Pheromone synthesis. Part 253: Synthesis of the racemates and enantiomers of triglycerides of male Drosophila fruit flies with special emphasis on the preparation of enantiomerically pure 1-monoglycerides

Article abstract of DOI:10.1016/j.tet.2012.07.086

The racemates and enantiomers of triglycerides 1aee (2,3-ditigloyloxypropyl esters of palmitic, palmitoleic, stearic, oleic, and linoleic acids) of male Drosophila fruit flies were synthesized in three steps from the racemate and enantiomers of 2,3-acetoneglycerol (2) via 1-monoglycerides 4aee derived from the above fatty acids. Appropriate conditions were established for the preparation of enantiomerically pure 1-monoglycerides 4aee, and their enantiomeric purities were determined by NMR analysis of the corresponding bis-(R)-MTPA esters.

Full text of DOI:10.1016/j.tet.2012.07.086

Tetrahedron 68 (2012) 8441e8449
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Pheromone synthesis. Part 253: Synthesis of the racemates and enantiomers
of triglycerides of male Drosophila fruit flies with special emphasis on the
preparation of enantiomerically pure 1-monoglyceridesq
*
Kenji Mori
Photosensitive Materials Research Center, Toyo Gosei Co., Ltd, 4-2-1 Wakahagi, Inzai-shi, Chiba 270-1609, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2012
Received in revised form 23 July 2012
Accepted 24 July 2012
Available online 31 July 2012
The racemates and enantiomers of triglycerides 1aee (2,3-ditigloyloxypropyl esters of palmitic, palmi-
toleic, stearic, oleic, and linoleic acids) of male Drosophila fruit flies were synthesized in three steps from
the racemate and enantiomers of 2,3-acetoneglycerol (2) via 1-monoglycerides 4aee derived from the
above fatty acids. Appropriate conditions were established for the preparation of enantiomerically pure
1-monoglycerides 4aee, and their enantiomeric purities were determined by NMR analysis of the cor-
responding bis-(R)-MTPA esters.
In memory of Professor Masanao Matsui, my
Dr. thesis advisor, who deceased on 12
March 2012 at the age of 94
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Acetonide deprotection
Drosophila fruit flies
Enantiomeric purity determination
1-Monoglycerides
Mosher’s MTPA ester
Triglycerides
1. Introduction
Recently, Yew (2011)5 and Ruther (2012)6 found triglycerides as
components of insect cuticular lipids. Yew demonstrated the
Triglycerides are naturally occurring and abundant tri-
carboxylic esters of glycerol (A, Fig. 1). Triglycerides B with the
same three acyl groups as well as glycerol (A) itself are symmet-
rical and therefore achiral. However, triglycerides with different
acyl groups, such as C and D are dissymmetric and chiral. Naturally
occurring triglycerides are believed to be biosynthesized in
a stereoselective fashion, although their specific rotations are al-
presence of triglycerides in epicuticle of two Drosophila fruit flies,
Drosophila arizonae and Drosophila mojavensis.5 The triglycerides of
D. mojavensis are male-specific, transferred from male to females
during copulation, and therefore may serve as a class of courtship-
most zero; for example, [
a
]
D 0.00 to þ0.09 in the case of C, R1¼n-
C11H23 and R2¼n-C15H31
.
2,3 Two exceptions were reported in 1930
with [
a
]
D values ꢀ0.149 for peanut oil and þ1.970 for castor bean
oil.4 Extremely facile ester exchange of the three acyl groups
causes randomization and racemization. Accordingly, synthesis of
enantiomerically pure triglycerides of type C is not at all a trivial
work even at present.
q
For Part 252, see Ref. 1.
* Tel.: þ81 3 3816 6889; fax: þ81 3 3813 1516; e-mail address: kjk-mori@
arion.ocn.ne.jp.
Fig. 1. Structures of glycerol (A) and triglycerides (BeD).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.07.086

8442
K. Mori / Tetrahedron 68 (2012) 8441e8449
related semiochemicals in Drosophila species.5 In Ruther’s case,
triglycerides with common fatty acids of 16 and 18 carbon atoms
occur in the cuticle of a parasitic wasp Lariophagus distinguendus,
and they are essential for a full pheromone response of the wasp.6
In January 2012, Jacqueline Chin of Yew’s group at National
University of Singapore announced the identification of tri-
glycerides in epicuticular lipids of male Drosophila fruit flies as
1aee (Scheme 1).7 These structures were tentatively proposed
entirely on the basis of mass spectroscopic analysis, and nothing
was known about their absolute configuration. In order to verify the
unique structures 1aee with two tiglic acids for each triglyceride,
Dr. Joanne Y. Yew requested me to synthesize 1aee in amounts
sufficient for their biological studies.
presence of N,N-dicyclohexylcarbodiimide (DCC) and DMAP in
CH2Cl2 to give them in almost quantitative yield.9,10 Small amounts
of DCC and N,N0-dicyclohexylurea were the contaminants in the
esters (ꢂ)-3b and (ꢂ)-3e.
Removal of the acetonide protective group of (ꢂ)-3aee was
achieved by treatment with 80% acetic acid [AcOH/H2O¼4:1 (v/v)]
at 130 ꢁC for 30 min to give (ꢂ)-4aee in 68% to quantitative yield.11
Rather harsh conditions such as these were not problematic for the
synthesis of (ꢂ)-4aee, because possible ester exchange or 1,3-acyl
migration gave the same (ꢂ)-4aee. Finally, acylation of diol
(ꢂ)-4aee with tigloyl chloride and DMAP in pyridine gave the
desired triglycerides (ꢂ)-1aee in 72e93% yield. Comparison of the
mass spectra of (ꢂ)-1aee with those of the natural triglycerides
proved them to be nearly identical, supporting the structural
assignment.12
2.2. Preparation of the enantiomers of 1-monoglyceride 4a by
removal of the acetonide protective group of 3a
2.2.1. Determination of the enantiomeric purity of 4a by NMR anal-
ysis of its bis-(R)-MTPA ester. Preparation of the pure enantiomers
of 1-monoglycerides 4aee was the prerequisite to the synthesis of
the enantiomers of 1aee. Baer and Fischer were the first to prepare
(R)-4a with high enantiomeric purity, although there was no reli-
able method available in 1945 to determine its enantiomeric pu-
rity.8 They treated enantiomerically pure (R)-3a, [
a
]
50 þ4.95 (neat),
D
with concd HCl and Et2O at 0 ꢁC for 30 min to give (R)-4a, [
a
]
D ꢀ4.37
50
(c 7.8, pyridine). The product (R)-4a gave back (R)-3a, [
a
]
þ4.86
D
(neat), upon acetonide formation. Since the loss in the specific ro-
tation of (R)-3a was only 1.8%, their (R)-4a was thought to be almost
enantiomerically pure (98% optical purity).
In the present task, it was necessary to prepare unsaturated 1-
monoglycerides, such as 4b, 4d, and 4e. Use of concd HCl must be
avoided due to its possible interaction with the olefinic double
bond(s) of palmitoleic, oleic, and linoleic acids. An attempt was
therefore made to prepare (S)-4a by treatment of (S)-3a with
aqueous acetic acid.11,13 Treatment of commercially available (R)-2
[¼L-(ꢀ)-2,3-acetoneglycerol] with palmitoyl chloride gave (S)-3a
(Scheme 2). The acetonide protective group of (S)-3a was then re-
moved quantitatively by heating it with 80% acetic acid at 130 ꢁC for
30 min. The specific rotation of the crystalline (S)-4a thus obtained
Scheme 1. Structures of triglycerides 1aee of male Drosophila fruit flies and their
synthesis as racemates. Reagents: (a) RCOCl, DMAP, C5H5N (80e93%); (b) RCO2H, DCC,
DMAP, CH2Cl2 (95%-quant.); (c) 80% AcOH, 130 ꢁC, 30 min (68%-quant.); (d) MeCH]
C(Me)COCl, DMAP, C5H5N, C6H6 (72e93%).
was [
their (R)-4a to show [
a
]
þ1.89 (c 1.54, pyridine), while Baer and Fischer reported
D
a]
D ꢀ4.37 (c 7.8, pyridine). Apparently heating
at 130 ꢁC in 80% acetic acid caused racemization of (S)-4a as shown
in Scheme 2.
I decided to synthesize not only the racemates but also the
enantiomers of 1aee with a hope to determine the absolute con-
figuration of the naturally occurring triglycerides. This paper re-
ports the synthetic results of my endeavor in that direction.
