An Efficient Synthesis of Enantiomerically Pure (1R,2S,5S)- and (1S,2R,5R)-Rosaprostol Methyl Esters

Abstract

We report a concise synthesis of the enantiomerically pure 1,2-trans-1,5-cis-methyl esters of rosaprostol, a prostaglandin derivative used for the treatment of gastric and duodenal ulcers, ­using as key step the chemo- and stereoselective Michael addition of a Grignard reagent to an unprotected hydroxycyclopentenone.

Key words

cyclopentenones - Grignard reactions - Michael additions - stereoselective synthesis - prostanoids

References and Notes

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8

According to ref. 7, condensation of furan with suberic acid monomethyl ester afforded the corresponding furylketone, which was reduced to methyl-8-(2-furyl)-8-hydroxy-octanoate. This was transformed into methyl 7-(2-hydroxy-5-oxocyclopent-3-enyl)heptanoate by a Nazarov cyclization. Isomerization to rac-2 was best performed upon treatment with an aqueous phosphate buffer solution: To a solution of methyl 7-(2-hydroxy-5-oxocyclopent-3-enyl)heptanoate (1.28 g, 5.33 mmoL) in 1,4-dioxane (50 mL) was added a phosphate buffer solution (pH 8, 37 mL) and the mixture was heated at reflux for 30 h. Concentration under reduced pressure followed by extraction with EtOAc afforded an oil which was purified by chromatography (hexane-EOtAc, 8:2) to give rac-2 in 80% yield.

10

Enzymatic resolution of 2 was carried out according to ref. 9. For a more recent report of the resolution of 2, see ref. 7. Compounds (+)-2 and (-)-2 are commercially available (Aldrich).

12

(-)-Methyl 7-[(1 R ,2 R ,3 S )-2-Hexyl-3-hydroxy-5-oxocyclopentyl]heptanoate [(-)-3]
[α]_D ²⁵ -22 (c 3.5, CHCl₃). R _f = 0.22 (CH₂Cl₂-EtOAc, 8:2). ¹H NMR (300 MHz, CDCl₃): δ = 4.48 (m, 1 H), 3.67 (s, 3 H), 2.36-2.28 (m, 4 H), 2.13-2.05 (m, 1 H), 1.90-1.80 (m, 1 H), 1.66-1.50 (m, 8 H), 1.38-1.25 (m, 12 H), 0.93 (t, J = 6.6 Hz, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 219.8 (s), 175.0 (s), 75.2 (d), 51.8 (q), 50.6 (d), 48.6 (d), 47.0 (t), 39.7 (t), 32.5 (t), 30.5 (t), 30.0 (t), 28.6 (t), 28.3 (t), 27.6 (t), 27.02 (t), 26.8 (t), 23.8 (t), 23.1 (t), 14.5 (q) ppm.

13

(+)-Methyl 7-[(1 R ,2 S )-2-Hexyl-5-oxocyclopent-3-enyl)heptanoate [(+)-4]
[α]_D ²⁵ +34 (c 2.7, CHCl₃). R _f = 0.89 (CH₂Cl₂-EtOAc, 8:2). ¹H NMR (300 MHz, CDCl₃): δ = 7.60 (dd, ³ J = 1.59 Hz, ³ J = 5.67 Hz, 1 H), 6.1 (dd, ³ J = 1.68 Hz, ³ J = 5.70 Hz, 1 H), 3.67 (s, 3 H), 2.62-2.53 (m, 1 H), 2.30 (t, J = 7.35 Hz, 2 H), 1.98-1.89 (m, 1 H), 1.65-1.56 (m, 2 H), 1.37-1.23 (m, 18 H), 0.91-0.86 (m, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 212.9 (s), 174.6 (s), 167.7 (d), 133.2 (d), 52.2 (d), 51.8 (q), 48.6 (d), 35.0 (t), 34.4 (t), 32.2 (t), 32.1 (t), 31.6 (t), 29.8 (t), 29.3 (t), 27.2 (t), 25.3 (t), 23.1 (t), 22.9 (t), 14.5 (q) ppm.

