General information - Studies towards the total synthesis of canataxpropellane

8. Experimental

8.1. General information

All moisture and oxygen sensitive reactions were performed in flame-dried glassware under a slight nitrogen overpressure. All reactions were stirred magnetically. Sensitive solutions, solvents or reagents were transferred via cannula or syringe. Reactions were monitored by thin-layer chromatography (TLC) or NMR of the crude mixture.

Evaporations were conducted under reduced pressure at temperatures less than 40°C, unless otherwise noted. Further dryings of the residues were accomplished using a high vacuum pump.

All solvents were purchased as the highest available grade from Sigma-Aldrich, Acros-Organics or Fisher-Chemicals. Hexane, ethyl acetate and dichloromethane for column chromatography were distilled and used without further purification. All other reagents were used as received from Sigma-Aldrich, Acros-Organics, TCI or Fisher-Chemicals unless otherwise noted.

Thin-layer chromatography (TLC) was carried out on pre-coated Merk silica gel 60 F254 to monitor all reactions. Preparative column chromatography was performed with silica gel 60 from Merk (0.040-0.063 μm, 240-400 mesh).

All NMR spectra were measured on a Bruker DPX 200, AV400 or DRX600. Chemical shifts are given in ppm and were referenced to the solvent residual peaks (CDCl31H, δ = 7.26 ppm, ¹³C, δ = 77.16 ppm; benzene-d6, ¹H, δ = 7.16 ppm, ¹³C, δ = 128.06 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constant J, integration.

Infrared spectra were recorded as thin films of pure products on an ATR-unit on a Bruker Vector 22 or Shimadzu IRAffinity 1S. High-resolution mass spectra were measured on Waters QTOF-Premier (Waters Aquity Ultra Performance, electron spray ionization).

70 8.2. Experimental procedures

8.2.1. First approach

(E)-4-((tert-butyldimethylsilyl)oxy)-3-methylbut-2-enal (181)

To a stirred solution of corresponding alcohol (211 mg, 0.97 mmol, 1 equiv.) in 2 ml of DMSO, IBX (421 mg, 1.5 mmol, 1.5 equiv.) was added in one portion. Stirring was continued for one hour. The crude mixture was filtrated through Celite and the solvent was removed under reduced pressure. Purification via flash column chromatography using 10:1 PE:EtOAc yielded 182 mg of aldehyde 181 (0.85 mmol, 87%).

1H NMR (200 MHz, CDCl3): δ = 10.07 (d, J = 8.1 Hz, 1H), 6.21 (dd, J = 8.1, 1.3 Hz, 1H), 4.18 (dd, J = 1.8, 0.8 Hz, 2H), 2.08 (s, 3H), 0.92 (s, 9H), 0.09 (s, 6H) ppm.

(E)-((4-(1,3-dithian-2-ylidene)-2-methylbut-2-en-1-yl)oxy)(tert-butyl)dimethylsilane (183)

HWE reagent 182 (324 mg, 1.27 mmol, 1.5 equiv.) was dissolved in 1.2 ml of THF and cooled to –78 °C. To this solution nBuLi (0.5 ml, 1.27 mmol, 1.5 equiv.) was added dropwise and stirring was continued at this temperature for 15 min. Aldehyde 181 (181 mg, 0.84 mmol, 1 equiv.) in 1.2 ml of THF was added dropwise to this solution.

The reaction was stirred for 1 h at –78 °C and an additional h after warming to 0 °C.

The reaction mixture was quenched with saturated aqueous NH4Cl and extracted three times with Et2O. The combined organic layers were dried over MgSO4 and the

solvent was removed under reduced pressure. Purification via flash column chromatography using 10:1 PE:EtOAc yielded 207 mg (0.65 mmol, 77%) of 183.

1H NMR (200 MHz, CDCl3): δ = 6.65 (d, J = 11.4 Hz, 1H), 6.54 – 6.38 (m, 1H), 4.10 (s, 2H), 3.05 – 2.79 (m, 4H), 2.26 – 2.03 (m, 2H), 1.71 (s, 3H), 0.92 (s, 9H), 0.91 – 0.76 (m, 2H), 0.08 (s, 6H) ppm.

2-methyl-3-((2-(trimethylsilyl)ethoxy)methoxy)propanal (176)

To a stirred solution of corresponding alcohol (778 mg, 3.53 mmol, 1 equiv.) in 7 ml of DMSO, IBX (1.48 g, 5.3 mmol, 1.5 equiv.) was added in one portion. Stirring was continued for one hour. The crude mixture was filtrated through Celite and the solvent was removed under reduced pressure. Purification via flash column chromatography using 20:1 PE:EtOAc yielded 452 mg of aldehyde 176 (2.07 mmol, 59%).

1H NMR (200 MHz, CDCl3): 9.73 (d, J = 1.6 Hz, 1H), 4.66 (s, 2H), 3.83 – 3.68 (m, 2H), 3.60 (d, J = 16.9 Hz, 1H), 2.77 – 2.51 (m, 1H), 1.14 (d, J = 7.1 Hz, 3H), 0.94 (d, J = 16.9 Hz, 1H), 0.02 (s, 9H) ppm.

