Lipase-catalyzed resolution of 1-[4-(benzyloxy)phenyl]hex-5-en-3-ol: Synthesis of (-)-centrolobine

Article abstract of DOI:10.14233/ajchem.2017.20816

A practical and efficient method for the preparation of homoallylic alcohol and its successful enzymatic resolution has been developed. This lipase-catalyzed resolution process has been optimized with respect to different lipases and solvents. Moreover, M

Full text of DOI:10.14233/ajchem.2017.20816

Asian Journal of Chemistry; Vol. 29, No. 10 (2017), 2321-2326
ASIAN JOURNAL OF CHEMISTRY
https://doi.org/10.14233/ajchem.2017.20816
Lipase-Catalyzed Resolution of 1-[4-(Benzyloxy)phenyl]hex-5-en-3-ol: Synthesis of (-)-Centrolobine
2
KRISHNAJI TADIPARTHI1,2,*, S. RAGHAVENDRA2,3 and AHMED KAMAL
1Department of Chemistry, Christ University, Hosur Road, Bangalore-560 029, India
2Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
3Department of Pharmaceutical Chemistry, School of Pharmacy and Health Sciences, International Medical University, Kuala Lumpur 57000,
Malaysia
*Corresponding author: E-mail: krishnaji.tadiparthi@christuniversity.in; tkrishnaji@gmail.com
Received: 26 May 2017;
Accepted: 17 July 2017;
Published online: 31 August 2017;
AJC-18542
A practical and efficient method for the preparation of homoallylic alcohol and its successful enzymatic resolution has been developed.
This lipase-catalyzed resolution process has been optimized with respect to different lipases and solvents. Moreover, Mitsunobu strategy
has been applied to recover the unwanted isomer. Further optically enriched homoallylic alcohol has been employed for the synthesis of
(-)-centrolobine.
Keywords: Kinetic resolution, Lipases, Enantioselectivity, Mitsunobu reaction and Metathesis.
[46-48], chelation controlled diastereoselective synthesis from
carbohydrate [49], intramolecular amide enolate alkylation
[50], enantioselective hetero Diels-Alder reaction (HDA) [51],
the reduction of a β-ketosulfoxide [52,53], intra molecular
reductive etherification [54], asymmetric reduction [55]. However,
most of these reported methods have certain limitations like
use of expensive chiral reagents, low selectivity and moderate
yields. Herein, we demonstrated the synthesis of optically pure
(-)-centrolobine using lipase catalyzed resolution protocol.
INTRODUCTION
The natural products containing of 2,5-disubstituted
tetrahydrofuran and 2,6-disubstituted tetrahydropyran units
exhibits different biological activities. These motifs can also
be found in various monocyclic and polycyclic compounds,
cyclic ethers or spiroketals [1-7]. (-)-Centrolobine (1) is a six
membered heterocyclic natural product in which tetrahydro-
pyran ring is present in syn-fashion. Basically it is isolated
from the heartwood of Centrolobium robustum and from the
stem of Broginum potabile in the Amazon forest. It is active
ingredient in an herbal tea made from the wood of Centrolobum
robustum and is used by the native people of the Amazon as a
tonic cure for a variety of ailments [8-13]. Moreover, it exhibits
various therapeutic activities like antibiotic and antifungal.
Furthermore, it exhibits activity against Leishmania amazonensis
promastigotes, a parasite associated with leishmaniasis, a major
health problem in Brazil.
EXPERIMENTAL
Unless specified all solvents and reagents were reagent
grade and used without further purification. Reactions involving
moisture-sensitive reagents were performed under an atmos-
phere of nitrogen in glassware, which had been oven dried.
Pseudomonas cepacia lipase immobilized on diatomite (PS-
D), Pseudomonas cepacia (PS), Pseudomonas cepacia lipase
immobilized on modified ceramic particals (PS-C), Pseudo-
monas fluorescens lipase (AK)are obtained from Amano
Pharmaceutical company, Japan, Pseudomonas fluorescens
lipase immobilized in Sol-Gel-AK on sintered glass (P), lipase
immobilized from Mucormeihei (Lipozyme), Candida
antartica lipase immobilized in Sol-Gel-AK on sintered glass
(CAL B) are from Fluka, Candida rugosa lipase (CRL)
(Sigma).
However, the structure of centrolobine was elucidated in
1964 and its absolute configuration was assigned in 2002 by
its enantioselective synthesis [14]. Owing to excellent biolo-
gical activities and its simple chemical structure, many research
groups have been paid attention for its synthesis in racemic
form [15-19] as well as in enantiomerically form [14,20-38].
The enantiomerically pure core unit of tetrahydropyran
unit has been constructed by various methods like Prins-
cyclization [39,40], ring rearrangement metathesis [41],
asymmetric allylation [42-45], asymmetric hydrogenation
Melting points were recorded on an S.D. Fine 9100 Electro-
thermal melting point apparatus and are uncorrected. Infrared

2322 Tadiparthi et al.
Asian J. Chem.
spectra were recorded on Perkin-Elmer model 683 or 1310
1
1-[4-(Benzyloxy)phenyl]hex-5-en-3-ol (5): To a stirred
solution of allyl bromide (1.5 g, 12.5 mmol) in dry THF (20 mL),
zinc powder (0.8 g, 12.5 mmol) was added and stirred at room
temperature for 1 h. To the reaction mixture aldehyde 4 (1.2 g,
5 mmol) in THF (5 mL) was added and stirred at room tempe-
rature for 1.5 h. After completion of the reaction, the reaction
mixture was washed with 5 % HCl (1 × 5 mL), dried over
anhydrous Na2SO4. Purification was accomplished by column
chromatography using EtOAc-hexane (30:70) as eluant to give
the required homoallylic alcohol 5 as a solid (1.3 g, 90 %);
m.p. : 68-70 °C; IR (KBr, νmax, cm–1): 3361, 2925, 1510, 1236,
1008; 1H NMR (300 MHz, CDCl3): δ 1.55 (bs, 1H), 1.70 (q,
2H, J = 8.3 Hz), 2.08-2.33 (m, 3H), 2.54-2.77 (dddd, 2H, J =
7.5, 13.5, 21.1, 28.7 Hz), 3.54-3.65 (m, 1H), 5.01 (s, 2H),
5.11 (d, 2H, J = 12.0 Hz), 5.70-5.85 (m, 1H), 6.83 (d, 2H, J =
9.0 Hz), 7.06 (d, 2H, J = 8.3 Hz), 7.23-7.41 (m, 5H); 13C NMR
(75 MHz, CDCl3): δ 31.2, 38.7, 42.1, 70.0, 70.2, 114.9, 118.2,
127.6, 127.9, 128.7, 129.4, 134.5, 134.7, 137.4, 157.2 ppm;
Mass (EI): 305 (M+Na)+, 265, 223, 197, 91.
