Synthesis of L-lyxo-phytosphingosine and its 1-phosphonate analogue using a threitol acetal synthon

Article abstract of DOI:10.1021/jo0493065

The first synthesis of an isosteric phosphonate analogue of the aminotriol lipid phytosphingosine (3), together with an improved synthesis of (2S,3S,4S)-phytosphingosine (2), are described. A key intermediate is 3-pentylidene acetal 9, which was prepared in two steps from dimethyl 2,3-0-benzylidene-D-tartrate (7).

Full text of DOI:10.1021/jo0493065

Syn th esis of L-lyxo-P h ytosp h in gosin e a n d Its 1-P h osp h on a te
An a logu e Usin g a Th r eitol Aceta l Syn th on
Xuequan Lu, Hoe-Sup Byun, 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 April 26, 2004
The first synthesis of an isosteric phosphonate analogue of the aminotriol lipid phytosphingosine
(3), together with an improved synthesis of (2S,3S,4S)-phytosphingosine (2), are described. A key
intermediate is 3-pentylidene acetal 9, which was prepared in two steps from dimethyl 2,3-O-
benzylidene-D-tartrate (7).
In tr od u ction
sylphosphatidylinositol (GPI) of the membrane-anchored
proteins in yeast.6
The trihydroxy sphingoid base phytosphingosine (4D-
hydroxysphinganine, PHS) consists of an aliphatic chain
(predominantly octadecyl) bearing a 2-amino-1,3,4-triol
headgroup. PHS differs from sphingosine in that it
possesses an additional hydroxy group (at C4) but does
not possess a 4,5-trans double bond. PHS is the major
sphingoid base in fungi, plants, and several mammalian
tissues.1 In addition to its structural role in membranes,
PHS has a number of physiological roles, many of which
remain to be elucidated. PHS is involved in the heat
stress response of yeast cells2 and induces apoptosis in
cancer cells.3 Amide-linked derivatives of PHS, which
constitute ∼30% of the total ceramide content of the
stratum corneum (the water permeability barrier of
human skin),4 self-associate extensively via hydrogen
bonds even in the hydrated state and have different
chain-packing properties than ceramides with a sphin-
gosine backbone.4d PHS is also the backbone of (a)
KRN7000, an R-galactosylsphingolipid that stimulates
natural killer cells to produce cytokines and strongly
inhibits tumor metastasis in mice5 and (b) the glyco-
The construction of the aminotriol moiety of the
phytosphingosines represents a synthetic challenge. A
number of routes to naturally occurring (2S,3S,4R or
D-ribo)-PHS (Chart 1, 1) and some of its diastereomers
have been reported.7 The chiral centers of the PHS
molecule have generally been derived from carbohydrate8
and serine precursors.9 In addition, chiral induction into
PHS has been achieved by the Sharpless asymmetric
epoxidation10 and asymmetric dihydroxylation reac-
tions,11 asymmetric aldol reactions,12 and other stereo-
selective methods.13 In this paper, we describe an efficient
method for the preparation of L-lyxo-PHS (2)11,14 that
utilizes a pentylidene group to protect the 1,2-diol moiety
of 3-O-protected-D-threitol 8 as an acetal. To further
illustrate the utility of this method, we synthesized an
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Chem. 1993, 268, 26365-26374. (c) Fontaine, T.; Magnin, T.; Melhert,
A.; Lamont, D.; Latge, J .-P.; Ferguson, M. A. Glycobiology 2003, 13,
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Org. Chem. 2002, 6, 365-391.
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(b) Chiu, H.-Y.; Tzou, D.-L. M.; Patkar, L. N.; Lin, C.-C. J . Org. Chem.
2003, 68, 5788-5791.
* To whom correspondence should be addressed. Phone: (718) 997-
3279. Fax: (718) 997-3349.
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7, 2291-2300. (c) Bouhours, D.; Bouhours, J .-F. Biochim. Biophys. Acta
1984, 794, 169-171. (d) Okabe, K.; Keenan, R. W.; Schmidt, G.
Biochem. Biophys. Res. Commun. 1986, 31, 137-143. (e) Higuchi, R.;
Kagoshima, M.; Komori, T. Liebigs Ann. Chem. 1990, 659-663.
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and: (a) Wild, R.; Schmidt, R. R. Tetrahedron: Asymmetry 1994, 11,
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10.1021/jo0493065 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/14/2004
J . Org. Chem. 2004, 69, 5433-5438
5433

Lu et al.
CHART 1. Str u ctu r es of D-r ibo-P HS (1) a n d Its
P h osp h a te Ester (4) a n d of L-lyxo-P HS (2) a n d Its
Isoster ic 1-P h osp h on a te Der iva tive (3)
SCHEME 1. Retr osyn th etic P la n
isosteric phosphonate derivative of 2, L-lyxo-phytosphin-
gosine 1-phosphonate (3). Our interest in the latter
compound arises from the recent finding that a phosphate
ester of PHS, D-ribo-phytosphingosine 1-phosphate (4),
possesses a higher affinity than sphingosine-1-phosphate
for a widely distributed cell-surface G protein coupled
receptor.15 Since the carbon-phosphorus bond is resis-
tant to the action of lipid phosphohydrolases, a phos-
phonate derivative16 of a bioactive lysosphingolipid such
as 4, in which the phosphate oxygen at C1 of 4 is replaced
with a methylene group, is expected to have a long half-
life in cells and thus be a valuable pharmacological tool
to probe receptor-specific interactions. In previous work,
we have found that isosteric phosphonate analogues of
glycerophospholipids retain the biological activity of the
parent phosphate esters.17 It should also be noted that
nonhydrolyzable phosphonolipids with a 2-amino-3,4-
dihydroxy headgroup are found in some bacteria18 and
mollusks.19
SCHEME 2. P r ep a r a tion of Th r eitol Der iva tive 9a
a
Reagents and conditions: (a) LiAlH4, AlCl3, Et2O, reflux and
(b) pentanone, HClO4, MS (method A), or 3,3-dimethoxypentane,
10% CSA, THF, reflux, 30 min, then K2CO3 (method B).
protecting groups at C3 and C4 were removed in a one-
pot reaction. For the synthesis of the isosteric phos-
phonate analogue 3, azide 17 was converted to protected
R-(N,N-dibenzyl)amino alcohol 19. Condensation of the
aldehyde derived from 19 with tetramethyl methylene-
diphosphonate, followed by ester hydrolysis, reduction of
the unsaturation, and hydrogenolysis of the protecting
groups, afforded PHS-phosphonate 3.
