An efficient preparation of isosteric phosphonate analogues of sphingolipids by opening of oxirane and cyclic sulfamidate intermediates with α-lithiated alkylphosphonic esters

Article abstract of DOI:10.1021/jo0487404

D-erythro-(2S,3R,4E)-Sphingosine-1-phosphonate (1), the isosteric phosphonate analogue of naturally occurring sphingosine 1-phosphate (1a), and D-ribo-phytosphingosine 1-phosphonate (2), the isosteric phosphonate analogue of D-ribo-phytosphingosine- 1-phosphate (2a), were synthesized starting with methyl 2,3-O-isopropylidene-D-glycerate (4) and D-ribo-phytosphingosine (3), respectively. Oxirane 12 was formed in eight steps from 4, and cyclic sulfamidate 22 was formed in five steps from 3. The phosphonate group was introduced via regioselective ring-opening reactions of oxirane 12 and cyclic sulfamidate 22 with lithium dialkyl methylphosphonate, affording 13 and 23, respectively. The synthesis of 1 was completed by S_N2 displacement of chloromesylate intermediate 14b with azide ion, followed by conversion of the resulting azido group to a NHBoc group and deprotection. The synthesis of 2 was completed by cleavage of the acetal, N-benzyl, and alkyl phosphonate ester groups.

Full text of DOI:10.1021/jo0487404

An Efficien t P r ep a r a tion of Isoster ic P h osp h on a te An a logu es of
Sp h in golip id s by Op en in g of Oxir a n e a n d Cyclic Su lfa m id a te
In ter m ed ia tes w ith r-Lith ia ted Alk ylp h osp h on ic Ester s
Chaode Sun and Robert Bittman*
Department of Chemistry and Biochemistry, Queens College of The City University of New York,
Flushing, New York 11367-1597
robert_bittman@qc.edu
Received J uly 22, 2004
D-erythro-(2S,3R,4E)-Sphingosine-1-phosphonate (1), the isosteric phosphonate analogue of naturally
occurring sphingosine 1-phosphate (1a ), and D-ribo-phytosphingosine 1-phosphonate (2), the isosteric
phosphonate analogue of D-ribo-phytosphingosine-1-phosphate (2a ), were synthesized starting with
methyl 2,3-O-isopropylidene-D-glycerate (4) and D-ribo-phytosphingosine (3), respectively. Oxirane
12 was formed in eight steps from 4, and cyclic sulfamidate 22 was formed in five steps from 3.
The phosphonate group was introduced via regioselective ring-opening reactions of oxirane 12 and
cyclic sulfamidate 22 with lithium dialkyl methylphosphonate, affording 13 and 23, respectively.
The synthesis of 1 was completed by SN2 displacement of chloromesylate intermediate 14b with
azide ion, followed by conversion of the resulting azido group to a NHBoc group and deprotection.
The synthesis of 2 was completed by cleavage of the acetal, N-benzyl, and alkyl phosphonate ester
groups.
In tr od u ction
than 1a to a widely distributed cell-surface G-protein
coupled receptor.5 Metabolically stable analogues of 1a
and 2a in which the scissile O-P bond is replaced by a
C-P bond are of interest in biological studies because
they are resistant to phosphohydrolase action. As part
of our program to study sphingolipid bioactivity,6 the
availability of isosteric 1-phosphonate derivatives 1 and
2 became a requirement; therefore, we sought to develop
efficient syntheses of these phosphonolipids.
The previous synthetic efforts to prepare phosphonate
derivatives of sphingolipids have all employed a Michael-
is-Arbuzov reaction7 for installation of the carbon-
phosphorus bond. A major limitation of previous synthe-
ses is low diastereoselectivity. In the first report of the
preparation of sphinganine 1-phosphonate, a racemic
analogue was synthesized from ethyl 2-aminohydroxy-
Sphingolipids are ubiquitous membrane components
of mammalian cells and are also implicated in the
regulation of diverse cellular processes.1 The three long-
chain bases that form the backbones of sphingomyelin
and glycosphingolipids are (2S,3R)-sphingosine (4-trans-
sphingenine), 4,5-dihydrosphingosine (sphinganine), and
(2S,3S,4R)-phytosphingosine (4D-hydroxysphinganine).2
The roles of sphingolipids in signal transduction and lipid
raft formation have received intense interest in recent
years. Among the many sphingolipids that are second
messengers are phosphorylated sphingolipids, such as the
naturally occurring (2S,3R)-sphingosine 1-phosphate (1a).
The latter compound induces a wide range of bioactivi-
ties, many of which involve the vascular system.3 Com-
pound 1a and the 4,5-dihydro analogue of 1a serve as
extracellular ligands for a family of G-protein coupled
receptors present in different cell types; they also act
intracellularly, mediating calcium release and cell growth
and survival.4
(1) (a) Sweeley, C. C. In Biochemistry of Lipids, Lipoproteins, and
Membranes; Vance, D. E., Vance, J . E., Eds.; Elsevier: Amsterdam,
1991; pp 327-361. (b) Merrill, A. H., J r.; Sandhoff, K. In Biochemistry
of Lipids, Lipoproteins, and Membranes, 4th ed.; Vance, D. E., Vance,
J . E., Eds.; Elsevier: Amsterdam, 2002; pp 373-407.
(2) (a) Sperling, P.; Ternes, P.; Moll, H.; Franke, S.; Za¨hringer, U.;
Heinz, E. FEBS Lett. 2001, 494, 90-94. (b) Smith, W. L.; Merrill, A.
H., J r. J . Biol. Chem. 2002, 277, 25841-25842.
(3) (a) Siess, W. Biochim. Biophys. Acta 2002, 1582, 204-215. (b)
Osborne, N.; Stainier, D. Y. Annu. Rev. Physiol. 2003, 65, 23-43. (c)
Hla, T. Pharmacol. Res. 2003, 47, 401-407.
(4) (a) Spiegel, S.; Milstien, S. Biochem. Soc. Trans. 2003, 31, 1216-
1219. (b) Olivera, A.; Rosenfeldt, H. M.; Bektas, M.; Wang, F.; Ishii,
I.; Chun, J .; Milstien, S.; Spiegel, S. J . Biol. Chem. 2003, 278, 46452-
26460.
(5) Candelore, M. R.; Wright, M. J .; Tota, L. M.; Milligan, J .; Shei,
G.-J .; Bergstrom, J . D.; Mandala, S. M. Biochem. Biophys. Res.
Commun. 2002, 297, 600-606.
(6) Bittman, R. Chem. Phys. Lipids 2004, 129, 111-131.
(7) Bittman, R. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley: Chichester, 1995; pp 5456-5458.
