Modular approach to the synthesis of unsaturated 1-monoacyl glycerols

Article abstract of DOI:10.1055/s-2004-825616

A modular synthesis of unsaturated 1-monoacylglycerols (1) from cis-1-iodo-1-alkenes [cis-RCH=CHI] and unsaturated carboxylic acids [CH ₂=CH(CH₂)_nCO₂H] is described. The method revolves around a Suzuki coupling to establish olefin geometry.

Full text of DOI:10.1055/s-2004-825616

LETTER
1339
Modular Approach to the Synthesis of Unsaturated 1-Monoacyl Glycerols
M
odular
A
pproac
r
h to the
i
Synthe
d
sis of
U
nsatu
g
rated 1-Mon
e
oacyl
G
lyc
t
erols t E. Coleman, Valerie Cwynar, David J. Hart,* Fabien Havas, Jakkam Madan Mohan, Suzanne Patterson,
Sam Ridenour, Michael Schmidt, Eboney Smith, Angela J. Wells
Department of Chemistry, The Ohio State University, 100 W. 18th Avenue, Columbus, Ohio 43210, USA
Fax +1(614)2921685; E-mail: hart@chemistry.ohio-state.edu
Received 10 February 2004
This paper is dedicated to Professor Clayton Heathcock who has served as a role model and friend to chemists worldwide
Abstract: A modular synthesis of unsaturated 1-monoacylglycer-
ols (1) from cis-1-iodo-1-alkenes [cis-RCH=CHI] and unsaturated
carboxylic acids [CH2=CH(CH2)nCO2H] is described. The method
revolves around a Suzuki coupling to establish olefin geometry.
Key Words: Suzuki coupling, 1-monoacylglycerol, protein crys-
tallization, diimide reduction, vinyl iodide
Figure 1
We needed to prepare a series of cis unsaturated 1-mono-
cis-Iodoalkenes were prepared using established proce-
dures (Scheme 1). Terminal alkynes 2 were deprotonated
with n-butyllithium and the resulting acetylides were
quenched with iodine to provide iodoalkynes 3.6 The io-
doalkynes were reduced with diimide to provide iodoalk-
enes of type 4 with excellent control of olefin geometry.6
A problem that always accompanied this step was reduc-
tion of 4 to the corresponding iodoalkane. Thus, these re-
actions were usually run to partial completion. The
mixture of products and starting material was treated with
aqueous trimethylamine to convert the alkane to a quarter-
nary ammonium salt that was easily separated from the
mixture of iodoalkene and starting iodoalkyne.6 The start-
ing material and iodoalkene 4 were then separated by col-
umn chromatography over silica gel. Esterification of the
appropriate unsaturated acids 5 with solketal provided the
alkenes 6 needed for the Suzuki coupling (Scheme 2).
acylglycerols (1-MAG) of type 1 in connection with a
project directed toward developing and understanding the
in meso method for crystallization of membrane-associat-
ed proteins.1 Standard procedures for the synthesis of 1-
MAGs were used to prepare several compounds of type 1
(Figure 1) from commercially available fatty acids with
the appropriate neck (N) and tail (T) length.2,3 Not all of
the fatty acids required for our studies, however, were
commercially available. Thus, we developed a modular
approach to the synthesis of compounds of type 1 that
should be amenable to the synthesis of a wide variety of
1-MAGs. The details of this approach are described
herein.
The aforementioned crystallization studies dictated that
we prepare 1-MAGs with at least 99% homogeneity of cis
olefin geometry. It was our experience that catalytic hy-
drogenation of alkynes was unsatisfactory in this regard
and thus, we turned to other methods that would be less
capricious in regard to olefin geometry.4 We eventually
settled on an approach that revolves around the coupling
of alkenes with iodoalkenes, methodology pioneered
by the Suzuki group.5 The preparation of the coupling
partners for this approach is shown in Scheme 1 and
Scheme 2.
Scheme 1
Scheme 2
SYNLETT 2004, No. 8, pp 1339–1342
0
1.
0
7.
2
0
0
4
Advanced online publication: 18.05.2004
DOI: 10.1055/s-2004-825616; Art ID: Y00604ST
© Georg Thieme Verlag Stuttgart · New York

