Synthesis of sphingosine-1-phosphonate and homosphingosine-1-phosphonate

Article abstract of DOI:10.1002/ejoc.200400671

In the first approach to homosphingosine-1-phosphonate, D-glucofuranose was selectively deoxygenated at C-5. Bond cleavage between C-1 and C-2 afforded a 5-deoxy-D-threopentose intermediate. (E)-Selective Wittig reaction with a C ₁₄-chain gave a C₁₉-intermediate, which was readily transformed into homosphingosine. Formation of a cyclic urethane containing the 3-amino and the 4-hydroxy group of the C₁₉-intermediate permitted regioselective introduction of the phosphonate group at C-1, thus affording the target molecule after deprotection. In a second and shorter route, C ₁₈-sphingosine was converted to a cyclic urethane containing the 2-amino and the 3-hydroxy group of the C₁₈-chain. C₁-Chain extension by a hydroxymethyl group by introduction of cyanide led to the same C₁₉ cyclic urethane as obtained in the first route. Similarly, the C₁₈ cyclic urethane led to the other target molecule, namely sphingosine-1-phosphonate. The third and shortest route to homosphingosine-1- phosphonate could be based on regioselective 1-O-tosylation of 1,2,3-(trihydroxy)octadec-4-ene. Transformation into a 1,2-epoxide, then combination of C₁-chain extension and introduction of a phosphonate group with methylphosphonate as reagent, and finally azide introduction, led after functional group liberation to the target molecule. As shown, also truncated derivatives are readily accessible by this route. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400671

FULL PAPER
Synthesis of Sphingosine-1-phosphonate and Homosphingosine-1-phosphonate
Andrej Tarnowski,[a] Oliver Retz,[a] Thomas Bär,[a] and Richard R. Schmidt*[a]
Keywords: Sphingosines / Phosphonates / Epoxide opening / Wittig reaction
In the first approach to homosphingosine-1-phosphonate,
glucofuranose was selectively deoxygenated at C-5. Bond
cleavage between C-1 and C-2 afforded a 5-deoxy- -threo-
pentose intermediate. (E)-Selective Wittig reaction with a
C14-chain gave a C19-intermediate, which was readily trans-
formed into homosphingosine. Formation of a cyclic urethane
D
-
nide led to the same C19 cyclic urethane as obtained in the
first route. Similarly, the C18 cyclic urethane led to the other
target molecule, namely sphingosine-1-phosphonate. The
third and shortest route to homosphingosine-1-phosphonate
could be based on regioselective 1-O-tosylation of 1,2,3-(tri-
hydroxy)octadec-4-ene. Transformation into a 1,2-epoxide,
then combination of C1-chain extension and introduction of
a phosphonate group with methylphosphonate as reagent,
and finally azide introduction, led after functional group lib-
eration to the target molecule. As shown, also truncated de-
rivatives are readily accessible by this route.
D
containing the 3-amino and the 4-hydroxy group of the C19
-
intermediate permitted regioselective introduction of the
phosphonate group at C-1, thus affording the target molecule
after deprotection. In a second and shorter route, C18-sphin-
gosine was converted to a cyclic urethane containing the 2-
amino and the 3-hydroxy group of the C18-chain. C1-Chain
extension by a hydroxymethyl group by introduction of cya-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
Phosphosphingolipids, derivatives of sphingosine
(Scheme 1, 1), are important membrane constituents. For
instance, sphingomyelin (2) and ceramide-1-phosphoinosi-
tol (3), were found as constituents of a variety of different
cell types.[1] The phosphorylated metabolites of sphingo-
myelin, as sphinogosine-1-phosphate (4), sphingosine-1-
phosphocholine (= lysosphingomyelin), and ceramide-1-
phosphate were found to participate in cell regulation and
transmembrane signalling.[1Ϫ6] Sphingosine-1-phosphate
(4) has received special attention because it possesses sec-
ond messenger properties.[2,7,8] The levels of 4 increase
rapidly, for instance, in response to platelet derived growth
factor (PDGF) and tissue platelet activator (TPA).[8,9] 4 is a
mitogen in several cell types, a strong inhibitor of cell motil-
ity and phagokinesis, and an inhibitor of chemoinvasion of
tumour cells.[8,10,11,12] 4 also induces platelet shape changes,
aggregation, and intracellular calcium mobilisation, thus
having implications in thrombosis, haemostasis and wound
healing.[13] Efficient syntheses of 4 have been reported.[14,15]
In order to clearly distinguish the biological effects of 4
from that of the dephosphorylated product, namely sphin-
gosine (1), a hydrolytically stable analogue of 4 is required.
Therefore, we planned to synthesize the corresponding
phosphonate 5, which is formally a derivative of 1-deoxy-
sphingosine. Considering the distance between the func-
Scheme 1. Structure of compounds 1–6.
tional groups in 4, a better analogue of 4 should be homo-
sphingosine-1-phosphonate 6, which is a derivative of
homosphingosine or 1-deoxyhomosphingosine. Efficient
syntheses of compounds 5 and 6 are reported in this pa-
per.[16Ϫ18] The sphinganine analogue of 5 has been pre-
viously synthesized as racemic mixture[19] and also the syn-
[a] Fachbereich Chemie, Universität Konstanz,
Fach M 725, 78457 Konstanz, Germany
Fax: +49-7531-88 3135
E-mail: Richard.Schmidt@uni-konstanz.de
Eur. J. Org. Chem. 2005, 1129–1141
DOI: 10.1002/ejoc.200400671
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A. Tarnowski, O. Retz, T. Bär, R. R. Schmidt
FULL PAPER
thesis of a protected derivative of 5 has been reported.[20]
Syntheses of homosphinganine and homophytosphingosine
analogs of 6 have also been recently reported.[21Ϫ23]
Results and Discussion
In our previously reported efficient sphingosine synthe-
sis,[24,25] 2,4-di-O-protected d-threose was a decisive inter-
mediate; hence, homosphingosine and presumably also its
phosphonate 6, should be readily available from 2,5-di-O-
protected 4-deoxy-d-threo-pentose following (E)-selective
chain extension by Wittig reaction.[16] To this end, known
1,2-O-isopropylidene-d-glucose 7[26] (Scheme 2) was pre-
pared in two steps from d-glucose. Transformation with
thiocarbonyl diimidazole (TCDI) into thionocarbonate 8
and then deoxygenation with tributyltin hydride in the pres-
ence of azoisobutyronitrile (AIBN) afforded selectively the
5-deoxygenated intermediate 9 in good yield; the 6-deoxy-
genated isomer was not observed. The structural assign-
ment of 9 was also confirmed by O-acetylation to 10, which
showed the expected downfield shifts for 6a-H/6b-H and 3-
H. O-Benzylation of 9 with sodium hydride/benzyl bromide
gave compound 11, which on treatment with acid led to de-
O-isopropylidenation (Ǟ 12). Formal 1,2-diol cleavage in
12 with sodium metaperiodate gave the 3-O-formyl-pro-
tected 4-deoxypentose 14. However, it was found that first
reduction of the aldehyde group in 12 (Ǟ 5-deoxy-hexitol
13) and then 1,2-diol cleavage, which provides 3-O-unpro-
tected 4-deoxypentaose 15, gives better results in the follow-
ing chain extension. The (E)-selective Wittig reaction with
14 and (triphenyl)tetradecylphosphonium bromide with
phenyllithium as base in the presence of lithium bromide
gave C19-intermediate 16, though only in 39% yield. With
15 and the same reagents and reaction conditions, 16 was
obtained in 50% yield.
Scheme 2. Reagents and conditions: (a) TCDI, THF refl., 2 h
(76%); (b) Bu3SnH, AIBN, dioxane refl., 2 h, (71%); (c) Ac2O, Pyr,
15 h (79%); (d) BnBr, NaH, DMF, room temp., 5 h (89%); (e) HCl
in H2O, THF, room temp., 60 h (82%); (f) NaIO4, THF/H2O, room
temp., 5 h (90%); (g) NaBH4, MeOH (81%); NaIO4, THF/H2O,
room temp., 1 h (91%); (h) Triphenyl(tetradecyl)phosphonium bro-
mide in Tol, PhLi and LiBr in Et2O, THF, –40 °C Ǟ room temp.
(39%); (i) see (h), 50% yield; (j) MeSO2Cl, NEt3, CH2Cl2, 6 h,
room temp. (87%).
Activation of the 3-OH group for azide introduction was
carried out by O-mesylation (Ǟ 17). Treatment with so-
dium azide gave the 3-azido compound 18 (Scheme 3),
which had the desired d-erythro-configuration of homo-
sphingosine. The same compound could be directly ob-
tained from 3-O-unprotected 16 in a Mitsunobu reaction[27]
by activation with (triphenylphosphane)/diisopropyl azod- straints. Hence, the amino group of 20 was selectively pro-
icarboxylate (DIAD) and then reaction with the zinc azide- tected with the trifluoroacetyl (TFA) group (Ǟ 22) and then
Ϫpyridine complex[28] in toluene at 50 °C, however, in lower the primary 1-OH group was protected with the sterically
overall yield. Liberation of the amino group in 18 by azide demanding tert-butyldimethylsilyl (TBDMS) group (Ǟ 23).
reduction with triphenylphosphane in pyridine/water[29] (Ǟ Base-supported cleavage of the TFA group (Ǟ 24) and then
19), and then O-debenzylation with lithium in liquid ammo- treatment with carbonyldiimidazole (CDI) afforded the cy-
nia at low temperature, furnished unprotected homosphin- clic urethane 25 in high yield. 1-O-Desilylation under acid
gosine 20.[16,30] The structural assignment of 20 was sup- catalysis furnished the desired 1-O-unprotected homosphin-
ported by per-acetylation affording triacetyl derivative 21, gosine derivative 26, which could be directly obtained in
which showed the expected downfield shifts in the 1H NMR low yield by the treatment of 20 with CDI. However, the
spectrum for 1-H, 3-H, and 4-H.
main product in this reaction is the cyclic urethane incorpo-
For the synthesis of target molecule 6 from 20, selective rating 1-O and 3-N;[31] therefore, the synthesis via 22–25 is
protection of the 4-OH group and the amino group was more efficient. 1-O-Mesylation of 26 (Ǟ 27), then mesylate/
required. To this end, formation of a cyclic urethane was bromide exchange by reaction with lithium bromide in THF
envisaged because any undesired intramolecular interaction at 60 °C (Ǟ 28), and Arbuzov reaction[32] with neat tri-
with 1-O-activated C-1 should be precluded by steric con- methyl phosphite at elevated temperature, afforded the pro-
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Sphingosine-1-phosphonate and Homosphingosine-1-phosphonate
FULL PAPER
(Ǟ 33), and then treatment with CDI afforded the cyclic
urethane 34. Reaction of this compound with cyanide in
triethyleneglycol (TEG) at 60 °C led to the required C19-
intermediate 35 in high overall yield. Transformation of this
compound into the protected homosphingosine 26 was best
performed by reduction of the cyano group with diisobutyl-
aluminum hydride (DIBAH) to the aldehyde 36, which was
then reduced with sodium borohydride to 26, thus leading
in four additional steps to 6. In terms of number of steps
and overall yield this d-galactose-based route to 6 is more
efficient than the first route. In addition, readily available
34 is an ideal precursor for the synthesis of the phosphonate
5. Treatment with lithium bromide in THF at 60 °C af-
forded the bromide 37 in quantitative yield. Heating in tri-
methyl phosphite furnished the dimethyl phosphonate 38,
which on base-catalyzed hydrolysis gave the unprotected
sphingosine-1-phosphonate 5 in 80% yield.
This reaction scheme could be also exploited, for in-
stance, for the synthesis of the (l)-threo-isomer 43 of 5. To
this end, treatment of N-Boc-protected 31 with excess mesyl
chloride in pyridine furnished the 1,3-di-O-mesyl com-
pound 39 as intermediate, which in an SN2-reaction be-
tween the Boc group and the highly reactive allylic C-3 car-
bon, having a mesylate leaving group, afforded immediately
the cyclic urethane 40. As described above, via bromide 41,
phosphonate 42, and then hydrolysis, 43 was obtained in
very good yield. This efficient transformation of 31 into a
cyclic urethane could be employed for shortening the syn-
thesis of 5 and 6 by selecting as corresponding carbohydrate
precursor d-glucose; however, an even more efficient syn-
thesis could be delineated from the results obtained so far.
Quite a few steps were required for the C1-chain exten-
Scheme 3. Reagents and conditions: (a) NaN3, DMF, 100 °C, 5 h sion and the introduction of the phosphonate group. There-
(82%); (b) PPh3, DIAD, Zn(N3)2·Pyr2, Tol, 50 °C (50%); (c) PPh3,
Pyr/H2O, 50 °C, 15 h (80%); (d) Li, NH3(l), THF, –78 °C Ǟ
group introduction was investigated with the help of meth-
–45 °C, 3 h, (52%); (e) Ac2O, Pyr, room temp., 30 h, (87%); (f)
CF3COSEt, NEt3, MeOH, room temp., 4 h (90%); (g) CDI, THF,
–78 °C (byprod. 10–15%); (h) TBDMS–Cl, Pyr, CH2Cl2, room
fore, C1-chain extension and concomitant phosphonate
ylphosphonate. To this end, the 1,3-O-benzylidene group
in the readily available compound 30a[24,25] (Scheme 5) was
temp., 1,5 h (89%); (i) K2CO3, MeOH/H2O, refl. 1 h (75%); (j)
CDI, THF, room temp., 5 h (85%); (k) pTsOH, THF/H2O, room
temp., 30 h (93%); (l) MeSO2Cl, NEt3, CH2Cl2, room temp., 3 h
(99%); (m) LiBr, THF, 60 °C, 60 h (93%); (n) (MeO)3P, refl., 50 h
(97%); (o) LiOH, EtOH/H2O, refl., 3 d (31%).
cleaved by acid catalysis and afforded the (d)-threo-triol
44a. Chemoselective 1-O-tosylation at –15 °C afforded 45a
in 72% yield, which gave on base treatment the epoxide
46a. In order to obtain regioselectivity in the following reac-
tions, the 3-OH group was protected by treatment with ben-
zyloxymethyl (BOM) chloride in the presence of Hünig’s
tected phosphonate 29 in high yield. Hydrolysis of 29 with base (Ǟ 47a). The carbon chain extension with lithio meth-
lithium hydroxide furnished target compound 6, the only ylphosphonate dibenzyl ester and boron trifluoride diethyl
step along this route in modest yield. The structural assign- etherate, in order to support regioselective epoxide open-
ments of all intermediates and of the final product are sup- ing,[35] afforded the desired C19-phosphonate 48a in very
ported by the NMR spectroscopic data.
good yield. The introduction of an azide group was again
Alternatively, the synthesis of the target compounds 5 performed in a Mitsunobu reaction[27] and afforded cleanly
and 6 should be directly accessible from one precursor, na- 49a. Treatment of 49a with sodium in liquid ammonia at
mely the readily available sphingosine (1).[24,25,33] Hence, for –60 °C led to O-debenzylation and azide group reduction.
the synthesis of 6 a C1-chain extension at C-1 is required. This directly afforded the target molecule 6, which had
To this end, a synthesis of 1 via 30a[24,25] and then a 2-N,3- physical data in accordance with those of the material ob-
O-protection again via urethane formation was envisaged. tained via the other routes. Thus, also the structural assign-
This could be readily gained by introduction of an N-tert- ments were confirmed.
butoxycarbonyl (Boc) group (Scheme 4, Ǟ 31) and selective
The same sequence of reactions was applied to the C8-
mesylation (Ǟ 32) following previously reported pro- precursor 44b, which was obtained from 30b.[36,37] Via the
cedures.[16,25,34] Acid-catalyzed cleavage of the Boc group intermediates 45b, 46b, 47b, and 48b the truncated homo-
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A. Tarnowski, O. Retz, T. Bär, R. R. Schmidt
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Scheme 5. Reagents and conditions: (a) Ion exchange resin: H+
form, MeOH, 50 °C, 10 h (a: 61%, b: 65%); (b) pTSCl, Pyr, –15 °C,
24 h (a: 72%, b: 67%); (c) NaH, THF/DMSO, room temp., 2 h (a:
73%, b: 64%); (d) BOMCl, DIPEA, CH2Cl2, room temp., 48 h
(a:95%, b: 95%); (e) MePO(OBn)2, BuLi, THF, –80 °C, 2 h;
BF3·OEt2, 2 h (a, b ~ 90%); (f) Zn(N3)2·Pyr2, PPh3, DIAD, Tol,
50 °C, 5 h (a: 83%, b: 83%); (g) Na, NH3(l), –60 °C, 5 min (qu);
(h) pTsOH, tBuOH, refl., 6 h (47%); (i) PPh3, H2O, 50 °C, 16 h
(73%).
sodium in liquid ammonia both compounds afforded the
target compound 50 in high yield.