Ethyl (E)-4-methyl-5-((2-(trimethylsilyl)ethoxy)methoxy)pent-2-enoate (177)

Triethyl phosphonoacetate (690 µl, 3.47 mmol, 1.7 equiv.) was added dropwise to a suspension of NaH (64 mg, 2.65 mmol, 1.3 equiv.) in 18 ml of Et2O. After stirring for 5 min aldehyde 176 (446 mg, 2.04 mmol, 1 equiv.) was added dropwise. After 1.5 h the reaction mixture was diluted with water and extracted three times with DCM. The combined organic layers were dried over MgSO4 and the solvent was removed under

reduced pressure. Purification via flash column chromatography using 12:1 PE:EtOAc yielded 487 mg (1.69 mmol, 83%) of ester 177.

1H NMR (200 MHz, CDCl3): 6.94 (dd, J = 15.8, 7.1 Hz, 1H), 5.87 (dd, J = 15.8, 1.4 Hz,

Afterwards DIBAL (3.8 ml, 3.8 mmol, 2.25 equiv.) was added dropwise and reaction was stirred for 1 h at –78 °C. The reaction was quenched with 1 ml of MeOH and warmed to room temperature. Dilution with saturated aqueous Rochelle salt solution followed, and aqueous media was extracted three times with Et2O. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. Purification via flash column chromatography using 3:1 PE:EtOAc yielded 394 mg (1.6 mmol, 95%) of alcohol 303 as a clear oil.

1H NMR (200 MHz, CDCl³): 5.74 – 5.60 (m, 2H), 4.67 (s, 2H), 4.19 – 4.03 (m, 1H), 3.68 – 3.52 (m, 2H), 3.42 (dd, J = 6.6, 2.7 Hz, 2H), 2.63 – 2.34 (m, 1H), 1.04 (d, J = 6.8 Hz, 3H), 1.02 – 0.87 (m, 2H), 0.02 (s, 9H) ppm.

(E)-4-methyl-5-((2-(trimethylsilyl)ethoxy)methoxy)pent-2-enal (178)

To a stirred solution of alcohol 303 (394 mg, 1.6 mmol, 1 equiv.) in 3 ml of DMSO, IBX (671 mg, 2.4 mmol, 1.5 equiv.) was added in one portion. Stirring was continued for 1

h. The crude mixture was filtrated through Celite and the solvent was removed under reduced pressure. Purification via flash column chromatography using 7:1 PE:EtOAc yielded 349 mg of aldehyde 178 (1.43 mmol, 89%).

1H NMR (200 MHz, CDCl3): 9.53 (d, J = 7.8 Hz, 1H), 6.86 (dd, J = 15.8, 6.7 Hz, 1H), 6.16 (ddd, J = 15.8, 7.8, 1.4 Hz, 1H), 4.67 (s, 2H), 3.76 – 3.38 (m, 4H), 2.92 – 2.58 (m, 1H), 1.14 (d, J = 6.8 Hz, 3H), 1.02 – 0.81 (m, 2H), 0.02 (s, 9H) ppm.

Trimethyl(2-(((2-methylallyl)oxy)methoxy)ethyl)silane (304)

To a stirred solution of alcohol 185 (0.3 ml, 3.57 mmol, 1 equiv.) in 2 ml of DCM were added consequently DIPEA (0.87 ml, 5 mmol, 1.4 equiv.) and SEMCl (0.69 ml, 3.9 mmol, 1.1 equiv.) dropwise at 0 °C. The reaction was stirred for 3 h at room temperature, before the reaction mixture was diluted with 1M HCl and extracted three times with DCM. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. Purification via flash column chromatography using 30:1 PE:EtOAc yielded 700 mg (3.46 mmol, 97%) of 304 as a clear oil.

1H NMR (200 MHz, CDCl3): 5.07 – 4.82 (m, 2H), 4.69 (s, 2H), 3.98 (dt, J = 0.9, 0.4 Hz, 2H), 3.78 – 3.52 (m, 2H), 1.75 (td, J = 1.0, 0.5 Hz, 3H), 1.05 – 0.85 (m, 2H), 0.02 (s, 9H) ppm.

1-((2-(trimethylsilyl)ethoxy)methoxy)propan-2-one (305)

Through the solution of the olefin 304 (700 mg, 3.46 mmol) in 24 ml DCM and 6 ml MeOH was bubbled O3 at –78 °Cuntil the solution turned blue. Then O2 was bubbled

through the solution for 10 min. Thiourea (264 mg, 3.46 mmol) was added in one portion at –78 °C and after 10 min the reaction mixture was warmed to room temperature and stirred for an additional 30 min. The reaction mixture was diluted with 1M HCl and extracted three times with DCM. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. Purification via flash column chromatography using 10:1 PE:EtOAc yielded 603 mg (2.95 mmol, 85%) of 305 as a clear oil.

1H NMR (200 MHz, CDCl3): 4.73 (s, 2H), 4.24 – 4.11 (m, 2H), 3.72 – 3.53 (m, 2H), 2.16 (s, 3H), 1.05 – 0.78 (m, 2H), 0.02 (s, 9H) ppm.

Ethyl-4-methyl-5-((2-(trimethylsilyl)ethoxy)methoxy)pent-3-enoate (186)

Triethyl phosphonoacetate (3.1 ml, 15.52 mmol, 2.1 equiv.) was added dropwise to a suspension of NaH (355 mg, 14.8 mmol, 2 equiv.) in 35 ml of Et2O. After stirring for 15 min ketone 305 (1.51 g, 7.39 mmol, 1 equiv.) was added dropwise. After 2 h the reaction mixture was diluted with water and extracted three times with DCM. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. Purification via flash column chromatography using 20:1 PE:EtOAc yielded mixture 1.86 g (6.77 mmol, 92%) of esters 186 (E/Z = 2:1).

