Asymmetric synthesis of half-cage alcohol compounds

Article abstract of DOI:10.1016/S0957-4166(02)00549-9

To obtain enantiopure pentacyclic chlorinated and dechlorinated alcohols, we evaluated various synthetic routes. Enantiopure acetate (-)-5 (ee >95%) was obtained from an enantioselective inversion of a stereogenic center of the pentacyclic acetate (+)-4 in an acidic medium. Conversely, enantiopure alcohols (+)-11 and (+)-15 were obtained by the kinetic resolution of alcohol (±)-11 by transesterification using lipase from Candida rugosa. It was verified that the lipase recognized alcohol (±)-11, producing the alcohol (+)-11 (ee >98%) and acetate (-)-13 (ee >99%) with a high degree of enantioselectivity (E >100) and a conversion of 50% after only 1 h.

Full text of DOI:10.1016/S0957-4166(02)00549-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2019–2024
Asymmetric synthesis of half-cage alcohol compounds
Joa˜o Alifantes, Aline G. Nichele and Valentim E. U. Costa*
Departamento de Qu´ımica Orgaˆnica, Instituto de Qu´ımica, Universidade Federal do Rio Grande do Sul,
Av. Bento Gonc¸alves 9500, Porto Alegre 91501-970, RS, Brazil
Received 19 July 2002; accepted 27 August 2002
Abstract—To obtain enantiopure pentacyclic chlorinated and dechlorinated alcohols, we evaluated various synthetic routes.
Enantiopure acetate (−)-5 (ee >95%) was obtained from an enantioselective inversion of a stereogenic center of the pentacyclic
acetate (+)-4 in an acidic medium. Conversely, enantiopure alcohols (+)-11 and (+)-15 were obtained by the kinetic resolution of
alcohol ( )-11 by transesterification using lipase from Candida rugosa. It was verified that the lipase recognized alcohol ( )-11,
producing the alcohol (+)-11 (ee >98%) and acetate (−)-13 (ee >99%) with a high degree of enantioselectivity (E >100) and a
conversion of 50% after only 1 h. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
strained stereochemistry by X-ray diffraction were
analysed.9
Polycyclic compounds represent a key research topic
with numerous investigations in the literature into their
theoretical1 and experimental properties (e.g. carboca-
tions,2 mechanistic and other features of their
reactions3). An interesting example of polycyclic com-
pounds is provided by pentacyclo[6.2.1.13,6.02,7.05,9]-
dodecane derivatives, also known as ‘half-cage’ com-
pounds, which can have C-4 substituents on the ‘inside’
or ‘outside’.
The resolution of racemic polycyclic compounds deriva-
tives has been one of our recent focal points with the
aim of obtaining enantiopure alcohols. Enzymatic
kinetic resolution has been utilized with good enan-
tioselectivities for bicyclic alcohol derivative ( )-1.10 On
the other hand, the attempted enantiomeric resolution
of
the
tetracyclic
alcohol,
endo-tetracyclic
[6.2.1.13,6.02,7]dodecan-4-ol ( )-2, using a chiral auxil-
iary afforded poor enantiomeric excesses.11 More
recently, we communicated the enzymatic resolution of
a hindered secondary pentacyclic alcohol endo-( )-
1,8,9,10,11,11 - hexachloropentacyclo[6.2.1.13,6.02,7.05,9]-
dodecan-4-ol, alcohol ( )-3 using lipase from Candida
rugosa.12
In recent years, our group has synthesised4 and studied
constrained polycyclic compounds by NMR spec-
troscopy.5 The enantiomeric analysis of chiral poly-
cyclic derivatives by NMR using a mixture of chiral
and achiral shift reagents was reported,6 as well as an
approach to determine the optimal position of the
lanthanide ion in complexes formed by shift reagents
Herein, we describe an efficient synthesis of enantiopure
chlorinated and dechlorinated half-cage alcohols. The
enantiopure chlorinated alcohol (+)-7 was obtained
from the acetate (−)-5. The latter was formed by the
enantioselective inversion of a stereogenic center of the
acetate (+)-4 in acidic medium. On the other hand, the
enantiopure alcohols (+)-11 and (+)-15 were obtained
via kinetic resolution of alcohol ( )-11 by transesterifi-
cation using lipase from C. rugosa. This resolution
demonstrates the high degree of enantioselectivity of
and compounds using the pseudocontact model.7
A
study of the mechanism of skeletal rearrangements in
acid media on the basis of theoretical and experimental
investigations was performed,8 and the effects of con-
* Corresponding author. Tel.: 055 051 33166300; fax: 055 051
33167304; e-mail: valentim@iq.ufrgs.br
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00549-9

2020
J. Alifantes et al. / Tetrahedron: Asymmetry 13 (2002) 2019–2024
Table 1. Specific rotation values of half-cage derivatives
for a c=1 g/100 mL in CH2Cl2 at 20°C
the enzyme with these substrates (E >100 with a conver-
sion of 50% after only 1 h).
