2016 Volume 64 Issue 7 Pages 845-855
We describe an efficient regioselective formation of six-/seven-membered cyclic ethers based on gold-catalyzed intramolecular hydroalkoxylation. Sequential gold-catalyzed cyclization and palladium-catalyzed cross-coupling reactions afforded 6,6-bicyclic ethers, while reversing the reaction sequence (cross-coupling then cyclization) afforded 6,7-bicyclic ethers. This methodology should provide access to a range of functional polycyclic ethers.
(Poly)cyclic ethers are key structural units in many natural products and materials of structural and biological interest1–5) (Fig. 1). Therefore, regio- and chemoselective construction of these structures has long been of interest in organic synthesis. Homogeneous gold catalysis has emerged over the last two decades as a powerful tool for heterocyclization reactions, and the gold-catalyzed intramolecular addition of alcohol across a carbon-carbon triple bond has been employed for the construction of cyclic ethers in various total syntheses.6–17) However, its application to the formation of medium-sized cyclic ethers has been generally limited by 1) enthalpic and entropic difficulties, and 2) low regioselectivity in ring-closure to the triple bond.18) Furthermore, the applicability of the reaction to polycyclic ethers is not well established.19) With total syntheses of polycyclic ether-containing natural products in mind, we therefore designed the alkyne alcohol (alkynol) 1 as a cyclization precursor obtainable within 10 steps from 2,3-dihydrofuran20,21) (Chart 1). Herein, we report our investigations on the gold-catalyzed intramolecular hydroalkoxylation of 1, focusing in particular upon the influence of the electronic and/or steric properties of alkynes on the 6-exo/7-endo selectivity. We also show that changing the order in which gold-catalyzed cyclization and palladium-catalyzed cross-coupling reactions are carried out provides a means to rapidly diversify polyether structures.
We commenced our studies by treating 1a (X=3,5-syn-OMe; Y=Me) with various gold catalysts. After extensive experimentation, we found that the use of gold–oxo complex, tris[(triphenylphosphine)gold]oxonium tetrafluoroborate ([(Ph3PAu)3O]BF4) in the presence or absence of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) promotes the intramolecular cyclization smoothly to give 6-exo and 7-endo bicyclic ethers (2a and 3a) in high yields. Simple heating of 1a at 60°C in tetrahydrofuran (THF) in the presence of 5 mol% of [(Ph3PAu)3O]BF4 (Condition A) afforded the desired cyclic ethers as a 13 : 87 mixture of 2a and 3a in 81% yield. Addition of 2 eq. of HFIP (Condition B) increased the total chemical yield of 2a and 3a to 92%, but lowered the 7-endo selectivity (Fig. 2). With these optimal conditions in hand, we then systematically examined the influence of the substituents at the propargylic (X) and terminal (Y) positions of alkynols 1 on the regioselectivity of the ring closure (Chart 1). Stereochemistry of the MeO moiety at the propargylic position did not greatly influence the product distribution (2b, 3b). The reaction of 1c gave the 7-endo product 3c exclusively in 63% yield via an intramolecular Michael-type addition of alcohol to ynone. For comparison, the yield of cyclic ethers was less than 1% when the gold catalyst was omitted, while deprotonative activation of the OH group of 1c with NaH failed completely to promote the desired cyclization. Interestingly, reduction of the carbonyl group (C=O) to methylene (CH2) induced the opposite regioselectivity, selectively providing the 6-exo product 2d, together with a small amount of 3d. The reaction of 1e bearing a phenyl group at the terminus of the alkyne moiety (X=H, H; Y=Ph) showed comparable reactivity and selectivity to those obtained with 1d (X=H, H; Y=Me). As part of an ongoing program directed to the development of new methodologies for the syntheses of marine polycyclic ethers in our laboratory, we next focused on substrates bearing an MeO group at the propargylic position (X=3,5-syn-OMe), and the 6-exo/7-endo selectivity was evaluated using two sets of conditions. Comparison of compounds 1f and g having phenyl and p-MeO-phenyl groups, respectively, shows that an electron-rich alkyne favors 7-endo selectivity, and the corresponding cyclized products 2f/3f and 2g/3g were obtained in 79% (35 : 65) and 64% (9 : 91) yield, respectively. Cyclization of enyne 1h (Y=cis-propene) under condition B proceeded quantitatively and exhibited similar 7-endo selectivity. On the other hand, a terminal alkyne 1i (Y=H) and compound 1j with an electron-withdrawing substituent (Y=Br) at the terminus of alkyne showed altered regioselectivity upon ring closure. It is interesting to note that the 6-exo-dig cyclization of 1k having a N-methyliminodiacetic acid boronate (BMIDA) protecting group22) occurred in preference to the 7-endo-dig cyclization, presumably for steric reasons.
a Ratios were determined by 1H-NMR analysis. bCombined isolated yields. c [(Ph3PAu)3O]BF4 10 mol% was used. d 1,4-Dioxane was used as a solvent. e NMR yield. MP=p-methoxyphenyl. BMIDA=N-methyliminodiacetic acid boronate.
Finally, we examined the synthetic utility of this methodology as a means to provide facile access to various functionalized polyether derivatives (Chart 2). The present gold-catalyzed reaction is compatible with palladium-catalyzed cross-coupling reactions, and the primary cyclization product can act as a nucleophile to afford the corresponding 6,6-bicyclic ether 2h in one pot.17) On the other hand, the reverse procedure, that is, primary cross-coupling with cis-1-bromopropene followed by gold-catalyzed cyclization, afforded 6,7-bicyclic ether 3h in high yield.
a Pd(OAc)2 10 mol%, SPhos 20 mol%, 3 M K3PO4 in H2O, 7.7 eq, cis-1-bromopropene 1.3 eq, THF (0.1 M), 60°C. b NMR yield of 3h. SPhos=2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl.
In conclusion, the methodology described here provides a regioselectivity-switchable strategy for constructing cyclic ethers, using gold-catalyzed cyclization. Applications to the synthesis of polycyclic ethers are under study in our laboratory.
All reactions were carried out under an inert atmosphere of dry argon, unless the reaction procedure states otherwise. Column chromatography was performed with silica gel 60 (40–50 µm) purchased from Merck. THF was purchased from Kanto Chemical Co., Inc. (Japan). NMR spectra were recorded on a Bruker AVANCE III HD spectrometer (500 MHz for 1H and 125 MHz for 13C). Chemical shifts are expressed in δ (ppm) values, and coupling constants are expressed in hertz (Hz). The following abbreviations are used: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br s=broad singlet and br d=broad doublet. The value was determined with respect to tetramethylsilane for 1H (1H(δ)=0.00 ppm) and solvent for 1H (C6D6: 1H(δ)=7.16 ppm, CD3CN: 1H(δ)=1.94 ppm), 13C (CDCl3: 13C(δ)=77.16 ppm, C6D6: 13C(δ)=128.06 ppm). Electrospray ionization (ESI)-MS was taken on a Bruker micrOTOF-II.
Syntheses of SubstratesSyntheses of 6a and 6bDiisobutylaluminum hydride (DIBAH) (1.02 M in n-hexane, 15.7 mL, 16.0 mmol) was slowly added to a solution of the ester 421) (2.02 g, 6.99 mmol) in CH2Cl2 (35 mL) at −78°C under an argon atmosphere. After the reaction was stirred for 2.5 h, SiO2, H2O (3 mL), and i-PrOH (5 mL) were added and the mixture was warmed to room temperature (r.t.). After addition of MgSO4 and Celite, the mixture was filtrated through Celite pad, and concentrated in vacuo. The residue containing aldehyde 5 was submitted to the next reaction without purification (Chart 3).
1-PropynylMgBr (0.5 M in THF, 3.6 mL, 1.8 mmol) was added to a solution of the crude aldehyde 5 (387.6 mg, 1.5 mmol) in THF (15 mL) at 0°C under an argon atmosphere. After the reaction was stirred for 1.5 h, the reaction was quenched with sat. NH4Cl aq., and the mixture was diluted with Et2O. The aqueous layer was extracted with Et2O and the combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane–EtOAc=20 : 1 to 3 : 1) to give 3,5-syn-OH 6a (183.8 mg, 615.7 µmol, 31% yield, 2 steps) as a pale yellow oil and 3,5-anti-OH 6b (195.3 mg, 654.3 µmol, 33% yield, 2 steps) as a pale yellow solid.
