Facile synthesis of plasmalogens via barbier-type reactions of vinyl dioxanes and vinyl dioxolanes with alkyl halides in LiDBB solution

Article abstract of DOI:10.1021/jo025640u

Plasmalogens (i.e. plasmenylcholines or plasmenylethanolamines) are a biologically important class of glycerophospholipids that have been difficult to synthesize due to the presence of an acid and oxidatively labile (Z)-vinyl ether substituent at the sn-1 position and a base-labile sn-2 acyl substituent that easily migrates during silica gel purification. We report two facile synthetic methods for the preparation of racemic plasmenylcholines via a tandem reductive vinyl dioxane/dioxolane ring opening and alkyliodide coupling process that proceeds in a single pot reaction. The key step in the formation of (Z)-vinyl ether precursors for the production of plasmenylcholines is accomplished using LiDBB under Barbier-type conditions to give the corresponding TBDMS-protected 1-O-Z′-vinylglycerol intermediate in moderate yields. This pathway is the most direct synthetic route for the formation of plasmenylcholines to date, requiring a total of six transformations from acrolein and glycerol or solketal as inexpensive starting materials, to generate glycerophosphocholine-type plasmalogens in 4% overall yield.

Full text of DOI:10.1021/jo025640u

F a cile Syn th esis of P la sm a logen s via Ba r bier -Typ e Rea ction s of
Vin yl Dioxa n es a n d Vin yl Dioxola n es w ith Alk yl Ha lid es in LiDBB
Solu tion
J unhwa Shin, Oleg Gerasimov, and David H. Thompson*
Department of Chemistry, Purdue University, West Lafayette, Indiana 47907-1393
davethom@purdue.edu
Received February 21, 2002
Plasmalogens (i.e. plasmenylcholines or plasmenylethanolamines) are a biologically important class
of glycerophospholipids that have been difficult to synthesize due to the presence of an acid and
oxidatively labile (Z)-vinyl ether substituent at the sn-1 position and a base-labile sn-2 acyl
substituent that easily migrates during silica gel purification. We report two facile synthetic methods
for the preparation of racemic plasmenylcholines via a tandem reductive vinyl dioxane/dioxolane
ring opening and alkyliodide coupling process that proceeds in a single pot reaction. The key step
in the formation of (Z)-vinyl ether precursors for the production of plasmenylcholines is accomplished
using LiDBB under Barbier-type conditions to give the corresponding TBDMS-protected 1-O-Z′-
vinylglycerol intermediate in moderate yields. This pathway is the most direct synthetic route for
the formation of plasmenylcholines to date, requiring a total of six transformations from acrolein
and glycerol or solketal as inexpensive starting materials, to generate glycerophosphocholine-type
plasmalogens in 4% overall yield.
In tr od u ction
choline extracts derived from a number of animal sources;
however, they are difficult to obtain as discrete molecular
species. Commercially available plasmalogens contain
mixtures of alkyl chain lengths at the sn-1 and sn-2
positions, greatly limiting their utility in biological and
biophysical studies due to the lack of pure compounds.
Rui and Thompson developed the first synthetic pathway
to pure plasmenylcholines with (Z)-stereospecificity via
transformation of acylglycerols to the corresponding vinyl
1
Plasmalogens (i.e. plasmenylcholines or plasmenyl-
ethanolamines) are phospholipids containing sn-1-Z-1′-
O-vinyl chains of varying lengths and degrees of unsat-
uration. They are predominantly found in the electrically
active tissues of mammals such as brain, myelin, and
heart,2 and are believed to be involved in important
2
-4
biological functions such as cell signaling,
membrane
fusion,5 and lipid peroxidation. Plasmenylcholines have
also been successfully utilized for the delivery of low
molecular weight drugs, proteins, and genes by using
,6
7
1
6
phosphates, followed by reductive cleavage. Bittman
and co-workers have also reported a multistep synthesis
of plasmenylcholine using Lindlar catalyst reduction of
triggering mechanisms that are activated by acidic or
1
7
alkynyl ethers as the key step in vinyl ether formation.
oxidative environments.5
,8-15
Naturally occurring plas-
Due to the difficulties surrounding the previous synthetic
pathways and the biological importance of these com-
pounds, we sought to develop a more expedient synthetic
method.
malogen mixtures are generally isolated from phospho-
*
Address correspondence to this author.
(
1) Lee, T.-c. Biochim. Biophys. Acta 1998, 1394, 129-145.
(
2) Sugiura, T.; Waku, K. In Platelet Activating Factor and Related
The synthetic challenges of plasmalogens include (1)
stereoselective formation of the naturally occurring (Z)-
vinyl ether bond at the sn-1 position to avoid tedious
purification of geometric isomers, (2) instability of this
linkage toward acidic or oxidative conditions, which
Lipid Mediators; Snyder, F., Ed.; Plenum Press: New York, 1987; pp
5
5-85.
(
3) Fonteh, A. N.; Chilton, F. H. J . Immunol. 1992, 148, 1784-1791.
(4) Snyder, F.; Lee, T.-c.; Blank, M. L. In Advances in Lipobiology;
Gross, R. W., Ed.; J AI Press: Stamford, CT, 1997; Vol. 2, pp 261-
86.
5) Thompson, D. H.; Gerasimov, O. V.; Wheeler, J . J .; Rui, Y.;
2
1
8
(
limits the choice of reagents and isolation conditions,
Anderson, V. C. Biochim. Biophys. Acta 1996, 1279, 25-34.
(6) Glaser, P. E.; Gross, R. W. Biochemistry 1994, 33, 5805-5812.
(7) Murphy, R. C. Chem. Res. Toxicol. 2001, 14, 463-472.
