Direct synthesis of plasmenylcholine from allyl-substituted glycerols

Article abstract of DOI:10.1021/jo026826w

We report a new method for the facile preparation of plasmenylcholine via reaction of lithioalkoxy allyl intermediates with 1-iodoalkanes as the key step in the stereoselective formation of 1′-(Z)-alkenyl glyceryl ethers. The allyl anion intermediate is prepared by treating mono- or disiloxy-protected 1-allylglycerol precursors with s-BuLi at -65 to -80°C. Subsequent addition of 1-iodoalkane solutions at low temperature gives moderate yields of γ-coupled, Z-vinyl ethers as the major product and α-coupled product as the minor component. Several different preparative strategies for the total synthesis of plasmalogens are enabled by this simple transformation.

Full text of DOI:10.1021/jo026826w

Dir ect Syn th esis of P la sm en ylch olin e fr om Allyl-Su bstitu ted
Glycer ols
J unhwa Shin and David H. Thompson*
Department of Chemistry, Purdue University, West Lafayette, Indiana 47907-1393
davethom@purdue.edu
Received December 9, 2002
We report a new method for the facile preparation of plasmenylcholine via reaction of lithioalkoxy
allyl intermediates with 1-iodoalkanes as the key step in the stereoselective formation of 1′-(Z)-
alkenyl glyceryl ethers. The allyl anion intermediate is prepared by treating mono- or disiloxy-
protected 1-allylglycerol precursors with s-BuLi at -65 to -80 °C. Subsequent addition of
1-iodoalkane solutions at low temperature gives moderate yields of γ-coupled, Z-vinyl ethers as
the major product and R-coupled product as the minor component. Several different preparative
strategies for the total synthesis of plasmalogens are enabled by this simple transformation.
Plasmalogens1 are sn-1 (Z)-1′-alkenyl ether glycero-
phospholipids found in abundance in the electrically
active tissues of mammals.2 These unique phospholipids
play important roles in biological processes such as signal
transduction,2-4 membrane fusion,5,6 and lipid peroxida-
tion.7 Plasmenylcholines have also been utilized for drug
and gene delivery using triggering mechanisms that are
activated under acidic or photooxidative conditions.6,8
Interest in the biochemical and biophysical properties of
this unique phospholipid family has prompted several
investigations into their stereocontrolled synthesis.9-12
Stereoselective formation of the 1′-(Z)-alkenyl ether
moiety at the glycerol sn-1 position is the major challenge
in plasmenylcholine synthesis. This linkage is sensitive
to acidic and oxidative conditions, whereas the sn-2 acyl
chain undergoes rapid migration under basic13 or acidic14,15
conditions or high temperature.16 These considerations
greatly limit the choice of reagents that can be employed
after formation of the alkenyl ether bond. The most
notable previous attempts to synthesize plasmenylcho-
lines have been based on elimination reactions;17 how-
ever, these approaches typically give poor stereoselectiv-
ity and low yields. The first synthetic pathway to
plasmenylcholine with pure (Z)-alkenyl ether stereo-
chemistry was accomplished via transformation of acyl
glycerol precursors to vinyl phosphates, followed by Pd-
catalyzed reduction.9 The reduction of glyceryl 1′-hexa-
decynyl ether to glyceryl 1′-(Z)-hexadecenyl ether via
Lindlar-catalyzed hydrogenation has also been reported;10
however, this pathway requires multiple steps to prepare
the alkynyl ether precursor.
Recently, a pathway for the facile stereoselective
synthesis of (Z)-alkenyl ethers via reductive cleavage of
vinyl acetals in the presence of 1-iodoalkanes has been
used for the synthesis of racemic plasmenylcholine and
plasmenylcholine analogues.11,12 In this approach, Bar-
bier-type reactions of vinyl acetals and 1-iodoalkanes
produced (Z)-alkenyl ethers with high stereoselectivity
* To whom correspondence should be addressed. Fax: 765-496-2592.
(1) Lee, T.-c. Biochim. Biophys. Acta 1998, 1394, 129-145.
(2) Sugiura, T.; Waku, K. In Platelet Activating Factor and Related
Lipid Mediators; Snyder, F., Ed.; Plenum Press: New York, 1987; pp
55-85.
(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-
286.
(5) Glaser, P. E.; Gross, R. W. Biochemistry 1994, 33, 5805-5812.
(6) Thompson, D. H.; Gerasimov, O. V.; Wheeler, J . J .; Rui, Y.;
Anderson, V. C. Biochim. Biophys. Acta 1996, 1279, 25-34.
(7) Murphy, R. C. Chem. Res. Toxicol. 2001, 14, 463-472.
(8) (a) Gerasimov, O. V.; Schwan, A.; Thompson, D. H. Biochim.
Biophys. Acta 1997, 1324, 200-214. (b) Rui, Y.; Wang, S.; Low, P. S.;
Thompson, D. H. J . Am. Chem. Soc. 1998, 120, 11213-11218. (c)
Gerasimov, O. V.; Boomer, J . A.; Qualls, M. M.; Thompson, D. H. Adv.
Drug. Deliv. Rev. 1999, 38, 317-338. (d) Wymer, N. J .; Gerasimov, O.
V.; Thompson, D. H. Bioconjug. Chem. 1998, 9, 305-308. (e) Qualls,
M. M.; Thompson, D. H. Int. J . Cancer 2001, 93, 384-392. (f) 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. (g)
Boomer, J . A.; Thompson, D. H.; Sullivan, S. Pharm. Res. 2002, 19,
1292-301.
(13) Dodd, G. H.; Golding, B. T.; Ioannou, P. V. J . Chem. Soc., Chem.
Commun. 1975, 249-250.
(14) van Lohuizen, O. E.; Verkade, P. E. Rec. Trav. Chim. Pays-
Bas 1960, 79, 133-159.
