Straightforward access to simplified sphingosine-1-phosphate analogues

Article abstract of DOI:10.1080/00397910701466030

A straightforward approach for the synthesis of a new series of amino phosphates structurally related to sphingosine-1-phosphate is described. The commercial availability of the required starting building blocks, the reduced number of steps, and the ease

Full text of DOI:10.1080/00397910701466030

This article was downloaded by: [University of North Dakota]
On: 21 December 2014, At: 13:56
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Straightforward Access to Simplified
Sphingosine‐1‐phosphate Analogues
Santiago Grijalvo a b , Amadeu Llebaria a & Antonio Delgado a b
a Department of Organic and Biological Chemistry, Chemical and
Environmental Research Institute of Barcelona (IIQAB‐CSIC) , Research
University on Bioactive Molecules (RUBAM) , Barcelona, Spain
b Faculty of Pharmacy , University of Barcelona, Unit of Pharmaceutical
Chemistry , Barcelona, Spain
Published online: 14 Aug 2007.
To cite this article: Santiago Grijalvo , Amadeu Llebaria & Antonio Delgado (2007) Straightforward Access to
Simplified Sphingosine‐1‐phosphate Analogues, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:16, 2737-2751, DOI: 10.1080/00397910701466030
To link to this article: http://dx.doi.org/10.1080/00397910701466030
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”)
contained in the publications on our platform. However, Taylor & Francis, our agents, and our
licensors make no representations or warranties whatsoever as to the accuracy, completeness, or
suitability for any purpose of the Content. Any opinions and views expressed in this publication
are the opinions and views of the authors, and are not the views of or endorsed by Taylor &
Francis. The accuracy of the Content should not be relied upon and should be independently
verified with primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities
whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 37: 2737–2751, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701466030
Straightforward Access to Simplified
Sphingosine-1-phosphate Analogues
Santiago Grijalvo
Research University on Bioactive Molecules (RUBAM), Department of
Organic and Biological Chemistry, Chemical and Environmental Research
Institute of Barcelona (IIQAB-CSIC), Barcelona, Spain and Faculty of
Pharmacy, University of Barcelona, Unit of Pharmaceutical Chemistry,
Barcelona, Spain
Amadeu Llebaria
Research University on Bioactive Molecules (RUBAM), Department of
Organic and Biological Chemistry, Chemical and Environmental Research
Institute of Barcelona (IIQAB-CSIC), Barcelona, Spain
Antonio Delgado
Research University on Bioactive Molecules (RUBAM), Department of
Organic and Biological Chemistry, Chemical and Environmental Research
Institute of Barcelona (IIQAB-CSIC), Barcelona, Spain and Faculty of
Pharmacy, University of Barcelona, Unit of Pharmaceutical Chemistry,
Barcelona, Spain
Abstract: A straightforward approach for the synthesis of a new series of amino phos-
phates structurally related to sphingosine-1-phosphate is described. The commercial
availability of the required starting building blocks, the reduced number of steps,
and the ease of purification of the intermediate and final compounds make the
approach amenable to combinatorial protocols.
Keywords: amino phosphate, combinatorial, phosphorylation, sphingolipids
Received in the U.K. June 14, 2006
Address correspondence to Antonio Delgado, Research University on Bioactive
Molecules (RUBAM), CID-CSIC, Department of Organic and Biological Chemistry,
Jordi Girona 18-26, 08034 Barcelona, Spain. E-mail: adelgado@cid.csic.es
2737

2738
S. Grijalvo, A. Llebaria, and A. Delgado
INTRODUCTION
Sphingolipids constitute a structurally diverse group of biomolecules with
essential roles in cell regulation.[1] Among them, sphingosine-1-phosphate
(S1P) (Fig. 1), a sphingolipid metabolite formed by phosphorylation of sphin-
gosine, has been recognized as an endogenous second messenger with both
intra- and extracellular actions.[2,3] Thus, it binds cell surface specific
receptors (S1P receptors, formerly called EDG or endothelial differentiation
gene receptors),[4] eliciting a wide variety of cellular effects, including differ-
entiation, motility, and cell survival.[5] Interest in S1P analogues has also been
boosted by the discovery of FTY720 (Fig. 1), an immunosupressor resulting
from chemical modifications of the antifungal antibiotic myriocin,[6] whose
O-phosphorylated metabolite acts as an agonist on some S1P receptors
through specific signaling pathways.[7] Chemical modifications of FTY720
have revealed that the C2-hydroxymethyl group is not essential for activity,
because several simplified 2-amino phosphate analogues have been shown
to be selective toward some S1P receptors.[8]
RESULTS AND DISCUSSION
In this context, we herein report on a straightforward approach to the synthesis
of 2-amino phosphate derivatives (1a–f, 2a–e) by the synthetic sequence
shown in Scheme 1. The analogues here described incorporate an oxygen
atom or a bioisosteric sulphur atom on the sphingoid base chain. Interestingly,
these modifications can be viewed as reminiscent of the hydroxyl or hydroxy-
methyl functionalities present in parent S1P and FTY720, respectively. In
addition, the use of commercially available phenols and thiols as starting
Figure 1. Structures of sphingosine-1-phosphate, the immunosupresor phospho-FTY
720, and the simplified sphingosine analogues described in this work (1a–f, 2a–e).

Sphingosine-1-phosphate Analogues
2739
Scheme 1. Reagents and Conditions: (a) 4a–f or 5a–e, NaH, DMF, 60–808C;
(b) pTsOH, MeOH, rt; (c) DMPC, NMI, CH2Cl2, rt, 24 h; (d) i, TMSBr, CH3CN, rt;
ii, MeOH/H2O 95/5, rt.
building blocks make this approach easily amenable to combinatorial
strategies.
Selected thiols (4a–f) and phenols (5a–e) are shown in Fig. 2. They
were condensed under basic conditions with tosylate 3 to yield oxazolidine
derivatives 6a–f and 7a–e in good overall yields.[9] Deprotection of the
derivatives was carried out with pTsOH in MeOH to yield N-Boc amino
alcohols 8a–f and 9a–e in good yields after a simple purification. Among
the different phosphorylation methods described in the literature, we first
considered the use of the couple (MeO)3P/CBr4, as described in the
literature for the phosphorylation of structurally related systems.[10–12]
However, attempts to phosphorylate 8c under these conditions were unsuc-
cessful, because unreacted starting material was recovered after 24 h. Phos-
phorylation of model 3-pentenol and Garner alcohol afforded the
phosphorylated products in moderate yield. The use of other phosphorylating
systems based on P(III) species, such as phosphoramidites,[13] were
disregarded. These reagents afford an intermediate phosphite, which
Figure 2. Thiols and phenols used in this work as starting building blocks.