spectrometers and are reported in wave numbers (cm-1). H
NMR spectra were recorded as solutions in CDCl3, or acetone
(d6) and chemical shifts were reported in parts per million
(ppm) on a Varian Gemini 200 MHz or AV 300 MHz, instru-
ment using tetramethylsilane (TMS) as an internal standard.
Coupling constants were reported in hertz (Hz). Low-resolution
mass spectra were recorded on CEC-21-100B Finnigan Mat
1210 orVG 7070H micromass spectrometers. Analytical TLC
of all the reactions were performed on Merck prepared plates
(silica gel 60F-254 on glass). Column chromatography was
performed usingAcme silica gel (100–200 mesh). Percentage
yields were given for all the isolated compounds. HPLC
analysis was performed on an instrument that consisted of a
Shimadzu SIL-10AD auto injector, system controller with an
SPD-M10A UV monitor as detector. The chiral purity was
determined using Chiracel AS-H coloumn (Diacel). E-values
were calculated based on the enantiomeric excess of the
products (eep) and the conversion (c). Optical rotations were
measured using SEPA-300 (Horiba) digital polarimeter.
3-(4-Benzyloxy)phenylpropan-1-ol (3): To a stirred
solution of 4-(3-hydroxypropyl)phenol (2) (2.0 g, 13.5 mmol)
in acetone (50 mL), K2CO3 (3.6 g, 26.3 mmol), benzyl bromide
(2.3 g, 13.5 mmol) were added sequentially and stirred under
reflux conditions for 10 h. After completion of the reaction,
the reaction was taken into CH2Cl2 (25 mL), washed with brine
(1 × 10 mL), dried over anhydrous Na2SO4 and the solvent was
evaporated. The residue was purified by column chromatography
using EtOAc-hexane (15:85) as eluant to give the required
benzyl ether 3 as a solid (3.0 g, 90 %); m.p.: 54-56 °C; IR
Kinetic resolution of 1-[4-(benzyloxy)phenyl]hex-5-en-
3-ol (5): To the compound 5 (1.0 g, 3.5 mmol) in diisopropyl
ether (25 mL), lipase (1.0 g, w/w) and vinyl acetate (1.8 g, 21
mmol) were added successively and the mixture was stirred at
room temperature for nearly 17 h. After conversion to about
50 % which was monitored by HPLC on AS-H chiral Daicel
column, the reaction mixture was filtered and the two com-
pounds alcohol (S)-5a and acetate(R)-7a were separated by
column chromatography using EtOAc-hexane (85:15) as eluent.
1-[4-(Benzyloxy)phenyl]hex-5-en-3ylacetate (6): To a
stirred solution of homoallylic alcohol 5 (0.3 g, 0.9 mmol) in
CH2Cl2 (20 mL), acetic anhydride (0.3 g, 2.6 mmol), Et3N
(0.3 g, 2.6 mmol) and DMAP (cat.) were added successively
at 0 °C. After completion of the reaction, the reaction mixture
was taken into CH2Cl2 (10 mL), washed with 5 % HCl (1 × 5
mL), brine (1 × 5 mL), dried over anhydrous Na2SO4 and the
solvent was evaporated. The crude residue was purified by
column chromatography using EtOAc-hexane (20:80) as eluant
to give the required acetate 7 as a liquid (0.2 g, 80 %); IR (KBr,
1
(KBr, νmax, cm–1): 3362, 2927, 2860, 1510, 1241; H NMR
(200 MHz, CDCl3): δ 1.40 (bs, 1H), 1.76-1.94 (m, 2H), 2.66
(t, 2H, J = 6.9 Hz), 3.64 (t, 2H, J = 6.0 Hz), 5.04 (s, 2H), 6.86
(d, 2H, J = 8.6 Hz), 7.09 (d, 2H, J = 7.8 Hz), 7.20-7.50 (m,
5H) ppm; 13C NMR (75 MHz, CDCl3): δ 31.2, 34.4, 62.2, 70.1,
114.9, 127.5, 127.9, 128.4, 129.4, 134.3, 137.3, 157.1 ppm;
Mass (EI): 242 (M)+, 141, 91, 77, 65, 51.
3-(4-Benzyloxy)phenylpropanal (4): To a stirred solution
of oxalyl chloride (1.1 mL, 12.4 mmol) in CH2Cl2 (50 mL),
DMSO (1.8 mL, 24.8 mmol) was added slowly at –78 °C and
stirred the reaction mixture at the same temperature for 30 min.
Compound 3 (2.0 g, 8.3 mmol) in CH2Cl2 (10 mL) was added
to the reaction mixture slowly at –78 °C and stirred at the same
temperature for 2.5 h. To the reaction mixture triethylamine
(6.9 mL, 49.6 mmol) was added slowly at 0 °C and stirred for
another 30 min. The reaction mixture was taken into CH2Cl2
(20 mL), washed with 5 % HCl (1 × 5 mL), brine (1 × 5 mL),
dried over anhydrous Na2SO4 and the solvent was evaporated.
