A New Synthetic Route to Chiral Glycerolipid Precursors Using a Cyclic Sulfate Synthon: Preparation of 1-O-Hexadecyl-3-O-(4'-methoxyphenyl)-sn-glycerol and Its 1-Thio and 1-Aza Analogues

Full text of DOI:10.1021/jo980471s

5696
J . Org. Chem. 1998, 63, 5696-5699
A New Syn th etic Rou te to Ch ir a l
Glycer olip id P r ecu r sor s Usin g a Cyclic
Su lfa te Syn th on : P r ep a r a tion of
1-O-Hexa d ecyl-3-O-(4′-m eth oxyp h en yl)-
sn -glycer ol a n d Its 1-Th io a n d 1-Aza
An a logu es
butyldiphenylsilyl, or 4-methoxyphenyl ether.7 A wide
variety of cyclic sulfates have been shown to undergo
regioselective ring opening with nucleophiles, providing
precursors of natural products.8 Here we report the
application of the cyclic sulfate derived from (R)-1-PMP-
glycerol 4, (S)-1-(4′-methoxyphenyl)glycerol 2,3-cyclic
sulfate (5),9 to the preparation of the following four
important glycerolipid precursors: 1-O-hexadecyl-3-O-(4′-
methoxyphenyl)-sn-glycerol (8), 1-S-hexadecyl-3-O-(4′-
methoxyphenyl)-sn-thioglycerol (9), 1-N-hexadecyl-3-O-
(4′-methoxyphenyl)-sn-aminoglycerol (10), and 1-N-hexa-
decylamido-3-O-(4′-methoxyphenyl)-sn-glycerol (12). We
also demonstrate in this paper that (R)-1-PMP-glycerol
4 is readily converted to (R)-PMP-glycidol 7 in high yield.
Syn th esis of Glycid ol 7 via Cyclic Su lfa te 5.
Glycidol derivatives such as 7 are potential C-3 chiral
synthons for the synthesis of many natural/unnatural
products.10 For example, 7 has recently been used in the
synthesis of a chiral deoxysphingomyelin.11a There are
several existing methods for preparing PMP-glycidol 7.11
However, a one-pot synthesis using the reaction of PMP-
glycerol 4 with diisopropyl azodicarboxylate (DIAD) and
triphenylphosphine gave 7 in a yield of only 69%,11a and
other multistep synthetic routes presented also gave
yields of e73%.11b An improved method gave a very high
yield of 7, but special care was required to thoroughly
dry the cyclic stannylene intermediate, and a nonpolar
impurity (presumably p-toluenesulfonic anhydride) must
be removed before base-induced cyclization.11a We report
here a new and highly convenient method (Scheme 1)
that provides 7 in an overall yield of 94% from (R)-1-
PMP-glycerol 4. The diol 4 was prepared from p-
methoxyphenyl allyl ether in large scale and high ee by
using a modified asymmetric dihydroxylation reaction.12
Diol 4 was treated with SOCl2 in the presence of pyridine
followed by oxidation of the cyclic sulfite with NaIO4 in
the presence of a catalytic amount of RuCl3‚H2O to give
cyclic sulfate 5 in almost quantitative yield. The cyclic
sulfate 5 was opened by LiBr in THF to provide bromo-
hydrin 6. Cyclization of bromohydrin 6 in methanolic
Linli He, Hoe-Sup Byun, and Robert Bittman*
Department of Chemistry & Biochemistry, Queens College
of The City University of New York,
Flushing, New York 11367-1597
Received March 12, 1998
Phosphatidylcholines (PCs) are major components of
cell membranes and play important physiological roles
in many biological processes.1 Structurally modified PCs
have been widely used for drug delivery in liposomes2
and for physical studies of membrane structure and
function.3 Unnatural ether-linked phospholipids such as
alkyl lysophospholipids (ALPs, 1), which contain a 1-O-
16- or 18-carbon aliphatic chain at the sn-1 position and
an O-methyl group at the sn-2 position of glycerophos-
phocholine, have potent cytotoxic activity toward various
tumor cells, and are potential anticancer drugs in clinical
trials.4 Analogues of ALPs bearing an alkylthio or an
alkylamino group at the sn-1 position of the glycerol
backbone, for instance, 1-S-hexadecyl-2-O-methyl/ethyl-
rac-thioglycerol-3-phosphocholine (2) and 1-N-hexadecyl-
2-O-methyl-sn-aminoglycerol-3-phosphocholine (3), pos-
sess antineoplastic activity.5 Single-chain ether lipids
that bear an ω-carboxyl group at the sn-1 position6a
represent another unnatural analogue of platelet-activat-
ing factor. Coupling of ether phospholipids to mechani-
cally stable solid surfaces (e.g., silica propylamine)