Scheme 4. Reagents and conditions: (a) Boc2O, NEt3, dioxane/
H2O, room temp., 30 min (97%); (b) MsCl, Pyr, room temp.,
15 min (71%); (c) TFA, CH2Cl2, room temp., 30 min (qu); (d) CDI,
THF, room temp., 20 h (76%); (e) KCN, TEG, 60 °C, 5 h (79%);
(f) DIBAH, Tol, –20 °C, 2 h (77%); (g) NaBH4, MeOH, room
temp., 30 min (95%); (h) LiBr, THF, 60 °C, 24 h (98%); (i) P(OMe)3,
refl., 50 h (95%); (j) LiOH, EtOH/H2O, room temp., 5 h (80%);
(k) MeSO2Cl, Pyr, room temp., 1.5 h (71%); (l) LiBr, THF, 50 °C,
48 h (86%); (m) P(OMe)3, refl., 50 h (96%); (n) LiOH, EtOH/H2O,
room temp., 5 h (69%).
Conclusions
In conclusion, sphingosine-1-phosphonate (5) can be
readily obtained from sphingosine via the 2-N,3-O-urethane
formation and then introduction of the phosphonate group
by the use of an Arbuzov reaction. For the synthesis of
sphingosine derivative 49b was obtained. This was trans- homosphingosine-1-phosphonate (6) several routes were in-
formed into the target compound 50. Such truncated com- vestigated. In the routes starting from d-glucose via a 4-
pounds have proven useful in biological studies.[38] Also a deoxypentose and from d-galactose via sphingosine, most
slight variation of this scheme was investigated. The BOM steps are very efficient. However, the total number of steps
group was selectively cleaved under acidic conditions giving is high. Therefore, starting from d-galactose, an epoxide
access to the 4-O-unprotected derivative 51. Also the 3- route was investigated, which combined the C18-chain ex-
azido group in 49b could be selectively reduced by the ad- tension by one carbon atom with the introduction of the
dition of triphenylphosphane to a solution in THF/water phosphonate group by selective opening of the epoxide
and furnished the 3-amino derivative 52. On treatment with group with lithio methylphosphonate. This way target mole-
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Sphingosine-1-phosphonate and Homosphingosine-1-phosphonate
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Ac2O, 1:1 (2.0 mL) for 15 h. The reaction mixture was evaporated
under reduced pressure and purified by flash chromatography (pe-
troleum ether/EtOAc, 3:1) to afford 10 (56 mg, 79%) as a colourless
oil. TLC (petroleum ether/EtOAc, 3:1): Rf = 0.37. [α]D = +1.5 (c =
cule 6 was obtained from d-galactose in ten steps in very
good overall yield.
1
1.0, CHCl3). H NMR (250 MHz, CDCl3): δ = 1.31 (s, 3 H, CH3),
Experimental Section
1.52 (s, 3 H, CH3), 1.90–1.98 (m, 2 H, 5a-H, 5b-H), 2.04 (s, 3 H,
CH3CO), 2.11 (s, 3 H, CH3CO), 4.12 (m, 1 H, 6b-H), 4.24 (ddd,
General Remarks: Solvents were purified according to standard
procedures. NMR spectra were recorded at 22 °C with a Bruker
AC 250 Cryospec, JEOL JNM-GX 400 or Bruker DRX 600 spec-
trometer. Tetramethylsilane (TMS) or the resonance of the deuter-
ated solvent was used as the internal standard; solvent CDCl3, δ =
7.24; D2O, δ = 4.63 ppm; [D6]DMSO, δ = 2.49 ppm. For 31P NMR,
phosphoric acid was used as the external standard. 31P NMR spec-
3
3
2J6a,6b = 11.2, J5a,6a = 7.1, J5b,6a = 7.1 Hz, 1 H, 6a-H), 4.37 (m, 1
H, 4-H), 4.52 (d, 3J1,2 = 3.8 Hz, 1 H, 2-H), 5.17 (d, 1 H, 3-H), 5.89
(d, 1 H, 1-H) ppm. C13H20O7 (288.3): calcd. C 54.16, H 6.99; found
C 53.92, H 7.00.
3,6-Di-O-benzyl-5-deoxy-1,2-O-isopropylidene-α-D-glucofuranose (11):
Compound 9 (26.8 g, 132 mmol) and benzyl bromide (46.9 mL,
393 mmol) were dissolved in dry DMF (400 mL) and sodium hy-
dride added portionwise (8.2 g, 341 mmol) within five min, while
the temp. was kept between 25 °C and 30 °C. The mixture was
stirred for 5 h, poured into ammonium chloride solution, extracted
with diethyl ether, dried and purified by flash chromatography (pe-
troleum ether/EtOAc, 5:1) resulting in compound 11 (45.0 g, 89%)
as a yellow oil. TLC (petroleum ether/EtOAc, 6:1): Rf = 0.30, [α]D
1
tra were broadband H-decoupled. MALDI-mass spectra were re-
corded with a Kratos Kompact Maldi 2 spectrometer and 2,5-dihy-
droxybenzoic acid (DHB) or 6-aza-2-thiothymine (ATT) were used
as matrices. FAB-MS were recorded with a Finnigan MAT 312/
AMD 5000. Thin layer chromatography was performed on Merck
60 F254 silica gel plastic plates or Merck RP-18 glass plates. Com-
pounds were visualized by treatment with a solution of [(NH4)6-
Mo7O24·4H2O] (20 g) and Ce(SO4)2 (0.4 g) in 10% sulphuric acid
(400 mL). Flash chromatography was performed on J. T. Baker sil-
ica gel 60 (40–63 µm) at a pressure of 0.3 bar. Perparative HPLC
separations were performed with an Autochrom System equipped
with a Shimadzu LC8A preparative pump and a Rainin Dynamax
UV 1 Detector at 260 nm. A LiChrosorb RP-18 column was used,
(7 µm, 250×16 mm (Knauer, Germany). Optical rotations were
measured at 21 °C with a Perkin–Elmer 241/MS polarimeter at the
sodium D line.
1
= –39.8 (c = 1.0, CHCl3). H NMR (250 MHz, CDCl3): δ = 1.32
(s, 3 H, CH3), 1.49 (s, 3 H, CH3), 1.92–2.15 (m, 2 H, 5a-, 5b-H),
3
3.53–358 (m, 2 H, 6a-, 6b-H), 3.78 (d, J3,4 = 3.1 Hz, 1 H, 3-H),
4.30–4.38 (m, 1 H. 4-H), 4.41–4.53 (m, 3 H, C6H5CH2), 4.60 (d,
3J1,2 = 3.9 Hz, 1 H, 2-H), 4.66 (d, 1 H, C6H5CH2), 5.90 (d, 1 H, 1-
H), 7.22–7.34 (m, 10 H, C6H5CH2) ppm. C23H28O5 (384.5): calcd.
C 71.85, H 7.34; found C 71.46, H 7.37.
3,6-Di-O-benzyl-5-deoxy-α/β-D-glucofuranose (12): Compound 11
(32.0 g, 83.2 mmol) was dissolved in tetrahydrofuran (300 mL) and
cooled. HCl (50%, 200 mL) was slowly added dropwise. The reac-
tion mixture was stirred at room temp. for 60 h, neutralized with
powdered NaHCO3, diluted with water and the organic phase was
dried. The solvents were evaporated in vacuo. Purification by flash
chromatography (toluene/acetone, 4:1) afforded compound 12
(23.5 g, 82%) as a colourless oil. 12% of the starting material was
recovered. TLC (toluene/acetone, 3:1): Rf = 0.30. 1H NMR
(250 MHz, CDCl3): δ = 1.92–2.02 (m, 2 H, 5a-, 5b-H), 2.05–2.12
(m, 2 H, 5aЈ-, 5bЈ-H), 2.95–3.15 (br. s, 1 H, OH), 3.53–3.64 (m, 2
H, 6a-, 6b-/6aЈ-, 6bЈ-H), 3.77–3.83 (m, 1 H, 3-/3Ј-H), 4.00–4.10 (br.
s, 1 H, OH), 4.15–4.21 (m, 1 H, 2-/2Ј-H), 4.40–4.51 (m, 4 H, 4-/4Ј-
H, C6H5CH2), 4.60–4.68 (m, 1 H, C6H5CH2), 5.08 (d, 1 H, 1Ј-H),
5.45 (d, 1 H, 1-H), 7.25–7.73 (m, 10 H, C6H5CH2) ppm. C20H24O5
(344.4): calcd. C 69.75, H 7.02; found C 69.24, H 7.12.
1,2-O-Isopropylidene-5,6-O-thiocarbonyl-α-
D
-glucofuranose
(8):
Compound 7[26] (56 g, 255 mmol) was dissolved in boiling tetrahy-
drofuran (2000 mL). Thiocarbonyldiimidazole (50 g, 281 mmol)
was added after cooling and the reaction mixture was stirred at
boiling temp. for 2 h. The crimson reaction mixture was success-
ively washed with 1 n HCl, hydrogencarbonate solution and brine.
The organic phase was dried and the solvents were evaporated in
vacuo to afford 8 (51 g, 76%) as a colourless solid. TLC (CHCl3/
methanol, 6:1): Rf = 0.65, [α]D = –15.8 (c = 1.0, CH3OH); m.p.
1
162 °C. H NMR (250 MHz, CDCl3): δ = 1.30 (s, 3 H, CH3), 1.46
3
(s, 3 H, CH3), 4.42 (d, J3,4 = 3.2 Hz, 1 H, 3-H), 4.46–4.55 (m, 2
3
2
H, 2-H, 4-H), 4.67 (dd, J5,6a = 8.9, J6a,6b = 8.9 Hz, 1 H, 6a-H),
3
4.75 (dd, J5,6b = 7.6 Hz, 1 H, 6b-H), 5.24 (ddd, J4,5 = 2 Hz, 1 H,
5-H), 5.96 (d, 1 H, 1-H) ppm. C10H14O6S (262.3): calcd. C 45.80,
H 5.38 found C 46.05, H 5.41.
3,6-Di-O-benzyl-5-deoxy-D-glucitol (13): Compound 12 (500 mg,
1,2-O-Isopropylidene-5-deoxy-α-D-glucofuranose (9): Compound 8
14.5 mmol) was dissolved in methanol (15 mL), and the reaction
mixture was cooled. Within 30 min 1 m aqueous solution of sodium
borohydride (2.0 mL, stabilized with 1 m NaOH solution) was
added, stirred for 2 h (monitoring by TLC did not provide repro-
ducible data), almost neutralized, diluted with diethyl ether and
extracted with 50% ammonium chloride solution. The organic
phase was dried and the solvents were evaporated in vacuo. Purifi-
cation by flash chromatography (toluene/acetone, 1:1) afforded
compound 13 (407 mg, 81%) as a colourless oil. TLC (toluene/
acetone, 3:1): Rf = 0.31. [α]D = –3.3 (c = 1.0, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 1.73–1.82 (m, 1 H, 5a-H), 1.90–2.04 (m, 1
H, 5b-H), 3.05–3.25 (br. s, 3 H, 3 OH), 3.42 (dd, J2,3 = 4.8, J3,4
= 2.9 Hz, 1 H, 3-H), 3.52–3.86 (m, 5 H, 1a-, 1b-, 2-, 6a-, 6b-H), 4.04
(ddd, 3J4,5a = 10, 3J4,5b = 2 Hz, 1 H, 4-H), 4.50 (s, 2 H, C6H5CH2),
4.64 (s, 2 H, C6H5CH2), 7.25–7.38 (m, 10 H, C6H5CH2) ppm.
C20H26O5 (346.4): calcd. C 69.34, H 7.57; found C 69.01, H 7.54.
(26.5 g, 101 mmol) was dissolved in dry dioxane (700 mL) and
heated to boiling temp. Within 2 h a solution of tributyltin hydride
(100 mL, 377 mmol) and AIBN (7.4 g, 45 mmol) in dry toluene
(1000 mL) was added dropwise. The reaction mixture was evapo-
rated under reduced pressure and purified by flash chromatography
(toluene/acetone, 6:5) to afford 9 (14.6 g, 71%) as a colourless solid.
TLC (toluene/acetone, 6:5): Rf = 0.33. [α]D = –5.4 (c = 0.5,
CH3OH); m.p. 91.5–92.5 °C. 1H NMR (250 MHz, CDCl3): δ =
1.32 (s, 3 H, CH3), 1.50 (s, 3 H, CH3), 2.00 (m, 2 H, 5a-H, 5b-H),
2.55–2.75 (br. s, 1 H, OH), 3.30–3.50 (br. s. 1 H, OH), 3.74 (ddd,
2J6a,6b = 10.7, J = 7.9, J = 4.0 Hz, 1 H, 6a-H), 3.89 (ddd, J = 4.0,
3
3
3
J = 6.0 Hz, 1 H, 6b-H), 4.14 (d, J3,4 = 2.5 Hz, 1 H, 3-H), 4.26
(ddd, 3J4,5a = 7.2, 3J4,5b = 7.2 Hz, 1 H, 4-H), 4.55 (d, 3J1,2 = 3.8 Hz,
1 H, 2-H), 5.91 (d, 1 H, 1-H) ppm. C9H16O5 (204.2): calcd. C 52.93,
H 7.90; found C 53.34, H 7.61.
