Total Synthesis of Cardiolipins Containing Chiral Cyclopropane Fatty Acids

Article abstract of DOI:10.1021/acs.joc.7b00945

Cardiolipin (CL) is a phospholipid located in both the eukaryotic mitochondrial inner membrane and the bacterial cell membrane. Some bacterial CLs are known to contain cyclopropane moieties in their acyl chains. Although the CLs are thought to be involved in the innate immune response, there have been few attempts at chemical synthesis of the CLs, and detailed studies of their biological activities are scarce. Thus, we have developed a synthetic route to CLs containing chiral cyclopropane moieties.

Full text of DOI:10.1021/acs.joc.7b00945

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Article
Total Synthesis of Cardiolipins Containing Chiral Cyclopropane Fatty Acids
Shinsuke Inuki, Ippei Ohta, Shunichi Ishibashi, Masayuki Takamatsu, Koichi Fukase, and Yukari Fujimoto
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00945 • Publication Date (Web): 06 Jul 2017
Downloaded from http://pubs.acs.org on July 7, 2017
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The Journal of Organic Chemistry
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Total Synthesis of Cardiolipins Containing Chiral
Cyclopropane Fatty Acids
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†
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‡
‡
Shinsuke Inuki, Ippei Ohta, Shunichi Ishibashi, Masayuki Takamatsu, Koichi Fukase, and Yukari
,
†
Fujimoto*
†
Graduate School of Science and Technology, Keio University 3-14-1 Hiyoshi, Kohoku-ku, Yokohama,
Kanagawa 223-8522, Japan
‡
Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama-cho,
Toyonaka, Osaka 560-0043, Japan
fujimotoy@chem.keio.ac.jp.
TOC:
Abstract: Cardiolipin (CL) is a phospholipid located in both the eukaryotic mitochondrial inner
membrane and the bacterial cell membrane. Some bacterial CLs are known to contain cyclopropane
moieties in their acyl chains. Although the CLs are thought to be involved in the innate immune
response, there have been few attempts at chemical synthesis of the CLs, and detailed studies of their
biological activities. Thus, we have developed a synthetic route to CLs containing chiral cyclopropane
moieties.
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Indroduction
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Cardiolipin (CL) is a phospholipid located in both the eukaryotic mitochondrial inner membrane and
1
in the bacterial cell membrane. The structure consists of two phosphatidyl moieties linked by a glycerol
bridge, and characteristic four acyl groups (Figure 1). The fatty acid composition of CLs has been
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shown to be critical for their biological activities. In animal tissues, the CLs, which contain some kinds
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of fatty acid variations such as length and saturation, are involved in either the regulation of ATP
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biosynthesis or the initiation of the apoptotic program. Recently, Rauch et al. reported that CLs bind to
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CD1d, a non-polymorphic MHC class I-like molecule, and activate CD1d-restricted gd T cells.
5
Bacterial CLs often contain various cyclopropane fatty acids as acyl groups. Cyclopropane fatty acids
were also commonly found in membrane components of bacteria and protozoa, including phospholipids
or glycolipids. In the biosynthetic pathway, cyclopropane fatty acids are generally formed by the
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methylenation of cis-unsaturated fatty acids with S-adenosylmethionine Recently, Williams et al.
reported that cyclopropane fatty acid-containing glycolipid, GL1 from Lactobacillus plantarum, could
be recognized by the glycolipid pattern recognition receptor Mincle that plays important roles in the
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innate immune system. We are interested in these kinds of bacterial CLs due to their potential as
immunomodulators. However, their detailed structure–activity relationships have not been examined
thus far. In addition, although several synthetic studies of CLs with saturated and unsaturated fatty acids
8
have been reported, few attempts have been made at synthesizing cyclopropane-containing CLs. Thus,
we planned to synthesize these CLs containing chiral cyclopropane moieties in order to elucidate their
biological functions and activities in detail.
Figure 1. Structure of cardiolipins.
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The key steps for the total synthesis of CLs are the construction of the phosphate linkage between
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phosphatidyl moieties and glycerol, and the synthesis of enantiomerically pure cyclopropane fatty acids.
In terms of the construction of the phosphate linkage, Ahmad and colleagues reported a
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a,9
phosphoramidite approach enabling to obtain large quantities of CL analogues.
Miyoshi and
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colleagues developed a concise procedure for the synthesis of CLs having different fatty acid
8b,c
combinations.
On the other hands, some groups have reported synthetic methods for chiral
cyclopropyl fatty acids. Kobayashi et al. synthesized chiral cyclopropyl fatty acids starting from a
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homochiral cyclopropa-g-lactone. Minnikin et al. also reported a related synthetic route to chiral
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lactobacillic acid from a homochiral cyclopropane linchpin. Nicolaou et al. reported the synthesis of a
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fatty acid containing a chiral cyclopropane using a chiral borate ester. Corey et al. developed a
synthetic route to 9R, 10S-dihydrosterculic acid through an Rh(II) catalyzed enantioselective
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cyclopropanation. Katsuki et al. reported the enantioselective synthesis of the cis-9R, 10S-
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methylenehexadecanoic acid methyl ester in the use of a chiral Ir-salen catalyst. Nishizaki et al. have
accomplished the synthesis of a fatty acid with two sequential chiral cyclopropanes through enzymatic
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resolution. Manthorpe et al. have reported the synthesis of 9R, 10S-dihydrosterculic acid using the
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Corey-Chaykovsky cyclopropanation of an alkylidene bis(sulfoxide). More recently, Williams
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developed a synthetic route to the chiral cyclopropane fatty acid by using chiral auxiliaries. In this
study, optically pure chiral cyclopropyl fatty acid was required for biological investigation of the CLs.
Thus, we planned to develop a synthetic route to the chiral cyclopropane fatty acid.
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Scheme 1. Retrosynthetic analysis of cyclopropane-containing CL (1)
The retrosynthetic analysis of cyclopropane-containing CLs 1 is shown in Scheme 1. We postulated
that the phosphate linkage can be constructed using phosphoramidite intermediates 2, which can be
derived from (R)-3-[(4-methoxybenzyl)oxy]-propane-1,2-diol 3 and cyclopropane-containing fatty acid
4
. The stepwise cross-coupling reactions of alkyl (5), chiral iodocyclopropane (6), and functionalized
alkane moieties (7) could be feasible for synthesizing the fatty acid 4. The chiral iodocyclopropane 6
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could be accessed from cyclopropane carboxylic acid, following published procedures. This synthetic
route can be applied to the synthesis of fatty acids with plural cyclopropane rings, and enable the
introduction of cyclopropane moieties at various positions in the fatty acid portion.
Scheme 2. Synthesis of the chiral fatty acid 4
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Results and Discussion
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The synthesis of the chiral cyclopropane fatty acid 4 is shown in Scheme 2. The chiral
iodocyclopropane carboxylic acid 6 was prepared from cyclopropane carboxylic acid 8, following a
1
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modified published procedure. The cyclopropane carboxylic acid 8 was converted to the
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corresponding diisopropylamide, followed by cis-selective iodination at the β-position of the amide
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group using magnesium amide. Hydrolysis of 9 with H
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SO and AcOH gave the racemic
iodocyclopropane carboxylic acid rac-6. Optical resolution using the chiral amine provided the chiral
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iodocarboxylic acid 6 (>99% ee). Esterification and reduction with DIBAL-H produced the known
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alcohol 10. Next, we investigated the coupling reaction between 10 and the functionalized alkane
moiety 7 (Scheme 1) using palladium catalysts. After investigating the palladium-catalyzed coupling
reaction, we found that the copper-free Sonogashira reaction condition reported by Meyer and Cossy et
2
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al. permitted successful generation of the desired product. The reaction of 10 with the functionalized
alkyne 11, PdCl (MeCN) , 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), and Cs CO
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in THF gave the desired alkyne 12 with a high yield (73%, three steps from 6). Next, we examined the
reduction of alkyne 12 under several conditions using Pd/C, palladium-fibroin (Pd/Fib), Raney Ni, and
Wilkinson’s catalyst, but these conditions led to insufficient conversion. Moreover, ring-opening side
reactions of cyclopropane occurred. We therefore performed a two-step reduction of the alkyne instead.