produces immobilized artificial membranes (IAMs), which
have found wide applications in affinity chromatography.6b
The most widely used chiral synthons in the synthesis
of PCs are various glycerol and glycidol derivatives in
which a hydroxy group is masked as a trityl, benzyl, tert-
* Corresponding author. Telephone: (718)997-3279. Fax: (718)997-
3349. E-mail: bittman@qcvaxa.qc.edu.
(1) (a) Spector, A.; Yorek, M. A. J . Lipid Res. 1985, 26, 1015-1035.
(b) Cullis, P. R.; Hope, M. J .; de Kruijff, B.; Verkleij, A. J .; Tilcock, C.
P. S. In Phospholipids and Cellular Regulation; Kuo, J . F., Ed.; CRC
Press: Boca Raton, 1985; pp 1-59. (c) Gennis, R. B. In Biomem-
branes: Molecular Structure and Function; Springer-Verlag: New
York, 1989; pp 1-84.
(2) For relevant recent examples, see: (a) Kirpotin, D.; Park, J . W.;
Hong, K.; Zalipsky, S.; Li, W.-L.; Carter, P.; Benz, C. C.; Papahad-
jopoulos, D. Biochemistry 1997, 36, 66-75. (b) Shimada, K.; Kamps,
J . A. A. M.; Regts, J .; Ikeda, K.; Shiozawa, T.; Hirota, S.; Scherphof,
G. L. Biochim. Biophys. Acta 1997, 1326, 329-341. (c) Harding, J . A.;
Engbers, C. M.; Newman, M. S.; Goldstein, N. I.; Zalipsky, S. Biochim.
Biophys. Acta 1997, 1327, 181-192.
(7) (a) For a review, see: Bittman, R. In Phospholipids Handbook;
Cevc, G., Ed.; Marcel Dekker: New York, 1993; pp 141-232. (b) Byun,
H.-S.; Bittman, R. J . Org. Chem. 1994, 59, 668-671. (c) Vilche`ze, C.;
Bittman, R. J . Lipid Res. 1994, 35, 734-738. (d) Byun, H.-S.; Kumar,
E. R.; Bittman, R. J . Org. Chem. 1994, 59, 2630-2633. (e) Marino-
Albernas, J . R.; Bittman, R.; Peters, A.; Mayhew, E. J . Med. Chem.
1996, 39, 3241-3247.
(8) For reviews, see: (a) Lohray, B. B. Synthesis 1992, 1035-1052.
(b) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483-2547.
(9) Compound 5 was prepared from (R)-1-PMP-glycerol 4 in almost
quantitative yield using a published procedure (ref 13).
(10) For a review, see: Hanson, R. M. Chem. Rev. 1991, 91, 437-
475.
(11) (a) Byun, H.-S.; Sadlofsky, J . A.; Bittman, R. J . Org. Chem.
1998, 63, 2560-2563. (b) Takano, S.; Moriya, M.; Suzuki, M.; Iwabuchi,
Y.; Sugihara, T.; Ogasawara, K. Heterocycles 1990, 31, 1555-1562.
(12) Byun, H.-S.; Kumar, E. R.; Bittman, R. J . Org. Chem. 1994,
59, 2630-2633.
(3) Kan, C.-C.; Bittman, R.; Hajdu, J . Biochim. Biophys. Acta 1991,
1066, 95-101, and references therein.
(4) For recent reviews, see: (a) Lohmeyer, M.; Bittman, R. Drugs
Future 1994, 19, 1021-1037. (b) Houlihan, W. J .; Lohmeyer, M.;
Workman, P.; Cheon, S. H. Med. Res. Rev. 1995, 15, 157-223. (c)
Arthur, G.; Bittman, R. Biochim. Biophys. Acta 1998, 1390, 85-102.
(d) Bittman, R.; Arthur, G. In Liposomes: Rational Design; J anoff, A.
S., Ed.; Marcel Dekker: New York, 1998; in press.
