Stereodivergent synthesis of (2R)-2,3-diricinolein by lipase-catalyzed hydrolysis of triricinolein

Article abstract of DOI:10.1016/j.tetasy.2004.07.026

The preparation of 2,3-diricinolein by lipase-catalyzed hydrolysis of triricinolein has been developed. Lipase-catalyzed hydrolysis of triricinolein provided (2R)-2,3-diricinolein in high diastereoselectivity.

Full text of DOI:10.1016/j.tetasy.2004.07.026

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2451–2454
Stereodivergent synthesis of (2R)-2,3-diricinolein by
lipase-catalyzed hydrolysis of triricinolein
b
Iwao Hachiya,a Akihisa Makino,a Makoto Shimizu,a, Masatsugu Akita and
*
Takashi Hamaguchib
aDepartment of Chemistry for Materials, Mie University, Tsu, Mie 514-8507, Japan
bItoh OilChemicals Co., Ltd, Yokkaichi, Mie 510-0052, Japan
Received 9 July 2004; accepted 14 July 2004
Abstract—The preparation of 2,3-diricinolein by lipase-catalyzed hydrolysis of triricinolein has been developed. Lipase-catalyzed
hydrolysis of triricinolein provided (2R)-2,3-diricinolein in high diastereoselectivity.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
alyzed methanolysis of triricinolein in organic solvent to
produce 1,2(2,3)-diricinolein.3 However, little attention
has been paid to the stereodivergent synthesis of diricin-
oleins. In connection with the growing importance of the
structure-acting relationship of chiral materials, the ste-
reocontrolled hydrolysis of triricinolein is of increasing
importance. Herein, we report a diastereoselective prep-
aration of 2,3-diricinolein by lipase-catalyzed hydrolysis
of triricinolein (Scheme 1).
The development of synthetic methods for diacylglyce-
rols (DAG) is important because of their usefulness as
emulsifiers in food, pharmaceuticals, and cosmetics.
DAG oil is a useful substitute for triacylglycerol oil in
food.1 Castor oil consists of approximately 90% ricino-
leic (12-hydroxy-cis-octadecenoic) acid with a hydroxy
group and a double bond as the dominant constitutive
fatty acid, and is made mixed use of as lacquers, leath-
erettes, printing inks, lubricants, cosmetics, insulators,
and drugs. Although castor oil is saponified in industry
for the preparation of ricinoleic acid, which is useful in
the pharmaceutical and cosmetics industries, this meth-
od has some disadvantages such as the large amount of
by-products and coloring of the products. To solve the
above problems, lipase catalyzed hydrolysis of castor
oil has been studied.2 McKeon et al. reported lipase-cat-
2. Results and discussion
We first examined lipase PS-catalyzed hydrolysis of tri-
ricinolein4 in THF-phosphate buffer at room temperature
for several reaction times5 with the results shown in Table
1. When the hydrolysis was carried out for 10min, the de-
sired diricinolein 2 was obtained in 12% yield with 82.0%
OH
OH
OCOR
OCOR
OCOR
Lipase
OCOR
OH
+
RCO2H
OCOR
OCOR
+
THF-phosphate buffer
1: triricinolein
4: ricinoleic acid
2: diricinolein
3: 2-monoricinolein
OH
R=
Scheme 1.
*
Corresponding author. Tel./fax: +81-59-231-9413; e-mail: mshimizu@chem.mie-u.ac.jp
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.07.026

