LETTER
Synthesis of (1R,2S,5S)- and (1S,2R,5R)-Rosaprostol Methyl Esters
1555
5-oxocyclopent-3-enyl)heptanoate by a Nazarov
References and Notes
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.
(1) (a) Valcavi, U.; Caponi, R.; Brambilla, A.; Palmira, M.;
Minoja, F.; Bernini, F.; Musanti, R.; Fumagalli, R. Arzneim.-
Forsch. 1982, 32, 657. (b) Adami, M.; Scarpignato, C.;
Signorini, G.; Coruzzi, G.; Bertaccini, G. Farmaco Ed. Prat.
1984, 39, 409. (c) Fumagalli, R.; Caponi, R.; Corsini, A.;
Brambilla, A.; Palmira, M.; Bernini, F.; Valcavi, U.
Prostaglandins 1985, 29, 467. (d) Tincani, G. P.;
Maniscalco, G.; Gunelli, M.; Ciarrocchi, V. Minerva Medica
1987, 78, 847. (e) Aly, A. Scand. J. Gastroenterol. 1987,
Suppl. 137, 43. (f) Canonica, G. W.; Ciprandi, G.;
Scordamaglia, A.; Ruffoni, S.; Pizzorno, G.; Caria, M.;
Cheli, R. Ann. Allerg. 1988, 60, 541. (g) Di Murro, R.;
Camarri, E.; Ciani, D.; Mariotti, L.; Nencioni, C.;
Romagnoli, A. M. Int. J. Clin. Pharm. Res. 1988, 8, 345.
(h) Foschi, D.; Trabucchi, E.; Galeone, M.; Ferrante, F.;
Toti, G. L.; Castoldi, L.; Musazzi, M.; Centenero, A.;
Montorsi, W. Int. J. Tissue React. 1988, 10, 53.
(i) Ciprandi, G.; Ruffoni, S.; Ciani, D.; Tosca, M. A.;
Canonica, G. W. Int. J. Immunol. 1989, 5, 81.
(j) Calcamuggi, G.; Babini, G.; Arduino, C.; Lanzio, M.;
Anfossi, G.; Ciani, D.; Emanuelli, G. Adv. Prostaglandin
Thromboxane Leukotriene Res. 1991, 21B, 789.
(9) Babiak, K. A.; Ng, J. S.; Dygos, J. H.; Weyker, C. L. J. Org.
Chem. 1990, 55, 3377.
(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).
(11) For a recent preparation of (+)-2 from methyl oleate and 2,3-
O-isopropylidene-D-glyceraldehyde, see: Muhammad Nor,
O.; Hamilton, R. J. J. Palm Oil Res. 2004, 16, 37.
(12) (–)-Methyl 7-[(1R,2R,3S)-2-Hexyl-3-hydroxy-5-
oxocyclopentyl]heptanoate [(–)-3]
[a]D25 –22 (c 3.5, CHCl3). Rf = 0.22 (CH2Cl2–EtOAc, 8:2).
1H NMR (300 MHz, CDCl3): d = 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): d = 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.
(2) (a) Valcavi, U. DE 2535343, 1976. (b) Valcavi, U.;
Innocenti, S.; Bosone, E.; Farina, P.; Marotta, V.; Zabban, G.
B. EP 155392, 1985. (c) Shono, T.; Kise, N. Tetrahedron
Lett. 1990, 31, 1303. (d) Shono, T.; Kise, N.; Fujimoto, T.;
Tominaga, N.; Morita, H. J. Org. Chem. 1992, 57, 7175.
(e) Tanimori, S.; Kainuki, T.; Nakayama, M. Biosci.,
Biotechnol., Biochem. 1992, 56, 1807. (f) Mikolajczyk, M.;
Zurawinski, R. J. Org. Chem. 1998, 63, 8894.
(13) (+)-Methyl 7-[(1R,2S)-2-Hexyl-5-oxocyclopent-3-
enyl)heptanoate [(+)-4]
[a]D25 +34 (c 2.7, CHCl3). Rf = 0.89 (CH2Cl2–EtOAc, 8:2).
1H NMR (300 MHz, CDCl3): d = 7.60 (dd, 3J = 1.59 Hz,
3J = 5.67 Hz, 1 H), 6.1 (dd, 3J = 1.68 Hz, 3J = 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):
d = 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.
(14) Csaky, A. G.; Mba, M.; Plumet, J. Tetrahedron: Asymmetry
2004, 15, 647.
(g) Mikolajczyk, M.; Mikina, M.; Zurawinski, R. Pure Appl.
Chem. 1999, 71, 473. (h) Trost, B. M.; Pinkerton, A. B. Org.
Lett. 2000, 2, 1601. (i) Mikolajczyk, M.; Mikina, M.;
Jankowiak, A.; Mphahlele, M. J. Synthesis 2000, 1075.
(j) Trost, B. M.; Pinkerton, A. B. J. Org. Chem. 2001, 66,
7714. (k) Mikolajczyk, M. Phosphorus, Sulfur Silicon Relat.
Elem. 2002, 177, 1839. (l) Ghosh, A. K.; Bilcer, G.; Schiltz,
G. Synthesis 2001, 2203. (m) List, B.; Castello, C. Synlett
2001, 1687.
(3) 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.
(4) See for example: (a) West, F. G.; Gunawardena, G. U. J.
Org. Chem. 1993, 58, 2402. (b) West, F. G.; Gunawardena,
G. U. J. Org. Chem. 1993, 58, 5043. (c) Johnson, C. R.;
Golebiowski, A.; Braun, M. P.; Sundram, H. Tetrahedron
Lett. 1994, 35, 1833. (d) Pudukulathan, Z.; Manna, S.;
Hwang, S.-W.; Khnapure, S. P.; Lawson, J. A.; FitzGerald,
G. A.; Rokach, J. J. Am. Chem. Soc. 1998, 120, 11953.
(e) Usami, Y.; Numata, A. Synthesis 1999, 723.
(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).
(f) Harmata, M.; Lee, D. R. J. Am. Chem. Soc. 2002, 124,
14328. (g) Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett.
2002, 43, 4575.
(5) (a) Harre, M.; Raddatz, P.; Walenta, R.; Winterfeld, E.
Angew. Chem., Int. Ed. Engl. 1982, 21, 480. (b) Collins, P.
W.; Djuric, S. W. Chem. Rev. 1993, 93, 1533.
(6) (a) Csaky, A. G.; Mba, M.; Plumet, J. J. Org. Chem. 2001,
66, 9026. (b) Csaky, A. G.; Contreras, C.; Mba, M.; Plumet,
J. Synlett 2002, 1451. (c) Csaky, A. G.; Mba, M.; Plumet, J.
Synlett 2003, 2092.
(7) Rodríguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J. Eur.
J. Org. Chem. 1999, 2655.
(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-
(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
Synlett 2007, No. 10, 1553–1556 © Thieme Stuttgart · New York