2740
S. Grijalvo, A. Llebaria, and A. Delgado
require a further oxidation step to phosphate. This step was presumed to be
incompatible with the presence of the easily oxidazable sulphur atom present
in 8a–f. For this reason, we turned our attention to P(V) species, such as
chlorophosphates, for the phosphorylation of alcohols 8a–f and 9a–e. The
choice of the phosphorylating agent was also driven by the possibility of
carrying out a simultaneous deprotection of the phosphate ester and N-Boc
groups. In this context, di-tert-butyl phosphoryl chloride (DtBuPC)[14] was
initially considered. However, phosphorylation of 11b with DtBuPC in the
presence of N-methylimidazole (NMI) in CH2Cl2 at rt for 24 h led to the
recovery of unreacted starting material. The relative instability of the
phosphorylating reagent at rt over long reaction times can account for the
observed result (see Ref. 14). Gratifyingly, phosphorylation with dimethyl
chlorophosphate (DMPC) under these conditions afforded the required
phosphate esters 10a–f and 11a–e in yields ranging between 60 and 91%.
Interestingly, simultaneous deprotection of N-Boc and methyl phosphate
groups could be carried out simultaneously in the presence of TMSBr after
quenching the reaction mixture with 95/5 MeOH/H2O,[15,16] (Scheme 1).
The resulting amino phosphates did not require additional purification as
judged by their spectroscopic and analytical data.
In summary, we have optimized a simple and straightforward protocol for
the synthesis of 2-amino phosphates structurally related to S1P from a
common scaffold 3. The large repertory of commercially available thiols
and phenols as starting building blocks, together with the ease of purification
of the synthetic intermediates and final compounds, make the process
amenable to combinatorial protocols.
EXPERIMENTAL
General Methods
Starting materials were obtained commercially and used without further purifi-
cation. Solvents were freshly distilled under nitrogen before use; DMF, CH2Cl2,
and CH3CN were distilled from CaH2. Analytical samples were homogeneous
as confirmed by thin-layer chromatography (TLC) and afforded spectroscopic
results consistent with the assigned structures. Melting points were determined
with a SMP10 melting-point apparatus and were uncorrected. Optical rotations
were measured with a Perkin Elmer polarimeter 341. Column chromatography
was carried out on silica gel (Chromagel C 35–70 mm). IR spectra were
recorded on a Bomem MB-120. TLC was performed on silica gel (Alugram
1
SIL G/UV). H NMR spectra were recorded in CDCl3 and CD3OD on Unity
and Varian spectrometers at 300 and 500 MHz, respectively, with residual
chloroform and methanol as the internal references (dH ¼ 7.26 ppm and
dH ¼ 4.80 ppm, respectively). 13C NMR spectra were recorded in CDCl3
and CD3OD on a Mercury spectrometer at 125 MHz with residual chloroform

Sphingosine-1-phosphate Analogues
2741
and methanol as the internal references (dC ¼ 77.0 ppm and dC ¼ 49.9 ppm,
respectively). 31P NMR spectra were recorded on a Unity spectrometer at
121.5 MHz in CDCl3 with an external capillary of 85% H3PO4 as reference.
Amberlyst resin (technical grade) was washed with methanol and dichloro-
methane and dried in vaccum at 608C before use.
General Procedure for the Synthesis of N-Boc Amino Alcohols 8a–f
and 9a–e
To a solution of protected oxazolidines 6a–f and 7a–e (0.5 mmol) in MeOH
(3 mL), pTsOH (0.3 mmol) was added. The mixture was stirred for 3 h at rt.
The solvent was removed under reduced pressure, and the crude mixture
was purified by a simple filtration on a short pad of silica gel on the
required solvent system to give carbamates 8 and 9.
Data
(S)-tert-Butyl-N-[3-(hexadecylthio)-1-hydroxypropan-2-yl]carbamate
(8a)
Yield: 62%; TLC Rf ¼ 0.30 (4:1 n-Hex/EtOAc); 1H NMR (300 MHz, CDCl3)
d 5.02 (d broad, 1H), 4.10 (m, 1H), 3.93 (m, 1H), 3.76 (m, 1H), 2.76 (m, 4H),
2.67 (broad, 2H), 2.52 (m, 4H), 1.57 (m, 4H), 1.44 (s, 9H), 1.24 (s, 56H), 0.86
(t, J ¼ 6.8 Hz, 6H). The spectrum shows rotamers; 13C NMR (75 MHz,
CDCl3) d 155.2, 80.0, 64.1, 61.0, 50.8, 33.4, 32.7, 32.6, 32.2, 31.8, 29.6,
29.5, 29.5, 29.4, 29.2, 29.1, 29.0, 28.7, 28.6, 28.2, 22.5, 14.0. The spectrum
shows rotamers; IR (film) 3337, 2915, 2847, 1686, 1526, 1467, 1365, 1277,
1251, 1167, 1002 cm21; ESI-MS: m/z ¼ 454 [Mþ þ 23]; [a]D ¼ þ27.9 (c,
1.0, CHCl3, 208C).
(S)-tert-Butyl-N-[3-(decylthio)-1-hydroxypropan-2-yl]carbamate (8b)
Yield: 61%; TLC Rf ¼ 0.32 (3:1 n-Hex/EtOAc); 1H NMR (300 MHz, CDCl3)
d 5.10 (d broad, 1H), 4.10 (m, 1H), 3.94 (m, 1H), 3.77 (m, 4H), 2.78 (m, 3H),
2.69 (borad, 2H), 2.55 (m, 4H), 1.57 (m, 4H), 1.44 (m, 9H), 1.25 (m, 32H),
0.87 (t, J ¼ 6.5 Hz, 6H). The spectrum shows rotamers;13C NMR (75 MHz,
CDCl3) d 155.3, 79.8, 61.8, 50.8, 33.4, 32.6, 32.2, 31.8, 29.5, 29.4, 29.4,
29.4, 29.2, 29.1, 29.0, 28.7, 28.6, 28.2, 22.5, 14.0. The spectrum shows
rotamers; IR (film) 3331, 2925, 2851, 2360, 1690, 1505, 1362, 1248,
1168 cm21; ESI-MS: m/z ¼ 370 [Mþ þ 23]; [a]D ¼ þ23.6 (c, 1.0, CHCl3,
208C).