(15) Migration can occur during chromatography on silica gel:
Pfaendler, H. R.; Weimar, V. Synthesis 1996, 1345-1349.
(16) Crossley, A.; Freeman, I. P.; Hudson, B. J . F.; Pierce, J . H. J .
Chem. Soc. 1959, 760-764.
(17) (a) Craig, J . C.; Hamon, D. P. G.; Brewer, H. W.; Harle, H. J .
Org. Chem. 1965, 30, 907-910. (b) Piantadosi, C. F.; Hirsch, A. F.;
Yarbro, C. L.; Anderson, C. E. J . Org. Chem. 1963, 28, 2425-2428. (c)
Titov, V. I.; Serebrennikova, G. A.; Preobrazhenskii, N. A. Zh. Org.
Khim. 1970, 6, 1154-1159; Chem. Abstr. 1970, 73, 65983z; (d) Gigg,
J .; Gigg, R. J . Chem. Soc., (C) 1968, 16-21. (e) Vtorov, I. B.;
Serebrennikova, G. A.; Evstigneeva, R. P. Tetrahedron Lett. 1971, 48,
4605-4608. (f) de Wit, P. P.; van der Steeg, M.; van der Gen, A. Rec.
Trav. Chim. Pays-Bas. 1985, 104, 307-308. (g) Slotboom, A. J .; De
Haas, G. H.; Van Deenen, L. L. M. Chem. Phys. Lipids 1967, 1, 192-
208. (h) Chebyshev, A. V.; Serebrennikova, G. A.; Evstigneeva, R. P.
Zh. Org. Khim. 1977, 13, 703-709; Chem. Abstr. 1977, 87, 38790s. (i)
Pfaendler, H. R.; Muller, F. X. Synthesis 1992, 350-352.
(9) Rui, Y.; Thompson, D. H. Chem. Eur. J . 1996, 2, 1505-1508.
(10) Qin, D. H.; Byun, H. S.; Bittman, R. J . Am. Chem. Soc. 1999,
121, 662-668.
(11) Shin, J .; Qualls, M. M.; Boomer, J . A.; Robarge, J .; Thompson,
D. H. J . Am. Chem. Soc. 2001, 123, 508-509.
(12) Shin, J .; Gerasimov, O. V.; Thompson, D. H. J . Org. Chem. 2002,
67, 6503-6508.
10.1021/jo026826w CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/25/2003
6760
J . Org. Chem. 2003, 68, 6760-6766

Synthesis of Plasmenylcholine from Allyl-Substituted Glycerols
(Z/E > 95:5).11,12 These observations were attributed to
the formation of a cyclic lithioalkoxy allyl intermediate
after reductive ring opening of cyclic acetal precursors.18,19
These results naturally led us to investigate (Z)-alkenyl
ether bond formation from the reaction of 1-iodoalkanes
and lithioalkoxy allyl intermediates that could be gener-
ated by deprotonation of allyl ethers with s-BuLi. Allyl
ethers, widely used protecting groups in carbohydrate
chemistry,20 have not been utilized for the synthesis of
plasmenyl-type lipids, despite the well-documented cou-
pling chemistry of lithioalkoxy allyl intermediates with
electrophiles.21 This paper describes a facile new syn-
thetic pathway to chiral plasmenylcholines using lithio-
alkoxy allyl intermediates, generated from allyl ether
with s-BuLi, in the key (Z)-alkenyl ether bond formation
step. Two alternate strategies for plasmenylcholine syn-
thesis using this simple transformation are also de-
scribed.
TABLE 1. Syn th esis of (Z)-Alk en yl Glycer ol Eth er s fr om
Dip r otected Allyl Glycer ol Tr ieth er s
Resu lts a n d Discu ssion
Allyl An ion -Med ia ted F or m a tion of 1-(Z)-Alk en yl
Eth er s. Work by Evans et al.22 and Still and Macdonald19
has shown that lithioalkoxy allyl intermediates react
with haloalkanes to give γ- and R-coupled products in
moderate to high yields. In general, reactions between
allyl ether substrates bearing large alkyl substituents
give high γ/R ratios (i.e., >2:1) when iodoalkane electro-
philes are used. Higher γ/R ratios have also been achieved
using lithium-barium transmetalation prior to electro-
phile addition.23 The ease and flexibility of this trans-
formation led us to explore the utility of this coupling
reaction for the synthesis of 1-(Z)-alkenyl glycerol ether
intermediates. Deprotonation of doubly protected allyl
glycerol with s-BuLi, performed at -70 °C to avoid the
possibility of a 1,2-Wittig rearrangement,24 gave yellow-
brown solutions upon formation of the lithium allyl
intermediate. Subsequent addition of 1-iodotridecane
gave moderate yields of γ-coupled (Z)-alkenyl ether
intermediates as the major products, however, R-coupled
materials were also generated as minor byproducts
(Table 1). Since the desired γ-coupled products (2) typi-
cally displayed higher mobility on TLC than the byprod-
ucts (e.g., Rf values of 2 were usually about 0.1 units
higher than the corresponding regioisomer and 0.2 higher
than the starting materials when hexane-rich hexane:
CH2Cl2 mixtures were used as developing solvent), the
R- and γ-coupled regioisomers could readily be separated
by silica gel column chromatography. Alkenyl ether
stereocontrol was typically > 99% (Z), although occasion-
ally up to 2% (E)-alkenyl ether product was observed by
1H NMR.
a
1 was added to s-BuLi (1.3 equiv) at -70 °C and the mixture
stirred for 5 min before addition of R3I. 1 was added to s-BuLi
b
(1.3 equiv) at -70 °C and the mixture stirred for 2-5 min before
addition of R3I.