In order to determinetheenantiomeric purityof the present (S)-4a
more rigorously, Mosher’s
a-methoxy-a-trifluoromethylphenyl-
acetate (MTPA) derivatives of (ꢂ)-4a and the present sample of (S)-4a
were prepared by acylation with (S)-(þ)-MTPACl and DMAP in pyri-
dine,14,15 and their 1H NMR spectra were measured at 400 MHz in
CDCl3. As shown in Fig. 2(a), bis-(R)-MTPA ester of (ꢂ)-4a shows
several pairs of signals owing to the presence of the two di-
astereomeric esters. The triplet due to CH2CO appears as a pair of
2. Results and discussion
2.1. Synthesis of the racemates of triglycerides 1aee
triplets (J 7.5) at
of singlets due to OMe groups is observed at
at 3.42 being an overlapping signal. A pair of doubled doublets (J
6,12) due to one of the protons of CH2OCOC15H31 appears at 4.05 and
4.14, a pair of doubled doublets (J 4,12) due to one of the protons of
CH2OMTPA is observed at 4.32 and 4.39, a pair of doubled doublets (J
6,12) due to one of the protons of CH2OCOC15H31 appears at 4.34 and
4.41, and a pairof doubled doublets (J 4,12) dueto one of theprotons of
CH2OMTPA isobserved at 4.62 and 4.71. A pair of slightly overlapping
d
2.22 and 2.27. Although not shown in Fig. 2(a), a pair
The racemates of triglycerides 1aee were synthesized as shown
in Scheme 1. Commercially available (ꢂ)-2,2-dimethyl-1,3-
dioxolane-4-methanol (2, 2,3-acetoneglycerol) was esterified to
give (ꢂ)-esters 3aee. Since palmitoyl chloride (n-C15H31COCl),
stearoyl chloride (n-C17H35COCl), and oleoyl chloride [(Z)-n-
C8H17CH]CH(CH2)7COCl] were commercially available, (ꢂ)-3a,
(ꢂ)-3c, and (ꢂ)-3d were prepared by acylation of (ꢂ)-2 with each
acyl chloride in the presence of 4-dimethylaminopyridine (DMAP)
in pyridine in 80e93% yield (cf. Ref. 8). In the cases of the prepa-
ration of (ꢂ)-3b and (ꢂ)-3e, (ꢂ)-2 was esterified with palmitoleic
acid [(Z)-n-C6H13CH]CH(CH2)7CO2H] and linoleic acid [(9Z,12Z)-n-
d
3.40, 3.42 and 3.48, one
d
d
d
d
d
multiplets due to CHOMTPA appears at d 5.51 and 5.56.
The 1H NMR spectrum of bis-(R)-MTPA ester of the partially
24
racemized (R)-4a {[
a
]
D
ꢀ2.01 (c 1.09, pyridine)} prepared by
C5H11CH]CHCH2CH]CH(CH2)7CO2H],
respectively,
in
the
treatment of (R)-3a with hot 80% acetic acid (130 ꢁC, 30 min) is

K. Mori / Tetrahedron 68 (2012) 8441e8449
8443
Scheme 2. Preparation of bis-(R)-MTPA ester of (S)-4a and racemization of (S)-4 and
(R)-4 to give (ꢂ)-4. Reagents: (a) n-C15H31COCl, DMAP, C5H5N (93%); (b) 80% AcOH,
50 ꢁC, 2 h (quant.)*; (c) (S)-MTPACl, DMAP, C5H5N, CH2Cl2, room temp, 3 days (quant.).
*For other conditions, see Table 1.
shown in Fig. 2(b). It is clear that the signals at d 4.0e4.8 due to one
of the protons of CH2OCOC15H31 and one of the protons of
CH2OMTPA can be used for the determination of the diastereomeric
ratio of the NMR sample and hence the enantiomeric purity of the
original (R)-4a. The analyzed sample of (R)-4a was enantiomeri-
cally quite impure (52% ee).
The next thing to do was to find out the best conditions for the
removal of the acetonide protective group, employing the above
described MTPA/NMR method of analysis as a tool.
2.2.2. Searching the best conditions for the removal of the acetonide
protective group of (S)-4a with minimal racemization. A number of
deprotection methods are known for an acetonide protective
group. Several of them were carefully examined, which were be-
lieved to be mild enough to cause no racemization of 1-
monoglyceride due to the ester exchange. Treatment of (S)-3c
with Amberlyst 15 (Hþ form) in MeOH/CH2Cl2 was believed to give
(S)-4c (1-stearoylglycerol) without any racemization.9,10 In my
hands, however, this method resulted in extensive racemization,
(S)-3a giving (S)-4a of only 12% ee [see Table 1 (1)]. Kim et al.
recommended the use of FeCl3 adsorbed on SiO2 for the cleavage of
acetals.16 This method yielded (S)-4a of 65% ee [Table 1 (2)]. Al-
though there was a similar method to employ CuCl2$2H2O in
EtOH,17 it was not examined due to the use of the toxic copper salt
in an excessive amount.
Fig. 2. 1H NMR spectra of bis-(R)-MTPA esters of diol 4a (400 MHz, CDCl3). (a) Bis-(R)-
MTPA ester of (ꢂ)-diol 4a; (b) that of (R)-diol 4a of 52% ee; (c) that of (R)-4a; (d) that of
(S)-4a.
Recrystallization of the crude (S)-4a from EtOAc/pentane gave
enantiomerically pure (S)-4a [Table 1 (5)]. Similarly, under the
same conditions at 50 ꢁC for 2 h, enantiomerically pure (R)-4a
could also be obtained. The 1H NMR spectra of their bis-(R)-
MTPA esters are shown in Fig. 2(c) for (R)-4a and Fig. 2(d) for
(S)-4a. The present MTPA/NMR method of analysis was ex-
tremely useful for determining the enantiomeric purity of op-
tically active 1-monoglycerides, such as 4aee.
A method was proposed by Vijayasaradhi et al. to effect
selective
Zn(NO3)2$6H2O in MeCN.18 This procedure was mild enough to
give (S)-4a of 90% ee [Table (3)]. The drawback of
hydrolysis
of
a
terminal
acetonide
with
1
Zn(NO3)2$6H2O method was the use of a large amount of the
zinc salt and use of MeCN as the solvent. The latter caused
a slightly brown coloration of the resulting (S)-4a. Accordingly,
deprotection with 80% acetic acid was reexamined at a lower
temperature, although heating at 130 ꢁC for 30 min as before
caused extensive racemization to give (S)-4a of only 48% ee
[Table 1 (4)]. After 2 h at 50 ꢁC, (S)-3a disappeared as checked
by TLC to give (S)-4a as a colorless solid, which was of 92% ee.
2.3. Synthesis of the enantiomers of triglycerides 1aee
With the reliable analytical method in hands for the de-
termination of the enantiomeric purity of the enantiomers of 4aee,
the target triglycerides 1aee were synthesized from the enantio-
mers of 2,3-acetoneglycerol (2) as shown in Scheme 3. Acylation of

8444
K. Mori / Tetrahedron 68 (2012) 8441e8449
Table 1
Specific rotation and enantiomeric purity of 1-monoglyceride (S)-4a resulting from deprotection of the corresponding acetonide (S)-3a
Method of deprotection
Specific rotation of (S)-4a in pyridinea
Enantiomeric purity (% ee) of (S)-4ab
(1) Amberlyst 15 (Hþ form), MeOH/CH2Cl2, reflux, 2 h9,10
(2) FeCl3/SiO2, CHCl3, room temp, 6 h16
(3) Zn(N03)2$6H2O, MeCN, 50 ꢁC, 4 h18
(4) AcOH/H2O (4:1, v/v), 130 ꢁC, 30 min11
(5) AcOH/H20 (4:1, v/v), 50 ꢁC, 2 h
[a
[a
[a
[a
[a
]
]
]
]
]
þ0.21 (c 2.06)
þ1.40 (c 0.47)
þ3.51 (c 0.34)
þ1.89 (c 1.54)
þ4.14 (c 2.53)c
12
65
90
21
D
23
D
26
D
21
D
48
92 (100c)
26
D
a
Reported value of pure (R)-4a: [
Determined by MTPA/NMR analysis.
a
]
D ꢀ4.37 (c 7.8).8
b
c
After recrystallization from EtOAc/pentane.
(R)-2 with either acyl chlorides or acids afforded acetonide esters
(S)-3aee. Removal of the acetonide protective groups of (S)-3aee
furnished (S)-4aee. The crystalline (S)-4a and (S)-4c could be pu-
rified by recrystallization at this stage to give enantiomerically pure
diols. The remaining oily diols (S)-4b, 4d, and 4e (90e100% ee as
analyzed by the MTPA/NMR method) were employed in the final
step without further purification.
3. Conclusion
The racemates and enantiomers of triglycerides 1aee of male
Drosophila fruit flies were synthesized in amounts sufficient for
further biological studies. Synthesis of the enantiomers of 1aee
was made possible by developing reliable methods for preparation
and determination of their enantiomeric purities of the enantio-
mers of 1-monoglycerides 4aee. Biological studies on the role of
1aee in the courtship behavior of Drosophila fruit flies will be
reported in due course by Dr. J.Y. Yew at National University of
Singapore.