Compound 2a , the phosphate ester of D-ribo-phyto-
sphingosine, was recently shown to bind more tightly
* To whom correspondence should be addressed. Phone: (718) 997-
3279. Fax: (718) 997-3349.
10.1021/jo0487404 CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/07/2004
7694
J . Org. Chem. 2004, 69, 7694-7699

Sphingosine 1-Phosphonate and Phytosphingosine 1-Phosphonate
SCHEME 1. Retr osyn th etic P la n
SCHEME 2. P r ep a r a tion of Diol 9 fr om
D-Glycer a te 4 via HWE Rea gen t 5a
a
Reagents and conditions: (a) LiCH2P(O)(OMe)2, THF, -78 °C;
(b) C13H27CHO, Cs2CO3, 2-PrOH, 0 °C to rt; (c) L-Selectride, THF,
-78 °C; (d) PMBCl, NaH, DMF, 0 °C to rt; (e) 3 N HCl/CH3CN
(1:4), rt.
2-
octadecanoate in which the CH2OPO3 headgroup of
dihydro-1a is replaced by CH2PO3
at C3 and introduction of the E unsaturated chain at C4;
the stereocenter at C2 is derived from that in D-glycerate
4. After inversion at C2 by azide attack to provide 15,
the backbone of (2S,3R)-sphingosine 1-phosphonate was
fully built. As shown in Scheme 1, we achieved an
efficient preparation of target 2 by taking advantage of
the chirality of 3, a readily available lipid derived from
a yeast fermentation process, to provide the requisite
three stereocenters at C2, C3, and C4. Cyclic sulfamidate
22 was prepared from (2S,3S,4R)-3 via N-benzylamino
alcohol 2114 as a precursor. The regioselective ring-
opening reaction at C1 of 12 and 22 with a phosphonate-
stabilized carbanion was the key step in the synthetic
strategy.
2- 8
. More recently,
isosteric phosphonate analogues of 1a and sphinganine
1-phosphate were prepared as a mixture of isomers at
the C4 stereocenter.9 Sphingosine 1-phosphonate (1) and
sphinganine 1-phosphonate were synthesized starting
from D-erythro-sphingosine in 12 steps.10 An isosteric
phosphonate analogue of sphingomyelin was synthesized
from a 2-bromoethyloxazolidinone.11 In addition, a syn-
thetic strategy to gain access to phosphonosphingolipids
using a pentacovalent oxaphospholene has been sug-
gested.12 We recently reported the synthesis of the
phosphonate analogue of one of the seven unnatural
stereoisomers of phytosphingosine, L-lyxo- or 2S,3S,4S-
phytosphingosine, via the reaction of tetramethyl meth-
ylenediphosphonate with an aldehyde derived from a
threitol acetal synthon, followed by reduction of the
Wittig adduct.13 In this investigation, we report an
efficient synthesis of (2S,3R)-sphingosine 1-phosphonate
(1) and the first synthesis of D-ribo-phytosphingosine
1-phosphonate (2). These syntheses feature the use of a
ring-opening reaction of an oxirane and a cyclic sulfami-
date to install the phosphonate group.
F or m a tion of Ep oxid e 12. The synthesis of 12 began
with the preparation of acetonide 8 from methyl 2,3-O-
isopropylidene-D-glycerate (4) using a modification of
published procedures. As shown in Scheme 2, acylation
of the lithium salt of dimethyl methylphosphonate with
4 afforded the Horner-Wadsworth-Emmons (HWE)
reagent, ketophosphonate 5.15 HWE reaction with tetra-
decanal afforded (E)-6 as the sole product; no Z isomer
was detected by NMR. Diastereoselective reduction of
enone 6 with L-Selectride in THF at -78 °C gave the
desired erythro-alcohol 7 in good yield.16 Protection of the
3-hydroxy group as a 4-methoxybenzyl (PMB) ether
afforded acetonide 8, which was deprotected to give diol
9.17
Resu lts a n d Discu ssion
Scheme 1 outlines our retrosynthetic analysis for the
syntheses of targets 1 and 2. Cyclic intermediates 12 and
22, which were synthesized from methyl 2,3-O-isoprop-
ylidene-D-glycerate (4) and D-ribo-phytosphingosine (3),
respectively, possess the stereochemistry needed to com-
plete the syntheses. The preparation of target 1 via
oxirane 12 involved the generation of a new chiral center
Scheme 3 shows the route we used to prepare chiral
epoxide 12. Diol 9 was converted stereoselectively to
epoxide 12 in three steps. Heating at reflux with di-n-
butyltin oxide in CHCl3/MeOH (10:1) furnished cyclic
stannylene intermediate 10. Regioselective monotosyla-
(8) Stoffel, W.; Grol, M. Chem. Phys. Lipids 1974, 13, 372-388.
(9) Schick, A.; Kolter, T.; Giannis, A.; Sandhoff, K. Tetrahedron 1995,
51, 11207-11218.
(10) Tarnowski, A.; Ba¨r, T.; Schmidt, R. R. Bioorg. Med. Chem. Lett.
1997, 7, 573-576.
(11) Hakogi, T.; Monden, Y.; Taichi, M.; Iwama, S.; Fujii, S.; Ikeda,
K.; Katsumura, S. J . Org. Chem. 2002, 67, 4839-4846.
(12) McClure, C. K.; Mishra, P. K. Tetrahedron Lett. 2002, 43, 5249-
5253.
(14) (a) Kulmaca, K. J .; Kisic, A.; Schroepfer, G. J ., J r. Chem. Phys.
Lipids 1979, 23, 291-319. (b) Prostenic, M.; Majhofer-Orescanin, B.;
Ries-Lesic, B.; Stanacev, N. Z. Tetrahedron 1965, 21, 651-655.
(15) (a) Yamanoi, T.; Akiyama, T.; Ishida, E.; Abe, H.; Amemiya,
M.; Inazu, T. Chem. Lett. 1989, 335-336. (b) Gargano, J . M.; Lees, W.
J . Tetrahedron Lett. 2001, 42, 5845-5847.
(13) Lu, X.; Byun, H.-S.; Bittman, R. J . Org. Chem. 2004, 69, 5433-
(16) Kumar, P.; Schmidt, R. R. Synthesis 1998, 33-35.
(17) Somfai, P.; Olsson, R. Tetrahedron 1993, 49, 6645-6650.
5438.
J . Org. Chem, Vol. 69, No. 22, 2004 7695

Sun and Bittman
SCHEME 3. Con ver sion of Diol 9 to Ep oxid e 12a
SCHEME 5. Con ver sion of Azid op h osp h on a te 15
to (2S,3R)-Sp h in gosin e 1-P h osp h on a te (1)a
a
Reagents and conditions: (a) Bu2SnO, CHCl3/MeOH (10:1),
a
Reagents and conditions: (a) HS(CH2)3SH, MeOH, Et3N, 50
reflux, 2 h; (b) p-TsCl, CH2Cl2, rt; (c) K2CO3, MeOH, 0 °C.
°C; (b) (Boc)2O, Et3N, dioxane/water (5:2), 50 °C; (c) DDQ, CH2Cl2,
H2O, 0 °C; (d) TMSBr (10 equiv), CH2Cl2, rt.