Purification of the crude residue was accomplished by column
chromatography using EtOAc-hexane (10:90) as eluant to give
the required aldehyde 4 as a solid (1.8 g, 88 %); m.p.: 46-48
ν
max, cm–1): 2927, 1736, 1511, 1375, 1240, 1171, 1024; 1H NMR
(300 MHz, CDCl3): δ 1.75-1.92 (m, 2H), 2.10 (s, 3H), 2.30-
2.42 (t, 2H, J = 9.0 Hz), 2.52-2.70 (m, 2H), 4.90-5.00 (m,
1H), 5.05 (s, 2H), 5.10-5.20 (d, 2H, J = 4.5 Hz), 5.60-5.80 (m,
1H), 6.82-6.92 (d, 2H), 7.00-7.15 (d, 2H), 7.25-7.50 (m, 5H);
13C NMR (75 MHz, CDCl3): δ 21.1, 30.8, 35.4, 38.6, 70.0,
72.8, 114.8, 117.7, 127.4, 127.8, 128.5, 129.2, 133.5, 133.8,
137.2, 157.1, 170.6; Mass (EI): 325 (M)+, 265, 223, 197, 147, 91.
(S)-1-[4-(Benzyloxy)phenyl]hex-5-en-3-yl-4-nitro-
benzoate (S)-7: To solution of p-nitrobenzoic acid (0.7 g, 4.3
mmol) in toluene (20 mL), powdered PPh3 (1.1 g, 4.25 mmol)
was added followed by a solution of alcohol (S)-5a (1.0 g, 3.5
mmol) in toluene (5 mL) at –30 °C. To this, a solution of diethyl
azodicarboxylate solution (DEAD) (1 mL, 7 mmol) in toluene
(3 mL) was added slowly and stirred at the same temperaturefor
10 h. After completion of the reaction as indicated by TLC, the
reaction mixture was poured into saturated NaHCO3 (20 mL).
The phases were separated and the aqueous phase was further
extracted with Et2O (2 × 50 mL). The combined organic extracts
were washed with brine (30 mL), dried over anhydrous Na2SO4
1
°C; IR (KBr, νmax, cm–1): 2924, 1722, 1682, 1510, 1240; H
NMR (300 MHz, CDCl3): δ 2.70 (t, 2H, J = 7.5 Hz), 2.87 (t,
2H, J = 7.5 Hz), 5.01 (s, 2H), 6.84 (d, 2H, J = 8.3 Hz), 7.05 (d,
2H, J = 8.3 Hz), 7.23-7.41 (m, 5H), 9.78 (s, 1H) ppm; 13C
NMR (75 MHz, CDCl3): δ 27.1, 45.3, 69.9, 114.9, 127.3,
127.8, 128.5, 129.2, 132.5, 137.1, 157.2, 201.6; Mass: (EI):
240 (M)+, 239, 91, 77.

Vol. 29, No. 10 (2017)
Lipase-Catalyzed Resolution of 1-[4-(Benzyloxy)phenyl]hex-5-en-3-ol: Synthesis of (-)-Centrolobine 2323
and concentrated. Purification of the crude product by flash
chromatography (4 % EtOAc: hexane) provided p-
nitrobenzoate (R)-7 (1.4 g, 95 %) as a yellow solid; m.p. : 61-
chromatography using EtOAc-hexane (30:70) as eluent to give
25.2
(R)-9 as a solid (0.07 g, 80 %); m. p.: 103-105 °C; [α]D
+19.5° (c 1.0, CHCl3); IR (KBr, νmax, cm–1): 2924, 1720, 1511,
29.8
1
1238, 1018, 749; H NMR (200 MHz, CDCl3): δ 1.75-2.39
63 °C; [α]D -32.76° (c 1.9, CHCl3); IR (KBr, νmax, cm–1):
1
2949, 2221, 1714, 1607, 1524, 1515, 1281; H NMR (200
(m, 5H), 2.61-2.88 (m, 2H), 4.30-4.46 (m, 1H), 5.03 (s, 2H),
6.01 (d, 1H, J = 9.3 Hz), 6.80 (d, 2H, J = 7.6 Hz), 7.10 (d, 2H,
J = 8.4 Hz), 7.23-7.47 (m, 5H) ppm; 13C NMR (75 MHz,
CDCl3): δ 29.6, 30.1, 36.8, 70.2, 77.6, 115.0, 121.6, 127.5,
128.0, 128.7, 129.4, 133.4, 137.3, 145.1, 157.9, 164.5 ppm;
Mass (EI): 309 (M-1)+, 297, 197, 91.
MHz, CDCl3): δ 1.89-2.13 (m, 2H), 2.40-2.70 (m, 4H), 4.97
(s, 2H), 5.01-5.29 (m, 3H), 5.64-5.84 (m, 1H), 6.80 (d, 2H, J
= 8.9 Hz), 7.02 (d, 2H, J = 8.2 Hz), 8.12 (d, 2H, J = 8.9 Hz),
8.27 (d, 2H, J = 8.9 Hz), 8.30-8.42 (m, 5H) ppm; 13C NMR
(75 MHz, CDCl3): δ 30.8, 35.3, 38.5, 69.9, 74.8, 114.8, 118.3,
123.4, 127.3, 127.8, 128.5, 129.1, 130.6, 132.9, 133.4, 135.8,
137.1, 150.4, 157.2, 164.2 ppm; LCMS: 454 (M+Na).+
(S)-1-[4-(Benzyloxy)phenyl]hex-5-en-3-ol [(S)-5b]: To
a solution of p-nitrobenzoate (R)-7 (1.0 g, 2.3 mmol) in MeOH
(15 mL), K2CO3 (1.3 g, 9.3 mmol) was added at 0 °C and the
suspension was stirred for 15 min at room temperature. After
completion of the reaction, neutralized the reaction mass with
acetic acid (5 mL) and the solvent in the reaction mass was
removed. The resulting crude mixture was diluted with H2O
(15 mL) and extracted with EtOAc (2 × 25 mL). The combined
organic extracts were washed with brine (1 × 10 mL), dried
(Na2SO4) and concentrated. The crude residue was purified
(R)-6-(4-Hydroxyphenethyl)-tetrahydropyran-2-one
[(R)-10]: To a solution of (R)-9 (50 mg, 0.16 mmol) in ethyl
acetate (10 mL), Pd/C (50 mg) was added under hydrogen
atmosphere and stirred at room temperature for 4 h. After
completion of the reaction, filtered the reaction mass through
the celite pad and washed with ethyl acetate (3 × 20 mL). The
solvent was evaporated and the residue was purified by column
chromatography using EtOAc-hexane (40:60) as eluent to give
the required product (R)-10 as a solid (32 mg, 90 %); m.p. : 120-
124 °C; [α]D25.2-57.75° (c 1.0, CHCl3); IR (KBr, νmax, cm–1):
1
3296, 2954, 2926, 1707, 1516, 1256; H NMR (200 MHz,
CDCl3): δ 1.44-2.06 (m, 6H), 2.35-2.80 (m, 4H), 4.16-4.28
(m, 1H), 5.72 (bs, 1H), 6.74 (d, 2H, J = 8.3 Hz), 6.99 (d, 2H,
J = 8.3 Hz) ppm; 13C NMR (75 MHz, CDCl3): δ 17.6, 27.1,
28.7, 29.4, 36.8, 79.2, 114.7, 128.7, 131.7, 153.8, 172.6 ppm;
Mass (EI): 221 (M-1)+, 203, 185, 127, 107.