4. Experimental
4.1. General
Melting points are uncorrected values. Refractive indices (nD)
were measured on an Atago DMT-1 refractometer. Optical rotations
were measured on a Jasco P-1020 polarimeter. IR spectra were
measured on a Jasco FT/IR-410 spectrometer. 1H NMR spectra
(400 MHz, TMS at
spectra (100 MHz, CDCl3 at
recorded on a Jeol JNM-AL 400 spectrometer. GCeMS were mea-
sured on Agilent Technologies 5975 inert XL. HRMS were recorded
on Jeol JMS-SX102A or Waters Synapt G2 HDMS. Column chro-
matography was carried out on Merck Kieselgel 60 Art 1.07734.
d
¼0.00 as internal standard) and 13C NMR
d
¼77.0 as internal standard) were
4.2. General procedure for the preparation of 2,2-dimethyl-
1,3-dioxolane-4-methyl carboxylate (3)
4.2.1. Acylation of 2,2-dimethyl-1,3-dioxolane-4-methanol (2) with
acyl chloride. A solution of RCOCl [2.75 g (10 mmol) in the case of
n-C15H31COCl] in dry C6H6 (10 mL) was added dropwise to a stirred
and ice-cooled solution of (ꢂ)-2 (1.00 g, 7.6 mmol) and DMAP
(50 mg, 0.4 mmol) in dry pyridine (5 mL) at 5e10 ꢁC. Stirring was
continued for 1 h at 0e5 ꢁC, and the mixture was left to stand
overnight in a refrigerator. After dilution with ice and water, the
mixture was extracted with Et2O. The extract was washed succes-
sively with dil HCl, NaHCO3 solution and brine, dried (MgSO4), and
concentrated in vacuo. The residue was chromatographed over SiO2
(35 g). Elution with hexane/EtOAc (20:1) gave 2.60 g (93%) of
(ꢂ)-3a. Preparation of 3a, 3c, and 3d was executed by the above
procedure.
Scheme 3. Synthesis of the enantiomers of 1aee, the triglycerides of male Drosophila
fruit flies. Reagents: (a) RCOCl, DMAP, C5H5N (85e99%); (b) RCO2H, DCC, DMAP, CH2Cl2
(94%-quant.); (c) 80% AcOH, 50 ꢁC, 2 h (66%-quant.); (d) (E)-MeCH]C(Me)COCl, DMAP,
C5H5N, C6H6 (72%-quant.).
Esterification of (S)-4aee with an excess amount of tigloyl
chloride and DMAP in pyridine gave (R)-1aee after chromato-
graphic purification over SiO2. Their IR, 1H and 13C NMR, and mass
spectra supported the expected structures. The values of specific
rotation (at 25 or 26 ꢁC) of (R)-1aee (þ4.66wþ5.40 in hexane)
were not so small in contrast to those reported (0.00wþ0.09) for
4.2.2. Acylation of 2 with acid and DCC. A solution of DCC (824 mg,
4 mmol) in dry CH2Cl2 (7 mL) was added dropwise to a stirred and
the ordinary triglycerides of natural origin.2,3 Similarly, (S)-2 yiel-
23e26
ded triglycerides (S)-1aee with [
a
]
D
value of ꢀ4.71 to ꢀ5.45.
ice-cooled
solution
of
(9Z,12Z)-n-C5H11CH]CHCH2CH]
The enantiomeric purity of these final products (R)- and (S)-1aee
was regarded to be same as that of (S)- and (R)-4aee, because no
racemization was observed when the enantiomers of 4aee were
treated with excess amounts of (S)-(þ)-MTPACl to give their bis-
(R)-MTPA esters. The overall yield of the enantiomers of 1aee was
54e96% (average 73%) over three steps based on (R)- or (S)-2.
CH(CH2)7CO2H (linoleic acid, 560 mg, 2 mmol), (ꢂ)-2 (264 mg,
2 mmol), and DMAP (15 mg, 0.12 mmol) in dry CH2Cl2 (10 mL) over
30 min at 0e5 ꢁC. Stirring was continued for 1 h at 0e5 ꢁC, and the
mixture was left to stand overnight at room temperature. It was
then diluted with hexane and filtered through Celite. The Celite
layer was washed with hexane. The combined filtrate and washings

K. Mori / Tetrahedron 68 (2012) 8441e8449
8445
were concentrated in vacuo. The residue was chromatographed
4.5. 2,2-Dimethyl-1,3-dioxolane-4-methyl octadecanoate (3c)
over SiO2 (15 g). Elution with hexane/EtOAc (20:1) gave 836.5 mg
(quant.) of (ꢂ)-3e contaminated with DCC, which could be removed
in the next step. Preparation of 3b and 3e was executed by the
above procedure.
4.5.1. Racemate. Octadecanoyl chloride (3.03 g) and (ꢂ)-2 (1.58 g)
gave 3.55 g (89%) of (ꢂ)-3c as colorless rods, mp 38.0e38.5 ꢁC: nmax
(Nujol): 1733 (s),1163 (s), 851 (m); dH (CDCl3): 0.88 (3H, t, J 6.8),1.25
(28H, br), 1.37 (3H, s), 1.44 (3H, s), 1.63 (2H, m), 2.34 (2H, t, J 7.6),
3.72e3.74 (1H, m), 4.06e4.17 (3H, m), 4.29e4.33 (1H, m); GCeMS
[same conditions as those for (ꢂ)-3a]: tR 18.56 min (99.5%); MS of
(ꢂ)-3c (70 eV, EI): m/z 398 (<1)[Mþ], 383 (100) [(MꢀCH3)þ], 340
(8), 297 (4), 185 (5), 171 (9), 129 (14), 116 (13), 101 (21), 57 (11), 43
(18). HRMS calcd for C23H43O4 [(MꢀCH3)þ]: 383.3161, found:
383.3156.
4.3. 2,2-Dimethyl-1,3-dioxolane-4-methyl hexadecanoate (3a)
4.3.1. Racemate. Colorless prisms, mp 29e30 ꢁC; nmax (Nujol): 1742
(s),1220 (s), 849 (m); dH (CDCl3): 0.88 (3H, t, J 6.8),1.25 (24H, br),1.37
(3H, s), 1.44 (3H, s), 1.62 (2H, m), 2.34 (2H, t, J 7.2), 3.70e3.76 (1H, m),
4.05e4.11 (2H, m), 4.15e4.19 (1H, m), 4.30e4.33 (1H, m); GCeMS
[Column: HP-5MS 5% phenylmethylsiloxane, 30 mꢃ0.25 mm i.d.;
carrier gas, He; press: 52.7 kPa, temp: 50e160 ꢁC (þ10 ꢁC/min), then
160e220 ꢁC (þ4 ꢁC/min)]: tR17.56 min (96.7%); MS of (ꢂ)-3a (70 eV,
EI): m/z 355 (100) [(MꢀCH3)þ], 312 (10), 269 (7), 239 (6), 185 (6), 171
(10), 129 (16), 116 (16), 101 (28), 57 (8), 43 (18). HRMS calcd for
C21H39O4 [(MꢀCH3)þ]: 355.2848, found: 355. 2847.
4.5.2. (R)-Isomer. Octadecanoyl chloride (3.02 g) and (S)-2 (1.00 g)
gave 2.60 g (93%) of (R)-3c as colorless rhombs, mp 40e41 ꢁC (Ref. 8
mp 41e42 ꢁC); [
a
]
20 þ7.00 (c 3.35, hexane) {Ref. 8 [
a
]
D þ4.94 (neat
D
at 50e55 ꢁC)}; Its IR, 1H NMR, and mass spectra were identical with
those of (ꢂ)-3c. GCeMS [same conditions as those for (ꢂ)-3a]: tR
18.56 min (99.5%). HRMS calcd for C24H46O4Na: 421.3294, found:
421.3293.
4.3.2. (R)-Isomer. Hexadecanoyl chloride (3.02 g) and (S)-2 (Tokyo
Kasei, 1.00 g) gave 2.60 g (93%) of (R)-3a as rhombs, mp
4.5.3. (S)-Isomer. Octadecanoyl chloride (3.02 g) and (R)-2 (1.00 g)
23
31.0e31.5 ꢁC [Ref. 8 mp 33.0e34.5 ꢁC]; [
a
]
D
23 þ8.32 (c 3.41, hexane)
gave 2.37 g (85%) of (S)-3c as colorless rhombs, mp 41e42 ꢁC; [
a]
D
{Ref. 8 [
a
]
D þ4.95 (neat at 50 ꢁC)}. Its IR, 1H NMR, and mass spectra
ꢀ7.38 (c 3.95, hexane); Its IR, 1H NMR, and mass spectra were
identical with those of (ꢂ)-3c. GCeMS [same conditions as those
for (ꢂ)-3a]: tR 18.55 min (99.8%). HRMS calcd for C24H46O4Na:
421.3294, found: 421.3295.
were identical with those of (ꢂ)-3a. GCeMS [same conditions as
those for (ꢂ)-3a]: tR 17.53 min (99.7%). HRMS calcd for C21H39O4
[(MꢀCH3)þ]: 355.2848, found: 355.2833.