SCHEME 4. Ep oxid e Op en in g w ith
LiCH2P (O)(OMe)2 a n d F or m a tion of
Azid op h osp h on a te 15a
SCHEME 6. P r ep a r a tion of
D-r ibo-P h ytosp h in gosin e 1-P h osp h on a te (2)a
a
Reagents and conditions: (a) LiCH2P(O)(OMe)2, BF3‚Et2O (4
equiv), THF, -78 to -20 °C; (b) MsCl, Et3N, DMAP; (c)
ClCH2SO2Cl, Py, 0 °C to rt; (d) NaN3, DMF, 18-crown-6, reflux;
(e) NaN3, DMF, rt, overnight.
a
Reagents and conditions: (a) (i) PhCHO, THF/CH2Cl2, MgSO4,
rt, (ii) NaBH4, MeOH, rt; (b) TBDMSCl, imidazole (4 equiv), THF,
rt; (c) Me2C(OMe)2, p-TsOH, PhH, reflux, 3 h; (d) TBAF, THF, rt;
(e) (i) SOCl2, Et3N, CH2Cl2, -78 to -40 °C, (ii) NaIO4, RuCl3,
CH3CN/CCl4 (1:1), 0 °C; (f) (i) CH3P(O)(OPr-i)2, n-BuLi, THF, -78
°C, (ii) 20% H2SO4/Et2O (1:1), rt; (g) (i) TMSBr (4 equiv), CH3CN,
60 °C, overnight, (ii) 2 N HCl/THF (2:3), rt, overnight, (iii) 20%
Pd(OH)2/C, H2, MeOH, rt, overnight.
tion (p-TsCl, CH2Cl2) gave 11, which was treated with
K2CO3 in methanol at 0 °C to provide epoxide 12 in very
high yield.
Con ver sion of Ep oxid e 12 to Sp h in gosin e 1-P h os-
p h on a te (1). Regioselective ring opening of oxirane 12
with lithium dimethyl methylphosphonate in the pres-
ence of BF3‚Et2O (4 equiv) in THF at -78 °C furnished
phosphonate 13 in good yield (Scheme 4).18 These condi-
tions are similar to those described to prepare phospho-
nolipids with a glycerol backbone,19 but this strategy has
not been used previously to produce sphingophosphono-
lipids. Mesylation of the hydroxy group of 13 using the
usual conditions (MsCl, Et3N, DMAP) gave 14a ; however,
heating of the mesylate with sodium azide in DMF at
reflux, even in the presence of a catalytic amount of 18-
crown-6, gave a 1:3 mixture of 15 and 15a , in which one
of the methyl phosphonate ester groups was removed.
Successful azidation, without the formation of byproduct
15a , was achieved by chloromesylation of 13 with ClCH2-
SO2Cl, followed by displacement of the chloromethylsul-
fonyl group with NaN3 in DMF at room temperature.
Several methods were explored for the reduction of
azide 15. We found that azide 15 was smoothly converted
to the corresponding amine by using 1,3-dithiopropane20
as the reducing agent. After the amine was protected as
N-Boc derivative 16, oxidative cleavage of the PMB ether
group of 16 with DDQ gave alcohol 17 in high yield
(Scheme 5). The methyl phosphonate ester and N-Boc
functionalities were removed simultaneously by using an
excess of bromotrimethylsilane to afford 1 in good yield.
P r ep a r a tion of Aceton id e 21. The synthesis of
phytosphingosine 1-phosphonate (2) began with a readily
available precursor, D-ribo-phytosphingosine (3) (Scheme
6). The amino group of 3 was protected as a N-benzyl-
amine via condensation with benzaldehyde, followed by
reduction of the intermediate imine. After the primary
hydroxy group of 18 was selectively blocked as a TBDMS
ether, the vicinal 3,4-diol of 19 was protected as an acetal
with 2,2-dimethoxypropane in the presence of p-TsOH
(18) A trace of cyclic phosphonate 13a was obtained when the
reaction was stirred at room temperature. However, the formation of
the byproduct was avoided when the reaction was quenched at low
temperature.
(19) (a) Bittman, R.; Byun, H.-S.; Mercier, B.; Salari, H. J . Med.
Chem. 1993, 36, 297-299. (b) Bittman, R.; Byun, H.-S.; Mercier, B.;
Salari, H. J . Med. Chem. 1994, 37, 425-430. (c) Li, Z.; Racha, S.;
Abushanab, E. Tetrahedron Lett. 1993, 34, 3539-3542. (d) Leung, L.
W.; Lin, W.; Richard, C.; Bittman, R.; Arthur, G. J . Liposome Res. 1998,
8, 213-224.
(20) Bayley, H.; Standring, D. N.; Knowles, J . R. Tetrahedron Lett.
1978, 19, 3633-3634.
7696 J . Org. Chem., Vol. 69, No. 22, 2004

Sphingosine 1-Phosphonate and Phytosphingosine 1-Phosphonate
combined organic layers were washed with water and brine
and dried (MgSO4). The solvents were removed, and the
residue was purified by chromatography (hexane/EtOAc 8:1)
in benzene. After cleavage of the silyl protecting group,
acetonide 21 was obtained in 65% overall yield from 3.
Con ver sion of Aceton id e 21 to P h ytosp h in gosin e
1-P h osp h on a te (2). Although lithiated dialkyl meth-
ylphosphonates have been used as nucleophiles in the
regioselective opening of cyclic sulfates,21 such a reaction
has not yet been reported with a cyclic sulfamidate. Our
rationale for the use of a phosphonate-stabilized anion
to install the isosteric phosphonate group by opening of
a cyclic sulfamidate stems from the extensive study of
ring-opening reactions of five-membered cyclic sulfami-
dates with nucleophiles.22 The cyclic sulfamidite precur-
sor to sulfamidate 22 was prepared by treatment of 21
with thionyl chloride and triethylamine in CH2Cl2 at -40
°C. Oxidation with sodium periodate and catalytic ru-
thenium trichloride in CH3CN-H2O-CCl4 at 0 °C af-
forded cyclic sulfamidate 22 (90% yield), which under-
went reaction with lithiated diisopropyl methylphos-
phonate at -78 °C in THF. After the reaction was
quenched at -78 °C, acid hydrolysis (20% H2SO4 in Et2O)
gave amine 23 in 67% yield.
to afford 8 (2.4 g, 85%) as a colorless oil: Rf 0.44 (hexane/EtOAc
1
8:1); [R]25 -29.2 (c 5.75, CHCl3); H NMR (CD2Cl2) δ 0.93 (t,
D
3H, J ) 6.8 Hz), 1.31-1.46 (m, 22H), 1.37 (s, 3H), 1.43 (s, 3H),
2.13 (dt, 2H, J ) 7.2, 6.8 Hz), 3.69 (dd, 1H, J ) 8.4, 6.8 Hz),
3.77 (dd, 1H, J ) 7.8, 7.8 Hz), 3.83 (s, 3H), 3.92 (dd, 1H, J )
8.4, 6.4 Hz), 4.15 (dt, 1H, J ) 6.8, 6.8 Hz), 4.35 (d, 1H, J )
11.4 Hz), 4.58 (d, 1H, J ) 11.4 Hz), 5.35 (dd, 1H, J ) 15.6, 8.4
Hz), 5.78 (dt, 1H, J ) 15.6, 6.8 Hz), 6.90 (d, 2H, J ) 8.4 Hz),
7.29 (d, 2H, J ) 8.4 Hz); 13C NMR (CD2Cl2) δ 14.3, 23.1, 25.7,
26.7, 29.5, 29.5, 29.8, 29.9, 30.07, 30.11, 32.3, 32.7, 55.6, 66.4,
69.8, 78.3, 81.7, 109.8, 113.9, 126.4, 129.6, 131.2, 137.7, 159.5;
HR-MS (FAB, MNa+) m/z calcd for C29H48O4Na+ 483.3445,
found 483.3438.