(5) (a) Morris-Natschke, S. L.; Surles, J . R.; Daniel, L. W.; Berens,
M. E.; Modest, E. J .; Piantadosi, C. J . Med. Chem. 1986, 29, 2114-
2117. (b) Morris-Natschke, S. L.; Gumus, F.; Marasco, C. J ., J r.; Meyer,
K. L.; Marx, M.; Piantadosi, C.; Layne, M. D.; Modest, E. J . J . Med.
Chem. 1993, 36, 2018-2025.
(6) (a) Qiu, X.; Ong, S.; Bernal, C.; Rhee, D.; Pidgeon, C. J . Org.
Chem. 1994, 59, 537-543. (b) Ong, S.; Cal, S.-J .; Bernal, C.; Rhee, D.;
Qiu, X.; Pidgeon, C. Anal. Chem. 1994, 66, 782-792.
S0022-3263(98)00471-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/23/1998

Notes
J . Org. Chem., Vol. 63, No. 16, 1998 5697
Sch em e 1. Syn th esis of (R)-O-P MP -glycid ol 7 via
Sch em e 3. Op en in g of Cyclic Su lfa te 5 w ith
Nu cleop h iles
Cyclic Su lfa te 5
Sch em e 2. Op en in g of Ep oxid e 7 w ith
Nu cleop h iles
cylmercaptan in the presence of NaBH416 in THF at room
temperature proceeded smoothly and gave the desired
thioglycerol 9 in 93% yield; no regioisomer was detected
1
by either TLC or H NMR. Based on the rationale that
primary amines are stronger ligating reagents toward
Lewis acids than PMP-glycidol 7, direct reaction (without
any Lewis acid) of 1-hexadecylamine and PMP-glycidol
in THF was initially attempted. No reaction was ob-
served by TLC after 24 h of stirring under nitrogen. The
same reaction was also unsuccessful when Ti(O-i-Pr)4 (2
equiv) was tried. Not surprisingly, still no reaction
occurred after 24 h of stirring since a strong chelating
group (e.g. hydroxyl or carbonyl) next to the oxirane is
required for Ti(O-i-Pr)4 to mediate the ring opening.17
Both starting materials were recovered in more than 90%
yield. When 1-hexadecylamine was refluxed with PMP-
glycidol 7 in EtOH, a complex mixture was obtained.18
This was presumably due to polyalkylation of the amine.
Amido-linked glycerol derivative 12, which is a precur-
sor of several ALP analogues,19 was also prepared via
azide 11. PMP-glycidol 7 was opened with azide anion
in 8:1 MeOH-H2O in the presence of 2.5 equiv of NH4-
Cl.17a The reaction was complete after 1.5 h of reflux.
After separation by column chromatography, azide 11
was isolated in 95% yield; in addition, (2S)-2-azido-1-O-
(4′-methoxyphenyl)-1,3-propanediol, the regioisomer of
11, was obtained in 1.8% yield and characterized by
NMR. An alternative route to azide 11 was achieved by
reaction of cyclic sulfate 5 with NaN3 in 3:1 Me2CO-H2O
followed by hydrolysis (20% H2SO4/Et2O). This reaction
gave a similar chemical yield (94%), but a lower regiose-
lectivity (ratio of 11 to isomer ) 19:1). The reduction of
azide 11 with Ph3P-H2O in THF followed by in situ
acylation with p-nitrophenyl palmitate provided amide
12 in 80% overall yield from PMP-glycidol 7 or 79%
overall yield from cyclic sulfate 5, demonstrating that this
is an efficient synthesis of the important intermediate
12.20
K2CO3 solution led to PMP-glycidol 7. This synthetic
route is stereospecific.13,14
Op en in g Rea ction of Glycid ol 7 w ith Nu cleo-
p h iles. With (R)-1-PMP-glycidol 7 on hand, we next
tested its ring-opening reactions with 1-hexadecanol,
hexadecylmercaptan, and 1-hexadecylamine as shown in
Scheme 2. The opening of glycidol derivatives with
1-hexadecanol in the presence of a catalytic amount of
BF3‚Et2O at room temperature in CHCl3 is a well-known
method for preparing glycerides bearing a 1-O-alkyl
linkage.7,15 Therefore, we used catalytic BF3‚Et2O to open
7 with 1-hexadecanol and isolated the desired product
8, but obtained a yield of only 50%. The yield of the
reaction could not be improved by varying the reaction
temperature. Although the reaction still proceeded
rapidly at 0 °C, according to TLC several byproducts were
formed. In contrast, the opening reaction with hexade-
(13) Gao, Y.; Sharpless, K. B. J . Am. Chem. Soc. 1988, 110, 1538-
1539.