(8) Thompson, D. H.; Rui, Y.; Gerasimov, O. V. In Vesicles; Surfac-
(12) Gerasimov, O. V.; Boomer, J . A.; Qualls, M. M.; Thompson, D.
H. Adv. Drug. Del. Rev. 1999, 38, 317-338.
(13) Qualls, M. M.; Thompson, D. H. Int. J . Cancer 2001, 93, 384-
392.
tant Science Series, Vol. 62; Rosoff, M., Ed.; Marcel Dekker: New York,
996; pp 679-746; see also: Kim, J .-M.; Thompson, D. H. In Reactions
Synthesis in Surfactant Systems; Surfactant Science Series, Vol. 100;
Texter, J ., Ed.; Marcel Dekker: New York, 2001; pp 145-154.
9) Gerasimov, O. V.; Schwan, A.; Thompson, D. H. Biochim.
Biophys. Acta 1997, 1324, 200-214.
10) Rui, Y.; Wang, S.; Low, P. S.; Thompson, D. H. J . Am. Chem.
Soc. 1998, 120, 11213-11218.
11) Wymer, N. J .; Gerasimov, O. V.; Thompson, D. H. Bioconj.
Chem. 1998, 9, 305-308.
1
&
(14) Collier, J . H.; Hu, B. H.; Ruberti, J . W.; Zhang, J .; Shum, P.;
Thompson, D. H.; Messersmith, P. B. J . Am. Chem. Soc. 2001, 123,
9463-9464.
(
(15) Boomer, J . A.; Thompson, D. H.; Sullivan, S. Pharm. Res. 2001,
19, 1289-1298.
(
(16) Rui, Y.; Thompson, D. H. Chem. Eur. J . 1996, 2, 1505-1508.
(17) Qin, D. H.; Byun, H. S.; Bittman, R. J . Am. Chem. Soc. 1999,
121, 662-668.
(
1
0.1021/jo025640u CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/13/2002
J . Org. Chem. 2002, 67, 6503-6508
6503

Shin et al.
fore, is critically dependent on the attention given to the
details of reaction and column separation conditions.
Bittman and co-workers17 also employed a multistep
strategy, using PMB and TBDPS protection to prepare
a TBDPS derivative of 3a in their plasmenylcholine
synthesis. We now report the use of Barbier-type reac-
tions to generate 3a and 3c as key intermediates in the
total synthesis of plasmenylcholine-type plasmalogens.
The route employing 3c, a precursor of lysoplasmenyl-
choline, benefits from greater efficiency since it avoids
the acyl migration problem by introducing the acyl
substituent in the last step. Formation of plasmenylcho-
lines with stereocontrol at the sn-2 site, however, requires
the use of a different pathway involving chiral intermedi-
ate 3a . Effective plasmenylcholine syntheses, using either
F IGURE 1. Putative mechanism of the LiDBB-mediated
Barbier reaction with vinyl acetal and iodoalkanes. The
internally chelated, η -alkoxyallyllithium form of the allyloxy
1
carbanion is shown by analogy to ref 27.
SCHEME 1
3
a or 3c as intermediates, are described below.
Resu lts a n d Discu ssion
Str u ctu r a l Effects on th e LiDBB-Med ia ted Syn -
th esis of (Z)-Vin yl Eth er s u n d er Ba r bier -Typ e Con -
d ition s. Previous studies2
0,23
revealed that Barbier-type
reactions of vinyl acetals in LiDBB could potentially be
applied to the synthesis of plasmenylcholines via reduc-
tive acetal ring opening followed by reaction of the
resulting allyllithium species with 1-iodoalkanes (Figure
1
). The ring cleavage reaction proceeds most favorably
when catalytic amounts of DBB are used in the presence
of excess lithium.24 This modification is preferred since
it is fast (<1 h) and self-monitoring (reappearance of the
blue LiDBB radical anion species indicates the comple-
tion of the reaction). Further experimentation revealed
that Barbier conditions were critical for achieving the
highest reaction efficiencies, since the unstable allylic
anion generated by vinyl acetal reduction undergoes
rapid decomposition instead of alkylation if the iodo-
alkane is added after lithiation.25 Only the γ-coupled
vinyl ether product was obtained in high Z:E ratios (>20:
and (3) an sn-2 acyl group that is prone to rapid migration
to the primary sn-1/sn-3 sites under basic or mildly acidic
conditions (including silica gel chromatography with
aprotic solvents). The cytotoxic properties of plasmenyl-
choline-type analogues of ET-18-OMe have been re-
ported.1
9-21
These antitumor ether lipid derivatives have
2
2
been synthesized via Barbier-type reactions of vinyl
acetals and 1-iodoalkanes in lithium 4,4-di-tert-butylbi-
phenyl (LiDBB) solution (Figure 1).20 This route produces
1) under these conditions.20
involvement of a Michael-type process, since stepwise
addition of preformed C13 27Li to 2-vinyl-1,3-dioxolane
We excluded the possible
(Z)-vinyl ether lipid derivatives in moderate yields and
H
excellent stereoselectivity (Z:E > 95:5). On the basis of
this methodology, two important precursors for a new
plasmenylcholine synthesis, monosilyl-protected sn-1 (Z)-
vinyl ether glycerols (3-tert-butyldimethylsilyl-1-O-1′-(Z)-
hexadecenyl glycerol, 3a and 2-tert-butyldimethylsilyl-
gave low yields of vinyl ether product and poor stereo-
selectivity (Z:E 40:60).20 The high (Z)-stereoselectivity
observed is attributed, instead, to the formation of cyclic
lithioalkoxyallyl intermediates (e.g. I-Z in Scheme 2)
after reductive ring opening.2
3,26,27
The simplicity and
1
-O-1′-(Z)-hexadecenyl glycerol, 3c), can be prepared in
stereoselectivity of this transformation motivated us to
pursue LiDBB-mediated vinyl acetal reductions for the
synthesis of plasmenylcholine derivatives.
