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

M. Carmen Murcia; Gabriela de la Herran; Joaquín Plumet; Aurelio G. Csaky

doi:10.1055/s-2007-982558

LETTER

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

M. Carmen Murcia, Gabriela de la Herran, Joaquín Plumet, Aurelio G. Csaky*
Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, 28040 Madrid, Spain
e-Mail: csaky@quim.ucm.es;

Abstract

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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

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Referenzen

References and Notes

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<A NAME="RG11507ST-3">3</A> See for example: Breuer M. Ditrich K. Habicher T. Hauer B. Kesseler M. Stürmer R. Zelinski T. Angew. Chem. Int. Ed. 2004, 43: 788 ; and references cited therein

See for example:

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<A NAME="RG11507ST-4E">4e</A> Usami Y. Numata A. Synthesis 1999, 723

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<A NAME="RG11507ST-6A">6a</A> Csaky AG. Mba M. Plumet J. J. Org. Chem. 2001, 66: 9026

<A NAME="RG11507ST-6B">6b</A> Csaky AG. Contreras C. Mba M. Plumet J. Synlett 2002, 1451

<A NAME="RG11507ST-6C">6c</A> Csaky AG. Mba M. Plumet J. Synlett 2003, 2092

<A NAME="RG11507ST-7">7</A> Rodríguez A. Nomen M. Spur BW. Godfroid JJ. Eur. J. Org. Chem. 1999, 2655

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.

<A NAME="RG11507ST-9">9</A> Babiak KA. Ng JS. Dygos JH. Weyker CL. J. Org. Chem. 1990, 55: 3377

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).

<A NAME="RG11507ST-11">11</A> For a recent preparation of (+)-2 from methyl oleate and 2,3-O-isopropylidene-d-glyceraldehyde, see: Muhammad Nor O. Hamilton RJ. J. Palm Oil Res. 2004, 16: 37

(-)-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.

(+)-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.

<A NAME="RG11507ST-14">14</A> Csaky AG. Mba M. Plumet J. Tetrahedron: Asymmetry 2004, 15: 647

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).

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).

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).

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).

<A NAME="RG11507ST-19">19</A> For a previous use of L-Selectride with KH₂PO₄ as proton source to convert an enone into an alcohol, see: Bell RA. Turner JV. Tetrahedron Lett. 1981, 22: 4871

(+)-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.

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).