Studies in lipase catalyzed transesterifications: Synthesis of (+)- albicanol, (+)-albicanyl acetate and chiral intermediates useful in the synthesis of drimanes and labdanes

Article abstract of DOI:10.1016/S0040-4020(00)00096-X

Chiral intermediates [(-)-8, (+)-9, (-)-9, (+)-10, (-)-10, (+)-11] useful in the synthesis of drimanes and labdanes, as well as optically active albicanol 1 and albicanyl acetate 2, have been synthesized using enzymatic transesterification as the key step. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00096-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1899–1903
Studies in Lipase Catalyzed Transesterifications: Synthesis of
(ϩ)-Albicanol, (ϩ)-Albicanyl Acetate and Chiral Intermediates
Useful in the Synthesis of Drimanes and Labdanes
*
A. T. Anilkumar, Uma Sudhir, S. Joly and Mangalam S. Nair
Organic Chemistry Division, Regional Research Laboratory (CSIR), Thiruvananthapuram, Kerala 695-019, India
Received 9 November 1999; revised 11 January 2000; accepted 27 January 2000
Abstract—Chiral intermediates [(Ϫ)-8, (ϩ)-9, (Ϫ)-9, (ϩ)-10, (Ϫ)-10, (ϩ)-11] useful in the synthesis of drimanes and labdanes, as well as
optically active albicanol 1 and albicanyl acetate 2, have been synthesized using enzymatic transesterification as the key step. ᭧ 2000
Elsevier Science Ltd. All rights reserved.
Introduction
Synthetic efforts towards naturally occurring drimane
sesquiterpenes have been continuing for a while due to the
interesting biological activity profile of many of these
compounds.1 Asymmetric syntheses of drimanes and
labdanes have mostly commenced from higher terpenes
such as sclareol, abietic acid, manool, etc. However,
owing to their simpler structures, the two fish antifeedant
compounds (ϩ)-albicanol 1, first isolated from the liverwort
Diplophyllum albicans,2 and (ϩ)-albicanyl acetate 2,
isolated from the dorid nudibranch Cadlina luteomargi-
nata,3 have been synthesized by Fukumoto4 starting from
enantiomerically pure Wieland–Miescher ketone.
Results and Discussion
Ready availability of b-ionone and the ease with which it
could be converted to the b-ketoester 5 prompted us to
investigate various enzymatic approaches for its conversion
to optically pure intermediates.5 Compound 5 has been
found to be recalcitrant towards reduction using baker’s
yeast.6 Since it could be readily converted to the diol 6,
enzymatic resolution of 6 using various lipases was first
studied (Scheme 1).
Since any synthetic efforts towards 1 and 2 would also provide
chiral synthons, which have wide potential for the synthesis of
other drimanes, labdanes, etc., such a program was initiated in
our laboratory a few years ago. Accordingly, we set out with
the aim of obtaining chiral units 3 and 4 containing the bicyclo
[4.4.0] ring system with three pendant methyl groups and
necessary functionalities for further elaboration.
Treatment of (^)-6 with Porcine Pancreatic Lipase (PPL)
and Candida cylindracea Lipase (CCL) led to selective
Scheme 1.
Keywords: lipase; albicanol; albicanyl acetate; chiral intermediates; drimanes; labdanes.
* Corresponding author. Tel.: ϩ91-471-490674; fax: ϩ91-471-491712; e-mail: msn@csrrltrd.ren.nic.in
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00096-X

1900
A. T. Anilkumar et al. / Tetrahedron 56 (2000) 1899–1903
Table 1.