4.3.3. (S)-Isomer. Hexadecanoyl chloride (3.02 g) and (R)-2 (Tokyo
4.6. 2,2-Dimethyl-1,3-dioxolane-4-methyl (Z)-9-octadecenoate
Kasei, 1.00 g) gave 2.37
g
(85%) of (S)-3a as rhombs, mp
(3d)
32.0e32.5 ꢁC; [
a]
20 ꢀ7.91 (c 3.14, hexane); Its IR, 1H NMR, and mass
D
spectra were identical with those of (ꢂ)-3a. GCeMS [same condi-
tions as those for (ꢂ)-3a]: tR 17.52 min (99.7%). HRMS calcd for
C21H39O4 [(MꢀCH3)þ]: 355.2848, found: 355.2854.
4.6.1. Racemate. (Z)-9-Octadecenoyl chloride (3.00 g) and (ꢂ)-2
(1.58 g) gave 3.17 g (80%) of (ꢂ)-3d as a colorless oil, n2D1¼1.4582;
nmax (film): 2926 (s), 2855 (s), 1742 (s), 1161 (s), 844 (m); dH (CDCl3):
0.86 (3H, t, J 6.8), 1.24e1.35 (18H, br, two peaks at 1.27 and 1.30),
1.37 (3H, s), 1.44 (3H, s), 1.60e1.68 (2H, m), 1.96e2.10 (2H, m), 2.34
(2H, t, J 6.8), 3.70e3.76 (1H, m), 4.05e4.18 (3H, m), 4.28e4.40 (1H,
m), 5.30e5.42 (2H, m); GCeMS [same conditions as those for
(ꢂ)-3a]: tR 18.48 min (89.4%); MS of (ꢂ)-3d (70 eV, EI): m/z 396
(<1)[Mþ], 381 (100) [(MꢀCH3)þ], 338 (28), 295 (6), 253 (6), 239 (6),
185 (21),171 (11), 129 (53), 116 (16),101 (22), 83 (9), 69 (13), 55 (19),
43 (19). HRMS calcd for C24H44O4: 396.3240, found: 396.3232.
4.4. 2,2-Dimethyl-1,3-dioxolane-4-methyl (Z)-9-hexadecenoate
(3b)
4.4.1. Racemate. (Z)-9-Hexadecenoic acid (520 mg) and (ꢂ)-2
(264 mg) gave 717 mg (95%) of (ꢂ)-3b as a colorless oil, n2D1¼1.4632;
nmax (film): 2929 (s), 2855 (s), 2120 (contaminating DCC), 1742 (s),
1657 (w),1456 (m), 1370 (s), 1214 (s), 1161 (s), 1057 (s), 843 (m), 725
(m); dH (CDCl3): 0.88 (3H, t, J 7.2), 1.22e1.40 (16H, br), 1.37 (3H, s),
1.43 (3H, s), 1.58e1.70 (2H, m), 1.96e2.08 (4H, m), 2.34 (2H, t, J 7.6),
3.71e3.76 (1H, m), 4.05e4.12 (2H, m), 4.14e4.19 (1H, m), 4.29e4.34
(1H, m), 5.30e5.40 (2H, m); GCeMS [same conditions as those for
(ꢂ)-3a]: tR 17.46 min (76.9%), 12.93 min (11.3%, DCC); MS of (ꢂ)-3b
(70 eV, EI): m/z 368 (<1) [Mþ], 353 (100) [(MꢀCH3)þ], 310 (23), 267
(6), 253 (7), 239 (6),185 (20),171 (11),129 (54),116 (16),101 (24), 83
(9), 69 (13), 55 (21), 43 (22). HRMS calcd for C22H40O4: 368.2927,
found: 368.2924.
4.6.2. (R)-Isomer. (Z)-9-Octadecenoyl chloride (3.01 g) and (S)-2
(1.00 g) gave 3.01 g (99%) of (R)-3d as a colorless oil, n2D6¼1.4566;
[
a
]
21 þ7.14 (c 3.71, hexane); Its IR, 1H NMR, and mass spectra were
D
identical with those of (ꢂ)-3d. GCeMS [same conditions as those
for (ꢂ)-3a]: tR 18.45 min (92.1%). HRMS calcd for C24H44ONa:
419.3137, found: 419.3139.
4.6.3. (S)-Isomer. (Z)-9-Octadecenoyl chloride (3.01 g) and (R)-2
(1.00 g) gave 2.91 g (96%) of (S)-3d as a colorless oil, n2D0¼1.4564;
[
a
]
22 ꢀ7.07 (c 3.82, hexane); Its IR, 1H NMR, and mass spectra were
D
4.4.2. (R)-Isomer. (Z)-9-Hexadecenoic acid (690 mg) and (S)-2
identical with those of (ꢂ)-3d. GCeMS [same conditions as those
for (ꢂ)-3a]: tR 18.45 min (90.2%). HRMS calcd for C24H44O4Na:
419.3137, found: 419.3130.
(356 mg) gave 990.6 mg (99%) of (R)-3b as a colorless oil,
n2D4¼1.4572; [
a
]
D
þ7.80 (c 3.57, hexane); Its IR, 1H NMR, and mass
24
spectra were identical with those of (ꢂ)-3b. GCeMS [same condi-
tions as those for (ꢂ)-3a]: tR 17.45 min (98.2%). HRMS calcd for
C22H40O4Na: 391.2824, found: 391.2820.
4.7. 2,2-Dimethyl-1,3-dioxolane-4-methyl (9Z,12Z)-9,12-
octadecadienoate (3e)
4.4.3. (S)-Isomer. (Z)-9-Hexadecenoic acid (690 mg) and (R)-2
(360 mg) gave 940.3 mg (94%) of (S)-3b as a colorless oil,
4.7.1. Racemate. A colorless oil, n2D1¼1.4720; nmax (film): 3008 (m),
2929 (s),2856 (s), 2120 (contaminating DCC), 1742 (s), 1656 (w),
1453 (m), 1371 (s), 1215 (s), 1161 (s), 1087 (m), 1057 (m), 843 (m),
724 (m); dH (CDCl3): 0.89 (3H, t, J 6.8), 1.15e1.40 (14H, br), 1.37 (3H,
s), 1.43 (3H, s), 1.55e1.70 (2H, m), 2.00e2.10 (4H, m), 2.34 (2H, t, J
7.6), 2.77 (2H, t, J 6.8), 3.70e3.76 (1H, m), 4.05e4.10 (2H, m),
n2D4¼1.4568; [
a
]
23 ꢀ7.76 (c 3.62, hexane); Its IR, 1H NMR, and mass
D
spectra were identical with those of (ꢂ)-3b. GCeMS [same condi-
tions as those for (ꢂ)-3a]: tR 17.45 min (98.3%). HRMS calcd for
C22H40O4Na: 391.2824, found: 391.2820.

8446
K. Mori / Tetrahedron 68 (2012) 8441e8449
4.12e4.18 (1H, m), 4.28e4.36 (1H, m), 5.30e5.42 (4H, m); GCeMS
[same conditions as those for (ꢂ)-3a]: tR 12.93 min (19.2%, DCC),
18.44 min (80.7%); MS of (ꢂ)-3e (70 eV, EI): m/z 394 (<1) [Mþ], 379
(100) [(MꢀCH3)þ], 336 (38), 171 (9), 129 (22), 101 (25), 81 (20), 67
(25), 55 (20), 43 (21). HRMS calcd for C24H42O4: 394.3083, found:
394.3091.
2 h, there was no (S)-3a in the solution. The crude crystalline (S)-4a
was of 92% ee. Recrystallized (S)-4a was enantiomerically pure
(100% ee). In this case, crystals were colorless. This procedure was
therefore adopted for the preparative works.