Resu lts a n d Discu ssion
As illustrated in the retrosynthetic analysis (Scheme
1), our syntheses of L-lyxo-phytosphingolipids 2 and 3
started with readily available D-(-)-tartaric acid (5),
which was converted to pentylidene-protected D-threitol
derivative 9 (see Scheme 2). After Dess-Martin oxida-
tion,20 the aliphatic chain was installed with concomitant
construction of the third chiral center, the acetal of tetrol
11 was released, and regioselective azidation of the
secondary hydroxy group of the resultant 1,2-diol with
inversion of configuration was accomplished, affording
azido alcohol 17. For the synthesis of L-lyxo-PHS (2), the
azido group and triple bond of 17 were reduced, and the
Syn th esis of Th r eitol Der iva tive 9. D-(-)-Tartaric
acid (5) has been used extensively as a chiral precursor
of many natural products.21 Scheme 2 shows a short
synthesis of the protected threitol derivative 9. Ben-
zylidene acetal 7 is commercially available or can be
readily prepared by esterification of 5 (SOCl2, MeOH) to
give dimethyl ester 6, followed by acetal protection of the
hydroxy groups (PhCHO, p-TsOH, cyclohexane, reflux;
see Supporting Information); alternatively, 7 is accessible
from 5 in a one-pot reaction.22 Both ester and acetal
functionalities of 7 were reduced with LiAlH4 in the
presence of AlCl3,23 affording triol 8 in 80% yield. We
found that the 1,2-isopropylidene-protected derivative of
8, which is a widely used building block,24 was unstable
on storage, especially as a solution in chloroform. There-
fore, we converted triol 8 to pentylidene acetal 9, which
(15) 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.
(16) For recent examples of synthetic studies to prepare phosphonate
analogues of sphingolipids, see: (a) McClure, C. K.; Mishra, P. K.;
Grote, C. W. J . Org. Chem. 1997, 62, 2437-2441. (b) McClure, C. K.;
Mishra, P. K. Tetrahedron Lett. 2002, 43, 5249-5253.
(17) (a) Bittman, R.; Byun, H.-S.; Mercier, B.; Salari, H. J . Med.
Chem. 1994, 37, 425-430. (b) Lin, W.; Leung, L. W.; Bae, Y. S.;
Bittman, R.; Arthur, G. Biochem. Pharmacol. 1999, 57, 1153-1158.
(c) Samadder, P.; Bittman, R.; Byun, H.-S.; Arthur, G. J . Med. Chem.
2004, 47, 2710-2713.
(18) Watanabe, Y.; Nakajima, M.; Hoshino, T.; J ayasimhulu, K.;
Brooks, E. E.; Kaneshiro, E. S. Lipids 2001, 36, 513-519.
(19) Kariotoglou, D. M.; Mastronicolis, S. K. Comput. Biochem.
Physiol. B Biochem. Mol. Biol. 2003, 136, 27-44.
(20) For a review, see: Zhdankin, V. V.; Stang, P. J . Chem. Rev.
2002, 102, 2523-2584.
(21) For reviews, see: (a) Gawron´ski, J .; Gawron´ska, K. Tartaric
and Malic Acids in Synthesis; J ohn Wiley & Sons: New York, 1999.
(b) Ghosh, A. K.; Koltun, E. S.; Bilcer, G. Synthesis 2001, 1281-1301.
(22) Byun, H.-S.; Bittman, R. Synth. Commun. 1993, 23, 3201-3204.
(23) Steuer, B.; Wehner, V.; Lieberknecht, A.; J ager, V. Org. Synth.
1997, 74, 1-12.
5434 J . Org. Chem., Vol. 69, No. 16, 2004

Synthesis of L-lyxo-Phytosphingosine and Its Phosphonate Analogue
SCHEME 3. P r ep a r a tion of P r op a r gyl Alcoh ol 11a
SCHEME 4. Con ver sion of 11 to L-lyxo-P HS (2)a
a
Reagents and conditions: (a) BnBr, TBAB, NaH, THF, reflux,
3 h; (b) 5% H2SO4, MeOH, rt; (c) (i) PPh3, DIAD, CH2Cl2, 0 °C, (ii)
TMSN3, 0 °C to rt, and (iii) TBAF, THF, rt; and (d) Pd(OH)2/C,
H2, MeOH.
of propargyl alcohols 11 and 12 with the Dess-Martin
periodinane reagent afforded ketone 13 exclusively.