by flash chromatography (10 % EtOAc:hexane) to provide
25.2
the alcohol (R)-5b (0.6 g, 90 %) as a yellow solid; [α]D
15.33° (c 1.0, CHCl3).
-
(R)-1-[4-(Benzyloxy)phenyl]hex-5-en-3-ol [(R)-5a]:
[α]D 25.2 + 14.66° (c 1.25, CHCl3).
(S)-1-(4-(Benzyloxy)phenyl)hex-5-en-3-ol [(R)-5b]:
[α]D25.2 -14.31° (c 1.0, CHCl3).
(S)-1-[4-(Benzyloxy)phenyl]hex-5-en-3-ylacetate [(S)-
6a]: [α]D25.2 +7.0° (c 1.0, CHCl3).
(2R,6R)-6-(4-Hydroxyphenethyl)-2-(4-methoxyphenyl)-
tetrahydro-2H-pyran-2-ol (11): To a stirred solution of (R)-
10 (0.1 g, 0.5 mmol) in dry THF (15 mL), p-MeO-C6H4-MgBr
(4 mL, 0.5 M in THF, 2 mmol) was added at –78 °C over 1 h.
After completion of the reaction as indicated by TLC, the
reaction mixture was taken into CH2Cl2 (15 mL), washed with
5 % HCl (1 × 5 mL), dried over anhydrous Na2SO4 and the
solvent was evaporated. The crude residue was purified by
column chromatography using EtOAc-hexane (1:1) as eluant
(S)-1-[4-(Benzyloxy)phenyl]hex-5-en-3-ylacrylate [(S)-
8]: To a stirred solution of (R)-5b (1 g, 3.54 mmol) in dry
CH2Cl2 (20 mL), Et3N (1.0 mL, 7.1 mmol), DMAP (cat.) and
acryloyl chloride (0.3 g, 3.54 mmol) were added successively
under ice-cold conditions. The reaction mixture was stirred at
room temperature for 1 h. After completion of the reaction,
the reaction mixture was taken into CH2Cl2 (15 mL), washed
with 5 % HCl (1 × 5 mL), brine (1 × 5 mL) and dried over
anhydrous Na2SO4. The solvent was evaporated and the residue
was purified by column chromatography using EtOAc-hexane
(10:90) as eluant to give the acryl ester (R)-8 as a liquid (1.1
g, 90 %); [α]D25.2 -3.2° (c 1.0, CHCl3); IR (KBr, νmax, cm–1):
2925, 1720, 1510, 1195, 1045; 1H NMR (300 MHz, CDCl3):
δ 1.77-1.92 (m, 2H), 2.35 (t, 2H, J = 6.7 Hz), 2.45-2.65 (m,
2H), 5.0 (s, 2H), 5.02-5.10 (m, 3H), 5.65-5.83 (m, 2H), 6.03-
6.14 (m, 1H), 6.38 (d, 1H, J = 17.3 Hz), 6.82 (d, 2H, J = 8.3
Hz), 7.02 (d, 2H, J = 8.3 Hz), 7.21-7.42 (m, 5H) ppm; 13C
NMR (75 MHz, CDCl3): δ 29.6, 35.4, 38.6, 70.0, 72.9, 114.8,
117.8, 127.3, 127.8, 128.5, 128.7, 129.2, 130.4, 133.3, 133.7,
137.2, 157.1, 165.8 ppm; Mass (EI): 337 (M+H)+, 265, 223,
197, 147, 91.
25.1
to give the required product 11 as a liquid (0.1 g, 76 %); [α]D
+28.0° (c 1.5, CHCl3); IR (KBr, νmax, cm–1): 3386, 2926, 1599,
1514, 1258, 1173, 829; 1H NMR (300 MHz, CDCl3): δ 1.46-
1.96 (m, 6H), 2.50-3.08 (m, 4H), 3.57-3.67 (m, 1H), 3.87 (s,
3H), 6.75 (d, 2H, J = 8.3 Hz), 6.93 (d, 2H, J = 9.0 Hz), 7.03
(d, 2H, J = 8.3 Hz), 7.94 (d, 2H, J = 9.0 Hz); Mass (EI): 329
(M+H)+, 311, 279, 152, 102.