(14) He, L.; Byun, H.-S.; Bittman, R. Tetrahedron Lett. 1998, 39,
2071-2074.
(15) (a) Guivisdalsky, P. N.; Bittman, R. J . Am. Chem. Soc. 1989,
111, 3077-3079. (b) Guivisdalsky, P. N.; Bittman, R. J . Org. Chem.
1989, 54, 4637-4642. (c) Berkowitz, W. F.; Pan, D.; Bittman, R.
Tetrahedron Lett. 1993, 34, 4297-4300.
(16) The borohydride-mediated opening reaction of in situ generated
(S)-glycidol with hexadecylmercaptan provided 1-S-hexadecyl-sn-
thioglycerol in excellent yield: see ref 7b.
Su b st it u t ion R ea ct ion of Cyclic Su lfa t e 5 w it h
Nu cleop h iles. Although the above problems might have
been solved through further experimentation by either
changing the reaction conditions or using other activating
agents, we chose instead to try nucleophilic substitution
of the cyclic sulfate 5 with the corresponding alcohol,
thiol, and amine to synthesize 8, 9, and 10. It is well
known that cyclic sulfates are more reactive than ep-
oxides in many reactions.8a As illustrated in Scheme 3,
excellent yields were obtained for all three reactions with
different nucleophiles. Slightly different procedures were
(17) (a) Caron, M.; Sharpless, K. B. J . Org. Chem. 1985, 50, 1557-
1560. (b) Chong, J . M.; Sharpless, K. B. J . Org. Chem. 1985, 50, 1560-
1564.
(18) de Caro, P. S.; Mouloungui, Z.; Gaset, A. J . Am. Oil Chem. Soc.
1997, 74, 235-240.
(19) Marx, M. H.; Piantadosi, C.; Noseda, A.; Daniel, L. W.; Modest,
E. J . J . Med. Chem. 1988, 31, 858-863.
(20) Attempts to convert amidoglycerol 12 to aminoglycerol 10 with
BH3‚THF complex using published procedures23 were unsuccessful.

5698 J . Org. Chem., Vol. 63, No. 16, 1998
Notes
cyclic sulfite (8.5 g, 100%) was obtained as a colorless oil. To a
solution of the cyclic sulfite in 100 mL of CH3CN were added
10.4 g (48.7 mmol) of NaIO4 and 80 mg (0.35 mmol) of RuCl3‚
H2O in 20 mL of H2O. After the purplish suspension was stirred
at room temperature for 20 min, 80 mL of H2O and 100 mL of
Et2O were added. The layers were separated, and the aqueous
layer was extracted with two portions of Et2O (100 mL each).
The combined ether layer was dried over Na2SO4, and the
solvents were removed by rotary evaporation (i-PrOH was used
to remove the residual H2O) and further dried under vacuum.
Pure cyclic sulfate 5 (8.9 g, 98%) was obtained as a white solid;
employed for each reaction based on the nature of the
nucleophiles. Direct reaction of cyclic sulfate 5 with
hexadecylamine in THF followed by hydrolysis of the
sulfate with dilute H2SO4/ether and neutralization with
NaOH gave aminoglycerol 10 in 95% yield. The ring-
opening reactions with C16H33OH and C16H33SH were
carried out by first converting the alcohol and thiol into
their anions. As our first choice, NaH in THF was tried.
However, it seemed that even the conversion of the thiol
was very sluggish at room temperature. The reaction
between NaH and hexadecylmercaptan was not complete
after 4 h of stirring, while at higher temperature (60-
65 °C), hydrogen gas generated could be troublesome
since it made the soaplike NaSC16H33 into a foam which
pushed all the way up to the rim of the flask, making
stirring impossible. For a quick and quantitative conver-
sion, n-BuLi was used instead. Thus, 1 equiv of n-BuLi
and ROH or RSH was allowed to react in THF at 0 °C
for 10 min, followed by injection of cyclic sulfate 5 in THF
at room temperature. Immediate precipitation was
observed when the thiol was mixed with n-BuLi, whereas
no clear change was observed in the alcohol reaction.
