PAPER
Synthesis of 2-Phenyl- and 2-(1-Naphthyl)cyclohexanols
751
Table 2 Lipase-Mediated Kinetic Resolution of ( )-3a
Entry
Enzymeb
Reaction Time
(1S,2R)-3
(1R,2S)-5
Yield (%)c
ee (%)d
<50
Yield (%)c
ee (%)e
99
1
OF
14 d
7 d
90
9
2f
3
AK
AK
AK
AK
66
<50
29
>98
>99
>99
>99
10 d
20 d
10 d
49.5
49.5
49.5
>99
49.5
49.5
49.5
4
>99
5g
>99
a All reactions were carried out in t-BuOMe (0.285 M concentration) with 10 equiv of vinyl acetate at 35 °C unless otherwise mentioned. For
entries 1 and 2, ( )-3/enzyme = 0.22 mmol/44 mg; for entries 3–5, ( )-3/enzyme = 10 mmol/4.52 g.
b OF: lipase OF-360, AK: lipase AK.
c All yields are for the isolated compound. For entries 1 and 2, various amounts of the enantiomer were detected in the isolated material.
d ee was determined by HPLC analysis using a chiral column ChiralCel OD (i-PrOH–hexane, 1: 99; flow rate: 2 mL/min; tR 23.01 min for (+)-
3; 7.66 min for (+)-5, l = 254 nm).
e ee was determined by the HPLC analysis of the corresponding alcohol using a chiral column, ChiralCel OD (i-PrOH–hexane, 1:99; flow rate:
2 mL/min; tR 28.42 min for (–)-3, l = 254 nm).
f Reaction was carried out at r.t.
g Recovered enzyme was used.
mL) was stirred at 35 °C for 5 d. To determine the completion of the
reaction, aliquots were taken and purified by flash chromatography
on silica gel (EtOAc–hexanes, 5:95), and the optical purity was de-
termined by HPLC using chiral column chiralcel OD (i-PrOH–hex-
ane, 1:99; flow rate: 2 mL/min). After completion of the reaction,
the mixture was cooled to r.t., filtered through a sintered-glass fun-
nel, and rinsed with EtOAc (100 mL). The combined organic layers
were dried over anhyd MgSO4, concentrated in vacuo and chro-
matographed on silica gel (EtOAc–hexane, 5:95 to 10:90) to furnish
(+)-2 (0.87 g) as white crystals and (–)-4 (1.08 g) as a pale yellow
oil.
(+)-3
Mp 99.5–100.5 °C (Lit.13 100–101 °C); [a]D25 +72.2 (c 1.0, EtOH)
{Lit.13 [a]D26 +78.8 (c 1.0, CHCl3)}.
(+)-5
[a]D25 +34.9 (c 1.0, EtOH) {Lit.13 [a]D26 +36.2 (c 1.05, CHCl3)}.
Hydrolysis of (+)-5 (1.33 g, 4.9 mmol) using the same method de-
scribed in the preceding experiment gave pure (–)-3 (1.11 g).
(–)-3
Mp 99.5–100.5 °C (Lit.13 100–100.5 °C); [a]D25 –71.9 (c 1.1, EtOH)
{Lit.13 [a]D26 –72.6 (c 1.0, CHCl3)}.
(+)-2
25
Mp 63.5–64.5 °C (Lit.14 64–65 °C); [a]D +56.9 (c 1.0, EtOH)
{Lit.14 [a]D23 +55.0 (c 0.10, MeOH)}.
Acknowledgment
We thank the National Science Council of the Republic of China for
financial support.
(–)-4
[a]D25 –6.5 (c 0.32, EtOH) [Lit.15 [a]D –6.2].
The optically active ester (–)-4 was chemically hydrolyzed. To a so-
lution of (–)-4 (0.99 g, 4.5 mmol) in MeOH (10 mL), was added
K2CO3 (1.86 g, 13.5 mmol). After stirring at r.t. for 10 h, the reac-
tion mixture was concentrated in vacuo, and the residue was parti-
tioned between EtOAc (50 mL) and H2O (20 mL). The organic layer
was washed with brine (20 mL), dried over anhyd MgSO4, the
EtOAc evaporated under reduced pressure and the residue was
chromatographed on silica gel (EtOAc–hexanes, 10:90) to afford
pure (–)-2 (0.78 g).
References
(1) Whitesell, J. K. Chem. Rev. 1992, 92, 953.
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(4) (a) Maddaluno, J. F.; Fox, M. A. J. Org. Chem. 1994, 59,
793. (b) Dumas, F.; Mesrhab, B.; D’Angelo, J.; Riche, C.;
Chironi, A. J. Org. Chem. 1996, 61, 2293.
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4378.
Mp 64–65 °C (Lit.11b 64–65 °C); [a]D25 –56.8 (c 1.0, EtOH) {Lit.11b
[a]D23 –58.6 (c 1.19, MeOH)}.
1
The spectral properties (IR, H NMR, 13C NMR and MS) of the
above compounds were found to be in good agreement with those
reported.11b,16
(8) King, S. B.; Sharpless, K. B. Tetrahedron Lett. 1994, 35,
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(9) (a) Jeong, K. S.; Kim, S. H.; Park, H. J.; Chang, K. J.; Kim,
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Process Res. Dev. 2003, 7, 583. (b) Sekar, G.; Nishiyama,
H. J. Am. Chem. Soc. 2001, 123, 3603.
Optically Pure (+)- and (–)-2-(1-Naphthyl)cyclohexanol
A suspension of ( )-3 (2.26 g, 10 mmol), vinyl acetate (9.3 mL, 100
mmol), and lipase AK on Celite (4.52 g, Amano) in t-BuOMe (35
mL) was stirred at 35 °C for 10 d. The reaction was worked up as
mentioned above. Chromatography of the crude product on silica
gel (EtOAc–hexanes, 5:95 to 10:90) furnished (+)-3 (1.12 g) as
white crystals and (+)-5 (1.33 g) as a pale yellow oil.
Synthesis 2005, No. 5, 749–752 © Thieme Stuttgart · New York