1H NMR (200 MHz, CDCl3): 5.96 (d, J = 1.8 Hz, 2H), 5.74 (d, J = 1.4 Hz, 1H), 4.70 (s, 9H), 4.27 – 3.95 (m, 11H), 3.75 – 3.51 (m, 6H), 2.11 (d, J = 1.3 Hz, 6H), 1.97 (d, J = 1.2 Hz, 3H), 1.39 – 1.16 (m, 10H), 1.05 – 0.77 (m, 9H), 0.02 (s, 29H) ppm.

(E)-3-methyl-4-((2-(trimethylsilyl)ethoxy)methoxy)but-2-en-1-ol (306)

Substrate 186 (685 mg, 2.5 mmol, 1 equiv.) in 5 ml of Et2O was cooled to –78 °C.

DIBAL (5.6 ml, 5.6 mmol, 2.25 equiv.) was added dropwise and the reaction was stirred for 1 h at –78 °C. The reaction was quenched with 1 ml of MeOH and warmed to room temperature. Dilution with saturated aqueous Rochelle salt solution followed, and the aqueous media was extracted three times with Et2O. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure.

Purification via flash column chromatography using 7:1 PE:EtOAc yielded 297 mg (1.28 mmol, 51%) of pure E-olefin 306 as a clear oil.

1H NMR (200 MHz, CDCl3): 5.78 – 5.57 (m, 1H), 4.68 (s, 2H), 4.22 (t, J = 6.2 Hz, 2H), 3.97 (s, 2H), 3.75 – 3.50 (m, 2H), 1.71 (s, 3H), 1.03 – 0.89 (m, 2H), 0.02 (s, 9H) ppm.

(E)-3-methyl-4-((2-(trimethylsilyl)ethoxy)methoxy)but-2-enal (187)

To a stirred solution of alcohol 306 (290 mg, 1.25 mmol, 1 equiv.) in 2.5 ml of DMSO, IBX (525 mg, 1.88 mmol, 1.5 equiv.) was added in one portion. Stirring was continued for 1 h. The crude mixture was filtrated through Celite and the solvent was removed under reduced pressure. Purification via flash column chromatography using 5:1 PE:EtOAc yielded 227 mg of aldehyde 187 (0.99 mmol, 79%).

1H NMR (200 MHz, CDCl3): 10.07 (d, J = 8.0 Hz, 1H), 6.16 (dq, J = 8.0, 1.5 Hz, 1H), 4.71 (s, 2H), 4.12 (dd, J = 1.6, 0.7 Hz, 2H), 3.78 – 3.48 (m, 2H), 2.14 (dt, J = 1.4, 0.7 Hz, 3H), 1.03 – 0.83 (m, 2H), 0.02 (s, 9H) ppm.

(E)-(2-(((4-(1,3-dithian-2-ylidene)-2-methylbut-2-en-1-yl)oxy)methoxy)ethyl)trimethylsilane (188)

HWE reagent 182 (380 mg, 1.48 mmol, 1.5 equiv.) was dissolved in 1.5 ml of THF and cooled to –78 °C. To this solution nBuLi (0.6 ml, 1.48 mmol, 1.5 equiv.) was added dropwise and stirring was continued at this temperature for 15 min. Aldehyde 187 (227 mg, 0.99 mmol, 1 equiv.) in 1.5 ml of THF was added dropwise to this solution.

The reaction was stirred for 1 h at –78 °C and an additional h after warming to 0 °C.

The reaction mixture was quenched with saturated aqueous NH⁴Cl and extracted three times with Et2O. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. Purification via flash column chromatography using 10:1 PE:EtOAc yielded 206 mg (0.62 mmol, 63%) of 188 as clear oil. added intermediate 173 (2 g, 6.22 mmol, 1 equiv.) at 80 °C. After 4 h the reaction was cooled, diluted with water and extracted three times with Et2O. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure.

Purification via flash column chromatography using 10:1 PE:EtOAc yielded 1.6 g

77 added and the mixture was stirred overnight. The reaction was diluted with water and extracted three times with Et2O. The combined organic layers were dried over MgSO4

and the solvent was removed under reduced pressure. Purification via flash column chromatography using 5:1 PE:EtOAc yielded 223 mg (0.93 mmol, 38%) of selenobutenolide 167. The analytical data was in full accordance with literature.

1H NMR (200 MHz, CDCl3): δ = 7.73 – 7.59 (m, 2H), 7.49 – 7.32 (m, 3H), 6.82 (t, stirring for 30 min the reaction was diluted with 1M HCl and extracted three times with

DCM. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The crude alcohol was directly subjected to the next step.

Alcohol was dissolved in 5 ml of DMF and cooled to 0 °C. Imidazole (404 mg, 5.94 mmol, 1.5 equiv.) and TBSCl (716 mg, 4.75 mmol, 1.2 equiv.) were added sequentially. After stirring for 1 h the reaction was diluted with 1M HCl and extracted three times with DCM. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. Purification via flash column chromatography using 20:1 PE:EtOAc yielded 1 g (3.6 mmol, 86%) of dienone 171.

1H NMR (400 MHz, CDCl3): δ = 6.72 (d, J = 9.9 Hz, 1H), 6.19 (d, J = 9.8 Hz, 1H), 4.37 (s, 2H), 1.94 (s, 3H), 1.27 (s, 6H), 0.90 (s, 9H), 0.12 (s, 6H) ppm.

13C NMR (101 MHz, CDCl3): δ = 187.18, 157.44, 157.35, 133.89, 125.91, 59.77, 39.90, 25.94, 25.65, 18.41, 11.04, –5.40 ppm.