Data for 6a1H-NMR (500 MHz, CDCl3) δ: 4.59 (m, 1H), 3.85 (m, 1H), 3.63 (d, J=7.9 Hz, 1H), 3.60 (ddd, J=9.2, 2.4, 2.4 Hz, 1H), 3.37 (m, 2H), 2.12 (ddd, J=14.7, 6.1, 2.4 Hz, 1H), 2.01 (m, 1H), 1.86 (d, J=2.1 Hz, 3H), 1.79 (ddd, J=14.3, 9.8, 3.4 Hz, 1H), 1.71–1.64 (m, 2H), 1.47 (m, 1H), 0.88 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C-NMR (125 MHz, CDCl3) δ: 81.2, 80.7, 80.1, 70.9, 67.8, 61.4, 38.7, 33.4, 25.9 (3C), 25.5, 18.1, 3.8, −3.8, −4.5; high resolution (HR)-MS (ESI) Calcd for C16H30O3SiNa [M+Na]+ 321.1856. Found 321.1841.
Data for 6b1H-NMR (500 MHz, CDCl3) δ: 4.57 (m, 1H), 3.88 (m, 1H), 3.43 (d, J=2.4 Hz, 1H), 3.36–3.24 (m, 3H), 2.21 (ddd, J=14.3, 4.0, 2.4 Hz, 1H), 2.00 (m, 1H), 1.85 (d, J=2.1 Hz, 3H), 1.77–1.63 (m, 3H), 1.43 (m, 1H), 0.89 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H); 13C-NMR (125 MHz, CDCl3) δ: 83.1, 80.4, 80.1, 71.3, 67.8, 62.7, 40.5, 33.4, 26.0 (3C), 25.4, 18.1, 3.8, −3.9, −4.5; HR-MS (ESI) Calcd for C16H30O3SiNa [M+Na]+ 321.1856. Found 321.1852.
Synthesis of 1aNaH (50%, 59.2 mg, 1.23 mmol) was added to a solution of 6a in THF (2 mL) at 0°C. After the mixture was stirred at 0°C for 1 h, MeI (57.5 µL, 923.6 µmol) was added to the solution and stirred at r.t. for 4 h. The reaction mixture was quenched with H2O, and the whole was diluted with EtOAc. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was submitted to the next reaction without purification.
Tetra-n-butylammonium fluoride (n-Bu4NF) (1.0 M in THF, 3.1 mL, 3.1 mmol) was added to a solution of the crude in THF (3 mL) at 0°C. After the mixture was stirred at r.t. for 3 h, the reaction mixture was quenched with H2O, and the whole was diluted with EtOAc. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane–EtOAc=3 : 1) to give 3,5-syn-OMe 1a (107.8 mg, 543.7 µmol, 88% yield, 2 steps) as a colorless oil.
Data for 1a1H-NMR (500 MHz, CDCl3) δ: 4.14 (dddd, J=10.7, 4.3, 1.8, 1.8 Hz, 1H), 3.87 (dddd, J=11.3, 4.3, 1.8, 1.8 Hz, 1H), 3.41 (s, 3H), 3.35–3.26 (m, 2H), 3.15 (ddd, J=8.9, 6.7, 4.6 Hz, 1H), 2.74 (br s, 1H), 2.20 (ddd, J=14.7, 9.8, 4.6 Hz, 1H), 2.11 (m, 1H), 1.88 (ddd, J=15.0, 6.4, 2.8 Hz, 1H), 1.86 (d, J=2.1 Hz, 3H), 1.73–1.64 (m, 2H), 1.38 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ: 82.0, 79.7, 78.0, 70.7, 68.4, 67.8, 56.4, 40.9, 32.7, 25.7, 3.7; HR-MS (ESI) Calcd for C11H18O3Na [M+Na]+ 221.1148. Found 221.1157.
Synthesis of 1bNaH (50%, 62.8 mg, 1.31 mmol) was added to a solution of 6b in THF (2.2 mL) at 0°C. After the mixture was stirred at 0°C for 1 h, MeI (61.1 µL, 981.4 µmol) was added to the solution and stirred at r.t. for 4 h. The reaction mixture was quenched with H2O, and the whole was diluted with EtOAc. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was submitted to the next reaction without purification.
n-Bu4NF (1.0 M in THF, 3.3 mL, 3.3 mmol) was added to a solution of the crude in THF (3.3 mL) at 0°C. After the mixture was stirred at r.t. for 3 h, the reaction mixture was quenched with H2O, and the whole was diluted with EtOAc. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane–EtOAc=4 : 1 to 3 : 1) to give 3,5-anti-OMe 1b (128.8 mg, 649.7 µmol, 99% yield, 2 steps) as a colorless oil.
Data for 1b1H-NMR (500 MHz, CDCl3) δ: 4.18 (dddd, J=7.6, 6.1, 1.8, 1.8 Hz, 1H), 3.87 (dddd, J=11.3, 4.3, 2.1, 1.5 Hz, 1H), 3.41 (s, 3H), 3.36–3.25 (m, 3H), 2.96 (br s, 1H), 2.12–1.98 (m, 2H), 1.87 (d, J=2.1 Hz, 3H), 1.74–1.65 (m, 3H), 1.41 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ: 82.9, 79.9 (2C), 70.1, 68.8, 67.9, 56.5, 39.7, 32.2, 25.8, 3.8; HR-MS (ESI) Calcd for C11H18O3Na [M+Na]+ 221.1148. Found 221.1153.
Synthesis of 1cMolecular sieves 4A (MS4A) (133.2 mg) and N-methylmorpholine-N-oxide (NMO) (39.2 mg, 335.0 µmol) were added to a stirred solution of the mixture of 6a and 6b (66.6 mg, 223.0 µmol) in CH2Cl2 (2.2 mL) at r.t. Stirring was continued for 15 min, and then tetra-n-propylammonium perruthenate (TPAP) (3.9 mg, 11.2 µmol) was added at the same temperature. The mixture was further stirred for 2 h, and then filtered through a pad of silica gel and eluted with EtOAc. The filtrate was concentrated in vacuo, and the residue was used for the next reaction without purification.
n-Bu4NF (1.0 M in THF, 1.12 mL, 1.12 mmol) and AcOH (63.8 µL, 1.12 mmol) were added to a solution of the crude in THF (1.1 mL) at 0°C. After the mixture was stirred at r.t. for 27 h, the reaction mixture was quenched with H2O, and the whole was diluted with EtOAc. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane–EtOAc=5 : 1 to 1 : 1) to give 1c (19.3 mg, 106.0 µmol, 47% yield, 2 steps) as a colorless oil and tert-butyldimethylsilyl (TBS)-protected 1c (7.1 mg, 23.9 µmol, 11% yield, 2 steps) as a colorless oil.
Data for 1c1H-NMR (500 MHz, CDCl3) δ: 3.88 (ddd, J=11.6, 4.3, 1.8 Hz, 1H), 3.63 (ddd, J=8.9, 8.2, 4.0 Hz, 1H), 3.41–3.32 (m, 2H), 3.04 (dd, J=15.9, 4.0 Hz, 1H), 2.73 (dd, J=15.9, 7.9 Hz, 1H), 2.14 (m, 1H), 2.03 (s 3H), 1.76–1.66 (m, 3H), 1.44 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ: 186.5, 91.0, 80.6, 78.8, 70.5, 67.9, 48.9, 33.3, 25.7, 4.4; HR-MS (ESI) Calcd for C10H14O3Na [M+Na]+ 205.0835. Found 205.0844.
Synthesis of 8TBSCl (592.3 mg, 3.93 mmol), imidazole (891.8 mg, 13.1 mmol) and 4-dimethylaminopyridine (DMAP) (8.0 mg, 65.5 µmol) were added to a solution of 723) containing some impurity (264.4 mg, 1.31 mmol) in N,N-dimethylformamide (DMF) (2.62 mL) at r.t. After the mixture was stirred at 70°C for 3.5 h, the reaction was quenched with H2O, and the whole was diluted with EtOAc. The mixture was extracted with EtOAc. The organic layer was washed with H2O for 3 times, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane–EtOAc=5 : 1 to 4 : 1) to give 8 (227.0 mg, 717.2 µmol, 55% yield) as a colorless oil (Chart 4).