2742
S. Grijalvo, A. Llebaria, and A. Delgado
(S)-tert-Butyl-N-[1-hydroxy-3-(pentylthio)propan-2-yl]carbamate (8c)
Yield: 63%; TLC Rf ¼ 0.34 (3:1 n-Hex/EtOAc); 1H NMR (300 MHz, CDCl3)
d 5.12 (d broad, 1H), 4.09 (m, 1H), 3.89 (m, 1H), 3.75 (m, 4H), 2.77 (m, 3H),
2.68 (broad, 2H), 2.52 (m, 4H), 1.57 (m, 4H), 1.43 (s, 9H), 1.32 (m, 8H), 0.87
(t, J ¼ 6.9 Hz, 6H). The spectrum shows rotamers; 13C NMR (75 MHz,
CDCl3) d 155.5, 80.1, 61.8, 50.9, 33.3, 32.5, 32.5, 32.1, 30.8, 30.7, 29.1,
29.1, 28.2, 22.1, 22.1, 13.8, 13.8. The spectrum shows rotamers: IR
(film) 3398, 2956, 2923, 2872, 1691, 1502, 1164, 1056 cm21; ESI-MS:
m/z ¼ 300 [Mþ þ 23]; [a]D ¼ þ36.1 (c, 0.5, CHCl3, 208C).
(S)-tert-Butyl-N-[3-(ethylthio)-1-hydroxypropan-2-yl]carbamate (8d)
Yield: 67%; TLC Rf ¼ 0.40 (3:1 n-Hex/EtOAc); 1H NMR (300 MHz, CDCl3)
d 5.17 (d broad, 1H), 4.09 (m, 1H), 3.87 (m, 1H), 3.71 (m, 4H), 2.73 (m, 3H),
2.68 (broad, 2H), 2.55 (m, 4H), 1.41 (s, 9H), 1.23 (t, J ¼ 7.3 Hz, 6H). The
spectrum shows rotamers; 13C NMR (75 MHz, CDCl3) d 156.1, 61.6, 51.0,
32.8, 31.6, 28.3, 26.3, 26.2, 14.6, 14.5. The spectrum shows rotamers; IR
(film) 3374, 2973, 2930, 2359, 1694, 1508, 1367, 1172 cm21; ESI-MS:
m/z ¼ 259 [Mþ þ 23]; [a]D ¼ þ28.5 (c, 0.5, CHCl3, 208C).
(S)-tert-Butyl-N-[3-(4-chlorobencylthio)-1-hydroxypropan-2-yl]
carbamate (8e)
Yield: 75%; mp: 95ºC; TLC Rf ¼ 0.32 (3:1 n-Hex/EtOAc); 1H NMR
(300 MHz, CDCl3) d 7.28 (m, 8H), 4.98 (d broad, 1H), 4.09 (m, 1H), 3.84
(m, 1H), 3.70 (m þ s, 8H), 2.82 (m, 2H), 2.78 (m, 2H), 1.42 (s, 9H). The
spectrum shows rotamers; 13C NMR (75 MHz, CDCl3) d 157.3, 156.0
(rotamer), 136.4, 136.1 (rotamer), 133.1, 132.9 (rotamer), 130.3, 130.2
(rotamer), 128.7, 128.6 (rotamer), 79.9, 63.9, 61.8, 51.3, 50.3, 35.6, 32.4,
31.3, 29.6, 28.3. The spectrum shows rotamers; IR (film) 3402, 2979, 2924,
2357, 1691, 1488, 1364, 1246, 1164, 1090 cm21; ESI-MS: m/z ¼ 354
[Mþ þ 23]; [a]D ¼ 23.5 (c, 1.0, CHCl3, 208C).
(S)-tert-Butyl-N-[1-hydroxy-3-(2-naphtylthio)propan-2-yl]carbamate (8f)
Yield: 72%; mp: 928C; TLC Rf ¼ 0.34 (3:1 n-Hex/EtOAc); 1H NMR
(300 MHz, CDCl3) d 7.90 (s, 1H), 7.89 (s, 1H), 7.78 (m, 6H), 7.49 (m, 6H),
5.12 (d broad, 1H), 4.15 (m, 1H), 3.95 (m, 2H), 3.75 (m, 3H), 3.33 (m, 1H),
3.15 (m, 3H), 1.41 (s, 9H). The spectrum shows rotamers; 13C NMR
(75 MHz, CDCl3) d 155.9, 133.7, 132.8, 131.9, 131.8, 128.8, 128.6, 127.6,
127.5, 127.3, 127.2, 127.1, 126.7, 126.6, 126.0, 125.8, 79.9, 63.5, 61.3,
51.7, 50.8, 34.8, 33.2, 29.6, 28.2. The spectrum shows rotamers; IR (film)
3339, 2979, 2929, 1689, 1501, 1370, 1170, 1054 cm21
; ESI-MS:

Sphingosine-1-phosphate Analogues
2743
m/z ¼ 356 [Mþ þ 23], 689 [2Mþ þ 23]; [a]D ¼ þ63.9 (c, 1.0, CHCl3,
208C).
(S)-tert-Butyl-N-[1-hydroxy-3-[4-(2-methoxyethyl)phenoxy]propan-2-yl]
carbamate (9a)
Yield: 76%; TLC Rf ¼ 0.31 (4:1 n-Hex/EtOAc); 1H NMR (300 MHz, CDCl3)
d 7.13 (d, J ¼ 8.6, 2H), 6.83 (d, J ¼ 8.6 Hz, 2H), 5.21 (d broad, 1H), 4.02
(m, 3H), 3.81 (dd, J ¼ 10.9 Hz, 4.0 Hz, 2H), 3.55 (t, J ¼ 7.1 Hz, 2H), 3.33
(s, 3H), 2.81 (t, J ¼ 7.1 Hz, 2H), 1.44 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 156.7, 155.9, 131.5, 129.7, 114.3, 79.8, 73.7, 67.2, 62.6, 58.5, 51.3, 35.1,
28.2; IR (film) 3425, 2936, 1714, 1514, 1363, 1241, 1169, 1116, 1034,
828 cm21; ESI-MS: m/z ¼ 348 [Mþ þ 23]; [a]D ¼ 218.3 (c, 1.0, CHCl3,
208C).
(S)-tert-Butyl-N-[3-(4-benzylphenoxy)-1-hydroxypropan-2-yl]
carbamate (9b)
Yield: 88%; mp: 708C; TLC Rf ¼ 0.35 (4:1 n-Hex/EtOAc); 1H NMR
(300 MHz, CDCl3) d 7.28 (m, 2H), 7.18 (m, 3H), 7.11 (d, J ¼ 8.6 Hz, 2H),
6.84 (d, J ¼ 8.6 Hz, 2H), 5.23 (d broad, 1H), 4.10 (m, 3H), 3.92 (s, 2H),
3.81 (m, 2H), 1.45 (s, 9H); 13C NMR (75 MHz, CDCl3) d 156.6, 155.9,
141.3, 133.8, 129.8, 128.7, 128.3, 125.9, 114.4, 79.8, 67.2, 62.5, 51.3, 40.9,
28.3; IR (film) 3336, 2979, 2926, 1695, 1509, 1238, 1173, 1046 cm21
ESI-MS: m/z ¼ 380 [Mþ þ 23]; [a]D ¼ 223.6 (c, 0.5, CHCl3, 208C).
;
(S)-tert-Butyl-N-[3-(4-chloro-3-methylphenoxy)-1-hydroxypropan-2-yl]
carbamate (9c)
1
Yield: 73%; mp: 89–908C; TLC Rf ¼ 0.33 (4:1 n-Hex/EtOAc); H NMR
(300 MHz, CDCl3) d 7.21 (d, J ¼ 8.7 Hz, 1H), 6.77 (d, J ¼ 2.9 Hz, 1H),
6.67 (dd, J ¼ 8.7 Hz, 3.1 Hz, 1H), 5.16 (d ancho, 1H), 4.05 (m, 3H), 3.81
(dd, J ¼ 10.9 Hz, 4.2 Hz, 2H), 2.59 (s broad, 1H), 2.32 (s, 3H), 1.44
(s, 9H); 13C NMR (75 MHz, CDCl3) d 156.8, 155.9, 137.1, 129.4, 126.3,
117.0, 113.0, 80.0, 67.3, 62.4, 51.3, 28.3, 20.2; IR (film) 3411, 2970, 2935,
1692, 1499, 1479, 1241, 1164, 1038 cm21; ESI-MS: m/z ¼ 338 [Mþ þ 23],
653 [2Mþþ 23]; [a]D ¼ 217.5 (c, 1.0, CHCl3, 208C).
(S)-tert-Butyl-N-[1-hydroxy-3-(4-propylphenoxy)propan-2-yl]
carbamate (9d)
Yield: 86%; TLC Rf ¼ 0.38 (4:1 n-Hex/EtOAc); 1H NMR (300 MHz, CDCl3)
d 7.08 (d, J ¼ 8.6 Hz, 2H), 6.82 (d, J ¼ 8.6 Hz, 2H), 5.22 (d ancho, 1H), 4.06
(m, 3H), 3.82 (dd, J ¼ 11.3 Hz, 4.3 Hz, 2H), 2.65 (s broad, 1H), 6.77 (d, J ¼
2.9 Hz, 1H), 6.67 (dd, J ¼ 8.7 Hz, 3.1 Hz, 1H), 5.16 (d ancho, 1H), 2.52 (t,