Entrya
Lipase
Acyl donor/solvent
Time (h)
Ester 7 % yb (% ee)c
Diol 6 % yb
1
2
3
4
5
6
7
8
9
PPL
Vinyl acetate
Vinyl acetate
Vinyl acetate
Vinyl acetate/ethyl acetate
Vinyl acetate/Et2O-THF
Isopropenyl acetate
Isopropenyl acetate
Vinyl acetate
22
3
14
18
20
96
72
48
38 (4)
97 (0)
75 (0)
47 (5)
40 (5)
40 (10)
42 (0)
No reaction
34 (0)
50
–
CCL (700–1500 U/mg)
CCL (24.2 U/mg)
CCL (700–1500 U/mg)
CCL (700–1500 U/mg)
CCL (24.2 U/mg)
CCL (700–1500 U/mg)
WGL
20
34
50
58
53
–
SAM 2
Vinyl acetate
7 days
50
a All the reactions were carried out in triplicate.
b Isolated yield after column chromatography.
c Determined by 1H NMR in the presence of Eu(hfc)3.
acylation of the primary hydroxyl group leading to (^)-7,
albeit without enantioselectivity.7 Enzymatic transesterifi-
cation of (^)-6 was studied in detail and some of the salient
results are given in Table 1.
with CCL (Fluka, 24.2 U/mg) in vinyl acetate at 30ЊC for
24 h resulted in the formation of ketoacetate (ϩ)-9 in 47%
yield and 68% ee ꢀEˆ6:5†: First crystallization of the above
acetate using pentane as solvent readily yielded material of
92% ee, while a second crystallization delivered (ϩ)-9 of
100% ee (Scheme 3). Subsequently, the ketoalcohol recov-
ered with 53% ee was subjected to lipase catalyzed acyla-
tion once more, which resulted in ketoacetate of poor ee but
provided (Ϫ)-8 with 82% ee. On crystallization from hex-
ane, (Ϫ)-8 of 97% ee was obtained. The ee at each stage was
Next, we turned our attention to the enzymatic resolution of
the ketoalcohol (^)-8, which could be readily obtained in
three steps from (^)-5 as shown in Scheme 2.8
When the ketoalcohol (^)-8 was treated with CCL
(Aldrich) which had high activity (700–1500 U/mg) in
vinyl acetate at 28ЊC, transacylation proceeded rapidly
and produced 56% of the acetate 9 in 45 min. However,
1H NMR studies using Eu(hfc)3 as chiral shift reagent indi-
cated that no enantiodifferentiation has occurred. After
much experimentation, we found that treatment of (^)-8
1
ascertained by H NMR using Eu(hfc)3 as shift reagent.
Details of our studies on the effect of different solvent and
enzymes are given in Table 2.
(ϩ)-9 was rapidly converted to the chiral intermediate
(ϩ)-10 in 95% yield and 98% ee through elimination on
an alumina column as reported by us earlier.9 Conversion
of (ϩ)-10 to the marine natural product zonarol has been
reported by Mori et al.6 Furthermore, a much more versatile
chiral intermediate (ϩ)-11 especially useful in the synthesis
of ent-labdanes has been synthesized in 92% yield, through
the addition of nitromethane to (ϩ)-10 as shown in
Scheme 4.
Similarly, the bicyclic enone (Ϫ)-10 was synthesized from
the ketoalcohol (Ϫ)-8 through conversion to the acetate
(Ϫ)-9 and subsequent elimination on alumina as shown in
Scheme 5.
Scheme 2. Reagents and conditions: (a) Ethylene glycol, PTS, benzene,
reflux, 96%; (b) LiAlH4, Et2O, 0ЊC–rt, 86%; (c) PTS, acetone (wet), rt,
99%.
Scheme 3.

A. T. Anilkumar et al. / Tetrahedron 56 (2000) 1899–1903
1901
Table 2.
Entry
Lipase
Acyl donor/solvent
Time (h)
Temperature (ЊC)
Ester 9 % ya (% ee)b
Alcohol 8 % ya (% ee)c
d
1
2
3
4
5
6
7
8
9
10
PPL
Vinyl acetate
Vinyl acetate
Vinyl acetate
Vinyl acetate
Vinyl acetate
Vinyl acetate
Vinyl acetate/diisopropyl ether
Isopropenyl acetate/benzene
Vinyl acetate/pet. ether
Vinyl acetate
70
0.75
17
21
20
24
76
76
3.5
7 days
28–30
28
28
28
30
30
28
30
31
No reaction
56 (0)
33.6 (70)
41.6 (68)
43.5 (70)
47 (68)
55.8 (4)
47 (10)
31 (18)
CCL (700–1500 U/mg)
CCL (24.2 U/mg)
CCL (24.2 U/mg)
CCL (24.2 U/mg)
CCL (24.2 U/mg)
CCL (24.2 U/mg)
CCL (24.2 U/mg)
CCL (24.2 U/mg)
Lipase PS Amano
38 (n.d.)e
64 (n.d.)