Compounds
Specific rotation at four wavelengths (u)
2. Results and discussion
589
578
546
436
The synthesis of the enantiopure chlorinated half-cages
from the acetate (+)-4 were performed as shown in
Scheme 1. The enantiomerically pure acetate (+)-4 was
prepared by a previously reported method12 and its
treatment with acetic acid containing a catalytic
amount of sulfuric acid produced the acetate (−)-5 and
the birdcage 6 in a 7:3 ratio, respectively. This inversion
necessarily involves a cationic intermediate. However,
in this process no change in the enantiomeric excess of
the acetate (+)-4 to acetate (−)-5 was observed, due to
the cationic intermediate, and the mechanism of inver-
sion does not allow the rearrangement to the racemic
form, as shown in a previous paper.8a As chlorinated
compounds have high boiling points, the use of GC on
chiral columns with cyclodextrin is impossible and the
use of HPLC on chiral columns with cyclodextrin did
not result in a satisfactory separation. Hence, we chose
1H NMR as an analytical method, using chiral chemi-
cal shift reagents. A high resolution of the signals was
achieved for the CH3 signal of the acetate ( )-5, using
Alcohol (+)-3
Acetate (+)-4
Acetate (−)-5
Alcohol (+)-7
+1
+1
−6
+1
+1
+1
−5
+1
+2
+1
−4
+2
+3
+2
−2
+4
THF with a sodium and liquid ammonia solution.10a
The evaluation of these techniques was performed with
a racemic chlorinated half-cage obtained by a previ-
ously reported method.12
tris[3
(heptafluoropropylhydroxymethylene)(+)cam-
phorate]europium(III) (Eu(hfc)3) in CDCl3 solutions of
this compound.12 The analysis of these signals for the
acetate (−)-5 presented an ee >95%.
Scheme 2. Dechlorination of half-cage acetate ( )-4, alcohol
( )-3 and trimethylsilyl ether ( )-8.
Scheme 1. Synthesis of the enantiopure chlorinated half-cage
compounds from the acetate (+)-4.
The results of the two techniques show that the dechlor-
ination of half-cage acetate ( )-4 or alcohol ( )-3 with
substituents inside give the symmetric structure 9, and
the same behavior was observed for the reaction involv-
ing sodium and liquid ammonia, where the protecting
group trimethylsilane13 was added to the internal oxy-
gen, affording the half-cage ( )-8. This result is a
serious limitation for obtaining enantiomerically pure
dechlorinated half-cages from acetate (+)-4, the sym-
metrization of the skeletal carbon may be related to the
small distance between the internal oxygen and carbon
10.9a
The treatment of acetates (+)-4 and (−)-5 with saturated
solution of K2CO3 in methanol affords the alcohols
(+)-3 and (+)-7, respectively. The reactions were com-
plete within 2 h at room temperature (20°C) and yields
are above 95%. Table 1 shows the specific rotation
values of acetates (+)-4 and (−)-5 and alcohols (+)-3
and (+)-7 over four wavelengths.
