Chemo-enzymatic preparation of optically active endo- bicyclo[4.1.0]heptan-2-ols

Article abstract of DOI:10.1016/S0957-4166(99)00099-3

Resolutions of endo-bicyclo[4.1.O]heptan-2-ols were achieved by acylation in the presence of lipase from Candida antarctica (Novozym). The (1S,2R,6R) enantiomers reacted faster and the enantiomeric ratios were between 60 and 800 for the 6-substituted bicycloalkanols.

Full text of DOI:10.1016/S0957-4166(99)00099-3

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1107–1117
Chemo-enzymatic preparation of optically active
endo-bicyclo[4.1.0]heptan-2-ols
Jean-Pierre Barnier, Véronique Morisson, Isabelle Volle and Luis Blanco ∗
Laboratoire des Carbocycles (Associé au CNRS), Institut de Chimie Moléculaire d’Orsay, Bât. 420, Université de Paris-Sud,
91405 Orsay, France
Received 5 February 1999; accepted 15 March 1999
Abstract
Resolutions of endo-bicyclo[4.1.0]heptan-2-ols were achieved by acylation in the presence of lipase from
Candida antarctica (Novozym®). The (1S,2R,6R) enantiomers reacted faster and the enantiomeric ratios were
between 60 and 800 for the 6-substituted bicycloalkanols. © 1999 Published by Elsevier Science Ltd. All rights
reserved.
1. Introduction
The synthesis of optically active bicyclo[n.1.0]alkan-2-ols should be interesting in order to prepare
natural compounds with such a feature1 or analogs, but these compounds are also interesting intermedi-
ates for the synthesis of various types of compounds with one or several stereogenic carbon centers. For
example, oxymercuration of bicycloalkan-2-ols results in the diastereoselective formation of cycloalkan-
1,3-diols derivatives with three stereogenic centers by cleavage of the C(n+2)–C(n+3) cyclopropane bond.2
Substitution of the hydroxyl group by a homolytically cleavable substituent allows the synthesis of
cycloalkenes with at least one stereogenic carbon atom by cleavage of the C1–C(n+3) cyclopropane
bond.3–5
This cyclopropylcarbinyl-homoallyl rearrangement also allows the preparation of various fused or
spiro unsaturated compounds by cascade reactions including radical intramolecular cyclizations when the
starting bicycloalkanol bears an unsaturated alkyl chain.4 Moreover, oxidation of these bicycloalkanols
∗
Corresponding author. Fax: +33(1)69156278; e-mail: lublanco@icmo.u-psud.fr.
0957-4166/99/$ - see front matter © 1999 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00099-3

1108
J.-P. Barnier et al. / Tetrahedron: Asymmetry 10 (1999) 1107–1117
into bicyclo[n.1.0]alkan-2-ones enables the synthesis of various cycloalkanone derivatives by cleavage
of the C1–C(n+3) cyclopropane bond 6–14 and tandem cyclopropane bond cleavage intramolecular cycliza-
tions have also been reported when an unsaturated alkyl chain is present on the starting material.11b,12b,14
It was shown that cyclopropane bond cleavage occurred in various cases without an absolute con-
figurational change3,8a,11c,12 of carbon C(n+2) or with inversion of its configuration.2 The preparation
of enantiomerically enriched bicyclo[n.1.0]alkan-2-ol derivatives should give access to various types of
optically active compounds.
Optically active bicyclo[n.1.0]alkan-2-ols are generally prepared by hydroxyl directed
cyclopropanation15,16 of optically active cycloalk-2-en-1-ols9,17 or by diastereoselective addition
of nucleophiles to enantiomerically enriched bicyclo[n.1.0]alkan-2-ones.3,18 Recently we have reported
the lipase-catalyzed kinetic resolution of racemic endo-bicyclo[4.1.0]heptan-2-ol and that of the
corresponding 6-methyl and 1-methyl substituted compounds.19,20
In this paper we have focussed on the preparation of optically active 6-substituted endo-
bicyclo[4.1.0]heptan-2-ols by enzymatic resolution in order to show up the influence of the substituent
on the enantioselectivity.
2. Results and discussion
The endo-bicycloheptan-2-ols 4a–4g were prepared by reaction under air21 of cyclohex-2-en-1-ols
3a–3g with the reagent obtained by the addition of ClCH2I to Et2Zn.22 The required cyclohexenols
3a–3g were obtained by reduction of the corresponding cyclohex-2-en-1-ones 2a–2g with NaBH4 in the
presence of CeCl3·7H2O.23 Reaction of 3-ethoxycyclohex-2-en-1-one 124 with a Grignard reagent25
(R=C2H5, C8H17, C11H23) or with a halogenated compound in the presence of lithium (R=C4H9)26
followed by an aqueous treatment gave the 3-substituted cyclohexenones 2c–2f. It is noteworthy that
the 3-benzylcyclohexenone 2g was obtained by addition of the 4-benzyloxy-1-bromobutane to a mixture
of lithium and the 3-ethoxycyclohexenone 1.27
Transesterifications of isopropenyl hexanoate with these bicycloheptan-2-ols 4a–4g were run in tert-
butyl methyl ether at 37°C in the presence of Novozym® (an immobilized form of lipase B from
Candida antarctica) which was found to give higher reaction rates and higher enantioselectivities in the
transesterification of isopropenylacetate with 4a or 4b.19 Isopropenyl hexanoate was prepared by heating
at reflux a mixture of hexanoic acid and isopropenylacetate in the presence of para-toluenesulfonic
acid.28
Generally, enzyme-catalyzed transesterifications were stopped at about 50% conversion by removing
the enzyme by filtration, then bicycloheptyl hexanoates 5* and unreacted bicycloheptanols 4* were sepa-
rated by silica gel column chromatography. Enantiomeric excesses (ees) of bicycloheptanols 4b*–4g*
were determined by gas chromatography on a chiral capillary column (Cydex B) and those of 4a*

J.-P. Barnier et al. / Tetrahedron: Asymmetry 10 (1999) 1107–1117
1109
Table 1
Novozym®-catalyzed transesterification of isopropenyl hexanoate with bicyclo[4.1.0]heptan-2-ols
4a–4g
samples were determined by HPLC of the corresponding phenylcarbamate on a chiral OD-H column.