IR (neat sample): 2956, 2930, 2857, 1662, 1633, 1464, 1256, 1142, 1078, 1057, 832, 776, cm^–1. refluxed for 3 days. The solvent of the crude mixture was evaporated under reduced pressure. Purification via flash column chromatography using 10:1 PE:EtOAc yielded 1.24 g (5.9 mmol, 63%) of lactone 205.

1H NMR (200 MHz, CDCl3): δ = 5.74 (m, 2H), 4.46 (dd, J = 8.0, 7.0 Hz, 1H), 3.88 – 3.73 (m, 1H), 3.71 (s, 3H), 3.18 – 3.02 (m, 1H), 2.96 (dd, J = 19.1, 3.1 Hz, 1H), 2.21 – 2.11 (m, 1H), 1.62 (s, 3H) ppm.

8-iodo-4-methylhexahydro-4,7-methanofuro[3,4-d]oxepine-3,5-dione (207)

To a solution of carboxylic acid 206 (1.08 g, 5.5 mmol) in 15 ml of DCM were added 21 ml of 0.5 M aq. NaHCO3, 21 ml of 20% aq. KI and 1.7g of I2. The reaction mixture was stirred overnight and extracted three times with DCM. Collected organic phases were washed with saturated NaHSO3, then NaHCO3 and brine solutions. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. Purification via flash column chromatography using 5:1 PE:EtOAc yielded 1.33 g (4.13 mmol, 75%) of dilactone 207.

1H NMR (200 MHz, CDCl3): δ = 4.97 (dd, J = 6.2, 3.9 Hz, 1H), 4.64 (dd, J = 7.4, 3.7 Hz, 1H), 4.44 – 4.38(m, 2H), 2.96 (d, J = 13.2 Hz, 1H), 2.91 – 2.79 (m, 1H), 2.69 (dd, J = 8.0, 2.1 Hz, 1H), 2.26 (ddt, J = 13.2, 6.1, 1.8 Hz, 1H), 1.56 (s, 3H) ppm.

Methyl-7-((tert-butyldimethylsilyl)oxy)-4-methyl-3-oxooctahydroisobenzofuran-4-carboxylate (210)

Brominated lactone 209 (421 mg, 1 mmol, 1 equiv.) was refluxed with AIBN (82 mg, 0.5 mmol, 0.5 equiv.) and Bu3SnH (400 µl, 1.5 mmol, 1.5 equiv.) in benzene for 3 h.

The solvent of the crude mixture was evaporated under reduced pressure. Purification via flash column chromatography using 20:1 PE:EtOAc yielded 301 mg (0.88 mmol, 88%) of lactone 210. solution of nBuLi (46 µl, 0.115 mmol, 1.2 equiv.) was added dropwise at –78 °C. After stirring for 5 min at this temperature the reaction mixture was warmed to 0 °C. After stirring for 10 min it was again cooled to –78 °C. A solution of the ester 210 (33 mg, 0.096 mmol, 1 equiv.) in 40 µl THF was then added dropwise and stirred for 45 min at –78 °C. A solution of PhSeCl (22 mg, 0.115 mmol, 1.2 equiv.) in 200 µl THF was added slowly and the resulting mixture was stirred for 2 h. Afterwards it was warmed to room temperature, quenched with water and extracted three times with Et2O. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. Purification via flash column chromatography using 20:1 PE:EtOAc yielded 15 mg (0.31 mmol, 32%) of selenylated product 211.

1H NMR (200 MHz, CDCl3): δ = 7.69 – 7.52 (m, 2H), 7.43 – 7.28 (m, 3H), 4.73 (dd, J = 8.8, 3.9 Hz, 1H), 4.14 (d, J = 8.9 Hz, 1H), 3.80 (s, 3H), 3.42 (ddd, J = 11.1, 9.5, 4.9 Hz, 1H), 3.02 (dd, J = 9.4, 3.8 Hz, 1H), 2.17 – 1.95 (m, 1H), 1.86 (s, 3H), 1.83 –

1.67 (m, 1H), 1.66 – 1.45 (m, 1H), 1.42 – 1.20 (m, 1H), 0.87 (s, 9H), 0.05 (s, 3H), 0.03 (s, 3H) ppm.

Methyl 7-((tert-butyldimethylsilyl)oxy)-4-methyl-3-oxo-1,3,4,5,6,7-hexahydroisobenzofuran-4-carboxylate (212)

To a solution of selenylated 211 (22 mg, 0.043 mmol, 1 equiv.) in 0.5 ml of DCM with NaHCO3 (36 mg, 0.43 mmol, 10 equiv.) at 0 °C was added mCPBA (20 mg, 0.086 mmol, 2 equiv.) in one portion. After 10 min the reaction was diluted with a saturated solution of NaHCO3 and extracted three times with DCM. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. Purification via flash column chromatography using 5:1 PE:EtOAc yielded 14 mg (0.04 mmol, 91%) of lactone 212.

1.1 equiv.) in one portion. The reaction mixture was stirred for one day, then diluted with water and extracted three times with DCM. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. Purification via flash column chromatography using 5:1 PE:EtOAc yielded 809 mg (2.68 mmol, 86%) of epoxide 213 as colorless oil.