47 (n.d.)
54 (n.d.)
48 (53)
43 (n.d.)
51 (n.d.)
64 (n.d.)
62 (n.d.)
28–31
20.5 (10)
a Isolated yield after column chromatography.
1
b Determined by H NMR in the presence of Eu(hfc)3.
c Determined by comparison of the optical rotation with literature value.
d Almost complete recovery of alcohol (^)-8.
e n.d.ˆee not determined.
The natural product (ϩ)-albicanol 1 was synthesized from
(Ϫ)-8 in a modest yield of 30% through a Wittig type
methylenation using the Takai modification of adding PbI2
to the Nozaki–Lombardo methylenation reagent viz. TiCl4–
Zn–CH2I2.10 This was converted to (ϩ)-albicanyl acetate 2
through routine acetylation (Scheme 6).
Since the yield of the above methylenation reaction was
poor, it was decided to synthesize (^)-albicanol and carry
out the enzymatic acetylation as the last step. Accordingly,
the b-ketoester (^)-5 was converted to the methylene ester
12 through a Wittig reaction as reported by Liapis et al.11
and further reduced to (^)-albicanol with LiAlH4 at 0ЊC in
THF as shown in Scheme 7.12
Most interestingly, treatment of (^)-1 with CCL in vinyl
acetate at 28ЊC for 8 h gave (Ϫ)-albicanyl acetate in 57%
yield and 73% ee and (ϩ)-albicanol in 37% yield and 77%
ee (Scheme 8). The ee in these cases were determined by
comparison of their optical rotations with reported values.
In conclusion, we have shown that enzymatic transesterifi-
cation can be utilized to obtain (ϩ)-albicanol, both enantio-
mers of albicanyl acetate, as well as various versatile chiral
intermediates.
Scheme 4. Reagents and conditions: (a) Al2O3, 95%; (b) CH3NO2, TMG,
0ЊC, 92%.
Scheme 5. Reagents and conditions: (a) Ac2O, Py, 0ЊC, 91%; (b) Al2O3,
94%.
Scheme 7. Reagents and conditions: (a) Ph3PϩMeBrϪ, NaNH2, toluene,
reflux; (b) LiAlH4, 0ЊC–r.t, THF (45% for two steps).
Scheme 6. Reagents and conditions: (a) CH2I2–Zn–(PbI2)–TiCl4, THF,
CH2Cl2, 0ЊC–rt, 30%; (b) Ac2O, Py, 0ЊC, 90%.
Scheme 8.

1902
A. T. Anilkumar et al. / Tetrahedron 56 (2000) 1899–1903
Experimental
(ϩ)-9 (290 mg, 47%, 68% ee) and ketoalcohol (Ϫ)-8 as
white crystals (250 mg, 48%, 53% ee). (ϩ)-9 (100% ee);
Anhydrous reactions were carried out in oven dried glass-
ware under an atmosphere of argon or nitrogen using
distilled or dry solvents as required. PPL, Type II with
activity 110–220 U/mg and CCL, Type VIII with activity
700–1500 U/mg were purchased from Aldrich. CCL with
activity 24.2 U/mg and SAM 2 (Pseudomonas fluorescens
lipase) with activity 31.5 U/mg were purchased from Fluka.
