Total synthesis of 12-hydroxymethylprostaglandin F2? methyl ester

Abstract

The hydroxymethylation of the ester enolate derived from the ester (2) provided the hydroxymethylated adducts (3) snd (4) both of which have been successfully converted into 1 2-hydroxymethylprostaglandin F,, methyl ester(1).INTEREST in C-12 substituted prostaglandins has culminated in the synthesis of 12-methyl prostaglandin^,^ 1 2-fluoro-PGF,, methyl ester,, and 11-deoxy-12-hydroxy-rneth~l-PGE,.~ We report the total synthesis of 12hydroxymethylprostaglandin F,, methyl ester [ 12-hydroxymethyl-PGF,, methyl ester (l)] from the previously described bicyclo[2.2. llheptane derivative (2) .4

C-12 substituted prostaglandins: synthesis and biological evaluation of (.+-.)-12-hydroxyprostaglandin F2.alpha. methyl ester

“…After stirring at ca. 5 °C for 17 h the reaction was quenched by the addition of sodium thiosulfate. The reaction mixture was concentrated in vacuo and acidified to pH 5.5 with 2 M hydrochloric acid.…”

“…The product was purified on 40 g of silica gel. Elution with hexaneethyl acetate (1:5) provided 525 mg (77%) of pure alcohol 24 as a clear oil: IR (CHCI3) 3600, 3500, 3030, 3010, 2990, 2940, 2875,1770,1460, 1421,1415,1390,1380,1370,1355,1334,1301,1240,1198,1170,1148, 1120,1090,1040,1020,996, 970,960,900 cm-1; NMR (CDC13) 5.02 (t, 1 H, J = 5 Hz, -CHOCO), 4.67 (d, 1 H, J = 5 Hz, -CHO-C), 3.66 (s, 2 H, -CH2OH), 3.10 (s broad, 1 H, OH), 3.00-2.00 (m, 5 ), 1.45 (s, 3 ), 1.40 (s, 3 H); mass spectrum m/e (rel intensity) 213 (100, M+ -Me), 197 (6), 171 (5), 135 (4), 107 (3), 59 (3), 58 (10), 43 (10). Anal.…”

“…Elution with ether-ethyl acetate-methanol (10:10:1) provided 11 mg (26%) of a mixture of (±)-12-hydroxy-PGF2a methyl ester ( 5) and (±)-15-ept-12-hydroxy-PGF2l, methyl ester (35). The mixture of 5 and 35 was separated on SilicAR CC-7 employing ether-ethyl acetate (1:1). There was obtained in order of elution 5 mg of 35,6 mg of a mixture of 35 and 5, and 3 mg of (±)-12-hydroxy-PGF2" methyl ester (5) as a solid.…”

“…Our early work centered on the preparation of (±)-12-methyl-PGF2a (2).3 More recently we have described the synthesis of (±)-12-fluoro-PGF2n methyl ester (3)4 and (±)-12-hydroxymethyl-PGF2(, methyl ester (4). 5 We detail below the synthesis of (±)-12-hydroxy-PGF2n methyl ester (5) and present the preliminary biological data.…”

Total synthesis of racemic 12-methylprostaglandins

“…OH 0^09 14 15 Confirmation of the structure assigned to compound 7 was eventually resolved by conversion of 7 to sesquifenchene (20) via the sequence of reactions outlined in Scheme II. 22 Treat-Scheme II MeOOC Me OH ment of 7 with tributyltin hydride23 (1.5 equiv) in benzene containing azobisisobutyronitrile at 50-55 °C for 1.5 h resulted in a 94% isolated yield of pure ester 16 which was reduced (LiAlH4/ether, 4.5 h) to alcohol 17. Tosylation (/7-toluenesulfonyl chloride (1 equiv)/pyridine, 0 °C) of alcohol 17 and exchange with iodide (sodium iodide (3 equiv)/acetone, reflux) produced a 78% overall yield of iodide which underwent sulfone formation in 77% yield upon treatment with 2 equiv of sodium p-toluenesulfinate in anhydrous DMF at 135-140 °C (15 h).…”