1H-NMR (500 MHz, CDCl3) δ: 4.92 (dd, J=4.6, 4.6 Hz, 1H), 3.97–3.81 (m, 5H), 3.28 (m, 2H), 3.01 (ddd, J=8.9, 8.9, 2.8 Hz, 1H), 2.02–1.94 (m, 2H), 1.89–1.81 (m, 1H), 1.73–1.61 (m, 3H), 1.46–1.37 (m, 2H), 0.88 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C-NMR (125 MHz, CDCl3) δ: 104.9, 82.6, 71.5, 67.9, 65.1, 65.0, 33.8, 30.1, 26.6, 26.0 (3C), 25.9, 18.1, −3.8, −4.5; HR-MS (ESI) Calcd for C16H32O4SiNa [M+Na]+ 339.1962. Found 339.1959.
Synthesis of 1024)To a solution of acetal 8 (556.0 mg, 1.76 mmol) and 2,6-lutidine (1.23 mL, 10.6 mmol) in CH2Cl2 (17.6 mL) was added trimethylsilyl trifluoromethanesulfonate (TMSOTf) (1.27 mL, 7.04 mmol) slowly at 0°C. The reaction mixture was stirred at 0°C for 30 min, then H2O (20 mL) was added. The mixture was stirred at 0°C for 2.5 h and extracted with EtOAc. The combined organic layer was washed with brine and dried over MgSO4, and concentrated in vacuo. The residue containing aldehyde 9 was used for the next reaction without purification.
PPh3 (1.85 g, 7.04 mmol) and CBr4 (1.18 g, 3.52 mmol) in CH2Cl2 (10.5 mL) were stirred at 0°C for 1 h. To the solution was added Et3N (944.0 µL, 9.33 mmol) at 0°C, and a solution of the crude aldehyde 9 in CH2Cl2 (7.4 mL, total with rinses) was transferred into the reaction mixture via cannula at the same temperature. The mixture was further stirred at 0°C for 12.5 h, and then quenched with sat. NH4Cl aq. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane–EtOAc=20 : 1→2 : 1) to give dibromoolefin 10 (506.7 mg, 1.18 mmol, 67% yield, 2 steps) and aldehyde 9 (28.5 mg, 105.0 µmol, 6% yield, 2 steps) as pale yellow oils.
Data for 101H-NMR (500 MHz, CDCl3) δ: 6.41 (dd, J=7.3, 7.3 Hz, 1H), 3.88 (dddd, J=11.3, 4.3, 1.5, 1.5 Hz, 1H), 3.33–3.23 (m, 2H), 2.97 (ddd, J=8.9, 8.9, 2.4 Hz, 1H), 2.29–2.14 (m, 2H), 2.05–1.90 (m, 2H), 1.70–1.62 (m, 2H), 1.46–1.37 (m, 2H), 0.88 (s, 9H), 0.06 (s, 6H); 13C-NMR (125 MHz, CDCl3) δ: 138.9, 88.8, 82.0, 71.4, 67.9, 33.8, 30.4, 29.4, 26.0 (3C), 25.9, 18.1, –3.8, –4.5; HR-MS (ESI) Calcd for C15H28Br2O2SiNa [M+Na]+ 449.0118. Found 449.0115.
Synthesis of 1dn-BuLi (2.45 M in n-hexane, 1.17 mL, 2.85 mmol) was added to a solution of dibromoolefin 10 (489 mg, 1.14 mmol) in THF (5.7 mL) at −78°C under an argon atmosphere. Stirring was continued for 1 h, and then MeI (213.0 µL, 3.43 mmol) was added at the same temperature. The mixture was warmed to r.t., and further stirred for 4.5 h, and then the reaction mixture was quenched with sat. NH4Cl aq. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was submitted to the next reaction without purification.
n-Bu4NF (1.0 M in THF, 1.71 mL, 1.71 mmol) was added to a solution of the crude in THF (5.7 mL) at 0°C. After the mixture was stirred at r.t. for 13 h, the reaction mixture was quenched with H2O, and the whole was diluted with EtOAc. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane–EtOAc=5 : 1 to 2 : 1) to give 1d (186.8 mg, 1.11 mmol, 97% yield, 2 steps) as a pale yellow oil.
Data for 1d1H-NMR (500 MHz, CDCl3) δ: 3.89 (dddd, J=11.3, 3.7, 1.8, 1.8 Hz, 1H), 3.38–3.30 (m, 2H), 3.11 (ddd, J=8.9, 8.9, 2.8 Hz, 1H), 2.34 (m, 1H), 2.24 (m, 1H), 2.11 (m, 1H), 2.01 (m, 1H), 1.78 (dd, J=2.8, 2.8 Hz, 3H), 1.71–1.59 (m, 4H), 1.42 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ: 81.1, 79.3, 75.7, 70.3, 67.7, 33.0, 31.7, 25.8, 14.7, 3.7; HR-MS (ESI) Calcd for C10H16O2Na [M+Na]+ 191.1043. Found 191.1046.
Synthesis of 1en-BuLi (2.45 M in n-hexane, 1.64 mL, 4.01 mmol) was added to a solution of dibromoolefin 10 (687.0 mg, 1.60 mmol) in THF (16 mL) at −78°C under an argon atmosphere. Stirring was continued for 1 h, and then the reaction mixture was quenched with sat. NH4Cl aq. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane–EtOAc=98 : 2 to 10 : 1) to give 12 (403.6 mg, 1.50 mmol, 94% yield) as a pale yellow oil (Chart 5).
PhI (151 µL, 1.35 mmol) and PdCl2(Ph3P)2 (14.6 mg, 20.8 µmol) were added to a solution of 12 (279.0 mg, 1.04 mmol) in Et3N (3.5 mL) at r.t. under an argon atmosphere, and the solution was stirred at r.t. for 5 min. To the solution was added CuI (7.9 mg, 41.6 µmol). After stirring for 2.5 h, the reaction was quenched with sat. NH4Cl aq., and the whole was diluted with EtOAc. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was submitted to the next reaction without purification.
n-Bu4NF (1.0 M in THF, 1.56 mL, 1.56 mmol) was added to a solution of the crude in THF (5.2 mL) at 0°C. After the mixture was stirred at r.t. for 18 h, the reaction mixture was quenched with H2O, and the whole was diluted with EtOAc. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane–EtOAc=5 : 1 to 2 : 1) to give 1e (225.6 mg, 980 µmol, 94% yield, 2 steps) as a brown oil.
Data for 1e1H-NMR (500 MHz, CDCl3) δ: 7.40–7.38 (m, 2H), 7.30–7.26 (m, 3H), 3.92 (dddd, J=11.3, 4.3, 1.8, 1.8 Hz, 1H), 3.43–3.32 (m, 2H), 3.18 (ddd, J=8.9, 8.9, 2.8 Hz, 1H), 2.62 (ddd, J=17.1, 7.6, 5.5 Hz, 1H), 2.52 (ddd, J=17.1, 7.9, 7.9 Hz, 1H), 2.20–2.10 (m, 2H), 1.78–1.67 (m, 3H), 1.54 (m, 1H), 1.47–1.39 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ: 131.7 (2C), 128.3 (2C), 127.7, 124.1, 90.3, 81.2, 80.8, 70.4, 67.8, 33.1, 31.5, 25.8, 15.4; HR-MS (ESI) Calcd for C15H18O2Na [M+Na]+ 253.1199. Found 253.1204.
Synthesis of 1fPhenylethynylMgBr (1.0 M in THF, 1.80 mL, 1.80 mmol) was added to a solution of the crude aldehyde 5 (310.1 mg, 1.20 mmol) in THF (11 mL) at 0°C under an argon atmosphere. After the reaction was stirred for 6 h, the reaction was quenched with sat. NH4Cl aq. The mixture was extracted with Et2O and the combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was submitted to the next reaction without purification (Chart 6).