(-)-Centrolobine (1): To a stirred solution of (R)-11 (60
mg, 0.18 mmol) in dry dichloromethane (5 mL), BF3·Et2O
(0.1 g, 0.73 mmol), Et3SiH (0.1 g, 0.73 mmol) were added
successively at -78 °C and the reaction mixture was stirred at
room temperature for 1 h. After completion of the reaction,
the organic layer was washed with aq. NaHCO3 (2 × 5 mL),
brine (1 × 5 mL), dried over anhydrous Na2SO4. Purification
of the crude residue was accomplished by column chromato-
graphy using EtOAc-hexane (1:1) as eluant to afford the required
product 1 as a solid (0.04 g, 65 %); m.p.: 81-84 °C; {Lit. [1]
24
(S)-6-[(4-Benzyloxy)phen]ethyl-5,6-dihydropyran-2-
one [(S)-9]: To a stirred solution of (R)-8 (0.1 g, 0.3 mmol) in
CH2Cl2 (20 mL), Grubbs’ 2nd generation catalyst (0.01 g, 0.015
mmol) was added and the mixture was stirred under reflux
conditions for 30 h.After completion of the reaction, the reaction
mixture was directly adsorbed on silica and purified by column
85.5-86.5 °C}; [α]D25.1-90.0° (c 1.0, CHCl3) {Lit. [1] [α]D
-
91.7° (c 0.77, CHCl3)}; IR (neat, νmax, cm–1): 3401, 2934, 1613,
1513, 1247; 1H NMR (400 MHz, acetone-d6): δ 1.23-1.34 (m,
1H), 1.36-1.46 (m, 1H), 1.60-1.92 (m, 6H), 2.57-2.72 (m, 2H),
3.40-3.46 (m, 1H), 3.78 (s, 3H), 4.30 (dd, 1H, J = 11.2, 11.8
Hz), 6.74 (d, 2H, J = 8.5 Hz), 6.88 (d, 2H, J = 8.7 Hz), 7.02 (d,

2324 Tadiparthi et al.
Asian J. Chem.
2H, J = 8.5 Hz), 7.31 (d, 2H, J = 8.6 Hz), 8.07 (s, OH); 13
C
studied.Amongst all the solvents screened hydrophobic solvents
like hexane, diisopropyl ether, t-butyl methyl ether and toluene
provided better conversion compared to hydrophilic solvents
like acetone, THF, acetonitrile (Table-2). After the resolution,
the two optically pure compounds acetate (S)-6a and alcohol
(R)-5a have been separated by column chromatography. Enantio-
meric excess has been calculated using chiral AS-H column
on HPLC. The enantiomeric excess of alcohol (R)-5a is > 99 %
and acetate (S)-6a is > 99 % (E = 1046) respectively. The stereo-
chemical preference of lipase PS-C during lipase catalyzed
resolution was in line with Kazlauskas’ rule (Fig. 2) [70].
NMR (75 MHz, acetone-d6): δ 25.5, 32.2, 32.8, 35.4, 40.3,
56.2, 78.4, 80.5, 114.9, 116.7, 128.5, 130.9, 134.7, 137.8,
156.9, 160.4 ppm; LCMS: 313 (M+H)+, 335 (M+Na)+.
RESULTS AND DISCUSSION
In continuation of our earlier efforts towards [56-65] the
synthesis of optically active biologically important compounds
using lipase-catalyzed resolution, herein we wish to report the
synthesis of (-)-centrolobine (Fig. 1) using this method. The
synthesis of (-)-centrolobine has been commenced from 4-(3-
hydroxypropyl)phenol (2) as a starting material. The aromatic
alcohol 2 has been protected as benzyl ether (3) using benzyl
bromide (K2CO3, acetone, reflux, 10 h) in quantitative yield
and this on further oxidation to give the aldehyde (4) under
Swern conditions. The aldehyde (4) on Barber allylation using
allyl bromide and zinc in THF yielded the homoallylic alcohol
(5). The racemic homoallylic alcohol (5) has been subjected
for lipase screening for resolution. The screening has been
accomplished with different lipases using vinyl acetate as acyl
donor in diisopropylether as solvent. Amongst all the lipases
screened, Pseudomonas cepacia lipase adsorbed on ceramic
particles (PS-C) which is also known as Buckoldia cepacia
has given good conversion and high enantiomeric excess in
shorter reaction time (Table-1). By selecting lipase PS-C as
the best of choice, the effect of different solvents has also been
O
MeO
OH
Fig. 1. (-)-Centrolobine (1)
After separation of the two compounds alcohol and acetate
by coloumn chromatography, the alcohol (R)-5a was subjected
for Mitsunobu esterification [71,72] followed by hydrolysis
to give the alcohol (S)-5b. The acetate (S)-6a was hydrolyzed
using potassium carbonate in methanol to give the alcohol
(S)-5b. The compound (S)-5b upon esterificaton using acryloyl
TABLE-1
TRANSESTERIFICATION OF 1-[4-(BENZYLOXY)PHENYL]HEX-5-EN-3-OL (5) WITH VARIOUS LIPASES IN DIISOPROPYLETHERa
Alcohol
Yieldb (%)
Acetate
Yieldb (%)
Conversion
(%)
Entry
Lipase
Time (h)
Ed
eec (%)
> 99
> 99
81
eec (%)
> 99
> 99
> 99
> 99
> 99
97
1
2
3
4
5
6
7
8
PS-C
PS-D
PS
5
46
45
40
82
85
42
4
46
45
44
5
0.5
0.5
1046
1046
440
45
12
24
0.45
0.18
0.18
0.18
0.18
–
CRL
PPL
120
120
15
21
22
5
322
117
45
CAL-B
PF
95
43
6
120
21
> 99
MML
120
88
–
4
> 99
–
aConditions: Reactions were carried out in diisopropylether (15 mL), 5 (50 mg, 0.18 mmol), vinyl acetate (0.9 g, 1.08 mmol) and lipase (50 mg,
w/w) at 30 °C, 200 rpm; bIsolated yields; cDetermined by HPLC (Chiracel AS-H column; Daicel) employing n-hexane:iso-propanol (9:1) as mobile
phase at 0.5 mL/min and monitored at UV (254 nm); dCalculated according to Chen et al. [[69,,7700]] using the equation: E = (ln[1–c(1 + eep)])/(ln[1–
c(1–eep)]).