To obtain enantiomerically pure dechlorinated half-
cage compounds from acetate (+)-4, it was necessary to
investigate two possible dechlorination reactions
(Scheme 2). The first technique used consisted of
combining the chlorinated half-cage with a dry THF
solution containing Li and t-butanol in an ultrasound
bath.4a The second technique involved combining a
solution of the chlorinated half-cage and ethanol in dry
To establish parameters for GC analysis on chiral
cyclodextrin columns, the racemic dechlorinated half-
cage were obtained and are shown in Scheme 3. The
chlorinated compound 10 was prepared by a previously
reported method,12 and its ethanolic solution in dry
THF when treated with sodium and liquid ammonia

J. Alifantes et al. / Tetrahedron: Asymmetry 13 (2002) 2019–2024
2021
for the dechlorinated alcohol ( )-11 was observed. The
comparison of these results with those previously
reported12 for chlorinated alcohols ( )-3 and ( )-7 sug-
gests that the enantioselectivity of the lipase from C.
rugosa for half-cage alcohols does not depend on the
position (exo or endo) of the hydroxy group. Table 2
shows the compared data.
The treatment of alcohol (+)-11 with chromium(VI)
oxide at room temperature gave the ketone (−)-14 in
85% yield. The reduction of ketone (−)-14 with lithium
aluminum hydride selectively afforded the alcohol (+)-
15 in 90% yield with an ee >98%, determined by chiral
gas chromatography. Table 3 shows the specific rota-
tion of the alcohols (+)-11 and (+)-15, acetate (−)-13
and ketone (+)-14 over four wavelengths.
Scheme 3. Synthesis of the racemic dechlorinated half-cages.
gave a mixture of alcohols ( )-11 and ( )-12 in a
respective ratio of 2:1. As the alcohols ( )-11 and ( )-12
cannot be completely separated by column chromatog-
raphy, the purification of these compounds was per-
formed by treatment of the mixture of alcohols ( )-11
and ( )-12 in a solution of ethyl ether with a saturated
solution of AgNO3. The alcohol ( )-11 remains in the
organic phase, while the complex formed between Ag+
and alcohol ( )-12 remains in the aqueous phase. After
the addition of NH4OH and heating the aqueous phase,
the pure alcohol ( )-12 was obtained. This methodol-
ogy furnished better yields of alcohol ( )-11 than the
reported by Howe et al.14 via dechlorination of its
hexachloro-alcohol precursor ( )-3. The acetate ( )-13
was obtained from alcohol ( )-11 by treatment with
acetic anhydride, triethylamine and DMAP.
Table 3. Specific rotation values of half-cages derivatives
for a c=1 g/100 mL in CH2Cl2 at 20°C
Compounds
Specific rotation at four wavelengths (u)
589 578 546 436
+4 +5 +6 +10
Alcohol (+)-11
Acetate (−)-13
Ketone (−)-14
Alcohol (+)-15
−1
−87
+3
−1
−92
+3
−2
−110
+4
−4
−266
+7
3. Conclusion
The synthesis of the asymmetric dechlorinated half-
cages is shown in Scheme 4. The first step consists of a
kinetic resolution of the alcohol ( )-11 by a transester-
ification reaction using lipase from Candida rugosa with
excess vinyl acetate. After 1 h the conversion was 50%,
and the enantiomeric purity of the products was deter-
mined by chiral gas chromatography (alcohol (+)-11: ee
>98% and for the acetate (−)-13: ee >99%). A high
degree of enantioselectivity of the enzyme (E >100)15
Excellent results were obtained to access enantiopure
pentacyclic compounds by transesterification reactions
using lipase from C. rugosa. Starting from these enan-
tiopure compounds, it was possible to prepare other
chiral pentacyclic alcohols and acetates.
