M. Frank, R. Miethchen, H. Reinke
FULL PAPER
(17.7 mmol) of chloral and 2.6 g (12.6 mmol) of DCC were added
to a solution of 4 (0.90 g, 5.1 mmol) in dry 1,2-dichloroethane (15
mL), and the mixture refluxed for 6 h. After cooling to room temp.,
aqueous acetic acid (15 mL, 10%) was added and the mixture
shaken for 30 min. Then, the organic phase was separated and the
aqueous phase was extracted with 1,2-dichloroethane (2 ϫ 20 mL).
The combined organic phases were neutralised with a satd. aque-
ous NaHCO3 solution (25 mL), washed with water (25 mL), dried
(MgSO4), and concentrated under reduced pressure. The syrupy
residue was purified by column chromatography (Rf ϭ 0.16, tolu-
ene/ethyl acetate ϭ 5:1). Compound 6 was isolated as a syrupy
mixture of endo-H/exo-H diastereomers (23:1) in a yield of 1.53 g
(70%). After re-chromatography, the pure endo-H form was ob-
H, 6e-H), 1.31 (d, 1 H, acetal-CH3). Ϫ 13C NMR (62.9 MHz,
CDCl3): δ ϭ 100.9 (acetal-C), 79.3 (C-4), 78.4 (C-3), 77.4 (C-1),
68.8 (C-2), 67.6 (C-5), 57.7 (OϪCH3), 29.3 (C-6), 21.2 (acetal-
CH3). Ϫ C9H16O5 (204.22): calcd. C 52.93, H 7.90; found C 52.79,
H 7.76.
(1S,2S,3R,4S,5R)-5-O-(N-Cyclohexylcarbamoyl)-1-O-methylcyclo-
hexane-1,2,3,4,5-pentol (10): A solution of 6 (212 mg, 0.49 mmol),
Bu3SnH (0.5 g, 1.72 mmol) and AIBN (20 mg) in dry toluene (20
mL) was hydrodehalogenated as described for compound 8. The
syrupy crude product 9 was deacetalized by treatment with 80%
aqueous trifluoroacetic acid (10 mL) under stirring (6 h at room
temp.). After evaporation of the solvents under reduced pressure,
the residue was purified by column chromatography (Rf ϭ 0.13,
toluene/ethyl acetate ϭ 1:5). The overall yield (two steps) of crystal-
line colourless product 10 was 117 mg (79%); m.p. 129Ϫ130.5°C
25
tained as amorphous solid; [α]D ϭ Ϫ55.6 (c ϭ 1.20, CHCl3). Ϫ
1H NMR (400 MHz, CDCl3): δ ϭ 5.40 (s, 1 H, acetal-H), 4.75
(ddd, 1 H, J5,6a ഠ 11.7 Hz, J5,6e ഠ 4.3 Hz, 5-H), 4.74 (d, 1 H,
JNH,CH ഠ 7.9 Hz, NϪH), 4.68 (dd, 1 H, J3,4 ഠ 5.4 Hz, 3-H), 4.54
(dd, 1 H, J4,5 ഠ 8.0 Hz, 4-H), 4.28 (dd, 1 H, J2,3 ഠ 3.4 Hz, 2-H),
3.57 (ddd, 1 H, J1,2 ഠ 3.0 Hz, J1,6a ഠ 10.4 Hz, J1,6e ഠ 7.2 Hz, 1-
H), 3.50Ϫ3.41 (m, 1 H, C6H11ϪCH), 3.38 (s, 3 H, OϪCH3), 2.83
(br., 1 H, OH), 2.11 (ddd, 1 H, J6a,6e ഠ 12.5 Hz, 6e-H), 1.76 (ddd,
1 H, 6a-H), 1.73Ϫ1.53 (m, 4 H, C6H11ϪCH2), 1.39Ϫ1.05 (m, 6 H,
C6H11ϪCH2). Ϫ 13C NMR (100 MHz, CDCl3): δ ϭ 154.7 (CϭO),
105.8 (acetal-C), 99.1 (CCl3), 79.3 (C-4), 78.9 (C-3), 75.7 (C-1), 70.0
(C-5), 68.9 (C-2), 56.8 (OϪCH3), 49.9 (C6H11ϪCH), 27.3 (C-6),
33.3, 25.4, 24.7 (5 C6H11ϪCH2). Ϫ C16H24Cl3N1O6 (432.73): calcd.
C 44.41, H 5.59, N 3.24; found C 44.37, H 5.49, N 3.20.
