P. Bernardelli et al. / Tetrahedron: Asymmetry 15 (2004) 1451–1455
1453
25.7 g (17%th) of the desired racemic trans-1-(3-hy-
droxycyclohexyl)benzamide as a white crystalline solid.
1H NMR (360 MHz, (CD3)2SO, dH) 8.14 (d, J ¼ 8 Hz,
1H), 7.83 (d, J ¼ 7 Hz, 2H), 7.53–7.42 (m, 3H), 4.48 (s,
1H), 4.23 (m, 1H), 4.00 (br s, 1H), 1.79–1.31 (m, 8H);
13C NMR (75 MHz, (CD3)2SO, dC) 166.3, 135.8, 131.7,
128.9, 128.1, 65.6, 44.7, 33.1, 32.9, 20.0.
acetoxycyclohexane (5 g, 0.19 mol) portionwise. The
mixture was heated at reflux for 72 h, cooled and quen-
ched with water (2.90 mL) and 20% aqueous NaOH
(2.90 mL). Water (8.7 mL) was added, agitated for
20 min, and filtered. The lithium salts were washed with
THF (100 mL) and the solvents removed in vacuo at
40 ꢂC to provide the crude product as a tan oil, which was
subjected to chromatography on silica to give (S,S)-3N-
benzylaminocyclohexanol (2.61 g, 70%th). 1H NMR
(360 MHz, (CD3)2SO, dH) 7.36–7.21 (m, 5H), 4.28 (br s,
1H), 3.89 (br s, 1H), 3.70 (s, 2H), 2.81–2.79 (m,
1H), 1.66–1.63 (m, 2H), 1.52–1.38 (m, 6H), 1.21–1.18 (m,
1H).
4.3. (rac)-trans-1-Acetoxy-3-benzylamidocyclohexane 3
To a stirred suspension of the trans-1-(3-hydroxy-
cyclohexyl)benzamide (15 g, 0.68 mol) in THF (500 mL)
at 0–5 ꢂC, was charged triethylamine (25.8 mL,
2.75 equiv) and acetyl chloride (9.5 mL, 2.0 equiv) over
ca. 5 min (exothermic) while maintaining the tempera-
ture below 20 ꢂC. Two further portions (as above) of
Et3N and AcCl were added after 1 and 2 h. The precip-
itate was filtered and washed with THF (200 mL), the
filtrate concentrated in vacuo, and the residue taken up
in ethyl acetate (500 mL) and water (500 mL). The phases
were separated and the organic phase washed with brine
(200 mL), dried over magnesium sulfate, and concen-
trated in vacuo to give a sticky orange solid. The crude
material was slurried in TBME (100 mL) for 30 min at
ambient temperature, cooled to <10 ꢂC, and filtered. The
filter cake was washed with TBME (2 · 50 mL) and dried
in vacuo at 40 ꢂC to give 13.48 g (75%) of the (rac)-trans-
3-benzylamidoacetoxy cyclohexane as a pale orange
solid. 1H NMR (360 MHz, (CD3)2SO, dH) 7.78–7.62 (m,
2H), 7.53–7.43 (m, 3H), 6.03 (d, J ¼ 6 Hz), 5.18 (br s,
1H), 4.40–4.36 (m, 1H), 2.25–2.05 (m and s, 2H and 3H),
1.85–1.56 (m, 5H), 1.38–1.27 (m, 1H).
4.6. (S,S)-3-Aminocyclohexanol 6
To a stirred suspension of 10% palladium on carbon
(1.25 g) (50% wet Degussa type E101) in ethanol (25 mL)
was charged (S,S)-3N-benzylaminocyclohexanol (2.50 g,
0.013 mol) as a solution in ethanol (25 mL) under
nitrogen. The reaction vessel was purged with hydrogen
and the mixture stirred vigorously under 1 atm of
hydrogen for ca. 16 h. The reaction vessel was purged
with nitrogen, the catalyst removed by filtration, and
washed with ethanol (50 mL, 20 vol) under a blanket of
nitrogen. The filtrate was concentrated in vacuo at
40 ꢂC, taken up in chloroform (25 mL), and dried over
magnesium sulfate. The filtrate was concentrated in
vacuo at 40 ꢂC to give (S,S)-3-aminocyclohexanol as a
colorless solid (1.25 g, 87%). 1H NMR (360 MHz,
(CD3)2SO, dH) 4.15 (br s, 1H), 3.19–3.12 (m,1H), 1.89–
1.38 (m, 7H, br s, OH and NH2), 1.21–1.12 (m, 1H); 13
C
NMR (MHz, (CDCl3), dC) 67.1, 45.9, 43.3, 36.1,
20
33.4, 30.7, 19.6; ½aꢁ ¼ þ7:5 (c 1, CH3OH); ee (HPLC)6
D
4.4. (S,S)-1-Acetoxy-3-benzylamidocyclohexane 4 and
(R,R)-3-benzylamidocyclohexanol 5
95.46%.