(2R ,3R ,4E )-1,2-E p oxy-3-(4′-m e t h oxyb e n zyl)-4-oct a -
d ecen e [(-)-12]. A suspension of 9 (2.2 g, 5.2 mmol) and
dibutyltin oxide (1.4 g, 5.7 mmol) in 100 mL of CHCl3/MeOH
(10:1) was heated at reflux for 2 h. After removal of the
solvents, the residue was further dried under vacuum over-
night. The residue was dissolved in CH2Cl2 (25 mL), p-TsCl
(1.3 g, 6.7 mmol) was added, and the reaction mixture was
stirred overnight. The reaction was quenched with H2O (0.2
mL, 11.1 mmol) and stirred for 2 h, diluted with 100 mL of
hexane, and filtered through a short pad of silica gel. The pad
was washed with 200 mL of hexane/EtOAc (10:1) in order to
remove the excess of p-TsCl. The filtrate was concentrated,
and the residue was purified by chromatography (hexane/
EtOAc 4:1) to afford 2.9 g (98%) of 11 as a colorless oil: 1H
NMR (CD2Cl2) δ 0.84 (t, 3H, J ) 6.8 Hz), 1.23-1.33 (m, 22H),
2.00 (dt, 2H, J ) 6.8, 6.8 Hz), 2.40 (s, 3H), 2.63 (d, 1H, J ) 3.2
Hz), 3.65-3.68 (m, 2H), 3.74 (s, 3H), 3.88 (dd, 1H, J ) 10.0,
5.2 Hz), 4.03 (dd, 1H, J ) 10.2, 3.4 Hz), 4.16 (d, 1H, J ) 10.8
Hz), 4.45 (d, 1H, J ) 10.8 Hz), 5.24 (dd, 1H, J ) 15.2, 8.2 Hz),
5.66 (dt, 1H, J ) 15.2, 6.8 Hz), 6.81 (d, 2H, J ) 7.2 Hz), 7.14
(d, 2H, J ) 8.6 Hz), 7.32 (d, 2H, J ) 7.2 Hz), 7.71 (d, 2H, J )
8.6 Hz); 13C NMR (CD2Cl2) δ 14.5, 22.0, 23.3, 29.6, 29.8, 29.9,
30.0, 30.22, 30.24, 30.3, 32.5, 32.9, 55.8, 70.2, 71.0, 72.3, 80.1,
114.3, 126.1, 128.5, 130.1, 130.4, 130.6, 133.3, 139.0, 145.6,
159.9. To a suspension of crude 11 in 25 mL of MeOH was
added 2.86 g (20.7 mmol) of powdered K2CO3 at 0 °C. The
reaction mixture was stirred for 2.5 h at 0 °C, diluted with
100 mL of Et2O, and filtered through a short pad of silica gel,
which was washed with 200 mL of Et2O. The filtrate was
The reactions for removal of the protecting groups of
the isopropyl phosphate ester, N-benzyl group, and the
acetal of 23 were conducted in one pot. First, 23 was
treated with TMSBr in CH3CN at 60 °C. After the excess
TMSBr was removed, the residue was stirred with 2 N
HCl, and catalytic hydrogenolysis (20% Pd(OH)2/C, MeOH)
gave the fully deprotected product 2 in 71% overall yield.
Con clu sion
We developed a methodology to prepare nonhydrolyz-
2-
able sphingolipid analogues in which the CH2OPO3
headgroup of natural sphingosine 1-phosphate (1a ) is
2-
replaced by the isosteric CH2CH2PO3 group, affording
1. We also achieved an efficient conversion of naturally
occurring (2S,3S,4R)-2-amino-1,3,4-octadecanetriol (D-
ribo-phytosphingosine, 3) to its methylenephosphonate
analogue 2. Both of these syntheses involve the ring
opening of key intermediates (12 and 22) by LiCH2P(O)-
(OR)2; this is the first example of a phosphonate-
stabilized carbanion attack on a cyclic sulfamidate. The
phosphohydrolase-resistant phosphonate analogues 1
and 2 may be of value in understanding the pharmacol-
ogy of phosphate esters 1a and 2a in the absence of
formation of metabolites.
concentrated to give 12 (1.9 g, 96%) as a colorless oil: Rf 0.43
1
(hexane/EtOAc 8:1); [R]25 -12.1 (c 6.14, CHCl3); H NMR δ
D
0.88 (t, 3H, J ) 6.8 Hz), 1.26-1.41 (m, 22H), 2.05 (dt, 2H, J )
6.8, 6.8 Hz), 2.56 (dd, 1H, J ) 4.8, 2.8 Hz), 2.76 (dd, 1H, J )
4.6, 4.6 Hz), 3.07 (m, 1H), 3.54 (dd, 1H, J ) 7.0, 7.0 Hz), 3.80
(s, 3H), 4.48 (d, 1H, J ) 11.6 Hz), 4.57 (d, 1H, J ) 11.6 Hz),
5.43 (dd, 1H, J ) 15.6, 7.6 Hz), 5.72 (dt, 1H, J ) 15.6, 6.8 Hz),
6.87 (d, 2H, J ) 8.4 Hz), 7.28 (d, 2H, J ) 8.4 Hz); 13C NMR
(CD2Cl2) δ 14.0, 22.8, 29.15, 29.24, 29.5, 29.6, 29.70, 29.77,
29.8, 32.0, 32.4, 43.8, 54.3, 55.3, 69.7, 81.2, 113.7, 126.0, 129.4,
130.8, 136.4; HR-MS (FAB, MNa+) m/z calcd for C26H42O3Na+
425.3026, found 425.3026.
Exp er im en ta l Section 23
(2R,3R,4E)-1,2-O-P r op ylid en e-3-(4′-m eth oxyben zyl)-4-
octa d ecen e-1,2-d iol [(-)-8]. To an ice-cold solution of 7 (3.0
g, 8.8 mmol; see the Supporting Information) in DMF (60 mL)
was added NaH (0.7 g, 17.6 mmol, 60% in mineral oil) at 0
°C. After the reaction mixture was stirred at this temperature
for 30 min, PMBCl (2.8 g, 17.6 mmol) was added. The mixture
was warmed to room temperature, and the reaction was
monitored by TLC. The reaction was quenched by addition of
MeOH at 0 °C and diluted with 200 mL of Et2O/H2O (1:1).