1340
B. E. Coleman et al.
LETTER
Scheme 3 Synthesis of 1-monoacylglycerols via Suzuki coupling
Coupling of iodoalkene 4 with alkene 6 is shown in equiv) in DMF provided the 1-MAG acetonides 7 in good
Scheme 3. Thus, hydroboration of 6 (1 equiv) with 9- yields after purification by column chromatography over
BBN (1 equiv) followed by treatment of the resulting silica gel.5,7–9 Hydrolysis of 7 using hydrochloric acid in
alkylborane with iodoalkene 4 (1 equiv) in the presence of aqueous methanol provided the desired 1-MAG (8), al-
PdCl2(dppf) (5 mol%), Ph3As (5 mol%) and Cs2CO3 (1 ways accompanied by 7–9% of the corresponding 2-MAG
Table 1 Yields of Intermediates in Synthesis of Monoacylglycerols
Entry
1
[N.T]
[7.9]
3a
4d
6e
7f
8g
Mp (°C)h
–
89b
99b
99b
97b
91c
99b
81c
66b
93c
94b
94b
99b
99b
91b
97b
55 (24)
55 (24)
55 (24)
30 (57)
50 (36)
68 (58)
49 (79)
35 (39)
44 (50)
30 (36)
49 (35)
55 (24)
55 (24)
50 (36)
30 (57)
80
62
72
67
62
80
84
70
88
85
80
88
54
72
62
83
78
72
61
53
78
69
56
71
65
82
40
72
87
68
66 (56)
68
2
[8.9]
–
3
[9.9]
48
31–32
46–47
40–41
42–43
41–42
53–54
38–39
56–57
–
4
[10.8]
[8.10]
[7.11]
[6.12]
[12.6]
[5.13]
[13.5]
[7.7]
60 (55)
69 (47)
85 (65)
90 (72)
80 (64)
81 (55)
74 (48)
68 (52)
60
5
6
7
8
9
10
11
12
13
14
15
[5.9]
–
[11.9]
[9.10]
[8.8]
(76)
44–45
90–41
38–39
63 (53)
58 (46)
a Crude yield of material used in next reaction.
b Starting alkynes commercially available.
c Starting alkyne prepared from the commercially available alkyl iodide and lithium acetylide (ethylenediamine complex) in DMSO in 84–88%
yield.
d Yield based on converted starting material. Percent recovered starting material in parentheses.
e Carboxylic acid starting materials (5) were purchased (entries 1, 2, 5–9, 11, 12 and 15) or prepared from 1,7-octadiene (entries 3, 4 and 14),
undec-10-en-1-ol (entry 10) or 9-decen-1-ol (entry 13).
f Materials contain trace impurities derived from 9-BBN.
g Material contains 7–9% 2-MAG. The yield of recrystallized material containing none or only a trace of 2-MAG appears in parentheses.
h Melting point of recrystallized 1-MAG (8) containing none or only a trace of the corresponding 2-MAG (9). 1-MAGs for which no mp is
reported were liquids at r.t. and, with the exception of [5.9], were purified by recrystallization at low temperature.
Synlett 2004, No. 8, 1339–1342 © Thieme Stuttgart · New York