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2 2 4 2 2 2 2 2
Treating 12 with Ni(OAc) ·4H O, NaBH , and H N(CH ) NH under a H atmosphere followed by
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diimide reduction provided the desired product 13 (91%, 2 steps). After elaborating 13 to form the
bromide derivative, copper-mediated alkylation reaction with Grignard reagent, and removal of the TBS
3
group gave the alcohol 14, which was subsequently reacted with CrO to give the corresponding
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carboxylic acid 4. Using our optimized route, we have synthesized over 1 g of the chiral cyclopropane
fatty acid 4 for subsequent use.
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Scheme 3. Total synthesis of CLs containing chiral cyclopropane fatty acid 1a and 1b
With the chiral cyclopropane fatty acid 4 in hand, we converted the fatty acid into CLs (Scheme 3).
The esterification of (R)-3-[(4-methoxybenzyl)oxy]-propane-1,2-diol 3 with the fatty acid 4 and
subsequent removal of the PMB group gave the diester 16a. Next, treating 16a with the phosphitylating
23
reagent (2-cyanoethyl-N,N,N’,N’-tetraisopropyl phosphorodiamidite) in the presence of 1H-tetrazole
generated the phosphoramidite intermediate 2a with a 88% yield as a diastereomixture with a
stereogenic phosphorus atom. Subsequently, the coupling reaction between intermediate 2a and 2-[(4-
methoxybenzyl)oxy]-propane-1,3-diol gave the phosphite trimester 17a, which was subjected to
2 2
oxidation with H O to generate the protected CL 18a as a diastereomixture with two stereogenic
phosphorus atoms. Finally, total synthesis of CLs containing the chiral cyclopropane fatty acid 1a was
completed by removing the PMB and cyanoethyl groups.
To investigate the effect of cyclopropane chiralities on their biological activities, we went on to
synthesize the diastereomeric CL (1b) containing the enantiomeric chiral cyclopropane fatty acid ent-4
in the same manner, starting from the iodocyclopropane ent-6 (Scheme 2). The ent-4 was converted into
the CL 1b over six steps (Scheme 3). The final compounds 1a and 1b contained impurities, which were
quite difficult to remove at the final stage of the purification.
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The Journal of Organic Chemistry
In conclusion, we have successfully completed the total syntheses of CLs containing a chiral
1
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cyclopropane fatty acid. Our synthesis highlights a stepwise cross coupling reaction involving three
building blocks, namely, alkyl Grignard reagents, chiral iodocyclopropanes, and functionalized alkyne
moieties. Another key feature is a two-step reduction of the alkyne attached to the cyclopropane moiety
to provide the desired cyclopropane derivative at high yield. The cyclopropane-containing CLs can be
used as chemical tools to explore the mechanism of immune responses. The determination of their
biological activities is now underway.
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Experimental Section
General Methods. All moisture-sensitive reactions were performed using syringe-septum cap
techniques under an argon atmosphere and all glassware was dried in an oven at 80 °C for 2 h prior to
use. Analytical thin layer chromatography (TLC) was performed on Silica gel 60 F254 Plates (0.25 mm
thickness). For flash chromatography, Silica gel 60 N [spherical neutral (40-50 µm)] was employed.
Optical rotations were measured with a polarimeter. All NMR spectral data were recorded on a NMR
1
13
spectrometer for H (400 MHz) and C (100 MHz). Chemical shifts are reported in d (ppm) relative to
1
13
1
TMS in CDCl as internal standard ( H NMR) or the residual CHCl signal ( C NMR). H NMR spectra
3
3
are tabulated as follows: chemical shift, multiplicity (b = broad, s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet), number of protons, and coupling constant(s). Exact mass (HRMS) spectra were
recorded on an electrospray ionization quadrupole time of flight (ESI-QTOF) mass spectrometer.
Synthesis of cis-2-iodocyclopropyl-N,N-diethylcarboxamide (rac-9). The title compound was
1
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prepared according to the procedure reported by Shang, X. et al. To a flask charged with thionyl
chloride (18.6 mL, 256 mmol) was added cyclopropanecarboxylic acid 8 (20.0 mL, 253 mmol)
dropwise below 5 °C. After stirring for 1 h below 5 °C, the reaction mixture was warmed to room
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temperature and stirred for 1 h. Another flask was charged with a solution of diethylamine (53.8 mL,
27 mmol) in anhydrous CH Cl (80 mL) and cooled to 0 °C. The acid chloride solution was added
dropwise to the cooled diethylamine solution via a cannula. After stirring at room temperature for 1 h,
the reaction was quenched with water, and the extract was washed with 1 M HCl, saturated NaHCO aq.
and brine. The extract was dried over anhydrous Na SO and concentrated under reduced pressure. The
crude mixture was purified by vacuum distillation to give cyclopropyl-N,N-diethylcarboxamide (28.6 g,
0%) as a slight yellow oil: b.p. 113 °C (26 mmHg). All the spectral data were in agreement with those
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reported by Shang, X. et al. : H NMR (CDCl
Hz, 2H), 1.73-1.67 (m, 1H), 1.25 (t, J = 7.2 Hz, 3H), 1.11 (t, J = 7.2 Hz, 3H), 1.00-0.96 (m, 2H), 0.76-
.71 (m, 2H). To a flask charged with dibutylmagnesium (1.0 M solution in heptane, 74.4 mL, 74.4
3
, 400 MHz) d 3.49 (q, J = 7.2 Hz, 2H), 3.39 (q, J = 7.2
0
mmol) was added diisopropylamine (10.5 mL, 74.4 mmol) dropwise, keeping the internal temperature
below 40 °C. The reaction mixture was stirred without external heating for 1 h, then heated to reflux for
15 min and allowed to cool to room temperature. A solution of cyclopropyl-N,N-diethylcarboxamide
(
10.0 g, 70.8 mmol) in anhydrous THF (120 mL) was added to the above mixture via a cannula and the
mixture was refluxed for 70 min. Another flask was charged with a solution of I (53.9 g, 212 mmol) in
anhydrous THF (180 mL) and the solution was cooled to −15 °C. The reaction mixture containing the
cyclopropane derivative was cooled to 0 °C before being added dropwise to the I solution via a cannula.
After complete addition, the reaction mixture was stirred at 0 °C for 1 h. The reaction was quenched
with 1 M H SO (12.0 mL), and the whole was extracted with CH Cl three times. The combined extract
was washed with saturated Na aq. three times and brine once, and dried over anhydrous Na SO
2
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O
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The extract was concentrated under reduced pressure and the crude oil was purified by silica gel column
chromatography (n-hexane/EtOAc = 2:1) to give cis-2-iodocyclopropyl-N,N-diethylcarboxamide rac-9
(12.2 g, 65%) as a brown oil. All the spectral data were in agreement with those reported by Shang, X.