Unfortunately, during the purification of crude 13 by
silica gel column chromatography, some loss of configu-
ration at C3 took place. Therefore, the crude ketone 13
was used directly in the next step. Reduction of 13 with
L-Selectride (-78 °C, THF) afforded propargyl alcohol 11
as the major product (C3,C4 syn). The ratio of 11:12 was
10:1, and the overall yield of the isolated products was
90%. Pure propargyl alcohol 11 was obtained by column
chromatography (elution with hexane/EtOAc 6:1).29
Syn th esis of L-lyxo-P HS (2). Scheme 4 outlines the
synthesis of product 2 from alcohol 11. After the hydroxy
group of 11 was protected as a benzyl ether (BnBr, NaH,
catalytic n-Bu4NBr (TBAB)), selective deprotection of 15
with 5% H2SO4 provided 1,2-diol 16 in 87% yield for the
two steps. Diol 16 was converted to azido alcohol 17 in a
one-pot reaction.30a This was accomplished by adding the
diol to a mixture of diisopropyl azodicarboxylate (DIAD)
and Ph3P at 0 °C. After 3 h, TMSN3 was added to
accomplish the azide substitution reaction.30b Hydrolysis
of the silyl ether of the primary hydroxy group and
purification by column chromatography provided azido
alcohol 17 in 61% yield. Simultaneous reduction of the
azido group and the triple bond, together with hydro-
genolysis of the benzyl groups in the presence of Pearl-
man’s catalyst (Pd(OH)2/C), gave L-lyxo-PHS 2 in 82%
yield. The NMR spectra and rotation data were in full
accord with previously reported data.11
a
Reagents and conditions: (a) PCC, NaOAc, CH2Cl2, MS; (b)
n-BuLi, 1-tetradecyne, Et2O, ZnBr2, -20 °C to rt; (c) Dess-Martin
periodinane, CH2Cl2, 1 h, rt; and (d) L-Selectride, THF, -78 °C
to rt.
is less acid sensitive and thus more stable than the
isopropylidene acetal. The most suitable conditions for
the formation of this new acetal derivative entail the brief
heating of 8 with 3,3-dimethoxypentane25 (1.2 equiv) with
a catalytic amount of 10-camphorsulfonic acid (CSA) in
THF (reflux, 30 min; overall yield for the four steps
>50%).
Syn th esis of P r op a r gyl Alcoh ol 11. Alcohol 9 was
oxidized to the corresponding aldehyde 10 with PCC in
the presence of NaOAc and molecular sieves (Scheme 3).26
A chelation-controlled addition of tetradecynyllithium to
aldehyde 10 in the presence of anhydrous ZnBr2 in Et2O
afforded a mixture of 11 and 12 in a ratio of only 3:1.
The mild selectivity may be a result of 2,3-chelation of
Zn2+ to give the undesired diastereomer 12.27 In an
attempt to increase the yield of 11, the mixture of 11 and
12 was oxidized to the propargylic ketone and then
reduced diastereoselectively. Although PCC oxidation
gave a disappointing result,28 oxidation of the mixture
Syn th esis of L-lyxo-P HS 1-P h osp h on a te (3). We
used a Horner-Wadsworth-Emmons reaction to intro-
duce an (E)-enephosphonate moiety (Scheme 5). A low
yield was obtained in the reaction of tetramethyl meth-
ylenediphosphonate with the aldehyde derived by oxida-
(24) For examples, see: (a) Backstrom, A. D.; Austin, R.; McMordie,
A. S.; Begley, T. P. J . Carbohydr. Chem. 1995, 14, 171-175. (b)
Yoshino, T.; Nagata, Y.; Itoh, E.; Hashimoto, M.; Katoh, T.; Terashima,
S. Tetrahedron 1997, 53, 10239-10252. (c) Matsumura, R.; Suzuki,
T.; Hagiwara, H.; Hoshi, T.; Ando, M. Tetrahedron Lett. 2001, 42,
1543-1546.
(25) See the Experimental Procedures for an alternative method to
prepare 9. For methods to prepare 3,3′-dimethoxypentane, see: (a)
Napolitano, E.; Fiaschi, R.; Mastrorilli, E. Synthesis 1986, 122-125.
(b) Linclau, B.; Boydell, A. J .; Clarke, P. J .; Horan, R.; J acquet, C. J .
Org. Chem. 2003, 68, 1821-1826.
(28) PCC oxidation of the mixture of compounds 11 and 12 gave a
mixture of diastereomers 13 and 14 in a 1:1 ratio.
(26) The 1H and 13C NMR spectra of 10 indicate that epimerization
did not occur at C2. Furthermore, the configuration at C2 was not
altered on PCC oxidation of chiral 2-O-benzyl-3,4-O-isopropylidene-1-
butanol to the isopropylidene aldehyde analogue of 10: (a) Williams,
D. R.; Klingler, F. D. Tetrahedron Lett. 1987, 28, 869-872. (b) Valverde,
S.; Herradon, B.; Martin-Lomas, M. Tetrahedron Lett. 1985, 26, 3731-
3734. (c) Sa´nchez-Sancho, F.; Valverde, S.; Herrado´n, B. Tetrahedron:
Asymmetry 1996, 7, 3209-3246.
(29) The configuration at C4 of compound 11 was confirmed by the
4S configuration in product 2.
(27) Recent advances in enantioselective additions of alkynylmetals
to aldehydes (for a recent review, see Pu, L. Tetrahedron 2003, 59,
9873-9886) suggest that it will be possible to improve the ratio of 11:
12. On the other hand, 12 may predominate when the addition is
carried out under nonchelating conditions, thereby providing the
stereochemistry leading to the D-ribo-PHS backbone.
(30) (a) He, L.; Wanunu, M.; Byun, H.-S.; Bittman, R. J . Org. Chem.
1999, 64, 6049-6055. (b) For a postulated mechanism to account for
the conversion of a 1,2-diol to a 2-azido-1-ol with inversion, see: Scheme
1 of ref 30a and Mathieu-Pelta, I.; Evans, S. A., J r. J . Org. Chem. 1992,
57, 3409-3413.