15

To a suspension of LiCl (0.52 mmol) in THF (0.75 mL) at 0 °C was added hexylmagnesium bromide (2 M solution in Et₂O, 0.26 mL) and the mixture was stirred for 5 min. A solution of (-)-2 (0.23 mmol) in THF (0.75 mL) was added dropwise. The mixture was stirred at 0-10 °C for 18 h, and hydrolyzed with sat. NH₄Cl. The organic layer was decanted and the aqueous layer extracted with Et₂O. The combined organic layers were dried on MgSO₄. Filtration and elimination of the solvent under reduced pressure afforded an oil that was purified by chromatography (CH₂Cl₂-EtOAc, 8:2).

16

To a solution of (-)-3 (0.14 mmol) in Et₂O (2.2 mL) was added PTSA (0.035 mmol) and the solution was stirred at 25 °C for 18 h. The mixture was diluted with Et₂O and washed with sat. NaHCO₃ and brine. The organic layer was dried over MgSO₄ and the solvent was eliminated under reduced pressure. The resulting oil was purified by chromatography (CH₂Cl₂-EtOAc, 8:2).

17

To a solution of (-)-2 (0.23 mmol) in THF (0.75 mL) at 0 °C was added dropwise a 2 M solution of hexylmagnesium bromide in Et₂O (0.26 mL). The mixture was stirred from 0 °C to 30 °C for 36 h, and hydrolyzed with sat. NH₄Cl solution. The organic layer was decanted and the aqueous layer extracted with Et₂O. The combined organic layers were dried over MgSO₄. Filtration and elimination of the solvent under reduced pressure afforded an oil that was purified by chromatography (CH₂Cl₂-EtOAc, 8:2).

18

To a solution of L-Selectride (0.3 mL) in THF (0.3 mL) at -78 °C was added dropwise a solution of 3 (0.1 mmol) in t-BuOH (20 µL) and THF (0.5 mL) and the mixture was stirred at -78 °C for 1 h. The mixture was hydrolyzed with sat. NH₄Cl solution at -78 °C. The organic layer was decanted and the aqueous layer extracted with Et₂O. The combined organic layers were dried over MgSO₄. Filtration and elimination of the solvent under reduced pressure afforded an oil that was purified by chromatography (hexane-EtOAc, 8:2).

20

(+)-Methyl 7-[(1 R ,2 S ,5 S )-2-Hexyl-5-hydroxycyclopentyl]heptanoate [(+)-1]
[α]_D ²⁵ +13 (c 0.6, CHCl₃). R _f = 0.43 (hexane-EtOAc, 8:2). ¹H NMR (300 MHz, CDCl₃): δ = 4.25-4.18 (m,1 H), 3.68 (s, 3 H), 2.31 (t, J = 7.35 Hz, 2 H), 2.07-1.91 (m, 1 H), 1.91-1.77 (m, 1 H), 1.67-1.54 (m, 4 H), 1.37-1.22 (m, 20 H), 0.91-0.87 (m, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 174.8 (s), 74.8 (d), 51.9 (q), 42.3 (d), 39.6 (d), 35.5 (t), 34.5 (t), 33.9 (t), 32.3 (t), 32.3 (t), 30.1 (t), 29.5 (t), 29.4 (t), 28.7 (t), 28.6 (t), 28.0 (t), 25.3 (t), 23.1 (t), 14.5 (q) ppm.

21

The cis relative stereochemistry of the OH and R¹ groups in (+)-1 was unambiguously determined by COSY and NOE measurements. Saturation of the H5 signal (δ = 4.25-4.18 ppm, m, 1 H) afforded a 4% increase of the H2 signal (δ = 1.91-1.77 ppm, m, 1 H).