Ring opening with RS- proceeded rapidly and was
complete within 2 h. However, in the reaction of the fatty
alkoxide ion, 5-6 h was required for the full consumption
of the cyclic sulfate 5. Thioglyceride 9 was purified from
excess C16H33SH by flash chromatography. However,
because the polarity of C16H33OH and product 8 are very
similar in all of the solvent systems we tried, at least
two column separations by gravity were required to
obtain pure 8 (elution with chloroform only).21
In summary, a novel and efficient synthetic route
toward the preparation of three important intermediates,
8, 9, and 10, from cyclic sulfate 5 using the same strategy
has been developed. Substitution of cyclic sulfate 5 with
nucleophiles has the following advantages over the
corresponding opening reactions of PMP-glycidol 7: (i)
all three direct approaches begin with a common sub-
strate; (ii) the synthetic route is shorter; (iii) the reactions
are easier to handle; (iv) the yields are higher. The three
reactions of cyclic sulfate 5 with a long-chain alcohol,
thiol, and amine described here are, to the best of our
knowledge, the first examples of such reactions. Fur-
thermore, we also present a new and efficient method to
prepare PMP-glycidol 7, an important synthon in natural/
unnatural product synthesis, and an efficient synthesis
of amidoglycerol 12, an important intermediate in the
preparation of amidoglycerolipids.
mp 90.0-91.0 °C; Rf 0.46 (hexane/EtOAc 2/1); [R]25 -2.84° (c
D
4.3, CHCl3). The other physical data (mp, Rf, IR, 1H and 13C
NMR, and HR-MS) were identical to data reported for the
enantiomer.11a
4′-Meth oxyp h en yl (R)-2-Oxir a n ylm eth yl Eth er ((-)-7).
To a solution of 7.0 g (26.9 mmol) of cyclic sulfate 5 in 140 mL
of dry THF was added 9.4 g (108.2 mmol) of LiBr. The
suspension was stirred at room temperature until the disap-
pearance of 5 was noted by TLC. After the solvent was removed
under vacuum to give a slurry, 100 mL of ether and 100 mL of
20% aqueous H2SO4 were added. The heterogeneous solution
was stirred vigorously at room temperature overnight. The
layers were separated, and the aqueous layer was extracted with
two more portions of ether (100 mL each). The combined ether
layer was dried over Na2SO4 and concentrated to give 7.0 g of
1-O-(4′-methoxyphenyl)-3-bromo-1,2-propanediol (6) as a slightly
yellow oil. To a solution of crude 6 in 100 mL of MeOH at -23
°C was added 14.0 g (107.0 mmol) of ground K2CO3. The
heterogeneous solution was stirred at this temperature under
nitrogen until the disappearance of starting material (2 h), and
then 50 mL of saturated NH4Cl aqueous solution was added
slowly, followed by extraction with CH2Cl2 (3 × 100 mL). The
extracts were dried over Na2SO4 and concentrated to give 4.65
g (96% from 5) of pure glycidol 7 as a white solid; mp 41.0-41.8
°C; Rf 0.64 (hexane/EtOAc 2/1); [R]25 -10.2° (c 1.29, MeOH)
D
[lit.11b [R]30D -11.72° (c 1.06, MeOH)]; IR (NaCl) 1031, 1232 cm-1
;
1H NMR (CDCl3) δ 2.73 and 2.75 (ABq, 1H, J ) 2.6 Hz, ∆υ )
4.2 Hz), 2.89 (t, 1H, J ) 4.6 Hz), 3.31-3.35 (m, 1H), 3. 77 (s,
3H), 3.90 and 3.94 (ABq, 1H, J ) 5.6 Hz, ∆υ ) 9.24 Hz), 4.15-
4.19 (ABq, 1H, J ) 3.2 Hz, ∆υ ) 10.6 Hz), 6.86 (m, 4H); 13C
NMR (CDCl3) δ 44.72, 50.27, 55.69, 69.51, 114.64, 115.71, 152.64,
154.17.
1-O-Hexa d ecyl-3-O-(4′-m eth oxyp h en yl)-sn -glycer ol (8).