J . Org. Chem, Vol. 69, No. 16, 2004 5435

Lu et al.
method B it reacted with 3,3-dimethoxypentane. Method A:
a slurry of 8.4 g (39.6 mmol) of triol 8, 25.2 g of 4 Å molecular
sieves, and 42 mL (396 mmol) of 3-pentanone in 300 mL of
dry THF was treated with 4.1 mL (41 mmol) of concentrated
HClO4. The mixture was stirred overnight and then quenched
by adding 40 g (290 mmol) of anhydrous K2CO3. The solid
residue was removed by filtration and washed with Et2O (2 ×
100 mL). The solvent was evaporated, and the residue was
purified by column chromatography (elution with EtOAc/
hexane 1:3) to give 9 (9.8 g, 88%) as a colorless liquid. Method
B: to a solution of 8.4 g (39.6 mmol) of triol 8 and 930 mg (4.0
mmol) of CSA in 300 mL of dry THF was added 6.3 g (47.5
mmol) of 3,3-dimethoxypentane. The solution was stirred at
reflux for 2 h and then quenched by adding 4.0 g (29 mmol) of
anhydrous K2CO3. The solid residue was removed by filtration
and washed with Et2O (2 × 100 mL). The solvent was
evaporated, and the residue was purified by chromatography
(EtOAc/hexane 1:3) to give 10.2 g (91%) of 9 as a colorless
SCHEME 5. Con ver sion of 17 to L-lyxo-P HS
1-P h osp h on a te (3)a
liquid: [R]25 +15.4° (c 3.75, CHCl3); Rf 0.30 (EtOAc/hexane
D
1:3); 1H NMR (C6D6) δ 1.00-1.07 (m, 6H), 1.68-1.79 (m, 4H),
1.90 (s, 1H), 3.36 (m, 1H), 3.43 (m, 1H), 3.57 (m, 2H), 3.84 (t,
1H, J ) 6.4 Hz), 4.24 (m, 1H), 4.65 (d, 1H, J ) 12.0 Hz), 4.74
(d, 1H, J ) 12.0 Hz), 7.18 (m, 1H), 7.27 (m, 2H), 7.39 (m, 2H);
13C NMR (C6D6) δ 8.36, 8.42, 29.7, 30.1, 62.3, 66.4, 72.8, 78.1,
80.0, 113.2, 128.0, 139.2; HR-MS (FAB, MNa+) m/z calcd for
a
Reagents and conditions: (a) PPh3, THF/H2O 9:1, rt, 48 h; (b)
K2CO3, BnBr, H2O, NaOH; (c) Dess-Martin periodinane, CH2Cl2,
rt; (d) tetramethyl methylenediphosphonate, THF, NaH; (e)
TMSBr, CH2Cl2; and (f) Pd(OH)2/C, H2, MeOH.
tion of azido alcohol 17. Therefore, the azido group was
first reduced to an amino group with PPh3 in THF/H2O
(9:1) to afford 2-amino alcohol 18. Reaction of the amino
group with excess benzyl bromide in K2CO3/NaOH (1:1)
in water gave N,N-dibenzyl amino alcohol 19 (81% yield
for the two steps). Oxidation of 19 with the Dess-Martin
reagent afforded aldehyde 20,31 which reacted with the
anion derived from tetramethyl methylenediphosphonate
to provide unsaturated phosphonate ester 21 (82% for
the two steps). Treatment of 21 with trimethylsilyl
bromide, followed by 5% aqueous MeOH, afforded phos-
phonic acid 22 in 91% yield. Finally, reduction of the
double and triple bonds and deprotection of the N- and
O-benzyl groups all at the same time gave the desired
(2S,3S,4S)-PHS-phosphonate analogue 3 in 80% yield.
C
16H24O4Na+ 303.1568, found 303.1574.
(2R,3S)-2-O-Ben zyl-3,4-O-(3′-p en t ylid en e)-2,3,4-t r ih y-
d r oxybu ta n a l (10). A mixture of 5.6 g (20.0 mmol) of triol 8
and 5 g of 3 Å molecular sieves in 200 mL of dry CH2Cl2 was
stirred at room temperature for 2 h (mixture A). A slurry of
11.5 g (140 mmol) of NaOAc, 15.8 g (73.3 mmol) of PCC, and
5 g of 3 Å molecular sieves in 200 mL of CH2Cl2 was stirred at
room temperature for 2 h (mixture B). Mixture B was added
to mixture A, with stirring at room temperature for 4 h. After
400 mL of dry Et2O was added, stirring was continued for 30
min. The resulting precipitate was removed by filtration over
a short pad of silica gel and thoroughly washed with Et2O.
The solvent was evaporated, and the residue was dried to give
5.0 g (91%) of 10 as a pale yellow liquid, which was used in
the next reaction without further purification. A pure sample
of aldehyde 10 was obtained by flash chromatography (3:1
hexane/EtOAc); Rf 0.59 (EtOAc/hexane 1:3); 1H NMR (CDCl3)
δ 0.84-0.92 (m, 6H), 1.58-1.72 (m, 4H), 3.85 (m, 2H), 4.05 (t,
1H, J ) 6.8 Hz), 4.34 (m, 1H), 4.68 (d, 1H, J ) 12.0 Hz), 4.78
(d, 1H, J ) 12.0 Hz), 7.25-7.40 (m, 5H), 9.70 (d, 1H, J ) 4.8
Hz); 13C NMR (CDCl3) δ 8.09, 8.14, 28.7, 39.3, 65.8, 73.4, 75.6,
83.1, 113.7, 128.1, 128.2, 128.4, 128.5, 137.1, 202.0.
(2R,3R,4S)- a n d (2S,3R,4R)-3-O-Ben zyl-1,2-O-(3′-p en -
tylid en e)-5-octa d ecyn -1,2,3,4-tetr ol (11) a n d (12). To a
solution of 1.6 g (8.2 mmol) of 1-tetradecyne in 100 mL of dry
Et2O at -20 °C was added dropwise 3.3 mL (8.2 mmol) of
n-BuLi (a 2.89 M solution in hexane) under nitrogen. The
white suspension was stirred at -20 °C for 1 h, and then 2.15
g (9.5 mmol) of anhydrous ZnBr2 was added at 0 °C. After 1 h
at 0 °C and 1 h at room temperature, a solution of 1.9 g (6.8
mmol) of aldehyde 10 in 20 mL of dry Et2O was added drop-
wise at -20 °C. The mixture was allowed to warm to room
temperature overnight and then quenched by the addition of
20 mL of saturated aqueous NH4Cl solution at -20 °C. After
the mixture was diluted with 80 mL of water, the aqueous
layer was extracted with Et2O (2 × 100 mL). The combined
extracts were washed with saturated aqueous NaCl solution,
dried, and evaporated. The residue was purified by chroma-
tography (EtOAc/hexane 1:3) to give a 3:1 mixture of 11/12
(2.2 g, 70%) as a colorless liquid.