1H NMR (200 MHz, CDCl3): δ = 7.39 – 7.33 (m, 5H), 5.24 – 4.98 (m, 2H), 4.38 (dd, J = 9.7, 6.2 Hz, 1H), 4.24 (dd, J = 9.7, 0.9 Hz, 1H), 3.38 – 3.18 (m, 2H), 3.07 – 2.93 (m, 2H), 2.74 (dt, J = 15.6, 2.2 Hz, 1H), 1.97 (dd, J = 15.5, 1.2 Hz, 1H), 1.56 (s, 3H) ppm.

13C NMR (101 MHz, CDCl3): δ = 175.58, 175.55, 135.99, 128.68, 128.37, 128.32, 68.64, 66.96, 53.38, 52.72, 42.52, 40.10, 35.05, 30.57, 22.83 ppm.

Benzyl-6-bromo-7-hydroxy-4-methyl-3-oxooctahydroisobenzofuran-4-carboxylate (307)

Epoxide 213 (792 mg, 2.62 mmol) in 40 ml of MeCN was cooled to –40 °C and 1.7 ml of 48% HBr was added dropwise. After stirring overnight, the reaction mixture was diluted with water and extracted three times with DCM. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure.

Benzyl-6-bromo-7-((tert-butyldimethylsilyl)oxy)-4-methyl-3-oxooctahydroisobenzofuran-4-carboxylate (308)

Bromide 307 (763 mg, 1.99 mmol, 1 equiv.) was dissolved in 8 ml of DCM and cooled to 0 °C. Afterwards 2,6-lutidine (460 µl, 4 mmol, 2 equiv.) followed by TBSOTf (550 µl, 2.39 mmol, 1.2 equiv.) were slowly added to the reaction mixture. After stirring for 3 h it was diluted with 1M HCl and extracted three times with DCM. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure.

Purification via flash column chromatography using 10:1 PE:EtOAc yielded 864 mg (1.74 mmol, 87%) of TBS-ether 308. 75.87, 68.82, 67.56, 52.49, 45.98, 45.71, 44.79, 41.83, 26.24, 21.76, 18.68, –2.64, – 4.03 ppm.

Benzyl-7-((tert-butyldimethylsilyl)oxy)-4-methyl-3-oxooctahydroisobenzofuran-4-carboxylate (214)

Brominated lactone 308 (834 mg, 1.68 mmol, 1 equiv.) was refluxed with AIBN (55 mg, 0.335 mmol, 0.5 equiv.) and Bu3SnH (680 µl, 2.5 mmol, 1.5 equiv.) in 65 ml of toluene for 3 h. The solvent of the crude mixture was evaporated under reduced pressure.

Purification via flash column chromatography using 20:1 PE:EtOAc yielded 685 mg (1.64 mmol, 98%) of lactone 214. 69.81, 68.69, 67.16, 44.98, 44.95, 44.44, 31.79, 31.04, 25.85, 22.22, 18.01, –3.77, – 4.61 ppm.

IR (neat sample): 2950, 2854, 1763, 1726, 1493, 1456, 1364, 1235, 1178, 1150, 1087, 830, 776 cm^–1.

MS: calc. for [C²³H³⁴O⁵Si+Na]: 441.2073, found: 441.2078

Benzyl-7-((tert-butyldimethylsilyl)oxy)-4-methyl-3-oxo-3a-(phenylselanyl)octahydroisobenzofuran-4-carboxylate (309)

Bis(trimethylsilyl)amine (120 µl, 0.55 mmol, 1.05 equiv.) was dissolved in 2.5 ml of THF and cooled to 0 °C. Then nBuLi (220 µl, 0.55 mmol, 1.05 equiv.; 2.5M in hexane) was added dropwise and reaction was stirred for 15 min at this temperature. Afterwards it was cooled to –78 °C and stirred for 5 min. Addition of HMPA (190 µl, 1.1 mmol, 2.1 equiv.) followed and this mixture was stirred 30 min. Lactone 214 (220 mg, 0.53 mmol, 1 equiv.) in 2 ml of THF was then slowly added and the obtained mixture was stirred for 30 min at –78 °C. A solution of PhSeCl (101 mg, 0.53 mmol, 1. equiv.) in 0.3 ml of THF was added and after 20 min the reaction was quenched with 1.5 ml of MeOH at –78 °C. After 3 min it was warmed to room temperature, diluted with 1M HCl and extracted three times with DCM. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. Purification via flash column chromatography using 30:1 PE:EtOAc yielded 194 mg (0.34 mmol, 64%) of selenylated 309. 30.62, 25.82, 20.32, 17.98, –3.69, –4.62 ppm.

IR (neat sample): 2928, 2853, 1761, 1740, 1719, 1456, 1366, 1212, 1171, 1093, 836, 771, 741, 691cm^–1.

MS: calc. for [C29H38O5SeSi+Na]: 597.1551, found: 597.1554

Benzyl-7-((tert-butyldimethylsilyl)oxy)-4-methyl-3-oxo-1,3,4,5,6,7-hexahydroisobenzofuran-4-carboxylate (215)

Selenylated 309 (570 mg, 1 mmol, 1 equiv.) was dissolved in 20 ml of DCM and cooled to 0 °C. NaHCO3 (840 mg, 10 mmol, 10 equiv.) and mCPBA (480 mg, 2 mmol, 2 equiv.) were added sequentially and the resulting suspension was stirred for 20 min.

The reaction mixture was diluted with a saturated solution of NaHCO3 and extracted three times with DCM. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. Purification via flash column chromatography using 10:1 PE:EtOAc yielded 393 mg (0.94 mmol, 95%) of 128.19, 127.78, 69.83, 67.13, 66.45, 41.88, 34.48, 30.45, 25.76, 22.38, 18.11, –4.21, –4.89 ppm.