Sodium hydride (NaH) (50%, 115.2 mg, 2.40 mmol) was added to a solution of the crude product in THF (2.4 mL) at 0°C, and the mixture was stirred for 30 min at the same temperature. Then, MeI (112.1 µL, 1.80 mmol) was added at 0°C. After the mixture was stirred at r.t. for 3 h, the reaction mixture was quenched with H2O, and the whole was diluted with EtOAc. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was submitted to the next reaction without purification.
n-Bu4NF (1.0 M in THF, 6.0 mL, 6.0 mmol) was added to a solution of the crude product in THF (6 mL) at 0°C. After the mixture was stirred at r.t. for 12 h, the reaction mixture was quenched with H2O, and the whole was diluted with EtOAc. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; toluene–EtOAc=2 : 1) to give 3,5-syn-OMe 1f (102.0 mg, 391.8 µmol, 33% yield, 3 steps), 3,5-anti-OMe (133.8 mg, 514.0 µmol, 43% yield, 3 steps) and the mixture of both stereoisomers (26.6 mg, 102.2 µmol) as pale brown oils.
Data for 1f1H-NMR (500 MHz, CDCl3) δ: 7.47–7.43 (m, 2H), 7.33–7.29 (m, 3H), 4.43 (dd, J=9.8, 3.1 Hz, 1H), 3.90 (dddd, J=11.3, 4.3, 1.8, 1.8 Hz, 1H), 3.50 (s, 3H), 3.37–3.31 (m, 2H), 3.23 (ddd, J=9.2, 7.2, 4.0 Hz), 2.66 (br s, 1H), 2.37 (ddd, J=15.0, 9.8, 4.0 Hz), 2.13 (m, 1H), 1.98 (ddd, J=15.0, 7.3, 2.8 Hz, 1H), 1.74–1.65 (m, 2H), 1.41 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ: 131.8 (2C), 128.5, 128.4 (2C), 122.8, 87.9, 85.9, 79.4, 70.7, 68.4, 67.7, 56.6, 40.3, 32.8, 25.7; HR-MS (ESI) Calcd for C16H20O3Na [M+Na]+ 283.1305. Found 283.1310.
Synthesis of 15DIBAH (1.02 M in n-hexane, 14.6 mL, 14.9 mmol) was slowly added to a solution of the ester 4 (1.96 g, 6.79 mmol) in CH2Cl2 (34 mL) at −78°C under an argon atmosphere. After the reaction was stirred for 2 h, SiO2, H2O (4 mL), and i-PrOH (6 mL) were added and the mixture was warmed to r.t. After addition of MgSO4 and Celite, the mixture was filtrated through a Celite pad, and concentrated in vacuo. The residue containing aldehyde 5 was submitted to the next reaction without purification.
EthynylMgBr (0.5 M in THF, 16.3 mL, 8.15 mmol) was added to a solution of the crude aldehyde 5 in THF (52 mL) at 0°C under an argon atmosphere. After the reaction was stirred for 1.5 h, the reaction was quenched with sat. NH4Cl aq. The aqueous layer was extracted with Et2O and the combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane–EtOAc=20 : 1 to 5 : 1) to give 3,5-syn-OH 15 (676.3 mg, 2.38 mmol, 35% yield, 2 steps) as a pale yellow oil, 3,5-anti-OH (711.6 mg, 2.50 mmol, 37% yield, 2 steps) as a pale yellow solid and the mixture of both stereoisomers (182.6 mg, 641.9 µmol) as a pale yellow oil (Chart 7).
1H-NMR (500 MHz, CDCl3) δ: 4.63 (ddd, J=11.0, 5.2, 2.8 Hz, 1H), 3.89 (dddd, J=11.3, 4.3, 1.8, 1.8 Hz, 1H), 3.80 (br d, J=7.9 Hz, 1H), 3.64 (ddd, J=9.8, 9.8, 2.4 Hz, 1H), 3.42–3.33 (m, 2H), 2.46 (d, J=2.1 Hz, 1H), 2.17 (ddd, J=14.7, 5.8, 2.4 Hz, 1H), 2.02 (m, 1H), 1.83 (ddd, J=14.3, 9.8, 3.4 Hz, 1H), 1.73–1.64 (m, 2H), 1.47 (m, 1H), 0.88 (s, 9H), 0.07 (d, J=2.4 Hz, 6H); 13C-NMR (125 MHz, CDCl3) δ: 84.7, 81.2, 72.7, 70.9, 67.8, 61.2, 38.2, 33.4, 25.9 (3C), 25.5, 18.1, –3.8, –4.6; HR-MS (ESI) Calcd for C15H28O3Na [M+Na]+ 307.1700. Found 307.1699.
Synthesis of 16NaOH aq. (50%, 1.62 mL, 20.2 mmol) and tetra-n-butylammonium iodide (n-Bu4NI) (87.8 mg, 237.7 µmol) was added to a solution of 15 (676.3 mg, 2.38 mmol) in benzene (1.5 mL) at r.t. After vigorous stirring for 20 min, Me2SO4 (406 µL, 4.28 mmol) was added, and the resultant mixture was stirred at 50°C for 42 h. The reaction was quenched with NH3 aq. (28%) and stirred at r.t. for 2 h. The aqueous layer was extracted with Et2O and the combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane–EtOAc=98 : 2 to 1 : 1) to give 16 (623.2 mg, 2.09 mmol, 88% yield) as a pale yellow oil.
Data for 161H-NMR (500 MHz, CDCl3) δ: 4.23 (ddd, J=10.1, 3.1, 2.1 Hz, 1H), 3.86 (dddd, J=11.3, 4.0, 1.8, 1.8 Hz, 1H), 3.40 (s, 3H), 3.34–3.19 (m, 3H), 2.40 (d, J=1.8 Hz, 1H), 2.31 (ddd, J=14.3, 10.1, 2.1 Hz, 1H), 1.99 (m, 1H), 1.70–1.56 (m, 3H), 1.44 (m, 1H), 0.88 (s, 9H), 0.06 (d, J=4.9 Hz, 6H); 13C-NMR (125 MHz, CDCl3) δ: 83.4, 78.4, 73.3, 71.7, 67.8, 67.0, 56.2, 39.0, 33.8, 25.8, 26.0 (3C), 18.1, −3.9, −4.5; HR-MS (ESI) Calcd for C16H30O3SiNa [M+Na]+ 321.1856. Found 321.1848.
Synthesis of 1g4-Iodoanisole (104.1 mg, 446.0 µmol) and PdCl2(Ph3P)2 (12.1 mg, 17.2 µmol) was added to a solution of 16 (102.5 mg, 343.4 µmol) in Et3N (1.1 mL) at r.t. under an argon atmosphere, stirred for 15 min, and then CuI (3.6 mg, 18.9 µmol) was added. After stirring for 19 h at 50°C, the reaction was quenched with sat. NH4Cl aq., and the whole was diluted with EtOAc. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was submitted to the next reaction without purification.
n-Bu4NF (1.0 M in THF, 1.72 mL, 1.72 mmol) was added to a solution of the crude product in THF (1.7 mL) at 0°C. After the mixture was stirred at r.t. for 15 h, the reaction mixture was quenched with H2O, and the whole was diluted with EtOAc. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane–EtOAc=4 : 1 to 3 : 1) to give 1g (75.6 mg, 260.0 µmol, 76% yield, 2 steps) as a brown oil.
Data for 1g1H-NMR (500 MHz, CDCl3) δ: 7.37 (dd, J=8.9, 2.8 Hz, 2H), 6.83 (dd, J=8.9, 2.8 Hz, 2H), 4.40 (dd, J=9.8, 3.1 Hz, 1H), 3.89 (dddd, J=11.3, 4.0, 1.8, 1.8 Hz, 1H), 3.81 (s, 3H), 3.49 (s, 3H), 3.34 (m, 2H), 3.22 (ddd, J=11.3, 7.0, 4.6 Hz, 1H), 2.64 (br s, 1H), 2.34 (ddd, J=14.7, 9.8, 4.3 Hz, 1H), 2.13 (m, 1H), 1.99 (ddd, J=14.7, 7.0, 3.1 Hz, 1H), 1.74–1.66 (m, 2H), 1.40 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ: 159.8, 133.34, 133.30, 114.9, 114.0 (2C), 86.5, 85.9, 79.6, 70.7, 68.5, 67.8, 56.6, 55.4, 40.6, 32.8, 25.7; HR-MS (ESI) Calcd for C17H22O4Na [M+Na]+ 313.1410. Found 313.1418.