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et al. : H NMR (CDCl
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, 400 MHz) d 3.70-3.55 (m, 2H), 3.37 (m, 1H), 3.23 (m, 1H), 2.82 (ddd, J = 8.2,
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.2, 6.0 Hz, 1H), 1.94 (ddd, J = 8.2, 8.2, 6.4 Hz, 1H), 1.57 (m, 1H), 1.41 (ddd, J = 8.2, 8.2, 6.4 Hz, 1H),
.26 (t, J = 7.2 Hz, 3H), 1.17 (t, J = 7.2 Hz, 3H).
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Synthesis of cis-2-iodocyclopropanecarboxylic acid (rac-6). A mixture of cis-2-Iodocyclopropyl-N,N-
diethylcarboxamide rac-9 (9.24 g, 34.6 mmol), acetic acid (60 mL) and 3 M H SO (120 mL) was
refluxed for 10 days. The whole was extracted with EtOAc five times and washed with brine. The
extract was dried over anhydrous Na SO and concentrated under reduced pressure to give racemic cis-
2-iodocyclopropanecarboxylic acid 6 (7.28 g, 99%) as a brown solid. All the spectral data were in
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agreement with those reported by Shang, X. et al. : H NMR (CDCl
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, 400 MHz) d 10.30 (br s, 1H),
2
.91-2.87 (m, 1H), 1.92 (dd, J = 14.6, 8.3 Hz, 1H), 1.60 (dd, J = 14.6, 8.3 Hz, 1H), 1.45-1.41 (m, 1H).
Optical Resolution of cis-2-Iodocyclopropanecarboxylic Acid (6). The process of optical resolution
1
8
was carried out according to the procedure reported by Shang, X. et al. To a solution of racemic acid 6
4.60 g, 21.7 mmol) in 2-propanol (54 mL) was added (S)-(−)-N-benzyl-1-phenylethylamine (4.6 mL,
1 mmol). The mixture was stirred at 70 °C for 10 min and then cooled gradually to room temperature.
(
2
The resulting mixture was left overnight and the crystalline solid was collected by vacuum filtration.
The solid was washed with 2-propanol and dried under reduced pressure to give a crude crystalline solid
(
3.80 g, 9.00 mmol). A mixture of the crystalline solid (3.80 g) and 2-propanol (28 mL) was stirred at
0 °C for 10 min and then cooled gradually to room temperature. The precipitated crystal was collected
by vacuum filtration, washed with 2-propanol and dried under reduced pressure to give a crystalline
solid (3.01 g, 7.11 mmol). A solution of the crystalline solid (3.01 g) in CH Cl (9 mL) and NaOH aq.
0.5 M, 18 mL) was stirred for 5 min. After separating the organic layer, the aqueous solution was
extracted with CH Cl three times and then acidified with 1 M HCl. The whole was extracted with tert-
butylmethylether five times. The combined ether solutions were washed with brine, dried over
anhydrous Na SO and concentrated under reduced pressure to give (1R,2R)-2-
7
2
2
(
2
2
2
4
iodocyclopropanecarboxylic acid 6 (1.43 g, 62% yield for the (1R,2R)-isomer, >99% ee [determined by
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Page 10 of 24
chiral HPLC; Chiralpak-IA column, eluting with n-hexane/EtOH/TFA (97:3:0.1) at 0.5 mL/min, λ = 254
nm, t = 27.0 min for (1S,2S)-isomer, t = 28.5 min for (1R,2R)-isomer]). By a procedure identical with
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
2
that described above, the enantiomeric carboxylic acid ent-6 was resolved using (R)-(+)-N-benzyl-1-
phenylethylamine.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Synthesis of alkynyl-substituted cyclopropylmethylalcohol (12). A solution of (1R,2R)-2-
iodocyclopropanecarboxylic acid 6 (2.99 g, 14.1 mmol) and p-toluenesulfonic acid monohydrate (134
mg, 0.705 mmol) in anhydrous EtOH (36 mL) was refluxed overnight. The reaction mixture was then
concentrated to ca. 1/5 volume under reduced pressure and diluted with water. The whole was extracted
with EtOAc three times, washed with saturated NaHCO
anhydrous Na SO . The extract was concentrated under reduced pressure to give ethyl (1R,2R)-2-
iodocyclopropanecarboxylate (3.15 g) as a crude oil, which was used to the next reaction without further
purification. To a solution of the ethyl ester (2.70 g) in anhydrous CH Cl (10 mL) was added DIBAL-H
1.03 M in hexane, 27 mL) at −78 °C. After stirring at this temperature for 15 h, the reaction was
quenched with EtOAc and the resulting mixture was diluted with saturated aqueous solution of Rochelle
salt. The mixture was extracted with Et O five times, washed with brine once, and dried over anhydrous
Na SO The extract was concentrated under reduced pressure to give (1R,2R)-2-
iodocyclopropylmethylalcohol 10 (2.06 g) as a crude oil, which was used to the next reaction without
further purification. To a flask charged with the crude alcohol 10 (1.95 g), PdCl (MeCN) (76.6 mg,
.295 mmol), XPhos (423 mg, 0.886 mmol) and Cs CO (8.02 g, 24.6 mmol) was added a solution of
3
aq. and brine once, and then dried over
2
4
2
2
(
2
2
4
.
2
2
0
2
3
TBS-protected alkynol 11 (3.26 g, 13.6 mmol) in anhydrous THF (49 mL). After stirring at 60 °C
®
overnight, the reaction mixture was filtered through Celite and concentrated under reduced pressure to
obtain a crude oil, which was purified by silica gel column chromatography (n-hexane/EtOAc = 8:1) to
2
5
give alkynyl-substituted cyclopropylmethylalcohol 12 (2.58 g, 73% in 3 steps) as a colorless oil. [a]
D
1
=
−57.1 (c 0.83, CHCl
3
); H NMR (CDCl
3
, 400 MHz) d 3.93-3.85 (m, 1H), 3.60 (t, J = 6.5 Hz, 2H),
3
.56 (m, 1H), 2.14 (td, J = 7.0, 1.9 Hz, 2H), 1.91 (br s, 1H), 1.55-1.41 (m, 5H), 1.40-1.29 (m, 5H), 0.96-
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1
3
0
.92 (m, 1H), 0.89 (s, 9H), 0.57-0.52 (m, 1H), 0.05 (s, 6H); C NMR (CDCl
3
, 100 MHz) d 79.4, 78.3,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
64.1, 63.1, 32.7, 29.0, 28.6, 25.9 (3C), 25.3, 20.1, 18.7, 18.3, 12.6, 4.5, −5.3 (2C); HRMS (ESI-QTOF)
+
+
2
calcd C18H34NaO Si: [M+Na] , 333.2220; found: [M+Na] , 333.2226.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Synthesis of alkynyl-substituted cyclopropylmethylalcohol (ent-12). By a procedure identical with
that described for synthesis of 6 from 12, the carboxylic acid ent-6 (1.15 g) was converted into ent-12
25
1
(
1.18 g, 70% in 3 steps) as a colorless oil. [a]
d 3.93-3.88 (m, 1H), 3.60 (t, J = 6.6 Hz, 2H), 3.59-3.53 (m, 1H), 2.14 (td, J = 7.0, 1.9 Hz, 2H), 1.84-
.79 (m, 1H), 1.55-1.43 (m, 5H), 1.38-1.30 (m, 5H), 0.96-0.92 (m, 1H), 0.89 (s, 9H), 0.57-0.53 (m, 1H),
D 3 3
= +53.5 (c 0.61, CHCl ); H NMR (CDCl , 400 MHz)
1
1
3
0.05 (s, 6H); C NMR (CDCl
3
, 100 MHz) d 79.5, 78.4, 64.1, 63.2, 32.7, 29.0, 28.7, 26.0 (3C), 25.3,
+
2
0.2, 18.7, 18.4, 12.6, 4.5, −5.3 (2C); HRMS (ESI-QTOF) calcd C18
H
34NaO
2
Si: [M+Na] , 333.2220;
+
found: [M+Na] , 333.2226.