Several interesting trends were observed in Barbier
couplings of vinyl dioxanes and alkyl halides (Table 1).
The reactions of 5-O-TBDMS-protected vinyl dioxane and
a one-step Barbier-type reaction of TBDMS-protected
vinyl acetals and 1-iodoalkanes (Scheme 1). Rui and
Thompson first synthesized TBDPS-protected 3a using
a multistep protection/deprotection strategy.16 A key step
in that sequence is the successful removal of the sn-3
TBDPS group with TBAF in the presence of imidazole
at low temperature to minimize the sn-2 f sn-3 acyl
migration problem. The success of this pathway, there-
(
23) Gil, J . F.; Ramon, D. J .; Yus, M. Tetrahedron 1994, 50, 3437-
3
446.
(
24) Yus, M. Chem. Soc. Rev. 1996, 25, 155-161.
(
18) Vinyl ethers are also intermediates in the t-BuOK-mediated
allylic deprotection process. See: Guibe, F. Tetrahedron 1997, 53,
3509-13556.
19) Gajate, C.; Fonteriz, R. I.; Cabaner, C.; Alvarez-Noves, G.;
Alvarez-Rodriguez, Y.; Modolell, M.; Mollinedo, F. Int. J . Cancer 2000,
5, 674.
20) Shin, J .; Qualls, M. M.; Boomer, J . A.; Robarge, J .; Thompson,
D. H. J . Am. Chem. Soc. 2001, 123, 508-509.
21) Bittman, R.; Qin, D. H.; Wong, D. A.; Tigyi, G.; Samadder, P.;
Arthur, G. Tetrahedron 2001, 57, 4277-4282.
22) Barbier conditions, in this case, involve the addition of the vinyl
acetal/alkyl halide mixture to the LiDBB solution.
(25) Mudryk and Cohen reported that lithioallyl dianions are stable
at low temperature (-80 °C) when stoichiometric amounts of LiDBB
radical anion are used [Mudryk, B.; Cohen, T. J . Am. Chem. Soc. 1991,
113, 1866-1867]. These investigators also found that terminal allyl
anions tend to prefer the cis allyl configuration [Guo, B.-S.; Double-
day: W.; Cohen, T. J . Am. Chem. Soc. 1987, 109, 4710-4711; see also
refs 26 and 27]. Our results are consistent with these reported
observations.
(26) Evans, D. A.; Andrew, G. C.; Buckwalter, B. J . Am. Chem. Soc.
1974, 96, 5560-5561.
(27) Still, W. C.; Macdonald, T. L. J . Am. Chem. Soc. 1974, 96, 5561-
5563.
1
(
8
(
(
(
6
504 J . Org. Chem., Vol. 67, No. 18, 2002

Plasmalogen Synthesis Using LiDBB
SCHEME 2
F IGURE 2. Synthesis of plasmalogen precursor 3a from
solketal. Reagents: (a) TBDMSCl, imidazole, THF, 23 °C
(96.9%); (b) acrolein, n-BuSnCl
3
, 23 °C (54.5%); (c) Li, DBB,
13
C H
27I, THF, 0 °C, 0.5 h (18.4% 3a and 32.1% 3b).
Syn th esis of 3a Sta r tin g fr om Solk eta l (F igu r e 2).
TABLE 1. Ba r bier -Typ e Rea ction s of
Racemic solketal was protected with TBDMSCl to give
1 in 96.9% yield.28 Transformation of the isopropylidene
acetal to a vinyl acetal in the presence of the TBDMS
protecting group is achieved in a single step by using
2
-Vin yl-1,3-d ioxa n es w ith Alk yl Ha lid es in LiDBB
Solu tion
2
9
3
n-BuSnCl to give the vinyl dioxolane 2a in 54.5% yield.
This transformation was conducted with neat acrolein,
with removal of the acetone byproduct under vacuum
during the reaction, to give vinyl dioxolane 2a as a ca.
1
:1 mixture of cis/trans isomers. This mixture proved
difficult to separate, so it was used without further
purification. Barbier-type coupling conditions were then
initiated under Ar with use of a glass-coated stir bar, Li
powder (7 equiv), and catalytic amounts of DBB (0.1
o
equiv) in THF at 0 C to generate the dark blue LiDBB
radical anion solution. A mixture of 2a (1 equiv) and
R
E-X
Z:E
% yield
1
-iodotridecane (2 equiv, prepared in 96.3% yield by
/PPh /imidazole treatment of 1-tridecanol) in THF was
TBDMS
TBDMS
TBDMS
Me
n-C13H27Cl
n-C13H27Br
n-C13H27I
n-C13H27Cl
n-C13H27I
n-C13H27Cl
n-C13H27I
30:70
67:33
98:2
88:12
95:5
>98% E
>98% Z
57
32
47
49
53
14
33
I
2
3
added rapidly and all at once (fast addition of the mixture
usually gave a higher yield than sequential additions).
-
•
Me
The reaction mixture was stirred until the blue LiDBB
TIPS
TIPS
color was regenerated (ca. 0.5-1 h). Product analysis
showed that the desired product, 3a , was isolated as the
minor component in 18.4% yield, with 3b recovered as
the major product in 32.1% yield. Attempts to generate
the penultimate plasmenylcholine species in a single pot
reaction via addition of palmitoyl chloride to the LiDBB
reaction mixture were abandoned since the regioisomeric
products formed were difficult to separate.
Syn th esis of P la sm en ylch olin e fr om 3a (F igu r e
3). A synthesis of palmitoyl plasmenylcholine, utilizing
intermediate 3a in a nine-step sequence beginning with
monopalmitin, has already been described.16 We modified
this published method slightly by acylating compound 3a
with palmitoyl chloride to give compound 5 in 92.8%
yield, followed by deprotection of TBDMS with TBAF/
imidazole (10 equiv each) to give alcohol 6 in 55% yield.