Synthesis of 1hcis-1-Bromopropene (48.6 µL, 572.0 µmol) and PdCl2(Ph3P)2 (14.8 mg, 21.1 µmol) was added to a solution of 16 (131.3 mg, 439.9 µmol) in Et3N (1.5 mL) at r.t. under an argon atmosphere, stirred for 15 min, and then CuI (4.9 mg, 25.7 µmol) was added. After stirring for 19 h at 50°C, the reaction was quenched with sat. NH4Cl aq., and the whole was diluted with EtOAc. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was submitted to the next reaction without purification.
n-Bu4NF (1.0 M in THF, 2.2 mL, 2.2 mmol) was added to a solution of the crude product in THF (2.2 mL) at 0°C. After the mixture was stirred at r.t. for 15 h, the reaction mixture was quenched with H2O, and the whole was diluted with EtOAc. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane–EtOAc=4 : 1 to 3 : 1) to give 1h (60.6 mg, 270.0 µmol, 61% yield, 2 steps) as a brown oil.
Data for 1h1H-NMR (500 MHz, CDCl3) δ: 6.00 (dq, J=10.7, 6.7 Hz, 1H), 5.51 (ddq, J=11.0, 1.8, 1.8 Hz, 1H), 4.36 (ddd, J=9.8, 2.4, 2.4 Hz, 1H), 3.89 (m, 1H), 3.45 (s, 3H), 3.35–3.29 (m, 2H), 3.19 (ddd, J=11.3, 6.7, 4.3 Hz, 1H), 2.58 (br d, J=3.7 Hz, 1H), 2.29 (ddd, J=14.7, 10.1, 4.6 Hz, 1H), 2.13 (m, 1H), 1.94 (ddd, J=15.6, 7.0, 3.0 Hz, 1H), 1.87 (dd, J=6.7, 1.5 Hz, 3H), 1.71–1.65 (m, 2H), 1.39 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ: 139.1, 109.6, 92.4, 82.7, 79.7, 70.7, 68.6, 67.8, 56.5, 40.7, 32.8, 25.7, 16.1; HR-MS (ESI) Calcd for C13H20O3Na [M+Na]+ 247.1305. Found 247.1308.
Synthesis of 1in-Bu4NF (1.0 M in THF, 910.6 µL, 910.6 µmol) was added to a solution of 16 (90.6 mg, 303.5 µmol) in THF (2.1 mL) at 0°C. After the mixture was stirred at r.t. for 3 h, the reaction mixture was quenched with H2O, and the whole was diluted with EtOAc. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane–EtOAc=15 : 1 to 4 : 1) to give 1i (45.3 mg, 245.9 µmol, 81% yield) as a pale yellow oil.
Data for 1i1H-NMR (500 MHz, CDCl3) δ: 4.20 (ddd, J=10.1, 3.1, 2.1 Hz, 1H), 3.88 (m, 1H), 3.44 (s, 3H), 3.35–3.28 (m, 2H), 3.17 (ddd, J=11.3, 7.3, 4.0 Hz, 1H), 2.46 (d, J=2.1 Hz, 1H), 2.33 (br s, J=4.3 Hz, 1H), 2.28 (ddd, J=14.7, 10.1, 4.3 Hz, 1H), 2.13 (m, 1H), 1.89 (ddd, J=15.0, 7.6, 3.1 Hz, 1H), 1.71–1.65 (m, 2H), 1.38 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ: 82.7, 79.3, 73.9, 70.7, 67.7 (2C), 56.6, 40.1, 32.9, 25.7; HR-MS (ESI) Calcd for C10H16O3Na [M+Na]+ 207.0992. Found 207.0984.
Synthesis of 1jAgNO3 (2.4 mg, 14.1 µmol) and N-bromosuccinimide (NBS) (37.6 mg, 211.5 µmol) were added to a solution of 16 (52.6 mg, 176.2 µmol) in acetone (1.8 mL) at r.t. under an argon atmosphere. After the mixture was stirred for 3 h, the reaction mixture was quenched with H2O, and the whole was diluted with EtOAc. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, the mixture was filtrated through a short pad of silica gel and eluted with the mixture of n-hexane and EtOAc (10 : 1) and the filtrate was concentrated in vacuo. The residue was submitted to the next reaction without purification.
n-Bu4NF (1.0 M in THF, 528.6 µL, 528.6 µmol) was added to a solution of the crude product in THF (1.2 mL) at 0°C. After the mixture was stirred at r.t. for 22 h, the reaction mixture was quenched with H2O, and the whole was diluted with EtOAc. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane–EtOAc=5 : 1 to 3 : 1) to give 1j (38.8 mg, 147.5 µmol, 84% yield, 2 steps) as a pale yellow oil.
Data for 1j1H-NMR (500 MHz, C6D6) δ: 4.34 (dd, J=10.4, 2.8 Hz, 1H), 3.62 (dddd, J=11.3, 4.6, 1.5, 1.5 Hz, 1H), 3.19 (s, 3H), 3.18 (m, 1H), 2.97 (m, 2H), 2.44 (ddd, J=14.7, 10.4, 3.1 Hz, 1H), 1.79 (ddd, J=14.7, 8.9, 2.8 Hz, 1H), 1.73 (m, 1H), 1.37–1.28 (m, 1H), 1.14–1.01 (m, 2H); 13C-NMR (125 MHz, C6D6) δ: 80.5, 78.7, 70.7, 68.6, 67.5, 56.4, 45.3, 40.1, 33.2, 25.9; HR-MS (ESI) Calcd for C10H15BrO3Na [M+Na]+ 285.0097. Found 285.0100.
Synthesis of 1kn-BuLi (2.32 M in n-hexane, 457.7 µL, 1.06 mmol) was added to a solution of 16 (211.3 mg, 707.9 µmol) in THF (3.5 mL) at −78°C under an argon atmosphere. After stirring for 30 min at the same temperature, B(OMe)3 (118.6 µL, 1.06 mmol) was added, and the mixture was warmed to r.t. and stirred for 1 h. To another 2-necked round-bottom flask equipped with a dropping funnel and a reflux condenser were added N-methyliminodiacetic acid (312.5 mg, 2.12 mmol) and dimethyl sulfoxide (DMSO) (3.5 mL), and the reaction mixture was stirred at 160°C. Into this solution was added the above-mentioned reaction mixture of 16 dropwise via cannula and stirred at 160°C for 1 h, 115°C for 4 h. The reaction mixture was cooled to r.t., and diluted with EtOAc. The mixture was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane–EtOAc=20 : 1 to 2 : 98) to give MIDA boronate (containing some impurity, 154.8 mg) as a white solid and 16 (121.9 mg, 408.0 µmol, 58%).
HF·pyridine (70%, 682.0 µL, 682.0 µmol) was added to a solution of the MIDA boronate in THF (3.4 mL) at r.t. After stirring for 4 h, the reaction mixture was quenched with sat. NaHCO3 aq. at 0°C. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; MeCN–EtOAc=0 : 1 to 1 : 5) to give 1k (69.1 mg, 203.7 µmol, 29% yield, 2 steps) as a white solid.
Data for 1k1H-NMR (500 MHz, CDCl3) δ: 4.22 (dd, J=9.8, 3.4 Hz, 1H), 3.86 (m, 1H), 3.82 (d, J=16.5 Hz, 2H), 3.76 (dd, J=16.2, 1.2 Hz, 2H), 3.43 (s, 3H), 3.34–3.27 (m, 2H), 3.16 (ddd, J=8.9, 7.6, 3.7 Hz, 1H), 3.08 (s, 3H), 2.27 (ddd, J=14.7, 9.8, 4.0 Hz, 1H), 2.12 (m, 1H), 1.86 (ddd, J=14.7, 7.6, 3.1 Hz, 1H), 1.69–1.64 (m, 2H), 1.36 (m, 1H); 13C-NMR (125 MHz, CDCl3) δ: 166.2 (2C), 86.1, 79.2, 77.7, 70.6, 68.1, 67.8, 61.5 (2C), 56.9, 47.6, 39.9, 33.0, 25.7; HR-MS (ESI) Calcd for C15H22BNO7Na [M+Na]+ 362.1384. Found 362.1375.