4.8.6. Derivatization of 4a with (S)-(þ)-MTPACl. (S)-(þ)-MTPACl
(Aldrich or Tokyo Kasei, 12.6 mg, 0.05 mmol) was added to
a solution of (ꢂ)-, (R)- or (S)-4a (5.5 mg, 0.017 mmol) and DMAP
(2 mg, 0.02 mmol) in dry CH2Cl2 (3 drops) and dry pyridine (3
drops) in a vial. The vial was sealed with a stopper, shaken
vigorously, and left to stand for 3 d at room temperature. The
mixture was diluted with water, and extracted with Et2O. The
Et2O extract was washed with dil HCl, NaHCO3 solution and
brine, dried (MgSO4), and concentrated in vacuo. The residue was
dissolved in CHCl3. The solution was transferred to a small flask,
and concentrated in vacuo. The residue in CDCl3 was analyzed by
4.7.2. (R)-Isomer. (9Z,12Z)-9,12-Octadecadienoic acid (581 mg) and
(S)-2 (283 mg) gave 820 mg (quant.) of (R)-3e as a colorless oil,
n2D4¼1.4680; [
a
]
25 þ6.76 (c 3.57, hexane); Its IR, 1H NMR, and mass
D
spectra were identical with those of (ꢂ)-3e. GCeMS [same condi-
tions as those for (ꢂ)-3a]: tR 12.93 min (3.32%, DCC), 18.44 min
(95.1%). HRMS calcd for C24H42O4Na: 417.2981, found: 417.2979.
4.7.3. (S)-Isomer. (9Z,12Z)-9,12-Octadecadienoic acid (570.5 mg)
and (R)-2 (283 mg) gave 793 mg (99%) of (S)-3e as a colorless oil,
n2D4¼1.4682; [
a
]
23 ꢀ6.84 (c 3.58, hexane); Its IR, 1H NMR, and mass
NMR spectroscopy (see Fig. 2). Signals at d 4.0e4.8 were carefully
D
spectra were identical with those of (ꢂ)-3e. GCeMS [same condi-
tions as those for (ꢂ)-3a]: tR 12.93 min (5.46%, DCC), 18.44 min
(92.5%). HRMS calcd for C24H42O4Na: 417.2981, found: 417.2975.
analyzed to determine the diastereomeric ratio of the bis-MTPA
ester, which allowed the calculation of the enantiomeric purity
of 4a.
4.8. Scrutiny of the conditions to convert (S)-3a to (S)-4a with
minimal racemization
4.9. General procedure for the preparation of 2,3-
dihydroxypropyl carboxylate (1-monoglyceride 4)
4.8.1. With Amberlyst 15 (Hþ form). Amberlyst 15 (Hþ form, 1.0 g)
was added to a solution of (S)-3a (600 mg) in MeOH (6 mL) and
CH2Cl2 (3 mL), and the mixture was stirred for 2 h at 50 ꢁC. It was
then filtered, and the resin particles were washed with EtOAc. The
combined filtrate and washings were concentrated in vacuo. The
residue was recrystallized from EtOAc/pentane to give 322 mg
(61%) of crystalline (S)-4a, [
enantiomeric purity was 12% ee as determined by MTPA/NMR
analysis (see Section 4.8.6). The hydrolysis of (S)-3a could be fol-
lowed by SiO2-TLC developed with hexane/EtOAc¼4:1 (Rf of
3a¼0.82, Rf of 4a¼0.11).
4.9.1. Heating with 80% AcOH at 130 ꢁC. Aqueous acetic acid [AcOH/
H2O¼80:20 (v/v), 20 mL] was added to solid (ꢂ)-3a (3.20 g,
8.6 mmol), and the mixture was stirred and heated at 130 ꢁC (bath
temperature) for 30 min. After cooling, the mixture was diluted
with Et2O. The Et2O solution was washed with water, NaHCO3 so-
lution and brine, dried (MgSO4), and concentrated in vacuo to give
crude (ꢂ)-4a as a solid. This was recrystallized from EtOAc/pentane
to give 2.76 g (97%) of (ꢂ)-4a as colorless plates. All the racemates
were prepared by the present procedure.
21
a
]
þ0.21 (c 2.06, pyridine); whose
D
4.9.2. Heating with 80% AcOH at 50 ꢁC. Aqueous acetic acid [AcOH/
H2O¼80:20 (v/v), 12 mL] was added to solid (S)-3a (1.12 g, 3 mmol),
and the mixture was stirred and warmed at 50 ꢁC (bath tempera-
ture) for 2 h. TLC check at this point confirmed the disappearance of
3a. Work-up of the mixture yielded 792 mg (80%) of (S)-4a as
needles. All the optically active diols were prepared by the present
method.
4.8.2. With FeCl3/SiO2. FeCl3/SiO2 was prepared from FeCl3$6H2O
(1.2 g) and Merck silica gel 60 (10.0 g) in acetone (16 mL) according
to Kim.16 Yellow-colored FeCl3/SiO2 (100 mg) was added to a solu-
tion of (S)-3a (199 mg) in CHCl3 (10 mL), and the mixture was
stirred for 5 h at room temperature. It was then filtered, and the
solid was washed with EtOAc. The combined filtrate and washings
were concentrated in vacuo, and the residue was recrystallized
23
from EtOAc/pentane to give 112 mg (64%) of crystalline (S)-4a, [
a]
D
þ1.40 (c 0.47, pyridine), whose enantiomeric purity was 65% ee.
4.10. 2,3-Dihydroxypropyl hexadecanoate (1-monopalmitin,
4a)
4.8.3. With Zn(NO3)2$6H2O in MeCN. Zn(NO3)2$6H2O (742 mg,
2.5 mmol) was added to a solution of (S)-3a (199 mg, 0.53 mmol) in
MeCN (2.0 mL). The solution was stirred and heated at 50 ꢁC for 4 h,
and concentrated in vacuo. The residue was dissolved in EtOAc and
H2O. The organic layer was washed with water and brine, dried
(MgSO4), and concentrated in vacuo. The residue was recrystallized
4.10.1. Racemate. Colorless plates from EtOAc/pentane, mp 72 ꢁC
(sinter at 66 ꢁC); nmax (Nujol): 1731 (s), 1180 (m), 1047 (m), 720 (m);
dH (CDCl3): 0.88 (3H, t, J 6.8), 1.25 (24H, br), 1.62 (2H, m), 2.11 (1H,
m), 2.35 (2H, t, J 7.6), 2.55 (1H, d, J 4.8), 3.58e3.63 (1H, m),
3.67e3.72 (1H, m), 3.90e3.98 (1H, m), 4.12e4.24 (2H, m). For the
NMR spectrum of the corresponding bis-MTPA ester, see Fig. 2.
HRMS calcd for C19H38O4: 330.2770, found: 330.2755.
from EtOAc/pentane to give 105 mg (60%) of slightly tan and
26
crystalline (S)-4a, [
a
]
þ3.51 (c 0.34, pyridine), whose enantio-
D
meric purity was 90% ee. Use of MeCN as solvent seemed to make
crystals slightly tan-colored.
4.10.2. (R)-Isomer. Acetonide (R)-3a (1.119 g) gave 819 mg (83%) of
4.8.4. With 80% AcOH at 130 ꢁC, for 30 min. The procedure detailed
(R)-4a as colorless needles from EtOAc/pentane, mp 68e69 ꢁC
21
24
in Section 4.9.1 furnished a sample of (S)-4a, [
pyridine); whose enantiomeric purity was 52% ee.
a
]
þ1.89 (c 1.54,
(Ref. 8 mp 71e72 ꢁC); [
a
]
D
ꢀ4.16 (c 2.54, pyridine); 100% ee (by
D
MTPA/NMR analysis; see Fig. 2). Its IR and 1H NMR spectra were
identical with those of (ꢂ)-4a. HRMS calcd for C19H38O4: 330.2770,
found: 330.2768.
4.8.5. With 80% AcOH at 50 ꢁC for 2 h. The procedure detailed in
Section 4.9.2 was first tested with a small amount (187 mg) of (S)-
3a in 80% AcOH (2 mL) at 50 ꢁC. At first the mixture was turbid, and
it became homogeneous after 30 min. After 1 h, TLC check showed
that a small amount of (S)-3a was still present in the solution. After
4.10.3. (S)-Isomer. Acetonide (S)-3a (1.120 g) gave 792 mg (80%) of
(S)-4a as colorless needles from EtOAc/pentane, mp 68.5e69.5 ꢁC;
[a
]
24 þ4.14 (c 2.53, pyridine), 100% ee (by MTPA/NMR analysis; see
D

K. Mori / Tetrahedron 68 (2012) 8441e8449
8447
Fig. 2) Its IR and 1H NMR spectra were identical with those of
5.30e5.40 (2H, m). HRMS calcd for C21H40O4: 356.2927, found:
(ꢂ)-4a. HRMS calcd for C19H38O4: 330.2770, found: 330.2755.
356.2927.
