwise over 3 minutes. After 25 min at the same temperature, a solution of 1,2-diallylbenzene (0.158 g, 1.0 mmol) in dry THF (3 mL) was added dropwise. After 30 min at –78 °C the reaction mixture was allowed to warm to room temperature and stirred for 2.5 h. After cooling the reaction to –85 °C, a solution of 1,1-dibromoheptane (0.335 g, 1.3 mmol) in dry THF (1 mL) was added followed by dropwise addition of LDA (0.85 mL of a 1.8 M solution, 1.5 mmol). After 15 min a dropwise addition of lithium phenyl acetylide followed, [prepared from phenylacetylene (0.33 mL, 3.0 mmol) in dry THF (3 mL) and n-BuLi (1.2 mL of a 2.5 M solution in hexanes, 3.0 mmol) at –5 ^oC over 15 min]. The stirring was continued for 1 h during which time the reaction mixture was allowed to warm to –55 °C before addition of MeOH (5 mL) and a saturated aqueous solution of NaHCO₃ (6 mL). The whole mixture was allowed to warm to room temperature and left stirring overnight. The mixture was poured onto H₂O (100 mL), the products extracted with Et₂O (3 × 50 mL). The combined organic phases were washed with H₂O (3 × 100 mL) and brine (100 mL), dried over MgSO₄, filtered and concentrated in vacuo to give the crude product as a yellow oil. 

Purification of the crude material by column chromatography on SiO₂ (230 – 400 mesh) with hexanes as the eluent gave the title compounds as colourless oil in yield of 0.083 g (33%) as an inseparable mixture of compounds with the ratios 3.65:65%, 3.66:31% and 3.67:4% 

To a solution of Cp₂ZrCl₂ (0.293 g, 1.0 mmol) in dry THF (5 mL) cooled to –78 °C was added n-BuLi (0.80 mL of a 2.5 M solution in hexanes, 2.0 mmol) dropwise over 3 minutes. After 25 min at the same temperature, a solution of 1,7-octadiene (0.110 g, 1.0 mmol) in dry THF (3 mL) was added dropwise. After 30 min at –78 °C the reaction mixture was allowed to warm to room temperature and stirred for 2 h. After cooling the reaction to –78 °C, a solution of 1,1-dibromoheptane (0.335 g, 1.30 mmol) in dry THF (1 mL) was added followed by dropwise addition of LDA (0.83 mL of a 1.8 M solution, 1.50 mmol). The reaction mixture was stirred at –78 °C for 15 min before dropwise addition of lithium phenyl acetylide, [prepared from phenylacetylene (0.33 mL, 3.0 mmol) in dry THF (3 mL) and n-BuLi (1.2 mL of a 2.5 M solution in hexanes, 3.0 mmol) at –5 ^oC over 15 min]. The stirring was continued for 30 min during which time the reaction mixture was allowed to warm to –50 °C before addition of MeOH (5 mL) and a saturated aqueous solution of NaHCO₃ (6 mL). The whole mixture was allowed to warm to room temperature and left stirring overnight. The mixture was poured onto H₂O (100 mL), the products extracted with Et₂O (3 × 50 mL). The combined organic phases were washed with H₂O (3 × 100 mL) and brine (100 mL), dried over MgSO₄, filtered and concentrated in vacuo to give the crude product as an orange oil.

Purification of the crude material by column chromatography on SiO₂ (230 – 400 mesh) with hexanes as the eluant gave the title compounds as a pale yellow oil in combined yield of 0.165 g (53%).