It should be noted that the reaction temperature (-23
°C), time, and chromatographic separation (fast elution
from silica gel with cold solvent) require careful attention
to prevent acyl migration to the sn-3 position upon
TBDMS deprotection. The phosphocholine headgroup
was introduced as described previously by treatment with
2-oxo-2-chloro-1,3,2-dioxaphospholane, followed by excess
trimethylamine, to give a racemic 2-hexadecanoyl-1-O-
1′(Z)-hexadecenyl-rac-glycero-3-phosphocholine (7, palmi-
toyl plasmenylcholine) in 67.6% yield.16
1
(
-chlorotridecane gave high yields of E-coupled product
Z:E 30:70), whereas Z-products dominated the conver-
sions of 1-bromotridecane (Z:E 67:33) and iodotridecane
almost exclusively (Z)-coupled product, Z:E 98:2). We
attribute this effect to the disruption of allyllithium anion
chelation by the bulky TBDMS group, since the effects
of halogen are minor (1-chlorotridecane, Z:E 88:12;
(
1
-iodotridecane, Z:E 95:5) when substrates containing
smaller protecting groups (i.e. methyl) are present at the
sn-2 position. This interpretation is further supported by
the dramatic influences observed with the bulkier TIPS
protecting group (i.e. 1-chlorotridecane, >98% E; 1-iodo-
tridecane, >98% Z). These results are also consistent
with kinetic differences expected for the reactivity of alkyl
halides with allyllithium anion intermediates (i.e. alkyl
iodide coupling reactions should compete better than
alkyl chlorides with cis-trans allyl isomerization, leading
to greater Z:E ratios when iodoalkane substrates are
used). Alternatively, the reaction may proceed via an SET
mechanism involving the coupling of an alkyl halide and
2
5
a lithioalkoxyallyl radical intermediate; however, it is
unclear how this would lead to the stereoselective forma-
tion of Z-vinyl ether products.
J . Org. Chem, Vol. 67, No. 18, 2002 6505

Shin et al.
F IGURE 5. Synthesis of 7 from 3c. Reagents: (a) Li, DBB,
C
13
H
27I, THF, 0 °C, 1 h (47%); (b) (i) 2-oxo-2-chloro-1,3,2-
dioxaphospholane, Et N, C , 8 °C; (ii) Me N, MeCN/C
0 °C (53.6% for steps i and ii, combined); (c) TBAF, imidazole,
3 °C (98%); (d) palmitic anhydride, DMAP, CH Cl , 23 °C
F IGURE 3. Synthesis of 2-hexadecanoyl-1-O-1′(Z)-hexadecen-
yl-rac-glycero-3-phosphocholine (7, palmitoyl plasmenylcho-
line) from 3a . Reagents: (a) palmitoyl chloride, pyridine, THF,
3
6
H
6
3
6 6
H ,
7
2
2
2
2
2
3 °C (92.8%); (b) TBAF, imidazole, -23 °C (55%); (c) (i) 2-oxo-
-chloro-1,3,2-dioxaphospholane, Et N, C , 8 °C; (ii) Me N,
, 70 °C (67.6% for steps i and ii, combined).
(53%).
3
6
H
6
3
6 6
MeCN/C H
(37.1% yield), 3b (7.3% yield), and 3c (3.1% yield) after
column purification.
P la sm en ylch olin e Syn th esis fr om 2b a n d 3c (F ig-
u r e 5). Since acyl migration during the TBDMS depro-
tection step was a problematic side reaction, a new
synthetic route to plasmenylcholine was developed with
3
c as the key intermediate. This strategy employs the
phosphocholine headgroup as a blocking group to prevent
migration followed by TBDMS deprotection and acyla-
tion. Reaction of vinyl dioxane 2b with 1-iodotridecane
under Barbier conditions gave the sn-2 TBDMS-protected
alcohol 3c in 47% yield. This reaction must be quenched
as soon as the LiDBB blue color reappears, however, to
prevent TBDMS migration to 3a . Introduction of the
phosphocholine headgroup as previously described gives
the sn-2 TBDMS-protected lysoplasmenylcholine 8 in
53.6% yield. Deprotection of 8 with TBAF/imidazole gives
lysoplasmenylcholine 9 in 98% yield. This intermediate
was subsequently acylated with palmitic anhydride in
the presence of DMAP to give palmitoyl plasmenylcholine
F IGURE 4. Synthesis of 3a from glycerol. Reagents: (a)
acrolein, n-BuSnCl , THF, 23 °C (68.1%); (b) TBDMSCl,
imidazole, 23 °C (28.0% 2a , 19.9% trans 2b, 33.7% cis 2b); (c)
Li, DBB, C13 27I, THF, 0 °C, 1 h (37.1% 3a , 7.28% 3b, 3.12%
c).
3
H
3
7
in 53% yield. This is the most efficient route known
Syn th esis of 3a fr om Glycer ol (F igu r e 4). A modi-
for plasmenylcholines since it avoids regioselectivity and
acyl migration problems and circumvents the need for
inefficient protection/deprotection steps. The main limi-
tation of this approach, however, is that it is only
applicable for the synthesis of racemic plasmenylcholines
since reductive ring opening of 2b occurs with equal
probability at each acetal C-O bond.