Synthesis of alkyl-substituted cyclopropylmethylalcohol (13). To a solution of Ni(OAc)
2 2
·4H O (516
mg, 2.08 mmol) in MeOH (13 mL) was added NaBH (78.8 mg, 2.08 mmol) at 0 °C and the solution
4
was stirred at room temperature for 5 min. Anhydrous ethylenediamine (275 µL, 4.15 mmol) was then
added to the reaction mixture followed by stirring at room temperature for 5 min. After addition of a
solution of 12 (2.58 g, 8.31 mmol) in MeOH (15 mL), argon gas was replaced to hydrogen gas and the
reaction mixture was stirred at room temperature overnight. The mixture was filtered through Celite®
and concentrated under reduced pressure. The residual oil was diluted with water and the whole was
2 2 4
extracted with Et O three times. The combined extract was dried over anhydrous Na SO and
concentrated under reduced pressure to give the alkene intermediate (2.54 g) as a crude oil, which was
used to the next reaction without further purification. A mixture of the crude product (2.52 g), 2-
4
propanol (138 mL), acetic acid (1.1 mL), saturated CuSO aq. (1.1 mL) and hydrazine monohydride (11
mL) was heated to 70 °C and a solution of NaIO (17.2 g, 80.6 mmol) in hot water (50 mL) was added
4
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to the reaction mixture (dropwise, over 90 min). After additional stirring for 90 min, the mixture was
cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2 2 4
with water and extracted with Et O three times. The combined extract was dried over anhydrous Na SO
and concentrated under reduced pressure to give a crude oil, which was purified by silica gel column
chromatography (n-hexane/EtOAc = 8:1) to give alkyl-substituted cyclopropylmethylalcohol 13 (2.35 g,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
5
1
9
3
0
1% in 2 steps) as a colorless oil. [a]
D 3 3
= −12.5 (c 1.01, CHCl ); H NMR (CDCl , 400 MHz) d 3.68-
.54 (m, 4H), 1.55-1.36 (m, 6H), 1.29 (br s, 8H), 1.24-1.18 (m, 1H), 1.15-1.04 (m, 1H), 0.89 (s, 9H),
1
3
.87-0.82 (m, 1H), 0.70 (ddd, J = 8.3, 8.3, 4.5 Hz, 1H), 0.05 (s, 6H), −0.01-−0.06 (m, 1H); C NMR
(CDCl
3
, 100 MHz) d 63.30 (2C), 32.84, 30.12, 29.58, 29.47, 29.40, 28.52, 25.96 (3C), 25.76, 18.35,
+
1
8.11, 16.11, 9.45, −5.28 (2C); HRMS (ESI-QTOF) calcd C18
H
38
O
2
Si: [M+Na] , 337.2533; found:
+
[
M+Na] , 337.2541.
Synthesis of alkyl-substituted cyclopropylmethylalcohol (ent-13). By a procedure identical with that
described for synthesis of 13 from 12, the alcohol ent-12 (1.16 g, 3.74 mmol) was converted into ent-13
2
5
1
(0.84 g, 71% in 2 steps) as a colorless oil. [a]
D 3 3
= +13.2 (c 0.90, CHCl ); H NMR (CDCl , 400 MHz)
d 3.68-3.55 (m, 2H), 3.60 (t, J = 6.6 Hz, 2H), 1.61-1.37 (m, 6H), 1.29 (br s, 8H), 1.25-1.19 (m, 1H),
1.15-1.05 (m, 1H), 0.89 (s, 9H), 0.87-0.83 (m, 1H), 0.70 (ddd, J = 8.4, 8.4, 4.6 Hz, 1H), 0.05 (s, 6H),
13
−
0.01-−0.06 (m, 1H); C NMR (CDCl
3
, 100 MHz) d 63.4, 63.3, 32.9, 30.1, 29.6, 29.5, 29.4, 28.5, 26.0
+
(3C), 25.8, 18.4, 18.1, 16.1, 9.5, −5.3 (2C); HRMS (ESI-QTOF) calcd C18
H38NaO
2
Si: [M+Na] ,
+
3
37.2533; found: [M+Na] , 337.2540.
Synthesis of cyclopropane-containing alkanol (14). To a solution of cyclopropylmethylalcohol
derivative 13 (2.28 g, 7.25 mmol), imidazole (0.99 g, 14.5 mmol) and Ph P (3.80 g, 14.5 mmol) in
anhydrous CH Cl (36 mL) was added CBr (3.61 g, 10.9 mmol) at 0 °C. After stirring at 0 °C for 3 h,
3
2
2
4
2
the reaction mixture was concentrated under reduced pressure and reslurried with hexane/Et O = 3:1
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The Journal of Organic Chemistry
solution. Sticky solid was removed by filtration and the filtrate was concentrated under reduced pressure
to give the bromocyclopropylmethane derivative (3.33 g) as a crude oil, which was used to the next
reaction without further purification. To a mixture of CuI (413 mg, 2.18 mmol) and LiCl (0.5 M
solution in THF, 58 mL, 29 mmol) was added heptylmagnesium bromide (0.70 M solution in THF, 31.0
mL, 22 mmol) at 0 °C and the reaction mixture was stirred at this temperature for 10 min. A solution of
the crude bromocyclopropylmethane derivative (3.31 g) in anhydrous THF (15 mL) was added to the
reaction mixture dropwise. After stirring at 0 °C overnight, the reaction was quenched with saturated
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NH
4
Cl aq. and the mixture was diluted with 28% NH
4
OH. The whole was extracted with Et
2
O three
times. The extract was washed with brine, dried over anhydrous Na
2
SO and concentrated under
4
reduced pressure to give the TBS-protected alkanol (3.86 g) as a crude oil, which was used to the next
reaction without further purification. A solution of the TBS-protected alkanol (3.77 g) in 4 M HCl in
dioxane (6.8 mL, 27.2 mmol) and dioxane (48 mL) was stirred at room temperature overnight. The
reaction mixture was diluted with water and extracted with Et
with brine, dried over anhydrous Na SO and concentrated under reduced pressure to give a crude oil,
which was purified by silica gel column chromatography (n-hexane/EtOAc = 7:1) to give the title
2
O three times. The extract was washed
2
4
2
5
1
compound 14 (1.33 g, 67% in 3 steps) as a colorless oil. [a]
CDCl , 400 MHz) d 3.64 (t, J = 6.6 Hz, 2H), 1.61-1.52 (m, 2H), 1.44 (s, 1H), 1.40-1.10 (m, 26H), 0.88
(t, J = 6.7 Hz, 3H), 0.67-0.62 (m, 2H), 0.58-0.53 (m, 1H), −0.31-−0.36 (m, 1H); C NMR (CDCl
MHz) d 63.0, 32.8, 31.9, 30.20, 30.17, 29.7 (2C), 29.64, 29.58, 29.43, 29.35, 28.69, 28.67, 25.73, 22.67,
D 3
= +1.01 (c 0.77, CHCl ); H NMR
(
3
1
3
3
, 100
+
+
15.74, 15.71, 14.1, 10.9; HRMS (ESI-QTOF) calcd C19
05.2815.