Enantiomeric excesses of bicycloheptyl hexanoates 5a*–5g* were measured as described above from the
corresponding bicycloheptan-2-ols isolated after treatment of these esters with LiAlH4. For each reaction
the conversion ratio c and the enantiomeric ratio E were calculated from the enantiomeric excess of the
product (eep) and the enantiomeric excess of the unreacted substrate (ees) using the usual formulas:
(E=Ln[(1−ees)(eep/(ees+eep))]/Ln[(1+ees)(eep/(ees+eep))]; c=ees/(ees+eep)).29 Our results are reported
in Table 1.
With the parent bicycloheptanol 4a it was shown that it is possible to isolate, as expected, the unreacted
substrate or the ester product with a good ee by running the reaction to more or less than 50% conversion
(see entries 1 and 2). The enantioselectivity of the Novozym®-catalyzed transesterification of isopropenyl
hexanoate with the bicycloheptanol 4a (E=80–88)30 appears to be slightly higher than that observed using
isopropenyl acetate (E=51).19 It should be noticed that the Rf value of a bicycloheptyl hexanoate is higher
than that of the corresponding acetate and the separation of reaction products after transesterification was
easier when the reaction was performed with isopropenyl hexanoate.
With the 6-substituted bicycloheptanols 4b–4j the enantiomeric ratio was generally higher than 100
and it seems that the general trend was an increase in selectivity on going from the methyl substituted
compound to the one bearing the undecyl substituent. With the more crowded benzylated compound 4g

1110
J.-P. Barnier et al. / Tetrahedron: Asymmetry 10 (1999) 1107–1117
the enantioselectivity was sufficient to isolate in one experiment the ester and the unreacted alcohol with
very high enantiomeric excess (ee=98%).
Samples of ethylbicycloheptanol 4c and of butylbicycloheptanol 4d enriched in the (1R,2S,6S)-31,38
and (1S,2R,6R)-enantiomers, respectively, were synthesized by cyclopropanation of (S)-3-ethylcyclohex-
2-enol 3c* and (R)-3-butylcyclohex-2-enol 3d* prepared by reaction, in the presence of Li2CuCl4, of
EtMgBr and BuMgBr32 with the known optically active (S)- and (R)-3-iodocyclohex-2-enols 6 which
were available by the method described by Mori et al.33
Comparison of the specific rotation sign and of the retention time in gas chromatography on a
Cydex B column of the (1R,2S,6S)-ethylbicycloheptanol and the (1S,2R,6R)-butylbicycloheptanol with
those of the optically active bicycloheptanols isolated after the Novozym®-catalyzed transesterification
with 4c and 4d shows that this enzyme reacts faster with the (1S,2R,6R)-enantiomers. Comparison
of the chiroptical properties of optically active bicycloheptanols 4a* and 4b* with those reported
in the literature19 also show a fast reaction of this lipase with (1S,2R,6R)-alcohols and the same
enantioselectivity of the Novozym®-catalyzed reaction was postulated for all the other cases. The
homogeneousness of the specific rotation signs of bicycloheptanols (levorotatory for the unreacted
alcohols 4a*–4g* and dextrorotatory for those isolated after reduction of bicycloheptyl hexanoates
5a*–5g*) was in agreement with such an assumption.
3. Conclusion
In summary, this work shows that Novozym®-catalyzed transesterifications allow the preparation of
optically active 6-substituted endo-bicyclo[4.1.0]heptan-2-ols with a wide range of substituents. The
usual enantioselectivity for the ‘R’-isomer generally reported for Candida antarctica lipase34,35 and
various lipases36,37 was also noticed.
4. Experimental
4.1. General methods
1H and 13C NMR spectra were recorded on a Bruker AC-200 (200 and 50.3 MHz, respectively),
or on a AC-250 (250 and 62.9 MHz, respectively), instrument. Chemical shifts are expressed in parts

J.-P. Barnier et al. / Tetrahedron: Asymmetry 10 (1999) 1107–1117
1111
per million (δ) relative to tetramethylsilane. Abbreviations are as follows: s, singlet; d, doublet; dd,
doublet of doublet; t, triplet; tt, triplet of triplet; q, quartet; m, multiplet and b for a broadened signal.