LETTER
Modular Approach to the Synthesis of Unsaturated 1-Monoacyl Glycerols
1341
(8) For the conditions and additives used in this study see: Trost,
B. M.; Lee, C. B. J. Am. Chem. Soc. 1998, 120, 6818.
(9) Representative procedures for the preparation of [12.6] from
4 and 6 follow (entry 8 in Table 1).
(9). Samples of 1-MAG that contained less than 3% 2-
MAG could be obtained by low temperature recrystalliza-
tion of the 1-MAG/2-MAG mixture from an appropriate
solvent.
Preparation of [12.6] Acetonide.
To a solution of 7.94 g (26.7 mmol) of the appropriate ester
4 in 150 mL of THF in a 250 mL round-bottomed flask
cooled in an ice-salt bath was added 53.0 mL (26.5 mmol) of
0.5 M 9-BBN in THF over a 12 min period. The cold bath
was removed and the solution was stirred for 2 h. To the
mixture was added 10 mL of H2O and the solution was
stirred for 15 min. Concurrent with the hydroboration of 4,
1.95 g (2.7 mmol) of Pd(dppf)Cl2, 8.16 g (26.7 mmol) of
triphenylarsine, and 10.55 g (26.7 mmol) of Cs2CO3 were
sequentially added at 2 min intervals to a solution of 6.0 g
(26.7 mmol) of the appropriate vinyl iodide 6 in 100 mL of
DMF in a separate flask. The mixture was stirred at r.t. for 2
h followed by addition of the hydroboration mixture via
cannula. The resulting dark brown mixture was stirred at r.t.
for 4 h followed by addition of 300 mL of brine. The
resulting mixture was extracted with three 150 mL portions
of Et2O. The combined organic extracts were dried over
Na2SO4 and filtered. The filtrate was concentrated in vacuo
and the residue was purified by chromatography over 320 g
of silica gel (column diameter = 13 cm) using 1–10% EtOAc
in hexane as the eluant. Appropriate fractions were pooled
and concentrated and the chromatographic procedure was
repeated two times to provide 5.6 g (53%) of the desired
[12.6] acetonide as a pale yellow oil. IR (neat): 1742 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.85 (t, J = 7 Hz, 3 H),
1.20–1.40 (m with two s at d = 1.35 and 1.40 ppm, 26 H),
1.60 (quintet, 2 H), 2.00 (m, 4 H), 2.30 (t, J = 7 Hz, 2 H),
3.65 (m, 1 H), 4.00–4.15 (m, 3 H), 4.25 (m, 1 H), 5.30 (m, 2
H). 13C NMR (100 MHz, CDCl3): d = 14.00, 22.50, 24.80,
25.20, 26.60, 27.07, 27.09, 29.00, 29.15, 29.18, 29.35,
29.42, 29.46, 29.66, 31.40, 34.00, 64.40, 66.30, 73.60,
109.70, 129.74, 129.79, 173.40. MS (electrospray): m/z
calcd for C24H44O4Na: 419.3132; found: 419.3109.
The results for the synthesis of a series of 15 monoacyl-
glycerols are documented in Table 1. Whereas most of
these results are self explanatory, some comments are
warranted. The olefin geometry was rigorously proven for
entry 1. Suzuki coupling of 6 with trans-1-bromo-1-
decene gave the trans-acetonide corresponding to 7. The
isomeric acetonides were easily distinguished by 13C
NMR spectroscopy and it was established that the level of
contamination of the trans isomer in the cis isomer was no
more than 1%.10 Olefin geometry was also proven for en-
try 3. Monoolein [9.9] prepared as described in Table 1
was identical to commercially available material and
could be distinguished from a sample of the correspond-
ing trans isomer prepared from elaidic acid using standard
procedures.11 The hydrolysis of acetal 7 usually gave
small amounts of the methyl ester derived from methanol-
ysis of 8 along with trace amounts of the corresponding
carboxylic acid (from ester hydrolysis).10 The methyl es-
ter and fatty acid contaminants were removed from the
aforementioned mixture of 8 and 9 by chromatography.
Detection of the 2-MAG was easily accomplished by both
1H NMR and 13C NMR spectroscopy.12 Finally, we note
that this method was used to prepare gram quantities of
most of the 1-MAGs appearing in Table 1. Several of
these compounds have proven useful for crystallization in
meso of bacteriorhodopsin. Results of crystallization
studies will be reported elsewhere.
Acknowledgment
Preparation of [12.6].
To a solution of 5.6 g (14.2 mmol) of the acetonide in 250