Con clu sion
A novel synthesis of L-lyxo-PHS (2) and the first
synthesis of L-lyxo-PHS 1-phosphonate (3) via the new
D-threitol acetal derivative 9 have been reported here.
Coupling of 1-tetradecyne with aldehyde 10 gave a
mixture of alcohols 11 and 12, which were oxidized and
then reduced with L-Selectride to install the third chiral
center. After protection of the 4-hydroxy group and
deprotection of the 1,2-hydroxy groups, the 2-hydroxy
group was converted to an azido group with inversion of
configuration. Hydrogenolysis gave L-lyxo-PHS (2). An
unsaturated phosphonate moiety was introduced by
reaction of tetramethyl methylenediphosphonate with
aldehyde 20. Ester hydrolysis, followed by deprotection
and reduction of the double and triple bonds, gave L-lyxo-
PHS 1-phosphonate 3 in high yield. If L-tartaric acid is
used as the starting material, the methods shown here
can be used to prepare the enantiomers of these phyto-
sphingolipids. The availability of 1-phosphonate deriva-
tives of PHS diastereomers is expected to spur analysis
of the bioactivities of these lysolipids.
(2R,3R)-3-O-Ben zyl-1,2-O-(3′-p en tylid en e)-4-oxo-5-octa -
d ecyn -1,2,3-tr iol [(-)-13]. A solution of 2.00 g (5.0 mmol) of
the 3:1 mixture of 11/12 in 100 mL of dry CH2Cl2 at room
Exp er im en ta l P r oced u r es32
(31) For the Dess-Martin oxidation of a N,N-dibenzyl-R-amino
alcohol, see: Cooke, J . W. B.; Davies, S. G.; Naylor, A. Tetrahedron
1993, 49, 7955-7966.
(2R,3R)-2-O-Ben zyl-3,4-O-(3′-pen tyliden e)-1-bu tan ol [(+)-
9]. Two methods were used to prepare acetal 9. In method
A, triol 8 underwent reaction with 3-pentanone, whereas in
(32) See the Supporting Information for general methods.
5436 J . Org. Chem., Vol. 69, No. 16, 2004

Synthesis of L-lyxo-Phytosphingosine and Its Phosphonate Analogue
temperature was treated with 2.00 g (5.5 mmol) of Dess-
Martin periodinane. After 1 h, TLC analysis indicated the
complete consumption of starting material. An aqueous solu-
tion of 10% Na2S2O3 (50 mL, 20.2 mmol) was added. The
mixture was stirred until both layers became clear. The or-
ganic layer was separated and washed with saturated aqueous
NaHCO3 solution, water, and brine and dried (MgSO4). The
solvent was evaporated, and the residue was dried to afford
1.89 g (95%) of ketone 13 as a colorless liquid. A pure sample
of 13 was obtained by flash chromatography (hexane/EtOAc
3:1); [R]25D -28.4° (c 13.0, CHCl3); Rf 0.87 (hexane/EtOAc 3:1);
1H NMR (C6D6) δ 1.01 (m, 6H), 1.27 (t, 3H, J ) 6.0 Hz)
1.26-1.40 (m, 20H), 1.68 (q, 2H, J ) 7.2 Hz), 1.82 (q, 2H, J )
7.2 Hz), 2.02 (t, 2H, J ) 6.8 Hz), 4.05 (m, 3H), 4.35 (d, 1H, J
) 12.0 Hz), 4.66 (m, 2H), 7.17-7.36 (m, 5H); 13C NMR (CDCl3)
δ 8.56, 14.3, 19.0, 22.2, 27.8, 29.1, 29.4, 29.5, 29.8, 30.0, 30.1,
33.8, 66.9, 72.1, 73.4, 76.8, 85.9, 97.2, 114.0, 128.0, 128.1, 128.5,
137.8, 186.3; HR-MS (FAB, MNa+) m/z calcd for C30H46O4Na+
493.3288, found 493.3288.
4H); 13C NMR (CDCl3) δ 14.4, 19.0, 23.1, 28.9, 29.0, 29.3, 29.5,
29.8, 29.9, 30.0, 30.1, 32.3, 63.5, 70.8, 71.0, 72.1, 74.2, 77.1,
81.4, 89.2, 127.6, 127.7, 127.8, 127.9, 128.0, 128.1, 128.5, 128.6,
128.7, 138.2, 138.9; HR-MS (FAB, MNa+) m/z calcd for
C
32H46O4Na+ 517.3288, found 517.3303.
(2S,3S,4S)-2-Azid o-3,4-ben zyloxy-5-octa d ecyn -1,3,4-tr i-
ol [(+)-17]. To a solution of 1.63 g (3.4 mmol) of 16 and 1.34
g (5.1 mmol) of Ph3P (both thoroughly dried overnight at 0.7
Torr) in 150 mL of dry CH2Cl2 was added 1.06 mL (5.1 mmol)
of DIAD at 0 °C. After the yellow reaction mixture was stirred
at 0 °C for 3 h under nitrogen, 592 mL (4.4 mmol) of Me3SiN3
was added. The reaction mixture was stirred at 0 °C for 3 h
and then allowed to warm to room temperature overnight.