General Procedure for Gold-Catalyzed Cyclization ReactionCondition AA Schlenk tube was dried by a heat-gun under reduced pressure and filled with argon. The tube was charged with alkynylalcohol (1 eq.) and THF (0.1 M) under an argon atmosphere at r.t. [(Ph3PAu)3O]BF4 (5 mol%) was subsequently added, and the mixture was stirred at 60°C. After the reaction stopped (determined by TLC), the mixture was filtrated through a short pad of silica gel and eluted with Et2O, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane–Et2O=1 : 0 to 0 : 1) to give the corresponding cyclic enol ether.
Condition BA Schlenk tube was dried by a heat-gun under reduced pressure and filled with argon. To the tube was charged with alkynylalcohol (1 eq.) and THF (0.1 M) under an argon atmosphere at r.t. HFIP (2 eq.) was added to the solution. [(Ph3PAu)3O]BF4 (5 mol%) was subsequently added and the mixture was stirred at 60°C. After the reaction stopped (determined by TLC), the mixture was filtrated through a short pad of silica gel and eluted with Et2O and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane–Et2O=1 : 0 to 0 : 1) to give the corresponding cyclic enol ether.
Synthesis of 2a and 3a2a and 3a were obtained from 1a as a pale yellow oil (8.4 mg, 81%, 13 : 87) under the condition A, as a pale yellow oil (7.8 mg, 39.3 µmol, 92%, 25 : 75) under the condition B.
Data for 2a1H-NMR (500 MHz, C6D6) δ: 4.53 (q, J=6.4 Hz, 1H), 3.77 (ddd, J=11.6, 9.2, 4.3 Hz, 1H), 3.64 (m, 1H), 3.41 (m, 1H), 3.15 (m, 1H), 3.08 (m, 1H), 3.07 (s, 3H), 2.44 (m, 1H), 1.93 (m, 1H), 1.71 (m, 1H), 1.70 (d, J=6.4 Hz, 3H), 1.51 (m, 1H), 1.42–1.29 (m, 2H); 13C-NMR (125 MHz, C6D6) δ: 149.8, 108.6, 79.8, 78.1, 74.4, 67.9, 55.4, 36.9, 30.1, 26.0, 10.1; HR-MS (ESI) Calcd for C11H18O3Na [M+Na]+ 221.1148. Found 221.1143 (as a mixture of 2a, 3a).
Data for 3a1H-NMR (500 MHz, C6D6) δ: 4.78 (m, 1H), 4.20 (m, 1H), 3.64 (m, 1H), 3.57 (ddd, J=13.7, 6.7, 4.3 Hz, 1H), 3.41 (ddd, J=12.8, 6.4, 3.1 Hz, 1H), 3.16 (s, 3H), 2.94 (ddd, J=11.6, 11.6, 2.4 Hz, 1H), 2.44 (ddd, J=13.7, 10.7, 6.4 Hz, 1H), 2.23 (m, 1H), 1.84 (m, 1H), 1.71 (dd, J=1.2, 1.2 Hz, 3H), 1.42–1.28 (m, 2H), 1.13 (m, 1H); 13C-NMR (125 MHz, C6D6) δ: 155.5, 106.6, 79.4, 78.9, 73.9, 67.6, 55.8, 39.8, 31.4, 26.1, 21.9.
Synthesis of 2b and 3b2b and 3b were obtained from 1b under the condition B as a pale yellow oil (6.5 mg, 32.8 µmol, 87%, 32 : 68).
Data for 2b1H-NMR (500 MHz, C6D6) δ: 4.89 (ddd, J=13.4, 6.7, 1.2 Hz, 1H), 3.72–3.62 (m, 1H), 3.59–3.47 (m, 2H), 3.11 (s, 3H), 3.23–2.96 (m, 2H), 2.37 (m, 1H), 1.98 (m, 1H), 1.80 (m, 1H), 1.76 (dd, J=6.7, 1.2 Hz, 3H), 1.48–1.30 (m, 2H), 1.21–1.12 (m, 1H); 13C-NMR (125 MHz, C6D6) δ: 151.0, 101.7, 76.9, 76.7, 76.4, 67.7, 56.2, 36.4, 30.1, 25.5, 9.8; HR-MS (ESI) Calcd for C11H18O3Na [M+Na]+ 221.1148. Found 221.1149 (as a mixture of 2b, 3b).
Data for 3b1H-NMR (500 MHz, C6D6) δ: 4.95 (d, J=4.9 Hz, 1H), 3.78 (m, 1H), 3.72–3.62 (m, 2H), 3.23–3.17 (m, 1H), 3.19 (s, 3H), 3.03–2.96 (m, 1H), 2.34 (ddd, J=13.5, 5.5, 2.4 Hz, 1H), 2.02 (m, 1H), 1.94–1.90 (m, 1H), 1.67 (s, 3H), 1.48–1.30 (m, 2H), 1.21–1.12 (m, 1H); 13C-NMR (125 MHz, C6D6) δ: 155.8, 110.5, 80.1, 79.4, 74.9, 67.5, 56.1, 38.4, 31.5, 26.0, 21.6.
Synthesis of 3c3c was obtained from 1c under the condition B (temperature: 80°C) as a pale yellow oil (4.6 mg, 25.2 µmol, 63%).
Data for 3c1H-NMR (500 MHz, C6D6) δ: 5.28 (s, 1H), 3.51–3.43 (m, 2H), 3.19 (ddd, J=9.5, 7.0, 5.2 Hz, 1H), 2.99 (dd, J=16.5, 7.0 Hz, 1H), 2.81 (dd, J=16.5, 5.5 Hz, 1H), 2.75 (ddd, J=11.6, 11.6, 2.4 Hz, 1H), 1.69 (m, 1H), 1.48 (s, 3H), 1.24 (m, 1H), 1.14 (m, 1H), 1.01 (m, 1H); 13C-NMR (125 MHz, C6D6) δ: 194.1, 167.6, 108.6, 82.4, 76.3, 66.7, 50.4, 30.6, 24.8, 22.5; HR-MS (ESI) Calcd for C10H14O3Na [M+Na]+ 205.0835. Found 205.0839.
Synthesis of 2d and 3d2d and 3d were obtained from 1d under the condition B as a pale yellow oil (16.9 mg, 100.5 µmol, 75%, 91 : 9).
Data for 2d1H-NMR (500 MHz, C6D6) δ: 4.48 (dq, J=6.7, 1.8 Hz, 1H), 3.66 (m, 1H), 3.14–3.04 (m, 2H), 2.96 (ddd, J=11.0, 9.2, 4.6 Hz, 1H), 2.12 (m, 1H), 2.02 (ddd, J=14.0, 4.9, 2.8 Hz, 1H), 1.96 (m, 1H), 1.87 (m, 1H), 1.73 (dd, J=6.7, 2.1 Hz, 3H), 1.52 (m, 1H), 1.44–1.36 (m, 2H), 1.17 (m, 1H); 13C-NMR (125 MHz, C6D6) δ: 151.9, 102.5, 78.9, 78.3, 67.8, 30.4, 30.3, 29.2, 25.9, 10.3; HR-MS (ESI) Calcd for C10H18O3Ag [M+H2O+Ag]+ 293.0301. Found 293.0309 (as a mixture of 2d and 3d).