Infrared spectra were recorded on a Perkin–Elmer 682 spectrometer. Mass spectra were determined on
a GC–MS Nermag R10-10 (capillary column: CPSIL5, 25 m) at an ionizing voltage of 70 eV. Column
chromatography was carried out with 70–230 mesh silica gel. TLC was performed on 0.25 mm silica
gel (Merk 60F254). Dry solvents were obtained as follows: diethyl ether was distilled over LiAlH4,
THF was distilled over sodium–benzophenone radical anions, 1,2-dichloroethane and tert-BuOMe were
filtered through a short column of basic alumina (activity I). A 25 m×0.25 mm ID Cydex B column was
used for the ee measurements (flow carrier: helium). Cyclohexane-1,3-dione, cyclohex-2-en-1-one and
3-methylcyclohex-2-en-1-one were purchased from Acros Organics.
4.1.1. 3-Ethoxycyclohex-2-en-1-one 1
This compound was prepared as described in the literature24 by treatment of cyclohexane-1,3-dione
with ethanol in the presence of p-toluenesulfonic acid in a distillation apparatus, but the usual solvent
(benzene) was replaced by cyclohexane. With these solvents the boiling point of a ternary azeotrope
(cyclohexane–ethanol–water: 62.1°C or benzene–ethanol–water: 64.6°C) and that of a binary azeotrope
(cyclohexane–ethanol: 64.9°C or benzene–ethanol: 67.8°C) allow removal of first the water formed in
the reaction then the excess ethanol.
The 3-substituted cyclohex-2-enones 2c–g were prepared from the ethoxycyclohexenone 1 according
to literature procedures.25,26
4.1.2. 3-Ethylcyclohex-2-en-1-one 2c
The title compound was obtained from ethoxycyclohexenone 1 and ethylmagnesium bromide, 1.4 g,
56%; 1H NMR (250 MHz, CDCl3) δ 5.88 (t, J=1.6 Hz, 1H), 2.36 (t, J=6.9 Hz, 2H), 2.30 (bt, J=6.4 Hz)
and 2.25 (q, J=7.2 Hz) (4H), 2.00 (tt, J=6.9, 6.4 Hz, 2H), 1.12 (t, J=7.2 Hz, 3H); 13C NMR (62.9 MHz,
CDCl3) δ 199.4, 167.7, 123.9, 36.8, 30.3, 29.2, 22.2, 10.7.39
4.1.3. 3-Butylcyclohex-2-en-1-one 2d
The title compound was obtained from ethoxycyclohexenone 1, 1-bromobutane and lithium, 1.21 g,
56%.40
4.1.4. 3-Octylcyclohex-2-en-1-one 2e
The title compound was obtained from ethoxycyclohexenone 1 and octylmagnesium bromide, 3 g,
72%; 1H NMR (200 MHz, CDCl3) δ 5.88 (t, J=1.6 Hz, 1H), 2.38 (t, J=6.8 Hz) and 2.29 (bt, J=6.4 Hz)
and 2.22 (bt, J=7.6 Hz) (6H), 1.99 (tt, J=6.8, 6.4 Hz, 2H), 1.60–1.42 (m, 2H), 1.42–1.12 (m, 10H), 0.99
(bt, J=6.8 Hz, 3H); 13C NMR (59.3 MHz, CDCl3) δ 195.6, 163.5, 126.2, 38.0, 37.3, 31.5, 30.8, 29.1,
29.0, 26.5, 23.6, 22.5, 22.4, 12.2; IR (neat) 2940, 2860, 1680, 1630, 1460 cm−1; EI-MS (m/z) 208 (M+,
13), 137 (3.3), 123 (41), 109 (11), 95 (20), 82 (100).
4.1.5. 3-Undecylcyclohex-2-en-1-one 2f
The title compound was obtained from ethoxycyclohexenone 1 and undecylmagnesium bromide, 1.5
g, 43%.40

1112
J.-P. Barnier et al. / Tetrahedron: Asymmetry 10 (1999) 1107–1117
4.1.6. 3-Benzylcyclohex-2-en-1-one 2g
The title compound was obtained from ethoxycyclohexenone 1, 4-benzyloxy-1-bromobutane and
lithium, 1.3 g, 50%.41
Cyclohex-2-en-1-ols 3a–g were prepared by treatment in methanol of the cyclohex-2-enones 2a–g
with NaBH4 in the presence of CeCl3·7H2O.23
4.1.7. Cyclohex-2-en-1-ol 3a
882 mg, 90%.
4.1.8. 3-Methylcyclohex-2-en-1-ol 3b
1 g, 90%.
4.1.9. 3-Ethylcyclohex-2-en-1-ol 3c
1.07 g, 85%.38b
4.1.10. 3-Butylcyclohex-2-en-1-ol 3d
1
1.32 g, 86%; H NMR (200 MHz, CDCl3) δ 5.57–5.44 (m, 1H), 4.30–4.11 (m, 1H), 2.09–1.84 (m,
4H), 1.84–1.51 (m, 4H), 1.51–1.12 (m, 5H), 0.87 (bt, J=6.7 Hz, 3H); 13C NMR (59.3 MHz, CDCl3) δ
141.1, 124.7, 66.2, 31.5, 30.0, 28.1, 18.9, 18.7, 13.4, 12.3; IR (neat) 3360, 2940, 2860, 1670, 1450 cm−1;
EI-MS (m/z) 154 (M+, 18), 137 (35), 136 (12), 111 (41), 97 (60), 80 (100).42
4.1.11. 3-Octylcyclohex-2-en-1-ol 3e
1
1.34 g, 64%; H NMR (250 MHz, CDCl3) δ 5.56–5.44 (m, 1H), 4.27–4.11 (m, 1H), 2.06–1.87 (m,
4H), 1.87–1.51 (m, 4H), 1.51–1.13 (m, 13H), 0.88 (bt, J=6.8 Hz, 3H); 13C NMR (62.9 MHz, CDCl3) δ
137.9, 126.3, 67.5, 32.9, 31.8, 28.8, 28.5, 28.3, 27.8, 27.5, 25.3, 23.2, 22.6, 13.6; IR (neat) 3330, 2920,
2860, 1660, 1450 cm−1; EI-MS (m/z) 210 (M+, 12), 193 (4), 192 (10), 97 (100), 79 (10).