ous strategies involving stereoselective sn-1 (Z)-alkenyl
ether bond formation prior to sn-2 acylation and phos-
phocholine headgroup installation in the final step.9,10
These sequences require multiple protection and depro-
tection steps for controlled introduction of the alkenyl
ether and acyl substituents, often requiring more than
10 steps to produce advanced plasmenylcholine interme-
diates. The allyl anion route considerably shortens these
pathways. For example, treatment of 1-allyloxyglycerol
with 2 equiv of BPSCl gives 1 in 93% yield. Deprotonation
of this intermediate with s-BuLi at -70 °C followed by
addition of 1-iodotridecane provides plasmenylcholine
precursor 2d in 48% yield.9
Dia n ion ic Ap p r oa ch es to P la sm en ylch olin e. A
more direct dianion approach25 to the synthesis of plas-
menylcholine, via double deprotonation of 3 and stepwise
addition of 1-iodoalkane and acyl chloride, was then
investigated as a means to further expedite the synthesis
of plasmenylcholines (Table 2). Selective protection of
1-allyloxyglycerol with TBSCl or BPSCl gave 3a in 89%
yield and 3b in 94% yield, respectively. Treatment of
either 3a or 3b with 3 equiv of s-BuLi at -70 °C for 1 h,
followed by stepwise addition of 1-iodotridecane and
palmitoyl chloride gave 4a in 31% yield and 4b in 18%
yield. In this reaction, 4a and 4b are prepared in one
reaction vessel from 3a and 3b, respectively, enabling
Application of this transformation to the synthesis of
plasmenylcholines offers several advantages over previ-
(18) Gil, J . F.; Ramon, D. J .; Yus, M. Tetrahedron 1994, 50, 3437-
3446.
(19) Still, W. C.; Macdonald, T. L. J . Am. Chem. Soc. 1974, 96, 5561-
5563.
(20) Guibe, F. Tetrahedron 1997, 53, 13509-13556.
(21) Katritzky, A. R.; Piffl, M.; Lang, H.; Anders, E. Chem. Rev. 1999,
99, 665-722.
(22) Evans, D. A.; Andrews, G.; Buckwalter, B. J . Am. Chem. Soc
1974, 96, 5560-5561.
(23) Yanagisawa, A.; Yasue, K.; Yamamoto, H. Synlett 1993, 686-
688.
(25) Trost, B. M.; Latimer, L. H. J . Org. Chem. 1977, 42, 3212-
3214.
(24) Tomooka, K.; Inoue, T.; Nakai, T. Chem. Lett. 2000, 418-419.
J . Org. Chem, Vol. 68, No. 17, 2003 6761

Shin and Thompson
TABLE 2. Syn th esis of (Z)-Alk en yl Glycer ol Eth er s fr om Silyl Allyl Glycer ol Dieth er s
timea
(h)
isolated yield (%)
product ratio
reactant
R
base
of 4
γ/R/ub
3b
3a
3a
3a
3a
BPS
TBS
TBS
TBS
TBS
s-BuLi
s-BuLi
s-BuLi
t-BuLi
n-BuLi
1
1
2
1
1
4b: 18
4a : 31
4a : 12
4a : 18
4a : 0
1.5:1.3:1
2.6:1.8:1
4:n.d.:1
2:1:7
n.d.:n.d.:1
a
b
Reaction time with base at ca. -70 °C before addition of 1-iodotridecane. n.d. ) not detected.
SCHEME 1. Selective Dep r otection P a th w a y to
P la sm en ylch olin ea
the total synthesis of palmitoyl plasmenylcholine with
only two additional steps (i.e., silyl ether deprotection and
phosphocholine installation). R-Coupled and uncoupled
byproducts with acyl modification at the secondary
alcohol site were typically obtained along with the desired
product using this pathway. Longer reaction times (2 h)
of 3a with s-BuLi gave lower yields of all products,
suggesting that the dianion intermediate is not stable
under these reaction conditions. Lower yields of the
desired product (18%) and higher yields of the uncoupled
product (63%) were obtained in the reaction of 3a with
t-BuLi. Only uncoupled product (91% yield) was obtained
in reactions with n-BuLi. These results suggest that
different butyllithium reagents generate different dian-
ion:monoanion ratios under these reaction conditions.
The data also show that the dianionic approach is most
effective when the reaction is performed using s-BuLi at
-70 °C for 1 h. Even though 4a is formed in modest yields
using this approach, it is a one-pot transformation,
making it faster and competitive with the cumulative
yields of lengthier routes.
a
Reagents: (a) NaH, SEMCl, THF, 1a , 82% yield (1b, 89%
Syn th etic Ap p r oa ch es to P la sm en ylch olin e In -
volvin g Selective Dep r otection . The main drawback
of the synthetic pathway utilizing 4 as a plasmalogen
precursor is that acyl migrationswhich can occur during
TBAF-mediated desilylation, chromatographic purifica-
tion, and phosphocholine modification9sgenerates an
undesired 1-(Z)-alkenyl-3-acylglycerol byproduct. Instal-
lation of the phosphocholine headgroup before acylation
obviates this problem.12 We, therefore, adapted this
strategy for the synthesis of plasmenylcholine by differ-
entially protecting the hydroxymethyl groups of 3a and
3b with TBS or BPS and the secondary glycerol hydroxyl
groups with 2-(trimethylsilyl)ethoxymethyl (SEM)26
(Scheme 1). Treatment of 3a and 3b with SEMCl gives
the 1-allyl-3-silyl-2-SEM protected products, 1a and 1b
in 82% and 89% yield, respectively. These intermediates
were then sequentially treated with s-BuLi and 1-iodo-
tridecane to give the desired (Z)-alkenyl ether intermedi-
ates 2a and 2b, both in 44% yield. TBAF deprotection of
2a and 2b in the presence of imidazole (to give 5 in 80%
yield); (b) s-BuLi, C13H27I, THF (44% yield for both 2a and 2b);
(c) TBAF, imidazole, THF, 97% yield from 2b (80% yield from 2a );
(d) (i) 2-oxo-2-chloro-1,3,2-dioxaphospholane, Et3N, C6H6; (ii)
Me3N, MeCN/C6H6 (77% yield for steps i and ii, combined); (e)
TBAF, HMPA (80% yield); (f) palmitic anhydride, DMAP, CH2Cl2
(53% yield).