WGL (Wheat germ lipase) with activity 9.5 U/mg was
purchased from Sigma. Lipase PS ‘Amano’ (from Pseudo-
monas cepacia) with activity 30 U/mg was gifted by Amano
Pharmaceutical Co., Japan. b-ionone obtained from M/s
Kelkar & Co., Bombay, was purified by flash column
chromatography before use.
mp: 57–58.2ЊC; [a]2D4ˆϩ35.1 (c 0.96, CHCl3); IR (KBr):
1
2979, 2931, 1744, 1723, 1464, 1374, 1249, 1045 cmϪ1; H
NMR (200 MHz, CDCl3): 0.77 (3H, s), 0.86 (3H, s), 0.98
(3H, s), 1.20–1.80 (9H, m), 2.00 (3H, s), 2.05–2.60 (3H, m),
4.20 (2H, m); 13C NMR (22.4 MHz, CDCl3): 15.1, 18.6,
20.7, 21.4, 23.5, 33.3, 33.4, 38.9, 41.5, 41.7, 41.8, 53.6,
58.6, 62.1, 170.7, 209.1; Anal. Calcd for C16H26O3: C
72.14, H 9.84; Found: C 72.38, H 9.85.
(Ϫ)-8. [a]2D5ˆϪ37.6 (c 0.46, CHCl3) (97% ee) {lit4b
[a]2D6ˆϪ38.9 (c 1.24, CHCl3)}. The spectral data were in
accordance with those reported in literature.4b
(4aR, 8aR)-(ϩ)-1-Methylene-5,5,8a-trimethyl-2-oxodeca-
hydronaphthalene-(ϩ)-10
All melting points are uncorrected and were determined on a
Buchi-530 melting point apparatus. IR spectra were
recorded on a Perkin–Elmer Model 882 infrared spectro-
photometer. 1H NMR spectra were recorded on Bruker-200
and Bruker-300 NMR spectrometers and 13C NMR on JEOL
EX-90 spectrometer using tetramethylsilane as internal
standard. The mass spectra were recorded on a Hewlett
Packard 5890 Series II GC connected to a 5890 mass selec-
tive detector. Elemental analyses were obtained using
Perkin–Elmer Model 240C-CHN analyzer. Optical rota-
tions were recorded on JASCO DIP-370 digital polarimeter
in CHCl3. Column chromatography was performed using
100–200 mesh silica gel.
The ketoacetate (ϩ)-9 (100 mg, 0.38 mmol) of ϳ100% ee
was adsorbed on a short column of neutral alumina
(Brockmann grade 1, 5 g) and on elution with 10% ethyl
acetate in petroleum ether after 1 h readily furnished
optically pure enone (ϩ)-10 as an oil (73 mg, 95%, 98%
ee) [a]2D4ˆϩ73.6 (c 1.00, CHCl3) {lit6 [a]2D3ˆϩ71.9
(c 0.695, CHCl3)}. All spectral data matched with those
reported in the literature.6
1-(20-Nitroethyl)-5,5,8a-trimethyl-2-oxodecahydro-
naphthalene-(ϩ)-11
CCL catalyzed transesterification of diol-(^)-6
A solution of enone (ϩ)-10 (70 mg, 0.34 mmol) in nitro-
methane (2 mL) under argon was cooled to 0ЊC, and 1,1,3,3-
tetramethylguanidine (0.04 mL, 0.32 mmol) was added to it.