Data for 3d1H-NMR (500 MHz, C6D6) δ: 4.89 (m, 1H), 3.71–3.68 (m, 1H), 3.41 (ddd, J=10.7, 9.2, 4.6 Hz, 1H), 3.20 (ddd, J=8.9, 7.3, 4.6 Hz, 1H), 3.14–3.01 (m, 1H), 2.16–2.08 (m, 1H), 1.95–1.91 (m, 1H), 1.75–1.71 (m, 3H), 1.67–1.59 (m, 1H), 1.47–1.28 (m, 4H), 1.22–1.15 (m, 1H); 13C-NMR (125 MHz, C6D6) δ: 134.2, 106.9, 82.8, 79.4, 67.4, 32.0, 30.5, 30.2, 23.1, 14.4.
Synthesis of 2e and 3e2e and 3e were obtained from 1e under the condition B as a pale yellow solid (37.4 mg, 162.4 µmol, 89%, 86 : 14).
Data for 2e1H-NMR (500 MHz, C6D6) δ: 7.80 (m, 2H), 7.29 (m, 2H), 7.09 (m, 1H), 5.35 (d, J=1.5 Hz, 1H), 3.63 (m, 1H), 3.18 (ddd, J=10.4, 9.2, 4.3 Hz, 1H), 3.03 (ddd, J=11.9, 11.9, 1.8 Hz, 1H), 2.95 (ddd, J=10.7, 9.2, 4.9 Hz, 1H), 2.17 (m, 1H), 2.09 (ddd, J=14.7, 5.5, 3.7 Hz, 1H), 1.92 (m, 1H), 1.86 (m, 1H), 1.53 (m, 1H), 1.44–1.30 (m, 2H), 1.14 (m, 1H); 13C-NMR (125 MHz, C6D6) δ: 153.3, 137.0, 128.9 (2C), 128.5 (2C), 126.1, 108.1, 78.4, 77.5, 67.7, 30.1, 29.8, 29.6, 25.8; HR-MS (ESI) Calcd for C15H18O2Na [M+Na]+ 253.1199. Found 253.1201 (as a mixture of 2e, 3e).
Data for 3e1H-NMR (500 MHz, C6D6) δ: 7.62 (m, 2H), 7.31–7.27 (m, 1H), 7.13–7.11 (m, 2H), 5.64 (dd, J=7.3, 5.5 Hz, 1H), 3.69 (dddd, J=11.0, 4.9, 1.5, 1.5 Hz, 1H), 3.26 (m, 1H), 3.10–3.00 (m, 2H), 2.21–2.04 (m, 4H), 1.62–1.58 (m, 1H), 1.44–1.30 (m, 2H), 1.23 (m, 1H); 13C-NMR (125 MHz, C6D6) δ: 157.8, 137.5, 125.1, 110.1, 83.0, 80.9, 67.4, 32.9, 31.2, 26.3, 21.8 (4 carbons are missing due to overlapping with solvent peak).
Synthesis of 2f and 3f2f and 3f were obtained from 1f under the condition B (temperature: 80°C, solvent: dioxane) as a pale yellow oil (6.7 mg, 25.7 µmol, 79%, 35 : 65).
Data for 3f1H-NMR (500 MHz, C6D6) δ: 7.66 (m, 2H), 7.28 (m, 1H), 7.12 (m, 2H), 5.61 (dd, J=3.4, 1.2 Hz, 1H), 4.26 (ddd, J=10.1, 3.1, 3.1 Hz, 1H), 3.66 (m, 1H), 3.59 (m, 1H), 3.53 (ddd, J=9.5, 6.1, 4.0 Hz, 1H), 3.19 (s, 3H), 2.99 (m, 1H), 2.49 (m, 1H), 2.17 (m, 1H), 1.92 (m, 1H), 1.55–1.44 (m, 1H), 1.39–1.29 (m, 1H), 1.18 (m, 1H); 13C-NMR (125 MHz, C6D6) δ: 156.9, 137.3, 128.4 (2C), 126.0 (2C), 107.9, 80.5, 78.8, 74.0, 67.6, 56.0, 38.9, 31.0, 26.1 (1 carbon is missing due to overlapping with solvent peak); HR-MS (ESI) Calcd for C16H20O3Na [M+Na]+ 283.1305. Found 283.1305 (as a mixture of 2f, 3f).
Synthesis of 2g and 3g2g and 3g were obtained from 1g under the condition B (temperature: 80°C, solvent: dioxane) as a pale yellow oil (5.6 mg, 19.3 µmol, 64%, 9 : 91).
Data for 3g1H-NMR (500 MHz, C6D6) δ: 7.63 (dd, J=9.2, 2.2 Hz, 2H), 6.79 (dd, J=8.9, 2.2 Hz, 2H), 5.56 (dd, J=3.4, 1.2 Hz, 1H), 4.30 (dd, J=10.1, 3.1 Hz, 1H), 3.70–3.61 (m, 2H), 3.56 (ddd, J=9.5, 5.8, 4.0 Hz, 1H), 3.28 (s, 3H), 3.22 (s, 3H), 3.01 (ddd, J=12.2, 12.2, 2.4 Hz, 1H), 2.52 (ddd, 15.9, 8.2, 5.8 Hz, 1H), 2.20 (m, 1H), 1.96 (m, 1H), 1.51 (m, 1H), 1.42–1.30 (m, 1H), 1.20 (m, 1H); 13C-NMR (125 MHz, C6D6) δ: 160.5, 157.0, 129.9, 127.4 (2C), 113.9 (2C), 106.1, 80.4, 78.9, 74.1, 67.6, 56.0, 54.8, 39.0, 31.1, 26.2; HR-MS (ESI) Calcd for C17H22O4Na [M+Na]+ 313.1410. Found 313.1403 (as a mixture of 2g, 3g).
Synthesis of 2h and 3h2h and 3h were obtained from 1h under the condition B as a pale yellow oil (14.4 mg, 64.2 µmol, 100%, 11 : 89).
Data for 3h1H-NMR (500 MHz, C6D6) δ: 5.66 (m, 1H), 5.38 (m, 1H), 4.96 (br d, J=2.8 Hz, 1H), 4.15 (ddd, J=10.6, 2.8, 2.8 Hz, 1H), 3.56 (m, 1H), 3.49 (m, 1H), 3.35 (ddd, J=10.1, 6.0, 3.2 Hz, 1H), 3.07 (s, 3H), 2.88 (ddd, J=11.5, 11.5, 2.8 Hz, 1H), 2.37 (ddd, J=13.8, 10.6, 6.4 Hz, 1H), 2.10 (m, 1H), 1.92 (dd, J=7.4, 1.8 Hz, 3H), 1.78 (m, 1H), 1.59 (m, 1H), 1.33–1.19 (m, 1H), 1.06 (m, 1H); 13C-NMR (125 MHz, C6D6) δ: 157.1, 127.5, 127.4, 112.8, 80.0, 78.8, 74.0, 67.7, 55.9, 39.1, 31.1, 26.1, 15.2; HR-MS (ESI) Calcd for C12H17O2 [M−OMe]+ 193.1223. Found 193.1224 (as a mixture of 2h, 3h).
Synthesis of 2i2i was obtained from 1i under the condition B as a pale yellow oil (4.0 mg, 21.7 µmol, 55%).
Data for 2i1H-NMR (500 MHz, C6D6) δ: 4.76 (s, 1H), 4.11 (s, 1H), 3.73 (ddd, J=11.6, 9.2, 4.3 Hz, 1H), 3.61 (dddd, J=11.3, 4.6, 1.5, 1.5 Hz, 1H), 3.44 (dd, J=3.1, 3.1 Hz, 1H), 3.20 (ddd, J=11.3, 9.2, 4.0 Hz, 1H), 3.08 (s, 3H), 3.04 (ddd, J=12.2, 12.2, 2.4 Hz, 1H), 2.40 (ddd, J=12.8, 4.0, 3.4 Hz, 1H), 1.91 (m, 1H), 1.70 (ddd, J=12.5, 12.0, 3.4 Hz, 1H), 1.50–1.31 (m, 2H), 1.10 (m, 1H); 13C-NMR (125 MHz, C6D6) δ: 156.8, 97.6, 80.2, 77.2, 73.8, 67.8, 55.7, 36.5, 29.9, 25.8; HR-MS (ESI) Calcd for C10H16O3Na [M+Na]+ 207.0992. Found 207.0996.
Synthesis of 2j2j was obtained from 1j under the condition B as a pale yellow oil (5.8 mg, 22.0 µmol, 95%).