fied synthesis of racemic plasmenylcholine, starting from
glycerol and acrolein, was attempted since the reaction
of vinyl dioxolane 2a in LiDBB solution under Barbier
conditions gave 3a in low yield. Condensation of glycerol
and acrolein in the presence of n-BuSnCl
mixture of cis/trans-dioxolane 4a and cis/trans-dioxane
b in 68% yield. Subsequent TBDMSCl protection of
3
produced a
4
alcohols 4a and 4b gave a mixture of silyl ethers that
can be separated by silica gel column purification into
three components, cis-2b, trans-2b, and a mixture of cis/
trans-2a . We used this mixture, without separation, in
the Barbier-type coupling reaction since TBDMS group
migration under the basic workup conditions30 gives 3a
Con clu sion s
Facile syntheses of racemic plasmenylcholines have
been developed. The most efficient method that is also
adaptable for the synthesis of chiral plasmenylcholines,
requires only six steps beginning from the inexpensive
starting materials solketal or glycerol and acrolein. The
key step in this transformation, formation of (Z)-vinyl
ether intermediates via LiDBB-mediated coupling with
iodoalkanes, is accomplished under Barbier-type condi-
tions. Even though the reaction gives modest yields, its
simplicity, versatility, and applicability will be useful for
the synthesis of other plasmalogen-type compounds with
(Z)-vinyl ether configuration.
(28) The TBDPS-protected compound also was prepared; however,
this intermediate produced lower yields in the subsequent Barbier-
type reaction (only 7% of the desired coupling product was obtained
in this case).
(29) The selective removal of an isopropylidene acetal in the presence
of TBDMS is known to be difficult since the TBDMS group is usually
cleaved under the same conditions required for isopropylidene acetal
cleavage. An attempt with FeCl /SiO [Kim, K. S.; Song, Y. H.; Lee, B.
3 2
H.; Hahn, C. S. J . Org. Chem. 1986, 51, 404-407] failed to convert
any starting material over a 24-h period.
(30) Ogilvie, K.; Entwistle, D. Carbohydr. Res. 1981, 89, 203-210.
6
506 J . Org. Chem., Vol. 67, No. 18, 2002

Plasmalogen Synthesis Using LiDBB
Exp er im en ta l Section
g, 46.4 mmol) was added at 0 °C. The mixture was stirred at
3 °C overnight and was then diluted in Et O (500 mL) prior
to washing with H
O (3 × 50 mL). The organic layer was dried
over anhydrous MgSO and filtered, and the solvent was
removed by evaporation under reduced pressure. The residue
was purified by silica gel chromatography (hexane:acetone, 20:
2
2
Gen er a l P r oced u r es. 1H and 13C NMR spectra were
recorded at 200 MHz. Chemical shifts are reported in ppm
relative to the residual solvent peaks as the internal standard.
MS (EI/CI/ESI) was performed by the Purdue University
MCMP Mass Spectrometry Service. Liquid chromatography
was typically performed on 230-400 mesh silica gel, using
high-grade solvents for compound purification. THF was
distilled from Na. Benzene, triethylamine, MeCN, DMF, and
2
4
1
) to give trans-2b (1.506 g, 6.16 mmol, 19.9%), cis-2b (2.550
g, 10.43 mmol, 33.7%), and a mixture of trans/ cis-2a (2.118
1
g, 8.67 mmol, 28.0%). trans-2b: H NMR (CDCl ) δ 0.04 (s,
3
6
1
5
1
7
6
5
H), 0,85 (s, 9 H), 3.40 (t, 2H, J ) 11 Hz), 3.80 (tt, 1H, J ) 5,
2
pyridine were distilled from CaH . All other chemical were
used without further purification unless otherwise stated.
Syn th eses: 1-Iod otr id eca n e. Triphenylphosphine (43.4 g,
1 Hz), 4.07 (dd, 2H, J ) 5, 11 Hz), 4.81 (d, 1H, J ) 4 Hz),
.28 (d, 1H, J ) 11 Hz), 5.44 (d, 1H, J ) 17 Hz), 5.81 (ddd,
13
H, J ) 4,11,17 Hz); C NMR (CDCl
3
) δ -5.0, 18.0, 25.7, 61.9,
) δ 0.08 (s,
1
1
62 mmol) and imidazole (11.0 g, 162 mmol) were added to
-tridecanol (25.0 g, 125 mmol) in dichloromethane (200 mL)
1
2.0, 100.0, 118.9, 134.0. cis-2b, H NMR (CDCl
3
H), 0.90 (s, 9 H), 3.61 (s, 1H), 3.92 (s, 4H), 4.98 (d, 1H, J )
at 0 °C. Iodine (41,1 g, 162 mmol) was slowly added at 0 °C.
The reaction mixture was stirred at 0 °C for 0.5 h and at 23
Hz), 5.27 (d, 1H, J ) 10 Hz), 5.43 (d, 1H, J ) 17 Hz), 5.88
13
(
ddd, 1H, J ) 5,10,17 Hz); C NMR (CDCl
3
) δ -5.0, 18.4, 26.0,
°
C for 3 h. Hexane (200 mL) was added and the resulting
6
4.6, 71.4, 100.3, 119.0, 134.8.
precipitate removed by filtration. The organic liquid was
condensed and the resulting residue was purified by silica gel
3
-ter t-Bu tyld im eth ylsilyl-1-O-1′-(Z)-h exa d ecen yl Glyc-
er ol (3a ) a n d 1-ter t-Bu tyld im eth ylsilyl-2-O-1′-(Z)-h exa -
d ecen yl Glycer ol (3b). Li (224 mg, 30 wt % in mineral oil,
chromatography (hexane) to give a liquid (37.3 g, 120 mmol,
1
9
1
6.3%). H NMR (CDCl
3
) δ 0.82 (t, 3H, J ) 6 Hz), 1.24 (s, 20H),
9
.66 mmol) was quickly added under Ar to an airtight flask
.80 (quintet, 2H, J ) 6 Hz), 3.16 (t, 2H, J ) 6 Hz); 13C NMR
containing a glass-covered magnetic stirring bar. Hexane (30
mL) was added with stirring for 20 min, and then removed to
wash out the mineral oil. This procedure was repeated one
more time before addition of DBB (36 mg, 0.138 mmol) and
THF (30 mL) at 23 °C under Ar. The dark blue color of the
radical anion appeared within 10 s. The reaction mixture was
cooled to 0 °C, a mixture of 1-iodotridecane (856 mg, 2.76
mmol) and vinyl dioxolane 2a (336 mg, 1.38 mmol) in THF (3
mL) was added all at once at 0 °C, and the reaction mixture
was stirred at 0 °C for 30 min. Hexane (10 mL) was then added
(CDCl
3
) δ 7.3, 14.1, 22.7, 28.5, 29.3, 29.4, 29.5, 29.6, 30.5, 31.9,
3
3.6.