3,6-Di-O-acetyl-5-deoxy-1,2-O-isopropylidene-α-D-glucofuranose (10): (2S,3R)-2,5-Di-O-benzyl-3-O-formyl-2,3,5-trihydroxypentanal (14):
Compound 9 (50 mg, 0.245 mmol) was stirred in dry pyridine/
Compound 12 (36.5 g, 106 mmol) was dissolved in tetrahydrofuran/
Eur. J. Org. Chem. 2005, 1129–1141
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1133

A. Tarnowski, O. Retz, T. Bär, R. R. Schmidt
water, 4:1 (1500 mL) and sodium metaperiodate (45.0 g, 212 mmol) organic phase was extracted with half-saturated ammonium chlo-
FULL PAPER
added. After 5 h of stirring the reaction mixture is diluted with
diethyl ether, extracted with half-saturated NaHCO3 solution, dried
and evaporated under reduced pressure. The crude product (32.5 g,
90%) was used for the next step without further purification. TLC
(toluene/acetone, 3:1): Rf = 0.71. [α]D = +4.3 (c = 1.0, CHCl3). H
NMR (250 MHz, CDCl3): δ = 1.99–2.07 (m, 2 H, 4a-, 4b-H), 3.42–
ride solution, dried, evaporated under reduced pressure and puri-
fied by flash chromatography (petroluem ether/EtOAc, 6:1) fur-
nishing compound 16 (18.3 g, 39%) as a colourless oil. TLC (tolu-
ene/acetone, 6:1): Rf = 0.87, [α]D = –14.5 (c = 1.0, CHCl3). 1H
NMR (250 MHz, CDCl3): δ = 0.90 (t, 3 H, 19-H), 1.23–1.45 (m,
22 H, 11 CH2), 1.60–1.90 (m, 2 H, 2a-, 2b-H), 2.05–2.13 (m, 2 H,
7b-H), 2.92 (br. s, 1 H, OH), 3.55–3.80 (m, 4 H, 1a-, 1b-, 3-, 4-H),
1
3
3
3.47 (m, 2 H, 5a-, 5b-H), 3.93 (dd, J1,2 = 1.0, J2,3 = 3.3 Hz, 1 H,
3
3
3
3
2-H), 4.43–4.79 (m, 4 H, C6H5CH2), 5.53 (ddd, J3,4a = 6.5, J3,4b
= 6.5 Hz, 1 H, 3-H), 7.26–7.39 (m, 10 H, C6H5CH2), 8.01 (s, 1 H,
4.31–4.65 (m, 4 H, C6H5CH2), 5.31 (ddt, J4,5 = 8.0, J5,6 = 15.5,
3
3
3J5,7a Ͻ 1.0, J5,7b Ͻ 1.0 Hz, 1 H, 5-H), 5.72 (ddd, J6,7a = 6.7,
HCOO), 9.62 (d, 1 H, 1-H) ppm. C20H22O5 (342.4): calcd. C 70.16, 3J6,7b = 6.7 Hz, 1 H, 6-H), 7.26–7.39 (m, 10 H, C6H5CH2) ppm.
H 6.48; found C 69.61, H 6.66.
C33H50O3 (494.8): calcd. C 80.11, H 10.19; found C 80.11, H 10.10.
(2S,3R)-2,5-Di-O-benzyl-2,3,5-trihydroxypentanal (15). (a) From 12:
Compound 12 (0.83 g, 2.42 mmol) was dissolved in tetrahydrofu-
ran/water, 2:1 (25 mL), cooled and within 10 min 1 m aqueous so-
dium borohydride solution (2.0 mL, stabilized with 1 m NaOH
solution) added dropwise. The reaction mixture was stirred for 1 h
holding the pH value at pH 9. After the reaction mixture was
stirred at room temp. for 10 h, cooled, sodium metaperiodate
(775 mg, 3.63 mmol) was added and stirred again for 5 h holding
the pH value at pH 9. The reaction mixture was neutralized, diluted
with diethyl ether and extracted with water. The organic phase was
dried and the solvents were evaporated under reduced pressure. The
crude product 15 (752 mg, 99%, colourless oil) was used for the
next step without further purification. (b) From 13: Deoxyglucitol
13 (30 mg, 0.98 mmol) was dissolved in tetrahydrofuran/water, 2:1
(10 mL), sodium metaperiodate (250 mg, 1.18 mmol) added and ex-
tracted with half-saturated NaHCO3 solution. The organic phase
was dried and the solvents were evaporated under reduced pressure.
The crude product 15 (281 mg, 91%, colourless oil) was used for
the next step without further purification. TLC (toluene/acetone,
(3R,4R,5E)-1,4-Di-O-benzyl-3-O-(methylsulfonyl)nonadec-5-ene-
1,3,4-triol (17): Compound 16 (15.0 g, 30 mmol) was dissolved in
dry dichloromethane (300 mL), dry triethylamine (21.0 mL,
151 mmol) added, cooled and dropwise methanesulfonyl chloride
(3.0 mL, 39 mmol) in dry dichloromethane (30 mL) added within
15 min. The reaction mixture was then stirred for 6 h, quenched
with methanol, diluted with diethyl ether and extracted with half-
saturated brine. The organic phase was dried and evaporated under
reduced pressure. Purification by flash chromatography (petroleum
ether/EtOAc, 7:1) furnished compound 17 (15.0 g, 87%) as a yellow
oil. TLC (petroluem ether/EtOAc, 7:1): Rf = 0.30, [α]D = –10.6 (c
1
= 1.0, CHCl3). H NMR (250 MHz, CDCl3): δ = 0.88 (t, 3 H, 19-
H), 1.22–1.45 (m, 22 H, 11 CH2), 1.79–2.12 (m, 4 H, 2a-, 2b-, 7a-,
7b-H), 2.91 (s, 3 H, CH3SO2), 3.57–3.62 (m, 2 H, 1a-, 1b-H), 3.91
3
3
(dd, J3,4 = 7.3, J4,5 = 8.4 Hz, 1 H, 4-H), 4.28–4.63 (m, 4 H,
3
3
C6H5CH2), 4.82 (ddd, J2a,3 = 9.0, J2b,3 = 3.2 Hz, 1 H, 3-H), 5.31
3
4
4
(ddt, J5,6 = 15.5, J5,7a Ͻ 1.0, J5,7b Ͻ 1.0 Hz, 1 H, 5-H), 5.76
3
3
(ddd, J6,7a = 6.7, J6.7b = 6.7 Hz, 1 H, 6-H), 7.27–7.36 (m, 10 H,
C6H5CH2) ppm. C34H52O5S (572.9): calcd. C 71.29, H 9.15; found
C 71.77, H 9.14.
1
3:2): Rf = 0.69. H NMR (250 MHz, CDCl3): δ = 1.70–2.10 (m, 2
H, 4a-, 4b-H), 2.87 (bd, 1 H, OH), 3.53–3.71 (m, 2 H, 5a-, 5b-H),
3
3
(3S,4R,5E)-3-Azido-1,4-di-O-benzylnonadec-5-ene-1,4-diol (18). (a)
From 16: To a solution of 16 (230 mg, 0.46 mmol) in dry toluene
(2.5 mL) was added triphenylphosphane (246 mg, 0.93 mmol),
Zn(N3)2·Pyr2 (86 mg, 0.28 mmol) and dropwise within 10 min di-
isopropyl azodicarboxylate (180 µL, 0.93 mmol). The reaction mix-
ture was stirred for 1 h at room temp. and then for 1 h at 50 °C.
After filtration through celite the reaction mixture was dried and
the solvents were evaporated under reduced pressure. Purification
by flash chromatography (petroleum ether/EtOAc, 15:1) furnished
compound 18 (117 mg, 50%) as colourless oil. (b) From 17: To a
solution of the mesylate 17 (14.5 g, 25.3 mmol) in dry DMF
(200 mL) dried sodium azide (8.26 g, 127 mmol) was added and
stirred at 100 °C for 5 h. The reaction mixture was diluted with
diethyl ether and extracted with half-saturated brine. The organic
phase was dried and the solvents were evaporated under reduced
pressure. Purification by flash chromatography (petroleum ether/
EtOAc, 25:1) furnished compound 18 (10.8 g, 82%) as a colourless
oil. TLC (petroleum ether/toluene, 6:1): Rf = 0.78. [α]D = –54.0 (c
3.77 (dd, J1,2 = 1.4, J2,3 = 3.9 Hz, 1 H, 2-H), 4.15–4.26 (m, 1 H,
3-H), 4.48–4.84 (m, H, C6H5CH2), 7.23–7.39 (m, 10 H,
4
C6H5CH2), 9.77 (d, 1 H, 1-H) ppm. C19H22O4 (314.4).
(3R,4R,5E)-1,4-Di-O-benzylnonadec-5-ene-1,3,4-triol (16). (a) From
15: Wittig salt (triphenyl)tetradecylphosphonium bromide (680 mg,
1.62 mmol) was suspended in dry toluene (12 mL), cooled to –
30 °C, and a suspension of phenyllithium and lithium bromide in
dry diethyl ether (7.5 mL), which was obtained from bromobenzene
(440 µL, 4.19 mmol) and lithium granulate (58 mg, 8.36 mmol),
was added. The reaction mixture was stirred for 10 min and cooled
to –40 °C. To the resulting orange suspension compound 15
(250 mg, 0.8 mmol) in dry tetrahydrofuran (3.0 mL) was added
within 20 min. After complete addition, the cooling bath was re-
moved, and the reaction mixture was stirred for 45 min and
quenched with methanol. Water was added, diluted with diethyl
ether/half-saturated brine, the organic phase was extracted with
half-saturated ammonium chloride solution, dried, evaporated un-
der reduced pressure and purified by flash chromatography (petro-
leum ether/EtOAc, 7:1) furnishing compound 16 (200 mg, 50%) as
a colourless oil. (b) From 14: The Wittig salt (64.0 g, 119 mmol)
was suspended in dry toluene (700 mL), cooled to –30 °C and a
suspension of phenyllithium and lithium bromide in dry diethyl
ether (170 mL) Ϫ obtained from bromobenzene (43 mL, 428 mmol)
and lithium granulate (5.9 mg, 853 mmol) Ϫ added. The reaction
mixture was stirred for 10 min and cooled to –40 °C. To the re-
sulting orange suspension compound 14 (32.5 g, 95 mmol) in dry
tetrahydrofuran (140 mL) was added within 20 min. After complete
addition the cooling bath was removed, and the reaction mixture
was stirred for 45 min and quenched with methanol. Water was
added, and then diluted with diethyl ether/half-saturated brine. The
1
= 1.0, CHCl3). H NMR (250 MHz, CDCl3): δ = 0.87 (t, 3 H, 19-
H), 1.21–1.31 (m, 22 H, 11 CH2), 1.53–1.67 (m, 1 H, 2a-H), 1.78–
1.89 (m, 1 H, 2b-H), 1.93–2.14 (m, 2 H, 7a-, 7b-H), 3.52–3.57 (m,
2
2 H, 1a-, 1b-H), 3.68–3.80 (m, 2 H, 3-, 4-H), 4.48 (d, J = 12.3 Hz,
1 H, C6H5CH2), 4.48 (s, 2 H, C6H5CH2), 4.61 (d, 1 H, C6H5CH2),
3
3
4
3
5.42 (ddt, J4,5 = 8.1, J5,6 = 15.5, J5,7a Ͻ 1.0, J5,7b Ͻ 1.0 Hz, 1
3
3
H, 5-H), 5.69 (ddd, J6,7a = 6.7, J6.7b = 6.7 Hz, 1 H, 6-H), 7.24–
7.37 (m, 10 H, C6H5CH2) ppm. C33H49N3O2 (519.8): calcd. C
76.26, H 9.50, N 8.08; found C 76.72, H 9.62, N 8.20.
(3S,4R,5E)-3-Amino-1,4-di-O-benzylnonadec-5-ene-1,4-diol
(19):
Compound 18 (8.37 g, 16.1 mmol) and triphenylphosphane (7.60 g,
29 mmol) were dissolved in pyridine/water, 10:1 (200 mL), stirred
1134
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 1129–1141

Sphingosine-1-phosphonate and Homosphingosine-1-phosphonate
FULL PAPER
at room temp. for 3 h and then at 50 °C for 15 h. The reaction
mixture was evaporated under reduced pressure. Purification by
flash chromatography (toluene/acetone/triethylamine, 76:4:1) fur-
nished compound 19 (6.36 g, 80%) as a yellow oil. TLC (toluene/
acetone/triethylamine, 18:3:1): Rf = 0.36, [α]D = –22.1 (c = 1.0,
H, 3-H), 4.09 (dd, 3J4,5 = 6.8 Hz, 1 H, 4-H), 5.44 (ddt, 3J5,6 = 15.4,
4
3
4J5,7a Ͻ 1.0, J5,7b Ͻ 1.0 Hz, 1 H, 5-H), 5.73 (ddd, J6,7a = 6.7,
3J6,7b = 6.7 Hz, 1 H, 6-H) ppm. 13C NMR (62.9 MHz, CDCl3): δ
1
= 13.9 (C-19), 52.42 (C-3), 58.33 (C-1), 73.33 (C-4), 115.80 (q, J
= 287.3 Hz, CF3), 127.99 (C-5), 134.49 (C-6), 157.6 (q, 1J =
CHCl3). 1H NMR (250 MHz, CDCl3): δ = 0.88 (t, 3 H, 19-H), 37.2 Hz, CO) ppm. C21H38NO3 (409.5): calcd. C 61.59, H 9.35, N
1.23–1.43 (m, 22 H, 11 CH2), 1.48–1.52 (m, 1 h, 2a-H), 1.80–2.00 3.42; found C 61.94, H 9.42, N 3.46.
(m, 1 H, 2b-H), 2.03–2.14 (m, 2 H, 7a-, 7b-h), 2.73 (br. s, 2 H, NH2),
(3S,4R,5E)-1-O-(tert-Butyldimethylsilyl)-3-(trifluoroacetamido)non-
3.57–3.63 (m, 2 H, 3-, 4-H), 4.29–4.60 (m, 4 H, C6H5CH2), 5.37
adec-5-ene-1,4-diol (23): To a solution of 22 (630 mg, 1.54 mmol)
3
3
4
4
(ddt, J4,5 = 8.1, J5,6 = 15.5, J5,7a Ͻ 1.0, J5,7b Ͻ 1.0 Hz, 1 H, 5-
and dry pyridine (30 mL) TBDMS chloride (1.51 g, 10 mmol) in
dry dichloromethane (15 mL) was added dropwise within 5 min,
then stirred for 1.5 h, quenched with methanol and evaporated un-
der reduced pressure. Purification by flash chromatography (petro-
leum ether/EtOAc, 6:1) furnished compound 23 (720 mg, 89%) as
a colourless solid. TLC (petroleum ether/EtOAc, 6:1): Rf = 0.34.
[α]D = –2.6 (c = 1.0, CHCl3); m.p. 63 °C. 1H NMR (250 MHz,
CDCl3): δ = 0.09 (s, 6 H, SiMe2), 0.85–0.97 (m, 12 H, 19-H, tBu),
3
3
H), 5.71 (ddd, J6,7a = 6.7, J6,7b = 6.7 Hz, 1 H, 6-H), 7.22–7.38
(m, 10 H, C6H5CH2) ppm. C33H51NO2 (493.8): calcd. C 80.27, H
10.41, N 2.84; found C 79.89, H 10.36, N 2.80.
(3S,4R,5E)-3-Aminononadec-5-ene-1,4-diol (20): To liquid ammonia
(40 mL, dried over sodium) a mixture of 19 (1.85 g, 3.67 mmol)
and dry tetrahydrofuran was added dropwise within 10 min at
Ϫ78 °C and then lithium granulate (600 mg, 89.6 mmol). The reac-
tion mixture was stirred for 1.5 h increasing the temp. slowly to
–45 °C. At this temp. stirring was continued for 1.5 h. The reaction
mixture was quenched with solid ammonium chloride and tetrahy-
drofuran added, diluted with diethyl ether, washed with 1 n NaOH
and brine, dried and evaporated under reduced pressure. Purifica-
tion by flash chromatography (CHCl3/methanol/20% ammonia,
60:10:1) furnished compound 20 (598 mg, 52%) as colourless solid.
1.21–1.49 (m, 22 H, 11 CH2), 1.87–1.93 (m, 2 H, 2a-, 2b-H), 1.99–
2
2.08 (m, 2 H, 7a-, 7b-H), 3.03 (br. s, 1 H, OH), 3.70 (ddd, J1a,1b
=
10.8, J = 4.7, J = 6.0 Hz, 1 H, 1a-H), 3.83 (ddd, J = 4.8, J = 6.1 Hz,
3
3
1 H, 1b-H), 4.07–4.22 (m, 2 H, 3-, 4-H), (dd, J4,5 = 6.4, J5,6
=
3
3
15.4 Hz, 1 H, 5-H), 5.74 (ddd, J6,7a = 6.7, J6,7b = 6.7 Hz, 1 H, 6-
H), 7.30 (s, 1 H, NH) ppm. 13C NMR (62.9 MHz, CDCl3): δ =
–5.61 (SiMe2), 14.05 (C-19), 53.53 (C-3), 59.93 (C-1), 73-67 (C-4),
114.40 (q, J = 288.0 Hz, CF3), 128.36 (C-5), 134–79 (C-6), 157.00
(q, J = 36.8 Hz, CO) ppm. C27H52F3NO3Si (523.8): calcd. C 61.91,
H 10.01, N 2.68; found C 61.93, H 9.99, N 2.78.