Data for 2j1H-NMR (500 MHz, C6D6) δ: 5.08 (s, 1H), 3.65 (ddd, J=11.6, 9.2, 4.3 Hz, 1H), 3.55 (m, 1H), 3.20 (dd, J=3.4, 3.1 Hz, 1H), 3.13 (ddd, J=11.0, 9.5, 4.3 Hz, 1H), 2.87 (s, 3H), 2.96 (ddd, J=12.5, 12.1, 2.4 Hz, 1H), 2.25 (ddd, J=12.8, 4.3, 3.1 Hz, 1H), 1.95 (m, 1H), 1.51 (ddd, J=12.8, 11.6, 3.7 Hz, 1H), 1.44–1.38 (m, 1H), 1.29 (m, 1H), 1.05 (m, 1H); 13C-NMR (125 MHz, C6D6) δ: 152.6, 89.2, 80.1, 76.3, 73.5, 67.8, 55.7, 36.0, 29.7, 25.8; HR-MS (ESI) Calcd for C10H15BrO3Na [M+Na]+ 285.0097. Found 285.0094.
Synthesis of 2k2k was obtained from 1k under the condition A as a pale yellow oil (10.2 mg, 30.1 µmol, 99%).
Data for 2k1H-NMR (500 MHz, CD3CN) δ: 4.67 (s, 1H), 3.92 (dd, J=16.6, 6.9 Hz, 2H), 3.78 (dd, J=16.6, 11.0 Hz, 2H), 3.77 (m, 2H), 3.34 (m, 2H), 3.18 (s, 3H), 3.12 (ddd, J=11.3, 9.2, 4.1 Hz, 1H), 2.77 (s, 3H), 2.08–2.04 (m, 1H), 1.91–1.87 (m, 2H), 1.69 (m, 2H), 1.43 (m, 1H); 13C-NMR (125 MHz, CD3CN) δ: 170.0, 169.3, 161.6, 80.4, 79.2, 73.9, 68.3, 63.8, 63.1, 56.3, 48.1, 36.2, 29.7, 26.1 (1 carbon is missing due to overlapping with solvent peak); HR-MS (ESI) Calcd for C15H22BNO7Na [M+Na]+ 362.1384. Found 362.1371.
One-Pot Preparation of 2h from 1kA Schlenk tube was dried by a heat-gun under reduced pressure and filled with argon. A Schlenk tube was charged with alkynylalcohol 1k (20.2 mg, 59.6 µmol) and THF (600 µL) under an argon atmosphere at r.t. [(Ph3PAu)3O]BF4 (4.4 mg, 3.0 µmol) was subsequently added, and the mixture was stirred at 60°C for 13 h, then cis-1-bromopropene (6.6 µL, 77.5 µmol), Pd(OAc)2 (1.4 mg, 6.0 µmol), SPhos (4.9 mg, 11.9 µmol), and 3 M K3PO4 aq. (153.0 mL, 458.9 µmol) were added. The mixture was further stirred at 60°C for 9 h, and then cooled to r.t., and diluted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane–EtOAc=5 : 1) to give 2h (11.9 mg, 53.1 µmol, 89%) as a colorless oil (Chart 8).
1H-NMR (500 MHz, C6D6) δ: 6.75 (ddq, J=11.3, 11.3, 1.8 Hz, 1H), 5.55 (dd, J=11.5, 1.4 Hz, 1H), 5.42 (m, 1H), 3.71 (ddd, J=12.0, 9.2, 4.6 Hz, 1H), 3.56 (m, 1H), 3.39 (dd, J=3.2, 3.2 Hz, 1H), 3.10 (m, 1H), 3.00 (s, 3H), 2.98 (m, 1H), 2.38 (ddd, J=12.9, 4.1, 3.2 Hz, 1H), 1.86 (m, 1H), 1.74–1.63 (m, 2H), 1.59 (dd, J=7.4, 1.8 Hz, 3H), 1.32–1.22 (m, 1H), 1.05 (m, 1H); 13C-NMR (125 MHz, C6D6) δ: 150.2, 124.9, 123.3, 109.7, 80.1, 78.1, 74.1, 67.8, 55.6, 36.8, 29.9, 25.9, 13.5.
One-Pot Preparation of 2 from 1jSynthesis of 2fA Schlenk tube was charged with alkynylalcohol 1j (9.4 mg, 35.7 µmol) and THF (360 µL) under an argon atmosphere at r.t. HFIP (7.5 µL, 71.4 µmol) and [(Ph3PAu)3O]BF4 (2.6 mg, 1.8 µmol) were added, and the mixture was stirred at 60°C for 2 h, then PhB(OH)2 (5.5 mg, 45.1 µmol), Pd(PPh3)4 (2.1 mg, 1.8 µmol) and Cs2CO3 (33.5 mg, 102.8 µmol) were added. The mixture was further stirred at 60°C for 19 h, and then filtrated through a short pad of silica gel and eluted with Et2O and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (SiO2; n-hexane–Et2O=1 : 1) to give 2h (8.1 mg, 31.1 µmol, 86%) as a yellow solid (Chart 9).
1H-NMR (500 MHz, C6D6) δ: 7.83 (m, 2H), 7.28 (m, 2H), 7.11 (m, 1H), 5.46 (s, 1H), 3.80 (ddd, J=11.6, 9.5, 4.6 Hz, 1H), 3.62 (m, 1H), 3.46 (dd, J=3.4, 3.4 Hz, 1H), 3.19 (ddd, J=11.0, 9.2, 4.3 Hz, 1H), 3.09 (s, 3H), 3.06 (m, 1H), 2.45 (ddd, J=12.5, 4.6, 2.8 Hz, 1H), 1.92 (m, 1H), 1.74 (ddd, J=12.8, 11.6, 3.4 Hz, 1H), 1.52 (m, 1H), 1.33 (m, 1H), 1.10 (m, 1H); 13C-NMR (125 MHz, C6D6) δ: 150.7, 135.9, 129.4 (2C), 128.6 (2C), 127.0, 113.5, 79.8, 78.9, 73.8, 67.9, 55.7, 36.8, 30.0, 25.9; HR-MS (ESI) Calcd for C16H20O3Na [M+Na]+ 283.1305. Found 283.1314.
Synthesis of 2g2g was prepared from 1j (10.7 mg, 40.7 µmol) in the same manner as the synthesis of 2f as a yellow solid (9.0 mg, 31.0 µmol, 76%) (Fig. 3).
1H-NMR (500 MHz, C6D6) δ: 7.80 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.9 Hz, 2H), 5.47 (s, 1H), 3.83 (ddd, J=11.6, 9.5, 4.3 Hz, 1H), 3.64 (m, 1H), 3.51 (dd, J=3.0, 3.0 Hz, 1H), 3.34 (s, 3H), 3.22 (ddd, J=11.3, 9.5, 4.6 Hz, 1H), 3.12 (s, 3H), 3.09 (ddd, 11.3, 11.3, 2.1 Hz, 1H), 2.48 (ddd, J=12.8, 4.0, 3.1 Hz, 1H), 1.98 (m, 1H), 1.78 (ddd, J=11.6, 11.6, 3.4 Hz, 1H), 1.56 (m 1H), 1.37 (m, 1H), 1.13 (m, 1H); 13C-NMR (125 MHz, C6D6) δ: 159.1, 148.9, 130.7 (2C), 128.6, 114.1 (2C), 113.2, 79.7, 79.0, 74.0, 67.9, 55.6, 54.8, 37.0, 30.0, 25.9; HR-MS (ESI) Calcd for C17H22O4Na [M+Na]+ 313.1410. Found 313.1406.
This work was supported by JSPS KAKENHI (S) (No. 24229011), Takeda Science Foundation, The Asahi Glass Foundation, Daiichi-Sankyo Foundation of Life Sciences, Mochida Memorial Foundation, Tokyo Biochemical Research Foundation, Foundation NAGASE Science Technology Development, Sumitomo Foundation (to M.U.) and JSPS Grant-in-Aid for Young Scientists (B) (to T.S.) (No. 16K18841).
The authors declare no conflict of interest.