t er t -Bu t yld im e t h yl(2,2-d im e t h yl-1,3-d ioxola n -4-yl-
m eth oxy)sila n e (1). Imidazole (4.64 g, 68.1 mmol) was added
to a flask containing solketal (6.00 g, 45.4 mmol) in THF (30
mL). TBDMSCl (8.55 g, 56.6 mmol) in THF (30 mL) was added
slowly at 0 °C and the resulting mixture stirred at 23 °C
overnight. The precipitate generated during the reaction was
removed by filtration. The filtrate was then diluted in hexane
(
200 mL) and washed with water (3 × 50 mL). The organic
and the resulting mixture quenched slowly with H
at 0 °C. The organic layer was washed with water (2 × 10
mL), separated, dried over anhydrous Na CO , and filtered.
2
O (5 mL)
layer was dried over anhydrous MgSO and filtered, and the
4
solvent was removed by evaporation under reduced pressure
to give product 1 as an oil (10.857 g, 44.1 mmol, 96.9%). H
1
2
3
The solvent was removed by evaporation under reduced
pressure and the residue purified by silica gel chromatography
NMR (CDCl
3
) δ 0.03 (s, 6H), 0.86 (s, 9H), 1.33 (s, 3H), 1.38 (s,
1
3
3
2
H) 3.50-4.14 (m, 5H); C NMR (CDCl
5.8, 26.7, 63.9, 66.8, 76.1, 109.1.
ter t-Bu tyld im eth yl(2-vin yl-1,3-d ioxola n -4-ylm eth oxy)-
3
) δ -5.4, 18.2, 25.4,
(
hexane:Et
2
O, 8:1) to give the desired product 3a (109 mg,
.254 mmol, 18.4%) and a byproduct 3b (190 mg, 0.443 mmol,
2.1%). 3a : 1H NMR (C
) δ 0.00 (s, 6H), 0.89 (s, 12H), 1.20-
.50 (s, 24H), 2.16 (d, 1H, J ) 5 Hz), 2.27 (m, 2H), 3.57 (d, 2H,
0
3
1
6
D
6
3
1
sila n e (2a ). n-BuSnCl
3
(0.408 mL, 2.45 mmol) was added to
a flask containing 1 (12.08 g, 49.02 mmol). Acrolein (3.28 mL,
9.02 mmol) was slowly added and the resulting mixture
J ) 5 Hz), 3.63 (d, 2H, J ) 5 Hz), 3.77 (quintet, 1H, J ) 5
4
1
3
Hz), 4.40 (q, 1H, J ) 6 Hz), 5.87 (d, 1H, J ) 6 Hz); C NMR
) δ -5.4, 14.3, 18.2, 23.0, 24.5, 26.0, 29.8, 30.0, 30.1, 30.2,
stirred at 23 °C for 30 min. The reaction mixture was placed
under vacuum to remove the acetone byproduct. This sequence
of operations was repeated 5 times. The resulting mixture was
purified by silica gel chromatography (hexane:Et
give a trans/cis mixture of 2a (6.548 g, 26.79 mmol, 54.5%).
6 6
(C D
+
3
4
1
5
0.3, 32.3, 64.1, 70.8, 72.8, 107.3, 145.6; CI calcd (M + H)
29, found 429. 3b: H NMR (C
.20-1.50 (s, 24H), 1.65 (s, 1H), 2.27 (m, 2H), 3.50-3.67 (m,
1
6 6
D ) δ 0.02 (s, 6H), 0.93 (s, 12H),
2
O, 20:1) to
1
3
H), 4.40 (q, 1H, J ) 6 Hz), 5.94 (d, 1H, J ) 6 Hz); C NMR
) δ -5.4, 14.3, 18.4, 23.1, 24.5, 26.0, 29.8, 30.0, 30.2, 30.3,
2.3, 62.7, 63.2, 82.8, 107.3, 145.0.
-ter t-Bu tyld im eth ylsilyl-1-O-1′-(Z)-h exa d ecen yl Glyc-
er ol (3c). The Barbier-type reaction of compound 2b and
1
H NMR (CDCl
H), 5.18-5.50 (m, 3H), 5.71-5.90 (m, 1H); 13C NMR (CDCl
δ -5.4, 18.3, 25.8, 63.5, 63.8, 67.2, 67.5, 76.0, 76.4, 104.0, 104.3,
19.8, 120.4, 134.5, 134.6.
