Scheme 2
Using Rh/Al2O3 as catalyst, the high vacuum distillation of the reaction mixture was not necessary, and the mixture of reaction products was immediately separated by flash chromatography on silica gel, affording the desired all-cis-triol 1 in an improved yield of 50 %.
In conclusion, a convenient one step synthesis of (±)-all-cis-cyclohexane-1,2,4-triol 1, a useful scaffold for natural products synthesis, is reported.
Experimental Section
General Procedures. NMR spectra were run on a JEOL JNM EX 270 spectrometer, using CD3OD as the solvent. TLC was performed on Si gel plates Kieselgel 60F254. Flash chromatography was carried out on Si gel (Merck; particle size 40-63 µm). Raney-nickel, Rh/Al2O3, and 1,2,4-trihydroxybenzene were of commercial grade (Aldrich or Acros) and used without further purification.
(±)-All-cis-cyclohexane-1,2,4-triol (1). The hydrogenation of trihydroxy-1,2,4-benzene 3 was performed in a Parr apparatus. To a solution of 1,2,4-trihydroxybenzene (10 g, 76 mmol) in 50 ml of absolute ethanol, 15 g of Raney-nickel (type W4) was added, and the mixture was stirred for 15 hours at 100 atmospheres of pressure at 100°C. The cooled reaction mixture was filtered on celite and the solvent was evaporated in vacuo. The dark viscous reaction mixture was distilled at high vacuum to afford the crude triol 1, b.p. 130°C at 0.01 mmHg, contaminated by other reaction products (NMR).
This mixture was further separated by flash chromatography. A mixture of CH2Cl2/MeOH (95:5) was used to eluate the first two compounds [compound 4 (Rf = 0.44, in CH2Cl2/MeOH 9:1) and 5 (Rf = 0.29, in CH2Cl2/MeOH 9:1), Scheme 1], then CH2Cl2/MeOH (9:1) was necessary to eluate the desired triol 1 (Rf = 0.16) in 31 % yield. Anal. Calcd. for C6H12O3 (132): C, 54.53; H, 9.15. Found: C, 54.65; H, 9.54. 1H NMR (270 MHz, CD3OD) d 1.30-1.95 (6 H, m, 3 × CH2), 3.59 (2 H, m, 2 × CHOH), 3.77 (1 H, m, CHOH). 13C NMR (68 MHz, CD3OD) d 27.9 (CH2), 29.5 (CH2), 38.1 (CH2), 69.1(CHOH), 69.6 (CHOH), 71.5 (CHOH). Mass spectrum m/z, 70 eV (%): 132 (M+, 2), 114 (37), 96 (7), 88 (14), 86 (14), 83 (9), 75 (33), 74 (10), 73 (39), 71 (47), 70 (100), 69 (12), 68 (17), 67 (12), 60 (10), 58 (60), 57 (60), 55 (21), 45 (52), 44 (96), 43 (56), 42 (19), 41 (32), 39 (15).
The separation of the reaction products 1, 4, and 5, obtained from the hydrogenation reaction, by centrifugal counter current chromatography was performed as follows. An amount of 100 mg of the reaction mixture was separated using the following solvent system: CHCl3 / MeOH / i- PrOH / H2O (5 : 6 : 1 : 4) affording 30 mg of (±)-all-cis-cyclohexane-1,2,4-triol 1.
The high pressure hydrogenation reaction with Rh/Al2O3 was performed in an analogous way as the procedure described with Raney-nickel. The only difference was the amount of rhodium