4. Experimental
Melting points were measured on an Electrothermal IA
9100 digital apparatus. NMR spectra were measured
with a Varian VXR-200 spectrometer at a magnetic
field of 4.7 T and a temperature of 22°C. Chemical
shifts are expressed as l (ppm) relative to TMS as an
internal standard. Elemental analysis was recorded on a
Perkin–Elmer 2400 CHN elemental analyzer apparatus.
Products were analyzed by GC on a SHIMADZU
GC-171 model equipped with FID, using a DB-1
column (15 m×0.53 mm (i.d.)×1.5 mm) for racemic
compounds and, BETA-DEX™M 120 column (30 m×
0.22 mm (i.d.)×1.25 mm) for chiral compounds. Optical
Scheme 4. Synthesis of the asymmetric dechlorinated half-
cages.
Table 2. Comparison of kinetic resolutions employing lipase from Candida rugosa with excess vinyl acetate for exo and endo
half-cage alcohols
Alcohols
Enantiomeric ratio (E)
Conversion (%)
Time of reaction (h)
ee of acetates
endo-alcohol (9)-3
exo-alcohol (9)-7
exo-alcohol (9)-11
\100
-x-
\100
44
168
240
1
\95%
-x-
\99%
No reaction
50

2022
J. Alifantes et al. / Tetrahedron: Asymmetry 13 (2002) 2019–2024
(1H, s); 13C NMR (50 MHz, CDCl3) l 36.0 (CH2), 41.2
(CH), 45.3 (CH), 55.6 (CH), 58.9 (CH), 62.3 (CH), 64.6
(CH), 73.7 (CH), 74.3 (C), 79.6 (C), 85.1 (C), 98.6 (C).
rotations were measured with a Perkin–Elmer polarime-
ter model 341 with a 1 cm cell at a temperature of
20°C. Lipase, type VII (from C. rugosa) was providing
from Amano Enzime USA Co. Ltd.
4.1. exo-(−)-1,8,9,10,11,11-Hexachloropentacyclo-
[6.2.1.13,6.02,7.05,9]dodecan-4-yl acetate, (−)-5
4.3. endo-( )-1,8,9,10,11,11-Hexachloropentacyclo-
[6.2.1.13,6.02,7.05,9]dodecan-4-trimethylsilyloxy ( )-8
Concentrated sulfuric acid (1 mL) was added to a
solution of acetate (+)-4 (1.0 g, 2.5 mmol) in acetic acid
(10 mL) at a temperature of 125°C under magnetic
stirring. After stirring for 1 h, the system was cooled
down and neutralized with 10% aqueous NaHCO3 solu-
tion. A precipitate formed and was separated. An addi-
tional extraction with chloroform was undertaken. The
extract was combined with the precipitate. This solu-
tion was dried with MgSO4, and after concentration of
the filtrates, a mixture of two compounds was obtained
as a white solid. These products were purified by chro-
matography on a silica gel column (hexane/ethyl ace-
tate: 0–20%). The acetate (−)-5 (70% yield) and
compound 6 (30% yield) were obtained. Acetate, (−)-5:
mp 193–194°C (lit.16 194–195°C); [h]2D0 −6.0 (c=1,
To a solution of alcohol ( )-3 (1.0 g, 2.6 mmol) in THF
(70 mL) under nitrogen were added 380 mL of pyridine
and 230 mL of chlorotrimethylsilane. The solution was
stirred at room temperature (20°C) for 24 h. The salt
formed was filtered and the solvent was removed under
vacuum and the half-cage ( )-8 was obtained as a white
solid (93% yield). Anal. calcd: C, 39.56; H, 3.95.