After removal of the solvent, the residue was dissolved in 10
mL of THF and treated with 8.5 mL (8.5 mmol) of n-Bu4NF
(TBAF) (a 1 M solution in THF containing 5 wt % H2O). The
brown reaction mixture was stirred at room temperature until
the silyloxy azides were consumed completely (TLC). Concen-
tration gave a slurry that was dissolved in CH2Cl2 and passed
through a pad of silica gel in a sintered glass funnel to remove
Ph3P(O) and salts. The pad was washed with a mixture of
hexanes-EtOAc (6:1). The crude products were purified by
silica gel chromatography (hexanes/EtOAc 3:1) to give 17 (1.04
(2R,3S)-3-O-Ben zyl-1,2-O-(3′-p en tylid en e)-4-oxo-5-octa -
d ecyn -1,2,3-t r iol [(-)-14]. PCC oxidation of a mixture of
11/12 gave a 1:1 mixture of 13/14 in 92% total yield. A pure
sample of 14 was obtained by flash chromatography (hexane/
EtOAc 3:1); [R]25D -14.4° (c 2.5, CHCl3); Rf 0.93 (hexane/EtOAc
3:1); 1H NMR (C6D6) δ 1.03-1.18 (m, 9H), 1.26-1.43 (m, 20H),
1.70 (q, 2H, J ) 7.2 Hz), 1.85 (q, 2H, J ) 7.2 Hz), 2.02 (t, 2H,
J ) 6.8 Hz), 3.91 (d, 1H, J ) 5.2 Hz), 4.05 (m, 2H), 4.48 (d,
1H, J ) 12.0 Hz), 4.64 (m, 1H), 4.85 (d, 1H, J ) 12.0 Hz),
7.25-7.29 (m, 3H), 7.45 (d, 2H, J ) 7.2 Hz); 13C NMR (CDCl3)
δ 8.31, 8.36, 8.44, 14.4, 19.1, 23.1, 27.8, 29.1, 29.4, 29.5, 29.8,
30.0, 30.1, 32.3, 66.2, 73.2, 76.9, 81.0, 85.5, 97.4, 113.8, 128.0,
128.1, 128.5, 138.2, 186.6; MS (ESI) m/z 488.3 (MNH4+).
(2R,3R,4S)-3-O-Ben zyl-1,2-O-(3′-p en t ylid en e)-5-oct a -
d ecyn -1,2,3,4-tetr ol [(+)-11]. To a solution of 543 mg (1.19
mmol) of ketone 13 in 50 mL of dry THF was added 2.38 mL
(2.4 mmol) of L-Selectride (a 1 M solution in THF) dropwise
at -78 °C under nitrogen. The reaction mixture was stirred
for 0.5 h at -78 °C and then allowed to warm to room
temperature for 0.5 h. The mixture was diluted with 100 mL
of EtOAc and filtered through a pad of silica gel, which was
rinsed with 100 mL of EtOAc. The filtrate was concentrated,
and the residue was purified by chromatography (hexane/
EtOAc 6:1) to give 445 mg (82%) of propargyl alcohol 11 as a
colorless oil; [R]25D +11.2° (c 6.3, CHCl3); Rf 0.75 (hexane/EtOAc
3:1); 1H NMR (C6D6) δ 1.03-1.10 (m, 9H), 1.35-1.55 (m, 20H),
1.72-1.82 (m, 4H), 2.18 (m, 2H), 2.37 (d, 1H, J ) 6.8 Hz), 3.58
(m, 1H), 3.77 (d, 1H, J ) 8.4 Hz), 4.01 (m, 1H), 4.55 (m, 2H),
g, 61%) as a colorless oil; [R]25 +28.9° (c 1.75, CHCl3); Rf
D
1
0.70 (hexane/EtOAc 3:1); H NMR (C6D6) δ 1.03 (t, 3H, J )
6.8 Hz), 1.33-1.53 (m, 20H), 1.73 (t, 1H, J ) 4.4 Hz), 2.14 (m,
2H), 3.83 (m, 2H), 3.91 (m, 1H), 3.96 (m, 1H), 4.52 (m, 1H),
4.60 (d, 1H, J ) 11.6 Hz), 4.68 (d, 1H, J ) 11.6 Hz), 4.95 (d,
1H, J ) 11.6 Hz), 5.01 (d, 1H, J ) 11.6 Hz), 7.17-7.32 (m,
6H), 7.47 (m, 4H); 13C NMR (CDCl3) δ 14.4, 19.0, 23.1, 28.9,
29.2, 29.5, 29.8, 30.0, 30.1, 32.3, 62.4, 63.8, 70.4, 71.1, 75.1,
76.9, 81.8, 89.4, 127.8, 127.9, 128.0, 128.1, 128.2, 128.3, 128.5,
128.6, 138.3, 138.6; HR-MS (FAB, MNa+) m/z calcd for
C
32H45N3O3Na+ 542.3353, found 542.3328.
(2S,3S,4S)-P h ytosp h in gosin e [(-)-2]. To a solution of 63
mg (0.12 mmol) of 17 in 90 mL of MeOH was added 12.7 mg
(0.024 mmol) of 20% Pd(OH)2/C. The resulting suspension was
purged with H2 for approximately 10 min and then stirred with
a balloon filled with H2 overnight, when TLC indicated the
complete consumption of the starting material. The crude
reaction mixture was filtered through a short pad of Celite,
and the solvent was evaporated to provide 32 mg (82%) of 2
as a white solid; mp 104.2-105.5 °C [lit.11 mp 104.8-106.0
°C]; [R]25 -7.5° (c 1.00, C5H5N) [lit.11 [R]25 -7.4° (c 0.9,
D
D
C5H5N)]; Rf 0.56 (CHCl3/MeOH/NH4OH 130:25:4); 1H NMR
(CD3OD) δ 0.89 (t, 3H, J ) 6.4 Hz), 1.27-1.53 (m, 24H), 2.98
(m, 1H), 3.39 (m, 1H), 3.40 (m, 1H), 3.59 (m, 1H), 3.67 (m,
1H), 3.76 (m, 1H); 13C NMR (CD3OD) δ 15.0, 23.9, 27.2, 30.6,
30.9, 31.0, 33.2, 34.5, 34.7, 55.9, 64.4, 72.6, 75.1; HR-MS (FAB,
MNa+) m/z calcd for C18H39NO3Na+ 340.2822, found 340.2828.