To a suspension of (rac)-trans-3-benzylamidoacetoxy
cyclohexane (13.0g, 0.05mol) in toluene (325 mL) were
charged Novozymꢁ 435 (19.5 g) and ethanol (37 mL) at
18–22 ꢂC. The mixture was stirred for 120 h, after which
the catalyst was filtered through a pad of Celiteꢁ and the
filter cake washed with ethanol (300 mL). The filtrate was
concentrated in vacuo. The acetate and alcohol were sep-
arated by flash column chromatography on silica gel
(20 wt) [eluent: 1:1 ethyl acetate/heptane to elute the ace-
tate (Rf 0.76) and 100% ethyl acetate to elute the (R,R)-3N-
benzylamidocyclohexanol (Rf 0.36)] to give 5.2 g (47.5%)
4.7. (R,R)-3-Benzylaminocyclohexanol
To a suspension of LiAlH4 (2.63 g, 3 equiv) in anhy-
drous THF (150 mL) was charged (R,R)-3N-benzyl-
amidocyclohexanol (5.0 g, 0.023 mol) portionwise. Once
all the substrate was charged, the mixture was heated to
reflux for 72 h. The reaction was cooled to 0–5 ꢂC in an
ice/water bath and water (2.63 mL) added very carefully
to the mixture over ca. 20 min maintaining the temper-
ature below 15 ꢂC. This was followed by 15% sodium
hydroxide solution (2.63 mL), again added carefully
over 20 min while maintaining the temperature below
15 ꢂC. To this thick mixture was charged water
(7.89 mL) and the mixture stirred at 10–20 ꢂC for 15 min.
The solids were filtered and washed with THF (100 mL)
and the filtrate concentrated in vacuo at 40 ꢂC. The
crude material was purified by flash column chromato-
graphy on silica gel (20 wt) using 100% ethyl acetate to
8:2 ethyl acetate/methanol to elute the product. The
fractions were concentrated at 40 ꢂC to give 2.3 g, 52%th
(corrected for residual solvents) of the title compound as
1
of the alcohol. H NMR (360 MHz, (CD3)2SO, dH) 8.14
(d, J ¼ 8 Hz, 1H), 7.83 (d, J ¼ 7 Hz, 2H), 7.53–7.42 (m,
3H), 4.48 (s, 1H), 4.23 (m, 1H), 4.00 (br s, 1H), 1.79–1.31
(m, 8H); and 5.2 g (40%) of the (S),(S)-3-benzylamido-
1
acetoxycyclohexane. H NMR (360 MHz, (CD3)2SO, dH)
7.78–7.62 (m, 2H), 7.53–7.43 (m, 3H), 6.03 (d, J ¼ 6 Hz),
5.18 (br s, 1H), 4.40–4.36 (m, 1H), 2.25–2.05 (m and s, 2H
and 3H), 1.85–1.56 (m, 5H), 1.38–1.27 (m, 1H).
1
4.5. (S,S)-3-N-Benzylaminocyclohexanol
a yellow oil. H NMR (360 MHz, (CD3)2SO, dH) 7.36–
7.21 (m, 5H), 4.28 (br s, 1H), 3.89 (br s, 1H), (s, 2H),
2.81–2.79 (m, 1H), 1.66–1.63 (m, 2H), 1.52–1.38 (m,
6H), 1.21–1.18 (m, 1H).
To a suspension of LiAlH4 (2.90 g, 4 equiv) in anhydrous
THF (150 mL) was charged (S,S)-3N-benzylamido-