Found: C, 38.89; H, 3.89%. FTIR (KBr) w (cm−1) 842
1
(Si-CH3); H NMR (200 MHz, CDCl3) l 0.20 (9H, s),
1.34 (1H, d, J=9.8 Hz), 1.60 (1H, d, J=9.8 Hz), 2.58
(1H, br s), 2.77–3.04 (3H, m), 3.19 (1H, dd, J=6.4 Hz,
J=4.1 Hz), 4.00 (1H, d, J=6.4 Hz), 7.70 (1H, s); 13C
NMR (50 MHz, CDCl3) l 0.6 (CH3), 37.9 (CH2), 43.6
(CH), 45.2 (CH), 56.6 (CH), 57.1 (CH), 59.3 (CH), 64.8
(CH), 73.5 (C), 80.8 (CH), 81.9 (C), 82.0 (C), 99.2 (C).
1
CH2Cl2). FTIR (film, CHCl3) w (cm−1) 1735 (CꢀO); H
NMR (200 MHz, CDCl3) l 1.51 (1H, d, J=11.0 Hz),
2.09 (3H, s), 2.33 (1H, d, J=11.0 Hz), 2.88–3.15 (5H,
m), 5.50 (1H, s) and 5.80 (1H, s); 13C NMR (50 MHz,
CDCl3) l 21.1 (CH3), 36.5 (CH2), 41.6 (CH), 43.4 (CH),
55.6 (CH), 58.8 (CH), 60.0 (CH), 64.7 (CH), 74.0 (C),
76.4 (CH), 79.6 (C), 84.8 (C), 99.5 (C), 169.8 (CO).
4.4. Hexacyclo[.2.1.13,6.14,10.02,7.05,9]dodecan-4,10-oxo 9
Method A: Into a 250 mL flask equipped with reflux
condenser and under an inert atmosphere was placed
dry THF (88 mL). Small pieces (wire) of lithium (2.3 g,
0.33 mmol) were added along with tert-butyl alcohol
(16 mL, 0.17 mol). The apparatus was then immersed
into an ultrasound bath (45 KHz, 100 Watt) and a
solution of hexachlorinated compound, or acetate ( )-4
(13.6 mmol) of either alcohol ( )-3 in dry THF (10 mL)
was slowly added. The reaction was complete after 5 h
and crushed ice was added under an inert atmosphere.
The organic phase was extracted with ethyl ether and
this solution was washed with water, dried over magne-
sium sulfate, filtered and the solvents were evaporated.
Compound 9 (68% yield) was obtained as an oil.
1
Birdcage 6: mp 290°C (lit.16 287–289°C); H NMR (200
MHz, CDCl3) l 1.69 (1H, d, J=11.5 Hz), 1.90 (1H, d,
J=11.5 Hz), 3.05–3.23 (6H, m); 13C NMR (50 MHz,
CDCl3) l 39.8 (CH2), 43.4 (2CH), 54.4 (2CH), 58.4
(2CH), 78.2 (2C), 83.5 (2C), 97.5 (C).
4.2. endo- or exo-(+)-1,8,9,10,11,11-Hexachloropenta-
cyclo-[6.2.1.13,6.02,7.05,9]dodecan-4-ol (+)-3 and (+)-7
1.0 g (2.3 mmol) of acetate (+)-4 or acetate (−)-5 was
dissolved in a mixture of tetrahydrofuran (20 mL) and
CH3OH (50 mL). A saturated solution of K2CO3 was
added and the reaction was stirred at room temperature
(20°C) for 2 h. The mixture was washed three times
with CHCl3 (20 mL) and the combined organic phases
were dried with MgSO4. After concentration of the
solvent, alcohol (+)-3 or alcohol (+)-7 was obtained
(yield >95%) as a white solid. Alcohol (+)-3: mp 258–
Method B: A solution of the alcohol ( )-3, acetate ( )-4
or trimethylsilyl ether ( )-8 (13.1 mmol) in dry ethanol
(2.2 mL, 37.5 mmol) and dry THF (25 mL) was added
in small portions to a solution of sodium (4.0 g, 173.9
mmol) in ammonia (150 mL) at −78°C, and the reac-
tion mixture was stirred for 12 min. Then, the mixture
was treated with saturated aqueous ammonium chlo-
ride solution (25 mL). The ammonia was evaporated
and the usual ethereal extraction sequence followed to
produce the compound 9 (75% yield) as an oil. After
slow crystallization in CHCl3 a white solid was
obtained. Mp 190–192°C (lit.14 191–193°C). Anal.
calcd: C, 82.77; H, 8.04. Found: C, 82.49; H, 8.24%.