H38NaO: [M+Na] , 305.2815; found: [M+Na] ,
3
Synthesis of cyclopropane-containing alkanol (ent-14). By a procedure identical with that described
for synthesis of 14 from 13, the alcohol ent-13 (0.78 g, 2.67 mmol) was converted into ent-14 (0.22 g,
2
5
1
3
D 3 3
1% in 3 steps) as a colorless oil. [a] = −1.92 (c 0.36, CHCl ); H NMR (CDCl , 400 MHz) d 3.64 (t,
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Page 14 of 24
J = 6.6 Hz, 2H), 1.60-1.54 (m, 3H), 1.40-1.10 (m, 26H), 0.88 (t, J = 6.8 Hz, 3H), 0.67-0.62 (m, 2H),
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
0
.58-0.53 (m, 1H), −0.31-−0.36 (m, 1H); C NMR (CDCl
3
, 100 MHz) d 63.1, 32.8, 31.9, 30.21, 30.19,
2
9.68 (2C), 29.65, 29.59, 29.44, 29.36, 28.71, 28.69, 25.7, 22.7, 15.8, 15.7, 14.1, 10.9; HRMS (ESI-
+
+
QTOF) calcd C19H38NaO: [M+Na] , 305.2815; found: [M+Na] , 305.2809.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Synthesis of chiral cyclopropane fatty acid (4). A solution of cyclopropane-containing alkanol 14
1.24 g, 4.39 mmol) in acetone (88 mL) was cooled to 0 °C. Another mixture of CrO (1.88 g, 18.8
(
3
mmol), sulfuric acid (1.6 mL) and water (7.2 mL) was added to the above solution dropwise. After
stirring for 10 min, the reaction mixture was diluted with water and extracted with hexane three times.
The extract was washed with brine, dried over anhydrous Na
pressure to give a crude oil, which was purified by silica gel column chromatography (n-hexane/EtOAc
4:1) to give the title compound 4 (1.07 g, 82%) as a white solid. All the spectral data were in
2 4
SO and concentrated under reduced
=
1
7
25
24
agreement with those reported by Williams, S. J. et al. : [a]
D 3 D
= +0.97 (c 0.42, CHCl ) [lit. [a] =
1
+
0.95 (c 0.55, CHCl
3
)]; H NMR (CDCl
3
, 400 MHz) d 2.35 (t, J = 7.6 Hz, 2H), 1.66-1.61 (m, 2H), 1.41-
1
3
1.09 (m, 24H), 0.88 (t, J = 6.8 Hz, 3H), 0.67-0.62 (m, 2H), 0.58-0.53 (m, 1H), −0.31-−0.36 (m, 1H); C
NMR (CDCl , 100 MHz) d 179.5, 33.9, 31.9, 30.2, 30.1, 29.7, 29.4, 29.4 (2C), 29.3, 29.1, 28.7, 28.7,
3
24.7, 22.7, 15.8, 15.7, 14.1, 10.9.
Synthesis of chiral cyclopropane fatty acid (ent-4). By a procedure identical with that described for
synthesis of 4 from 14, the alkanol ent-14 (216 mg, 0.765 mmol) was converted into ent-4 (206 mg,
9
1%) as a white solid. All the spectral data were in agreement with those reported by Williams, S. J. et
1
7
25
24
1
al. : [a]
D 3 D 3 3
= −0.81 (c 0.78, CHCl ) [lit. [a] = −0.81 (c 0.295, CHCl )]; H NMR (CDCl , 400 MHz)
d 2.35 (t, J = 7.5 Hz, 2H), 1.66-1.61 (m, 2H), 1.40-1.10 (m, 24H), 0.88 (t, J = 6.8 Hz, 3H), 0.67-0.62 (m,
1
3
2H), 0.59-0.53 (m, 1H), −0.31-−0.36 (m, 1H); C NMR (CDCl
3
, 100 MHz) d 179.6, 33.9, 31.9, 30.2,
3
0.1, 29.7, 29.4, 29.4 (2C), 29.3, 29.1, 28.7, 28.7, 24.7, 22.7, 15.8, 15.7, 14.1, 10.9.
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The Journal of Organic Chemistry
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2
Synthesis of PMB-protected diacylglycerol (15a). To a mixture of chiral cyclopropane fatty acid 4
150 mg, 507 µmol), PMB-protected glycerol 3 (46.8 mg, 220 µmol), DMAP (8.1 mg, 66 µmol) and
CH Cl (1.5 mL) was added a solution of WSC·HCl (114 mg, 595 µmol) in CH Cl (0.7 mL) at 0 °C.
After stirring at room temperature overnight, the reaction was quenched with 10% citric acid aq. and the
mixture was extracted with CH Cl three times. The extract was washed with brine, dried over
anhydrous Na SO and concentrated under reduced pressure to give a crude oil, which was purified by
silica gel column chromatography (n-hexane/EtOAc = 30:1) to give the title compound 15a (137 mg,
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
2
4
2
5
1
8
1%) as a colorless oil. [a]
Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.25-5.20 (m, 1H), 4.51-4.42 (m, 2H), 4.33 (dd, J = 11.9, 3.8 Hz, 1H),
.17 (dd, J = 11.9, 6.5 Hz, 1H), 3.80 (s, 3H), 3.55 (d, J = 5.2 Hz, 2H), 2.35-2.25 (m, 4H), 1.65-1.57 (m,
D 3 3
= +2.59 (c 1.27, CHCl ); H NMR (CDCl , 400 MHz) d 7.23 (d, J = 8.6
4
4H), 1.41-1.07 (m, 48H), 0.88 (t, J = 6.8 Hz, 6H), 0.67-0.61 (m, 4H), 0.58-0.53 (m, 2H), −0.31-−0.36
13
(
3
m, 2H); C NMR (CDCl , 100 MHz) d 173.4, 173.1, 159.3, 129.7, 129.3 (2C), 113.8 (2C), 72.9, 70.0,
67.9, 62.7, 55.2, 34.3, 34.1, 31.9 (2C), 30.20 (2C), 30.15 (2C), 29.7 (2C), 29.5 (2C), 29.4 (4C), 29.13
(2C), 29.10 (2C), 28.71 (2C), 28.66 (2C), 25.0, 24.9, 22.7 (2C), 15.8 (2C), 15.7 (2C), 14.1 (2C), 10.9
+
+
(
6
2C); HRMS (ESI-QTOF) calcd C49H84NaO : [M+Na] , 791.6160; found: [M+Na] , 791.6169.
Synthesis of PMB-protected diacylglycerol (15b). By a procedure identical with that described for
synthesis of 15a from 4, the fatty acid ent-4 (38.7 mg, 182 µmol) was converted into 15b (105 mg,
2
5
1
7
D 3 3
5%) as a colorless oil. [a] = +2.94 (c 1.23, CHCl ); H NMR (CDCl , 400 MHz) d 7.23 (d, J = 8.5
Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 5.24-5.20 (m, 1H), 4.51-4.42 (m, 2H), 4.33 (dd, J = 11.8, 3.7 Hz, 1H),
4.17 (dd, J = 11.8, 6.5 Hz, 1H), 3.80 (s, 3H), 3.55 (d, J = 5.2 Hz, 2H), 2.34-2.25 (m, 4H), 1.59 (m, 4H),
1
.39-1.09 (m, 48H), 0.88 (t, J = 6.7 Hz, 6H), 0.66-0.62 (m, 4H), 0.58-0.53 (m, 2H), −0.32-−0.36 (m,
1
3
2H); C NMR (CDCl
3
, 100 MHz) d 173.4, 173.1, 159.3, 129.7, 129.3 (2C), 113.8 (2C), 72.9, 70.0, 67.9,
6
2.7, 55.2, 34.3, 34.1, 31.9 (2C), 30.20 (2C), 30.15 (2C), 29.7 (2C), 29.5 (2C), 29.4 (2C), 29.3 (2C),
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2
9.1 (4C), 28.71 (2C), 28.66 (2C), 25.0, 24.9, 22.7 (2C), 15.8 (2C), 15.7 (2C), 14.1 (2C), 10.9 (2C);
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
+
6
HRMS (ESI-QTOF) calcd C49H84NaO : [M+Na] , 791.6160; found: [M+Na] , 791.6160.