4.1.12. 3-Undecylcyclohex-2-en-1-ol 3f
1
1.85 g, 74%; H NMR (200 MHz, CDCl3) δ 5.56–5.42 (m, 1H), 4.27–4.10 (m, 1H), 2.06–1.85 (m,
2H), 1.85–1.51 (m, 4H), 1.51–1.12 (m, 19H), 0.89 (bt, J=6.7 Hz, 3H); 13C NMR (59.3 MHz, CDCl3)
δ 136.8, 127.3, 66.9, 33.4, 31.8, 29.8, 29.6, 27.9, 26.6, 25.4, 23.4, 22.4, 20.3, 15.3, 14.2, 13.2, 12.1; IR
(neat) 3380, 2940, 2860, 1670, 1450 cm−1.
4.1.13. 3-Benzylcyclohex-2-en-1-ol 3g
1
1.32 g, 70%; H NMR (200 MHz, CDCl3) δ 7.46–7.09 (m, 5H), 5.56–5.44 (m, 1H), 4.30–4.15 (m,
1H), 3.29 (s, 2H), 2.12–1.25 (m, 7H); 13C NMR (50.3 MHz, CDCl3) δ 139.6, 134.9, 128.8, 127.8, 125.9,
124.7, 66.5, 46.4, 29.6, 27.3, 23.4, 19.6, 12.9; IR (neat) 3360, 3100, 3080, 3060, 2940, 2860, 1670, 1450
cm−1; EI-MS (m/z) 188 (M+, 2), 171 (6), 170 (36), 97 (100), 79 (23), 77 (13).
4.2. Preparation of bicyclo[4.1.0]heptan-2-ol 4a. Representative procedure
To a solution of 196 mg of cyclohex-2-en-1-ol 3a (2 mmol) in 6 mL of 1,2-dichloroethane cooled
at 0°C was added under argon 4 mL of a 1 M solution of Et2Zn (4 mmol, 2 equiv.) in hexane. The
reaction mixture was stirred for 15 min at 0°C and 600 µL of ClCH2I (8 mmol, 4 equiv.) was added
dropwise. The reaction mixture was allowed to return to room temperature, after 15 min the argon flow

J.-P. Barnier et al. / Tetrahedron: Asymmetry 10 (1999) 1107–1117
1113
was stopped, the flask was equipped with a calcium chloride guard and stirring continued for one hour.
Then the reaction mixture was poured into a saturated ammonium chloride solution and extracted with
diethyl ether. The organic phases were washed with water and brine, and dried over sodium sulfate. The
solvent was removed under vacuum and the crude product was purified by column chromatography on
silica gel (pentane:diethyl ether: 80:20) to give 150 mg (67%) of bicyclo[4.1.0]heptan-2-ol 4a.22
Bicyclo[4.1.0]heptan-2-ols 4b–g were prepared following the same procedure.
4.2.1. 6-Methylbicyclo[4.1.0]heptan-2-ol 4b
151 mg, 60%; 1H NMR (250 MHz, CDCl3) δ 4.22 (dd, J=6.3, 12.3 Hz, 1H), 1.51–1.12 (m, 8H), 1.09
(s, 3H), 0.51 (dd, J=4.9, 4.9 Hz, 1H), 0.31 (dd, J=4.9, 8.9 Hz, 1H); 13C NMR (59.3 MHz, CDCl3) δ 67.7,
31.8, 29.6, 29.1, 28.3, 25.4, 22.2, 14.0.15
4.2.2. 6-Ethylbicyclo[4.1.0]heptan-2-ol 4c
1
274 mg, 98%; H NMR (250 MHz, CDCl3) δ 4.19 (dd, J=6.2, 11.8 Hz, 1H), 1.71–1.29 (m, 6H),
1.29–0.94 (m, 4H), 0.90 (bt, J=7.8 Hz, 3H), 0.49 (dd, J=4.8, 4.8 Hz, 1H), 0.35 (dd, J=4.8, 8.7 Hz, 1H);
13C NMR (62.9 MHz, CDCl3) δ 66.8, 33.7, 29.6, 27.2, 25.1, 24.2, 20.3, 13.4, 10.4; IR (neat) 3380, 3080,
3010, 2960, 2840, 1460 cm−1; EI-MS (m/z) 140 (M+, 1.3), 125 (2.6), 123 (5.5), 122 (22), 111 (39), 107
(29), 94 (26), 93 (100). Anal. calcd for C9H16O: C, 77.09; H, 11.50; O, 11.41, found: C, 76.82; H, 11.60;
O, 11.62.