and 97% yield, respectively), installation of the phospho-
choline headgroup (6, 77% yield), and removal of the SEM
protecting group with TBAF in HMPA at 90 °C gives
lysoplasmenylcholine 7 in 80% yield. Acylation27 of 7 with
palmitic anhydride in the presence of DMAP gives
plasmenylcholine 8 in 53% yield.12 31P NMR of 7 and 8
gave a single phosphorus resonance (Supporting Infor-
mation), indicating that no phosphorus-containing mi-
gration byproducts were produced during the SEM
deprotection and acylation steps. A major advantage of
this route is that lysoplasmenylcholine (7) serves as the
key precursor for a general plasmenylcholine synthesis,
allowing many different types of biologically important
plasmenylcholines with different sn-2 acyl chains (e.g.,
(26) Greene, T. W.; Wuts, P. G. M. Protective groups in organic
synthesis, 3rd ed.; Wiley: New York, 1999.
(27) Gupta, C. M.; Radhakrishnan, R.; Khorana, H. G. Proc. Natl.
Acad. Sci. U.S.A. 1977, 74, 4315-4319.
6762 J . Org. Chem., Vol. 68, No. 17, 2003

Synthesis of Plasmenylcholine from Allyl-Substituted Glycerols
SCHEME 2. Syn th esis of Ch ir a l P la sm en ylch olin e via th e Selective Dep r otection P a th w a ya
a
Reagents: (a) (i) NaH, allyl bromide; (ii) AG50W-X2 resin, THF/H2O; (iii) BPSCl, imidazole, DMF (84% yield, steps i-iii, combined);
(b) NaH, SEMCl, THF (74% yield); (c) s-BuLi, C13H27I, THF (37% yield); (d) TBAF, imidazole, THF (94% yield); (e) (i) 2-oxo-2-chloro-
1,3,2-dioxaphospholane, Et3N, C6H6; (ii) Me3N, MeCN/C6H6 (76% yield for steps i and ii, combined); (f) TBAF, HMPA (51% yield); (g)
palmitic anhydride, DMAP, CH2Cl2 (48% yield).
acetyl, arachidonyl) to be readily prepared via a single
acylation step.
material for conversion to 1-(Z)-alkenyl-2-acyl-3-silyl-
protected glycerols. Although the yields from this step
of the sequence are moderate to low, the overall efficiency
benefits from the use of a one-pot reaction. An alternative
route employing selective protection-deprotection schemes
that eliminate acyl migration problems to prepare lyso-
plasmenylcholine and plasmenylcholine has also been
developed. This pathway enables the synthesis of a wide
variety of plasmenylcholine derivatives containing dif-
ferent acyl groups via lysoplasmenylcholine acylation.
Syn th esis of Ch ir a l P la sm en ylch olin e fr om (R)-
(-)-2,2-Dim eth yl-1,3-d ioxola n e-4-m eth a n ol. Commer-
cially available racemic starting materials were used to
develop the previous three synthetic pathways to plas-
menylcholine (Tables 1 and 2 and Scheme 1). We utilized
commercially available (R)-(-)-2,2-dimethyl-1,3-dioxolane-
4-methanol as a starting material for the synthesis of
naturally occurring chiral plasmenylcholine and (S)-(+)-
2,2-dimethyl-1,3-dioxolane-4-methanol for the prepara-
tion of the congener with inverted stereochemistry
(Scheme 2). These compounds are readily protected with
allyl bromide, hydrolyzed in the presence of solid acid
catalysts and protected with BPSCl to give (R)-(+)-3b and
(S)-(-)-3b in 84 and 83% yield, respectively. Chiral
plasmenylcholines (R)-(-)-8 and (S)-(+)-8 were subse-
quently prepared using the selective deprotection route
described in Scheme 1. The reaction of (S)-(-)-5, (R)-(+)-
5, and racemic 5 with (R)-(-)-R-methoxy-â-trifluoro-
methyl-phenylacetic acid chloride (Mosher reagent) in the
presence of NEt3 and a catalytic amount of DMAP
showed that the stereochemistry at the sn-2 position was
retained during the formation of the (Z)-alkenyl ether
bond9 (i.e., 1H NMR spectroscopy of the Mosher ester
intermediates of (S)-(-)-5 and (R)-(+)-5 in d6-benzene
solution clearly showed that no racemization occurred,
Figure 1).
Exp er im en ta l Section
Gen er a l P r oced u r es. 1H and 13C NMR spectra were
recorded at 300 and 75 MHz, respectively. Chemical shifts are
reported in ppm relative to the residual solvent peaks as
internal standard. 31P NMR spectra were recorded at 121 MHz
and no internal standard material (85% H3PO4) was used since
7 and 8 are highly acid sensitive. MS (EI/CI/ESI) was
performed by the MCMP Mass Spectrometry Service of Purdue
University. Column chromatography was performed using
230-400 mesh silica gel and analytical grade solvents. THF
was distilled from sodium benzophenone ketyl. Benzene,
triethylamine, MeCN, DMF, and pyridine were distilled from
CaH2. All other chemical were used without further purifica-
tion. The highest yields obtained for each reaction are reported.
Yields were calculated without consideration of recovered
starting material since, in most cases, the amount of starting
material recovered was insignificant.