25
1
(methanol); [α]D ϭ Ϫ35.4 (c ϭ 0.25, MeOH). Ϫ H NMR (250
MHz, CD3OD): δ ϭ 4.69 (m, 5-H), 4.47 (br., 1 H, NϪH), 3.98
(ddd, 1 H, J2,3 ഠ 2.7 Hz, J2,6e ഠ 1.2 Hz, 2-H), 3.88 (dd, 1 H, J3,4
ഠ
4.6 Hz, 3-H), 3.72 (dd, 1 H, J4,5 ഠ 9.5 Hz, 4-H), 3.55 (ddd, 1 H,
J1,6a ഠ 11.2 Hz, J1,6e ഠ 4.5 Hz, 1-H), 3.30 (s, 3 H, OϪCH3),
3.28Ϫ3.22 (m, 1 H, cyclohexyl-CϪH), 2.01 (dddd, 1 H, J5,6e ഠ 4.6
Hz, J6a,6e ഠ 11.9 Hz, 6e-H), 1.89Ϫ176 (m, 2 H, cyclohexyl-CH2),
1.75Ϫ1.62 (m, 3 H, cyclohexyl-CH2), 1.56 (m, 1 H, 6a-H),
1.38Ϫ1.02 (m, 5 H, cyclohexyl-CH2). Ϫ 13C NMR (63 MHz,
CD3OD): δ ϭ 158.1 (CϭO), 77.0 (C-1), 73.5 (C-3), 72.9 (C-5), 71.7
(C-4), 70.5 (C-2), 56.7 (OϪCH3), 51.2 (cyclohexyl-CϪH), 34.1
(cyclohexyl-CH2), 30.3 (C-6), 26.6, 26.6, 26.1, 26.1 (4 cyclohexyl-
CH2). Ϫ C14H26NO6 (303.35): calcd. C 55.43, H 8.31, N 4.62;
found C 55.21, H 8.21, N 4.56.
(1S,2S,3R,4S,5R)-1-O-Methyl-3,4-O-(2,2,2-trichloroethylidene)-
cyclohexane-1,2,3,4,5-pentol (7): 0.68 g (1.57 mmol) of 6, dissolved
in anhydrous methanol (15 mL)/sodium methoxide (0.5 g, 9.5
mmol), was decarbamoylated by heating the solution under reflux
for 8 h. Subsequently, the reaction mixture was cooled and neutral-
ised with an acidic ion exchanger (Amberlite IR-120). After evapor-
ation of the solvent under reduced pressure and column chromato-
graphic purification (Rf ϭ 0.22, toluene/ethyl acetate ϭ 2:1), 483
(1S,2S,3R,4S,5R)-2,3,4,5-Tetra-O-acetyl-1-O-methylcyclohexane-
1,2,3,4,5-pentol (12): A solution of compound 10 (100 mg, 0.33
mmol) in 1% methanolic sodium methoxide (15 mL) was heated
for 15 h under reflux. When the reaction was finished (TLC con-
trol: CHCl3/MeOH ϭ 5:1, Rf ϭ 0.22), the mixture was cooled
down, neutralised with an acidic ion exchanger (Amberlite IR 120),
filtered, and the filtration residue was washed with methanol (2 ϫ
10 mL). The combined methanolic solutions were concentrated un-
der reduced pressure and the crude product 11 obtained treated
with a mixture of acetic anhydride (5 mL) and pyridine (5 mL)
under stirring (room temp., 24 h). After evaporation of the solvents
under reduced pressure, the residue was co-distilled with toluene (2
ϫ 10 mL) giving the syrupy tetra-O-acetyl derivative 12, which was
purified by column chromatography (Rf ϭ 0.20, toluene/ethyl ace-
tate ϭ 3:1). Yield: 94 mg (82%, related to 10), colourless crystals,
mg (85.3%) of the colourless crystalline compound 7 was obtained;
25
m.p. 114Ϫ115°C (heptane/diethyl ether ϭ 25:1, v/v), [α]D
ϭ
ϩ16.2 (c ϭ 1.51, CHCl3). Ϫ 1H NMR (400 MHz, CDCl3): δ ϭ
5.36 (s, 1 H, acetal-H), 4.69 (dd, 1 H, J3,4 ഠ 5.4 Hz, 3-H), 4.63
(dd, 1 H, J4,5 ഠ 5.0 Hz, 4-H), 3.98 (dd, 1 H, J2,3 ഠ 5.4 Hz, 2-H),
3.96 (dd, 1 H, J5,6a ഠ 6.7 Hz, 5-H), 3.64 (ddd, 1 H, J1,2 ഠ 3.0 Hz,
J1,6a ഠ 7.1 Hz, J1,6e ഠ 4.0 Hz, 1-H), (s, 3 H, OϪCH3), 1.99 (dd, 1
H, J6a,6e ഠ 13.3 Hz, 6a-H), 1.96 (ddd, 1 H, 6e-H). Ϫ 13C NMR
(100 MHz, CDCl3): δ ϭ 106.2 (acetal-C), 99.4 (CCl3), 81.4 (C-4),
79.9 (C-3), 77.9 (C-1), 69.1 (C-2), 67.7 (C-5), 57.9 (OCH3), 29.1 (C-
6). Ϫ C9H13Cl3O5 (307.56): calcd. C 35.15, H 4.26; found C 35.28,
H 4.33.