4.2.3. 6-Butylbicyclo[4.1.0]heptan-2-ol 4d
296 mg, 88%; 1H NMR (250 MHz, CDCl3) δ 4.20 (dd, J=6.2, 12.0 Hz, 1H), 1.73–0.96 (m, 14H), 0.89
(bt, J=7.6 Hz, 3H), 0.48 (dd, J=4.7, 4.7 Hz, 1H), 0.34 (dd, J=4.7, 8.7 Hz, 1H); 13C NMR (62.9 MHz,
CDCl3) δ 66.8, 40.9, 29.6, 28.7, 27.6, 25.3, 23.1, 22.7, 20.2, 14.0, 13.7; IR (neat) 3400, 3060, 3000,
2960, 2840, 1460 cm−1; EI-MS (m/z) 168 (M+, 0.9), 151 (3.3), 150 (13), 125 (9.1), 111 (46), 94 (23), 93
(99), 82 (58), 79 (100). Anal. calcd for C11H20O: C, 78.51; H, 11.98; O, 9.51, found: C, 78.35; H, 12.13;
O, 9.66.
4.2.4. 6-Octylbicyclo[4.1.0]heptan-2-ol 4e
269 mg, 60%; 1H NMR (250 MHz, CDCl3) δ 4.20 (dd, J=6.3, 11.8 Hz, 1H), 1.73–0.96 (m, 22H), 0.8
(bt, J=7.5 Hz, 3H), 0.49 (dd, J=4.6, 4.6 Hz, 1H), 0.35 (dd, J=4.6, 8.5 Hz, 1H); 13C NMR (62.9 MHz,
CDCl3) δ 66.8, 41.3, 31.8, 29.8, 29.7, 29.6, 29.3, 27.7, 26.5, 25.5, 23.3, 22.6, 20.3, 14.0, 13.7; IR (neat)
3360, 3060, 3000, 2960, 2840, 1460 cm−1; EI-MS (m/z) 224 (M+, 15), 207 (9.3), 206 (21), 111 (25), 97
(19), 94 (21), 93 (64), 82 (36). Anal. calcd for C15H28O: C, 80.29; H, 12.58; O, 7.13, found: C, 79.92; H,
12.62; O, 7.32.
4.2.5. 6-Undecylbicyclo[4.1.0]heptan-2-ol 4f
317 mg, 60%; 1H NMR (250 MHz, CDCl3) δ 4.18 (dd, J=6.2, 12.0 Hz, 1H), 1.71–0.95 (m, 26H), 0.89
(bt, J=7.5 Hz, 3H), 0.45 (dd, J=4.7, 4.7 Hz, 1H), 0.34 (dd, J=4.7, 8.6 Hz, 1H); 13C NMR (62.9 MHz,
CDCl3) δ 67.1, 41.3, 31.9, 29.9, 29.8, 29.7, 29.65, 29.6, 29.5, 29.3, 27.8, 26.6, 25.6, 23.4, 22.7, 20.3,
14.0, 13.6; IR (neat) 3370, 3070, 3005, 2960, 2840, 1460 cm−1; EI-MS (m/z) 247 (4.2), 92 (26), 91 (41),
82 (7.9), 79 (100). Anal. calcd for C18H34O: C, 81.13; H, 12.86; O, 6.00, found: C, 80.63; H, 12.98; O,
6.25.

1114
J.-P. Barnier et al. / Tetrahedron: Asymmetry 10 (1999) 1107–1117
4.2.6. 6-Benzylbicyclo[4.1.0]heptan-2-ol 4g
267 mg, 66%; 1H NMR (200 MHz, CDCl3) δ 7.43–7.16 (m, 5H), 4.27 (dd, J=4.8, 8.5 Hz, 1H), 2.63
(s, 2H), 1.72–0.96 (m, 8H), 0.60 (d, J=6.3 Hz, 2H); 13C NMR (62.9 MHz, CDCl3) δ 139.8, 129.0, 128.0,
125.9, 66.4, 46.1, 29.7, 27.5, 25.1, 23.4, 19.7, 12.8; IR (neat) 3360, 3080, 3060, 3020, 3000, 2960, 2840,
1450 cm−1; EI-MS (m/z) 202 (M+, 0.3), 185 (2.7), 184 (16), 111 (11), 94 (5), 93 (59), 91 (100), 77 (39).
Anal. calcd for C14H18O: C, 83.12; H, 8.97; O, 7.91, found: C, 83.37; H, 9.20; O, 7.82.
Table 2
Chromatographic conditions for the determination of the enantiomeric excesses of bicycloheptanols
4c–4g on a Cydex B column (P=0.8 bar)
4.3. Enzymatic resolution of endo-bicyclo[4.1.0]heptan-2-ols 4a. Representative procedure
Bicyclo[4.1.0]heptan-2-ol 4a (112 mg, 1 mmol) was dissolved in 4 mL of tert-BuOMe in a flask
equipped with a magnetic stirrer. To this solution 162 mg of Novozym® and 167 mg of isopropenyl
hexanoate (1.07 mmol, 1.07 equiv.) was added and the reaction mixture was stirred at 37°C. The reaction
was monitored by TLC; at around 50% conversion, the reaction was stopped by removing the enzyme by
filtration, and the solid was washed several times with tert-BuOMe. After concentration under reduced
pressure the reaction products were separated by silica gel column chromatography (pentane:diethyl
ether: 70:30) to give 107 mg of bicyclo[4.1.0]heptan-2-yl hexanoate 5a* (51%) and 46 mg of recovered
alcohol 4a* (41%).