2744
S. Grijalvo, A. Llebaria, and A. Delgado
J ¼ 7.3 Hz, 2H), 1.59 (sx, J ¼ 7.3 Hz, 2H), 1.45 (s, 9H), 0.91 (t, J ¼ 7.3 Hz,
3H); 13C NMR (75 MHz, CDCl3) d 156.2, 156.1, 135.4, 129.3, 114.1, 79.8,
67.4, 62.8, 51.3, 37.0, 28.2, 24.6, 13.6; IR (film) 3401, 2964, 2933, 2868,
1692, 1513, 1242, 1170, 1035 cm21; ESI-MS: m/z ¼ 320 [Mþ þ 23], 641
[2Mþþ 23]; [a]D ¼ 214.7 (c, 1.0, CHCl3, 208C).
(S)-tert-Butyl-N-[3-(4-decyloxyphenoxy)-1-hydroxypropan-2-yl]
carbamate (9e)
Yield: 77%; TLC Rf ¼ 0.40 (4:1 n-Hex/EtOAc); 1H NMR (500 MHz, CDCl3)
d 6.84 (m, 4H), 5.23 (d broad, 1H), 4.08 (dd, J ¼ 9.2 Hz, 3.9 Hz, 2H), 3.91
(t, J ¼ 6.8 Hz, 2H), 3.80 (m, 1H), 2.52 (s broad, 1H), 1.76 (q, J ¼ 6.5 Hz,
2H), 1.47 (s, 9H), 1.28 (m, 14H), 0.90 (t, J ¼ 6.8 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 156.2, 154.0, 152.5, 115.6, 115.5, 80.0, 69.2, 63.5,
32.2, 29.8, 29.7, 29.6, 29.5, 29.4, 28.6, 26.2, 22.9, 14.3, 156.1, 135.4, 129.3,
114.1, 79.8, 67.4, 62.8, 51.3, 37.0, 28.2, 24.6, 13.6; IR (film) 3370, 2918,
2851, 1672, 1512, 1527, 1475, 1232, 1173, 1087, 1039, 817, 778 cm21
;
ESI-MS: m/z ¼ 324 [Mþ-Boc], 446 [Mþ þ 23], 870 [2Mþ þ 23];
[a]D ¼ 24.7 (c, 1.0, CHCl3, 208C).
Phosphorylation of Alcohols 8–9 with Dimethylchlorophosphate
(DMPC)
A solution of the starting alcohol (0.1 mmol) in CH2Cl2 (10 mL) at rt was
treated successively with dimethylchlorophosphate (13 mL, 0.12 mol) and
N-methylimidazole (14 mL, 0.17 mmol). The reaction mixture was stirred at
rt for 24 h and quenched by the addition of sat. aqueous NH4Cl (5 mL) and
stirring for 5 min. The organic layer was next washed with 1 N HCl
(3 ꢀ 10 mL) and brine (3 ꢀ 10 mL) and dried over Na2SO4. Evaporation of
the solvent afforded a crude mixture, which was purified by flash chromato-
graphy on hexanes/EtOAc.
Data
(S)-tert-Butyl-N-[1-(dimethoxyphosphoryloxy)-3-(hexadecylthio)
propan-2-yl] carbamate (10a)
Yield: 91%; TLC Rf ¼ 0.40 (1:1 n-Hex/EtOAc); 1H NMR (300 MHz,
CDCl3) d 5.06 (d broad, 1H), 4.23 (m, 1H), 4.10 (m, 1H), 3.90 (m, 1H),
3.79 (s, 3H), 3.76 (s, 3H), 2.65 (m, 2H), 2.56 (t, J ¼ 7.3 Hz, 2H), 1.56
(m, 2H), 1.41 (s, 9H), 1.20 (m, 28H), 0.83 (t, J ¼ 7.3 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 155.3, 79.8, 67.4 (J ¼ 6.5 Hz), 54.3 (J ¼ 5.4 Hz),
49.8, 32.6, 29.6, 29.6, 29.6, 29.5, 29.5, 29.5, 29.4, 29.4, 29.4, 29.3, 29.3,