IR (neat sample): 2953, 2931, 2856, 2358, 1764, 1732, 1471, 1350, 1259, 1224, 1124, 1095, 1004, 935, 837, 781 cm^–1.

MS: calc. for [C23H32O5Si+H]: 417.2097, found: 417.2099

87 removed under reduced pressure delivering analytically pure carboxylic acid 201 (58 mg, 0.18 mmol, 100%). 34.32, 30.51, 25.78, 22.54, 18.14, –4.17, –4.92 ppm.

(2,6,6-trimethyl-3-oxocyclohex-1-en-1-yl)methyl-7-((tert-butyldimethylsilyl)oxy)-4-methyl-3-oxo-1,3,4,5,6,7-hexahydroisobenzofuran-4-carboxylate (199)

Acid 201 (170 mg, 0.52 mmol, 1 equiv.) with alcohol 200 (263 mg, 1.56 mmol, 3 equiv.) were dissolved in 5 ml of toluene. Addition of DMAP (127 mg, 1.04 mmol, 2 equiv.) and CSA (60 mg, 0.26 mmol, 0.5 equiv) followed. Then DIC (160 µl, 1.04 mmol, 2 equiv.)

was added dropwise at room temperature. After the completion of the reaction (indicated by TLC) it was diluted with 1M HCl and extracted three times with Et2O. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. Purification via flash column chromatography using 6:1 PE:EtOAc yielded 144 mg (0.3 mmol, 58%) of ester 199. 128.82, 69.83, 65.87, 61.85, 41.86, 37.31, 35.50, 34.41, 34.17, 30.35, 26.62, 26.56, 25.70, 22.06, 18.04, 11.61, –4.25, –4.92 ppm.

IR (neat sample): 2929, 2856, 2358, 2341, 1762, 1732, 1674, 1471, 1253, 1222, 1093, 1006, 837, 732 cm^–1.

MS: calc. for [C26H40O6Si+Na]: 499.2492, found: 499.2495

(2,6,6-trimethyl-3-oxocyclohex-1-en-1-yl)methyl-7-hydroxy-4-methyl-3-oxo-1,3,4,5,6,7-hexahydroisobenzofuran-4-carboxylate (216)

The ester 199 (23 mg, 0.049 mmol) was dissolved in 400 µl of THF and 200 µl of 1M HCl was added at room temperature. After stirring for 20 h the reaction mixture was diluted with water and extracted three times with DCM. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure.

Purification via flash column chromatography using 1:1 PE:EtOAc yielded 17.3 mg (0.048 mmol, 98%) of alcohol 216.

1H NMR (400 MHz, CDCl3): δ = 4.98 (d, J = 17.7 Hz, 1H), 4.83 – 4.67 (m, 3H), 4.54 (t, J = 6.4 Hz, 1H), 2.49 (dd, J = 7.5, 6.2 Hz, 2H), 2.42 (bs, 1H), 2.32 – 2.21 (m, 1H), 2.15 – 2.04 (m, 1H), 1.83 (dd, J = 7.5, 6.2 Hz, 2H), 1.76 (s, 3H), 1.73 – 1.61 (m, 1H), 1.50 (s, 3H), 1.14 (d, J = 4.1 Hz, 6H) ppm.

90 0.25 equiv.) and NaIO4 (17 mg, 0.08 mmol, 4 equiv.) at room temperature. After 20 min the reaction mixture was quenched with Et2O and dried with MgSO4. The crude mixture was filtrated through Celite and the solvent was removed under reduced pressure. Purification via flash column chromatography using 5:1 PE:EtOAc yielded 9.3 mg of 250 (0.019 mmol, 95%). 23.58, 20.98, 18.27, 10.10, –5.63, –5.64 ppm.

IR (neat sample): 2951, 2929, 2857, 1737, 1698, 1472, 1378, 1290, 1248, 1121, 1084, 856, 836, 776 cm^–1.

MS: calc. for [C27H40O6Si+Na]: 511.2492, found: 511.2494

10-(((tert-butyldimethylsilyl)oxy)methyl)-1,11,11-trimethyl-3,3a-dihydro-5H-1,5a,3,5-(epipropane[1,1,3,3]tetrayl)cyclopenta[c]isobenzofuran-2,6,9(1H)-trione (253)

To a solution of photoadduct 231 (16.5 mg, 0.036 mmol, 1 equiv.) in 0.6 ml of a MeCN/H2O mixture (5 : 1) was added Hg(NO3)2·H2O (11.5 mg, 0.034 mmol, 0.93 equiv.) in one portion at room temperature. After stirring for 5 h, the reaction was quenched with saturated Na2S2O3 solution and extracted three times with EtOAc. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. Purification via flash column chromatography using 12:1 PE:EtOAc yielded 9.4 mg (0.022 mmol, 60%) of enone 253.

1H NMR (400 MHz, CDCl3): δ = 6.84 (d, J = 10.5 Hz, 1H), 6.74 (d, J = 10.5 Hz, 1H), 5.21 (dd, J = 4.2, 1.4 Hz, 1H), 4.99 (dd, J = 4.5, 1.4 Hz, 1H), 3.75 (d, J = 11.1 Hz, 1H), 3.67 (d, J = 11.2 Hz, 1H), 2.88 (dd, J = 10.0, 4.5 Hz, 1H), 2.67 (dd, J = 10.0, 4.2 Hz, 1H), 1.25 (s, 3H), 1.15 (s, 3H), 0.99 (s, 3H), 0.84 (s, 9H), 0.00 (2s, 6H) ppm.