4.11. 2,3-Dihydroxypropyl (Z)-9-hexadecenoate (1-monopalmi-
tolein, 4b)
4.13.2. (R)-Isomer. Acetonide (R)-3d (1.188 g) gave 974 mg (91%) of
(R)-4d as a colorless oil, which solidified in a deep freezer. Its mp
could not be determined. n2D4 1.4660; [
a
]
27 ꢀ2.98 (c 4.38, pyridine);
D
4.11.1. Racemate. Acetonide (ꢂ)-3b (634 mg) gave 444 mg (79%) of
(ꢂ)-4b as a colorless and viscous oil, n2D2¼1.4696. This oil solidifies
in a deep freezer. nmax (Nujol): 3408 (s), 3005 (m), 2925 (s), 2855 (s),
1740 (s), 1653 (w), 1464 (m), 1379 (m), 1241 (m), 1177 (s), 1119 (m),
1052 (m), 724 (m); dH (CDCl3): 0.88 (3H, t, J 7.2), 1.22e1.48 (18H, br),
1.60e1.68 (2H, m), 1.98e2.05 (4H, m), 2.35 (2H, t, J 7.2), 3.57e3.62
(1H, m), 3.66e3.72 (1H, m), 3.82e3.96 (1H, m), 4.12e4.22 (2H, m),
5.30e5.39 (2H, m). HRMS calcd for C19H36O4: 328.2614, found:
328.2603.
96% ee (by MTPA/NMR analysis). Its IR and 1H NMR spectra were
identical with those of (ꢂ)-4d. HRMS calcd for C21H40O4Na:
379.2824, found: 379.2824.
4.13.3. (S)-Isomer. Acetonide (S)-3d (1.190 g) gave 1.070 g (quant.)
of (S)-4d as a colorless oil, which solidified in a deep freezer. Its mp
could not be determined. n2D4 1.4686; [
a
]
D
27 þ3.21 (c 4.09, pyridine);
95% ee (by MTPA/NMR analysis). Its IR and 1H NMR spectra were
identical with those of (ꢂ)4d. HRMS calcd for C21H40O4Na:
379.2824, found: 379.2827.
4.11.2. (R)-Isomer. Acetonide (R)-3b (454 mg) gave 390 mg (97%) of
(R)-4b as a colorless oil, n2D2¼1.4672; [
a
]
25 ꢀ3.60 (c 1.12, pyridine);
4.14. 2,3-Dihydroxypropyl (9Z,12Z)-9,12-octadecadienoate
(monolinolein 4e)
D
95% ee (by MTPA/NMR analysis). Its IR and 1H NMR spectra were
identical with those of (ꢂ)-4b. HRMS calcd for C19H36O4Na:
351.2511, found: 351.2504.
4.14.1. Racemate. Acetonide (ꢂ)-3e (758 mg) gave 467 mg (68%) of
(ꢂ)-4e as a colorless and viscous oil, n2D1 1.4774, which solidified in
a deep freezer. nmax (film): 3414 (s), 3009 (m), 2927 (s), 2855 (s),
1740 (s), 1654 (w), 1464 (m), 1241 (s), 1177 (s), 1051 (m), 723 (m); dH
(CDCl3): 0.89 (3H, t, J 7.2), 1.22e1.40 (16H, br), 1.48e1.70 (2H, m),
2.05 (4H, q-like, J 6.8), 2.35 (2H, t, J 6.8), 2.77 (2H, t, J 6.4), 3.56e3.62
(1H, m), 3.67e3.72 (1H, m), 3.80e3.97 (1H, m), 4.10e4.22 (2H, m),
5.28e5.42 (4H, m). HRMS calcd for C21H38O4: 354.2770, found:
354.2764.
4.11.3. (S)-Isomer. Acetonide (S)-3b (450 mg) gave 399 mg (99%) of
(S)-4b as a colorless oil, n2D6 1.4673; [
a
]
þ3.67 (c 2.61, pyridine);
25
D
95% ee (by MTPA/NMR analysis). Its IR and 1H NMR spectra were
identical with those of (ꢂ)-4b. HRMS calcd for C19H36O4Na:
351.2511, found: 351.2504.
4.12. 2,3-Dihydroxypropyl octadecanoate (1-monostearin, 4c)
4.12.1. Racemate. Acetonide (ꢂ)-3c (3.50 g) gave 3.20 g (quant.) of
(ꢂ)-4c as a colorless solid, which was recrystallized from EtOAc/
pentane to give 1.95 g (62%) of pure (ꢂ)-4c as plates, mp 76e78 ꢁC
(sinter at 44 ꢁC); nmax (Nujol): 1731 (s), 1179 (m), 1047 (m), 720 (m);
dH (CDCl3): 0.88 (3H, t, J 6.8), 1.25 (28H, br), 1.60e1.63 (2H, m), 2.08
(1H, br), 2.35 (2H, t, J 7.6), 2.51 (1H, br), 3.56e3.62 (1H, m),
3.66e3.74 (1H, m), 3.90e3.96 (1H, m), 4.15 (1H, dd, J 4.8, 7.8), 4.21
(1H, dd, J 4.8, 7.8). HRMS calcd for C21H42O4: 358.3083, found:
358.3077.
4.14.2. (R)-Isomer. Acetonide (R)-3e (630 mg) gave 540 mg (95%) of
(R)-4e as a colorless and viscous oil, n2D4¼1.4750; [
a]
24 ꢀ2.99 (c 3.52,
D
pyridine); 90% ee (by MTPA/NMR analysis). Its IR and 1H NMR
spectra were identical with those of (ꢂ)-4e. HRMS calcd for
C21H38O4Na: 377.2668, found: 377.2665.
4.14.3. (S)-Isomer. Acetonide (S)-3e (1.182 g) gave 701.5 mg (66%)
24
of (S)-4e as a colorless and viscous oil, n2D4¼1.4775; [
a]
þ3.23 (c
D
3.63, pyridine); ca. 100% ee (by MTPA/NMR analysis). Its IR and 1H
NMR spectra were identical with those of (ꢂ)-4e. HRMS calcd for
C21H38O4Na: 377.2668, found: 377.2664.
4.12.2. (R)-Isomer. Acetonide (R)-3c (1.203 g) gave 1.18 g (quant.) of
(R)-4c as a colorless solid, which was recrystallized from EtOAc/
pentane to give 842 mg (78%) of pure (R)-4c as leaflets, mp
4.15. General procedure for the preparation of 2,3-di[(E)-2-
methyl-2-butenoyloxy]propyl carboxylate (triglyceride 1)
73e74 ꢁC (Ref. 8 mp 76e77 ꢁC); [
a]
23 ꢀ3.83 (c 2.63, pyridine) {Ref. 8
D
[
a]
ꢀ3.58 (c 12.3, pyridine)}; 95% ee (by MTPA/NMR analysis). Its
D
IR and 1H NMR spectra were identical with those of (ꢂ)-4c. HRMS
A solution of (E)-2-methyl-2-butenoyl chloride (tigloyl chloride,
Tokyo Kasei, 700 mg, 5.8 mmol) in dry C6H6 (3 mL) was added
dropwise over 15 min to a stirred and ice-cooled solution of (ꢂ)-4a
(739 mg, 2.2 mmol) and DMAP (10 mg, 0.08 mmol) in dry C5H5N
(5 mL) at 0e5 ꢁC. Stirring was continued for 30 min at 0e5 ꢁC, and
1 h at room temperature. The mixture was then diluted with ice and
water, and extracted with Et2O. The Et2O solution was washed with
dil HCl, NaHCO3 solution and brine, dried (MgSO4), and concen-
trated in vacuo. The residue was chromatographed over SiO2 (20 g).
Elution with hexane/EtOAc (20:1) gave 837 mg (72%) of (ꢂ)-1a as
an oil. The product was further purified by rechromatography on
SiO2, if necessary, after checking its purity by GCeMS.
calcd for C21H42O4Na: 381.2981, found: 381.2976.
4.12.3. (S)-Isomer. Acetonide (S)-3c (1.234 g) gave 1.20 g (quant.)
of (S)-4c as a colorless solid, which was recrystallized from
EtOAc/pentane to give 785 mg (71%) of pure (S)-4c as leaflets,
23
mp 73e74 ꢁC; [
a
]
þ4.10 (c 2.58, pyridine); 96% ee (by MTPA/
D
NMR analysis). Its IR and 1H NMR spectra were identical with
those of (ꢂ)-4c. HRMS calcd for C21H42O4Na: 381.2981, found:
381.2975.