Meth od A (Sch em e 2): To a stirred solution of 364 mg (1.5
mmol) of 1-hexadecanol and 181 mg (1.0 mmol) of PMP-glycidol
7 in 25 mL of dry THF was injected 12 µL (0.1 mmol) of BF3‚
Et2O. The reaction mixture was stirred at room temperature
under nitrogen until the full consumption of 7. The solvent was
removed and the solid residue was purified by column chroma-
tography (elution with CHCl3) to give 211 mg (50%) of glycerol
822 as a white solid; mp 63.0-64.2 °C. Meth od B (Sch em e 3):
To an ice-cooled solution of 727 mg (3.0 mmol) of 1-hexadecanol
in 60 mL of THF was injected 1.2 mL (3.0 mmol) of 2.5 M n-BuLi
in hexane. The solution was stirred at this temperature for 10
min, and then the ice-bath was removed. A solution of cyclic
sulfate 5 (521 mg, 2.0 mmol) in 10 mL of THF was injected. The
solution was stirred at room temperature under nitrogen until
the disappearance of 5. Ether (40 mL) and 20% H2SO4 (40 mL)
were added, and the reaction mixture was stirred vigorously for
24 h at room temperature. The two layers were separated, and
the aqueous layer was extracted with two more portions of ether
(80 mL each). The combined ether layer was dried over Na2-
SO4 and concentrated to give a solid residue that was purified
by column chromatography (elution with CHCl3). Glycerol 8
(761 mg, 90%) was obtained as a white solid; mp 63.4-64.5 °C
[lit.12 mp 64-65 °C]; Rf 0.64 (hexane/EtOAc 2/1); IR (NaCl) 1043,
Exp er im en ta l Section
Gen er a l In for m a tion . See refs 7b and 12 for experimental
protocols. 1H and 13C NMR spectra were recorded on a 400-
MHz Bruker spectrometer.
(S)-1-(4′-Meth oxyp h en yl)glycer ol 2,3-Cyclic Su lfa te
((-)-5). To an ice-cooled solution of 6.9 g (34.8 mmol) of (R)-1-
(4′-methoxyphenyl)glycerol [4, 90% ee, [R]25 -7.35° (c 1.5,
D
MeOH)]12 and 7.7 g (97.0 mmol) of pyridine in 100 mL of CH2-
Cl2 was injected 3.5 mL (48.7 mmol) of SOCl2. The reaction
mixture was stirred at 0 °C for 30 min and then filtered through
a pad of silica gel, which was washed with 400 mL of hexanes-
EtOAc (2:1). The filtrate was concentrated in a rotary evapora-
tor and further dried using a vacuum pump (1 h, 0.5 Torr). The
1
1109, 1465, 1523 cm-1; H NMR (CDCl3) δ 0.86 (t, 3H, J ) 6.6
Hz), 1.24 (m, 26H), 1.56 (m, 2H), 2.37 (br s, 1H), 3.47 (dt, 2H, J
) 6.7 Hz,), 3.53 (dd, 1H, J ) 9.7, 6.0 Hz), 3.58 (dd, 1H, J ) 9.8,
4.5 Hz), 3.75 (s, 3H), 3.95 (m, 2H), 4.12 (m, 1H), 6.78-6.85 (m,
4H); 13C NMR (CDCl3) δ 14.11, 22.67, 26.08, 29.34, 29.45, 29.58,
29.68, 31.91, 55.68, 69.14, 69.72, 71.45, 71.74, 114.60, 115.51,
152.75, 154.03; HRMS [M+] Calcd for m/z C26H46O4 422.3396,
found 422.3397.
(21) When compound 8 was prepared on a large scale (e.g. g10 g),
purification by crystallization from hexane/EtOAc instead of column
chromatography provided chirally enriched, pure 8 (see ref 7d).
(22) The observed optical rotation value of compound 8 is zero (see
ref 7d).
1-S-Hexa d ecyl-3-O-(4′-m et h oxyp h en yl)-sn -t h ioglycer ol
((-)-9). Meth od A (Sch em e 2): To a solution of 517 mg (2.0
(23) Brown, H. C.; Heim, P. J . Org. Chem. 1973, 38, 912-916.

Notes
J . Org. Chem., Vol. 63, No. 16, 1998 5699
mmol) of hexadecylmercaptan in 30 mL of THF was added 79
mg (2.1 mmol) of NaBH4. The heterogeneous solution was
stirred for 4 h at room temperature under nitrogen, 270 mg (1.5
mmol) of PMP-glycidol 7 was added, and the solution was stirred
at room temperature until the full consumption of 7. MeOH (2
mL) was added, and the solution was stirred for an additional 1
h. The reaction mixture was filtered through a pad of silica gel
in a sintered funnel, which was rinsed with hexane/EtOAc 4/1.