TLC (CHCl3/methanol/25% ammonia, 40:10:1): Rf = 0.38. [α]D
=
+4.6 (c = 1.0, CHCl3); m.p. 80 °C. 1H NMR (250 MHz, CDCl3): δ
= 0.88 (t, 3 H, 19-H), 1.23–1.42 (m, 22 H, 11 CH2), 1.50 (dddd,
3
3
3
2J2a,2b = 14.7, J2a,3 = 10.0, J1a,2a = 6.7, J1b,2a = 6.7 Hz, 1 H, 2a-
(3S,4R,5E)-3-Amino-1-O-(tert-butyldimethylsilyl)nonadec-5-ene-
1,4-diol (24): To a mixture of 23 (334 mg, 0.637 mmol) and meth-
anol/water, 15:1 (25 mL) was added K2CO3 (440 mg, 3.19 mmol)
and stirred for 1 h at boiling temp. The reaction mixture was di-
luted with diethyl ether and extracted with brine. The organic phase
was dried, evaporated under reduced pressure and coevaporated
three times with toluene and then three times with CH2Cl2. The
colourless crude product 24 (204 mg, 75%) was used for the next
2
3
3
H), 1.70 (ddt, J2b,3 = 3.1, J1a,2b = 3.7, J1b,2b = 3.7 Hz, 1 H, 2b-
H), 2.02-2.10 (m, 2 H, 7a-, 7b-H), 2.20–2.60 (br. s, 4 H, 2 OH,
3
NH2), 2.94 (ddd, J3,4 = 4.7 Hz, 1 H, 3-H), 3.81–3.85 (m, 2 H,
3
3
1a-, 1b-H), 3.92 (dd, J4,5 = 6.9 Hz, 1 H, 4-H), 5.43 (ddt, J5,6
=
=
4
4
3
15.4, J5,7a Ͻ 1.0, J5,7b Ͻ 1.0 Hz, 1 H, 5-H), 5.74 (ddd, J6,7a
6.6, J6,7b = 6.6 Hz, 1 H, 6-H) ppm. C19H39NO2 (313.5): calcd. C
3
72.79, H 12.54, N 4.46; found C 72.53, H 12.54, N 4.71.
(3S,4R,5E)-3-Acetamido-1,4-di-O-acetylnonadec-5-ene-1,4-diol (21): step without further purification. TLC (CHCl3/methanol/25% am-
1
A mixture of compound 20 (20 mg, 63.8 µmol) and dry pyridine/
monia, 60:10:1): Rf = 0.60. H NMR (250 MHz, CDCl3): δ = 0.05
acetic anhydride, 1:1 (1.0 mL) was stirred for 30 h. The reaction (s, 6 H, SiMe2), 0.81–0.90 (m, 12 H, 19-H, tBu), 1.21–1.39 (m, 22
mixture was evaporated under reduced pressure and purified by
flash chromatography (toluene/acetone, 3:1), which furnished com-
pound 21 (24 mg, 87%) as a colourless solid. TLC (toluene/ace-
tone, 3:1): Rf = 0.23. [α]D = –33.6 (c = 1.0, CHCl3); m.p. 73 °C. 1H
H, 11 CH2), 1.95–2.08 (m, 5 H, 7a-, 7b-H, NH2, OH), 2.92–2.99
3
(m, 1 H, 3-H), 3.71–3.76 (m, 2 H, 1a-, 1b-H), 3.91 (dd, J3,4 = 8.1,
3J4,5 = 8.1 Hz, 1 H, 4-H), 5.42 (ddt, 3J5,6 = 15.4, 4J5,7a Ͻ 1.0, 4J5,7b
3
3
Ͻ 1.0 Hz, 1 H, 5-H), 5.71 (ddd, J6,7a = 6.7, J6,7b = 6.7 Hz, 1 H,
NMR (250 MHz, CDCl3): δ = 0.86 (t, 3 H, 19-H), 1.18–1.40 (m, 6-H) ppm. C25H53NO2Si (427.8).
22 H, 11 CH2), 1.56–1.73 (m, 2 H, 2a-, 2b-H), 1.90–2.07 (m, 11 H,
(3S,4R,5E)-3-Amino-1-O-(tert-butyldimethylsilyl)-3,4-N,O-(car-
bonyl)nonadec-5-ene-1,4-diol (25): To solution of crude 24
7a-, 7b-H, 3 CH3CO), 3.42–4.18 (m, 2 H, 1a-, 1b-H), 4.30 (dddd,
a
3
3
3
3J3,NH = 9.9, J2b,3 = 4.0, J3,4 = 4.0 Hz, 1 H, 3-H), 5.21 (dd, J4,5
(204 mg, 0.478 mmol) and dry tetrahydrofuran (15 mL) was added
carbonyl diimidazole (133 mg, 0.822 mmol) and stirred for 5 h. The
reaction mixture was quenched by the addition of methanol and
evaporated under reduced pressure. Purification by flash
chromatography (petroleum ether/EtOAc, 3:1) furnished com-
pound 25 (186 mg, 85%) as a colourless oil. TLC (petroleum ether/
EtOAc, 3:2): Rf = 0.59. [α]D = –3.7 (c = 1.0, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 0.05 (s, 6 H, SiMe2), 0.83–0.90 (m, 12 H,
19-H, tBu), 1.19–1.40 (m, 22 H, 11 CH2), 1.52–1.72 (m, 2 H, 2a-,
= 7.0 Hz, 1 H, 4-H), 5.33–5.46 (m, 2 H, 5-H, NH), 5.77 (ddd, 3J6,7a
= 6.9, J6,7b = 6.9 Hz, 1 H, 6-H) ppm. C25H45NO2 (439.6): calcd.
3
C 68.30, H 10.32, N 3.18; found C 68.48, H 10.42, N 3.01.
(3S,4R,5E)-3-(Trifluoroacetamido)nonadec-5-ene-1,4-diol (22): To a
solution of 20 (500 mg, 1.59 mmol) in dry methanol (30 mL) was
added triethylamine (260 µL, 1.96 mmol) followed by S-ethyl tri-
fluorothioacetate (260 µL, 1.96 mmol) in dry methanol (10 mL).
The reaction mixture was stirred for 4 h, evaporated under reduced
pressure and purified by flash chromatography (CHCl3/methanol,
15:1) furnishing compound 22 (585 mg, 90%) as colourless solid.
2
2b-H), 2.02–2.10 (m, 2 H, 7a-, 7b-H), 3.66 (ddd, J1a,1b = 10.5, J =
8.4, J = 4.3 Hz, 1 H, 1a-H), 3.78 (ddd, J = 4.8, J = 4.6 Hz, 1 H,
TLC (CHCl3/methanol/25% ammonia, 60:10:1): Rf = 0.54. [α]D
=
1b-H), 3.89–3.98 (m, 1 H, 3-H), 4.98 (dd, 3J3,4 = 8.1, 3J4,5 = 8.1 Hz,
–26.2 (c = 1.0, CHCl3/methanol, 1:1), m.p. 113.6–114.0 °C. 1H
1 H, 4-H), 5.42 (s, 1 H, NH), 5.47 (ddt, J5,6 = 15.3, J5,7a Ͻ 1.0,
3
4
NMR (250 MHz, CDCl3/CD3OD): δ = 0.89 (t, 3 H, 19-H), 1.20– 4J5,7b Ͻ 1.0 Hz, 1 H, 5-H), 5.81 (ddd, J6,7a = 6.7, J6,7b = 6.7 Hz,
3
3
3
1.41 (m, 22 H, 11 CH2), 1.72 (dddd, J2a,3 = 9.8, J = 5.0, J = 9.8, 1 H, 6-H) ppm. 13C NMR (151 MHz, CDCl3): δ = –5.53 (SiMe2), –
J = 9.8 Hz, 1 H, 2a-H), 1.94–2.08 (m, 3 H, 2b-, 7a-, 7b-H), 3.59– 5.44 (SiMe2), 14.12 (C-19), 32.22 (C-7), 33.10 (C-2), 55.79 (C-3),
3
3
3.65 (m, 2 H, 1a-, 1b-H), 3.98 (ddd, J2b,3 = 3.6, J3,4 = 6.0 Hz, 1
61.66 (C-1), 80.62 (C-4), 122.88 (C-5), 137.95 (C-6), 158.08 (CO)
Eur. J. Org. Chem. 2005, 1129–1141
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1135

A. Tarnowski, O. Retz, T. Bär, R. R. Schmidt
FULL PAPER
ppm. C26H51NO3Si (453.8): calcd. C 68.82, H 11.33, N 3.09; found
C 68.78, H 11.20, N 3.10.
3J6,7b = 6.7 Hz, 1 H, 6-H), 6.32 (s, 1 H, NH) ppm. 13C NMR
(151 MHz, CDCl3): δ = 14.10 (C-19), 29.66 (C-1), 33.25 (C-7),
33.71 (C-2), 54.50 (C-3), 80.54 (C-4), 122.00 C-5), 138.88 (C-6),
159.08 (CO) ppm. C20H36BrNO3 (402.4): calcd. C 59.69, H 9.02,
N 3.48; found C 60.00, H 9.03, N 3.79.
(3S,4R,5E)-3-Amino-3,4-N,O-(carbonyl)nonadec-5-ene-1,4-diol (26).
(a) From 25: To a solution of 25 (186 mg, 0.41 mmol) and tetrahy-
drofuran/water, 9:1 (15 mL) was added p-toluenesulfonic acid
(16 mg, 0.82 mmol). The reaction mixture was stirred for 30 h,
quenched with pyridine and evaporated under reduced pressure.
Purification by flash chromatography (CHCl3/methanol, 15:1) fur-
nished compound 26 (130 mg, 93%) as colourless solid. (b) From
36: To a solution of 36 (25 mg, 0.074 mmol) and methanol (1 mL)
was added 1 drop of an aqueous 1 m sodium borohydride solution
and stirred for 30 min. The reaction mixture was then diluted with
diethyl ether and extracted with water. The organic phase was dried
and the solvents were evaporated under reduced pressure. Purifica-
tion by flash chromatography (CHCl3/methanol, 15:1) furnished
compound 26 (24 mg, 95%) as colourless solid. TLC (CHCl3/meth-
Dimethyl (3S,4R,5E)-(3-Amino-3,4-N,O-carbonyl-4-hydroxynona-
dec-5-en-1-yl)phosphonate (29):
A solution of 28 (242 mg,
0.601 mmol) and freshly under argon distilled trimethyl phosphite
(20 mL) was refluxed for 50 h under argon. The solvent was then
distilled off under high vacuum. Purification by flash chromatog-
raphy (CHCl3/methanol, 15:1) furnished 29 (253 mg, 97%) as a
colourless solid. TLC (CHCl3/methanol, 15:1): Rf = 0.31. [α]D = –
1
13.7 (c = 1.0, CHCl3); m.p. 63 °C. H NMR (250 MHz, CDCl3): δ
= 0.85 (t, 3 H, 19-H), 1.221.40 (m, 22 H, 11 CH2), 1.64–1.92 (m,
4 H, 1a-, 1b-, 2a-, 2b-H), 2.02–2.10 (m, 2 H, 7a-, 7b-H), 3.71 (d,
3
3JMeO,P = 10.8 Hz, 3 H, CH3O), 3.72 (d, JMeO,P = 10.8 Hz, 3 H,
3
3
anol, 15:1): Rf = 0.28, [α]D = –2.7 (c = 1.0, CHCl3), m.p. 82.0– CH3O), 3.80–3.88 (m, 1 H, 3-H), 4.98 (dd, J3,4 = 8.0, J4,5
=
82.3 °C. 1H NMR (250 MHz, CDCl3): δ = 0.85 (t, 3 H, 19-H),
8.0 Hz, 1 H, 4-H), 5.48 (dd, J5,6 = 15.4 Hz, 1 H, 5-H), 5.85 (ddd,
3
3
1.19–1.39 (m, 22 H, 11 CH2), 1.60–1.78 (m, 2 H, 2a-, 2b-H), 1.89
3J6,7a = 6.8, J6,7b = 6.8 Hz, 1 H, 6-H), 6.70 (s, 1 H, NH) ppm.
(br. s, 1 H, OH), 2.20–2.10 (m, 2 H, 7a-, 7b-H), 3.66–3.75 (m, 2 H, 13C NMR (151 MHz, CDCl3): δ = 14.08 (C-19), 21.35 (d, J1.P
=
1
3
3
1a-, 1b-H), 3.95–4.04 (m, 1 H, 3-H), 5.00 (dd, J3,4 = 8.1, J4,5
=
Ͻ
142.4 Hz, C-1), 24.40 (C-2), 31.88 (C-8), 32.28 (C-7), 52.51-56.09
3
4
4
3
8.1 Hz, 1 H, 4-H); 5.48 (ddt, J5,6 = 15.3, J5,7a Ͻ 1.0, J5,7b
(CH3O), 56.04 (d, J3.P = 12.0 Hz, C-3), 80.64 (C-4), 122.05 (C-5),
3
3
1.0 Hz, 1 H, 5-H), 5.82 (ddd, J6,7a = 6.8, J6,7b = 6.8 Hz, 1 H, 6-
H), 6.03 (br. s, 1 H, NH) ppm. 13C NMR (151 MHz, CDCl3): δ =
14.12 (C-19), 32.24 (C-7), 32.85 (C-2), 55.39 (C-3), 60.79 (C-1),
80.90 (C-4), 122.71 (C-5), 138.25 (C-6), 159.27 (CO) ppm.
C20H37NO3 (339.5): calcd. C 70.75, H 10.98, N 4.13; found C
71.05, H 10.73, N 4.00.
138.77 (C-6), 159.02 (CO) ppm. 31P NMR (243 MHz, CDCl3): δ =
37.17 ppm. C22H42NO5P (431.6): calcd. C 61.22, H 9.81, N 3.25;
found C 61.23, H 9.73, N 3.48.
(2R,3S,4E)-(2-Amino-3-hydroxynonadec-4-en-1-yl)phosphonic Acid
(6). (a) From 29: To a solution of 29 (74 mg, 0.171 mmol) in ethanol
(7.5 mL) was slowly added water (2.5 mL) under vigorous stirring
(3S,4R,5E)-3-Amino-3,4-N,O-carbonyl-1-O-(methylsulfonyl)non- and then LiOH×H2O (216 mg, 5.14 mmol). The reaction mixture
adec-5-ene-1,4-diol (27): To a solution of 26 (220 mg, 0.648 mmol)
in dry CH2Cl2 (33 mL) was added triethylamine (220 µL) and then
dropwise mesyl chloride (76 µL, 0.978 mmol) in dry CH2Cl2
(1.2 mL). The reaction mixture was stirred for 3 h, quenched with
methanol and the solvents were evaporated under reduced pressure.