Sphingosine-1-phosphate Analogues
2745
29.2, 29.1, 28.6, 28.2, 22.5, 14.0; 31P NMR (300 MHz, CDCl3) d 21.70;
IR (film) 2924, 2855, 2365, 1711, 1520, 1464, 1269, 1169, 1039 cm21
ESI-MS: m/z ¼ 562 [Mþ þ 23]; [a]D ¼ þ4.6 (c, 1.0, CHCl3, 208C).
;
(S)-tert-Butyl-N-[3-(decylthio)-1-(dimethoxyphosphoryloxy)propan-2-yl]
carbamate (10b)
Yield: 76%; TLC Rf ¼ 0.35 (1:1 n-Hex/EtOAc); 1H NMR (300 MHz, CDCl3)
d 5.08 (d broad, 1H), 4.24 (m, 1H), 4.07 (m, 1H), 3.88 (m, 1H), 3.77
(d, J ¼ 11.1 Hz, 3H), 3.73 (d, J ¼ 11.1 Hz, 3H), 2.66 (m, 2H), 2.51
(t, J ¼ 7.3 Hz, 2H), 1.54 (m, 2H), 1.40 (s, 9H), 1.22 (m, 16H), 0.84
(t, J ¼ 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 155.2, 79.6, 67.4
(d, J ¼ 6.0 Hz), 54.3 (d, J ¼ 5.4 Hz), 49.9, 32.7, 32.5, 31.7, 29.5, 29.3,
29.3, 29.1, 29.0, 28.6, 28.2, 22.5, 13.9; 31P NMR (300 MHz, CDCl3)
d 21.72; IR (film) 2924, 2851, 1709, 1523, 1274, 1175, 1043 cm21; ESI-
MS: m/z ¼ 478 [Mþ þ 23]; [a]D ¼ þ4.6 (c, 1.0, CHCl3, 208C).
(S)-tert-Butyl-N-[1-(dimethoxyphosphoryloxy)-3-(pentylthio)
propan-2-yl] carbamate (10c)
Yield: 83%; TLC Rf ¼ 0.32 (1:1 n-Hex/EtOAc); 1H NMR (300 MHz, CDCl3)
d 5.07 (d broad, 1H), 4.24 (m, 1H), 4.08 (m, 1H), 3.88 (m, 1H), 3.77 (s, 3H),
3.73 (s, 3H), 2.66 (m, 2H), 2.51 (t, J ¼ 7.3 Hz, 2H), 1.54 (m, 2H), 1.40 (s, 9H),
1.29 (m, 6H), 0.85 (t, J ¼ 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 154.9,
79.6, 67.3 (d, J ¼ 6.04 Hz), 54.3 (d, J ¼ 6.04 Hz), 49.9, 32.8, 32.5, 30.8, 29.1,
28.2, 22.1, 29.1, 13.8; 31P NMR (300 MHz, CDCl3) d 21.70; IR (film) 2961,
2725, 2856, 1711, 1522, 1273, 1165, 1040 cm21; ESI-MS: m/z ¼ 408
[Mþ þ 23]; [a]D ¼ þ3.0 (c, 1.0, CHCl3, 208C).
(S)-tert-Butyl-N-[1-(dimethoxyphosphoryloxy)-3-(ethylthio)propan-2-
yl]carbamate (10d)
Yield: 60%; TLC Rf ¼ 0.30 (1:1 n-Hex/EtOAc); 1H NMR (300 MHz, CDCl3)
d 5.08 (d broad, 1H), 4.26 (m, 1H), 4.10 (m, 1H), 3.91 (m, 1H), 3.78
(d, J ¼ 11.1, 3H), 3.74 (d, J ¼ 11.1 Hz, 3H), 2.69 (m, 2H), 2.54
(c, J ¼ 7.3 Hz, 2H), 1.42 (s, 9H), 1.24 (t, J ¼ 7.3 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 155.2, 79.6, 67.3 (d, J ¼ 5.4 Hz), 54.4 (d, J ¼ 6.0 Hz)
49.9, 32.5, 28.6, 26.6, 14.6; 31P NMR (300 MHz, CDCl3) d 21.75; IR
(film) 2967, 2358, 1708, 1523, 1271, 1172, 1035 cm21
m/z ¼ 366 [Mþ þ 23]; [a]D ¼ þ3.4 (c, 0.5, CHCl3, 208C).
; ESI-MS:

2746
S. Grijalvo, A. Llebaria, and A. Delgado
(S)-tert-Butyl-N-[3-(4-chlorobenzylthio)-1-(dimethoxyphosphoryloxy)
propan-2-yl]carbamate (10e)
Yield: 78%; mp: 838C; TLC Rf ¼ 0.30 (3:1 n-Hex/EtOAc); 1H NMR
(300 MHz, CDCl3) d 7.25 (m, 5H), 5.04 (d broad, 1H), 4.21 (m, 1H), 4.07
(m, 1H), 3.92 (m, 1H), 3.76 (s, 2H), 3.72 (s, 3H), 3.69 (s, 3H), 2.56
(m, 2H), 1.43 (s, 9H); 13C NMR (75 MHz, CDCl3) d 155.0, 136.3, 132.8,
130.2, 128.5, 79.7, 67.4 (d, J ¼ 6.0 Hz), 54.4 (d, J ¼ 6.0 Hz), 49.6, 35.4,
31.8, 28.2; 31P NMR (300 MHz, CDCl3) d 21.70; IR (film) 2961, 1709,
1520, 1490, 1266, 1165, 1034, 850 cm21; ESI-MS: m/z ¼ 462 [Mþ þ 23],
901 [2Mþ þ 23]; [a]D ¼ þ36.2 (c, 1.0, CHCl3, 208C).
(S)-tert-Butyl-N-[1-(dimethoxyphosphoryloxy)-3-(2-naphthylthio)
propan-2-yl]carbamate (10f)
Yield: 80%; mp: 988C; TLC Rf ¼ 0.29 (1:1 n-Hex/EtOAc); 1H NMR
(300 MHz, CDCl3) d 7.89 (s, 1H), 7.75 (m, 3H), 7.46 (m, 3H), 5.17 (d
broad, 1H), 4.32 (m, 1H), 4.11 (m, 1H), 4.02 (m, 1H), 3.75 (s, 3H), 3.71
(s, 3H), 3.31 (m, 1H), 3.13 (m, 1H), 1.40 (s, 9H); 13C NMR (75 MHz,
CDCl3) d 154.9, 133.7, 132.5, 131.8, 128.6, 127.5, 127.1, 126.5, 125.8,
79.7, 67.2 (d, J ¼ 6.04 Hz), 54.3 (d, J ¼ 6.0 Hz), 49.9, 34.3, 29.5, 28.1; 31P
NMR (300 MHz, CDCl3) d 21.68; IR (film) 2972, 1709, 1518, 1497, 1270,
1172, 1034, 852 cm21; ESI-MS: m/z ¼ 464 [Mþ þ 23], 905 [2Mþ þ 23];
[a]D ¼ þ28.5 (c, 1.0, CHCl3, 208C).
(R)-tert-Butyl-N-[1-(dimethoxyphosphoryloxy)-3-[4-(2-methoxyethyl)
phenoxy]propan-2-yl]carbamate (11a)
Yield: 71%; TLC Rf ¼ 0.32 (1:1 n-Hex/EtOAc); 1H NMR (300 MHz, CDCl3)
d 7.10 (d, J ¼ 8.6 Hz, 2H), 6.82 (d, J ¼ 8.6 Hz, 2H), 5.17 (d broad, 1H), 4.16
(m, 4H), 3.95 (dd, J ¼ 9.3 Hz, 5.4 Hz, 1H), 3.72 (d, J ¼ 3.4 Hz, 3H), 3.69
(d, J ¼ 11.1 Hz, 3H), 3.53 (t, J ¼ 11.1 Hz, 2H), 3.32 (s, 3H), 2.79 (t, J ¼
7.1 Hz, 2H), 1.43 (s, 9H); 13C NMR (75 MHz, CDCl3) d 156.6, 155.1,
131.6, 129.7, 114.3, 79.8, 73.6, 65.7 (d, J ¼ 6.0 Hz), 65.6, 58.5, 54.3
(d, J ¼ 6.0 Hz), 49.4, 35.1, 28.2; 31P NMR (300 MHz, CDCl3) d 21.72; IR
(film) 2931, 1709, 1510, 1460, 1364, 1273, 1238, 1170, 1115, 1037, cm21
ESI-MS: m/z ¼ 465 [Mþ þ 23]; [a]D ¼ 229.8 (c, 0.5, CHCl3, 208C).
;
(R)-tert-Butyl-N-[3-(4-benzylphenoxy)-1-(dimethoxyphosphoryloxy)
propan-2-yl]carbamate (11b)
Yield: 84%; TLC Rf ¼ 0.35 (1:1 n-Hex/EtOAc); 1H NMR (300 MHz, CDCl3)
d 7.26 (m, 2H), 7.16 (m, 3H), 7.08 (d, J ¼ 8.7 Hz, 2H), 6.82 (d, J ¼ 8.7 Hz,
2H), 5.17 (d broad, 1H), 4.16 (m, 4H), 3.97 (m, 1H), 3.91 (s, 2H), 3.75
(d, J ¼ 11.1 Hz, 3H), 3.71 (d, J ¼ 11.1 Hz, 3H), 1.44 (s, 9H); 13C NMR