-Vin yl-1,3-d ioxola n -4-ylm eth a n ol (4a ) a n d 2-Vin yl-1,3-
d ioxa n e-5-ol (4b). n-BuSnCl (0.450 mL, 2.70 mmol) was
3
) δ 0.04 (s, 6H), 0.86 (s, 9H), 3.48-4.20 (m,
6 6
(C D
5
3
)
3
2
1
2
1
-iodotridecane was accomplished as described for compound
3
3
a /3b. 3c was isolated in 47% yield after silica gel purification.
added to a flask containing glycerol (10.0 g, 108 mmol) and
the vessel was cooled in an ice bath. Acrolein (3.60 mL, 54.3
mmol) was slowly added at 0 °C, the ice bath removed, and
the resulting mixture stirred at 23 °C for 45 min. The reaction
mixture was directly loaded onto a silica gel column and eluted
1
H NMR (C
.50 (m, 25H), 2.30 (m, 2H), 3.42 (m, 2H), 3.55 (d, 2H, J ) 6
Hz), 3.73 (m, 1H), 4.40 (1H, J ) 6 Hz), 5.83 (d, 1H, J ) 6 Hz);
6 6
D ) δ 0.04 (s, 3H), 0.08 (s, 3H), 0.92 (s, 12H), 1.20-
1
1
3
C NMR (C
6 6
D ) δ -5.2, 5.0, 13.8, 17.7, 22.6, 24.1, 25.5, 29.3,
2
9.6, 29.7, 29.8, 31.8, 63.7, 71.8, 73.5, 106.4, 145.2; CI calcd
with 25:1 CHCl
trans/ cis-4b (4.81 g, 37.0 mmol, 68.1%). H NMR (CDCl
3
:MeOH to give a mixture of trans/ cis-4a and
+
1
(M + H) 429, found 429.
3
) δ
.3-4.3 (m, 6H), 4.8. 5.5 (m, 3H), 5.7-5.9 (m, 1H); 1 C NMR
3
3-ter t-Bu tyld im eth ylsilyl-1-O-1′-(Z)-h exa d ecen yl Glyc-
er ol (3a ), 1-ter t-Bu tyld im eth ylsilyl-2-O-1′-(Z)-h exa d ecen -
yl Glycer ol (3b), a n d 2-ter t-Bu tyld im eth ylsilyl-1-O-1′-(Z)-
h exa d ecen yl Glycer ol (3c). The Barbier-type reaction of
dioxolane/dioxane 2a /2b and 1-iodotridecane was accomplished
as described for compound 3a /3b. 3a (3.260 g, 37.1%), 3b (639
mg, 7.3%), and 3c (274 mg, 3.1%) were isolated after silica gel
purification.
3
(CDCl ) δ 61.2, 63.0, 63.5, 64.3, 66.8, 67.0, 71.8, 72.2, 76.7,
3
7
1
7.2, 100.6, 101.3, 104.2, 104.9, 119.5, 120.5, 121.5, 134.2,
34.5.
ter t-Bu tyld im eth yl(2-vin yl-1,3-d ioxola n -4-ylm eth oxy)-
sila n e (2a ) a n d ter t-Bu tyld im eth yl(2-vin yl-1,3-d ioxa n -5-
yloxy)sila n e (2b). Imidazole (4.216 g, 61.93 mmol) was added
to a flask containing a mixture of trans/ cis-4a and trans/ cis-
4
b (4.03 g, 30.96 mmol) in DMF (100 mL) and TBDMSCl (7.00
3-ter t-Bu t yld im et h ylsilyl-2-h exa d eca n oyl-1-O-1′-(Z)-
h exa d ecen yl Glycer ol (5). Pyridine (3.50 mL) and palmitoyl
chloride (2.72 mL, 8.97 mmol) were added to a flask containing
alcohol 3a (2.565 g, 5.982 mmol) in THF (50 mL) and the
(31) Marton, D.; Tagliavini, G. Main Group Metal Chem. 1990, 13,
3
63-374.
J . Org. Chem, Vol. 67, No. 18, 2002 6507

Shin et al.
mixture stirred at 23 °C for 2 h. The reaction mixture was
concentrated under reduced pressure and the residue purified
2-ter t-Bu tyld im eth ylsilyl-1-O-1′-(Z)-h exa d ecen yl-glyc-
er o-3-p h osp h och olin e (8). The phosphocholine headgroup
by silica gel chromatography (hexane:CH
2
Cl
2
, 1:1) to give 5
) δ 0.03 (s, 6H),
was installed with use of compound 3c as described for
1
1
(3.705 g, 5.553 mmol, 92.8%). H NMR (C
6
D
6
compound 7 in 53.6% yield. H NMR (CDCl
3
) δ 0.04 (s, 6H),
0
.93 (m, 15H), 1.31 (m, 48H), 1.62 (m, 2H), 2.22 (t, 2H, J ) 7
0.83 (m, 12H), 1.21 (s, 24H), 1.98 (m, 2H), 3.35 (s, 9H), 3.60-
4.30 (m, 10H), 5.88 (d, 1H, J ) 6 Hz); 13C NMR (CDCl ) δ -4.8,
Hz), 2.29 (m, 2H), 3.72 (d, 1H, J ) 5 Hz), 3.73 (d, 1H, J ) 5
Hz), 3.80 (d, 2H, J ) 5 Hz), 4.43 (q, 1H, J ) 6 Hz), 5.21
3
14.0, 18.0, 22.6, 24.1, 25.7, 26.5, 29.3, 29.4, 29.5, 29.6, 29.8,
31.8, 54.1, 59.1, 66.1, 71.0, 71.2, 74.3, 106.2, 145.3; ESI calcd
1
3
(
6 6
quintet, 1H, J ) 5 Hz), 5.88 (d, 1H, J ) 6 Hz); C NMR (C D )
δ -5.4, 14.4, 18.4, 23.1, 24.5, 25.3, 26.0, 29.4, 29.7, 29.8, 29.9,
3
(M + H)
-O-1′-(Z)-h exa d ecen yl-glycer o-3-p h osp h och olin e (9).
Imidazole (50 mg, 0.732 mmol) was added to a flask containing
(124 mg, 0.209 mmol) in THF (3 mL). TBAF (0.626 mL, 0.626
+
594, found 594.
0.1, 30.2, 30.3, 32.3, 34.5, 61.7, 70.3, 73.0, 107.4, 145.6, 172.5;
1
+
CI calcd (M + H) 667, found 667.