The aqueous layer was extracted with Et2O (2 × 100 mL). The
(3R,4R,5E)-1-(Dim eth oxyp h osp h in yl)-3-h yd r oxy-4-(4′-
m eth oxyben zyl)-5-octa d ecen e [(-)-13]. To a solution of
dimethyl methylphosphonate (1.74 g, 14.0 mmol) in THF (100
mL) was added 5.4 mL of n-BuLi (13.4 mmol, a 2.5 M solution
in hexane) at -78 °C. After the mixture had stirred for 1 h at
-78 °C, a solution of BF3‚Et2O (13.4 mmol) and 12 (1.34 g,
3.36 mmol) in THF (10 mL) was added. The reaction mixture
was warmed to -20 °C. After being stirred at -20 °C for 0.5
h, the reaction mixture was quenched with saturated aqueous
NH4Cl solution and extracted with EtOAc (2 × 100 mL). The
combined organic extracts were washed with brine, dried
(MgSO4), and concentrated. Phosphonate 13 (1.31 g, 74%) was
obtained as a colorless oil after purification by chromatography
(21) For a review, see: Byun, H.-S.; He, L.; Bittman, R. Tetrahedron
2000, 56, 7051-7091.
(22) For a review, see: Mele´ndez, R. E.; Lubell, W. D. Tetrahedron
2003, 59, 2581-2616.
(23) See the Supporting Information for a statement describing
general experimental methods. NMR spectra were recorded in CDCl3
unless noted otherwise.
(hexane/EtOAc 2:5): Rf 0.41 (hexane/EtOAc 2:5); [R]25 -17.4
D
(c 1.72, CHCl3); 1H NMR δ 0.87 (t, 3H, J ) 6.8 Hz), 1.24-1.40
J . Org. Chem, Vol. 69, No. 22, 2004 7697

Sun and Bittman
(m, 22H), 1.56-2.03 (m, 4H), 2.06-2.11 (m, 2H), 2.59 (br s,
1H), 3.48-3.50 (m, 2H), 3.69 (s, 3H), 3.72 (s, 3H), 3.79 (s, 3H),
4.23 (d, 1H, J ) 10.8 Hz), 4.53 (d, 1H, J ) 10.8 Hz), 5.28 (dd,
1H, J ) 15.2, 8.2 Hz), 5.72 (dt, 1H, J ) 15.2, 6.8 Hz), 6.86 (d,
2H, J ) 8.6 Hz), 7.21 (d, 2H, J ) 8.6 Hz); 13C NMR δ 14.1,
20.6 (d, J ) 141.9 Hz), 22.6, 25.5 (d, J ) 4.0 Hz), 29.1, 29.2,
29.3, 29.4, 29.57, 29.60, 29.63, 31.9, 32.4, 52.2 (d, J ) 6.0 Hz),
55.2, 69.5, 73.1 (d, J ) 16.1 Hz), 83.3, 113.8, 126.3, 129.5,
130.1, 138.0, 159.2; 31P NMR δ 35.5; HR-MS (FAB, MNa+) m/z
calcd for C29H51O6PNa+ 549.3315, found 549.3313.
filtration and washed twice with MeOH. The combined fil-
trates were dried, dissolved in 7 mL of dioxane/water (5:2),
and cooled to 0 °C. Triethylamine (0.20 mL, 1.44 mmol) and
(Boc)2O (324 mg, 1.44 mmol) were added, the ice bath was
removed, and the mixture was heated overnight at 50 °C. After
removal of the volatiles, the product was extracted with EtOAc,
washed with brine, dried (Na2SO4), and concentrated. The
residue was purified by chromatography (CHCl3/MeOH 20:1)
to afford 16 (141 mg, 63%) as a colorless oil: Rf 0.37 (CHCl3/
1
MeOH 20:1); [R]25 -37.8 (c 2.78, CHCl3); H NMR δ 0.84 (t,
D
3H, J ) 6.8 Hz), 1.22-1.39 (m, 22H), 1.37(s, 9H), 1.59-1.92
(m, 4H), 2.01-2.06 (m, 2H), 3.57 (br s, 1H), 3.66-3.70 (m, 1H),
3.66 (s, 3H), 3.69 (s, 3H), 3.76 (s, 3H), 4.18 (d, 1H, J ) 11.4
Hz), 4.48 (d, 1H, J ) 11.4 Hz), 4.70 (d, 1H, J ) 9.6 Hz), 5.32
(dd, 1H, J ) 15.6, 7.8 Hz), 5.67 (dt, 1H, J ) 15.6, 6.8 Hz), 6.82
(d, 2H, J ) 8.4 Hz), 7.17 (d, 2H, J ) 8.8 Hz); 13C NMR δ 14.0,
21.3 (d, J ) 141.9 Hz), 22.6, 28.2, 29.0 (d, J ) 4.0 Hz), 29.2,
29.3, 29.50, 29.52, 29.6, 31.8, 32.2, 52.2 (d, J ) 7.0 Hz), 54.5
(d, J ) 16.1 Hz), 55.1, 69.7, 79.0, 81.3, 113.6, 126.7, 129.2,
130.2, 136.5, 155.6, 159.0; 31P NMR δ 35.3; HR-MS (FAB,
MNa+) m/z calcd for C34H60NO7PNa+ 648.4000, found 648.3997.
(3S,4R,5E)-3-Azido-1-(dim eth oxyph osph in yl)-4-(4′-m eth -
oxyben zyl)-5-octa d ecen e [(-)-15]. Meth od A. To a solution
of 13 (81 mg, 0.15 mmol) in CH2Cl2 (4 mL) at -20 °C were
added MsCl (17.6 µL, 0.23 mmol), Et3N (42.1 µL, 0.3 mmol),
and DMAP (1.8 mg, 0.015 mmol). The reaction mixture was
warmed to room temperature, stirred for 4 h, and then diluted
with 20 mL of Et2O/H2O (1:1). The organic layer was separated,
and the aqueous layer was extracted with Et2O (2 × 20 mL).
The combined organic layers were washed with brine and dried
(MgSO4). After removal of the solvents, crude mesylate 14a
(98 mg, 108%) was obtained, which was used in the next step
without purification. To a solution of 14a in 3 mL of DMF were
added 58.5 mg (0.90 mmol) of NaN3 and 4.0 mg (0.015 mmol)
of 18-crown-6. The mixture was heated overnight at 75 °C.
The resulting mixture was diluted with Et2O (50 mL) and
washed with water. The ether layer was dried (Na2SO4),
filtered, and concentrated. Compounds 15a (40 mg, 50%) and
15 (14 mg, 17%), both colorless oils, were isolated by chroma-
tography. For 15a : 1H NMR δ 0.88 (t, 3H, J ) 6.8 Hz), 1.26-
1.41 (m, 22H), 1.67-2.11 (m, 4H), 2.13 (br, 2H), 3.47 (br s,
1H), 3.62-3.71 (m, 4H), 3.80 (s, 3H), 4.28 (d, 1H, J ) 11.4
Hz), 4.55 (d, 1H, J ) 11.4 Hz), 5.41(m, 1H), 5.73 (m, 1H), 6.87
(d, 2H, J ) 7.8 Hz), 7.23 (d, 2H, J ) 7.8 Hz), 9.00 (br s, 1H);
13C NMR δ 14.1, 22.6, 23.5 (br), 29.0, 29.2, 29.3, 29.4, 29.60,
29.62, 29.7, 31.9, 32.4, 51.6 (br), 55.2, 65.6 (br), 69.4, 81.8,
113.8, 125.8, 129.2, 130.1, 138.3, 159.1; 31P NMR δ 35.6; MS
(FAB, MH+) m/z calcd for C28H48N3O5P 538.3, found 538.3.