mL of MeOH cooled to 0 °C in an ice-salt bath was added
dropwise 12 mL of 1.0 M aq HCl over a 7 min period. The
ice bath was removed and the reaction was allowed to warm
to r.t. The reaction was stirred for 7 h while the reaction
progress was monitored by TLC [silica gel; EtOAc–hexane
(15:85)]. To the reaction mixture was added 100 mL of sat.
aq NaHCO3 and the mixture was extracted with four 150 mL
portions of CH2Cl2. The combined extracts were dried over
MgSO4 and concentrated in vacuo. The crude product (5.2 g)
was chromatographed over 200 g of silica gel using 5%
EtOAc in hexane as the initial eluant and gradually
increasing the EtOAc concentration to 75%. The resulting
mixture of 1-MAG and 2-MAG (4.2 g; 95:5, respectively by
1H NMR) was dissolved in 100 mL of Et2O–petroleum ether
(bp 35–60 °C) was cooled to –20 °C. The resulting crystals
were harvested and rinsed with 20 mL of cold Et2O–
petroleum ether to provide 3.4 g (64%; 2 crops) of [12.6] 1-
MAG that contained maybe a trace of the 2-MAG by 1H
NMR; mp 53–54 °C. IR (neat): 3250 cm–1. 1H NMR (400
MHz, C6D6): d = 0.90 (t, J = 7 Hz, 3 H, 1.20–1.50 (m, 20 H),
1.60 (quintet, 2 H), 2.10 (m, 4 H), 2.20 (t, J = 7 Hz, 2 H),
3.35 (br s, 1 H, OH), 3.55 (m, 1 H), 3.60 (m, 1 H), 3.70 (br
We thank the National Institutes of Health for support of this re-
search and the ACS Project SEED for partial support for BEC. We
thank our collaborator Professor Martin Caffrey (OSU) for bringing
this problem in lipid chemistry to our attention.
References
(1) Caffrey, M. Structural Biology 2000, 10, 486.
(2) Jensen, R. G.; Pitas, R. E. Adv. Lipid. Res. 1977, 14, 213.
(3) In this paper we will refer to 1-MAGs in [N.T] space where
N = neck length and T = tail length. For example the 1-
MAG in which the fatty acid component is oleic acid will be
called [9.9].
(4) For example, in our hands, alkyne hydrogenation strategies
provided cis fatty acids with 2–10% contamination from the
corresponding trans fatty acids. In one case we examined
differences in oxidation state of the carboxyl terminus at the
stage of hydrogenation and catalyst type but were unable to
routinely obtain the olefin homogeneities of greater than
99% desired for protein crystallization studies. See:
Valicenti, A. M.; Pusch, F. M.; Holman, R. T. Lipids 1985,
20, 234.
s, 1 H, OH), 3.85 (m, 1 H), 4.15 (m, 2 H), 5.45 (m, 2 H). 13
NMR (100 MHz, C6D6): d = 14.30, 22.90, 25.20, 27.60,
21.70, 29.51, 29.72, 29.75, 29.86, 29.93, 30.00, 30.04,
30.24, 31.80, 34.30, 63.70, 65.40, 70.70, 130.50, 130.60,
174.30. MS(electrospray): m/z calcd for C21H40O4Na:
379.2819; found: 379.2845.
C
(5) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh,
M.; Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314.
(6) Dieck, H. A.; Heck, R. F. J. Org. Chem. 1975, 40, 1083.
(7) For a review of the Suzuki coupling using alkylboranes see:
Trauner, D.; Chemler, S. R.; Danishefsky, S. J. Angew.
Chem. Int. Ed. 2001, 40, 4544.
Synlett 2004, No. 8, 1339–1342 © Thieme Stuttgart · New York

1342
B. E. Coleman et al.
LETTER
(10) Whereas the 1H NMR spectra of acetonide 7 [cis-7.9] and the
corresponding trans isomer were indistinguishable, 1% of
(11) The olefinic carbons for monoolein [cis-9.9] appeared at d =
130.1 and 130.4 ppm in C6D6 whereas the olefinic carbons
for monoelaidin [trans-9.9] appeared at d = 130.6 and 130.9
ppm in C6D6. Other subtle differences between these 1-
MAG isomers were detected in the upfield region of their
13C NMR spectra.
the trans isomer could be detected in the cis isomer by 13
C
NMR spectroscopy. For example the olefinic carbons in the
cis isomer appeared at d = 130.0 and 130.5 ppm whereas the
olefinic carbons in the trans isomer appeared at d = 131.0
and 131.5 ppm.
(12) The 2-MAGs gave 1H NMR signature signals at
approximately d = 4.8 ppm (1 H quintet for secondary OCH)
and d = 3.5 ppm (4 H signal for CH2OH). The 2-MAGs gave
13C NMR signature signals at approximately d = 62 ppm
(OCH2) and d = 75 ppm (OCH).
Synlett 2004, No. 8, 1339–1342 © Thieme Stuttgart · New York