Racemic sulprostone

Abstract

SHORT COMMUNICATIONSSulprostone (I) is a metabolically more stable analog of prostaglandin E 2 , which is widely used in biomedical research [1,2] and is known in gynecologic practice as an efficient agent (in combination with RU-486 or without it) for abortion [3][4][5]. The chemical synthesis of sulprostone and structurally related compounds, N-methylsulfonyl-16-phenoxyprostaglandincarboxamides, was described in [6]. Corey et al. [7] obtained sulprostone from optically active aldehyde; it was isolated as a colorless powder with mp 78.5-79.5°C (from ethyl acetate-diethyl ether); however, no α D value was given. According to patent [8], the melting point of sulprostone is 76°C, but its optical rotation is also missing. Commercial sulprostone produced by Cayman has mp 84-86°C (purity ≥98%); insofar as its α D value is absent, it is not clear whether this product is racemic or optically active. To elucidate this problem and compare biological properties of the products we have synthesized racemic sulprostone according to a modified procedure [9].Using standard methods, stereoisomerically pure bis-trimethylsilyl ether II [9] was converted (through dihydroxy lactone III) into bis-ethoxyethyl ether IV which was reduced with i-Bu 2 AlH to the corresponding hydroxy lactone, and the latter was subjected to Wittig olefination with ylide generated from triphenylphosphonium salt V. The final steps in the synthesis of I were oxidation of the hydroxy group in VI with Collins' reagent and removal of protecting groups by acid hydrolysis.Sulprostone (I) thus obtained was purified first by column chromatography on silica gel and was then II, R = Me 3 Si; III, R = H; IV, VI, R = CH 3 CH 2 OCH(CH 3 ); a: 3% HCl-THF, yield 95%; b: ethyl vinyl ether, CH 2 Cl 2 , PPTS, yield 93%; c: i-Bu 2 AlH, CH 2 Cl 2 , -78°C, yield 95%; d: [Ph 3 P + (CH 2 ) 4 CONHSO 2 CH 3 ]Br -(V), t-BuOK, THF, 0°C, 1 h, yield 80%; e: CrO 3 · 2 Py, yield 85%. e, a O HO OH

Prostanoids: XC. Extension to the Synthesis of Enprostil of the o-Nitrophenylsulfonylhydrazine Method for Transformation of 2-Propynyl Alcohols into Allenes

“…The extract was dried over Na 2 SO 4 and evaporated under reduced pressure, and the residue was subjected to column chromatography on silica gel to isolate 0.145 g (40%) of diol VI (a ~1 : 1 mixture of epimers with respect to C 6 ) as an oily substance. 1 (±)-9-Acetoxy-11,15-bis(tert-butyldimethylsiloxy)-2-decarboxy-6-oxo-16-phenoxy-2-triphenylmethyloxymethyl-4,4,5,5-tetradehydro-17,18,19,20-tetranorprostaglandin F1α (VII). To a solution of 1.05 g (1.22 mmol) of hydroxy ketone IV in 5 ml of anhydrous pyridine we added 0.25 g (2.44 mmol) of acetic anhydride and 0.001 g of 4-dimethylaminopyridine.…”

“…1 phenoxy-4,4,5,5-tetradehydro-17,18,19,20-tetranorprostaglandin F1α (IX). To a solution of 0.200 g (0.22 mmol) of acetate VII in 4 ml of chloroform we added 0.030 g (0.22 mmol) of ZnCl 2 , and the mixture was stirred for 3 h. The mixture was then treated with 2 ml of a saturated solution of sodium chloride and extracted with chloroform, the extract was dried over Na 2 SO 4 and evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel to obtain 0.096 g (70%) of alcohol IX as an oily substance.…”

“…To a solution of 0.200 g (0.22 mmol) of acetate VII in 4 ml of chloroform we added 0.030 g (0.22 mmol) of ZnCl 2 , and the mixture was stirred for 3 h. The mixture was then treated with 2 ml of a saturated solution of sodium chloride and extracted with chloroform, the extract was dried over Na 2 SO 4 and evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel to obtain 0.096 g (70%) of alcohol IX as an oily substance. 1 -16-phenoxy-4,4,5,5-tetradehydro-17,18,19,20-tetranorprostaglandin F1α methyl ester (X). To a solution of 0.146 g (1.85 mmol) of anhydrous pyridine in 5 ml of methylene chloride we added at 0°C 0.092 g (0.92 mmol) of CrO 3 , and the mixture was stirred for 15 min.…”

“…By column chromatography on silica gel we isolated 0.030 g (40%) of ester X as an oily substance. 1 (±)-6-Acetoxy-11,15-bis(tert-butyldimethylsiloxy)-2-decarboxy-16-phenoxy-2-triphenylmethyloxymethyl-4,4,5,5-tetradehydro-17,18,19,20-tetranorprostaglandin F1α (XIII) (a mixture of epimers at C 6 ). By reaction of 0.021 ml (0.14 mmol) of diisopropyl azodicarboxylate, 0.035 g (0.14 mmol) of triphenylphosphine, 0.100 g (0.12 mmol) of alcohol 973 VIII, and 0.018 g (0.14 mmol) of o-nitrophenylsulfonylhydrazine in THF according to the procedure described above for the synthesis of compound XII, followed by heating for 6 h at 50°C, we obtained 0.032 g (32%) of C 6 -acetate XIII as an oily substance.…”

“…Scheme 2. R R H OH + o-O 2 NC 6 H 4 SO 2 NHNH 2 Ph 3 P, DEAD -15°C R R N OH H 2 N SO 2 C 6 H 4 NO 2 -o 23°C · R H H R DEAD is diethyl azodicarboxylate (EtOCON=NCOOEt).We tried to extend this approach to the key stages in the formation of allene fragment in the synthesis of enprostil from bis-silyl ether II [1]. In order to obtain a precursor of compound I with a 2-propynyl alcohol moiety in the α-chain, diastereoisomerically pure lactone II was brought into condensation with lithium derivative III of 5-triphenylmethoxy-1-pentyne under appropriate conditions [9].…”