Meth od B. To a solution of 13 (115 mg, 0.22 mmol) in pyridine
(3 mL) at 0 °C was added chloromethylsulfonyl chloride (30
µL, 0.33 mmol). The mixture was stirred at room temperature
for 2 h, diluted with water (50 mL), and extracted with EtOAc
(3 × 50 mL). The combined organic extracts were washed with
1 M HCl solution and brine and dried (Na2SO4). After removal
of the solvents, the crude product was passed through a short
pad of silica gel to give chloromethylsulfonate 14b (101 mg,
73%) as a pale yellow oil. Crude 14b was dissolved in 3 mL of
DMF, and 58.5 mg (0.90 mmol) of NaN3 was added. The
mixture was stirred overnight at room temperature (if the
reaction was carried out at 85 °C overnight, the yield was 46%
after silica gel chromatography). The resulting mixture was
diluted with Et2O (50 mL) and washed with water. The ether
layer was dried (Na2SO4), filtered, and concentrated. The
residue was purified by chromatography (hexane/EtOAc 1:1)
(3S,4R,5E)-3-ter t-Bu toxyca r bon yla m in o-1-(d im eth oxy-
p h osp h in yl)-4-h yd r oxy-5-octa d ecen e [(-)-17]. To a solu-
tion of 16 (60 mg, 0.10 mmol) in CH2Cl2 (5 mL) was added 0.5
mL of pH 7 buffer (KH2PO4-Na2HPO4). The solution was
cooled to 0 °C, and DDQ (28 mg, 0.12 mmol) was added with
stirring at 0 °C. After all of the starting material was
consumed, the reaction was quenched by addition of saturated
aqueous NaHCO3 solution and extracted with Et2O (2 × 50
mL). The organic phases were combined, washed with brine,
and dried (Na2SO4). After the solvents were removed, the
residue was purified by chromatography (hexane/EtOAc 5:1)
to give 17 (44 mg, 91%) as a colorless oil: Rf 0.14 (hexane/
1
EtOAc 1:4); [R]25 -11.6 (c 1.12, CHCl3); H NMR δ 0.87 (t,
D
3H, J ) 6.8 Hz), 1.25-1.37 (m, 20H), 1.44 (s, 9H), 1.59-1.88
(m, 4H), 2.03 (dt, 2H, J ) 6.8, 6.8 Hz), 2.30 (br s, 1H), 3.63
(m, 1H), 3.72 (s, 3H), 3.74 (s, 3H), 4.13 (m, 1H), 4.82 (d, 1H, J
) 7.6 Hz), 5.44 (dd, 1H, J ) 15.2, 6.6 Hz), 5.73 (dt, 1H, J )
15.2, 6.8 Hz); 13C NMR δ 14.1, 20.5 (d, J ) 142.9 Hz), 22.7,
28.3, 29.2 (d, J ) 9.0 Hz), 29.3, 29.5, 29.59, 29.64, 29.7, 31.9,
32.4, 52.4 (d, J ) 6.0 Hz), 75.2, 79.8, 128.2, 134.5; 31P NMR δ
35.0; HR-MS (FAB, MNa+) m/z calcd for C26H52NO6PNa+
528.3424, found 528.3427.
(3S,4R,5E)-3-Am in o-4-h yd r oxyn on a d ec-5-en yl-1-p h os-
p h on ic Acid [(2S,3R,4E)-Sp h in gosin e 1-P h osp h on a te]
(1). To a solution of 17 (26 mg, 0.052 mmol) in CH2Cl2 (10
mL) was added TMSBr (69 µL, 0.52 mmol) at room tempera-
ture. The reaction mixture was stirred overnight at room
temperature. After removal of the solvent, the residue was
dissolved in 10 mL of MeOH and stirred for 1 h. The solvent
was removed to give a pale yellow wax that was purified by
chromatography (CHCl3/MeOH/H2O/AcOH 30:30:2:5), afford-
ing 1 (16.8 mg, 86%) as a white solid: mp 140 °C [lit.10 mp
150 °C]; Rf 0.44 (CHCl3/MeOH/H2O/AcOH 30:30:2:5); [R]30
to give azide 15 (96 mg, 80%) as a colorless oil: Rf 0.35 (hexane/
D
1
EtOAc 1:1); [R]25 -53.6 (c 1.38, CHCl3); H NMR δ 0.87 (t,
1
+4.9 (c 0.15, CHCl3/MeOH 1:1); H NMR (CD3OD/CD3CO2D
D
3H, J ) 6.8 Hz), 1.25-1.45 (m, 22H), 1.54-1.94 (m, 4H), 2.06
(dt, 2H, J ) 6.8, 6.8 Hz), 3.44 (m, 1H), 3.70-3.75 (m, 7H), 3.80
(s, 3H), 4.27 (d, 1H, J ) 11.6 Hz), 4.55 (d, 1H, J ) 11.6 Hz),
5.41 (dd, 1H, J ) 15.2, 8.6 Hz), 5.73 (dt, 1H, J ) 15.2, 6.8 Hz),
6.87 (d, 2H, J ) 8.6 Hz), 7.23 (d, 2H, J ) 8.6 Hz); 13C NMR δ
14.1, 20.4 (d, J ) 141.9 Hz), 22.7, 23.5 (d, J ) 4.0 Hz), 29.0,
29.2, 29.3, 29.5, 29.61, 29.64, 29.7, 31.9, 32.4, 52.3 (d, J ) 6.0
Hz), 52.4 (d, J ) 6.0 Hz), 55.2, 65.6 (d, J ) 16.1 Hz), 69.4,
81.8, 113.8, 125.7, 129.2, 130.1, 138.3, 159.1; 31P NMR δ 34.1;
HR-MS (FAB, MNa+) m/z calcd for C29H50N3O5PNa+ 574.3380,
found 574.3388.
1:1) δ 0.85 (t, 3H, J ) 6.8 Hz), 1.26-1.39 (m, 20H), 1.87-1.99
(m, 4H), 2.06 (dt, 2H, J ) 6.8, 6.8 Hz), 3.42 (m, 1H), 4.36 (m,
1H), 5.43 (dd, 1H, J ) 15.2, 6.6 Hz), 5.88 (dt, 1H, J ) 15.2, 6.8
Hz); 13C NMR (CD3OD/CD3CO2D 1:1) δ 12.3, 21.5, 23.9 (d, J
) 146.9 Hz), 28.0, 28.20, 28.24, 28.4, 28.53, 28.56, 30.8, 31.3,
55.3 (d, J ) 14.1 Hz), 70.0, 125.2, 134.8; 31P NMR (CD3OD/
CD3CO2D 1:1) δ 28.4; MS (ESI, MH+) m/z calcd for C19H41
-
NO4P 378.3, found 378.2.
