Synthesis of acyclic precursors

5-Oxaoct-7-en-2-yn-1-ol (199). To a stirred suspension of NaH (120 mmol, 4.8 g of 60%

dispersion in oil) in anhydrous THF (50 mL) was gradually added 2-butyn-1,4-diol (17.2 g, 200 mmol) dissolved in anhydrous DMF (50 mL). After stirring under reflux for 1 h, a solution of allyl bromide (10.5 mL, 120 mmol) in anhydrous THF (30 mL) was gradually added by syringe pump within 2 h keeping a gentle refluxing of the reaction mixture. After the addition was complete, the mixture was stirred at reflux for additional 30 min and evaporated under reduced pressure (Tbath < 70 °C, 5 Torr). The residue was partitioned between ether (200 mL) and water (50 mL), organic layer was separated and the aqueous phase was extracted with ether (3 × 100 mL). The combined organic phases were washed with water (50 mL), brine (100 mL) and dried over MgSO4. The residue (12.6 g) obtained after evaporation of the solvents, was purified y flash” chromatography on 100 mL of flash silica gel, eluting with pentane/ether, 5:1 to 2:1, to yield 8.2 g (55%, from allyl bromide) of pure alcohol 199. Otherwise, by-product (1,4-bis-allyloxybutyn-2) and paraffin oil could be removed from the reaction mixture just by washing of dissolved in water (~100 mL) cru e alcohol with hexane. After removing the low-polar by-products (TLC control), the pure product could be regenerated by saturation of the aqueous phase with NaCl and subsequent extraction with ether. This procedure requires further optimization if necessary to increase

O OH

Methyl (5-oxa-oct-7-en-2-ynyl)carbonate (201). According to GP 12, alcohol 199 (11.4 g, 91 mmol) after distillation of the crude product under reduced pressure, gave 15.5 g (92%) of pure 201 as a colorless liquid. – B. p. 68–70 °C (0.2 Torr). – IR (film): ν = 3082, 3015, 2959, 2855, 2239 (C≡C), 2160, 1754 (C=O), 1649 (C=C), 1444, 1374, 1264, 1138, 1083, 1022, 994, 950, 901, 790 cm^–1. – ¹H NMR (250 MHz, CDCl3): δ = 3.80 (s, 3 H, OCH3), 4.04 (ddd, ³J = 5.7 Hz, ⁴J = 1.5 Hz, ⁴J = 1.2 Hz, 2

te (201). According to GP 12, alcohol 199 (11.4 g, 91 mmol) after distillation of the crude product under reduced pressure, gave 15.5 g (92%) of pure 201 as a colorless liquid. – B. p. 68–70 °C (0.2 Torr). – IR 3078, 3001, 2979, 2943, 2861, 2235 (C≡C), 1756 (C=O), 1640 (C=C), 1446, 1375, 1262, 1150, 1106, 1020, 994, 953, 916, 791 cm . – H 3078, 3001, 2979, 2943, 2861, 2235 (C≡C), 1756 (C=O), 1640 (C=C), 1446, 1375, 1262, 1150, 1106, 1020, 994, 953, 916, 791 cm . – H

nate (196). According to GP 12, alcohol 198 (8.1 g, 65 mmol) after distillation of the crude product under reduced pressure, gave 11.1 g (94%) of pure 196 as a colorless

–1 1

nate (196). According to GP 12, alcohol 198 (8.1 g, 65 mmol) after distillation of the crude product under reduced pressure, gave 11.1 g (94%) of pure 196 as a colorless

–1 1

4-Chlorobut-2-ynyl methyl carbonate (202). According to GP 12, 4-chlorobut-2-yn-1-ol 100 mmol) gave 16.0 g (98%) of sufficiently pure 202 tly yellow liquid, which physical property and spectral e identical to those reported in the literature.^[135]

Methyl [5,5-bis(methoxycarbonyl)oct-7-en-2-ynyl]carbonate (205). To a stirred suspension of NaH (3.27 g of 60% dispersion in mineral oil, 82 mmol) in anhydrous THF (80 mL) dimethyl allyl malonate (203) (13.4 g, 78 mmol) was added dropwise at ambient temperature. After the reaction mixture had become homogeneous, a solution of 202 (13.3 g, 82 mmol) in the same solvent (40 mL) was gradually added at ambient temperature within 1 h. The reaction mixture was stirred for an additional 16 h and then evaporated under reduced pressure at ambient temperature. The residue was partitioned between ether (200 mL) and water (50mL) and the a

O OMe extracted with ether (2×50 mL). The combined organic layers were washed with water (2×50

pressure gave 21.1 g of the crude res h

p ^[135]

g ve 14.3 g of a brown oil, which

was purified by flash” chromatography on 100 mL of flash silica gel, eluting with pentane/ether, 10:1 to 5:1, to yield 8.1 g (55%) of pure 206 as a slightly yellow viscous oil. –

Cl O OMe

mL), brine (100 mL) and dried over MgSO4. Evaporation of the solvents under reduced idue, which was subjected to flash chromatography on

hexane/tBuOMe, 5:1, to yield 9.3 g (40%) of pure 205 physical properties and spectral data of the compound orted in the literature.