The bicycloheptyl hexanoate 5a* was then treated at 0°C in diethyl ether with lithium aluminum
hydride. After stirring for one hour at room temperature, wet sodium sulfate was added in order to obtain
a clear supernatant solution. After filtration, the solution was concentated under reduced pressure and the
optically active bicyclo[4.1.0]heptan-2-ol (yield ∼90%) was separated from the hexan-1-ol by silica gel
column chromatography (pentane:diethyl ether: from 80:20 to 50:50).
Transesterifications with the bicycloheptanols 4b–4g were made following the same procedure.
For the experiment reported in entry 2 of Table 1, except for the amount of Novozym® (54 mg), the
above conditions were used.
Specific rotations of these optically active alcohols 4* and of those isolated after reduction of esters 5*
are reported in Table 1.
4.4. Determination of enantiomeric excesses
The enantiomeric excesses of bicycloheptanol 4a samples were determined by HPLC on a Chiracel
OD-H column of the corresponding carbamate which was prepared by reaction, over 14 hours, of 4a with
phenylisocyanate in Et2O.19
The enantiomeric excesses of compounds 4b–4g were determined by GLC on a Cydex B column. The
chromatographic conditions used for the separation of compounds 4c–4g and the retention times of the
enantiomers are shown in Table 2, those of 4b were reported in the literature.19

J.-P. Barnier et al. / Tetrahedron: Asymmetry 10 (1999) 1107–1117
1115
4.5. Chemical correlation
4.5.1. Preparation of optically active 3-ethylcyclohex-2-en-1-ol 3c*
To a solution of 84 mg of Li2CuCl4 (0.38 mmol, 0.15 equiv.) in 4 mL of THF maintained at −20°C
under argon, 10.5 mL of a 1 M solution of EtMgBr in THF (10.5 mmol, 4 equiv.) and 586 mg of (−)-3-
iodocyclohex-2-en-1-ol 633 in 4 mL of THF were added. After stirring for 14 hours at −20°C and 4 hours
at 20°C, the reaction mixture was poured into a saturated ammonium chloride solution and extracted with
diethyl ether. The organic phases were washed with water and dried over sodium sulfate. The solvent
was removed under vacuum and the crude product was purified by column chromatography on silica
gel (pentane:diethyl ether: 90:10) to give 219 mg (66%) of (−)-3-ethylcyclohex-2-en-1-ol 3c; ee=77%,
determined by GLC on a Cydex B column (P=0.8 bar, 70°C), retention time (S)-3c: 27 min, (R)-3c: 30
min.
4.5.2. Preparation of optically active 3-butylcyclohex-2-en-1-ol 3d*
The title compound was obtained from 467 mg of (+)-3-iodocyclohex-2-en-1-ol 633 and BuMgBr,
following the same procedure as above, 199 mg (72%) of (+)-3-butylcyclohex-2-en-1-ol 3d; ee=97%,
determined by GLC on a Cydex B column (P=0.8 bar, 85°C), retention time (S)-3d: 39 min, (R)-3d: 40
min.
Acknowledgements
We are grateful to Novo Nordisk A/S (Denmark) for a gift of Novozym®.
References
1. trans- and cis-2-Methyl-5-(1-methylethyl)bicyclo[3.1.0]hexan-2-ols (sabinene hydrates) are present in many plants. Some
bicyclo[4.1.0]heptan-2-ols are also presents in plants, for the 4,7,7-trimethylated compound (caran-5-ol) see: Handilou,
E.; Kokkini, S.; Kokkalou, E. Biochem. Syst. Ecol. 1992, 20, 33–40. Handilou, E.; Kokkalou, E.; Kokkini, S. Planta Med.
1992, 58, 105–107. Komaitis, M. E.; Ifanti-Papatragianni, N.; Melissari-Panagiotou, E. Food Chem. 1992, 45, 117–118.
Chen, Y.; Li, Z.; Li, H. Chromatographia 1987, 23, 502–506, for the 3,7,7-trimethylated compound (caran-2-ol) see Chen,
Y.; Li, X. Linchan Huaxue Yu Gongye 1992, 12, 159–163, for the 2,5-dimethyl-5-(4-methylpent-3-enyl)bicycloheptanol
(chenopodanol) see: Tori, M.; Hamaguchi, T.; Aoki, M.; Sono, M.; Asakawa, Y. Can. J. Chem. 1997, 75, 634–640. For
another example of a natural compound isolated from a marine mollusc with a 6-oxabicyclo[6.1.0]nonan-2-ol framework
see: Miyamoto, T.; Ebisawa, Y.; Higuchi, R. Tetrahedron Lett. 1995, 36, 6073–6074.
2. Collum, D. B.; Still, W. C.; Mohamadi, F. J. Am. Chem. Soc. 1986, 108, 2094–2096. For another use of the organomercurial
intermediates see: Kocˇovsky, P.; Grech, J. M.; Mitchell, W. L. J. Org. Chem. 1995, 60, 1482–1483; Kocˇovsky, P.; Grech,
J. M.; Mitchell, W. L. Tetrahedron Lett. 1996, 37, 1125–1128.
3. Clive, D. L. J.; Daigneault, S. J. Org. Chem. 1991, 56, 3801–3814. For related reactions also see: Corey E. J.; Shiner, C.