Methyl-9-(benzoyloxy)-10-(((tert-butyldimethylsilyl)oxy)methyl)-1,6,11,11-

tetramethyl-2-oxooctahydro-5H-1,5a,3,5-(epipropane[1,1,3,3]tetrayl)cyclopenta[c]isobenzofuran-6-carboxylate (251)

A solution of ester 242 (4 mg, 0.007 mmol, 1 equiv.) was stirred in 0.35 ml of CCl4/MeCN/H2O (2 : 2 : 3) in the presence of RuCl3·H2O (1 mg, 0.005 mmol, 0.7 equiv.) and NaIO4 (12 mg, 0.056 mmol, 8 equiv.) at room temperature. After 3 h, the reaction was quenched with propanol and dried over MgSO4. The crude mixture was filtrated through Celite and washed with DCM. The solvent was removed under reduced pressure providing substantially pure benzoate 251 (4 mg, 0.0067 mmol, 98%).

1H NMR (400 MHz, CDCl3): δ = 7.94 – 7.89 (m, 2H), 7.58 – 7.52 (m, 1H), 7.43 (t, J = 7.7 Hz, 2H), 5.45 (t, J = 9.6 Hz, 1H), 5.36 (dd, J = 4.5, 1.3 Hz, 1H), 4.45 – 4.34 (m, 2H), 3.72 (d, J = 10.9 Hz, 1H), 3.70 (s, 3H), 3.63 (d, J = 10.9 Hz, 1H), 2.78 (dd, J = 10.0, 4.7 Hz, 1H), 2.60 – 2.52 (m, 2H), 2.50 – 2.34 (m, 1H), 2.02 – 1.82 (m, 2H), 1.61 (s, 3H), 1.38 (s, 3H), 1.12 (s, 3H), 0.96 (s, 3H), 0.89 (s, 9H), 0.06 (2s, 6H) ppm.

MS: calc. for [C34H46O7Si+Na]: 617.2911, found: 617.2910

93 removed under reduced pressure. Purification via flash column chromatography using 5:1 PE:EtOAc yielded lactone 254.

9-hydroxy-10-(iodomethyl)-1,11,11-trimethyltetrahydro-5H-1,5a,3,5-(epipropane[1,1,3,3]tetrayl)cyclopenta[c]isobenzofuran-2,6(1H,7H)-dione (255)

Ketone 232 (6 mg, 0.014 mmol, 1 equiv.) was heated at 50 °C with TMSCl (17 µl, 0.14 mmol, 10 equiv.) and NaI (21 mg, 0.14 mmol, 10 equiv.) in 0.2 ml of MeCN for 4 h. Afterwards the reaction was diluted with water and extracted three times with DCM. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. Purification via flash column chromatography using 1:1 PE:EtOAc yielded iodide 255.

1H NMR (600 MHz, CDCl3): δ = 4.95 (dd, J = 4.2, 1.3 Hz, 1H), 4.76 (dd, J = 4.7, 1.3 Hz, 1H), 3.98 (dd, J = 10.6, 3.8 Hz, 1H), 3.35 (d, J = 11.4 Hz, 1H), 3.21 (d, J = 11.3 Hz, 1H), 2.87 (dd, J = 10.0, 4.7 Hz, 1H), 2.60 – 2.53 (m, 2H), 2.29 – 2.13 (m, 2H), 2.13 – 2.08 (m, 1H), 1.65 (s, 3H), 1.23 (s, 3H), 1.08 (s, 3H) ppm.

13C NMR (151 MHz, CDCl3): δ = 212.27, 208.50, 130.04, 126.99, 88.97, 82.73, 69.50, 62.71, 57.91, 54.87, 53.10, 51.63, 43.67, 38.50, 29.86, 29.11, 24.55, 21.64, 10.84, 0.29. ppm.

Rf: 0.5 (1:2 PE/EtOAc)

95 0.043 mmol, 1.5 equiv.) in 1 ml of benzene for one day. Then the solvent was removed under reduced pressure. Purification via flash column chromatography using 2:1 PE:EtOAc yielded carbamate 310 (15 mg, 0.025 mmol, 88%).

1H NMR (400 MHz, CDCl3): δ = 8.09 (s, 1H), 7.29 (t, J = 1.4 Hz, 1H), 7.08 (dd, J = 1.6, 29.47, 26.00, 25.92, 24.83, 23.90, 22.00, 18.29, 11.28, –5.63, –5.66 ppm.

IR (neat sample): 2987, 2950, 2889, 2859, 1759, 1731, 1471, 1399, 1316, 1289, 1280, 1240, 1174, 1132, 1076, 999, 840, 769, 733 cm^–1.

MS: calc. for [C31H44N2O7Si+H]: 585.2996, found: 585.2999

Methyl-10-(((tert-butyldimethylsilyl)oxy)methyl)-1,6,11,11-tetramethyl-2-oxo-9-

(((2,2,2-trifluoroethyl)carbamoyl)oxy)octahydro-5H-1,5a,3,5-(epipropane[1,1,3,3]tetrayl)cyclopenta[c]isobenzofuran-6-carboxylate (261)

Carbamate 310 (41 mg, 0.07 mmol) was heated in 0.3 ml of trifluoroethylamine at 200

°C in sealed tube overnight. Solvent was removed under reduced pressure. Purification via flash column chromatography using 2:1 PE:EtOAc yielded carbamate 361 (27 mg, 0.044 mmol, 63%). 24.87, 23.88, 22.17, 18.30, 11.16, –5.64 ppm.