Synthesis of diacylglycerol (16a). To a solution of PMB-protected diacylglycerol 15a (132 mg, 172
µmol) in MeCN/H O (v/v = 10/1, 14 mL) was added Ce(NH (NO (941 mg, 1.72 mmol) at 0 °C and
the reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with water and
extracted with CH Cl three times. The extract was washed with saturated NaHCO aq. and saturated
NaHSO aq., dried over anhydrous Na SO and concentrated under reduced pressure to give a crude oil,
which was purified by silica gel column chromatography (toluene/EtOAc = 10:1) to give the title
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4
)
2
3 6
)
2
2
3
3
2
4
2
5
1
compound 16a (105 mg, 94%) as a colorless oil. [a]
MHz) d 5.12-5.05 (m, 1H), 4.32 (dd, J = 11.9, 4.4 Hz, 1H), 4.24 (dd, J = 11.9, 5.6 Hz, 1H), 3.75-3.71
br m, 2H), 2.38-2.30 (m, 4H), 2.08 (br s, 1H), 1.66-1.59 (m, 4H), 1.41-1.09 (m, 48H), 0.88 (t, J = 6.5
D 3 3
= −0.89 (c 0.14, CHCl ); H NMR (CDCl , 400
(
1
3
Hz, 6H), 0.68-0.61 (m, 4H), 0.59-0.53 (m, 2H), −0.31-−0.36 (m, 2H); C NMR (CDCl
3
, 100 MHz) d
1
73.8, 173.4, 72.1, 62.0, 61.5, 34.3, 34.1, 31.9 (2C), 30.2 (2C), 30.1 (2C), 29.7 (2C), 29.5 (2C), 29.4
(2C), 29.3 (2C), 29.13 (2C), 29.10 (2C), 28.71 (2C), 28.66 (2C), 24.94, 24.89, 22.7 (2C), 15.8 (2C),
+
1
5.7 (2C), 14.1 (2C), 10.9 (2C); HRMS (ESI-QTOF) calcd C41
H
76NaO
5
: [M+Na] , 671.5585; found:
+
[M+Na] , 671.5594.
Synthesis of diacylglycerol (16b). By a procedure identical with that described for synthesis of 16a
from 15a, the PMB-protected diacylglycerol 15b (77.5 mg, 101 µmol) was converted into 16b (56.8 mg,
25
1
8
7%) as a colorless oil. [a]
D 3 3
= +12.0 (c 0.10, CHCl ); H NMR (CDCl , 400 MHz) d 5.11-5.06 (m,
1H), 4.32 (dd, J = 11.9, 4.3 Hz, 1H), 4.23 (dd, J = 11.9, 5.6 Hz, 1H), 3.75-3.71 (m, 2H), 2.37-2.30 (m,
4
0
3
H), 2.00 (br s, 1H), 1.66-1.60 (m, 4H), 1.40-1.10 (m, 48H), 0.88 (t, J = 6.5 Hz, 6H), 0.67-0.61 (m, 4H),
1
3
3
.59-0.53 (m, 2H), −0.32-−0.36 (m, 2H); C NMR (CDCl , 100 MHz) d 173.8, 173.4, 72.1, 62.0, 61.5,
4.3, 34.1, 31.9 (2C), 30.2 (2C), 30.1 (2C), 29.7 (2C), 29.4 (2C), 29.34 (2C), 29.30 (2C), 29.12 (2C),
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The Journal of Organic Chemistry
2
9.09 (2C), 28.70 (2C), 28.65 (2C), 24.93, 24.87, 22.7 (2C), 15.74 (2C), 15.69 (2C), 14.1 (2C), 10.9
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
+
5
(2C); HRMS (ESI-QTOF) calcd C41H76NaO : [M+Na] , 671.5585; found: [M+Na] , 671.5594.
Synthesis of diacylglycerol-phophoramidite (2a). A mixture of diacylglycerol 16a (28.6 mg, 44.1
µmol), 1H-tetrazole (6.2 mg, 88.5 µmol), 2-cyanoethyl-N,N,N’,N’-tetraisopropylphophordiamidite (28
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
µL, 27 mg, 88 µmol) and CH
The reaction was quenched with saturated NaHCO
times. The combined extract was washed with brine, dried over anhydrous Na
under reduced pressure to give a crude oil, which was purified by silica gel column chromatography (n-
hexane/EtOAc = 10:1, 3% Et N) to give the title compound 2a (36.3 mg, 88%, ~1:1 diastereomeric
2
Cl
2
/MeCN (v/v = 2:3, 0.55 mL) was stirred at room temperature for 3 h.
aq. and the whole was extracted with CH Cl three
SO and concentrated
3
2
2
2
4
3
25
1
mixture) as a colorless oil. [a]
D 3 3
= +3.14 (c 0.44, CHCl ); H NMR (CDCl , 400 MHz) δ 5.23-5.16 (m,
1
2
H), 4.39-4.29 (m, 1H), 4.21-4.12 (m, 1H), 3.89-3.74 (m, 3H), 3.73-3.66 (m, 1H), 3.65-3.54 (m, 2H),
.64 (t, J = 6.4 Hz, 2H), 2.35-2.28 (m, 4H), 1.65-1.58 (br m, 4H), 1.40-1.11 (m, 60H), 0.88 (t, J = 6.9
1
3
Hz, 6H), 0.67-0.61 (m, 4H), 0.59-0.53 (m, 2H), −0.31-−0.36 (m, 2H); C NMR (CDCl
3
, 100 MHz) δ
173.4, 173.0, 117.5, 70.6, 62.4, 61.6, 58.4, 43.2, 43.1, 34.3, 34.1, 31.9 (2C), 30.20 (2C), 30.15 (2C),
2
2
1
8
9.7 (2C), 29.5 (2C), 29.4 (4C), 29.14 (2C), 29.12 (2C), 28.70 (2C), 28.66 (2C), 24.92, 24.89, 24.6 (2C),
3
1
4.5 (2C), 22.7 (2C), 20.4, 15.74 (2C), 15.69 (2C), 14.1 (2C), 10.9 (2C); P NMR (CDCl
3
, 161 MHz) δ
+
+
50.2, 150.0; HRMS (ESI-QTOF) calcd C50
71.6670.