2452
I. Hachiya et al. / Tetrahedron: Asymmetry 15 (2004) 2451–2454
Table 1. Lipase PS-catalyzed hydrolysis of triricinolein at rt
Entry
Temp. (°C)
Time (min)
Yield (%)
2R:2Sa
1
2
3
4
1
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
10
20
57
52
12
20
26
25
25
21
25
25
11
12
11
23
19
20
23
28
18
13
15
12
14
32
51
65
53
35
5
9
91.0:9.0
95.2:4.8
96.1:3.9
89.1:10.9
88.3:11.7
72.9:27.1
66.0:34.0
50.5:49.5
51.7:48.3
93.7:6.3
94.6:5.4
92.4:7.6
90.9:9.1
92.9:7.1
86.1:13.9
86.6:13.4
88.1:11.9
2
18
20
16
28
42
54
54
57
6
3
30
40
51
47
4
5
50
60
18
9
6
7
120
360
720
10
Trace
Trace
Trace
80
8
9
10
11
12
13
14
15
16
17
0
20
30
72
49
3
12
25
11
21
23
19
17
0
12
12
16
28
35
24
0
40
50
61
49
0
0
60
90
44
45
0
0
120
32
a Diastereomeric excesses were determined by the HPLC analysis using the chiral column, Chiralcel-OD after transformation of 2 into its tribenzoate
ester.
Table 2. Lipase AK or PPL-catalyzed hydrolysis of triricinolein at rt
Entry
Lipase
Time (min)
Yield (%)
2R:2Sa
1
2
3
4
1
2
3
4
5
6
7
8
9
AK
15
30
75
41
19
35
30
40
46
16
26
27
22
Trace
18
11
9
96.4:3.6
96.0:4.0
95.7:4.3
96.5:3.5
89.3:10.7
65.6:34.4
58.4:41.6
60.6:39.4
50.6:49.4
21
23
24
49
13
40
19
45
45
60
45
30
11
28
120
20
Trace
62
21
PPL
19
46
40
60
38
Trace
34
59
90
a Diastereomeric excesses were determined by the HPLC analysis using the chiral column, Chiralcel-OD after the transformation of 2 into its
tribenzoate ester.
de along with the recovered triricinolein 1 (57%), 2-
monoricinolein 3 (13%), and ricinoleic acid (9%). The
diastereomeic excess of diricinolein 2 was determined as
being 82.0% by HPLC analysis of its tribenzoate ester.6
The highest (92.2% de) was obtained, when the hydrolysis
was conducted for 30min (entry 3). As the reaction times
increased, the des of 2 decreased presumably due to the
competing acyl migration. The hydrolysis proved sensi-
tive to the reaction temperature. The lipase PS-catalyzed
hydrolysis at 0°C generally gave lower discriminations.
solvents, the observed des of 2 were lower than those in
THF (entries 1–7). Although hydrolysis proceeded in the
phosphate buffer itself, a low de of 2 was obtained (entry
8).
The absolute configuration of diricinolein 2 was deter-
mined by measuring the specific rotation of 6 trans-
formed according to the method reported by Meguro
et al. as shown in Scheme 2.7 The result indicated that
the major diastereomer of diricinolein 2 prepared by lip-
ases PS, AK, and PPL-catalyzed hydrolysis of tricino-
lein 1 was 2,3-di-O-ricinoleoyl-sn-glycerol.
We next examined lipase AK and PPL-catalyzed hydrol-
ysis of triricinolein 1 in THF-phosphate buffer at room
temperature with the results shown in Table 2. Lipase
AK gave superior yields and des when compared to
those in lipase PS-catalyzed hydrolysis of triricinolein
1. In particular, when the hydrolysis was carried out
for 60min, the desired 2,3-diricinolein 2 was obtained
in 40% yield with 93.0% de (entry 4). On the other hand,
lipase PPL-catalyzed hydrolysis of triricinolein 1 gave
lower des of diricinolein 2.
3. Conclusion
In summary, we have found a diastereoselective prepa-
ration of (2R)-2,3-diricinolein by lipase-catalyzed
hydrolysis of triricinolein. Although lipase-catalyzed
hydrolysis or methanolysis of triricinolein have been
studied, to the best of our knowledge, the diastereoselec-
tive preparation of 2,3-diricinolein by lipase-catalyzed
hydrolysis of triricinolein has not been reported. In the
present reaction, 2,3-diricinolein can be easily obtained
The effects of organic solvents on the lipase AK-cata-
lyzed hydrolysis are shown in Table 3. In all the organic