1
260°C dec., [h]D20 +1.0 (c=1, CH2Cl2); H NMR (200
MHz, CDCl3) l 1.40 (1H, d, J=10.8 Hz), 1.62 (1H, d,
J=10.8 Hz), 2.68 (1H, br s), 2.90–3.16 (3H, m), 3.26
(1H, dd, J=5.9 Hz, J=3.9 Hz), 4.23 (1H, d, J=5.9
Hz), 7.43 (1H, s); 13C NMR (50 MHz, CDCl3) l 38.0
(CH2), 42.9 (CH), 44.1 (CH), 56.0 (CH), 56.3 (CH),
58.5 (CH), 64.6 (CH), 72.7 (C), 79.8 (CH), 81.1 (C),
83.3 (C), 99.3 (C); Anal. calcd: C, 37.60; H, 2.61.
Found: C, 37.58; H, 2.59. Alcohol (+)-7: mp 217°C
(lit.16 218°C), [h]D20 +1.0 (c=1, CH2Cl2). FTIR (KBr) w
1
FTIR (KBr) w (cm−1) 1093 (CꢁOꢁC); H NMR (200
MHz, CDCl3) l 1.14–3.13 (12H, overlapping signals),
4.44 (2H, d, J=9.8 Hz); 13C NMR (50 MHz, CDCl3) l
41.7 (2CH2), 38.2 (2CH), 43.0 (CH), 47.6 (2CH), 51.1
(2CH), 56.6 (CH), 86.4 (2CH).
1
(cm−1) 3471 (C−OH); H NMR (200 MHz, CDCl3) l
1.43 (1H, d, J=10.9 Hz), 2.64 (1H, d, J=10.9 Hz),
2.72–2.79 (2H, m), 3.00–3.11 (3H, m), 5.02 (1H, s), 5.42

J. Alifantes et al. / Tetrahedron: Asymmetry 13 (2002) 2019–2024
2023
4.5. ( )-exo-Pentacyclo[6.2.1.13,6.02,7.05,9]dodecan-4-ol
CDCl3) l 35.9 (CH2), 38.5 (CH), 39.5 (CH2), 39.6 (CH),
42.8 (CH), 45.4 (CH2), 46.0 (2CH), 46.5 (CH), 49.9
(CH), 54.7 (CH), 74.6 (CH). Acetate (−)-13: [h]2D0 −1.0
(c=1, CH2Cl2). Anal. calcd: C, 77.08; H, 8.25. Found:
C, 76.35; H, 8.23%. FTIR (KBr) w (cm−1) 1724 (CꢀO);
1H NMR (200 MHz, CDCl3) l 1.17 (1H, dd, J=9.9
Hz, J=4.5 Hz), 1.34 (1H, d, J=9.9 Hz), 1.54 (1H, d,
J=9.9 Hz), 1.58–1.65 (2H, m), 2.00 (3H, s), 2.05–2.38
(9H, overlapping signals), 5.48 (1H, s); 13C NMR (50
MHz, CDCl3) l 22.2 (CH3), 35.8 (CH2), 38.5 (CH),
39.5 (CH), 40.3 (CH2), 43.1 (CH), 44.1 (CH), 45.3
(CH2), 45.8 (CH), 45.9 (CH), 47.3 (CH), 54.7 (CH),
78.8 (CH), 171.4 (CO).