4.94 (m, 2H), 7.20-7.32 (m, 3H), 7.52 (d, 2H, J ) 6.8 Hz); 13
C
NMR (CDCl3) δ 8.43, 14.4, 19.0, 23.1, 28.9, 29.3, 29.5, 29.8,
29.9, 30.0, 30.1, 32.3, 63.8, 66.8, 74.8, 78.0, 80.0, 83.0, 86.4,
113.0, 127.4, 127.7, 127.9, 128.0, 128.1, 128.5, 139.1; HR-MS
(FAB, MNa+) m/z calcd for C30H48O4Na+ 495.3445, found
495.3437.
(2S,3S,4S)-2-N,N-Diben zyla m in o-3,4-ben zyloxy-5-octa -
d ecyn -1,3,4-tr iol [(-)-19]. To a solution of 0.94 g (1.86 mmol)
of 17 in 30 mL of THF/H2O 9:1 was added 0.63 g (2.3 mmol)
of Ph3P. The reaction mixture was stirred at room temperature
under nitrogen for 48 h. After the solvents were removed, a
solution of 520 mg (3.72 mmol) of K2CO3 and 150 mg (3.72
mmol) of NaOH in 10 mL of water was added. The solution
was heated at reflux with stirring for 30 min. To the refluxing
mixture was added 0.96 g (5.58 mmol) of benzyl bromide. The
mixture was heated for an additional 2 h and then cooled to
room temperature. The organic phase was separated, dried
(Na2SO4), and concentrated. The residue was purified by
chromatography (hexane/EtOAc 3:1) to give 0.99 g (81% for
two steps) of 19 as a colorless oil; [R]25D -25.5° (c 2.15, CHCl3);
(2R,3R,4S)-3,4-Ben zyloxy-5-octadecyn -1,2,3,4-tetr ol [(+)-
16]. To a mixture of 272 mg (6.78 mmol) of NaH (60%) and
1.60 g (3.39 mmol) of 11 in 100 mL of THF were added 870
mg (5.09 mmol) of benzyl bromide and 32 mg (0.10 mmol) of
TBAB. The mixture was heated at reflux for 3 h and then
quenched by the addition of 50 mL of water. The organic layer
was separated, washed with saturated aqueous NaHCO3
solution, water, and then dried (MgSO4); and concentrated.
To the dry residue of 15 in 100 mL of MeOH was added 5 mL
of 5% aqueous H2SO4. The mixture was stirred at room
temperature overnight. After 5.0 g (36 mmol) of solid K2CO3
was added, the mixture was filtered. The filtrate was evapo-
rated to provide a residue that was purified by chromatography
(hexane/EtOAc 3:1), affording 1.46 g of 16 (87% for two steps)
1
Rf 0.74 (hexane/EtOAc 3:1); H NMR (CDCl3) δ 0.88 (t, 3H, J
) 6.4 Hz), 1.22-1.47 (m, 20H), 2.12 (m, 2H), 2.72 (s, 1H), 3.30
(m, 1H), 3.44 (d, 2H, J ) 13.6 Hz), 3.71 (m, 1H), 3.86 (d, 1H,
J ) 8.8 Hz), 3.90 (d, 2H, J ) 13.6 Hz), 4.04 (m, 1H), 4.35 (m,
1H), 4.39 (d, 1H, J ) 11.6 Hz), 4.64 (d, 1H, J ) 11.2 Hz), 4.79
(d, 1H, J ) 11.6 Hz), 5.01 (d, 1H, J ) 11.2 Hz), 7.17-7.35 (m,
20H); 13C NMR (CDCl3) δ 14.1, 18.9, 22.7, 28.5, 29.0, 29.1, 29.4,
29.6, 29.7, 30.3, 31.9, 54.0, 58.4, 59.9, 71.0, 71.1, 72.1, 73.2,
as a colorless oil; [R]25 +8.9° (c 2.7, CHCl3); Rf 0.24 (hexane/
D
1
EtOAc 3:1); H NMR (C6D6) δ 1.03 (t, 3H, J ) 6.8 Hz), 1.33-
1.53 (m, 20H), 2.14 (m, 2H), 2.82 (s, 1H), 3.54 (d, 1H, J ) 4.4
Hz), 3.98 (m, 3H), 4.44 (m, 1H), 4.58 (d, 1H, J ) 11.6 Hz),
4.65 (m, 1H), 4.70 (d, 1H, J ) 11.6 Hz), 4.89 (d, 1H, J ) 11.6
Hz), 4.95 (d, 1H, J ) 11.6 Hz), 7.17-7.22 (m, 6H), 7.44 (m,
J . Org. Chem, Vol. 69, No. 16, 2004 5437

Lu et al.
76.4, 78.9, 89.4, 127.0, 127.6, 127.7, 127.8, 128.0, 128.2, 128.3,
128.4, 129.0, 130.1, 132.4, 137.9, 138.3, 139.6; HR-MS (FAB,
MNa+) m/z calcd for C46H59NO3Na+ 696.4387, found 696.4414.
Dim eth yl (3S,4S,4S)-3-N,N-Diben zyla m in o-4,5-d iben -
zyloxy-6-octa d ecyn -(1E)-en ep h osp h on a te [(+)-21]. A solu-
tion of 336 mg (0.50 mmol) of alcohol 19 in 50 mL of dry CH2Cl2
at room temperature was treated with 252 mg (0.60 mmol) of
Dess-Martin periodinane. After 1 h, TLC analysis indicated
the complete consumption of starting material. An aqueous
solution of 10% Na2S2O3 (50 mL) was added. The mixture was
stirred until both layers became clear. The organic layer was
separated and washed with saturated aqueous NaHCO3 solu-
tion, water, and dried (MgSO4). The solvent was evaporated,
and the residue was dried to afford crude aldehyde 20 as a
colorless liquid. To a mixture of 36 mg (1.5 mmol) of NaH and
50 mL of THF was added 348 mg (1.5 mmol) of tetramethyl
methylenediphosphonate in 10 mL of THF at 0 °C. After the
mixture was stirred for 10 min, a solution of aldehyde 20 in
10 mL of THF was added. The reaction mixture was stirred
for 2 h, diluted with Et2O (20 mL), and extracted in successive
order with 1 M NaOH/MeOH (7:3) (2 × 30 mL) to remove the
excess diphosphonate, H2O/brine (1:1) (1 × 30 mL), and brine.