After the removal of solvents, the residue was purified by flash
chromatography (elution with hexanes-EtOAc 6/1). There was
obtained 612 mg (93%) of the desired product 9 as a white solid;
(2R)-3-Azido-1-O-(4′-m eth oxyph en yl)-1,2-pr opan ediol ((+)-
11). Meth od A (Sch em e 2): To a solution of 361 mg (2.0 mmol)
of PMP-glycidol 7 in 27 mL of MeOH and H2O 8/1 was added
235 mg (4.4 mmol) of NH4Cl, followed by 650 mg (10.0 mmol) of
NaN3. The reaction mixture was heated under reflux until the
full consumption of 7 was noted (1.5 h). Water (40 mL) was
added, and the solution was extracted with CH2Cl2 (30 mL ×
3). The combined organic layer was dried over Na2SO4 and
concentrated to give a solid residue that was purified by column
chromatography (elution with hexane/EtOAc 2/1), giving 436 mg
(95%) of product 11 as an oil and 8 mg (1.8%) of the regioisomer.
Meth od B (Sch em e 3): To a solution of 521 mg (2.0 mmol) of
cyclic sulfate 5 in 30 mL of acetone and 10 mL of H2O was added
260 mg (4.0 mmol) of NaN3. The heterogeneous solution was
stirred at room temperature until the disappearance of 5 (2 h).
After most of the acetone was removed in a rotary evaporator,
50 mL of ether and 20 mL of 20% H2SO4 were added, and the
heterogeneous solution was stirred vigorously at room temper-
ature overnight. The two layers were separated, and the
aqueous layer was extracted with two more portions of ether
(50 mL each). The combined organic layer was dried over Na2-
SO4. Concentration gave a light yellow oil that was purified by
column chromatography (elution with hexane/EtOAc 2/1) to give
431 mg (94%) of the desired product 11 and 21 mg (4.7%) of the
mp 71.0-72.0 °C; [R]25 -2.7° (c 2.2, CHCl3). Meth od
B
D
(Sch em e 3): To an ice-cooled solution of 776 mg (3.0 mmol) of
hexadecylmercaptan in 60 mL of THF was injected 1.2 mL (3.0
mmol) of a solution of n-BuLi (2.5 M in hexane). The milklike
suspension was stirred at this temperature for 10 min, and then
the ice-bath was removed. A solution of cyclic sulfate 5 (520
mg, 2.0 mmol) in 10 mL of THF was injected, and the solution
was stirred at room temperature under nitrogen until the
disappearance of 5. Diethyl ether (40 mL) and 20% aqueous
H2SO4 (40 mL) were added to the above reaction mixture, and
the reaction mixture was stirred vigorously for 24 h at room
temperature. The two layers were separated, and the aqueous
layer was extracted with two more portions of ether (80 mL
each). The combined ether layer was dried over Na2SO4 and
concentrated to give a solid residue that was purified by flash
chromatography (elution with hexanes-EtOAc 6/1), affording
825 mg (94%) of the desired product 9 as a white solid; mp 71.5-
regioisomer, both as oils; 11: Rf 0.49 (hexane/EtOAc 2/1); [R]25
D
+15.76° (c 3.93, CHCl3); IR (NaCl) 1042, 1059, 2106, 2253, 3580
1
cm-1; H NMR (CDCl3) δ 2.48 (br s, 1H), 3.49 (m, 2H), 3.75 (s,
3H), 3.95 (m, 2H), 4.12 (m, 1H), 6.82 (m, 4H); 13C NMR (CDCl3)
δ 53.36, 55.70, 69.38, 69.79, 114.71, 115.57, 152.32, 154.32.
1-N -H e xa d e cyla m id o-3-(4′-m e t h oxyp h e n yl)-sn -glyc-
er ol ((+)-12). To a solution of 229 mg (1.0 mmol) of 1-(4′-
methoxyphenyl)-3-azido-1,2-propanediol 11 in 18 mL of THF and
2 mL of H2O was added 755 mg (2.0 mmol) of 4-nitrophenyl
palmitate followed by 524 mg (2.0 mmol) of Ph3P. The reaction
mixture was stirred at room temperature for 48 h under
nitrogen. Concentration gave a yellow solid that was purified
by column chromatography (elution with EtOAc) to give 367 mg
(84%) of amidoglycerol 12 as a white solid; mp 102.0-103.5 °C;
Rf 0.6 (EtOAc); [R]25D +8.7° (c 2.7, CHCl3); IR (NaCl) 1045, 1527,
72.4 °C; Rf 0.6 (hexane/EtOAc 4/1); [R]25 -2.9° (c 2.45, CHCl3);
D
IR (NaCl) 1040, 1466, 1508 cm-1
;
1H NMR (CDCl3) δ 0.86 (t,
3H, J ) 6.6 Hz), 1.24 (m, 24H), 1.35 (m, 2H), 1.57 (m, 2H), 2.19
(br s, 1H), 2.54 (t, 2H, J ) 7.4 Hz), 2.70 (dd, 1H, J ) 13.7, 5.2
Hz), 2.83 (dd, 1H, J ) 13.6, 7.2 Hz), 3.75 (s, 3H), 3.94-4.06 (m,
3H), 6.80-6.85 (m, 4H); 13C NMR (CDCl3) δ 14.11, 22.68, 28.83,
29.21, 29.36, 29.51, 29.59, 29.65, 29.69, 31.92, 32.61, 35.88, 55.70,
68.64, 71.16, 114.65, 115.55, 152.61, 154.13; HRMS [M+] Calcd
for m/z C26H46O3S 438.3168, found 438.3171.