( )-11
Into a 250 mL flask under inert atmosphere a solution
of sodium (4.0 g, 173.9 mmol) in liquid ammonia
($150 mL) was obtained. A solution of 10 (5.0 g, 13.1
mmol) and dry ethanol (2.2 mL, 37.5 mmol) in 25 mL
of dry THF was slowly added. The reaction was stirred
for 12 min. After, a saturated solution of NH4OH (25
mL) was added. The system was opened and the ammo-
nia was allowed to evaporate over 24 h. The organic
phase was extracted with ethyl ether and this solution
was washed with water, dried over magnesium sulfate,
and after solvent evaporation of the filtrates, a white
solid was obtained as a mixture of the alcohols ( )-11
and ( )-12. Purification of these compounds was per-
formed by treating the mixture of alcohols ( )-11 and
( )-12 in a solution of ethyl ether with a saturated
solution of AgNO3. The heterogeneous mixture was
stirred, and after 4 h was separated. The complex
formed between Ag+ and alcohol ( )-12 remained in the
aqueous phase, whereas the alcohol ( )-11 remained in
the organic phase. After separation, the organic solvent
was evaporated producing the alcohol ( )-11 (66%
yield) as a white solid. Mp 131°C (lit.17 130°C), FTIR
(KBr) w (cm−1) 3425 (C−OH); 1H NMR (200 MHz,
CDCl3) l 1.12 (1H, dd, J=6.0 Hz, J=2.6 Hz), 1.28
(1H, d, J=3.6 Hz), 1.53 (1H, d, J=10.2 Hz), 1.58–1.75
(2H, m), 1.94–2.43 (9H, overlapping signals), 4.58 (1H,
d); 13C NMR (50 MHz, CDCl3) l 35.9 (CH2), 38.5
(CH), 39.5 (CH2), 39.6 (CH), 42.8 (CH), 45.4 (CH2),
46.0 (2CH), 46.5 (CH), 49.9 (CH), 54.7 (CH), 74.6
(CH). The aqueous phase was treated with a 30%
NH4OH solution and heated for 30 min. After extrac-
tion with ethyl ether the alcohol ( )-12 (33% yield) was
obtained as a white solid. Mp 103°C (lit.18 102.5–
103.5°C); FTIR (KBr) w (cm−1) 3425 (CꢁOH); 1H NMR
(200 MHz, CDCl3) l 1.08–2.67 (12H, overlapping sig-
nals) 3.69 (1H, d, J=6.1 Hz), 5.92 (1H, dd, J=5.2 Hz,
J=3.0 Hz), 5.97 (1H, dd, J=5.2 Hz, J=3.0 Hz); 13C
NMR (50 MHz, CDCl3) l 38.3 (CH2), 39.6 (CH), 44.3
(CH2), 44.9 (CH), 45.1 (CH), 46.5 (CH), 47.1 (CH),
48.8 (CH), 59.4 (CH2), 71.6 (CH), 132.6 (CH), 133.3
(CH).
4.7. (−)-Pentacyclo[6.2.1.13,6.02,7.05,9]dodecan-4-one
(−)-14
Alcohol (+)-11 (0.50 g, 2.9 mmol) was dissolved in dry
methylene chloride (60 mL) under stirring. To this
solution were added small portions of pyridinium
chlorochromate (PCC, 1.2 g, 5.6 mmol) at 0°C. The
suspension was stirred at room temperature for 4 h.
Ethyl ether (30 mL) was added and a black precipitate
formed, which was filtered off with a small column
fitted with silica gel and eluted with ethyl ether. The
organic solvent was evaporated producing the pure
ketone (−)-14 (85% yield), mp 165°C (lit.19 165–167°C),
[h]D20 −87.0 (c=1, CH2Cl2). FTIR (KBr) w (cm−1) 1731
1
(CꢀO); H NMR (200 MHz, CDCl3) l 1.23–2.85 (14H,
overlapping signals); 13C NMR (50 MHz, CDCl3) l
35.4 (CH2), 37.9 (CH2), 38.3 (CH), 39.4 (CH), 41.8
(CH), 43.8 (CH2), 44.9 (CH), 47.3 (CH), 51.2 (CH),
53.9 (CH), 54.5 (CH), 217.9 (CO).