4.13. 2,3-Dihydroxypropyl (Z)-9-octadecenoate (1-monoolein
4d)
4.16. 2,3-Di[(E)-2-methyl-2-butenoyloxy]propyl hex-
4.13.1. Racemate. Acetonide (ꢂ)-3d (3.57 g) gave 3.04 g (95%) of
(ꢂ)-4d as a colorless oil, which solidified in a deep freezer as
prisms, mp 26e28 ꢁC. nmax (Nujol): 1731 (s), 1466 (m), 1183 (m),
1062 (m), 721 (m); dH (CDCl3): 0.88 (3H, t, J 6.8), 1.20e1.40 (22H, br,
peaks at 1.26, 1.27, and 1.30), 1.58e1.68 (2H, m), 1.82e1.88 (1H),
1.95e2.08 (3H, m), 2.30e2.40 (2H, m), 3.56e3.62 (1H, m),
3.66e3.73 (1H, m), 3.90e4.00 (1H, m), 4.12e4.22 (2H, m),
adecanoate (1a)
4.16.1. Racemate. A pale yellow oil, n2D0¼1.4704; nmax (film): 2925
(vs), 2854 (s), 1740 (s), 1718 (vs), 1652 (m), 1250 (vs), 1133 (s), 1076
(m), 733 (m); dH (CDCl3): 0.88 (3H, t, J 6.8), 1.26 (24H, br), 1.60 (2H,
br), 1.80 (6H, d, J 7.2), 1.82 (6H, s), 2.31 (2H, t, J 7.2), 4.22e4.29 (2H,
m), 4.32e4.38 (2H, m), 5.38 (1H, m), 6.87 (2H, m); dC (CDCl3): 11.95,

8448
K. Mori / Tetrahedron 68 (2012) 8441e8449
11.97, 14.08, 14.38, 14.40, 22.62, 22.66, 24.87, 29.09, 29.24, 29.33,
29.43, 29.60, 29.63, 29.67, 31.56, 31.90, 34.08, 62.24, 62.35, 69.14,
128.08, 128.14, 138.09, 138.24, 166.95, 167.42, 173.34; GCeMS [col-
umn: HP-5MS. 5% phenylmethylsiloxane, 30 mꢃ0.25 mm i.d.; car-
rier gas He; press: 52.8 kPa, temp 50 ꢁC (2 min), then þ15 þꢁC/min,
300 ꢁC (60 min): tR 10.28 min (4.25%, unknown impurity M ¼154),
22.55 min (95.75%); MS (70 eV, EI): m/z 494 (<1) [Mþ], 395 (26)
[(MꢀC5H7O2)þ], 238 (25), 83 (100), 55 (18). HRMS calcd for
C29H50O6: 494.3607, found: 494.3604. The unidentified impurity
showed the following IR spectral properties: nmax (film): 1771 (vs),
1713 (s), 1649 (m), 1223 (s), 1014 (vs).
(CDCl3): 0.88 (3H, t, J 6.8), 1.26 (28H, br), 1.56e1.65 (2H, m), 1.79
(6H, d, J 6.8), 1.82 (6H, s), 2.31 (2H, t, J 3.2), 4.23e4.38 (4H, m),
5.32e5.40 (1H, m), 6.82e6.90 (2H, m); dC (CDCl3): 11.96, 11.98,
14.09, 14.40, 22.63, 22.67, 24.87, 29.09, 29.25, 29.34, 29.44, 29.60,
29.64, 29.68, 31.57, 31.91, 34.08, 62.24, 62.35, 69.13, 128.08, 128.13,
138.09, 138.25, 166.95, 167.42, 173.35; GCeMS [same conditions as
those for (ꢂ)-1a]: tR 25.01 min (93.93%); MS (70 eV, EI) m/z: 522
(<1) [Mþ], 423 (22), 238 (23), 83 (100), 55 (18). HRMS calcd for
C31H54O6: 522.3920, found: 522.3928.
4.18.2. (R)-Isomer. Diol (S)-4c (501.3 mg) gave 704 mg (96%) of (R)-
1c, which was further purified by SiO2 chromatography to give
26
4.16.2. (R)-Isomer. Diol (S)-4a (501.5 mg) gave 737.2 mg (98%) of
(R)-1a, which was further purified by SiO2 chromatography to give
183 mg of pure (R)-1c as a colorless oil, n2D6¼1.4702; [
a
]
þ4.91 (c
D
1.63, hexane). Its IR, NMR, and mass spectra were identical with those
of (ꢂ)-1c. GCeMS [same conditions as those for (ꢂ)-1a]: tR 25.04 min
(97.64%). HRMS calcd for C31H59O6Na: 545.3818, found: 545.3810.
202 mg of pure (R)-1a as a colorless oil, n2D5¼1.4690. This oil so-
25
lidifies in a deep freezer. [
a
]
þ5.40 (c 1.84, hexane). Its IR, NMR,
D
and mass spectra were identical with those of (ꢂ)-1a. GCeMS
[same conditions as those for (ꢂ)-1a]: tR 22.55 min (100%). HRMS
calcd for C29H50O6: 494.3607, found: 494.3608.
4.18.3. (S)-Isomer. Diol (R)-4c (530.5 mg) gave 732 mg (95%) of (S)-
1c, which was further purified by SiO2 chromatography to give
25
161 mg of pure (S)-1c as a colorless oil, n2D6¼1.4701; [
a
]
ꢀ4.88 (c
D
4.16.3. (S)-Isomer. Diol (R)-4a (497.8 mg) gave 637.6 mg (80%) of
(S)-1a, which was further purified by SiO2 chromatography to give
412 mg of pure (S)-1a as a colorless oil, n2D5¼1.4680. This oil solid-
1.40, hexane). Its IR, NMR, and mass spectra were identical with
those of (ꢂ)-1c. GCeMS [same conditions as those for (ꢂ)-1a]: tR
25.01 min (96.14%). HRMS calcd for C31H59O6NaNa: 545.3818,
found: 545.3810.
ifies in a deep freezer. [
a
]
25 ꢀ5.45 (c 2.85, hexane). Its IR, NMR, and
D
mass spectra were identical with those of (ꢂ)-1a. GCeMS [same
conditions as those for (ꢂ)-1a]: tR 22.55 min (96.26%). HRMS calcd
for C29H50O6: 494.3607, found: 494.3602.
4.19. 2,3-Di[(E)-2-methyl-2-butenoyloxy]propyl (Z)-9-
octadecenoate (1d)
4.17. 2,3-Di[(E)-2-methyl-2-butenoyloxy]propyl (Z)-9-
hexadecenoate (1b)
4.19.1. Racemate. Diol (ꢂ)-4d (429 mg) gave 546 mg (93%) of
(ꢂ)-1d as a colorless oil, nD21¼1.4752; nmax (film): 2925 (s), 2855 (s),
1740 (s), 1718 (vs), 1653 (m), 1250 (s), 1133 (s), 1076 (s), 733 (m); dH
(CDCl3): 0.88 (3H, t, J 6.8), 1.20e1.40 (20H, br, peaks at 1.27 and
1.29), 1.55e1.64 (2H, m), 1.79 (6H, d, J 7.2), 1.82 (6H, s), 1.95e2.08
(4H, m), 2.31 (2H, t, J 7.2), 4.23e4.37 (4H, m), 5.30e5.40 (3H, m),
6.80e6.90 (2H, m); dC (CDCl3): 12.00, 12.02, 14.13, 14.43, 14.45,
22.71, 24.90, 25.64, 27.19, 27.24, 29.09, 29.12, 29.20, 29.34, 29.55,
29.73, 29.79, 31.55, 31.93, 62.27, 62.38, 69.17, 128.12, 128.17, 129.74,
130.01, 138.11, 138.27, 166.95, 167.42, 173.35; GCeMS [same condi-
tions as those for (ꢂ)-1a]: tR 24.71 min (93.20%); MS (70 eV, EI) m/z:
520 (<1) [Mþ] 420 (8), 239 (27), 83 (100), 55 (20). HRMS calcd for
C31H52O6: 520.3764, found: 520.3757.
4.17.1. Racemate. Diol (ꢂ)-4b (351 mg) gave 404 mg (82%) of
(ꢂ)-1b as a colorless oil, nD21¼1.4744; nmax (film): 3002 (m), 2929 (s),
2855 (s), 1744 (s), 1718 (vs), 1652 (m), 1458 (m), 1381 (m), 1250 (vs),
1133 (s), 1077 (s), 733 (s); dH (CDCl3): 0.88 (3H, t, J 6.8), 1.20e1.40
(16H, br), 1.56e1.65 (2H, m), 1.80 (6H, d, J 7.6), 1.82 (6H, s), 1.95e2.10
(4H, m), 2.31 (2H, t, J 7.6), 4.22e4.37 (4H, m), 5.30e5.40 (3H, m),
6.82e6.92 (2H, m); dC (CDCl3): 11.77, 11.85,13.97, 14.28, 14.70, 22.54,
24.74, 27.04, 27.09, 28.86, 28.91, 28.96, 29.05, 29.57, 29.61, 31.66,
33.94, 62.13, 62.23, 69.03, 127.98, 128.03, 129.59, 129.85, 137.95,
138.10, 166.79, 167.26, 173.15; GCeMS [same conditions as those for
(ꢂ)-1a]: 22.51 min (95.21%); MS (70 eV, EI) m/z: 492 (<1) [Mþ] 392
(7), 239 (20), 157 (6), 83 (100), 55 (45). HRMS calcd for C29H48O6:
492.3451, found: 492.3446.