S.; Volante, R. P.; Cyr, C. R. Tetrahedron Lett. 1975, 1161–1164. Beckwith, A. L. J.; Philippou, G. Aust. J. Chem. 1976,
29, 123–131.
4. Harling, J. D.; Motherwell, W. B. J. Chem. Soc., Chem. Commun. 1988, 1380–1381. Batey, R. A.; Harling, J. D.;
Motherwell, W. B. Tetrahedron 1992, 48, 8031–8052.
5. For a rearrangement of cyclopropylcarbinyl radicals generated by other methods see: Batey, R. A.; Grice, P.; Harling, J.
D.; Motherwell, W. B.; Rzepa, H. S. J. Chem. Soc., Chem. Commun. 1992, 942–944. Clive, D. L. J.; Daigneault, S. J. Org.
Chem. 1991, 56, 5285–5289. Friedrich, E. C.; Holmstead, R. L. J. Org. Chem. 1971, 36, 971–975; 1972, 37, 2546–2550;
1972, 37, 2550–2554. Roberts, C.; Walton, J. C. J. Chem. Soc., Perkin Trans. 2 1983, 879–885. Davies, A. G.; Muggleton,
B.; Godet, J.-Y.; Pereyre, M.; Pommier, J.-C. J. Chem. Soc., Perkin Trans. 2 1976, 1719–1724.
6. Pellacani, L.; Tardella, P. A.; Loreto, M. A. J. Org. Chem. 1976, 41, 1282–1283.

1116
J.-P. Barnier et al. / Tetrahedron: Asymmetry 10 (1999) 1107–1117
7. Norin, T. Acta Chem. Scand. 1965, 19, 1289–1292.
8. (a) Dauben, W. G.; Deviny, E. J. J. Org. Chem. 1966, 31, 3794–3798. (b) Dauben, W. G.; Schutte, L.; Wolf, R. E.; Deviny,
E. J. J. Org. Chem. 1969, 34, 2512–2517.
9. Hill, R. K.; Morgan, J. W. J. Org. Chem. 1968, 33, 927–928.
10. Attah-Poku, S.; Antczak, K.; Alward, S. J.; Fallis, A.-G. Can. J. Chem. 1984, 62, 1717–1721.
11. (a) Cossy, J.; Aclinou, P.; Bellosta, V.; Furet, N.; Baranne-Lafont, J.; Sparfel, D.; Souchaud, C. Tetrahedron Lett. 1991,
32, 1315–1316. (b) Cossy, J.; Furet, N.; Bouzbouz, S. Tetrahedron 1995, 51, 11751–11764. (c) Cossy, J.; Bouzbouz, S.
Tetrahedron Lett. 1996, 37, 5091–5094.
12. (a) Bishof, E. W.; Mattay, J. J. Photochem. Photobiol. A 1992, 63, 249–251. Mattay, J.; Banning, A.; Bischof, E. W.;
Heidbreder, A.; Runsink, J. Chem. Ber. 1992, 125, 2119–2127. (b) Kirschberg, T.; Mattay, J. Tetrahedron Lett. 1994, 35,
7217–7220.
13. Pandey, B.; Rao, A. T.; Dalvi, P. V.; Kumar, P. Tetrahedron 1994, 50, 3843–3848.
14. Batey, R. A.; Motherwell, W. B. Tetrahedron Lett. 1991, 32, 6211–6214. Batey, R. A.; Harling, J. D.; Motherwell, W. B.
Tetrahedron 1996, 52, 11421–11444.
15. Winstein, J.; Sonneberg, J.; Devries, L. J. Am. Chem. Soc. 1959, 81, 6523–6524. Dauben, W. G.; Berezin, G. H. J. Am.
Chem. Soc. 1963, 85, 468–472.
16. For a review where there are various reported examples of hydroxyl directed cyclopropanations of allylic alcohols see:
Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307–1370.
17. Barbachyn, M. R.; Johnson, C. R.; Glick, M. D. J. Org. Chem. 1984, 49, 2746–2748.
18. Paukstelis, J. V.; Kao, J.-L. Tetrahedron Lett. 1970, 42, 3691–3694.
19. Barnier, J. P.; Rayssac, V.; Morisson, V.; Blanco, L. Tetrahedron Lett. 1997, 38, 8503–8506.
20. For other examples of lipase-catalyzed preparations of optically active cyclopropyl alcohol derivatives see: Csuk, R.; von
Scholz, Y. Tetrahedron 1996, 52, 6383–6396. Krief, A.; Surleraux, D.; Ropson, N. Tetrahedron: Asymmetry 1993, 4,
289–292; Theil, F.; Schick, H.; Winter, G.; Reck, G. Tetrahedron 1991, 47, 7569–7582; Theil, F.; Kunath, A.; Schick, H.
Tetrahedron Lett. 1992, 33, 3457–3460; Granjean, D.; Pale, P.; Chuche, J. Tetrahedron 1991, 47, 1215–1230; Ader, U.;
Breitgoff, D.; Klein, P.; Laumen, K. E.; Schneider, M. P. Tetrahedron Lett. 1989, 30, 1793–1796; Laumen, K.; Schneider,
M. Tetrahedron Lett. 1985, 26, 2073–2076; Rasel, W.; Hultin, P. G.; Jones, J. B. J. Chem. Soc., Chem. Commun. 1985,
1563–1564; Rogers, D. H.; Yi, E. C.; Poulter, C. D. J. Org. Chem. 1995, 60, 941–945.