4.8. (+)-endo-Pentacyclo[6.2.1.13,6.02,7.05,9]dodecan-4-ol
(+)-15
Ketone (−)-14 (0.70 g, 4.0 mmol) was dissolved in ethyl
ether (50 mL). To this solution was added LiAlH4
(0.038 g, 1.0 mmol), and the reaction was stirred for 5
days at room temperature. Afterwards, a solution of
15% HCl (15 mL) was added. The mixture was neutral-
ized with a 10% NaHCO3 solution and extracted with
ethyl ether. Evaporation of the solvent produced the
corresponding alcohol (+)-15, 90% yield. Mp 196°C
(lit.19 197–198°C), [h]D20 +3.0 (c=1, CH2Cl2). FTIR
(KBr) w (cm−1) 3322 (C−OH); 1H NMR (200 MHz,
CDCl3) l 0.92 (1H, dd, J=11.7 Hz, J=7.0 Hz), 1.38
(1H, d, J=9.3 Hz), 1.68 (1H, d, J=9.3 Hz), 2.00–2.36
(10H, overlapping signals), 3.55 (1H, dm, J=12.2 Hz),
4.03 (1H, d, J=6.1 Hz); 13C NMR (50 MHz, CDCl3) l
33.9 (CH2), 37.9 (CH), 40.3 (CH), 40.8 (CH2), 41.5
(CH), 44.3 (CH), 44.8 (CH), 45.2 (CH), 46.1 (CH2),
47.5 (CH), 55.9 (CH), 81.8 (CH).
4.6. (+)-exo-Pentacyclo[6.2.1.13,6.02,7.05,9]dodecan-4-ol
(+)-11; and (−)-exo-pentacyclo[6.2.1.13,6.02,7.05,9]-
dodecan-4-yl (−)-13
Lipase (50% w/w of substrate) was added to a solution
of pentacyclic alcohol ( )-11 (0.18 g, 10.23 mmol) in
vinyl acetate (10 mL) and the suspension was stirred at
25°C. The appropriate degree of conversion (50%) was
achieved in 1 h. Thereafter, the enzyme was filtered and
the excess vinyl acetate was evaporated. The products
were separated by flash column chromatography (hex-
ane/ethyl ether, 4:1), giving the alcohol (+)-11 and
acetate (−)-13. Alcohol (+)-11: mp 130°C (lit.17 130°C),
[h]D20 +4.0 (c=1, CH2Cl2). FTIR (KBr) w (cm−1) 3425
Acknowledgements
1
(C–OH); H NMR (200 MHz, CDCl3) l 1.12 (1H, dd,
The authors thank CNPq and FAPERGS for financial
support, CAPES for fellowships for J.A. and A.G.N.
The authors are also indebted to Amano Enzime USA
Co. Ltd., for kindly providing the type VII lipase (from
J=6.0 Hz, J=2.6 Hz), 1.28 (1H, d, J=3.6 Hz), 1.53
(1H, d, J=10.2 Hz), 1.58–1.75 (2H, m), 1.94–2.43 (9H,
overlapping signals), 4.58 (1H, d); 13C NMR (50 MHz,

2024
J. Alifantes et al. / Tetrahedron: Asymmetry 13 (2002) 2019–2024
7. Gonc¸alves, P. F. B.; Axt, M.; Costa, V. E. U.; Livotto, P.
R. Comput. Chem. 1998, 22, 399.
Candida rugosa). Help from Dr. J. Spencer (James
Black Foundation, England) in the proof reading of the
manuscript is greatly appreciated.
8. (a) Alifantes, J.; Lapis, A. A. M.; Martins, J. E. D.;
Costa, V. E. U. J. Chem. Soc., Perkin Trans. 2 2001, 1, 7;
(b) Carneiro, J. W. M.; Costa, V. E. U.; Alifantes, J.;
Taft, C. A.; de Paula e Silva, C. H. T.; Tostes, J. G. R.;
Seild, P. S.; Pinto, P. S.; da, S. Chem. Phys. Lett. 2001,
345, 189.
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