Sphingosine-1-phosphate Analogues
2747
(75 MHz, CDCl3) d 156.5, 155.1, 141.3, 133.9, 129.8, 128.6, 128.3, 125.9,
114.4, 79.8, 65.8 (d, J ¼ 6.0 Hz), 65.6, 54.3 (d, J ¼ 6.0 Hz), 40.9, 28.2; 31P
NMR (300 MHz, CDCl3) d 21.70; IR (film) 2957, 2534, 1714, 1608, 1510,
1270, 1240, 1172, 1041, 849 cm21; ESI-MS: m/z ¼ 485 [Mþ þ 23], 953
[2Mþ þ 23]; [a]D ¼ 231.9 (c, 0.5, CHCl3, 208C).
(R)-tert-Butyl-N-[3-(4-chloro-3-methylphenoxy)-1-
(dimethoxyphosphoryloxy)propan-2-yl]carbamate (11c)
Yield: 76%; TLC Rf ¼ 0.33 (1:1 n-Hex/EtOAc); 1H NMR (300 MHz, CDCl3)
d 7.20 (d, J ¼ 8.7 Hz, 1H), 6.77 (d, J ¼ 2.9 Hz, 1H), 6.67 (dd, J ¼ 8.6 Hz,
2.9 Hz, 1H), 5.14 (d broad, 1H), 4.17 (m, 3H), 4.07 (m, 1H), 3.93 (dd,
J ¼ 9.3 Hz, 5.85 Hz, 1H), 3.75 (d, J ¼ 11.1 Hz, 3H), 3.70 (d, J ¼ 11.1 Hz,
3H), 2.31 (s, 3H), 1.44 (s, 9H); 13C NMR (75 MHz, CDCl3) d 156.6, 155.1,
137.0, 129.5, 126.3, 116.9, 113.0, 79.9, 65.7, 65.6, 54.0 (d, J ¼ 6.04 Hz),
28.2, 20.1; 31P NMR (300 MHz, CDCl3) d 21.76; IR (film) 2984, 1710,
1530, 1479, 1276, 1245, 1163, 1041, 849 cm21; ESI-MS: m/z ¼ 446
[Mþ þ 23], 869 [2Mþ þ 23]; [a]D ¼ 221.9 (c, 1.0, CHCl3, 208C).
(R)-tert-Butyl-N-[1-(dimethoxyphosphoryloxy)-3-(4-propylphenoxy)
propan-2-yl]carbamate (11d)
Yield: 83%; TLC Rf ¼ 0.35 (1:1 n-Hex/EtOAc); 1H NMR (300 MHz, CDCl3)
d 7.07 (d, J ¼ 8.7 Hz, 2H), 6.81 (d, J ¼ 8.7 Hz, 2H), 5.15 (d broad, 1H), 4.18
(m, 3H), 4.09 (m, 1H), 3.96 (dd, J ¼ 9.3 Hz, 5.4 Hz, 1H), 3.74 (d, J ¼ 11.1 Hz,
3H), 3.70 (d, J ¼ 11.1 Hz, 3H), 2.51 (t, J ¼ 7.3 Hz, 2H), 1.59 (sx, J ¼ 7.3 Hz,
2H), 1.44 (s, 9H), 0.90 (t, J ¼ 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
156.2, 155.0, 135.7, 128.2, 114.0, 80.0, 66.1 (d, J ¼ 6.0 Hz), 66.0, 54.1
(d, J ¼ 6.0 Hz), 37.3, 28.1, 24.0, 13.9; 31P NMR (300 MHz, CDCl3) d
21.71; IR (film) 2956, 2935, 2873, 1709, 1611, 1509, 1463, 1276, 1239,
1175, 1042, 845 cm21; ESI-MS: m/z ¼ 440 [Mþ þ 23], 857 [2Mþ þ 23];
[a]D ¼ 223.2 (c, 1.0, CHCl3, 208C).
(R)-tert-Butyl-N-[3-(4-decyloxyphenoxy)-3-(dimethoxyphosphoryloxy)
propan-2-yl]carbamate (11e)
Yield: 82%; TLC Rf ¼ 0.37 (1:1 n-Hex/EtOAc); 1H NMR (500 MHz, CDCl3)
d 6.82 (m, 4H), 5.18 (d broad, 1H), 4.27 (m, 1H), 4.17 (m,2H), 4.06 (m, 1H),
3.95 (m, 1H), 3.89 (t, J ¼ 6.3 Hz, 2H), 3.76 (d, J ¼ 11.1 Hz, 3H), 3.72
(d, J ¼ 11.1 Hz, 3H), 1.75 (q, J ¼ 7.3 Hz, 2H), 1.45 (s, 9H), 1.27 (m, 14H),
0.88 (t, J ¼ 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 155.5, 153.9,
152.4, 115.5, 80.0, 68.9, 66.6, 54.7 (d, J ¼ 5.4 Hz), 32.1, 29.8, 29.7, 29.6,
29.5, 29.4, 28.5, 26.2, 22.9, 21.2, 14.3; IR (film) cm21 2929, 2854, 1713,
1526, 1272, 1171, 1037, 850 cm21; ESI-MS: m/z ¼ 432 [Mþ-Boc], 554
[Mþ þ 23], 1085 [2Mþ þ 23]; [a]D ¼ 22.6 (c, 1.0, CHCl3, 208C).