The organic layer was dried (MgSO4) and concentrated. The
residue was purified by chromatography (hexane/EtOAc 1:1)
to give 318 mg (82% for the two steps) of 21 as a colorless oil;
reactant had been consumed. The solvent was removed, and
the residue was dried. A solution of the residue in 1 mL of
95% MeOH was stirred for 1 h, and the solvent was removed
to afford 174 mg (91%) of 22 as a white solid, mp 65.1-65.7
°C; [R]25 +40.9° (c 1.6, CHCl3/MeOH 1:1); Rf 0.76 (CHCl3/
D
MeOH 1:1); 1H NMR (CDCl3) δ 0.88 (t, 3H, J ) 6.4 Hz), 1.22-
1.35 (m, 20H), 1.84 (m, 2H), 4.30 (m, 3H), 4.37 (d, 1H, J )
11.2 Hz), 4.48 (m, 2H), 4.65 (d, 1H, J ) 11.2 Hz), 4.75 (d, 1H,
J ) 11.6 Hz), 4.85 (d, 1H, J ) 11.2 Hz), 4.96 (m, 1H), 5.19 (m,
1H), 6.45 (m, 1H), 7.07-7.60 (m, 21H); 13C NMR (CDCl3) δ
14.1, 18.7, 22.7, 28.3, 29.0, 29.1, 29.4, 29.6, 29.7, 31.9, 56.1,
64.7 (d, J CP ) 22.0 Hz), 71.3, 71.4, 72.6, 73.9, 74.6, 91.5, 127.8,
128.3, 128.4, 128.5, 128.6, 128.7, 128.9, 129.3, 129.7, 130.9,
131.6, 135.6, 137.2; 31P NMR (CDCl3) δ 13.1; HR-MS (FAB,
MNa+) m/z calcd for C47H60NO5PNa+ 772.4101, found 772.4132.
(2S,3S,4S)-P h ytosp h in gosin e 1-P h osp h on a te [(-)-3].
To a solution of 116 mg (0.17 mmol) of unsaturated phosphonic
acid 22 in 90 mL of MeOH was added 18 mg (0.034 mmol) of
20% Pd(OH)2/C. The resulting suspension was purged with H2
for approximately 10 min and then stirred with a balloon filled
with H2 overnight, when TLC indicated the complete con-
sumption of the starting material. The crude reaction mixture
was filtered through a short pad of Celite, and the solvent was
evaporated to provide 49 mg (80%) of 3 as a white solid; mp
214.0-214.8 °C; [R]25D -6.6° (c 0.64, CHCl3/MeOH 1:1); Rf 0.45
(CHCl3/MeOH/H2O/HOAc 65:25:4:1); 1H NMR (CDCl3/CD3OD
1:1) δ 0.88 (t, 3H, J ) 6.4 Hz), 1.22-1.35 (m, 24H), 1.60 (m,
2H), 1.89 (m, 2H), 2.06 (m, 2H), 3.47 (m, 1H), 3.68 (m, 1H),
3.79 (m, 1H); 13C NMR (CDCl3/CD3OD 1:1) δ 14.3, 23.1, 23.4,
23.8, 26.1, 29.8, 30.1, 30.2, 32.4, 34.0, 56.7 (d, J CP ) 13.0 Hz),
70.6, 71.5; 31P NMR (CDCl3/CD3OD 1:1) δ 27.9; HR-MS (FAB,
MNa+) m/z calcd for C19H42NO5PNa+ 418.2693, found 418.2712.
[R]25 +22.8° (c 1.3, CHCl3); Rf 0.73 (hexane/EtOAc 1:1); 1H
D
NMR (CDCl3) δ 0.88 (t, 3H, J ) 6.4 Hz), 1.22-1.35 (m, 20H),
1.99 (m, 2H), 3.56-3.68 (m, 8H), 3.86 (m, 3H), 4.08 (m, 1H),
4.30 (d, 1H, J ) 6.4 Hz), 4.37 (d, 1H, J ) 11.2 Hz), 4.67 (d,
1H, J ) 10.8 Hz), 4.73 (d, 1H, J ) 11.2 Hz), 5.03 (d, 1H, J )
10.8 Hz), 5.85 (dd, 1H, J ) 17.2, 22.0 Hz), 6.98 (m, 1H), 7.17-
7.35 (m, 20H); 13C NMR (CDCl3) 14.1, 18.6, 22.7, 28.4, 29.0,
29.2, 29.4, 29.6, 29.7, 31.9, 52.2, 54.9, 61.6 (d, J CP ) 22.0 Hz),
70.9, 74.2, 76.2, 89.4, 126.4, 126.9, 127.1, 127.3, 127.5, 127.7,
127.9, 128.0, 128.2, 128.4, 128.5, 128.6, 128.9, 129.0, 137.9,
138.3; HR-MS (FAB, MNa+) m/z calcd for C49H64NO5PNa+
800.4414, found 800.4408.
(3S,4S,4S)-3-N,N-Diben zyla m in o-4,5-ben zyloxy-6-octa -
d ecyn -(1E)-en ep h osp h on ic a cid [(+)-22]. To a solution of
200 mg (0.22 mmol) of dimethyl phosphonate 21 in 10 mL of
dry CH2Cl2 at room temperature was added 0.29 mL (2.2
mmol) of bromotrimethylsilane. The reaction mixture was
stirred for 4 h, at which time TLC indicated that all of the
Ack n ow led gm en t. This work was supported in part
by USPHS Grant HL16660.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal information, preparation of compounds 7 and 8, and copies
of 1H and 13C NMR spectra for compounds 2, 3, 7-11, 13, 14,
16, 17, 19, 21, and 22. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O0493065
5438 J . Org. Chem., Vol. 69, No. 16, 2004