H
93
N
2
NaO
6
P: [M+Na] , 871.6663; found: [M+Na] ,
Synthesis of diacylglycerol-phophoramidite (2b). By a procedure identical with that described for
synthesis of 2a from 16a the diacylglycerol 16b (47.1 mg) was converted into 2b (50.1 mg, 81%, ~1:1
2
5
1
diastereomeric mixture) as a colorless oil. [a]
D 3 3
= +3.70 (c 1.12, CHCl ); H NMR (CDCl , 400 MHz)
d 5.22-5.17 (m, 1H), 4.38-4.30 (m, 1H), 4.22-4.13 (m, 1H), 3.88-3.75 (m, 3H), 3.72-3.67 (m, 1H), 3.63-
3.54 (m, 2H), 2.64 (t, J = 6.4 Hz, 2H), 2.33-2.29 (m, 4H), 1.64-1.59 (m, 4H), 1.40-1.14 (m, 60H), 0.88 (t,
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1
3
J = 6.4 Hz, 6H), 0.66-0.62 (m, 4H), 0.59-0.53 (m, 2H), −0.31-−0.36 (m, 2H); C NMR (CDCl
3
, 100
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
MHz) d 173.4, 173.0, 117.5, 70.6, 62.3, 61.6, 58.4, 43.2, 43.1, 34.3, 34.1, 31.90, 31.88, 30.2 (2C), 30.1
(2C), 29.7 (2C), 29.5 (2C), 29.3 (4C), 29.13 (2C), 29.11 (2C), 28.69 (2C), 28.65 (2C), 24.90, 24.87,
3
1
2
4.6 (2C), 24.5 (2C), 22.7 (2C), 20.4, 20.3, 15.72 (2C), 15.67 (2C), 14.1 (2C), 10.9 (2C); P NMR
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(CDCl
, 161 MHz) δ 150.2, 150.0; HRMS (ESI-QTOF) calcd C50
H
93
N
NaO
P: [M+Na] , 871.6663;
3
2
6
+
found: [M+Na] , 871.6671.
Synthesis of PMB/cyanoethyl-protected cardiolipin (17a). A mixture of diacylglycerol-
phophoramidite 2a (120 mg, 145 µmol), PMB-protected glycerol (14.0 mg, 66.1 µmol), 1H-tetrazole
(
13.9 mg, 198 µmol) and CH
aq. (30 wt%, 37 µL) was then added to the mixture and the reaction mixture was stirred for 15 min.
The reaction was quenched with saturated Na aq., and the whole was extracted with CH Cl three
times. The combined extract was washed with saturated NH Cl aq., saturated NaHCO aq. and brine,
dried over anhydrous Na SO and concentrated under reduced pressure to give a crude oil, which was
purified by silica gel column chromatography (CHCl /MeOH = 50:1) to give the title compound 17a
2 2
Cl /MeCN (v/v = 2:1, 0.72 mL) was stirred at room temperature for 2 h.
2 2
H O
2
S
2
O
3
2
2
4
3
2
4
3
2
5
(
101 mg, 88% based on PMB-protected glycerol, ~1:1 diastereomeric mixture) as a colorless oil. [a]
D
1
3 3
= +2.25 (c 0.80, CHCl ); H NMR (CDCl , 400 MHz) δ 7.29 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz,
2
4
8
1
H), 5.27-5.21 (m, 2H), 4.60 (s, 2H), 4.35-4.07 (m, 16H), 3.87-3.81 (m, 1H), 3.80 (s, 3H), 2.81-2.66 (m,
H), 2.36-2.28 (m, 8H), 1.64-1.57 (m, 8H), 1.40-1.09 (m, 96H), 0.88 (t, J = 6.8 Hz, 12H), 0.67-0.61 (m,
1
3
H), 0.59-0.53 (m, 4H), −0.31-−0.36 (m, 4H); C NMR (CDCl
3
, 100 MHz) δ 173.2 (2C), 172.8 (2C),
59.5, 129.7, 129.7, 129.1, 116.4 (2C), 113.9 (2C), 75.7, 72.0, 69.23, 69.15, 65.92 (2C), 65.86 (2C),
62.2 (2C), 61.5 (2C), 55.2, 34.1 (2C), 34.0 (2C), 31.9 (4C), 30.2 (4C), 30.1 (4C), 29.67 (2C), 29.65 (2C),
2
1
9.5 (4C), 29.4 (4C), 29.3 (4C), 29.12 (4C), 29.09 (4C), 28.68 (4C), 28.65 (4C), 24.8 (4C), 22.7 (4C),
3
1
3
9.5 (2C), 15.72 (4C), 15.66 (4C), 14.1 (4C), 10.9 (4C); P NMR (CDCl , 161 MHz) δ −0.83, −0.88,
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The Journal of Organic Chemistry
2
NaO18P : [M+Na] , 1762.1973; found: [M+Na] ,
+
+
−0.96, −1.04; HRMS (ESI-QTOF) calcd C99
H
172
N
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
762.1979.
Synthesis of PMB/cyanoethyl-protected cardiolipin (17b). By a procedure identical with that
described for synthesis of 17a from 2a, the diacylglycerol-phophoramidite 2b (12.7 mg) was converted
into 17b (3.6 mg, 29% based on PMB-protected glycerol (1.5 mg, 21 µmol), ~1:1 diastereomeric
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
5
1
mixture) as a colorless oil. [a]
D 3 3
= +4.15 (c 0.14, CHCl ); H NMR (CDCl , 400 MHz) d 7.29 (d, J =
8
1
.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 5.26-5.21 (m, 2H), 4.60 (s, 2H), 4.33-4.10 (m, 16H), 3.86-3.81 (m,
H), 3.80 (s, 3H), 2.74-2.66 (m, 4H), 2.35-2.29 (m, 8H), 1.62-1.57 (m, 8H), 1.39-1.10 (m, 96H), 0.88 (t,
1
3
3
J = 6.8 Hz, 12H), 0.66-0.61 (m, 8H), 0.58-0.53 (m, 4H), −0.32-−0.36 (m, 4H); C NMR (CDCl , 100
MHz) d 173.2 (2C), 172.8 (2C), 159.6, 129.7, 129.0, 128.2, 116.4 (2C), 113.9 (2C), 72.0, 69.3, 69.2,
66.0 (2C), 65.9 (2C), 62.2 (2C), 61.6 (2C), 55.3, 53.4, 34.1 (2C), 34.0 (2C), 31.9 (4C), 30.21 (4C),
3
2
0.16 (4C), 29.69 (2C), 29.68 (2C), 29.5 (4C), 29.38 (4C), 29.36 (4C), 29.2 (4C), 29.1 (4C), 28.71 (4C),
3
1
8.67 (4C), 24.8 (4C), 22.7 (4C), 19.6, 19.5, 15.74 (4C), 15.69 (4C), 14.1 (4C), 10.9 (4C); P NMR
(CDCl
3
, 161 MHz) δ −0.80, −0.86, −0.96, −1.02; HRMS (ESI-QTOF) calcd C99H N NaO18P :
172 2 2
+
+
[M+Na] , 1762.1973; found: [M+Na] , 1762.1977.
Synthesis of cyanoethyl-protected cardiolipin (18a). To a solution of PMB/cyanoethyl-protected
cardiolipin 17a (23.5 mg, 13.5 µmol) in MeCN/H O (v/v = 10/1, 1.35 mL) was added Ce(NH (NO
74.0 mg, 135 µmol) at 0 °C and the reaction mixture was stirred at room temperature for 3 h. The
mixture was diluted with water and extracted with CH Cl three times. The extract was washed with
saturated NaHCO aq. and saturated NaHSO aq., dried over anhydrous Na SO and concentrated under
reduced pressure to give a crude oil, which was purified by silica gel column chromatography
2
4
)
2
3 6
)
(
2
2
3
3
2
4
2
5
(CHCl
3
D
/MeOH = 100:1) to give the title compound 18a (9.0 mg, 41%) as a colorless oil. [a] = +1.50
1
(c 0.51, CHCl
3
); H NMR (CDCl
3
, 400 MHz) d 5.29-5.25 (m, 2H), 4.36-4.10 (m, 17H), 2.79 (t, J = 5.8
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Hz, 4H), 2.37-2.31 (m, 8H), 1.65-1.58 (m, 8H), 1.40-1.10 (m, 96H), 0.88 (t, J = 6.7 Hz, 12H), 0.67-0.62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
(
m, 8H), 0.59-0.53 (m, 4H), −0.31-−0.36 (m, 4H); C NMR (CDCl
2C), 116.5 (2C), 69.2 (2C), 68.48 (2C), 68.45 (2C), 66.1 (2C), 62.4 (2C), 61.5, 34.1 (2C), 34.0 (2C),
1.9 (4C), 30.2 (4C), 30.1 (4C), 29.7 (4C), 29.5 (4C), 29.3 (8C), 29.12 (4C), 29.08 (4C), 28.68 (4C),
3
, 100 MHz) d 173.3 (2C), 173.0
(
3
3
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
28.65 (4C), 24.8 (4C), 22.7 (4C), 19.7, 19.6, 15.72 (4C), 15.67 (4C), 14.1 (4C), 10.9 (4C); P NMR
+
(CDCl
3
, 161 MHz) δ −0.26, −0.51; HRMS (ESI-QTOF) calcd C91
H
164
N
2
NaO17
P
2
: [M+Na] ,
+
1
642.1397; found: [M+Na] , 1642.1403.