2748
S. Grijalvo, A. Llebaria, and A. Delgado
Synthesis of Aminophosphates 1–2
TMSBr (0.5 mmol, 66 mL) were added dropwise over a solution of the starting
N-Boc dimetylphosphate 10–11 (0.05 mmol) in CH3CN (5 mL). The reaction
mixture was stirred at rt for 3 h and evaporated to dryness. The residue
was taken up in a 95/5 MeOH/H2O mixture (5 mL) and stirred for an
additional 1 h. The reaction mixture was diluted with H2O (10 mL) and
lyophilized to give a spongy solid, which did not require additional
purification.
Data
(S)-2-Amino-3-(hexadecylthio)propyl Dihydrogenphosphate (1a)
Yield: 91%; mp: .2208C; 1H NMR (500 MHz, CD3OD) d 4.20 (m, 2H), 3.53
(m, 1H), 2.81 (m, 2H), 2.61 (m, 2H), 1.60 (m, 2H), 1.23 (m, 26H), 0.85
(t, J ¼ 6.3 Hz, 3H); 13C NMR (125 MHz, CD3OD), selected signals: d 60.7,
51.1, 33.5, 32.0, 32.0, 31.8, 29.7, 29.6, 29.5, 29.4, 29.2, 29.0, 28.6, 28.5,
22.5, 13.2; ESI-MS: m/z ¼ 410 [Mþ 2 1]; [a]D ¼ þ4.1 (c, 1.0, MeOH,
208C).
(S)-2-Amino-3-(decylthio)propyl Dihydrogenphosphate (1b)
Yield: 91%; 1H NMR (500 MHz, CD3OD) d 4.23 (m, 2H), 3.55 (m, 1H), 2.82
(m, 2H), 2.58 (m, 2H), 1.58 (m, 2H), 1.25 (m, 14H), 0.85 (t, J ¼ 6.3 Hz, 3H);
13C NMR (125 MHz, CD3OD), selected signals: d 60.8, 51.2, 33.1, 32.1–29.2,
28.6, 28.5, 22.5, 13.2; ESI-MS: m/z ¼ 326 [Mþ 2 1]; [a]D ¼ þ3.3 (c, 1.0,
MeOH, 208C).
(S)-2-Amino-3-(pentylthio)propyl Dihydrogenphosphate (1c)
Yield: 98%; 1H NMR (500 MHz, CD3OD) d 4.26 (m, 2H), 3.58 (m, 1H), 2.90
(m, 2H), 2.63 (t, J ¼ 7.3 Hz, 2H), 1.64 (m, 2H), 1.38 (m, 6H), 0.94 (t, J ¼
7.0 Hz, 3H); 13C NMR (125 MHz, CD3OD), selected signals: d 64.5, 53.6,
51.1, 32.0, 30.8, 30.4, 29.0, 22.1, 13.1; ESI-MS: m/z ¼ 256 [Mþ 2 1];
[a]D ¼ þ1.8 (c, 1.0, MeOH, 208C).
(S)-2-Amino-3-(ethylthio)propyl Dihydrogenphosphate (1d)
Yield: 72%; 1H NMR (500 MHz, CD3OD) d 4.21 (m, 2H), 3.59 (m, 1H), 2.80
(m, 1H), 2.78 (m, 1H), 2.60 (m, 2H), 1.25 (m, 3H); 13C NMR (125 MHz,
CD3OD) d 65.0, 54.3, 51.5, 28.8, 16.3; ESI-MS: m/z ¼ 214 [Mþ 2 1]
[a]D ¼ þ2.6 (c, 1.0, MeOH, 208C).

Sphingosine-1-phosphate Analogues
2749
(S)-3-(4-Chlorobenzylthio)-2-aminopropyl Dihidrogenphosphate (1e)
1
Yield: 83%; H NMR (500 MHz, CD3OD) d 7.39 (AA0 of an AA0BB0,
J ¼ 8.5 Hz, 2H), 7.34 (BB0 of an AA0BB0, d, J ¼ 8.3 Hz, 4H), 4.24
(m, 2H), 3.79 (s, 2H), 3.48 (m, 1H), 2.80–2.70 (m, 2H); 13C NMR
(125 MHz, CD3OD) d 136.8, 132.9, 130.6, 128.5, 64.6, 64.5, 60.8, 50.7,
50.7, 35.0; ESI-MS: m/z ¼ 310, 312 [Mþ 2 1]; [a]D ¼ þ24.9 (c, 1.0,
MeOH, 208C).
(S)-2-Amino-3-(2-naphthyltio)propyl Dihydrogenphosphate (1f)
Yield: 86%; 1H NMR (500 MHz, CD3OD) d 8.32 (s, 1H), 8.16 (m, 3H), 7.85
(m, 1H), 7.80 (m, 2H), 4.60 (dd, J ¼ 6.1 Hz, 4.39 Hz, 2H), 3.86 (m, 1H), 3.69
(dd, J ¼ 7.0 Hz, 5.37 Hz, 2H); 13C NMR (125 MHz, CD3OD) d 134.1, 132.6,
130.9, 129.0, 128.8, 127.7, 127.6, 127.2, 126.7, 126.3, 64.5, 50.7, 32.3;
ESI-MS: m/z ¼ 312 [Mþ 2 1]; [a]D ¼ þ4.7 (c, 1.0, MeOH, 208C).
(R)-2-Amino-3-[4-(2-methoxyethyl)phenoxy]propyl
Dihydrogenphosphate (2a)
1
Yield: 93%; H NMR (500 MHz, CD3OD) d 7.20 (AA0 of an AA0BB0, d,
J ¼ 8.3 Hz, 2H), 6.96 (BB0 of an AA0BB0, d, J ¼ 8.3 Hz, 4H), 4.33–4.22
(m, 4H), 3.85 (m, 1H), 3.57 (m, 2H), 3.33 (s, 3H), 2.81 (m, 2H); 13C NMR
(125 MHz, CD3OD) d 156.6, 132.6, 129.9, 114.5, 73.6, 57.6, 51.1, 34.9;
ESI-MS: m/z ¼ 304 [Mþ 2 1], 609 [2Mþ 2 1]; [a]D ¼ þ2.3 (c, 1.0,
MeOH, 208C).
(R)-2-Amino-3-(4-benzylphenoxy)propyl Dihydrogenphosphate (2b)
Yield: 90%; 1H NMR (300 MHz, CD3OD) d 7.25 (m, 3H), 7.18 (m, 4H), 6.94
(m, 2H), 4.28 (m, 2H), 4.21 (m, 1H), 3.91 (s, 2H), 3.87 (m, 2H); 13C NMR
(75 MHz, CD3OD) d 160.1, 145.3, 138.7, 133.4, 132.2, 131.8, 129.4, 126.9,
118.1, 64.6, 62.1, 49.3, 44.3. ESI-MS: m/z ¼ 336 [Mþ 2 1]; [a]D ¼ þ3.1
(c, 1.0, MeOH, 208C).
(R)-2-Amino-3-(4-chloro-3-metylphenoxy)propyl
Dihydrogenphosphate (2c)
1
Yield: 91%; H NMR (500 MHz, CD3OD) d 7.25 (broad, 1H), 6.96 (broad,
1H), 6.82 (broad, 1H), 4.40–4.28 (broad, 2H), 3.90 (broad, 1H), 3.31
(broad, 2H), 2.32 (s, 3H); 13C NMR (125 MHz, CD3OD) d 156.7, 137.2,
129.7, 126.7, 117.4, 113.7, 65.6, 64.0, 51.2, 19.3; ESI-MS: m/z ¼ 294, 296
[Mþ 2 1]; [a]D ¼ þ2.1 (c, 1.0, MeOH, 208C).