Purification by flash chromatography (CHCl3/methanol, 15:1) fur-
nished compound 27 (269 mg, 99%) as a colourless solid. TLC
was stirred at room temp. for 5 h and then refluxed for 3 d, concen-
trated acetic acid (2.0 mL) added and the volatiles were evaporated
under reduced pressure. The residue was dissolved in hot acetic
acid (5.0 mL) and then water (2.0 mL) added until clouding. After
leaving the mixture in the refrigerator for 3 d the precipitate was
filtered off and washed with acetic acid/water, 1:1, water and tetra-
hydrofuran. Recrystallisation of the product from acetic acid/water
(CHCl3/methanol, 15:1): Rf = 0.42. [α]D = –10.1 (c = 1.0, CHCl3); furnished compound 6 (20 mg, 31%) as a colourless solid. (b) From
1
m.p. 64.5–64.8 °C. H NMR (250 MHz, CDCl3): δ = 0.86 (t, 3 H,
49a: Compound 6 was obtained from 49a in practically quantitative
19-H), 1.19–1.42 (m, 22 H, 11 CH2), 1.71–2.01 (m, 2 H, 2a-, 2b-H), yield as reported for the transformation of 49b into 50. TLC (n-
2.04–2.12 (m, 2 H, 7a-, 7b-H), 3.04 (s, 3 H, CH3SO2), 3.96–4.05 (m, butanol/acetic acid/water, 5:1:1): Rf = 0.41. [α]D = –1.0 (c = 0.2,
3
1 H, 3-H), 4.29–4.34 (m, 2 H, 1a-, 1b-H), 5.06 (dd, 3J3,4 = 8.0, J4,5 acetic acid); m.p. 150 °C (decomposition). 1H NMR (250 MHz,
3
4
4
= 8.0 Hz, 1 H, 4-H), 5.46 (ddt, J5,6 = 15.4, J5,7a Ͻ 1.0, J5,7b
Ͻ
CD3COOD): δ = 0.79 (t, 3 H, 19-H), 1.15–1.39 (m, 22 H, 11 CH2),
1.70–2.06 (m, 6 H, 1a-, 1b-, 2a-, 2b-, 7a-, 7b-H), 3.42–3.52 (m, 1 H,
3-H), 4.29–4.33 (m, 1 H, 4-H), 5.43 (dd, 3J4,5 = 6.6, 3J5,6 = 15.7 Hz,
3
3
1.0 Hz, 1 H, 5-H), 5.89 (ddd, J6,7a = 6.7, J6,7b = 6.7 Hz, 1 H, 6-
H), 6.04 (s, 1 H, NH) ppm. 13C NMR (151 MHz, CDCl3): δ =
14.12 (C-19), 30.91 (C-2), 37.56 (C-7), 52.69 (C-3), 66.48 (C-1),
3
3
1 H, 5-H), 5.79 (ddd, J6,7a = 6.7, J6,7b = 6.7 Hz, 1 H, 6-H) ppm.
80.46 (C-4), 121.88 (C-5), 139.09 (C-6), 158.68 (CO) ppm. 13C NMR (151 MHz, CD3COOD): δ = 14.41 (C-19), 27.50 (d, 2J1,P
C21H39NO5S (417.6): calcd. C 60.40, H 9.41, N 3.35; found C
60.56, H 9.49, N 3.65.
= 136.0 Hz, C-1), 32.94 (C-7), 58.06 (C-3), 73.21 (C-4), 126.67 (C-
5), 137.25 (C-6) ppm. 31P NMR (243 MHz, CD3COOD): δ = 30.78
ppm. FAB-MS (negative mode): Matrix: DMSO/nitrobenzyl
alcohol/glycerol, 1:1:1): m/z (%) = 376 (50) [M – H+], 753 (5) [2M –
H+]. C19H40NO4P (377.5): calcd. C 60.45, H 10.68, N 3.71; found
C 60.16, H 10.36, N 3.80.
(3S,4R,5E)-3-Amino-3,4-N,O-carbonyl-4-hydroxynonadec-5-en-1-yl
Bromide (28): A solution of 27 (250 mg, 0.599 mmol) and lithium
bromide (1.04 g, 11.9 mmol) in dry tetrahydrofuran (30 mL) was
stirred at 60 °C for 16 h, diluted with diethyl ether and extracted
with half-saturated brine. The organic phase was dried, the solvents
were evaporated under reduced pressure. Purification by flash
chromatography (petroleum ether/EtOAc, 3:2), furnished com-
pound 28 (224 mg, 93%) as a colourless solid. TLC (CHCl3/meth-
(2S,3R,4E)-2-(tert-Butyloxycarbonylamino)-4-octadecene-1,3-diol
(31): Compound 30 (425 mg, 1.42 mmol) was dissolved in dioxane/
water (10 mL, 4:1) and triethylamine (0.2 mL) added. Under stir-
ring di-tert-butyl dicarbonate (370 mg, 1.70 mmol) dissolved in di-
anol, 15:1): Rf = 0.60, [α]D = –10.3 (c = 1.0, CHCl3), m.p. 62.5– oxane (10 mL) was slowly added. After 30 min (TLC monitoring)
62.8 °C. 1H NMR (250 MHz, CDCl3): δ = 0.86 (t, 3 H, 19-H),
1.23–1.44 (m, 22 H, 11 CH2), 1.95–2.12 (m, 4 H, 2a-, 2b-, 7a-, 7b-
H), 3.31–3.51 (m, 2 H, 1a-, 1b-H), 4.00–4.09 (m, 1 H, 3-H), 5.04
the mixture was evaporated and then coevaporated with toluene.
Purification of the product was performed by filtration through
silica gel with CHCl3/methanol, (9:1) as eluent, leading to 31
3
3
3
(dd, J3,4 = 8.1, J4,5 = 8.1 Hz, 1 H, 4-H), 5.47 (ddt, J5,6 = 15.3,
(550 mg, 97%) as colourless oil. TLC (CHCl3/methanol, 9:1): Rf =
4
3
1
4J5,7a Ͻ 1.0, J5,7b Ͻ 1.0 Hz, 1 H, 5-H), 5.87 (ddd, J6,7a = 6.7, 0.61. [α]D = +2.4 (c = 1.0, CHCl3). H NMR (250 MHz, CDCl3):
1136
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 1129–1141

Sphingosine-1-phosphonate and Homosphingosine-1-phosphonate
FULL PAPER
δ = 0.88 (t, J17,18 = 6.6 Hz, 3 H, CH3), 1.22–1.40 (m, 22 H, 11 stirred at 60 °C for 5 h. The reaction mixture was diluted with
CH2), 1.45 (s, 9 H, C4H9), 2.05 (m, 2 H, 6-Ha, 6-Hb), 3.21 (br. s, 2 diethyl ether and extracted with half-saturated brine. The organic
H, 2 OH), 3.58 (m, 1 H, 2-H), 3.68 (m, 1 H, 1-Ha), 3.91 (m, 1 H, phase was washed with water, dried and the solvents were evapo-
1-Hb), 4.28 (m, 1 H, 3-H), 5.37 (d, J2,NH = 8.2 Hz, 1 H, NH), 5.51
(dd, J3,4 = 6.4, J4,5 = 15.4 Hz, 1 H, 4-H), 5.76 (dt, J4,5 = 15.4, J5,6
rated under reduced pressure. Purification by flash chromatography
(petroleum ether/EtOAc, 1:1) furnished compound 35 (650 mg,
= 6.8 Hz, 1 H, 5-H) ppm. C23H45NO4 (399.6): calcd. C 69.13, H 79%) as colourless solid. TLC (petroleum ether/EtOAc, 1:1): Rf =
11.35, N 3.50; found C 69.28, H 11.32, N 3.47.
0.23. [α]D = –23.2 (c = 1.0, CHCl3); m.p. 68 °C. 1H NMR
(250 MHz, CDCl3): δ = 0.86 (t, 3 H, 19-H), 1.19–1.42 (m, 22 H,
11 CH2), 2.07–2.15 (m, 2 H, 7a-, 7b-H), 2.52–2.55 (m, 2 H, 2a-, 2b-
(2S,3R,4E)-2-(tert-Butyloxycarbonylamino)-1-methylsulfonyloxy-4-
octadecen-3-ol (32): Compound 31 (960 mg, 2.40 mmol) was dis-
solved in dry pyridine (20 mL). Under stirring methanesulfonyl
chloride (550 mg, 4.80 mmol) was added at room temp. and the
reaction monitored by TLC. After 15 min the reaction was stopped
by adding water (100 mL). Extraction with ethyl acetate
(2×80 mL) and silica gel chromatography (CHCl3/methanol, 97:3)
afforded compound 32 (812 mg, 71%). TLC (petroleum ether/ethyl
acetate, 1:1): Rf = 0.59. [α]D = +3.4 (c = 1.0, CHCl3) 1H NMR
(250 MHz, CDCl3): δ = 0.88 (t, J17,18 = 6.6 Hz, 3 H, CH3), 1.22–
1.41 (m, 22 H, 11 CH2), 1.44 (s, 9 H, C4H9), 2.04 (m, 2 H, 6-Ha,
6-Hb), 2.22 (br. s, 1 H, OH), 3.04 (s, 3 H, S–CH3), 3.86 (m, 1 H,
2-H), 4.17 (m, 1 H, 3-H), 4.34 (dd, J1a,1b = 10.4, J1a,2 = 3.5 Hz, 1
H, 1-Ha), 4.48 (dd, J1a,1b = 10.4, J1b,2 = 4.8 Hz, 1 H, 1-Hb), 4.91
(br. d, 1 H, NH), 5.49 (dd, J3,4 = 7.1, J4,5 = 15.4 Hz, 1 H, 4-H),
5.78 (dt, J4,5 = 15.4, J5,6 = 6.7 Hz, 1 H, 5-H) ppm. C24H47NO6S
(477.7): calcd. C 60.34, H 9.92, N 2.93; found C 60.38, H 9.86, N
2.90.
3
3
H), 4.13 (ddd, J3,4 = 7.5 Hz, 1 H, 3-H), 5.13 (dd, J4,5 = 7.5 Hz,
4
1 H, 4-H), 5.48 (ddt, 3J5,6 = 15.4, J5,7a = 1.4, 4J5,7b = 1.4 Hz, 1 H,
3
3
5-H), 5.99 (ddd, J6,7a = 6.7, J6,7b = 6.7 Hz, 1 H, 6-H), 6.58 (s, 1
H, NH) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 14.10 (C-19),
20.75 (C-2), 32.34 (C-7), 52.61 (C-3), 79.30 (C-4), 116.29 (C-1),
120.29 (C-5), 140.37 (C-6), 157.73 (CO) ppm. C20H34N2O5 (334.5):
calcd. C 71.81, H 10.25, N 8.37; found C 71.69, H 10.40, N 8.31.
(3S,4R,5E)-3-Amino-3,4-N,O-carbonyl-4-hydroxynonadec-5-enal
(36): A solution of 35 (450 mg, 1.34 mmol) in dry toluene (7.5 mL)
was added dropwise within 15 min to a solution of diisobutylalumi-
nium hydride (1 m in toluene, 3.4 mL, 3.40 mmol) in dry toluene
(10 mL) cooled to –20 °C. The reaction mixture was stirred for 2
h, ethyl acetate (5 mL) added, stirred for 1 h, diluted with diethyl
ether, stirred for a few min with 1 n HCl and extracted with 1 n
HCl (adding brine to separate the phases). The organic phase was
washed with half-saturated hydrogencarbonate solution, dried and
the solvents were evaporated under reduced pressure. Purification
by flash chromatography (CHCl3/methanol, 30:1) furnished com-
pound 36 (348 mg, 77%) as colourless solid. TLC (CHCl3/meth-
anol, 15:1): Rf = 0.26. [α]D = –14.2 (c = 0.5, CHCl3); m.p. 75 °C.
1H NMR (250 MHz, CDCl3): δ = 0.86 (t, 3 H, 19-H), 1.18–1.39
(m, 22 H, 11 CH2), 2.01–2.15 (m, 2 H, 7a-, 7b-H), 2.71–2.74 (m, 2
(2S,3R,4E)-2-Amino-1-methylsulfonyloxy-4-octadecen-3-ol
(33):
Compound 32 (180 mg, 377 µmol) and trifluoroacetic acid (5 mL)
were dissolved in CH2Cl2 (15 mL). After 30 min at room temp. the
mixture was evaporated and then coevaporated with toluene. Puri-
fication by flash chromatography (CHCl3/methanol, 95:5) afforded
33 (143 mg, qu), which was immediately used in the next step. TLC
(CHCl3/methanol, 9:1): Rf = 0.41. [α]D = +3.1 (c = CHCl3). 1H
NMR (250 MHz, CDCl3): δ = 0.85 (t, J17,18 = 6.6 Hz, 3 H, CH3),
1.17–1.39 (m, 22 H, 11 CH2), 2.03 (m, 2 H, 6-Ha, 6-Hb), 2.88 (br.
s, 3 H, NH2, OH), 3.04 (s, 3 H, S–CH3), 3.15 (m, 1 H, 2-H), 4.10
(m, 1 H, 3-H), 4.22 (dd, J1a,1b = 10.2, J1a,2 = 7.3 Hz, 1 H, 1-Ha),
3
3
H, 2a-, 2b-H), 4.21–4.30 (m, 1 H, 3-H), 5.05 (dd, J3,4 = 7.9, J4,5
3
4
4
= 7.9 Hz, 1 H, 4-H), 5.41 (ddt, J5,6 = 15.3, J5,7a = 1.4, J5,7b
=
3
3
1.4 Hz, 1 H, 5-H), 5.57 (s, 1 H, NH), 5.87 (ddd, J6,7a = 6.6, J6,7b
= 6.6 Hz, 1 H, 6-H), 9.74 (m, 1 H, 1-H) ppm. C20H35NO3 (337.5):
calcd. C 71.18, H 10.45, N 4.15; found C 70.80, H 10.38, N 4.36.
4.32 (dd, J1a,1b = 10.2, J1b,2 = 3.7 Hz, 1 H, 1-Hb), 5.41 (dd, J3,4
7.0, J4,5 = 15.4 Hz, 1 H, 4-H), 5.77 (dt, J4,5 = 15.4, J5,6 = 6.6 Hz,
1 H, 5-H) ppm.
=
(2S,3R,4E)-2-Amino-2,3-N,O-carbonyl-3-hydroxyoctadec-4-en-1-yl
Bromide (37): A solution of 34 (330 mg, 0.818 mmol) and lithium
bromide (1.42 g. 16.4 mmol) in dry tetrahydrofuran (40 mL) was
stirred at 60 °C for 24 h. The reaction mixture was diluted with
diethyl ether, extracted with water and the organic phase was dried
and the solvents were evaporated under reduced pressure. Purifica-
tion by flash chromatography (petroleum ether/EtOAc, 2:1) fur-
nished 37 (310 mg, 98%) as colourless solid. TLC (CHCl3/meth-
anol, 15:1): Rf = 0.58. [α]D = –14.4 (c = 1.0, CHCl3); m.p. 57 °C.
1H NMR (250 MHz, CDCl3): δ = 0.86 (t, 3 H, 18-H), 1.22–1.42
(m, 22 H, 11 CH2), 2.04–2.12 (m, 2 H, 6a-, 6b-H), 3.25–3.40 (m, 2
(2S,3R,4E)-2-Amino-2,3-N,O-carbonyl-1-O-(methylsulfonyl)octa-
dec-4-ene-1,3-diol (34):
A
solution of 33[16,25,34] (771 mg,
1.57 mmol) and dry tetrahydrofuran (100 mL) was added carbonyl
diimidazole (300 mg, 1.88 mmol) and stirred for 20 h. The reaction
mixture was then quenched with methanol, evaporated under re-
duced pressure and purified by flash chromatography (petroleum
ether/EtOAc, 3:1), which furnished compound 34 (480 mg, 76%)
as colourless solid. TLC (CHCl3/methanol, 9:1): Rf = 0.53. [α]D
=
3
3
–25.8 (c = 1.0, CHCl3); m.p. 103 °C. 1H NMR (250 MHz, CDCl3):
δ = 0.85 (t, 3 H, 18-H), 1.21–142 (m, 22 H, 11 CH2), 2.04–2.12 (m,
2 H, 6a-, 6b-H), 3.07 (s, 3 H, CH3SO2), 4.05–4.79 (m, 3 H, 1a-,
1b-, 2-H), 5.10 (dd, 3J2,3 = 7.8, 3J3,4 = 7.8 Hz, 1 H, 3-H), 5.47 (ddt,
3J4,5 = 15.3, 4J4,6a = 1.3, 4J4,6b = 1.3 Hz, 1 H, 4-H), 5.96 (ddd, 3J5,6a
H, 1a-, 1b-H), 4.06–4.14 (m, 1 H, 2-H), 5.06 (dd, J2,3 = 7.9, J3,4
3
4
4
= 7.9 Hz, 1 H, 3-H), 5.56 (ddt, J4,5 = 15.3, J4,6a Ͻ 1.0, J4,6b
Ͻ
3
3
1.0 Hz, 1 H, 4-H), 5.58 (s, 1 H, NH), 5.94 (ddd, J5,6a = 6.8, J5,6b
= 6.8 Hz, 1 H, 5-H) ppm. 13C NMR (151 MHz, CDCl3): δ = 14.10
(C-18), 32.27 (C-6), 32.40 (C-1), 57.05 (C-2), 79.68 (C-3), 120.63
(C-4), 139.48 (C-5), 158.00 (CO) ppm. C19H34BrNO2 (388.4): calcd.