1-N-H exa d ecyl-3-O-(4′-m et h oxyp h en yl)-sn -a m in oglyc-
er ol ((+)-10). A solution of 362 mg (1.5 mmol) of 1-hexadec-
ylamine and 261 mg (1.0 mmol) of cyclic sulfate 5 in 25 mL of
THF was stirred under nitrogen until the disappearance of 5.
Ether (40 mL) and 20% H2SO4 (20 mL) were added, and the
white suspension was stirred vigorously at room temperature
for 24 h. Sodium hydroxide pellets were added to the ice-cooled
reaction mixture slowly until the pH reached >12. The layers
were separated, and the aqueous layer was extracted with three
more portions of ether (40 mL each). The combined ether layer
was dried over Na2SO4. After the removal of solvents, the
residue was purified by flash chromatography (elution with
CHCl3/MeOH 9/1). The aminoglycerol 10 was dissolved in CHCl3
and passed through a Cameo filter (Fisher Scientific) to remove
the dissolved silica gel. After lyophilization from benzene, 401
mg (95%) of the desired aminoglycerol 10 was obtained as a
white solid; mp 255.0-258.5 °C (dec); Rf 0.64 (CHCl3/MeOH 9/1);
1659, 3450 cm-1 1H NMR (CDCl3) δ 0.86 (t, 3H, J ) 6.6 Hz),
;
1.23 (m, 26H), 1.62 (m, 2H), 2.21 (t, 2H, J ) 7.5 Hz), 3.40 (m,
1H), 3.60 (m, 1H), 3.75 (s, 3H), 3.87 (m, 1H), 4.07 (m, 1H), 6.02
(br s, 1H), 6.81 (m, 4H); 13C NMR (CDCl3) δ 14.12, 22.68, 25.78,
29.24, 29.32, 29.35, 29.47, 29.61, 29.65, 29.68, 31.92, 26.30, 43.09,
55.71, 69.58, 69.99, 114.70, 115.44, 152.41, 154.21, 175.34;
HRMS [M+] Calcd for m/z C26H46NO4 436.3427, found 436.3423.
Ack n ow led gm en t. This work was supported by the
NIH Grant HL-16660. We thank Professor W. F. Berkow-
itz for helpful discussions. We also thank the mass
spectrometry facility at Michigan State University for
the HR-FAB MS. We gratefully acknowledge NSF Grant
CHE-9408535 for funds for the purchase of the 400-MHz
NMR spectrometer.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for compounds 8-12 (10 pages). This material
is contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
[R]25 +25.8° (c 3.15, CHCl3); IR (NaCl) 1037, 1463, 1508 cm-1
;
D
1H NMR (CDCl3) δ 0.86 (t, 3H, J ) 6.5 Hz), 1.14-1.28 (m, 28H),
1.69 (br s, 1H), 3.07 (m, 2H), 3.30 (m, 1H), 3.70 (s, 3H), 3.71 (m,
1H), 4.08-4.16 (m, 2H), 5.06 (m, 1H), 6.72-6.79 (m, 4H); 13C
NMR (CDCl3) δ 14.12, 22.69, 25.64, 26.63, 29.22, 29.38, 29.59,
29.62, 29.69, 29.75, 31.94, 48.79, 49.19, 55.55, 68.13, 71.80,
114.64, 115.41, 151.91, 154.40; HRMS [MH+] Calcd for m/z
C
26H48NO3 422.3634, found 422.3635.
J O980471S