Synthesis of cyanoethyl-protected cardiolipin (18b). By a procedure identical with that described for
synthesis of 18a from 17a, the cardiolipin derivative 17b (7.2 mg) was converted into 18b (2.9 mg,
25
1
4
2
1
4
6
2
D 3 3
3%) as a colorless oil. [a] = +2.83 (c 0.15, CHCl ); H NMR (CDCl , 400 MHz) d 5.29-5.25 (m,
H), 4.36-4.10 (m, 17H), 2.79 (t, J = 5.8 Hz, 4H), 2.37-2.31 (m, 8H), 2.01 (br s, 1H), 1.65-1.58 (m, 8H),
.40-1.10 (m, 96H), 0.88 (t, J = 6.7 Hz, 12H), 0.67-0.62 (m, 8H), 0.59-0.53 (m, 4H), −0.31-−0.36 (m,
1
3
3
H); C NMR (CDCl , 100 MHz) d 173.3 (2C), 172.9 (2C), 116.5 (2C), 69.2 (2C), 68.5 (2C), 68.1 (2C),
6.1 (2C), 62.5 (2C), 61.5, 34.1 (2C), 34.0 (2C), 31.9 (4C), 30.21 (4C), 30.16 (4C), 29.7 (4C), 29.5 (4C),
9.4 (8C), 29.14 (4C), 29.11 (4C), 28.71 (4C), 28.66 (4C), 24.8 (4C), 22.7 (4C), 19.7, 19.6, 15.74 (4C),
3
1
15.69 (4C), 14.1 (4C), 10.9 (4C); P NMR (CDCl
3
, 161 MHz) δ −0.27, −0.51; HRMS (ESI-QTOF)
+
+
calcd C91
H
164
N
2
NaO17
P
2
: [M+Na] , 1642.1397; found: [M+Na] , 1642.1395.
Synthesis of cardiolipin containing chiral cyclopropane moiety (1a). To a solution of cyanoethyl-
protected cardiolipin 18a (5.4 mg, 3.3 µmol) in CH Cl /MeOH (v/v = 1/1, 830 µL) was added 28%
NH (aq.) (830 µL). After stirring at room temperature for 1 h, the reaction mixture was lyophilized with
dioxane to give the crude compound 1a (5.6 mg) as a colorless oil, the part of which (0.8 mg) was
2
2
3
purified by silica gel column chromatography (CHCl
3
/MeOH/28% NH
3
(aq.) = 7:2:0.3) to obtain the title
, 400 MHz) d 5.28-5.23
2
5
1
compound 1a (0.2 mg, 28%). [a]
D
= +2.72 (c 0.22, CHCl
3
); H NMR (CDCl
3
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(
m, 2H), 4.45-3.35 (m, 21H), 2.39-2.25 (m, 8H), 1.70-1.60 (m, 8H), 1.43-1.09 (m, 96H), 0.88 (t, J = 5.7
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7
8
9
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1
3
Hz, 12H), 0.66-0.62 (m, 8H), 0.59-0.53 (m, 4H), −0.31-−0.36 (m, 4H); C NMR (CDCl
d 173.8 (2C), 173.4 (2C), 72.1 (2C), 68.4 (2C), 65.0 (2C), 62.0 (2C), 61.5, 34.3 (2C), 34.1 (2C), 31.9
4C), 30.2 (4C), 30.1 (4C), 29.7 (4C), 29.5 (2C), 29.43 (2C), 29.36 (2C), 29.32 (4C), 29.29 (2C), 29.12
(4C), 29.09 (4C), 28.71 (4C), 28.65 (4C), 24.9 (4C), 22.7 (4C), 15.74 (4C), 15.69 (4C), 14.1 (4C), 10.9
3
, 100 MHz)
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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7
8
9
0
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7
8
9
0
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7
8
9
0
31
2-
3 156 17 2 4
(4C); P NMR (CDCl , 161 MHz) δ1.82; HRMS (ESI-QTOF) calcd C85H O P : [M−2NH ] ,
2
-
7
4
55.5414; found: [M−2NH ] , 755.5417.
Synthesis of cardiolipin containing chiral cyclopropane moiety (1b). By a procedure identical with
that described for synthesis of 1a from 18a, the cardiolipin derivative 18b (2.7 mg) was converted into
1b (2.5 mg) as a colorless oil, the part of which (1.1 mg) was purified by silica gel column
chromatography (CHCl
3
/MeOH/28% NH
3
(aq.) = 7:2:0.3) to give the title compound 1b (0.3 mg, ca.
1
2
2
0
7%). H NMR (CDCl
3
, 400 MHz) d 5.28-5.17 (m, 2H), 4.40-3.59 (m, 21H), 2.35 (t, J = 7.6 Hz, 8H),
.01 (br s, 1H), 1.65-1.59 (m, 8H), 1.40-1.10 (m, 96H), 0.88 (t, J = 6.6 Hz, 12H), 0.67-0.62 (m, 8H),
1
3
3
.59-0.53 (m, 4H), −0.31-−0.36 (m, 4H); C NMR (CDCl , 100 MHz) d 174.0 (2C), 173.9 (2C), 72.1
(2C), 68.4 (2C), 65.0 (2C), 62.0 (2C), 61.5, 34.3 (2C), 34.1 (2C), 31.9 (4C), 30.2 (4C), 30.1 (4C), 29.7
(4C), 29.5 (2C), 29.43 (2C), 29.35 (2C), 29.33 (4C), 29.29 (2C), 29.12 (4C), 29.09 (4C), 28.71 (4C),
3
1
2
8.65 (4C), 24.9 (4C), 22.7 (4C), 15.8 (4C), 15.7 (4C), 14.1 (4C), 10.9 (4C); P NMR (CDCl
3
, 161
2
-
2-
MHz) δ 2.75; HRMS (ESI-QTOF) calcd C85
H
156
O
17
P
2
: [M−2NH
4
] , 755.5414; found: [M−2NH
4
] ,
7
55.5419.
Supporting Information
This material is available free of charge via the Internet at http://pubs.acs.org.
1
13
H and C NMR spectral data
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Acknowledgments
This research was financially supported by grants from the JSPS KAKENHI (Nos. JP26282211,
JP26102732, JP26882036, and JP16K16638), NEXT Program (LR025) from JSPS and CSTP, the
Mizutani Foundation for Glycoscience, and the Nagase Science Technology Foundation and Protein
Research Foundation. We thank Prof. K. Suenaga for assistance in measuring the chiroptical data.
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