I. Hachiya et al. / Tetrahedron: Asymmetry 15 (2004) 2451–2454
2453
Table 3. Effects of the organic solvents in the lipase AK-catalyzed hydrolysis of triricinolein
Entry
Organic solvent
Time (min)
Yield (%)
2R:2Sa
1
2
3
4
1
2
3
4
5
6
7
8
Et2O
Et2O
Et2O
30
60
31
9
40
44
48
42
37
11
4
19
39
28
38
73.5:26.5
73.2:26.8
69.5:30.5
87.1:12.9
83.7:16.3
95.7:4.3
120
60
11
7
25
29
48
50
1,4-Dioxane
1,4-Dioxane
Toluene
Toluene
None
120
60
Trace
83
93
24
46
60
3
Trace
Trace
21
120
60
Trace
25
92.3:7.7
69.4:30.6
36
a Diastereomeric excesses were determined by HPLC analysis using the chiral column, Chiralcel-OD after the transformation of 2 into its tribenzoate
ester.
OTBDMS
OCOR2
OCOR2
OH
OTBDMS
OBz
1. EtMgBr, Et2O, rt
TBDMSCI
imidazole
DMF, rt
OCOR1
OCOR1
2. BzCl, pyridine
0oC, to rt
OBz
69%
56%
5
2
6
OH
R1 =
R2 =
OTBDMS
Scheme 2.
1461, 1375, 1173, 1052, 857, 756, 667cmꢀ1 1H NMR
.
with high diastereoselectivity (up to 93.0% de) because
lipase-AK is commercially available and hydrolysis
can be carried out under mild reaction conditions.
(500MHz, CDCl3): 5.53–5.58 (m, 2H), 5.38–5.43 (m, 2H),
5.06–5.10 (m, 1H), 4.32 (dd, J = 11.9, 4.6Hz, 1H), 4.23 (dd,
J = 11.9, 5.8Hz, 1H), 3.73 (br s, 2H), 3.59–3.64 (m, 2H),
2.31–2.36 (m, 4H), 2.20–2.25 (m, 5H), 2.03–2.07 (m, 4H),
1.60–1.63 (m, 6H), 1.43–1.51 (m, 4H), 1.25–1.31 (m, 32H),
0.89 (t, J = 6.7Hz, 6H). 13C NMR (67.8MHz, CDCl3):
173.7, 173.4, 133.2, 125.2, 72.1, 71.5, 62.1, 61.3, 36.8, 35.3,
34.2, 34.0, 31.8, 29.5, 29.3, 29.0, 27.3, 25.7, 24.8, 24.7, 22.6.
References
1. Nagao, T.; Watanabe, H.; Goto, N.; Onizawa, K.; Taguchi,
H.; Matsuo, N.; Yasukawa, T.; Tsushima, R.; Shimasaki,
H.; Itakura, H. J. Nutr. 2000, 130, 792.
24
½aꢁD ¼ þ4:45 (c 0.245, CHCl3).
2. For examples, see: (a) Yamamoto, K.; Fujiwara, N. Agric.
Biol. Chem. 1988, 52, 3015; (b) Tagiri, M.; Endo, Y.;
Fujimoto, K.; Suzuki, T. Biosci. Biotech. Biochem. 1992, 56,
1490; (c) Yamamoto, K.; Fujiwara, N. Biosci. Biotech.
Biochem. 1995, 59, 1262; (d) Foglia, T. A.; Jones, K. C.;
Sonnet, P. E. Eur. J. Lipid Sci. Technol. 2000, 102, 612; (e)
Goto, M.; Hatanaka, C.; Haraguchi, T. Kagaku Kogaku
Ronbunshu 2000, 26, 402.
3. Turner, C.; He, X.; Nguyen, T.; Lin, J.-T.; Wong, R. Y.;
Lundin, R. E.; Harden, L.; McKeon, T. Lipids 2003, 38,
1197.
4. Triricinolein was obtained by purification of castor oil
using silica gel column chromatography.
6. General procedure for the synthesis of the tribenzoate ester
of diricinolein 2. To a solution of diricinolein 2 (24.5mg,
0.038mmol) in CH2Cl2 (2.5mL) was added pyridine
(19.5mg, 0.24mmol) at 0°C under an argon atmosphere,
and the mixture stirred at 0°C for 5min. Benzoyl chloride