The reaction mixture was stirred at 0ЊC for 2 h. When the
reaction was complete as shown by TLC, it was diluted with
ether (10 mL), washed with aqueous 5% HCl, water satu-
rated NaHCO3, brine and dried over Na2SO4. Solvent was
removed under reduced pressure and the residue chromato-
graphed over silica gel using 10% ethyl acetate in petroleum
ether as eluent to furnish nitro compound (ϩ)-11 as a low
melting solid (82 mg, 90%) [a]2D4ˆϩ19.7 (c 1.45, CHCl3);
IR (film): 2952, 2865, 1708, 1552, 1440, 1372, 1185,
A mixture of diol 6 (100 mg, 0.44 mmol) and CCL (700–
1500 U/mg, 200 mg) in vinyl acetate (15 mL) was stirred at
30ЊC for 3 h. Lipase was then removed by filtration through
a small layer of silica gel. Solvent was removed under
reduced pressure and the residue purified by rapid chroma-
tography on a silica gel column using 15% EtOAc in petro-
leum ether as eluent which furnished acetate 7, which was
crystallized from dichloromethane as white crystals
(115 mg, 97%). mp 70–71ЊC; IR (KBr): 3553, 2925,
1745, 1462, 1267 cmϪ1 1H NMR (300 MHz, CDCl3):
;
0.85 (3H, s), 0.88 (3H, s), 1.05 (3H, s), 1.05–1.95 (13H,
m), 2.06 (3H, s), 3.90–3.91 (1H, m), 4.17 (1H, dd, Jˆ10.9,
3.8 Hz) 4.45 (1H, dd seen as apparent triplet Jˆ10.7 Hz,
Jˆ10.6 Hz); 13C NMR (22.4 MHz, CDCl3): 16.4, 16.9,
18.2, 21.0, 21.7, 33.2, 33.6, 34.6, 37.0, 39.5, 41.8, 53.0,
55.7, 62.0, 66.3, 171.8; GC–MS m/z: 208 (MϩϪ60, 15),
193 (25), 190 (20), 178 (27), 174 (25), 163 (30), 149 (30),
136 (40), 124 (68), 123 (58), 109 (100), 95 (72). Anal. Calcd
for C16H28O3: C 71.59, H 10.52; Found: C 71.68, H 10.54.
1079 cmϪ1 1H NMR (200 MHz, CDCl3): 0.76 (3H, s),
;
0.87 (3H, s), 0.98 (3H, s), 1.10–1.80 (9H, m), 2.00–2.55
(5H, m), 4.25–4.53 (2H, m); 13C NMR (22.4 MHz, CDCl3):
14.4, 18.6, 20.3, 21.4, 23.4, 33.2, 33.4, 38.8, 41.5, 41.9,
42.0, 53.6, 60.0, 74.7, 210.7; Anal. Calcd for C15H25O3N:
C 67.39; H 9.43, N 5.24; Found C 67.45, H 9.45, N 5.28.
(ϩ)-Albicanol 1
A mixture of Zn (244 mg, 3.73 mmol), catalytic amount of
PbI2 (8 mg), diiodomethane (0.09 mL, 215 mg, 1.24 mmol)
and TiCl4 (0.1 mL, 0.91 mmol) in dry THF (4 mL) was
stirred at 0ЊC for 1 h. A solution of (Ϫ)-8 (38 mg,
0.17 mmol, ϳ97% ee) was added and stirred at 0–28ЊC
for 12 h. Reaction mixture was diluted with hexane
(8 mL) and a saturated aqueous NaHCO3 solution was
added. The hexane layer was separated and aqueous layer
extracted with hexane (3×5 mL). The combined extracts
were washed with water, brine and dried over Na2SO4/
NaHCO3 mixture. Solvent was removed under reduced
pressure and the residue purified over silica gel using 6%
CCL catalyzed transesterification of ketoalcohol-(^)-8
To a solution of (^)-8 (520 mg, 2.32 mmol) in vinyl acetate
(45 mL) was added CCL (24.2 U/mg, 490 mg and stirred at
30ЊC for 12 h, following which an additional amount of
lipase (490 mg) was added. The reaction mixture was stirred
for a total period of 24 h. Lipase was then filtered off and
washed with ethyl acetate. Combined filtrate was concen-
trated under reduced pressure and the residue chromato-
graphed over silica gel using 10% EtOAc in petroleum
ether as eluent to furnish the ketoacetate as white crystals

A. T. Anilkumar et al. / Tetrahedron 56 (2000) 1899–1903
1903
EtOAc in petroleum ether as eluent to furnish (ϩ)-albicanol
(11.5 mg, 30%). Spectral data matched with those reported
in literature.4b
and M/s Kelkar & Co., Bombay, for b-ionone. ATA, US
and SJ thank CSIR for research fellowship.