TABLE-2
EFFECT OF DIFFERENT SOLVENTS ON THE TRANSESTERIFICATION
1-[4-(BENZYLOXY)PHENYL]HEX-5-EN-3-OL (5) BY LIPASE PS-Ca
Alcohol
Yieldc (%)
Acetate
Yieldc (%)
Conversion
(%)
Entry
Solvent
log Pb
Time (h)
Ee
eed (%)
> 99
> 99
89
eed (%)
> 99
> 99
> 99
97
1
2
3
4
5
6
7
8
iPr2O
n-Hexane
tBuOMe
Toluene
CH3CN
Acetone
THF
3.5
2.5
5
12
65
5
44
43
40
41
69
80
85
88
46
45
42
40
23
12
6
0.5
0.5
0.47
0.18
19
1046
1046
281
117
4
1.9
2.5
95
-0.33
-0.23
0.49
-1.1
65
65
20
120
13
54
15
98
13
10
–
94
–
–
CHCl3
–
5
> 99
–
–
aConditions: Reactions were carried out in diisopropylether (15 mL), 5 (50 mg, 0.18 mmol), vinyl acetate (0.9 g, 1.08 mmol) and lipase (50 mg,
b
[71,72]
w/w) at 30 °C, 200 rpm; Source of data: references [71,72]; Isolated yields; Determined by HPLC (Chiracel AS-H column; Daicel) employing n-
c
d
e
[69,70]
hexane:iso-propanol (9:1) as mobile phase at 0.5 mL/min and monitored at UV (254 nm); Calculated according to Chen et al. [69,70] using the
equation: E = (ln[1–c(1+eep)])/(ln[1–c(1–eep)]).

Vol. 29, No. 10 (2017)
Lipase-Catalyzed Resolution of 1-[4-(Benzyloxy)phenyl]hex-5-en-3-ol: Synthesis of (-)-Centrolobine 2325
OAc
OH
OH
OH
i,ii, iii
iv
+
BnO
BnO
HO
BnO
R-5(a)
S- 6(a)
2
5
v(b)
v(a,b)
O
O
OH
O
O
O
vii
vi
viii
ix
MeO
BnO
BnO
BnO
OH
S-5(b)
1
S
-9
S-8
Scheme-I: Reagents and conditions: (i). BnBr, K2CO3, acetone, reflux, 10 h, 95 %; (ii). (COCl)2, DMSO, -78 °C, 2 h, then NEt3, -78 to -10
°C, 80 %; (iii). Allyl bromide, Zn, THF, 3 h, 90 %; (iv). Lipase PS-C, vinylacetate, diisopropyl ether; (v). (a) 4-Nitrobenzoic acid,
PPh3, DEAD, toluene, –30 °C, 95 %; (b) K2CO3, MeOH, r.t., 1 h, 90 %; (vi). Acryloyl chloride, NEt3, CH2Cl2, 1 h, 90 %; (vii).
Grubb’s catalyst-2nd generation, CH2Cl2, reflux, 30 h, 80 %; (viii). Pd/C, H2, EtOAc, 4 h, 80 %; (ix). (a) p-MeO-Ph-MgBr, THF,
-78 °C, 1 h, 76 %; (b) BF3·Et2O, Et3SiH, CH2Cl2, -78 °C then r.t., 1 h, 65 %
4. M.C. Elliott, J. Chem. Soc., Perkin Trans. 1, 4175 (1998);
H
OAc
OH
L
https://doi.org/10.1039/a805170d.
M
5. M.C. Elliott, Contemp. Org. Synth., 4, 238 (1997);
https://doi.org/10.1039/co9970400238.
6. C.J. Burns and D.S. Middleton, Contemp. Org. Synth., 3, 229 (1996);
https://doi.org/10.1039/co9960300229.
BnO
7. M.C. Elliott, Contemp. Org. Synth., 1, 457 (1994);
https://doi.org/10.1039/co9940100457.
M = medium sized group
L = large gruop
(Resolved using PS-C
preferred enantiomer shown)
8. I.L. DeAlbuquerque, C. Galeffi, C.G. Casinovi and G.B. Marini-Bettolo,
Gazz. Chim. Ital., 94, 287 (1964);
Fig. 2
9. C. Galeffi, C.G. Casinovi and G.B. Marini-Bettolo, Gazz. Chim. Ital.,
95, 95 (1965).
chloride followed by ring closing metathesis using Grubbs’
2nd generation catalyst to provide the α,β-unsaturated lactone
(S)-9. This upon hydrogenation in the presence of Pd/C in
ethyl acetate resulted (S)-10 via debenzylation and hydroge-
nation of the double bond in one pot. The lactone (S)-10 upon
treatment with p-MeO-Ph-MgBr gave lactol 11, which on further
reduction with Et3SiH in the presence of BF3.Et2O afforded
the optically pure (-)-centrolobine 1 (Scheme-I). The spectral
data of 1H and 13C NMR as well as its optical rotation closely
match with the previously reported data of the natural product
1 [54,55].
10. A.Aragão Craveiro,A. da Costa Prado, O.R. Gottlieb and P.C. Welerson
de Albuquerque, Phytochemistry, 9, 1869 (1970);
https://doi.org/10.1016/S0031-9422(00)85606-X.
11. A.F. Alcantara, M.R. Souza and D. Pilo-Veloso, Fitoterapia, 71, 613
(2000);
https://doi.org/10.1016/S0367-326X(00)00196-9.
12. L. Jurd and R.Y. Wong, Aust. J. Chem., 37, 1127 (1984);
https://doi.org/10.1071/CH9841127.
13. C.A.C.Araujo, L.V.Alegrio and L.L. Leon, Phytochemistry, 49, 751 (1998);
https://doi.org/10.1016/S0031-9422(97)00976-X.
14. F. Colobert, R.D. Mazery, G. Solladié and M.C. Carreño, Org. Lett., 4,
1723 (2002);
https://doi.org/10.1021/ol025778z.