(48.4mg, 0.34mmol) was added to the resulting mixture at
0°C. The mixture was warmed to room temperature and
then stirred for 21h. 1M HCl was added to quench the
reaction. The mixture was extracted with EtOAc. The
combined extracts were washed with H2O, saturated
aqueous NaHCO3 and brine, and dried over Na2SO4. The
solvents were evaporated in vacuo and then the residue
purified on preparative TLC (n-hexane/EtOAc = 2/1) to
give 1-benzoyl-2,3-di(12-benzoyloxy-cis-9-octadecenoyl)-
sn-glycerol along with small amounts of impurities. Further
purification on preparative TLC (n-hexane/EtOAc = 4/1)
gave pure 1-benzoyl-2,3-di[(12R)-benzoyloxy-cis-9-octa-
decenoyl]-sn-glycerol (33.6mg, 87%). IR (neat): 3065,
3010, 2929, 2856, 1718, 1602, 1453, 1358, 1314, 1274,
5. General procedure for the synthesis of diricinolein 2. To a
solution of triricinolein 1 (93.3mg, 0.100mol) in THF
(0.5mL) and phosphate buffer (1.5mL) was added lipase
AK (5.0mg) at room temperature. The mixture was stirred
at room temperature for 60min and then filtered through a
Celite pad, which was washed with EtOAc. The filtrate was
washed with brine and dried over Na2SO4. The solvents
were evaporated in vacuo, and then the residue purified by
silica gel column chromatography (n-hexane/EtOAc = 3/1)
to give diricinolein 2 (26.0mg, 40%) as a colorless oil,
2-monoricinolein 3 (4.2mg, 11%), and a mixture of recov-
ered 1 and ricinoleic acid (28.3mg, 30%, 24%, respectively,
1
1174, 1113, 1069, 1025, 910, 733, 713, 649cmꢀ1. H NMR
(270MHz, CDCl3): 8.00–8.05 (m, 6H), 7.52–7.60 (m, 3H),
7.40–7.47 (m, 6H), 5.30–5.50 (m, 5H), 5.09–5.18 (m, 2H),
4.52 (dd, J = 11.9, 4.3Hz, 1H), 4.29–4.42 (m, 2H), 4.24 (dd,
J = 11.9, 5.9Hz, 1H), 2.39–2.46 (m, 4H), 2.27–2.35 (m, 4H),
1.99–2.04 (m, 4H), 1.55–1.75 (m, 8H), 1.22–1.38 (m, 32H),
0.85 (t, J = 6.6Hz, 6H). 13C NMR (67.8MHz, CDCl3):
1
by H NMR analysis). IR (neat): 3384, 2927, 2855, 1739,

2454
I. Hachiya et al. / Tetrahedron: Asymmetry 15 (2004) 2451–2454
173.2, 172.8, 166.2, 165.9, 133.2, 132.7, 130.7, 129.7, 129.5,
128.4, 128.2, 124.1, 74.6, 68.8, 62.8, 62.1, 34.1, 34.0, 33.7,
32.0, 31.7, 29.5, 29.1, 29.1, 29.1, 29.0, 29.0, 27.3, 25.4, 24.8,
(DAICEL CHIRALCEL OD), hexane/2-propanol=50/1 (v/
v), at a flow rate of 0.7mLminꢀ1. The 2,3-diricinolein was
eluted first (t2,3 = 22.0min), followed by 1,2-diricinolein
(t1,2 = 29.2min).
23
24.8, 22.5, 14.0. ½aꢁD ¼ þ11:3 (c 0.336, CHCl3). The de of 1-
benzoyl-2,3-di[(12R)-12-benzoyloxy-cis-9-octadecenoyl]-sn-
glycerol was determined to be 93.0% by HPLC analysis
7. Uzawa, H.; Noguchi, T.; Nishida, Y.; Ohrui, H.; Meguro,
H. Biochim. Biophys. Acta 1993, 1168, 253.