-H exa d eca n oyl-1-O-1′-(Z)-h exa d ecen yl Glycer ol (6).
Imidazole (101 mg, 1.49 mmol) was added to a flask containing
(100 mg, 0.149 mmol) in THF (1.5 mL) and the vessel cooled
2
8
mmol) was added and the mixture stirred at 23 °C for 5 h.
The solution was directly loaded onto a silica gel column and
5
to -23 °C before addition of TBAF (1.49 mL, 1.49 mmol). After
purified by step gradient elution (CH
2 2 2
Cl :MeOH:H O, 80:20:
the mixture was stirred at -23 °C for 1 h, the solution was
0
, 65:35:6). Suspended silica gel from the chromatographic
2
loaded onto silica gel and eluted quickly with 2:1 hexane:Et O
fractions was removed by using PTFE syringe filters (0.45 µm)
to give the desired product (98 mg, 0.204 mmol, 98%) after
solution that had been cooled to -40 °C to give alcohol 6 (45
1
6 6
mg, 0.814 mmol, 55%). H NMR (C D ) δ 0.91 (t, 6H, J ) 6
1
lyophilization from benzene. H NMR (CD
3
OD) δ 0.89 (t, 3H,
Hz), 1.20-1.50 (m, 49H), 1.57 (m, 2H), 2.16 (t, 2H, J ) 7 Hz),
J ) 6 Hz), 1.28 (s, 9H), 2.04 (m, 2H), 3.22 (s, 9H), 3.6-3.96
2
4
1
2
7
.27 (m, 2H), 3.51 (d, 2H, J ) 5 Hz), 3.64 (d, 2H, J ) 5 Hz),
.43 (q, 1H, J ) 6 Hz), 5.05 (quintet, 1H, J ) 5 Hz), 5.82 (d,
(
m, 7H), 4.22-4.38 (m, 3H), 4.90 (s, 1H), 6.00 (d, 1H, J ) 6
1
3
1
3
Hz); C NMR (CD
3
OD) δ 14.5, 23.7, 25.0, 30.5, 30.6, 30.7, 30.8,
6 6
H, J ) 6 Hz); C NMR (C D ) δ 14.3, 23.1, 24.4, 25.3, 29.4,
3
1.0, 33.1,54.7, 60.4, 67.5, 68.0, 70.8, 73.9, 107.9, 146.3; ESI
9.7, 29.8, 29.9, 30.0, 30.1, 30.2, 30.3, 32.3, 34.4, 61.8, 70.6,
3.4, 107.7, 145.4, 172.9.
+
calcd (M + H) 480, found 480.
-Hexadecan oyl-1-O-1′-(Z)-h exadecen yl-glycer o-3-ph os-
p h och olin e (7). DMAP (46 mg, 0.37 mmol) was added to a
flask containing alcohol 9 (90 mg, 0.19 mmol) in CH Cl (10
2
2
-Hexadecan oyl-1-O-1′-(Z)-h exadecen yl-glycer o-3-ph os-
p h och olin e (7). A solution of alcohol 6 (131 mg, 0.237 mmol)
in benzene (25 mL) was added to a flask under Ar. Pyridine
2
2
(
57 µL, 0.71 mmol) and 2-oxo-2-chloro-1,3,2-dioxaphospholane
mL). Palmitic anhydride (167 mg, 0.338 mmol) was added and
the mixture stirred at 23 °C for 20 h. The solution was directly
loaded onto a silica gel column and purified by step gradient
(33 µL, 0.36 mmol) were then added to a flask that had been
cooled to 5 °C. After the mixture was stirred at 8 °C overnight
under Ar, the solvent was removed under vacuum. The residue
was transferred to a pressure bottle with benzene (2 mL) and
acetonitrile (5 mL). Trimethylamine (∼3 mL, 33 mmol) was
then distilled into the reaction vessel, the vessel sealed, and
the mixture stirred at 70 °C for 24 h. After slow release of
reactor pressure at 0 °C, the resulting solution was purified
2 2 2
elution (CH Cl :MeOH:H O, 80:20:0, 65:35:6). Suspended silica
gel from the chromatographic fractions was removed with use
of PTFE syringe filters (0.45 µm) to give the desired product
(71 mg, 0.099 mmol, 53%) after lyophilization from benzene.
Ack n ow led gm en t. The authors gratefully acknowl-
edge the very helpful comments of the reviewers and
also the assistance of Mr. J ason Robarge. This work was
supported by the NIH (R01 GM55266 and F31 GM18546)
and a generous gift of Avanti Polar Lipids.
with use of a silica gel column (gradient elution with CH
MeOH:H O, 100:0:0, 80:20:0, 65:35:6). Suspended silica gel
from the chromatographic fractions was removed with PTFE
syringe filters (0.45 µm) to give a white solid (115 mg, 0.160
mmol, 67.6%) after lyophilization from benzene. 1H NMR
2 2
Cl :
2
(
1
CDCl
3
) δ 0.82 (t, 6H, J ) J Hz), 1.20 (s, 48H), 1.51 (m, 2H),
.94 (m, 2H), 2.24 (t, 2H, J ) 7 Hz), 3.33 (s, 9H), 3.70-4.35
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectral data for compounds 1-9. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
3
(
m, 9H), 5.09 (m, 1H), 5.84 (d, 1H, J ) 6 Hz); C NMR (CDCl
δ 14.0, 22.6, 23.9, 24.9, 29.1, 29.3, 29.5, 29.6, 29.7, 29.9, 31.9,
4.4, 54.3, 59.2, 63.1, 66.2, 70.5, 71.7, 107.6, 144.7, 173.2; ESI
3
)
3
+
calcd (M + H) 718, found 718.
J O025640U
6
508 J . Org. Chem., Vol. 67, No. 18, 2002