Conclusion
15. Y. Jeong, D.-Y. Kim, Y. Choi and J.-S. Ryu, Org. Biomol. Chem., 9,
374 (2011);
In summary, a practical and efficient method for the
preparation of homoallylic alcohol and its successful enzymatic
resolution has been described. This lipase-catalyzed resolution
process has been optimized with respect to different lipases
and solvents. Further, optically enriched homoallylic alcohol
has been employed in the synthesis of (-)-centrolobine. This
method has potential for the synthesis of similar natural
products.
https://doi.org/10.1039/C0OB00701C.
16. P.A. Clarke and W.H.C. Martin, Tetrahedron Lett., 45, 9061 (2004);
https://doi.org/10.1016/j.tetlet.2004.10.035.
17. H. Zhou and T.-P. Loh, Tetrahedron Lett., 50, 4368 (2009);
https://doi.org/10.1016/j.tetlet.2009.05.053.
18. H. Fuwa, K. Noto and M. Sasaki, Heterocycles, 82, 641 (2010);
https://doi.org/10.3987/COM-10-S(E)37.
19. P.A. Clarke and W.H.C. Martin, Tetrahedron, 61, 5433 (2005);
https://doi.org/10.1016/j.tet.2005.04.011.
20. J.R.Vyvyan, H.E. Longworth and S.K. Nguyen, Synlett, 27, 2221 (2016);
https://doi.org/10.1055/s-0035-1562463.
ACKNOWLEDGEMENTS
21. H. Kim and D. Lee, Synlett, 26, 2583 (2015);
https://doi.org/10.1055/s-0035-1560479.
The authors K.T. and S.R. thank CSIR, New Delhi, India
for the award of research fellowship.
22. B. Nagarjuna, B. Thirupathi, C. Venkata Rao and D.K. Mohapatra,
Tetrahedron Lett., 56, 4916 (2015);
REFERENCES
https://doi.org/10.1016/j.tetlet.2015.06.084.
23. V.K. Yadav, A.K. Verma, P. Kumar and V. Hulikal, Chem. Commun., 50,
15457 (2014);
1. M.C. Elliott, J. Chem. Soc., Perkin Trans. 1, 2301 (2002);
https://doi.org/10.1039/b201515n.
https://doi.org/10.1039/C4CC07796B.
2. M.C. Elliott and E. Williams, J. Chem. Soc., Perkin Trans. 1, 2303 (2001);
https://doi.org/10.1039/b007290g.
24. K. Nakata, T. Tokumaru, H. Iwamoto,Y. Nishigaichi and I. Shiina, Asian
J. Org. Chem., 3, 9 (2014);
3. M.C. Elliott, J. Chem. Soc., Perkin Trans. 1, 1291 (2000);
https://doi.org/10.1039/a903885j.
https://doi.org/10.1002/ajoc.201300258.

2326 Tadiparthi et al.
Asian J. Chem.
25. J. Zeng, Y.J. Tan, J. Ma, M.L. Leow, D. Tirtorahardjo and X.-W. Liu,
Chem. Eur. J., 20, 405 (2014);
https://doi.org/10.1002/chem.201303328.
50. M. Latif, J.I. Yun, K. Seshadri, H.R. Kim, C.H. Park, H. Park, H. Kim and
J. Lee, J. Org. Chem, 80, 3315 (2015);
https://doi.org/10.1021/acs.joc.5b00046.
26. K. Nakata, T. Tokumaru, H. Iwamoto, Y. Nishigaichi and I. Shiina,
Asian J. Org. Chem., 2, 920 (2013);
https://doi.org/10.1002/ajoc.201300139.
51. W. Chaladaj, R. Kowalczyk and J. Jurczak, J. Org. Chem., 75, 1740 (2010);
https://doi.org/10.1021/jo902167r.
52. T. Takeuchi, M. Matsuhashi and T. Nakata, Tetrahedron Lett., 49, 6462
(2008);
https://doi.org/10.1016/j.tetlet.2008.08.102.
27. K. Sudarshan and I. Aidhen, Eur. J. Org. Chem., 12, 2298 (2013);
https://doi.org/10.1002/ejoc.201300097.
28. H. Fuwa, Heterocycles, 85, 1255 (2012);
https://doi.org/10.3987/REV-12-730.
53. M.C. Carreño, R. Des Mazery, A. Urbano, F. Colobert and G. Solladié,
J. Org. Chem, 68, 7779 (2003);
https://doi.org/10.1021/jo034817x.
29. G. Sabitha, G. Chandrashekhar, K.Yadagiri and J.S.Yadav, Tetrahedron
Asymm., 22, 1729 (2011);
https://doi.org/10.1016/j.tetasy.2011.09.012.
54. P.A. Evans, J. Cui and S.J. Gharpure, Org. Lett., 5, 3883 (2003);
https://doi.org/10.1021/ol035438t.
30. C.R. Reddy, P.P. Madhavi and S. Chandrasekhar, Synthesis, 123 (2011);
https://doi.org/10.1055/s-0030-1258341.
55. E. Lee, H.-J. Kim and W.-S. Jang, Bull. Korean Chem. Soc., 25, 1609
(2004);
31. C.R. Reddy, P.P. Madhavi and S. Chandrasekhar, Tetrahedron Asymm.,
21, 103 (2010);
https://doi.org/10.1016/j.tetasy.2010.01.002.
https://doi.org/10.5012/bkcs.2004.25.11.1609.
56. A. Kamal, M.A. Azhar, T. Krishnaji, M.S. Malik and S. Azeeza, Coord.
Chem. Rev., 252, 569 (2008);
32. D.K. Mohapatra, R. Pal, H. Rahaman and M.K. Gurjar, Heterocycles,
80, 219 (2010);
https://doi.org/10.3987/COM-08-S(S)1.
https://doi.org/10.1016/j.ccr.2007.12.010.
57. A. Kamal, T. Krishnaji and M.N.A. Khan, J. Mol. Catal. B, 54, 55 (2008);
https://doi.org/10.1016/j.molcatb.2007.12.003.