(2S,3S,4R)-2-(N,N-Ben zyla m in o)-1-(ter t-bu tyld im eth yl-
silyl)octa d eca n e-3,4-d iol [(+)-19]. To a cooled (0 °C) solution
of 18 (see the Supporting Information) (2.0 g, 4.91 mmol) in
THF (100 mL) were added imidazole (1.30 g, 19.6 mmol) and
TBDMSCl (1.48 g, 9.82 mmol). The reaction mixture was
warmed to room temperature and stirred overnight. The
reaction was diluted with water and extracted with CH2Cl2.
The layers were separated, the aqueous layer was extracted
with CH2Cl2, and the combined organic layers were washed
(3S,4R,5E)-3-ter t-Bu toxyca r bon yla m in o-1-(d im eth oxy-
p h osp h in yl)-4-(4′-m eth oxyben zyl)-5-octa d ecen e [(-)-16].
To a solution of 15 (197 mg, 0.36 mmol) in MeOH (1.8 mL)
were added Et3N (0.19 mL, 1.8 mmol) and 1,3-dithiopropane
(0.25 mL, 1.8 mmol). The reaction mixture was stirred
overnight at 50 °C. The white precipitate was removed by
7698 J . Org. Chem., Vol. 69, No. 22, 2004

Sphingosine 1-Phosphonate and Phytosphingosine 1-Phosphonate
with brine, dried (Na2SO4), and concentrated. Chromatography
of the residue (elution with CHCl3/MeOH 20:1) gave 19 (2.3
a short pad of silica gel (hexane/EtOAc 4:1) to afford 1.13 g
(90%) of 22 as a colorless oil: Rf 0.61 (hexane/CHCl3 4:1); [R]25
D
g, 88%) as a colorless oil: Rf 0.50 (CHCl3/MeOH 9:1); [R]25
+2.31 (c 5.2, CHCl3); 1H NMR δ 0.88 (t, 3H, J ) 6.8 Hz), 1.26-
1.47 (m, 26H), 1.32 (s, 3H), 1.40 (s, 3H), 2.61 (m, 1H), 4.03 (m,
1H), 4.19 (dd, 1H, J ) 7.5, 7.5 Hz), 4.28 (dd, 1H, J ) 12.0, 8.6
Hz), 4.42 (s, 2H), 4.51 (dd, 1H, J ) 8.0, 4.0 Hz), 7.32-7.40 (m,
5H); 13C NMR δ 14.1, 22.7, 25.1, 26.5, 27.4, 29.40, 29.47, 29.52,
29.60, 29.65, 29.68, 30.0, 31.9, 52.2, 58.5, 68.1, 75.7, 108.3,
128.6, 128.8, 128.9, 134.5; HR-MS (FAB, MNa+) m/z calcd for
D
+23.4 (c 7.6, CHCl3); 1H NMR δ 0.08 (s, 3H), 0.09 (s, 3H), 0.88
(t, 3H, J ) 6.8 Hz), 0.90 (s, 9H), 1.40-1.71 (m, 26H), 2.81 (m,
1H), 3.43 (dd, 1H, J ) 7.6, 7.6 Hz), 3.63 (dt, 1H, J ) 2.8, 8.0
Hz), 3.76-3.86 (m, 4H), 7.25-7.30 (m, 5H); 13C NMR δ -5.5,
14.1, 18.2, 22.7, 25.3, 25.8, 29.4, 29.65, 29.68, 29.8, 31.9, 33.9,
51.4, 60.2, 61.7, 72.2, 74.5, 127.4, 128.3, 128.6, 139.1; HR-MS
(FAB, MH+) m/z calcd for C31H59NO3SiH+ 522.4337, found
522.4323.
C
28H47NO5SNa+ 532.3067, found 532.3073.
(2S,3S,4R)-Diisop r op yl 3-(N-Ben zyla m in o)-3-(2,2-d i-
m et h yl-5-t et r a d ecyl-1,3-d ioxola n -4-yl)p r op ylp h osp h o-
n a te [(+)-23]. To a solution of diisopropyl methylphosphonate
(487 mg, 2.70 mmol) in 10 mL of THF was added dropwise
n-BuLi (1.35 mL, 2.70 mmol, a 2.0 M solution in THF) at -78
°C. After the reaction was stirred at -78 °C for 1 h, a solution
of cyclic sulfamidate 22 (360 mg, 0.71 mmol) in THF (15 mL)
was added via cannula. The reaction mixture was stirred for
2 h at -78 °C and then quenched with H2O (1 mL) at -78 °C
and allowed to warm to room temperature. After removal of
the volatiles, 40 mL of Et2O/20% H2SO4 (1:1) was added. The
mixture was neutralized with Na2CO3 in an ice bath, extracted
with EtOAc, washed with brine, dried (Na2SO4), and concen-
trated. Purification of the residue by chromatography (CHCl3/
MeOH 40:1) afforded 23 as a colorless oil (290 mg, 67%): Rf
0.38 (CHCl3/MeOH 20:1); [R]25D +14.7 (c 1.8, CHCl3); 1H NMR
δ 0.87 (t, 3H, J ) 6.8 Hz), 1.25-1.43 (m, 24H), 1.31 (s, 3H),
1.33 (s, 3H), 1.78-1.98 (m, 4H), 2.78 (m, 1H), 3.70 (d, 1H, J )
12.8 Hz), 3.84 (d, 1H, J ) 12.8 Hz), 3.95 (m, 1H), 4.12 (m, 1H),
4.70 (m, 2H), 7.23-7.28 (m, 5H); 13C NMR δ 14.1, 21.9 (d, J )
141.8 Hz), 22.7, 23.0 (br), 24.0 (d, J ) 4.5 Hz), 24.1 (d, J ) 4.5
Hz), 26.0 (d, J ) 56.0 Hz), 27.9, 29.3, 29.5, 29.60, 29.63, 29.7,
31.9, 50.4, 55.4 (d, J ) 17.0 Hz), 69.9 (d, J ) 6.0 Hz), 77.9,
78.1, 107.5, 127.1, 128.3, 128.4; 31P NMR δ 31.3; HR-MS (FAB,
MNa+) m/z calcd for C35H64NO5PNa+ 632.4414, found 632.4424.
(3S,4S,5R)-3-Am in o-4,5-d ih yd r oxyn on a d ecyl-1-p h os-
p h on ic Acid (D-r ibo-P h ytosp h in gosin e 1-P h osp h on a te)
(2). To a solution of 23 (59 mg, 0.10 mmol) in CH3CN (3 mL)
was added TMSBr (54 µL, 0.40 mmol) at room temperature.
After the mixture was heated overnight at 60 °C, the volatiles
were removed with an oil pump. To the crude product was
added 5 mL of 2 N HCl/THF (2:3). The mixture was stirred
overnight at room temperature and then pumped to dryness.