C 58.76, H 8.82, N 3.61; found C 58.72, H 8.66, N 3.73.
3
= 6.7, J5,6b = 6.7 Hz, 1 H, 5-H), 6.07 (br. s, 1 H, NH) ppm. 13C
NMR (151 MHz, CDCl3): δ = 14.10 (C-18), 37.72 (CH3SO2), 54.54
C-2), 67.42 (C-1), 78.78 (C-3), 120.66 (C-4), 140.12 (C-5), 158.65
(CO) ppm. EI-MS (70 eV, 190 °C): m/z (%) = 403 (10) [M+], 307
(15) [(M – CH3SO3H)+], 294 (10) [(M – CH3SO3CH2)+], 250 (100)
[(M – CH3SO3CH2 – CO2)+]. C20H37NO5S (403.6): calcd. C 59.51,
H 9.24, N 3.47; found C 59.24, H 9.21, N 3.43.
Dimethyl (2R,3R,4E)-(2-Amino-2,3-N,O-carbonyl-3-hydroxyocta-
dec-4-en-1-yl)phosphonate (38):
A solution of 37 (161 mg,
0.414 mmol) and trimethyl phosphite (15 mL) was stirred for 50
h under reflux. The solvent was distilled off under high vacuum.
Purification by flash chromatography (CHCl3/methanol, 25:1) fur-
(3S,4R,5E)-3-Amino-3,4-N,O-carbonyl-4-hydroxynonadec-5-eneni- nished 38 (164 mg, 95%) as colourless solid. TLC (CHCl3/meth-
trile (35): A solution of 34 (1.0 g, 2.47 mmol) and potassium cya-
nide (410 mg, 6.31 mmol) in dry triethylene glycol (120 mL) was
anol, 20:1): Rf = 0.31. [α]D = –20.4 (c = 1.0, CHCl3); m.p. 77 °C.
1H NMR (250 MHz, CDCl3): δ = 0.85 (t, 3 H, 18-H), 1.10–1.49
Eur. J. Org. Chem. 2005, 1129–1141
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1137

A. Tarnowski, O. Retz, T. Bär, R. R. Schmidt
FULL PAPER
(m, 22 H, 11 CH2), 1.79–1.89 (m, 2 H, 1a-, 1b-H), 2.03–2.11 (m, 2 (214 mg, 86%) as a colourless solid. TLC (CHCl3/methanol, 20:1):
3
H, 6a-, 6b-H), 3.75 (d, JH,P = 11.0 Hz, 3 H, CH3O), 4.05–4.17 (m,
Rf = 0.28. [α]D = –34.4 (c = 1.0, CHCl3); m.p. 58 °C. 1H NMR
(250 MHz, CDCl3): δ = 0.85 (t, 3 H, 18-H), 1.21–1.44 (m, 22 H,
11 CH2), 2.04–2.12 (m, 2 H, 6a-, 6b-H), 3.34–3.47 (m, 2 H, 1a-, 1b-
1 H, 2-H), 5.01 (dd, 3J2,3 = 7.7, 3J3,4 = 7.7 Hz, 1 H, 3-H), 5.39 (dd,
3J4,5 = 15.4 Hz, 1 H, 4-H), 5.74–5.93 (m, 2 H, 5-H), NH) ppm. 13
C
3
3
NMR (151 MHz, CDCl3): δ = 14.10 (C-18), 27.40 (C-1), 32.28 (C-
H), 3.82 (ddd, J2,3 = 5.5 Hz, 1 H, 2-H), 4.68 (dd, J3,4 = 7.4 Hz,
6), 51.24 (d, 2J2,P = 3.5 Hz, C-2), 52–75–52.83 (m, MeO), 79.93 (d, 1 H, 3-H), 5.54 (ddt, J4,5 = 15.4, J4,6a Ͻ 1.0, J4,6b Ͻ 1.0 Hz, 1
3
4
4
3J3,P = 13.0 Hz, C-3), 121.76 (C-4), 139.20 (C-5), 157.88 (CO) ppm. H, 4-H), 5.79 (br. s, 1 H, NH), 5.90 (ddd, J5,6a = 6.7, J5,6b
=
3
3
31P NMR (243 MHz, CDCl3): δ = 34.47 ppm. C21H40NO5P 6.7 Hz, 1 H, 5-H) ppm. 13C NMR (151 MHz, CDCl3): δ = 14.10
(417.5): calcd. C 60.41, H 9.66, N 3.35; found C 60.15, H 9.61, N
3.20.
(C-18), 33.35 (C-1), 59.50 (C-2), 81.60 (C-3), 125.30 (C-4), 137.86
(C-5), 158.15 (CO) ppm. C19H34BrNO5 (338.4): calcd. C 58.76, H
8.82, N 3.61; found C 58.81, H 8.77, N 3.86.
(2R,3R,4E)-(2-Amino-3-hydroxyoctadec-4-en-1-yl)phosphonic Acid
(5): To a solution of 38 (40 mg, 0.0958 mmol) in ethanol (1.3 mL)
was slowly added water (0.5 mL) under vigorous stirring and then
Dimethyl
(2R,3S,4E)-(2-Amino-2,3-N,O-carbonyl-3-hydroxyocta-
solution of 41 (66 mg,
dec-4-en-1-yl)phosphonate (42):
A
LiOH×H2O (120 mg, 2.87 mmol). The reaction mixture was 0.17 mmol) and trimethyl phosphite (2.0 mL) was stirred for 50 h
stirred for 5 h and then for 18 h under reflux, concentrated acetic
acid (2.0 mL) added and evaporated under reduced pressure. The
residue was dissolved in hot acetic acid (5.0 mL) and then water
(2.0 mL) added until clouding. After leaving this mixture in the
refrigerator it was filtered and the precipitate washed with acetic
acid/water, 1:1, water and tetrahydrofuran furnishing 5 (28 mg,
80%) as a colourless solid. TLC (n-butanol/acetic acid/water, 5:1:1):
Rf = 0.42. [α]D = –2.6 (c = 0.5, acetic acid); m.p. 190 °C (decompo-
under reflux. The solvent was distilled off under high vacuo. Purifi-
cation by flash chromatography (CHCl3/methanol, 20:1) furnished
42 (68 mg, 96%) as a colourless solid. TLC (CHCl3/methanol,
20:1): Rf = 0.23. [α]D = –31.0 (c = 1.0, CHCl3); m.p. 57 °C. 1H
NMR (250 MHz, CDCl3): δ = (t, 3 H, 18-H), 1.22–1.43 (m, 22 H,
11 CH2), 1.87–2.12 (m, 4 H, 1a-, 1b-, 6a-, 6b-H), 3.76–3.85 (m, 7 H,
3
2-H, 2 CH3O), 4.50 (dd, 3J2,3 = 7.5, J3,4 = 7.5 Hz, 1 H, 3-H), 5.50
4
4
(ddt, 3J4,5 = 15.4, J4,6a = 1.3, J4,6b = 1.3 Hz, 1 H, 4-H), 5.78 (s, 1
1
3
3
sition). H NMR (250 MHz, CD3COOD): δ = 0.79 (t, 3 H, 18-H),
H, NH), 5.89 (ddd, J5,6a = 6.7, J5,6b = 6.7 Hz, 1 H, 5-H). 13C
1.18–1.35 (m, 22 H, 11 CH2), 1.90–2.05 (m, 4 H, 1a-, 1b-, 6a-, 6b-
H), 3.73–3.81 (m, 1 H, 2-H), 4.32–4.38 (m, 1 H, 3-H), 5.40 (dd,
3J3,4 = 6.3, 3J4,5 = 15.5 Hz, 1 H, 4-H), 5.79 (ddd, 3J5,6a = 6.8, 3J5,6b
= 6.8 Hz, 1 H, 5-H) ppm. 13C NMR (151 MHz, CD3COOD): δ =
NMR (151 MHz, CDCl3): δ = 14.10 (C-18), 29.90 (C-1), 52.74 (d,
2
2JMeO,P = 6.6 Hz, MeO), 52.82 (d, JMeO,P = 6.6 Hz, MeO), 53.74
3
(d, J3,P = 21.4 Hz, C-3), 124.56 (C-4), 138.78 (C-5), 157.68 (CO).
31P NMR (161.7 MHz, CD3COOD): δ = 29.71. C21H40NO5P
(417.5): calcd. C 60.41, H 9.66, N 3.35; found C 60.30, H 9.51, N
3.57.
1
14.40 (C-18), 27.00 (d, J1,P = 135.5 Hz, C-1), 33.20 (C-6), 53.47
3
(C-2), 73.13 (d, J3,P = 16.2 Hz, C-3), 126.59 (C-4), 137.36 (C-5)
ppm. 31P NMR (161.7 MHz, CD3COOD): δ = 26.25 ppm. FAB-
MS (negative mode): Matrix: DMSO/nitrobenzyl alcohol/glycerol,
1:1:1): m/z (%) = 362 (40) [M – H+]. C18H38NO4P (363.5): calcd.
C 59.48, H 10.54, N 3.85; found C 59.02, H 10.24, N 4.08.
(2R,3S,4E)-(2-Amino-3-hydroxyoctadec-4-en-1-yl)phosphonic Acid
(43): To a solution of 42 (45 mg, 0.108 mmol) in ethanol (1.3 mL)
was slowly added water (0.5 mL) under vigorous stirring and then
LiOH×H2O (136 mg, 3.23 mmol). Stirring was continued at room
temp. for 5 h and then refluxed for 12 h. Acetic acid was added
and the reaction mixture evaporated in vacuo. The residue was then
diluted in hot acetic acid (3.0 mL) and then water added until
clouding. After leaving this mixture in the refrigerator the precipi-
tate was filtered off and washed with water and ethanol.
Recrystallisation from acetic acid/water furnished compound 43
(27 mg, 69%) as colourless solid. TLC (n-butanol/acetic acid/water,
5:1:1): Rf = 0.49. [α]D = –5.8 (c = 0.5, acetic acid); m.p. 180 °C
(2S,3S,4E)- 2-Amino-2,3-N,O-carbonyl-1-O-(methylsulfonyl)octa-
dec-4-ene-1,3-diol (40): To a solution of 31 (25 mg, 0.063 mmol) in
dry pyridine (1.0 mL) was injected methanesulfonyl chloride
(25 µL, 0.313 mmol) affording 39 as intermediate, which was di-
rectly transformed into 40. The reaction mixture was stirred for 1.5
h, quenched with methanol, concentrated, diluted with diethyl
ether, extracted with half-saturated brine and the organic phase
dried. Then the solvents were evaporated in vacuo. Purification by
flash chromatography (toluene/acetone, 4:1) furnished compound
40 (18 mg, 71%) as a colourless solid. TLC (CHCl3/methanol,
1
(decomposition). H NMR (250 MHz, CD3COOD): δ = 0.81 (t, 3
H, 18-H), 1.18–1.35 (m, 22 H, 11 CH2), 1.94–2.05 (m, 4 H, 1a-, 1b-
14:1): Rf = 0.32, [α]D = –41.5 (c = 1.0, CHCl3); m.p. 101 °C. 1H , 6a-, 6b-H), 3.51–3.66 (m, 1 H, 2-H), 4.15 (dd, J2,3 = 7.7, J3,4
NMR (250 MHz, CDCl3): δ = 0.88 (t, 3 H, 18-H), 1.22–1.45 (m, 7.7 Hz, 1 H, 3-H), 5.39 (ddt, J4,5 = 15.4, J4,6a Ͻ 1.0, J4,6b
22 H, 11 CH2), 2.05–2.13 (m, 2 H, 6a-, 6b-H), 3.10 (s, 3 H,
=
Ͻ
3
3
3
4
4
3
3
1.0 Hz, 1 H, 4-H), 5.83 (ddd, J5,6a = 6.7, J5,6b = 6.7 Hz, 1 H, 5-
3
3
3
CH3SO2), 3.86 (ddd, J1a,2 = 6.2, J1b,2 = 3.9, J2,3 = 6.1 Hz, 1 H,
H) ppm. 13C NMR (151 MHz, CD3COOD): δ = 14.50 (C-18),
2-H), 4.19 (dd, 2J1a,1b = 10.8 Hz, 1 H, 1a-H), 4.30 (dd, 1 H, 1b-H), 32.86 (C-6), 53.78 (d, 2J2,P = 6.1 Hz, C-2), 74.27 (d, 3J3,P = 17.0 Hz,
4.69 (dd, 3J3,4 = 7.6 Hz, 1 H, 3-H), 5.55 (ddt, J4,5 = 15.5, J4,6a
Ͻ
C-3), 128.20 (C-4), 138.50 (C-5) ppm. 31P NMR (161.7 MHz,
3
4
4
1.0, J4,6b Ͻ 1.0 Hz, 1 H. 4-H), 5.71 (br. s, 1 H, NH), 5.90 (ddd, CD3COOD): δ = 22.89 ppm. FAB-MS (negative mode): Matrix:
3J5,6a = 6.7, J5,6b = 6.7 Hz, 1 H, 5-H) ppm. 13C NMR (151 MHz, DMSO/nitrobenzyl alcohol/glycerine, 1:1:1): m/z (%) = 362 (40)
3
CDCl3): δ = 14.15 (C-18), 37.76 (CH3SO2), 57.23 (C-2), 68.20 (C- [M – H+], 725 (5) [(2M) – H+]. C18H38NO4P (363.5): calcd. C 59.48,
1), 79.14 (C-3), 124.94 (C-4), 138.52 (C-5), 158.63 (CO) ppm.
C20H37NO5S (403.6): calcd. C 59.52, H 9.24, N 3.47; found C
60.25, H 9.31, N 3.56.
H 10.54, N 3.88; found C 59.41, H 10.28, N 4.23.
(2R,3R,4E)-Octadec-4-ene-1,2,3-triol (44a): To
a solution of
30a[24,25] (8.56 g, 22 mmol) and methanol (100 mL) was added ion
(2R,3S,4E)-2-Amino-2,3-N,O-carbonyl-3-hydroxyoctadec-4-en-1-yl exchange resin (IR-120, H+ form) and stirred at 50 °C for 10 h.
Bromide (41): A solution of 40 (259 mg, 0.642 mmol) and lithium
bromide (1.12 g, 12.8 mmol) in dry tetrahydrofuran (25 mL) was
stirred at 50 °C for 48 h. The reaction mixture was diluted with
diethyl ether, extracted with water and the organic phase dried. The
solvents were evaporated in vacuo. Purification by flash chromatog-
raphy (petroleum ether/EtOAc, 2:1) furnished compound 41
The reaction mixture was filtered and extracted with pyridine.