58. A. Kamal, T. Krishnaji and M.N.A. Khan, J. Mol. Catal. B, 47, 1 (2007);
https://doi.org/10.1016/j.molcatb.2007.03.002.
59. A. Kamal, G.B.R Khanna and T. Krishnaji, Helv. Chim. Acta, 90, 1723
(2007);
33. A. He, N. Sutivisedsak and C.D. Spilling, Org. Lett., 11, 3124 (2009);
https://doi.org/10.1021/ol900980s.
34. C.R. Reddy, P. Madhavi and S. Chandrasekhar, Synthesis, 2939 (2008);
https://doi.org/10.1055/s-2008-1067218.
35. T. Washio, R.Yamaguchi, T.Abe, H. Nambu, M.Anada and S. Hashimoto,
Tetrahedron, 63, 12037 (2007);
https://doi.org/10.1016/j.tet.2007.09.003.
https://doi.org/10.1002/hlca.200790180.
60. A. Kamal, T. Krishnaji and P. Venkat Reddy, Tetrahedron Lett., 48, 7232
(2007);
https://doi.org/10.1016/j.tetlet.2007.07.139.
36. K.R. Prasad and P. Anbarasan, Tetrahedron, 63, 1089 (2007);
https://doi.org/10.1016/j.tet.2006.11.062.
61. A. Kamal, T. Krishnaji and G.B.R. Khanna, Tetrahedron Lett., 47, 8657
(2006);
https://doi.org/10.1016/j.tetlet.2006.09.155.
37. P.A. Clarke and S. Santos, Eur. J. Org. Chem., 2045 (2006);
https://doi.org/10.1002/ejoc.200500964.
38. K.-P. Chan and T.-P. Loh, Org. Lett., 7, 4491 (2005);
https://doi.org/10.1021/ol051951q.
62. A. Kamal, G.B.R. Khanna, T. Krishnaji and R. Ramu, Tetrahedron:Asymm.,
17, 1281 (2006);
39. S. Marumoto, J.J. Jaber, J.P. Vitale and S.D. Rychnovsky, Org. Lett., 4,
3919 (2002);
https://doi.org/10.1021/ol026751i.
https://doi.org/10.1016/j.tetasy.2006.04.019.
63. A. Kamal, G.B.R. Khanna, T. Krishnaji and R. Ramu, Bioorg. Med. Chem.
Lett., 15, 613 (2005);
40. M. Dziedzic and B. Furman, Tetrahedron Lett., 49, 678 (2008);
https://doi.org/10.1016/j.tetlet.2007.11.128.
https://doi.org/10.1016/j.bmcl.2004.11.054.
64. A. Kamal, G.B.R. Khanna, T. Krishnaji, V. Tekumalla and R. Ramu,
Tetrahedron Asymm., 16, 1485 (2005);
41. V. Böhrsch and S. Blechert, Chem. Commun., 18, 1968 (2006);
https://doi.org/10.1039/B602056A.
https://doi.org/10.1016/j.tetasy.2005.02.015.
65. A. Kamal, G.B.R. Khanna, R. Ramu and T. Krishnaji, Tetrahedron Lett.,
44, 4783 (2003);
42. L. Boulard, S. BouzBouz, J. Cossy, X. Franck and B. Figadère, Tetrahedron
Lett., 45, 6603 (2004);
https://doi.org/10.1016/j.tetlet.2004.07.025.
https://doi.org/10.1016/S0040-4039(03)00945-6.
66. C.-S. Chen and C.J. Sih, Angew. Chem. Int. Ed. Engl., 28, 695 (1989);
https://doi.org/10.1002/anie.198906951.
43. M.P. Jennings and R.T. Clemens, Tetrahedron Lett., 46, 2021 (2005);
https://doi.org/10.1016/j.tetlet.2005.01.156.
44. S. Chandrasekhar, S. Prakash and T. Shyamsunder, Tetrahedron Lett.,
46, 6651 (2005);
https://doi.org/10.1016/j.tetlet.2005.07.162.
67. C.-S. Chen, Y. Fujimoto, G. Girdaukas and C.J. Sih, J. Am. Chem. Soc.,
104, 7294 (1982);
https://doi.org/10.1021/ja00389a064.
45. B. Schmidt and F. Hölter, Chem. Eur. J., 15, 11948 (2009);
https://doi.org/10.1002/chem.200902053.
68. F. Secundo, S. Riva and G. Carrea, Tetrahedron Asymm., 3, 267 (1992);
https://doi.org/10.1016/S0957-4166(00)80206-2.
69. K. Nakamura, M. Kinoshita andA. Ohno, Tetrahedron, 51, 8799 (1995);
https://doi.org/10.1016/0040-4020(95)00470-S.
70. R.J. Kazlauskas, A.N.E. Weissfloch, A.T. Rappaport and L.A. Cuccia,
J. Org. Chem., 56, 2656 (1991);
46. M. Zhao, B. Lu, G. Ding, K. Ren, X. Xie and Z. Zhang, Org. Biomol.
Chem., 14, 2723 (2016);
https://doi.org/10.1039/C5OB02622A.
47. J.-H. Xie, L.-C. Guo, X.-H. Yang, L.-X. Wang and Q.-L. Zhou, Org. Lett.,
14, 4758 (2012);
https://doi.org/10.1021/ol3020144.
https://doi.org/10.1021/jo00008a016.
71. O. Mitsunobu, Synthesis, 1 (1981);
48. G. Kumaraswamy and D. Rambabu, Tetrahedron Asymm., 24, 196 (2013);
https://doi.org/10.1016/j.tetasy.2013.01.005.
https://doi.org/10.1055/s-1981-29317.
72. S.F. Martin and J.A. Dodge, Tetrahedron Lett., 32, 3017 (1991);
https://doi.org/10.1016/0040-4039(91)80675-V.
49. Z. Yang and H.-D. Kim, Tetrahedron Asymm., 25, 305 (2014);
https://doi.org/10.1016/j.tetasy.2013.12.019.