A mixture of the dry residue and 20% Pd(OH)2/C (12.1 mg) in
dry MeOH (10 mL) was stirred under H2 atmosphere over-
night. The black suspension was passed through a short pad
of Celite, which was washed twice with MeOH. Concentration
and purification of the residue by chromatography (CHCl3/
MeOH/H2O 65:25:4) provided 28 mg (71%) of 2 as a white
(2S,3S,4R)-Ben zyl-[2-(ter t-bu tyld im eth ylsila n yloxy)-1-
(2,2-d im e t h y l-5-t e t r a d e c y l[1,3]d io x o la n -4-y l)e t h y l]-
a m in e [(+)-20]. 2,2-Dimethoxypropane (4.9 mL, 38.3 mmol)
and p-TsOH (134 mg, 7.0 mmol) were added to a solution of
19 (2.0 g, 3.83 mmol) in benzene (100 mL) at room tempera-
ture. The mixture was stirred at reflux for 3 h, and the solvent
was removed. The residue was extracted with 150 mL of Et2O/
H2O (2:1), and the organic phase was separated. The aqueous
phase was extracted with Et2O (50 mL), and the combined
organic extracts were washed with saturated aqueous NaHCO3
solution, dried (MgSO4), and concentrated. Purification of the
residue by chromatography (hexane/EtOAc 20:1) afforded 2.2
g (84%) of 20 as a colorless oil: Rf 0.36 (hexane/EtOAc 10:1);
[R]25 +46.7 (c 5.8, CHCl3); 1H NMR δ 0.08 (s, 3H), 0.09 (s,
D
3H), 0.89 (t, 3H, J ) 6.8 Hz), 0.91 (s, 9H), 1.27-1.38 (m, 26H),
1.32 (s, 3H), 1.41 (s, 3H), 2.68 (d, 1H, J ) 9.6 Hz), 3.65 (d, 1H,
J ) 12.4 Hz), 3.77 (dd, 1H, J ) 10.0, 2.2 Hz), 3.89-3.41 (m,
2H), 4.01-4.05 (m, 1H), 4.15 (m, 1H), 7.24-7.29 (m, 5H); 13C
NMR δ -4.4, 14.1, 18.3, 22.7, 25.9, 26.0, 28.5, 29.4, 29.5, 29.60,
29.64, 29.66, 29.7, 31.9, 51.0, 57.1, 59.3, 76.1, 78.2, 107.3, 126.9,
128.3, 128.4, 129.2, 140.6; HR-MS (FAB, MH+) m/z calcd for
C
34H63NO3SiH+ 562.4650, found 562.4651.
(2S,3S,4R)-2-(N-Ben zyla m in o)-2-(2,2-d im eth yl-5-tetr a -
d ecyl-1,3-d ioxola n -4-yl)eth a n ol [(+)-21]. A solution of (n-
Bu)4NF (4.0 mL, 4.0 mmol, a 1 M solution in THF) was added
to a solution of 20 (1.90 g, 3.38 mmol) in THF (70 mL) and
stirred for 1 h at room temperature. The reaction was
monitored by TLC (CHCl3/MeOH 20:1). After water (20 mL)
was added, most of the solvents were removed. The residue
was extracted with Et2O (2 × 50 mL), and the extract was
dried (MgSO4) and concentrated. The residue was purified by
chromatography (CHCl3/MeOH 20:1) to give 21 (1.26 g, 92%)
as a colorless oil: Rf 0.47 (CHCl3/MeOH 20:1); [R]25 +30.1 (c
D
6.3, CHCl3); 1H NMR δ 0.88 (t, 3H, J ) 6.8 Hz), 1.26-1.51 (m,
26H), 1.33 (s, 3H), 1.42 (s, 3H), 2.83 (m, 1H), 3.74-3.84 (m,
3H), 3.92 (d, 1H, J ) 12.8 Hz), 4.09-4.13 (m, 1H), 4.15-4.20
(m, 1H), 7.25-7.31 (m, 5H); 13C NMR δ 14.1, 22.7, 25.6, 26.4,
27.9, 29.4, 29.56, 29.61, 29.66, 29.69, 31.9, 51.1, 57.1, 61.3, 77.9,
78.1, 107.8, 127.2, 128.3, 128.4, 140.0; HR-MS (FAB, MNa+)
m/z calcd for C28H49NO3Na+ 470.3604, found 470.3604.
(2S,3S,4R)-N-Ben zyl-2-(2,2-d im et h yl-5-t et r a d ecyl-1,3-
d ioxola n -4-yl)-1,2-cyclic Su lfa m id a te [(+)-22]. To a solu-
tion of 21 (1.0 g, 2.46 mmol) in CH2Cl2 (55 mL) was added
Et3N (1.40 mL, 9.84 mmol), and the solution was cooled to -78
°C. After SOCl2 (0.24 mL, 3.20 mmol) was added over a 5-min
period, the solution was warmed to -40 °C and stirred at this
temperature for 0.5 h. The reaction was quenched by addition
of cold Et2O, and the mixture was washed with water and
brine, dried (MgSO4), and concentrated. After the residue was
dried thoroughly using a vacuum pump, 1.22 g (100%) of crude
cyclic sulfamidite was obtained as a colorless oil. To a cooled
(0 °C) mixture of cyclic sulfamidite in 60 mL of CH3CN/CCl4
(1:1) was added a solution of 1.05 g (4.92 mmol) of NaIO4 and
6.75 mg (0.030 mmol) of RuCl3‚H2O in 12 mL of water. After
the purple suspension was stirred at 0 °C for 20 min, 100 mL
of Et2O and 50 mL of H2O were added. The layers were
separated, and the aqueous layer was extracted with Et2O (2
× 50 mL). The combined ether layer was dried (MgSO4) and
concentrated. The residue was purified by filtration through
powder: mp 180 °C dec; Rf 0.18 (CHCl3/MeOH/H2O 65:25:4);
1
[R]25 +3.0 (c 0.56, CHCl3/MeOH 3:1); H NMR (CDCl3/CD3-
D
OD 3:1) δ 0.84 (t, 3H, J ) 6.8 Hz), 1.22-1.52 (m, 26H), 1.78-
2.08 (m, 4H), 3.45 (m, 3H); 13C NMR (CDCl3/CD3OD 3:1) δ 13.5,
20.1, 22.2, 24.8, 28.9, 29.16, 29.20, 31.4, 33.8, 54.2 (J ) 11.0
Hz), 71.8, 72.9; 31P NMR (CD3OD/CD3CO2D 1:1) δ 27.6; HR-
MS (FAB, MNa+) m/z calcd for C19H42NO3PNa+ 418.2693,
found 418.2707.
Ack n ow led gm en t. This work was supported in part
by USPHS Grant No. HL16660. We thank Dr. Hoe-Sup
Byun for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal information, preparation of compounds 5-9 and 18, and
1
copies of H and 13C NMR spectra for compounds 1, 2, 5-9,
11-14, 15a , 15-17, and 19-23 and 31P NMR spectra for
compounds 1, 2, 5, 13, 15a , 15-17, and 23. This material is
available free of charge via the Internet at http://pubs.acs.org..
J O0487404
J . Org. Chem, Vol. 69, No. 22, 2004 7699