Syn th esis. 1-Allyl-2,3-bis-ter t-bu tyld ip h en ylsilyl-r a c-
glycer ol (1d ). Imidazole (3.268 g, 48.0 mmol) was added to
3-allyloxy-1,2-propanediol (1.32 g, 10.0 mmol) in DMF (25 mL)
at 0 °C. BPSCl (6.00 g, 24.0 mmol) was slowly added at 0 °C
and the mixture stirred overnight under Ar at 23 °C. Diethyl
ether (150 mL) was added and the reaction mixture extracted
with water (2 × 50 mL). The ether layer was dried over MgSO4
and evaporated under reduced pressure, and the residue was
purified by silica gel chromatography (hexane/Et2O, 16:1) to
give 1d as an oil (5.68 g, 9.33 mmol, 93% yield): 1H NMR
(CDCl3) δ 1.03 (s, 9H), 1.06 (s, 9H), 3.44 (dd, 1H, J ) 5, 10
Hz), 3.58 (dd, 1H, J ) 5, 10 Hz), 3.70 (d, 2H, J ) 5 Hz), 3.75-
3.84 (m, 2H), 3.94-4.01 (m, 1H), 5.07-5.20 (m, 2H), 5.72-
Con clu sion s
A facile synthetic method has been developed for the
preparation of (Z)-alkenyl glyceryl ethers using lithio-
alkoxy allyl anion coupling with 1-iodoalkanes. Interme-
diates from this key alkenyl ether bond-forming step have
been used for the total synthesis of plasmenylcholines
such that each element of the plasmenylcholine structure
can be varied. The most direct of these synthetic routes
uses 1-allyl-3-silyl-protected glycerols as the starting
J . Org. Chem, Vol. 68, No. 17, 2003 6763

Shin and Thompson
F IGURE 1. 1H NMR spectra of Mosher esters of chiral and racemic 5.
5.85 (m, 1H), 7.27-7.43 (m, 12H), 7.60-7.72 (m, 8H); 13C NMR
(CDCl3) δ 19.3, 19.4, 26.9, 27.0, 65.0, 71.2, 72.1, 72.9, 116.5,
127.5, 127.6, 129.6, 133.7, 134.1, 134.3, 135.0, 135.6, 135.7,
135.9; CI (M - H)+ calcd 607, found 607.
6764 J . Org. Chem., Vol. 68, No. 17, 2003

Synthesis of Plasmenylcholine from Allyl-Substituted Glycerols
2,3-Bis-ter t-bu tyld ip h en ylsilyl-1-O-1′-(Z)-h exa d ecen yl-
r a c-glycer ol (2d ). sec-BuLi (0.61 mL, 1.3 M in cyclohexane)
was added to THF (7 mL) at -70 °C. 1d (371 mg, 0.609 mmol)
in THF (1 mL) was added slowly, and the reaction mixture
was stirred under Ar at -70 °C for 2 min. 1-Iodotridecane (245
mg, 0.792 mmol) in THF (4 mL) was slowly added and the
mixture stirred at -70 °C for 10 min before warming to 0 °C.
Hexane (30 mL) was then added and the mixture washed with
H2O (2 × 5 mL). Silica gel chromatography (hexane/CH2Cl2,
8:1) of the organic residue gave 2d 9 as an oil (229 mg, 29.0
mmol, 48% yield): 1H NMR (CDCl3) δ 0.93 (t, 3H, J ) 6 Hz),
1.06 (s, 9H), 1.10 (s, 9H), 1.3 (m, 24H), 2.04 (m, 2H), 3.66-
4.18 (m, 5H), 4.28 (q, 1H, J ) 6 Hz), 5.82 (d, 1H, J ) 6 Hz),
7.30-7.45 (m, 12H), 7.61-7.74 (m, 8H); 13C NMR (CDCl3) δ
14.2, 19.3, 19.4, 22.8, 23.4, 24.1, 26.9, 27.0, 29.5, 29.7, 29.8,
30.0, 32.0, 64.5, 72.8, 106.5, 127.6, 127.7, 129.6, 129.7, 133.6,
134.0, 135.6, 135.7, 135.9, 136.0, 145.5.
34.5, 62.2, 70.0, 72.6, 107.8, 127.8, 129.8, 133.2, 135.6, 144.9,
173.1; ESI calcd (M + Na)+ 813, found 813.
1-Ally l-3-t er t -b u t y lm e t h y ls ily l-2-(2-t r im e t h y ls ila -
n yleth oxym eth yl)-r a c-glycer ol (1a ). Compound 3a (1.48 g,
6.00 mmol) in THF (5 mL) was slowly added to a solution
containing NaH (182 mg, 7.20 mmol) in THF (30 mL) and the
reaction mixture stirred under Ar at 23 °C for 30 min. SEMCl
(0.90 mL, 5.08 mmol) was added and the reaction mixture
heated at reflux for 1 h. Hexane (200 mL) was added after
cooling and the mixture extracted with water (2 × 20 mL).
Silica gel chromatographic purification (hexane/Et2O, 8:1) gave
1a as an oil (1.569 g, 4.16 mmol, 82% yield). 1a : 1H NMR
(CDCl3) δ 0.00-0.07 (m, 15H), 0.88-0.95 (m, 11H), 3.35-3.68
(m, 6H), 3.78 (quintet, 1H, J ) 5 Hz), 3.98 (d, 2H, J ) 5 Hz),
4.76 (s, 2H), 5.14 (d, 1H, J ) 10 Hz), 5.24 (d, 1H, J ) 17 Hz),
5.87 (ddt, 1H, J ) 10, 17, 5 Hz); 13C NMR (CDCl3) δ -5.4,
-1.4, 18.0, 18.2, 25.9, 62.9, 65.0, 70.0, 72.3, 76.6, 94.5, 116.7,
134.8.
1-Allyl-3-ter t-bu tyld im eth ylsilyl-r a c-glycer ol (3a ). Imi-
dazole (3.268 g, 48.0 mmol) was added to 3-allyloxy-1,2-
propanediol (2.64 g, 20.0 mmol) in DMF (25 mL) at 0 °C. TBSCl
(3.620 g, 24.0 mmol) was slowly added at 0 °C and the mixture
stirred under Ar at 23 °C for 3 h. Hexane (300 mL) was added
and the reaction mixture washed with water (2 × 50 mL).