Crystallisation from n-hexane furnished compound 44a (4.0 g,
61%) as colourless crystals. TLC (CHCl3/methanol, 14:1): Rf =
0.28. [α]D = +0.2 (c = 1.0, CHCl3); m.p. 62 °C. 1H NMR (250 MHz,
CDCl3): δ = 0.86 (t, 3 H, 18-H), 1.22–1.41 (m, 22 H, 11 CH2),
1.99–2.07 (m, 2 H, 6a-, 6b-H), 2.46–2.50 (m, 3 H, OH), 3.52–3.75
1138
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 1129–1141

Sphingosine-1-phosphonate and Homosphingosine-1-phosphonate
FULL PAPER
dium hydride (50–60%, 110 mg, 2.48 mmol) added. After removing
the cooling, the reaction mixture was stirred for 2 h, filtered and
worked up with diethyl ether/half-saturated brine. The organic
3
(m, 3 H, 1a-, 1b-, 2-H), 4.08 (dd, 3J2,3 = 5.2, J3,4 = 7.3 Hz, 1 H, 3-
3
4
4
H), 5.46 (ddt, J4,5 = 15.4, J4,6a = 1.3, J4,6b = 1.3 Hz, 1 H, 4-H),
5.76 (ddd, J5,6a = 6.7, J5,6b = 6.7 Hz, 1 H, 5-H) ppm. 13C NMR
3
3
(151 MHz, CDCl3): δ = 63.85 (C-1), 73.92 (C-3), 74.24 (C-2), phase was dried and the solvents were evaporated in vacuo. Purifi-
128.37 (C-4), 135.57 (C-5) ppm. C18H36O3 (300.5): calcd. C 70.95, cation by flash chromatography (petroleum ether/EtOAc, 3:1) fur-
H 12.08; found C 71.27, H 11.55.
nished compound 46a (460 mg, 73%) as a colourless solid. TLC
(toluene/acetone, 4:1): Rf = 0.59. [α]D = +0.8 (c = 1.0, CHCl3); m.p.
39 °C. 1H NMR (250 MHz, CDCl3): δ = 0.88 (t, 3 H, 18-H), 1.20–
1.41 (m, 22 H, 11 CH2), 1.92 (bd, 1 H, OH), 2.02–2.10 (m, 2 H,
(2R,3R,4E)-Oct-4-ene-1,2,3-triol (44b): To a solution of 30b[36,37]
(14.16 g, 57 mmol) and methanol (250 mL) was added ion ex-
change resin (IR-120, H+ form) and stirred at 50–60 °C for 24 h.
The ion exchange resin was filtered off and washed with methanol.
The reaction mixture was evaporated in vacuo and purified by flash
chromatography (petroleum ether/EtOAc/methanol, 5:4:1) furnish-
ing compound 44b (5.92 g, 65%) as a colourless oil. TLC (petro-
2
3
6a-, 6b-H), 2.73 (dd, J1a,2b = 4.9, J1a,2 = 2.7 Hz, 1 H, 1a-H), 2.82
3
3
(dd, J1b,2 = 4.2 Hz, 1 H, 1b-H), 3.05 (ddd, J2,3 = 4.9 Hz, 1 H, 2-
3
4
H), 3.90–3.98 (m, 1 H, 3-H), 5.55 (dddd, J4,5 = 15.5, J4,6a = 1.3,
4J4,6b = 1.3 Hz, 1 H, 4-H), 5.81 (dddd, J5,6a = 6.7, J5,6b = 6.7 Hz,
1 H, 5-H) ppm. C18H34O2 (282.4): calcd. C 76.54, H 12.13; found
C 76.48, H 12.07.
3
3
leum ether/EtOAc/methanol, 5:4:1): Rf = 0.25. [α]D = +2.2 (c = 0.5,
CHCl3). 1H NMR (250 MHz, CDCl3): δ = 0.87–0.93 (t, J7,8
=
3
3
3
7.4 Hz, 3 H, 8-H), 1.33–1.47 (se, J6,7 Ϸ J7,8 = 7.4 Hz, 2 H, 7-H),
(2R,3R,4E)-1,2-Anhydrooct-4-ene-1,2,3-triol (46b): A solution of
45b (7.5 g, 23.8 mmol) in dry DMF was cooled to –20 °C, then
sodium hydride (687 mg, 28.6 mmol) added and slowly heated to
room temp. After 7 h the reaction was stopped by the addition of
water. The reaction mixture was extracted three times with diethyl
ether. The organic phase was dried with sodium sulfate and the
solvents were evaporated in vacuo. Purification by flash chromatog-
raphy (petroleum ether/EtOAc, 8:2.5) furnished compound 46b
(2.17 g, 15.2 mmol) as a yellow liquid. TLC (toluene/acetone, 4:1):
Rf = 0.52. [α]D = +2.6 (c = 1.0, CHCl3). 1H NMR (250 MHz,
4
3
3
1.98–2.07 (tdd, J4,6 = 1.2, J5,6 = 6.7, J6,7 = 7.4 Hz, 2 H, 6-H),
3
4
3.52–3.71 (bm, 3 H, 1a-, 1b-, 2-H), 4.01–4.07 (bm, J3,4 = 7.3, J3,5
Ͻ 1.0 Hz, 1 H, 3-H), 5.41–5.51 (ddt, J3,4 = 7.3, J4,5 = 15.4, J4,6
= 1.2 Hz, 1 H, 4-H), 5.70–5.81 (ddt, J3,5 Ͻ 1.0, J4,5 = 15.4, J5,6
= 6.7 Hz, 1 H, 5-H) ppm. C8H16O3 (160.2): calcd. C 59.98, H 10.07;
found C 59.76, H 10.04.
3
3
4
4
3
3
(2R,3R,4E)-1-O-(p-Tolylsulfonyl)octadec-4-ene-1,2,3-triol (45a): A
solution of 44a (8.32 g, 27.7 mmol) and dry pyridine (100 mL) was
cooled to –10 °C and tosyl chloride (6.07 g, 31.8 mmol) in dry pyri-
dine (40 mL) added dropwise within 15 min. The reaction mixture
was stirred for 24 h, quenched with methanol, concentrated and
worked up with diethyl ether/half-saturated brine. The organic
phase was dried and the solvents were evaporated in vacuo. Purifi-
cation by flash chromatography (CHCl3/MeOH, 20:1) gave 45a
(9.03 g, 75%) as a colourless solid. TLC (CHCl3/MeOH, 8:1): Rf =
0.75. [α]D = +8.3 (c = 1.0, CHCl3); m.p. 54 °C. 1H NMR (250 MHz,
CDCl3): δ = 0.85 (t, 3 H, CH3), 1.25–1.38 (m, 22 H, 11 CH2), 1.97–
3
CDCl3): δ = 0.88–0.94 (t, J7,8 = 7.3 Hz, 3 H, 8-H), 1.35–1.68 (se,
3
4
3
3J6,7 Ϸ J7,8 = 7.4 Hz, 2 H, 7-H), 2.00–2.10 (m, J4,6 = 1.2, J5,6
=
=
3
2
3
6.7, J6,7 = 7.5 Hz, 2 H, 6-H), 2.72–2.75 (dd, J1a,1b = 4.9, J1a,2
2.8 Hz, 1 H, 1a-H), 2.80–2.84 (t, J1a,1b Ϸ J1a,2 = 4.9 Hz, 1 H, 1b-
H), 3.03–3.07 (ddd, J1a,2 = 2.8, J1b,2 = 4.9, J2,3 = 5.4 Hz, 1 H,
2-H), 3.90–3.98 (ddd, J2,3 = 5.4, J3,4 = 6.4, J3,5 = 1.1 Hz, 1 H,
3-H), 5.51–5.61 (ddt, J3,4 = 6.4, J4,5 = 15.5, J4,6 = 1.2 Hz, 1 H,
4-H), 5.75–5.87 (ddt, J3,5 = 1.1, J4,5 = 15.5, J5,6 = 6.7 Hz, 1 H,
2
3
3
3
3
3
3
3
3
3
4
4
3
3
5-H).
3
2.05 (m, 2 H, 6a-, 6b-H), 2.46 (s, 3 H, CH3C6H4), 3.72 (ddd, J1a,2
3
3
2
= 6.1, J1b,2 = 4.0, J2,3 = 5.9 Hz, 1 H, 2-H), 4.01 (dd, J1a,1b
=
(2R,3R,4E)-1,2-Anhydro-3-O-(benzyloxymethyl)octadec-4-ene-
1,2,3-triol (47a): Compound 47a was prepared as reported for 47b.
Flash chromatography (petroleum ether/EtOAc, 16:1). TLC (petro-
3
10.4 Hz, 1 H, 1a-H), 4.14 (dd, 1 H, 1b-H), 5.42 (dd, J4,5 = 15.4,
4
3
4J4,6a Ͻ 1.0, J4,6b Ͻ 1.0 Hz, 1 H, 4-H), 5.74 (ddd, J5,6a = 6.6,
3J5,6b = 6.6 Hz, 1 H, 5-H), 7.34–7.82 (m, 4 H, CH3C6H4).
C25H42O5S (454.7): calcd. C 66.04, H 9.31; found C 65.83, H 9.19.
1
leum ether/EtOAc, 9:1): Rf = 0.54. H NMR (250 MHz, CDCl3):
3
3
δ = 0.84–0.93 (t, J17,18 = 7.4 Hz, 3 H, 18-H), 1.22–1.34 (s, J17,18
= 7.4 Hz, 22 H, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-H),
2.00–2.10 (q, 3J5,6 Ϸ 3J6,7 = 7.4 Hz, 2 H, 6-H), 2.59–2.63 (dd, 2J1a,1b
(2R,3R,4E)-1-O-(p-Tolylsulfonyl)oct-4-ene-1,2,3-triol (45b): A solu-
tion of 44b (5.8 g, 36 mmol) in dry pyridine (100 mL) was cooled
to –12 °C. p-Toluenesulfonyl chloride in 40 mL dry pyridine was
slowly added dropwise and stirred at –12 °C for 3 h. Stirring was
continued at room temp. overnight, and then the reaction mixture
was diluted with water and extracted with diethyl ether. The or-
ganic phase was dried with sodium sulphate and the solvents were
evaporated in vacuo. Purification of the residue by flash
chromatography (petroleum ether/EtOAc, 3:2) furnished com-
pound 45b (7.62 g, 67%) as colourless oil. TLC (toluene/acetone,
4:1): Rf = 0.27. [α]D = +12.9 (c = 1.0, CHCl3). 1H NMR (250 MHz,
3
2
3
= 4.9, J1a,2 = 2.8 Hz, 1 H, 1a-H), 2.76–2.81 (t, J1a,1b Ϸ J1b,2
4.9 Hz, 1 H, 1b-H), 3.05–3.11 (ddd, J1a,2 = 2.8, J1b,2 = 4.9, J2,3
= 5.9 Hz, 1 H, 2-H), 3.85–3.92 (ddd, J2,3 = 5.9, J3,4 = 6.0, J3,5
Ͻ 1.0 Hz, 1 H, 3-H), 4.51–4.90 (m, 4 H, O–CH2–O–CH2–C6H5),
5.33–5.45 (ddt, J3,4 = 6.0, J4,5 = 14.2, J4,6 = 1.1 Hz, 1 H, 4-H),
=
3
3
3
3
3
3
3
3
4
4
3
3
5.70–5.82 (ddt, J3,5 Ͻ 1.0, J4,5 = 14.2, J5,6 = 7.4 Hz, 1 H, 5-H),
7.30–7.40 (m, 5 H, O–CH2–O–CH2–C6H5) ppm.
(2R,3R,4E)-1,2-Anhydro-3-O-(benzyloxymethyl)oct-4-ene-1,2,3-triol
(47b): Compound 46b (124 mg, 870 µmol) was dissolved in dry
dichloromethane (10 mL) under argon and HünigЈs base (N,N-di-
isopropylethylamine 500 µL, 376 mg, 2.9 mmol) added. To the re-
action mixture was added benzyloxymethyl chloride (550 µL,
620 mg corresponding to 2.4 mmol pure BOM–Cl), stirred at room
temp. for 48 h, quenched with methanol, poured on water and ex-
tracted twice with diethyl ether. The organic phase was dried with
sodium sulphate. Purification by flash chromatography (petroleum
ether/EtOAc, 16:1) furnished compound 47b (217 mg, 827 µmol,
95%). TLC (petroleum ether/EtOAc, 9:1): Rf = 0.53. 1H NMR
3
CDCl3): δ = 0.85–0.91 (t, J7,8 = 7.4 Hz, 3 H, 8-H), 1.29–1.42 (se,
3J6,7
Ϸ
3J7,8 = 7.4 Hz, 2 H, 7-H), 1.96–2.04 07 (tdd, J4,6 = 1.4,
4
3
3J6,7 = 7.3, J5,6 = 6.7 Hz, 2 H, 6-H), 2.45 (s, 1 H, C6H4–CH3),
3.69–3.75 (m, 1 H, 2-H), 3.98–4.16 (m, 3J2,3 = n.z., 3J3,4 = 7.2, 4J3,5
3
3
Ͻ 1.0 Hz, 3 H, 1a-, 1b-H, 3-H), 5.37–5.48 (ddt, J3,4 = 7.2, J4,5
=
=
4
4
3
15.5, J4,6 = 1.4 Hz, 1 H, 4-H), 5.68–5.80 (dtd, J3,5 Ͻ 1.0, J4,5
3
15.5, J5,6 = 6.7 Hz, 1 H, 5-H), 7.34–7.82 (m, 4 H, C6H4–CH3)
ppm. C15H22O5S (314.4): calcd. C 57.30, H 7.05; found C 57.35, H
7.11.
3
(2R,3R,4E)-1,2-Anhydrooctadec-4-ene-1,2,3-triol (46a): A solution
of 45a (1.02 g, 2.24 mmol) in dry tetrahydrofuran (20 mL) and dry
dimethyl sulfoxide (1.0 mL) was cooled, and a suspension of so-
(250 MHz, CDCl3): δ = 0.85–0.96 (t, J7,8 = 7.4 Hz, 3 H, 8-H),
1.33–1.49 (se, 3J6,7 Ϸ 3J7,8 = 7.4 Hz, 2 H, 7-H), 1.98–2.12 (dq, 4J4,6
3
2
= 1.2, J5,6
Ϸ
3J6,7 = 7.4 Hz, 2 H, 6-H), 2.59–2.63 (dd, J1a,1b
=
Eur. J. Org. Chem. 2005, 1129–1141
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1139

A. Tarnowski, O. Retz, T. Bär, R. R. Schmidt
= 6.8, J2Јa,2Јb = 11.7 Hz, 4 H, O–C(1Ј)H2–O–C(2Ј)H2–C6H5),
FULL PAPER
4.9, J1a,2 = 2.8 Hz, 1 H, 1a-H), 2.77–2.81 (t, J1a,1b
3
2
2
Ϸ
3J1b,2
=
3
3
3
3
4.9 Hz, 1 H, 1b-H), 3.07–3.12 (ddd, J1a,2 = 2.8, J1b,2 = 4.9, J2,3 4.90–5.12 (m, 4 H, 2 O–CH2–C6H5), 5.23–5.47 (ddt, J4,5 = 6.9,
3
3
3
4
4
= 5.9 Hz, 1 H, 2-H), 3.85–3.94 (ddd, J2,3 = 5.9, J3,4 = 6.0, J3,5
3J5,6 = 15.4, J5,7 Ͻ 1.0 Hz, 1 H, 5-H), 5.63–5.78 (ddt, J4,6 Ͻ 1.0,
= 1.0 Hz, 1 H, 3-H), 4.52–4.93 (m, 4 H, O–CH2–O–CH2–C6H5), 3J5,6 = 15.4, 3J6,7 = 6.7 Hz, 1 H, 6-H), 7.30–7.36 (m, 15 H, O–CH2–
3
3
4
5.35–5.49 (ddt, J3,4 = 6.0, J4,5 = 14.2, J4,6 = 1.2 Hz, 1 H, 4-H),
O–CH2–C6H5, 2 O–CH2–C6H5) ppm. MALDI-MS (positive mode,
Matrix DHB, THF): m/z = 727 [M + Na]+, 744 [M + K]+.