23
m.p. 109Ϫ110°C (toluene); [α]D ϭ Ϫ5.90 (c ϭ 1.15, CHCl3). Ϫ
1H NMR (250 MHz, CDCl3): δ ϭ 5.37 (dd, 1 H, J3,4 ഠ 4.9 Hz, 3-
H), 5.28 (ddd, 1 H, J2,3 ഠ 3.2 Hz, J2,6e ഠ 1.4 Hz, 2-H), 5.17 (dd,
(1S,2S,3R,4S,5R)-3,4-O-Ethylidene-1-O-methylcyclohexane-1,2,3,4,5-
pentol (8): A solution of 7 (485 mg, 1.58 mmol), Bu3SnH (1.61 g,
5.53 mmol) and AIBN (35 mg) in dry toluene (20 mL) was refluxed
for 12 h under argon. After cooling, the solution was shaken with a
satd. aqueous KF solution (30 mL) for 30 min and the precipitated
Bu3SnF removed by filtration. Then the organic phase was sepa-
rated, washed with water (2 ϫ 15 mL), dried (Na2SO4), and con-
centrated under reduced pressure. The residue was purified by col-
umn chromatography (Rf ϭ 0.24, ethyl acetate/toluene ϭ 2:1) giv-
1 H, J4,5 ഠ 9.6 Hz, 4-H), 5.07 (ddd, 1 H, J5,6e ഠ 4.6 Hz, J5,6a
ഠ
10.6 Hz, 5-H), 3.62 (ddd, 1 H, J1,2 ഠ 3.0 Hz, J1,6a ഠ 11.2 Hz,
J1,6e ഠ 4.3 Hz, 1-H), 3.30 (s, 3 H, OϪCH3), 2.20 (dddd, 1 H,
J6a,6e ഠ 12.5 Hz, 6e-H), 2.11, 2.07, 2.02, 1.96 (4 s, 4 ϫ 3 H, 4
C(O)CH3), 1.85 (ddd, 1 H, 6a-H). Ϫ 13C NMR (63 MHz, CDCl3):
δ ϭ 170.1, 169.8, 169.4, 169.0 (4 C(O)CH3), 73.8, 70.2, 67.9, 67.8,
67.3 (C-1, C-2, C-3, C-4, C-5), 57.2 (OϪCH3), 29.8 (C-6), 20.9,
20.8, 20.7, 20.6 [4 C(O)CH3]. Ϫ C15H22O9 (346.33): calcd. C 52.02,
H 6.40; found C 52.25, H 6.46.
25
ing 285 mg (89%) of 8 as colourless syrup; [α]D ϭ ϩ48.0 (c ϭ
1
1.05, CHCl3). Ϫ H NMR (250 MHz, CDCl3): δ ϭ 5.34 [q, 1 H,
J(acetal-H,acetal-CH3) ഠ 4.9 Hz, acetal-H], 4.24 (dd, 1 H, J3,4
5.2 Hz, 3-H), 4.16 (dd, 1 H, J4,5 ഠ 5.2 Hz, 4-H), 3.92 (dd, 1 H,
J2,3 ഠ 5.3 Hz, 2-H), 3.87 (dd, 1 H, J5,6 ഠ 7.3 Hz, 5-H), 3.60 (ddd,
ഠ
Acknowledgments
1 H, J1,2 ഠ 3.1 Hz, J1,6a ഠ 7.2 Hz, J1,6e ഠ 4.0 Hz, 1-H), 3.43 (s, 3 The authors are grateful to Dr. Rhett Kempe (Institut für Organi-
H, OϪCH3), 1.95 (dd, 1 H, J6a,6e ഠ 14.0 Hz, 6a-H), 1.90 (ddd, 1
sche Katalyseforschung e.V., Rostock) for recording the X-ray data
1262
Eur. J. Org. Chem. 1999, 1259Ϫ1263