Silica gel chromatographic purification (hexane/Et2O, 2:1) from
the organic residue gave 3a as an oil (4.377 g, 17.8 mmol, 89%
yield). 3a : 1H NMR (CDCl3) δ 0.01 (s, 6H), 0.84 (s, 9H), 2.58
(m, 1H), 3.37-3.47 (m, 2H), 3.59 (d, 2H, J ) 5 Hz), 3.75
(quintet, 1H, J ) 5 Hz), 3.95 (d, 2H, J ) 6 Hz), 5.12 (d, 1H, J
) 10 Hz), 5.20 (d, 1H, J ) 17 Hz), 5.84 (ddt, 1H, J ) 10, 17,
6 Hz); 13C NMR (CDCl3) δ -5.5, 18.2, 25.7, 64.0, 70.6, 70.9,
72.2, 117.0, 134.5; CI (M + H)+ calcd 247, found 247.
1-Allyl-3-ter t-bu tyldiph en ylsilyl-r a c-glycer ol (3b). Com-
pound 3b was prepared as described for 3a using BPSCl in
94% yield. 3b: 1H NMR (CDCl3) δ 1.08 (s, 9H), 2.50 (s, 1H),
3.49-3.59 (m, 2H), 3.73 (d, 2H, J ) 5 Hz), 3.92 (quintet, 1H,
J ) 5 Hz), 4.00 (dt, 2H, J ) 6, 1 Hz), 5.18 (ddt, 1H, J ) 10, 1,
1 Hz), 5.26 (ddt, 1H, J ) 17, 1, 1 Hz), 5.89 (ddt, 1H, J ) 10,
17, 6 Hz), 7.36-7.46 (m, 6H), 7.66-7.70 (m, 4H); 13C NMR
(CDCl3) δ 19.3, 26.9, 64.9, 70.8, 71.0, 72.4, 117.2, 127.8, 129.9,
133.3, 134.6, 135.6.
1-Allyl-3-t er t -b u t yld ip h e n ylsilyl-2-(2-t r im e t h ylsila -
n yleth oxym eth yl)-r a c-glycer ol (1b). Compound 1b was
prepared from 3b as described for 1a in 89% yield. 1b: 1H
NMR (CDCl3) δ -0.02 (s, 9H), 0.88 (t, 2H, J ) 7 Hz), 1.05 (s,
9H), 3.51-3.69 (m, 4H), 3.75 (d, 2H, J ) 6 Hz), 3.89 (quintet,
1H, J ) 5 Hz), 4.00 (dt, 2H, J ) 6, 1 Hz), 4.75 (s, 2H), 5.16
(ddt, 1H, J ) 10, 1, 1 Hz), 5.25 (ddt, 1H, J ) 17, 1, 1 Hz), 5.89
(ddt, 1H, J ) 10, 17, 6 Hz), 7.33-7.44 (m, 6H), 7.66-7.70 (m,
4H); 13C NMR (CDCl3) δ -1.4, 18.1,19.3, 26.9, 63.5, 65.1, 70.1,
72.4, 76.4, 94.4,116.9, 127.7, 129.7, 133.5, 134.9, 135.6; CI (M
+ H)+ calcd 501, found 501.
(R)-(+)-1b. This was prepared as described above using (R)-
(+)-3b: [R]25 +13.0 (c 1.00, CHCl3).
D
(S)-(-)-1b. This was prepared as described above using (S)-
(-)-3b: [R]25 -11.2 (c 1.00, CHCl3).
D
3-ter t-Bu tyld im eth ylsilyl-1-O-1′-(Z)-h exa d ecen yl-2-(2-
t r im et h ylsila n ylet h oxym et h yl)-r a c-glycer ol (2a ) a n d
3-ter t-Bu tyld ip h en ylsilyl-1-O-1′-(Z)-h exa d ecen yl-2-(2-tr i-
m eth ylsila n yleth oxym eth yl)-r a c-glycer ol (2b). The prod-
ucts 2a (44% yield) and 2b (44% yield) were prepared from
1a and 1b, respectively, as described for 2d . 2a : 1H NMR
(CDCl3) δ -0.01-0.04 (m, 15H), 0.84-0.94 (m, 14H), 1.24 (m,
24H), 2.03 (q, 2H, J ) 6 Hz), 3.59-3.85 (m, 7H), 4.29 (q, 1H,
J ) 6 Hz), 4.75 (s, 2H), 5.90 (d, 1H, J ) 6 Hz); 13C NMR
(CDCl3) δ -5.4, -1.4, 14.1, 18.1, 18.3, 22.7, 24.0, 25.8, 25.9,
29.4, 29.6, 29.7, 29.9, 31.9, 62.7, 65.2, 71.9, 76.6, 94.6, 107.0,
145.2; CI (M + H)+ calcd 559, found 559. 2b: 1H NMR (CDCl3)
δ -0.02 (s, 9H), 0.88 (m, 5H), 1.06 (s, 9H), 1.26 (m, 24H), 2.03
(q, 2H, J ) 6 Hz), 3.55-3.98 (m, 7H), 4.32 (q, 1H, J ) 6 Hz),
4.73 (s, 2H), 5.95 (d, 1H, J ) 6 Hz), 7.35-7.44 (m, 6H), 7.67
(d, 4H, J ) 7 Hz); 13C NMR (CDCl3) δ -1.4, 14.2, 18.1, 19.3,
22.7, 24.0, 26.9, 29.4, 29.6, 29.7, 29.8, 29.9, 32.0, 63.3, 65.2,
72.1, 76.3, 94.5, 107.2, 127.7, 129.7, 133.4, 135.6, 145.2; CI (M
+ H)+ calcd 683, found 683.