4.19.2. (R)-Isomer. Diol (S)-4d (934 mg) gave 1.254 g (92%) of (R)-1d,
which was further purified by SiO2 chromatography to give 347 mg
25
of pure (R)-1d as a colorless oil, n2D4¼1.4752; [
a]
D
þ4.66 (c 3.30,
4.17.2. (R)-Isomer. Diol (S)-4b (313 mg) gave 446 mg (quant.) of (R)-
hexane). Its IR, NMR, and mass spectra were identical with those of
(ꢂ)-1d. GCeMS [same conditions as those for (ꢂ)-1a]: tR 24.77 min
(96.08%). HRMS calcd for C31H52O6Na: 543.3662, found: 543.3653.
1b, which was further purified by SiO2 chromatography to give
26
121 mg of pure (R)-1b as a colorless oil, n2D3¼1.4758, [
a]
D
þ4.96 (c
1.02, hexane). Its IR, NMR, and mass spectra were identical with those
of (ꢂ)-1b. GCeMS [same conditions as those for (ꢂ)-1a]: tR 22.54 min
(100.00%). HRMS calcd for C29H48O6Na: 515.3349, found: 515.3338.
4.19.3. (S)-Isomer. Diol (R)-4d (992 mg) gave 1.421 g (98%) of (S)-
1d, which was further purified by SiO2 chromatography to give
511 mg of pure (S)-1d as a colorless oil, n2D4¼1.4754; [
a
]
26 ꢀ4.71 (c
D
4.17.3. (S)-Isomer. Diol (R)-4b (289 mg) gave 413 mg (quant.) of (S)-
2.12, hexane). Its IR, NMR, and mass spectra were identical with
those of (ꢂ)-1d. GCeMS [same conditions as those for (ꢂ)-1a]: tR
24.74 min (96.96%). HRMS calcd for C31H52O6Na: 543.3662, found:
543.3671.
1b, which was further purified by SiO2 chromatography to give
23
84 mg of pure (S)-1b as a colorless oil, n2D3¼1.4754, [
a
]
ꢀ5.15 (c
D
0.66, hexane). Its IR, NMR, and mass spectra were identical with
those of (ꢂ)-1b. GCeMS [same conditions as those for (ꢂ)-1a]: tR
22.43 min (99.70%). HRMS calcd for C29H48O6Na: 515.3349, found:
515.3350.
4.20. 2,3-Di[(E)-2-methyl-2-butenoyloxy]propyl (9Z,12Z)-9,12-
octadecadienoate (1e)
4.18. 2,3-Di[(E)-2-methyl-2-butenoyloxy]propyl octadeca-
noate (1c)
4.20.1. Racemate. Diol (ꢂ)-4e (372 mg) gave 410 mg (80%) of
(ꢂ)-1e as a pale yellow oil, n2D1¼1.4804; nmax (film): 3008 (m), 2928
(s), 2856 (s), 1745 (s), 1714 (vs), 1651 (m), 1457 (m), 1381 (m), 1251
(s), 1133 (s), 1077 (m), 733 (m); dH (CDCl3): 0.89 (3H, t, J 6.8),
1.22e1.40 (14H, br) 1.55e1.66 (2H, m), 1.79 (6H, d, J 7.2), 1.82 (6H, s),
2.01e2.10 (4H, m), 2.32 (2H, t, J 7.6), 2.77 (4H, t, J 6.4) 4.22e4.30 (2H,
4.18.1. Racemate. Diol (ꢂ)-4c (796 mg) gave 903 mg (83%) of (ꢂ)-1c
as a colorless oil, n2D0¼1.4698; nmax (film): 2925 (vs), 2854 (s), 1740
(s), 1719 (vs), 1652 (m), 1250 (vs), 1133 (s), 1076 (s), 733 (m); dH

K. Mori / Tetrahedron 68 (2012) 8441e8449
8449
m), 4.32e4.37 (2H, m), 5.28e5.42 (5H, m), 6.83e6.91 (2H,m); dC
(CDCl3): 11.87, 11.89, 13.98, 14.32, 14.34, 22.48, 24.77, 25.54, 27.11,
28.98, 29.01, 29.09, 29.26, 29.52, 31.43, 33.98, 62.16, 62.27, 69.06,
127.81, 127.96, 128.00, 128.05, 129.91, 130.10, 138.02, 138.17, 166.85,
167.32, 173.20; GCeMS [same conditions as those for (ꢂ)-1a]: tR
24.74 min (92.06%); MS (70 eV, EI) m/z: 518 (<1) [Mþ], 418 (7), 239
(23), 157 (7), 83 (100), 55 (21). HRMS calcd for C31H50O6: 518.3607,
found: 518.3605.
Sciences Laboratory, National University of Singapore) for her
suggestion to undertake the present work. Dr. T. Tashiro (RIKEN)
prepared the Figures and Schemes. Mr. Y. Shikichi (Toyo Gosei Co.,
Ltd) is thanked for NMR and GCeMS measurements. Drs. T. Naka-
mura and Y. Hongo (both at RIKEN) kindly executed the HRMS
analysis.
References and notes
4.20.2. (R)-Isomer. Diol (S)-4e (400 mg) gave 449 mg (77%) of (R)-1e,
which was further purified by SiO2 chromatography to give 250 mg of
1. Shikichi, Y.; Mori, K. Biosci. Biotechnol. Biochem., in press.
2. Bentley, R. Molecular Asymmetry in Biology; Academic: New York, NY, 1970; Vol.
2, pp 407e430.
pure (R)-1e as a colorless oil, n2D4¼1.4792; [
a]
D
26 þ4.88 (c 1.21, hexane).
3. Fischer, H. O. L.; Baer, E. Chem. Rev. 1941, 29, 287e316.
4. Suzuki, B.; Inoue, Y. Proc. Imp. Acad. (Tokyo) 1930, 6, 71e74.
5. Yew, J. Y.; Dreisewerd, K.; de Oliveira, C. C.; Etges, W. J. PLoS ONE 2011, 6,
e16898, 1e15.
Its IR, NMR, and mass spectra were identical with those for (ꢂ)-1e.
GCeMS[same conditionsasthosefor(ꢂ)-1a]:tR 24.73 min(100.00%).
HRMS calcd for C31H50O6Na: 541.3505, found: 541.3506.
€
6. Kuhbandner, S.; Sperling, S.; Mori, K.; Ruther, J. J. Exp. Biol. 2012, 215,
2471e2478.
4.20.3. (S)-Isomer. Diol (R)-4e (388 mg) gave 479 mg (84%) of (S)-1e,
7. Chin, J. 10th Temasek Life Sciences Laboratory Life Sciences Symposium: Chemical
Communication, Singapore, 30e31 January 2012.
8. Baer, E.; Fischer, H. O. L. J. Am. Chem. Soc. 1945, 67, 2031e2037.
9. Kubiak, R. J.; Bruzik, K. S. J. Org. Chem. 2003, 68, 960e968.
10. Nakamura, H.; Ueda, N.; Ban, H. S.; Ueno, M.; Tachikawa, S. Org. Biomol. Chem.
2012, 10, 1374e1380.
which was further purified by SiO2 chromatography to give 203 mg
25
of pure (S)-1e as a colorless oil, n2D4¼1.4793; [
a
]
ꢀ4.95 (c 1.81,
D
hexane). Its IR, NMR, and mass spectra were identical with those of
(ꢂ)-1e. GCeMS [same conditions as those for (ꢂ)-1a]: tR 24.76 min
(99.57%). HRMS calcd for C31H50O6Na: 541.3505, found: 541.3504.
11. Lewbart, M. L.; Schneider, J. J. J. Org. Chem. 1969, 34, 3505e3512.
12. Yew, J. Y. E-mail dated 18 May 2012.
13. Howe, R. J.; Malkin, T. J. Chem. Soc. 1951, 2663e2667.
14. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 3505e3512.
15. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512e519.
16. Kim, K. S.; Song, Y. H.; Lee, B. H.; Hahn, C. S. J. Org. Chem. 1986, 51, 404e407.
17. Iwata, M.; Ohrui, H. Bull. Chem. Soc. Jpn. 1981, 54, 2837e2838.
18. Vijayasaradhi, S.; Singh, J.; Aidhen, I. S. Synlett 2000, 110e112.
Acknowledgements
I thank Mr. M. Kimura (President, Toyo Gosei Co., Ltd) for his
support. My thanks are due to Dr. Joanne Y. Yew (Temasek Life