2750
S. Grijalvo, A. Llebaria, and A. Delgado
(R)-2-Amino-3-(4-propylphenoxy)propyl Dihydrogenphosphate (2d)
1
Yield: 94%; H NMR (500 MHz, CD3OD) d 7.12 (AA0 of an AA0BB0, d,
J ¼ 8.3 Hz, 2H), 6.92 (BB0 of an AA0BB0, d, J ¼ 8.3 Hz, 2H), 4.28–4.19
(m, 4H), 3.88 (m, 1H), 2.52 (m, 2H), 1.59 (m, 2H), 0.90 (m, 3H); 13C NMR
(125 MHz, CD3OD) d 156.2, 136.1, 129.3, 114.4, 65.0, 63.8, 53.7, 36.9,
24.7, 12.8; ESI-MS: m/z ¼ 288 [Mþ 2 1], 577 [2Mþ 2 1]; [a]D ¼ þ3.1 (c,
1.0, MeOH, 208C).
(R)-2-Amino-3-[(4-decyloxy)phenoxy)]propyl Dihydrogenphosphate (2e)
1
Yield: 94%; H NMR (500 MHz, CD3OD) d 6.95 (broad, 2H), 6.88 (broad,
2H), 4.46–4.30 (broad, 4H), 4.17 (broad, 1H), 3.92 (m, 2H), 1.75 (m, 2H),
1.46 (m, 2H), 1.32 (m, 12H), 0.91 (m, 3H); 13C NMR (125 MHz, CD3OD)
d 154.5, 152.1, 115.6, 115.3, 68.3, 65.7, 53.6, 31.9, 29.5, 29.5, 29.3, 29.2,
26.0, 22.5, 13.2; ESI-MS: m/z ¼ 402 [Mþ 2 1], 804 [2Mþ 2 1];
[a]D ¼ þ2.1 (c, 1.0, MeOH, 208C).
ACKNOWLEDGMENTS
´
Partial financial support from Ministerio de Ciencia y Tecnologıa (Spain)
´
(Project MCYT CTQ2005-00175/BQU), Fondos Feder (EU), Fundacio “La
´ ´ ´
Marato de TV3” (Projects 040730 and 040731), Fundacion Ramon Areces,
and Generalitat de Catalunya (Project 2005SGR0163) is acknowledged.
REFERENCES
1. Liao, J. Y.; Tao, J. H.; Lin, G. Q.; Liu, D. G. Chemistry and biology of sphingo-
lipids. Tetrahedron 2005, 61, 4715–4733.
2. Spiegel, S.; Foster, D.; Kolesnick, R. Signal transduction through lipid second
messengers. Curr. Opin. Cell Biol. 1996, 8, 159–167.
3. Chalfant, C. E.; Spiegel, S. Sphingosine 1-phosphate and ceramide 1-phosphate:
Expanding roles in cell signaling. J. Cell Sci. 2005, 118, 4605–4612.
4. Taha, T. A.; Argraves, K. M.; Obeid, L. M. Sphingosine-1-phosphate receptors:
Receptor specificity versus functional redundancy. Biochim. Biophys. Acta Mol.
Cell Biol. Lipids 2004, 1682, 48–55.
5. Spiegel, S.; Milstien, S. Sphingosine-1-phosphate: An enigmatic signalling lipid.
Nat. Rev. Mol. Cell Biol. 2003, 4, 397–407.
6. Kiuchi, M.; Adachi, K.; Kohara, T.; Minoguchi, M.; Hanano, T.; Aoki, Y.;
Mishina, T.; Arita, M.; Nakao, N.; Ohtsuki, M.; Hoshino, Y.; Teshima, K.;
Chiba, K.; Sasaki, S.; Fujita, T. Synthesis and immunosuppressive activity of
2-substituted 2-aminopropane-1,3-diols and 2-aminoethanols. J. Med. Chem.
2000, 43, 2946–2961.
7. Brinkmann, V.; Davis, M. D.; Heise, C. E.; Albert, R.; Cottens, S.; Hof, R.;
Bruns, C.; Prieschl, E.; Baumruker, T.; Hiestand, P.; Foster, C. A.;

Sphingosine-1-phosphate Analogues
2751
Zollinger, M.; Lynch, K. R. The immune modulator FTY720 targets sphingosine
1-phosphate receptors. J. Biol. Chem. 2002, 277, 21453–21457.
8. Clemens, J. J.; Davis, M. D.; Lynch, K. R.; Macdonald, T. L. Synthesis of para-
alkyl aryl amide analogues of sphingosine-1-phosphate: Discovery of potent
S1P receptor agonists. Bioorg. Med. Chem. Lett. 2003, 13, 3401–3404.
9. Grijalvo, S.; Bedia, C.; Triola, G.; Casas, J.; Llebaria, A.; Teixido, J.; Rabal, O.;
Levade, T.; Delgado, A.; Fabrias, G. Chem. Phys. Lipids. 2006, 144, 69–84.
10. Murakami, T.; Furusawa, K.; Tamai, T.; Yoshikai, K.; Nishikawa, M. Synthesis
and biological properties of novel sphingosine derivatives. Bioorg. Med. Chem.
Lett. 2005, 15, 1115–1119.
11. Lim, H. S.; Park, J. J.; Ko, K.; Lee, M. H.; Chung, S. K. Syntheses of
sphingosine-1-phosphate analogues and their interaction with EDG/S1P
receptors. Bioorg. Med. Chem. Lett. 2004, 14, 2499–2503.
12. Lim, H. S.; Oh, Y. S.; Suh, P. G.; Chung, S. K. Syntheses of sphingosine-1-phosphate
stereoisomers and analogues and their interaction with EDG receptors. Bioorg. Med.
Chem. Lett. 2003, 13, 237–240.
13. Zamyatina, A. Y.; Bushnev, A. S.; Shvets, V. I. Phosphitetriester] and H-phosphonate
approaches in the synthesis of phospholipids. Bioorg. Khim. 1994, 20, 1253–1296.
14. Prepared as described in Gajda, T.; Zwierzak, A. Organophosphorus Esters, 9:
Phase-transfer catalysed halogenation of di-tert-butyl phosphite—Preparation of
di-tert-butyl phosphorohalidates. Synthesis-Stuttgart 1976, 243–244.
15. Taguchi, M.; Sugimoto, K.; Goda, K.-I.; Akama, T.; Yamamoto, K.; Suzuki, T.;
Tomishima, Y.; Nishiguchi, M.; Arai, K.; Takahashi, K.; Kobori, T. Sphingomye-
lin analogues as inhibitors of sphingomyelinase. Bioorg. Med. Chem. Lett. 2003,
13, 1963–1966.
16. Arenz, C.; Gartner, M.; Wascholowski, V.; Giannis, A. Synthesis] and biochemical
investigation of scyphostatin analogues as inhibitors of neutral sphingomyelinase.
Bioorg. Med. Chem. 2001, 9, 2901–2904.