3-phenylmethoxypropanal

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A methanolic solution of 2-(1-amino-1-methylethyl)-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide (prepared as described in WO2003035076 A1) was treated with 3-(benzyloxy)propanal (1.5 eq.) and sodium cyanoborohydride (1.5 eq.). The mixture was stirred at room temperature overnight, solution was applied on a cation exchange resin. The resin was washed with methanol and desired product was eluted with 2 N ammonia solution in methanol. Evaporation of appropriate fractions followed by trituration with Et2O gave intermediate 2-(1-{[3-(benzyloxy)propyl]amino}-1-methylethyl)-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide. MS (ES) C25H29FN4O4 requires 468. Found: 469 (M+H+). The crude organic product was taken in methanol, treated with 1 eq. of 6N HCl and stirred under hydrogen atmosphere in the presence of catalytic amount of 10% palladium on charcoal. After overnight stirring, mixture was filtered through celite, filtrate was concentrated under reduced pressure and purified by cation exchange resin. The resin was washed with methanol and desired product was eluted with 2 N ammonia solution in methanol. Evaporation of appropriate fractions followed by trituration with Et2O gave title compound as a pink solid. MS (ES) C18H23FN4O4 requires 378. Found: 379 (M+H+). The resin was washed with methanol and desired product was eluted with 2 N ammonia solution in methanol Evaporation of appropriate fractions

Conditions: temp:-65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5.47 g (79.17 mmol) of isobutyric acid nitrile is added in drops at −65° C. to an LDA solution (produced from 33.64 g (79.17 mmol) of n-butyllithium 15% in hexane, (1.6 M) and 80.1 g (79.17 mmol) of diisopropylamine), and it is stirred for 20 minutes at −65° C. Then, a solution that consists of 10 g (60.9 mmol) of 3-benzyloxy-1-propanaldehyde in 20 ml of THF is added in drops (over 60 minutes). The temperature is kept at −65° C.! Then, it is stirred for one more hour. It is now heated to −20° C., a solution that consists of 20% sulfuric acid is added in drops, and the temperature is allowed to reach +10° C. Then, 50 ml of MTB-ether is added, and then the organic phase is separated. The organic phase is washed with water and then with saturated sodium bicarbonate. Finally, it is washed once more with water and then evaporated to the dry state in a vacuum. is added in drops (over 60 minutes) is kept at −65° C. Then, it is stirred for one more hour It is now heated to −20° C. is added in drops to reach +10° C the organic phase is separated The organic phase is washed with water Finally, it is washed once more with water evaporated to the dry state in a vacuum

Conditions: temp:-65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5.47 g (79.17 mmol) of isobutyric acid nitrile is added in drops at −65° C. to an LDA solution (produced from 33.64 g (79.17 mmol) of n-butyllithium 15% in hexane, (1.6 M) and 80.1 g (79.17 mmol) of diisopropylamine), and it is stirred for 20 minutes at −65° C. Then, a solution that consists of 10 g (60.9 mmol) of 3-benzyloxy-1-propanaldehyde in 20 ml of THF is added in drops (over 60 minutes). The temperature is kept at −65° C.! Then, it is stirred for one more hour. It is now heated to −20° C., a solution that consists of 20% sulfuric acid is added in drops, and the temperature is allowed to reach +10° C. Then, 50 ml of MTB-ether is added, and then the organic phase is separated. The organic phase is washed with water and then with saturated sodium bicarbonate. Finally, it is washed once more with water and then evaporated to the dry state in a vacuum. is added in drops (over 60 minutes) is kept at −65° C. Then, it is stirred for one more hour It is now heated to −20° C. is added in drops to reach +10° C the organic phase is separated The organic phase is washed with water Finally, it is washed once more with water evaporated to the dry state in a vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To generate indolizidine alcohol and aldehyde intermediates useful in the synthesis of pumiliotoxin B, it is necessary to assemble a chiral silylalkyne from esters of (S)-5-(benzyloxy)-1-trimethyl-silyl-1-pentyn-3-ol. This involves the reduction of 3-(benzyloxy)propanitrile, the latter reagent being prepared from acrylonitrile and benzyl alcohol as described by Gaiffe and Launay in Academy of Science, Serial C, Pages 1379-1380 (1968), with i-Bu2AlH to give 3-benzyloxy propanal which is condensed with ethynyllithium, prepared as described by Midland in the Journal of Organic Chemistry, Volume 40, Page 2250 (1975), to yield the racemic propargylic alcohol in about 50% yield following distillation. Reaction of the propargylic alcohol with R-(+)-2-methylbenzylamine gives the corresponding diastereomeric carbamates that upon chromatographic separation and carbamate cleavage with Cl3SiH as described by Pirkle in the Journal of Organic Chemistry, Volume 42, Page 2781 (1971) yields the (S)-alcohol and (R)-alcohol derivatives in yields of about 20%.

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under nitrogen, a mixture of trimethylsilyl cyanide (1.335 mL, 10 mmoles) and 15 (1.64 g, 10 mmoles) is heated at 100° C. for 6 hours. The reaction is monitored by NMR (88% conversion after 6 hours). The mixture is cooled to 5° C. (ice bath), and CH2Cl2 (12 mL) is added, followed by diethylaminosulfurtrifluoride, (0.46 g, 9.1 mmoles), dissolved in CH2Cl2 (8 mL) at about 5° C. is monitored by NMR (88% conversion after 6 hours) is added

Conditions: temp:-50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under nitrogen, a solution of DMSO (8.4 mL, 118 mmoles) in dry dichloromethane (125 mL) is cooled to -60° C., and oxalyl chloride (5 mL, 59 mmoles) in CH2Cl2 (40 mL) is added slowly. After stirring for 5 min at -50° C., 3-benzyloxy-1-propanol (14), 8.9 g, 53.7 mmoles) in CH2Cl2 (27 mL) is added at -60° C. Stirring is continued for 15 min, then triethylamine (47 mL) is added slowly at -60° C. After 5 min at this temperature, the mixture is allowed to warm up to room temperature. After addition of 0.5N HCl and phase separation, the organic phase is washed with water until neutral. Drying (Na2SO4) and evaporation gives the crude aldehyde as an oil: 10.6 g. Distillation under vacuum gives pure 15: 6.54 g (74%), bp 170° C. (15 mm Hg). Stirring is continued for 15 min After 5 min at this temperature to warm up to room temperature the organic phase is washed with water until neutral Drying (Na2SO4) and evaporation