(ϩ)-Albicanyl acetate 2
References
Acetic anhydride (21 mg, 0.20 mmol) was added to a solu-
tion of the (ϩ)-albicanol (11.5 mg, 0.05 mmol) in pyridine
at 0ЊC and stirred at rt for 6 h and worked up. The residue
was chromatographed over silica gel using 4% ethyl acetate
in petroleum ether as eluent to afford (ϩ)-Albicanyl acetate
(12 mg, 88%) [a]D24ˆϩ21.6 (c 0.46, CHCl3) {lit4b [a]2D6ˆ
ϩ21.9 (c 0.37, CHCl3)}. All spectral data were identical
with those reported in literature.4b
1. (a) Jansen, B. J. M.; de Groot, A. Nat. Prod. Rep. 1991, 8, 309
and references cited therein. (b) Jansen, B. J. M.; de Groot, A. Nat.
Prod. Rep. 1991, 8, 319 and references cited therein.
2. Ohta, Y.; Andersen, N. H.; Liu, C. B. Tetrahedron 1977, 33,
617.
3. Hellou, J.; Andersen, R. J.; Thompson, J. E. Tetrahedron 1982,
38, 1875.
4. (a) Shishido, K.; Tokunaga, Y.; Omachi, N.; Hiroya, K.;
Fukumoto, K.; Kametani, T. J. Chem. Soc., Chem. Commun.
1989, 1093. (b) Shishido, K.; Tokunaga, Y.; Omachi, N.; Hiroya,
K.; Fukumoto, K.; Kametani, T. J. Chem. Soc., Perkin Trans. 1
1990, 2481.
5. Bu¨chi, G.; Wu¨est, H. Helv. Chim. Acta 1989, 72, 996.
6. Mori, K.; Komatso, M. Bull. Soc. Chim. Belg. 1986, 95, 771.
7. Nair, M. S.; Anilkumar, A. T. Biotechnol. Lett. 1994, 16, 161.
8. Kato, M.; Tooyama, Y.; Yoshikushi, A. Bull. Chem. Soc. Jpn
1991, 64, 50.
9. (a) Nair, M. S.; Anilkumar, A. T. Synth. Commun. 1994, 24,
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1996, 7, 511.
10. (a) Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. Bull. Chem
Soc. Jpn 1980, 53, 1698. (b) Lombardo, L. Org. Synth. 1987, 65,
81. (c) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org.
Chem., 1994, 59, 2668.
CCL catalyzed resolution of (^)-albicanol
To a solution of racemic albicanol (40 mg, 0.18 mmol) in
vinyl acetate (4 mL) was added CCL (24.2 U/mg, 23 mg)
and stirred at 30ЊC for 8 h, until TLC showed nearly half
completion of the reaction. Lipase was then filtered off and
the solvent removed under reduced pressure. The crude
product was purified by column chromatography using 4%
ethyl acetate in petroleum ether as eluent to afford the (Ϫ)-
albicanyl acetate (27.2 mg, 57%, 73% ee). [a]2D8ˆϪ17.6
(c 1.08, CHCl3). Further elution of the column with 6%
ethyl acetate in petroleum ether gave (ϩ)-albicanol 1
(14.8 mg, 37%, 77% ee) [a]2D8ˆϩ9.98 (c 0.59, CHCl3)
{lit4b [a]D20ˆϩ13 (c 0.60, CHCl3)}. The spectral data
matched with those reported in literature.4b The ee was
calculated based on comparison of optical rotation.
11. Liapis, M.; Ragoussis, V.; Ragoussis, N. J. Chem. Soc., Perkin
Trans. 1 1985, 815.
Acknowledgements
12. (a) Armstrong, R. J.; Harris, F. L.; Weiler, L. Can. J. Chem.
1982, 60, 673. (b) Armstrong, R. J.; Harris, F. L.; Weiler, L. Can. J.
Chem. 1986, 64, 1002.
MSN thanks DST, India, and IFS, Sweden, for financial
assistance, Professor M. V. George for a gift of Eu(hfc)3