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-r a c-glycer ol (4a ). s-BuLi (2.3 mL, 1.3 M in
cyclohexane) was slowly added to 3a (246 mg, 1.00 mmol) in
THF (8 mL) at -70 °C and the reaction mixture stirred under
Ar at -70 °C for 1 h. 1-Iodotridecane (680 mg, 2.09 mmol) was
added and the reaction mixture stirred for an additional 10
min at -70 °C before warming to 0 °C. Palmitoyl chloride (450
µL, 1.50 mmol) was then added with stirring at 0 °C for 10
min. Hexane (30 mL) was then added and the mixture
extracted with water (2 × 5 mL). Silica gel chromatographic
purification (hexane/CH2Cl2, 2:1) of the organic residue gave
4a 12 as an oil (206 mg, 0.309 mmol, 31% yield). During silica
gel column purification, the desired γ-coupled product, 4a , was
isolated from early fractions due to its lower polarity compared
to the R-coupled byproducts. 4a : 1H NMR (C6D6) δ 0.03 (s,
6H), 0.93 (m, 15H), 1.31 (m, 48H), 1.62 (m, 2H), 2.22 (t, 2H, J
) 7 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
(quintet, 1H, J ) 5 Hz), 5.88 (d, 1H, J ) 6 Hz); 13C NMR (C6D6)
δ -5.4, 14.4, 18.4, 23.1, 24.5, 25.3, 26.0, 29.4, 29.7, 29.8, 29.9,
30.1, 30.2, 30.3, 32.3, 34.5, 61.7, 70.3, 73.0, 107.4, 145.6, 172.5;
CI calcd (M + H)+ 667, found 667.
3-ter t-Bu t yld ip h en ylsilyl-2-h exa d eca n oyl-1-O-1′-(Z)-
h exa d ecen yl-r a c-glycer ol (4b). Compound 4b9,10 was pre-
pared from 3b as described for 4a in 18% yield. 4b: 1H NMR
(CDCl3) δ 0.88 (m, 6H), 1.05 (s, 9H), 1.25 (m, 48H), 1.59 (m,
2H), 2.00 (q, 2H, J ) 7 Hz), 2.27 (td, 2H, J ) 7, 2 Hz), 3.79 (d,
1H, J ) 5 Hz), 3.93 (m, 2H), 4.34 (q, 1H, J ) 6 Hz), 5.10
(quintet, 1H, J ) 5 Hz), 5.91 (d, 1H, J ) 6 Hz), 7.34-7.45 (m,
6H), 7.64-7.70 (m, 4H); 13C NMR (CDCl3) δ 14.2, 19.3, 22.7,
24.0, 25.0, 26.8, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 32.0,
(R)-(+)-2b. This was prepared as described above using (R)-
(+)-1b: [R]25 +7.0 (c 1.00, CHCl3).
D
(S)-(-)-2b. This was prepared as described above using (S)-
(-)-1b: [R]25 -6.6 (c 1.00, CHCl3).
D
1-O-1′-(Z)-Hexa d ecen yl-2-(2-tr im eth ylsila n yleth oxym -
eth yl)-r a c-glycer ol (5). Imidazole (276 mg, 4.06 mmol) and
TBAF (3.5 mL, 1.0 M in THF) were added to 2b (794 mg, 1.16
mmol) in THF (20 mL) and the reaction mixture stirred at 23
°C for 2 h. The reaction mixture was filtered through a silica
gel plug and the plug washed with Et2O. The organic solution
was concentrated and purified by silica gel chromatography
(hexane/Et2O, 1:1) to give 5 as an oil (500 mg, 1.13 mmol, 97%
yield). 5 was similarly prepared from 2a in 80% yield: 1H NMR
(CDCl3) δ -0.02 (s, 9H), 0.84 (t, 3H, J ) 7 Hz), 0.92 (t, 2H, J
) 8 Hz), 1.22 (m, 24H), 2.00 (q, 2H, J ) 7 Hz), 2.88 (dd, 1H,
J ) 5, 8 Hz), 3.53-3.78 (m, 7H), 4.31 (q, 1H, J ) 6 Hz), 4.70
(d, 1H, J ) 7 Hz), 4.77 (d, 1H, J ) 7 Hz), 5.87 (d, 1H, J ) 6
Hz); 13C NMR (CDCl3) δ -1.4, 14.1, 18.1, 22.7, 24.0, 29.3, 29.4,
29.6, 29.7, 29.8, 31.9, 63.0, 65.7, 71.7, 79.1, 95.2, 107.8, 144.7;
CI (M + H)+ calcd 445, found 445.
J . Org. Chem, Vol. 68, No. 17, 2003 6765

Shin and Thompson
(S)-(-)-5. This was prepared as described above using (R)-
(S)-(+)-7. This was prepared as described above using (S)-
(+)-2b: [R]25 -16.0 (c 1.00, CHCl3).
(-)-6: [R]25 +12.0 (c 1.00, CHCl3).
D
D
(R)-(+)-5. This was prepared as described above using (S)-
2-Hexa d eca n oyl-1-O-1′-(Z)-h exa d ecen yl-r a c-glycer o-3-
p h osp h och olin e (8), (R)-(-)-6, a n d (S)-(+)-8. Racemic 8,12
chiral (R)-(-)-8,9,10 and (S)-(+)-8 was prepared from 7, (R)-
(-)-7, and (S)-(+)-7, respectively, by the reaction of palmitic
anhydride in the presence of DMAP:12 31P NMR (CDCl3) δ
(-)-2b: [R]25 +19.0 (c 1.00, CHCl3).
D
1-O-1′-(Z)-Hexa d ecen yl-2-(2-tr im eth ylsila n yleth oxym -
eth yl)-r a c-glycer o-3-p h osp h och olin e (6). Triethylamine
(550 µL, 3.94 mmol) and 2-oxo-2-chloro-1,3,2-dioxaphospholane
(155 µL, 1.69 mmol) were added to a flask containing 5 (500
mg, 1.13 mmol) in benzene (25 mL) that had been cooled to 5
°C. The solvent was removed under vacuum after stirring at
23 °C for 3 h under Ar. The residue was transferred to a
pressure vessel with benzene (10 mL) and acetonitrile (20 mL).