21. Miyano, S.; Izumi, Y.; Fujii, H.; Hashimoto, H. Synthesis 1977, 700–701.
22. Denmark, S. E.; Edwards, J. P. J. Org. Chem. 1991, 56, 6974–6981. In these reactions the exo diastereoisomers were not
noticed by NMR spectroscopy.
23. Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
24. Gannon, F. W.; House, H. O. Org. Syntheses 1960, 40, 41–42.
25. Woods, G. F.; Tucker, I. W. J. Am. Chem. Soc. 1948, 70, 2174–2177.
26. Mori, K.; Uchida, M.; Matsui, M. Tetrahedron 1977, 33, 385–387.
27. Tetrahydrofuran was probably released in this reaction which was under investigation.
28. Rothman, E. S.; Serota, S.; Perlstein, T.; Swern, D. J. Org. Chem. 1962, 27, 3123–3127. Wang, Y.-F.; Lalonde, J. L.;
Momongan, M.; Bergbreiter, D. E.; Wong, C.-H. J. Am. Chem. Soc. 1988, 110, 7200–7205.
29. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294–7299.
30. Small excesses of isopropenyl hexanoate were used in these reactions to allow an easier separation of the products. Care
was taken that water was absent from the reaction mixture in order to ensure that isopropenyl hexanoate was still present
when the reaction was stopped. If the isopropenyl hexanoate was totally consumed, a decrease in the enantiomeric ratio
was observed, probably because the bicycloheptyl hexanoate had become the acylating agent.
31. The synthesis of optically active 3-ethylcyclohex-2-enol was reported38 and its absolute configuration was proposed on
the basis of chiroptical properties. A chemical correlation was made between this ethylcyclohexenol and a compound
with a known absolute configuration because some discrepancies between the specific rotation sign and the absolute
configuration were noticed in this family of 3-substituted cyclohex-2-enols: Aranda, G.; Bertranne, M.; Azerad, R.; Maurs,
M. Tetrahedron: Asymmetry 1995, 6, 675–678.
32. Tamura, M.; Kochi, J. Synthesis 1971, 303–305.
33. Mori, K.; Tamada, S.; Uchida, M.; Mizumachi, N.; Tachibana, Y.; Matsui, M. Tetrahedron 1978, 34, 1901–1905.
34. For recent reports of the enantioselectivity of Candida antarctica lipase for the ‘R’-isomer see: Forró, E.; Kanerva, L. T.;
Fülöp, F. Tetrahedron: Asymmetry 1998, 9, 513–520; Conti, P.; Dallanoce, C.; De Amici, M.; De Micheli, C.; Carrea, G.;
Zambianchi, F. Tetrahedron: Asymmetry 1998, 9, 657–665; Ziegler, T.; Bien, F.; Jurisch, C. Tetrahedron: Asymmetry 1998,
9, 765–780; Conde, S.; Fierros, M.; Rodríguez-Franco, M. I.; Puig, C. Tetrahedron: Asymmetry 1998, 9, 2229–2232; Bit,

J.-P. Barnier et al. / Tetrahedron: Asymmetry 10 (1999) 1107–1117
1117
C.; Mitrochkine, A. A.; Gil, G.; Pierrot, M.; Réglier, M. Tetrahedron: Asymmetry 1998, 9, 3263–3273. For a deviation
from this rule see: Adam, W.; Díaz, M. T.; Saha-Möller, C. R. Tetrahedron: Asymmetry 1998, 9, 791–796.
35. For crystallographic data of lipase B from Candida antarctica which reveal a stereospecific pocket for secondary alcohols
see: Uppenberg, J.; Öhrner, N.; Norin, M.; Hult, K.; Kleywegt, G. J.; Patkar, S.; Waagen, V.; Anthonsen, T.; Jones, T. A.
Biochemistry 1995, 34, 16838–16851.
36. Gupta, A. K.; Kazlauskas, R. J. Tetrahedron: Asymmetry 1993, 4, 879–888.
37. For a hydrolase specific ‘S’-enantiomer of open chain secondary alcohols see: Lloyd, R. C.; Dickman, M.; Jones, J. B.
Tetrahedron: Asymmetry 1998, 9, 551–561.
38. (a) Carrea, G.; Danieli, B.; Palmisano, G.; Riva, S.; Santagostino, M. Tetrahedron: Asymmetry 1992, 3, 775–784. (b) Satoh,
T.; Motohashi, S.; Tokutake, N.; Yamakawa, K. Bull. Chem. Soc. Jpn. 1992, 65, 2966–2973
39. Dauben, W. G.; Shaffer, G. W.; Vietmeyer, N. D. J. Org. Chem. 1969, 33, 4060–4069. Jacquesy, R.; Patoiseau, J. F. Bull.
Soc. Chim. Fr. 1978, 255–262.
40. Inokuchi, T.; Tsuji, M.; Kawafuchi, H.; Torii, S. J. Org. Chem. 1991, 56, 5945–5948.
41. Jubert, C.; Knochel, P. J. Org. Chem. 1992, 57, 5425–5431.
42. Rawal, V. H.; Newton, R. C.; Krishnamurthy, V. J. Org. Chem. 1990, 55, 5181–5183.