10-(((tert-butyldimethylsilyl)oxy)methyl)-1,11,11-trimethyl-2,6-dioxooctahydro-5H-1,5a,3,5-(epipropane[1,1,3,3]tetrayl)cyclopenta[c]isobenzofuran-9-yl

sulfamate (256)

To an ice cooled solution of alcohol 233 (8 mg, 0.0185 mmol, 1 equiv.) in 0.2 ml of DMA with 20 µl of Et3N (0.272 mmol, 15 equiv.), 100 µl of a sulfamoyl chloride stock solution (0.95 M, 0.0925 mmol, 5 equiv.) in MeCN were added dropwise. As addition was complete, the solution was warmed to room temperature. Stirring was continued at this temperature for 1.5 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted two times with Et2O. The solvent was removed under reduced pressure. Purification via flash column chromatography using 2:1 PE:EtOAc yielded sulfamate 256 (3.9 mg, 0.0076 mmol, 41%).

1H NMR (400 MHz, CDCl3): δ = 5.03 (dd, J = 4.1, 1.4 Hz, 1H), 4.95 (dd, J = 4.7, 1.4 Hz, DMA with 20 µl of Et3N (0.272 mmol, 27 equiv.), 100 µl of a sulfamoyl chloride stock solution (0.95 M, 0.0925 mmol, 9 equiv.) in MeCN were added dropwise. As addition was complete, the solution was warmed to room temperature. Stirring was continued at this temperature for 1.5 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted two times with Et2O. The solvent was removed under

reduced pressure. Purification via flash column chromatography using 2:1 PE:EtOAc yielded sulfamate 258 (1.5 mg, 0.003 mmol, 30%).

1H NMR (400 MHz, CDCl3): 5.32 (dd, J = 4.5, 1.4 Hz, 1H), 5.01 (t, J = 9.6 Hz, 1H), 4.79 hydrogen atmosphere in the presence of Pd/C (10 mg, 0.0093 mmol, 30 mol%). After completion of the reaction, the solution was filtrated through pad of celite. The solvent was removed under reduced pressure providing pure alcohol 260 (13.7 mg, 24.89, 23.85, 18.30, 11.01, –5.63, –5.66 ppm.

MS: calc. for [C27H42O6Si+Na]: 513.2648, found: 513.2645

11-(((tert-butyldimethylsilyl)oxy)methyl)-1,12,12-trimethyl-6- ((triisopropylsilyl)oxy)hexahydro-5H-1,5a,3,5-(epipropane[1,1,3,3]tetrayl)-6,9-epioxacyclopenta[c]isobenzofuran-2(1H)-one (234)

To a solution of keto alcohol 233 (76 mg, 0.176 mmol, 1 equiv.) with 2,6-lutidine (40 µl, 0.406 mmol, 2.3 equiv.) in 1.2 ml of DCM, TIPSOTf (70 µl, 0.2 mmol, 1.1 equiv) was added dropwise at 0 °C. After the addition was complete, the solution was warmed to room temperature and stirring was continued for 1 h. Afterwards the reaction mixture was diluted with 1M HCl and extracted three times with DCM. The solvent was removed under reduced pressure. Purification via flash column chromatography using 30:1 PE:EtOAc yielded 234 (70 mg, 0.12 mmol, 68%).

1H NMR (400 MHz, CDCl3): δ = 4.78 (d, J = 4.3 Hz, 1H), 4.52 (d, J = 11.5 Hz, 1H), 4.48

100

Methyl-10-(((tert-butyldimethylsilyl)oxy)methyl)-1,11,11-trimethyl-2,9-

dioxooctahydro-5H-1,5a,3,5-(epipropane[1,1,3,3]tetrayl)cyclopenta[c]isobenzofuran-6-carboxylate (264)

Benzyl-protected alcohol 241 (64.6 mg, 0.114 mmol) was stirred with Pd/C (12 mg, 0.0114 mmol, 0.1 equiv.) in 1 ml of EtOAc for 3 h under hydrogen atmosphere. After filtration through the pad of celite solvent was removed under the reduced pressure delivering crude alcohol. It was further dissolved in 1 ml of CCl4/MeCN/H2O (2 : 2 : 3) and RuCl³·H2O (5 mg, 0.024 mmol, 0.2 equiv.) with NaIO4 (40 mg, 0.187 mmol, 1.6 equiv.) were added in one portion. After 20 min the reaction was quenched with Et2O, dried with MgSO4 and filtrated through a pad of celite. The solvent was removed under reduced pressure. Purification via flash column chromatography using 5:1 PE:EtOAc yielded ketone 264 (42 mg, 0.088 mmol, 77% over two steps).

1H NMR (400 MHz, CDCl3): δ = 5.23 (dd, J = 4.4, 1.4 Hz, 1H), 4.77 (dd, J = 4.5, 1.3 Hz,

101

Exo Diels-Alder adduct 228 (3.7 mg, 0.008 mmol, 1 equiv.) was dissolved in 0.3 ml of MeCN. A solution of CAN (11 mg, 0.02mmol, 2.5 equiv.) in 0.15 ml of water was added dropwise at 0 °C. After stirring for 1 h, the reaction was diluted with water and extracted three times with DCM. Collected organic fractions were dried over MgSO4 and the solvent was removed under reduced pressure. Purification via flash column

Im Dokument Studies towards the total synthesis of canataxpropellane (Seite 81-0)