Methyl [5,5-bis(ethoxycarbonyl)oct-7-en-2-ynyl]carbonate (206). To a stirred suspension of NaH (1.9 g of 60% dispersion in mineral oil) in anhydrous DMF (45 mL) diethyl allyl malonate (204) (9.01 g, 45 mmol) was added in one portion and then 202 (7.4 g, 46 mmol) was added dropwise at 10 °C (ice water bath) within 30 min. The mixture was stirred at ambient temperature for 24 h, DMF was

“bulb-to-bulb” distilled off (0.1 Torr, Tbath < 60 °C), the residue was diluted with ether (200 mL), washed with 5% aqueous H2SO4 (50 mL), water (50 mL), brine (50 mL) and dried over M SO4. Evaporation of the solvent under reduced pressure ga

O CO₂Et

EtO₂C

200 mL of flash silica gel, eluting wit as a slightly yellow viscous oil. The synthesized were identical to those re

O

2

O OMe

1031, 954, 901, 861, 792 cm^–1. – ¹H NMR (250 MHz, CDCl3): δ = 1.23 (t, ³J = 7.2 Hz, 6 H, 251.2 (4), 177 (2). – Anal. Calculate 58.58, H 7.08.

3 2 4

tography (150 mL of silica gel, eluent pentane) to yield 400 mg (35% yield) of pure 197. Spectral data of the synthesized

Methyl 2-(pent-4-enyl)buta-2,3-dienoa

1-(1-Phenylethenyl)bicyclo[3.1.0]hexane (197). A solution of enyne 196 (911 mg, 5 mmol), PPh (262 mg, 1 mmol), Pd(OAc) (112 mg, 0.5 mmol) and NaBPh (1.711 g, 5 mmol) in degassed anisole (10 mL) was stirred at 80 °C for 18 h. After cooling to room temperature, the mixture was diluted with pentane (50 mL) and filtered through a pad of flash silica gel (10 mL), which was rinsed with pentane (2 × 10 mL). The combined filtrates were evaporated under reduced pressure to give 1.2 g of crude oil, which was purified by column chroma

Ph

compound corresponded to literature.^[113]

te (210) was isolated as a by-product in attempted of (196) by following conditions. To a stirred solution yl) (46 mg, 0.2 mmol) and PPh (26 mg, 0.1 mmol) in degassed methanol (25 mL) was added Pd(OAc) (22 mg, 0.1 mmol) under argon. After the mixture had become dark brown and completely homogenous (about 30 min), was added enyne 196 (364 mg, 2 mmol) all at once and the reaction atmosphere was replaced with CO. After stirring at ambient temperature for 5 h, the brown color is disappeared and no changes of reactions mixture were observed (less, then 50%

conversion according TLC). Then, PPh (50 mg) and LiI (50 mg) were added and the red-brown mixture was stirred overnight under 1 bar of CO. After the starting material was

CO₂Me

•

completely consumed (< 3% according to GC), the mixture was evaporated under reduced pressure at ambient temperature to give 550 mg of residue, which was suspended by stirring with pentane (30 mL) and filtered through a pad of flash” silica gel (10 mL). This was washed with pentane/ether mixture, 10:1 (2 × 20 mL), and the combined filtrates were evaporated under reduced pressure to give 350 mg of the residue, which was then subjected to column chromatography on 50 mL of silica gel, eluting with pentane/ether, 20:1, to yield ∼100 mg of 130, about 60 mg of unindentified substance and 90 mg (27%) of the crude 210, contaminated with 10–15% of 130. – ¹H NMR (250 MHz, CDCl3): δ = 1.55 (tt, ³J

dd, ³J = 17.5 Hz, ³J = 10.3 Hz, ³J = 7.5 Hz, 1 H, 7-H).

clizations of 1,6-enines to 2-bicyclo[3.1.0]acrylates

mmol) and P(O Pd(OAc)2 (112 for additional 1

en ate (130) was prepared by stirring of enyne 196 (0.91 g, 5 mmol) in presence 2 mol% of CSA (0.1 mmol, 25 mL of 0.004 M methanolic chromatography (20 mL of f

after evaporation of solven (94%, 97.5% purity). The s reported above.

= 7.5 Hz, ³J = 7.5 Hz, 2 H, 5-H), 2.08 (tddd, ³J = 7.5 Hz, ³J = 7.5 Hz, ⁵J = 1.5 Hz, ⁵J = 1 Hz, 2 H, 6-H), 2.24 (tt, ³J = 8 Hz, ⁵J = 3 Hz, 2 H, 4-H), 3.74 (s, 3 H, OCH3), 4.94 (ddd, ³J = 10.3 Hz, ²J = 2 Hz, ⁵J = 1.5 Hz, 1 H, 8-Htrans), 5.00 (ddd, ³J = 17.5 Hz, ²J = 2 Hz, ⁵J = 1 Hz, 1 H, 8-Hcis), 5.13 (t, ⁵J = 3 Hz, 2 H, 1-H), 5.79 (d