Trimethylamine (∼15 mL) was then condensed into the vessel
with liquid nitrogen cooling and the mixture stirred at 70 °C
for 24 h. After slow release of high NMe3 pressure at 0 °C, the
resulting solution was purified using a silica gel column (100:
0:0, 80:20:0, and 65:35:6 CH2Cl2/MeOH/H2O step gradient).
Suspended silica gel from the chromatographic fractions was
removed using a 0.45 µm PTFE syringe filter to give a white
solid (529 mg, 0.867 mmol, 77% yield) after lyophilization from
benzene: 1H NMR (CDCl3) δ -0.07 (s, 9H), 0.79 (m, 5H), 1.17
(m, 24H), 1.93 (q, 2H, J ) 6 Hz), 3.29 (s, 9H), 3.47-3.83 (m,
9H), 4.21 (m, 3H), 4.64 (d, 1H, J ) 7 Hz), 4.70 (d, 1H, J ) 7
Hz), 5.85 (d, 1H, J ) 6 Hz); 13C NMR (CDCl3) δ -1.4, 14.1,
18.0, 22.6, 24.0, 29.3, 29.4, 29.6, 29.7, 29.8, 31.9, 54.3, 59.2,
64.4, 65.3, 66.3, 72.4, 75.0, 94.3, 107.0, 145.1; ESI (M + H)+
calcd 610, found 610.
0.156. (R)-(-)-8: [R]25D -1.7 (c 1.00, CHCl3). (S)-(+)-8: [R]25
+0.5 (c 1.00, CHCl3).
D
(R)-(+)-1-Allyl-3-ter t-bu tyldiph en ylsilyl-sn -glycer ol ((R)-
(+)-3b). (R)-(-)-2,2-Dimethyl-1,3-dioxolane-4-methanol (5.00
g, 37.8 mmol) was added to a solution containing NaH (1.43
g, 56.7 mmol) in THF (150 mL) at 0 °C and the mixture stirred
at 23 °C until gas evolution ceased. Allyl bromide (4.9 mL,
56.7 mmol) was added slowly and the mixture stirred under
Ar at 23 °C for 2 h. Hexane (200 mL) was then added and the
solution extracted with H2O (2 × 50 mL). The organic layer
was dried over MgSO4 and concentrated to give an oil. AG50W-
X2 (1 g) and THF/H2O (4:1, 50 mL) solution were added to
the oil. The reaction mixture was heated at reflux overnight
before the solid resin was removed by filtration. The solution
was evaporated under reduced pressure and CH2Cl2 (100 mL)
added. The organic layer was dried over MgSO4 and concen-
trated to give an oil (4.80 g). The oil was further dried under
high vacuum. Imidazole (5.44 g, 80 mmol) was added to the
oil in DMF (80 mL). BPSCl (9.3 mL, 36.3 mmol) was slowly
added at 0 °C and the mixture stirred under Ar at 23 °C for 1
h. Hexane (200 mL) was added and the reaction mixture
washed with water (2 × 50 mL). Silica gel chromatographic
purification (CH2Cl2) of the organic residue gave (R)-(+)-3b
(R)-(+)-6. This was prepared as described above using (S)-
(-)-5: [R]25 +20.8 (c 1.00, CHCl3).
D
(S)-(-)-6. This was prepared as described above using (R)-
(+)-5: [R]25 -16.9 (c 1.00, CHCl3).
D
1-O-1′-(Z)-H e xa d e ce n yl-r a c-glyce r o-3-p h osp h och o-
lin e (7). TBAF (2.4 mL, 1.0 M in THF) was added to 6 (260
mg, 0.426 mmol) in HMPA (5 mL) and the mixture stirred at
90 °C for 18 h. The solution was directly loaded onto a silica
gel column and purified via step gradient elution with CH2-
Cl2/MeOH/H2O (80:20:0, then 65:35:6). Suspended silica gel
from the chromatographic fractions was removed using a 0.45
µm PTFE syringe filter to give 712 (164 mg, 0.342 mmol, 80%
yield) after lyophilization from benzene: 1H NMR (CD3OD) δ
0.89 (t, 3H, J ) 6 Hz), 1.28 (s, 9H), 2.04 (m, 2H), 3.22 (s, 9H),
3.6-3.96 (m, 7H), 4.22-4.38 (m, 3H), 4.90 (s, 1H), 6.00 (d, 1H,
J ) 6 Hz); 13C NMR (CD3OD) δ 14.5, 23.7, 25.0, 30.5, 30.6,
30.7, 30.8, 31.0, 33.1,54.7, 60.4, 67.5, 68.0, 70.8, 73.9, 107.9,
146.3; 31P NMR (CDCl3) δ 1.468; ESI calcd (M + H)+ 480, found
480.
as an oil (11.75 g, 31.7 mmol, 84% yield): [R]25 +2.9 (c 1.00,
D
CHCl3).
(S)-(-)-1-Allyl-3-ter t-bu tyldiph en ylsilyl-sn -glycer ol ((S)-
(-)-3b). This was prepared as described above using (S)-(+)-
2,2-dimethyl-1,3-dioxolane-4-methanol in 83% yield: [R]25
-3.5 (c 1.00, CHCl3).
D
Ack n ow led gm en t. This work was supported by the
NIH (GM55266) and Avanti Polar Lipids.
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 1a ,b,d , 2a ,b,d , and 3-8. 31P NMR
spectral data for compounds 7 and 8. This material is available
free of charge via the Internet at http://pubs.acs.org.
(R)-(-)-7. This was prepared as described above using (R)-
(+)-6: [R]25 -8.3 (c 1.00, CHCl3).
J O026826W
D
6766 J . Org. Chem., Vol. 68, No. 17, 2003