4
3
3
5.68–5.82 (ddt, J3,5 = 1.0, J4,5 = 14.2, J5,6 = 7.4 Hz, 1 H, 5-H),
7.30–7.39 (m, 4 H, O–CH2–O–CH2–C6H5) ppm. C16H22O3 (262.4):
calcd. C 73.25, H 8.45; found C 72.78, H 8.30.
Dibenzyl (3S,4R,5E)-(3-Azido-4-O-benzyloxymethyl-4-hydroxynon-
5-en-1-yl)phosphonate (49b): A solution of Zn(N3)2·Pyr2 (1.05 g,
Dibenzyl (3R,4R,5E)-(4-O-Benzyloxymethyl-3,4-dihydroxynonadec- 3.4 mmol) and triphenylphosphane (1.77 g, 6.8 mmol) was sus-
5-en-1-yl)phosphonate (48a): Compound 48a was prepared as re-
pended under argon in dry toluene (20 mL), then crude 48b
ported for 48b. TLC (toluene/acetone, 2:1): Rf = 0.68. [α]D = –41.9
(362 mg, 0.67 mmol) in dry toluene (10 mL) was added quickly.
1
(c = 1.0, CHCl3). H NMR (250 MHz, CDCl3): δ = 0.85–0.91 (t, The reaction was started by adding diisopropyl azodicarboxylate
3
3J18,19 = 7.2 Hz, 3 H, 19-H), 1.24–1.36 (s, J18,19 = 7.2 Hz, 22 H, (1.3 mL, 1.36 g, 6.73 mmol), then stirred at 50 °C for 5 h and then
8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-H), 1.57–2.10 (m, 6 left to cool. Excess of starting material and byproducts were pre-
3
3
H, 1-, 2-, 7-H), 3.46–3.55 (m, J2,3 = n.z., J3,4 = 8.5 Hz, 1 H, 3-
cipitated by adding dry hexane (20 mL). The reaction mixture was
H), 3.80–3.86 (ddd, J3,4 = 8.5, J4,5 = 6.9, J4,6 Ͻ 1.0 Hz, 1 H, 4- filtered, the remaining solid washed with little hexane and then the
3
3
4
2
2
H), 4.47–4.83 (m, J1Јa,1Јb = 6.8, J2Јa,2Јb = 11.7 Hz, 4 H, O–C(1Ј)
H2–O–C(2Ј)H2–C6H5), 4.92–5.10 (m, 4 H, 2 O–CH2–C6H5), 5.15–
5.28 (ddt, J4,5 = 6.9, J5,6 = 15.4, J5,7 = 1.1 Hz, 1 H, 5-H), 5.65–
solvent evaporated in vacuo. Purification by flash chromatography
(toluene/acetone, 14:1) furnished 49b (313 mg, 0.56 mmol, 83%).
TLC (toluene/acetone, 9:1): Rf = 0.59. [α]D = –36.9 (c = 1.0,
3
3
4
4
3
3
1
5.78 (ddt, J4,6 Ͻ 1.0, J5,6 = 15.4, J6,7 = 6.7 Hz, 1 H, 6-H), 7.28–
7.36 (m, 15 H, O–CH2–O–CH2–C6H5, 2 O–CH2–C6H5) ppm.
CHCl ), IR: azide specific absorption at ν = 2103 cm–1. H NMR
˜
3
3
(250 MHz, CDCl3): δ = 0.84–0.90 (t, J8,9 = 7.3 Hz, 3 H, 9-H),
MALDI-MS (positive mode, Matrix DHB, THF): m/z = 702 [M + 1.32–1.41 (m, 3J7,8, J8,9 = 7.3 Hz, 2 H, 8-H), 1.64–2.06 (m, J7,8
=
3
3
Na]+, 717 [M +K]+.
7.3 Hz, 6 H, 1-, 2-, 7-H), 3.38–3.40 (m, J3,4 = 8.5 Hz, 1 H, 3-H),
3.80–3.86 (ddd, J3,4 = 8.5, J4,5 = 6.9, J4,6 Ͻ 1.0 Hz, 1 H, 4-H),
4.47–4.82 (m, J1Јa,1Јb = 6.8, J2Јa,2Јb = 11.7 Hz, 4 H, O–C(1Ј)H2–
O–C(2Ј)H2–C6H5), 4.91–5.09 (m, 4 H, 2 O–CH2–C6H5), 5.18–5.28
(ddt, J4,5 = 6.9, J5,6 = 15.4, J5,7 = 1.4 Hz, 1 H, 5-H), 5.64–5.76
(ddt, J4,6 Ͻ 1.0, J5,6 = 15.4, J6,7 = 6.7 Hz, 1 H, 6-H), 7.28–7.36
(m, 15 H, O–CH2–O–CH2–C6H5, 2 O–CH2–C6H5) ppm. MALDI-
MS (positive mode, Matrix DHB, THF): m/z = 586 [M + Na]+,
602 [M + K]+. C31H38O5P (563.6): calcd. C 66.06, H 6.80, N 7.46;
found C 66.67, H 6.97, N 7.43.
3
3
3
4
Dibenzyl (3R,4R,5E)-(4-O-Benzyloxymethyl-3,4-dihydroxynon-5-en-
1-yl)phosphonate (48b): A solution of dibenzyl methylphosphonate
(4.3 g, 15.6 mmol) in dry tetrahydrofuran (55 mL) was cooled to –
80 °C, then butyllithium (1.6 m in hexane, 10 mL, 16 mmol) added
and stirred for 2 h. Borontrifluoride diethyl etherate (1 mL, 1.13 g,
8 mmol) in dry tetrahydrofuran (8 mL) was added quickly and the
reaction mixture stirred for 30 min. Then a solution of 47 b (1.15 g,
4.38 mmol) in dry tetrahydrofuran (10 mL) was slowly added drop-
wise, stirred for 2 h and then added again undiluted borontrifluo-
ride diethyl etherate (0.6 mL, 4.8 mmol). After 2 h triethylamine
(6 mL) and then hydrogencarbonate solution (16 mL) were added.
The mixture was defrosted, diluted with water and extracted three
times with diethyl ether. The organic phase was dried with sodium
sulphate, the solvents were evaporated under reduced pressure. Pu-
rification of the crude material by flash chromatography (toluene/
acetone, 4:1) furnished 48b (2.14 g, 3.98 mmol, 90% assigned by
NMR), which was contaminated with traces of dibenzyl methyl-
phosphonate. MPLC (toluene/acetone, 4:1) furnished pure 48b.
2
2
3
3
4
4
3
3
(3S,4R,5E)-(3-Amino-4-hydroxynon-5-en-1-yl)phosphonic Acid (50):
Gaseous ammonia was condensed in a flask cooled to –60 °C (5–
10 mL). Sodium (20 equiv.) was added and stirred for 3 min. Com-
pound 49b (225 mg, 0.4 mmol) in dry tetrahydrofuran (1 mL) was
slowly added dropwise and the reaction mixture was stirred for
5 min, then defrosted, diluted with little water, and the ammonia
evaporated. The solution was then lyophilized and purified by RP-
flash chromatography (water/methanol, 3:1), which furnished com-
pound 50 as a white solid (93 mg) in almost quantitative yield. RP-
TLC (water/methanol, 3:1): Rf = 0.42. [α]D = –8.2 (c = 0.5, CHCl3).
TLC (toluene/acetone, 2:1): Rf = 0.66. [α]D = –49.9 (c = 1.0,
CHCl3). 1H NMR (250 MHz, CDCl3): δ = 0.84–0.90 (t, J8,9
=
1H NMR (250 MHz, D2O): δ = 0.75–0.78 (t, J8,9 = 7.3 Hz, 3 H,
3
3
7.3 Hz, 3 H, 9-H), 1.32–1.41 (m, J7,8 Ϸ J8,9 = 7.3 Hz, 2 H, 8-H), 9-H), 1.26–1.31 (m, J7,8 „ 3J8,9 = 7.3 Hz, 2 H, 8-H), 1.50–1.84 (m,
3
3
3
4
3
3
4
4
3
1.64–2.06 (m, J5,7 = 1.42, J6,7 = 6.7, J7,8 = 7.3 Hz, 6 H, 1-, 2-,
4 H, 1-,2-H), 1.94–1.98 (m, J5,7 Ͻ 1.0, J6,7 = 6.8, J7,8 = 7.3 Hz,
7-H), 3.48–3.50 (bm, 3J3,4 = 8.5 Hz, 1 H, 3-H), 3.80–3.86 (ddd, 3J3,4
2 H, 7-H), 3.20–3.22 (m, 1 H, 3-H), 4.21–4.23 (m, J4,5 = 7.1, J4,6
Ͻ 1.0 Hz, 1 H, 4-H), 5.36–5.39 (ddt, J4,5 = 7.1, J5,6 = 15.4, J5,7
3
4
3
4
2
3
3
4
= 8.5, J4,5 = 6.9, J4,6 Ͻ 1.0 Hz, 1 H, 4-H), 4.47–4.82 (m, J1Јa,1Јb
2
4
3
3
= 6.8, J2Јa,2Јb = 11.7 Hz, 4 H, O–C(1Ј)H2–O–C(2Ј)H2–C6H5), Ͻ 1.0 Hz, 1 H, 5-H), 5.79–5.84 (ddt, J4,6 Ͻ 1.0, J5,6 = 15.4, J6,7
4.91–5.09 (m, 4 H, 2 O–CH2–C6H5), 5.18–5.28 28 (ddt, 3J4,5 = 6.9,
= 6.8 Hz, 1 H, 6-H) ppm. 13C NMR (151 MHz, D2O): δ = 12.90
(C-9), 21.41 (C-8), 22.77 (C-2), 24.23–25.10 (2JP,1–C = 132.4 Hz, C-
3J5,6 = 15.4, J5,7 = 1.4 Hz, 1 H, 5-H), 5.64–5.76 (ddt, J4,6 Ͻ 1.0,
4
4
3J5,6 = 15.4, 3J6,7 = 6.7 Hz, 1 H, 6-H), 7.28–7.36 (m, 15 H, O–CH2– 1), 33.71 (C-7), 56.47-56.55 (3JP,3–C = 13.0 Hz, C-3), 71.32 (C-4),
O–CH2–C6H5, 2 O–CH2–C6H5) ppm. MALDI-MS (positive mode, 124.70 (C-5), 137.50 (C-6) ppm. 31P NMR (243 MHz, D2O): δ =
Matrix DHB, THF): m/z = 561 [M + Na]+, 577 [M + K]+.
C31H39O6P (538.6): calcd. C 69.13, H 7.29; found C 68.38, H 7.40.
26.20 ppm. FAB-MS (negative mode, glycerol/DMSO/1% tri-
fluoroacetic acid, 2:2:1): m/z = 113 [CF3COOH – H+]–, 236 [M –
H+]–, 350 [M + CF3COOH – H+]–, 372 [M – CF3COONa – H+]–,
473 [2M – H+]–.
Dibenzyl (3S,4R,5E)-(3-Azido-4-O-benzyloxymethyl-4-hydroxynon-
adec-5-en-1-yl)phosphonate (49a): Compound 49a was prepared as
reported for 49b. TLC (petroleum ether/EtOAc, 3:2): Rf = 0.46. 1H
NMR (250 MHz, CDCl3): δ = 0.85–0.92 (t, J18,19 = 7.3 Hz, 3 H,
19-H), 1.34–1.40 (s, J18,19 = 7.3 Hz, 22 H, 8-, 9-, 10-, 11-, 12-, 13-
Dibenzyl (3S,4R,5E)-(3-Azido-4-hydroxynon-5-en-1-yl)phosphonate
(51): To a solution of 49b (30 mg, 53 µmol) and tert-butyl alcohol
(5 mL) was added pyridinium p-toluenesulfonate (170 mg,
0.68 mmol) and refluxed for 6 h. After cooling, the reaction mix-
ture was diluted with water (5 mL) and extracted twice with diethyl
ether. The organic phase was dried with sodium sulphate. Purifica-
3
3
, 14-, 15-, 16-, 17-, 18-H), 1.50–2.09 (m, 6 H, 1-, 2-, 7-H), 3.39–
3.47 (m, 3J2,3 = n.z., 3J3,4 = 8.5 Hz, 1 H, 3-H), 3.98–4.06 (ddd, 3J3,4
3
4
2
= 8.5, J4,5 = 6.9, J4,6 Ͻ 1.0 Hz, 1 H, 4-H), 4.48–4.79 (m, J1Јa,1Јb
1140
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 1129–1141

Sphingosine-1-phosphonate and Homosphingosine-1-phosphonate
FULL PAPER
[10] D.-S. Im, J. Clemens, T. L. Macdonald, K. R. Lynch, Biochem-
istry 2001, 40, 14053–14060.
[11] Y. Miyake, Y. Kozutsumi, S. Nakamura, T. Fujita, T. Kawa-
saki, Biochem. Biophys. Res. Commun. 1995, 211, 396–403.
[12] Y. Sadahira, F. Ruan, S.-i. Hakomori, Y. Igarashi, Proc. Natl.
Acad. Sci. USA 1992, 89, 9686–9690.
tion by flash chromatography (toluene/acetone, 4:1) furnished com-
pound 51 (11 mg, 24.8 µmol, 47%) as a colourless oil. TLC (tolu-
ene/acetone, 3:2): Rf = 0.69. 1H NMR (250 MHz, CDCl3): δ =
3
3
3
0.86–0.93 (t, J8,9 = 7.4 Hz, 3 H, 9-H), 1.32–1.47 (se, J7,8, J8,9
=
3
3
7.4 Hz, 2 H, 8-H), 1.58–2.06 (m, J6,7 = 6.7, J7,8 = 7.4 Hz, 6 H,
3
1-, 2-, 7-H), 3.44–3.50 (m, 1 H, 3-H), 4.03–4.07 (m, J3,4 = n.z.,
[13] Y. Yatomi, F. Ruan, S.-i. Hakomori, Y. Igarashi, Blood 1995,
3J4,5 = 7.4, 4J4,6 Ͻ 1.0 Hz, 1 H, 4-H), 4.91–5.10 (m, 4 H, 2 O–CH2–
C6H5), 5.42–5.51 (ddt, 3J4,5 = 7.4, 3J5,6 = 15.4, 4J5,7 Ͻ 1.0 Hz, 1 H,
86, 193–202.
[14] B. Kratzer, R. R. Schmidt, Liebigs Ann. Chem. 1995, 957–963;
and references cited therein.
[15] Z. M. Szulc, Y. A. Hannun, A. Bielawska, Tetrahedron Lett.
2000, 41, 7821–7824; the method described in this paper starts
from expensive sphingosine.
[16] Part of this work has been communicated in preliminary form:
A. Tarnowski, T. Bär, R. R. Schmidt, Bioorg. Med. Chem. Lett.
1997, 7, 573–576.
[17] A. Tarnowski, Dissertation, University of Konstanz, 1997.
[18] O. Retz, Diplomarbeit, University of Konstanz, 1997.
[19] W. Stoffel, M. Grol, Chem. Phys. Lipids 1974, 13, 372–388.
[20] C. K. McClure, P. K. Mishra, Tetrahedron Lett. 2002, 43, 5249–
5253.
4
3
3
5-H), 5.68–5.79 (ddt, J4,6 Ͻ 1.0, J5,6 = 15.4, J6,7 = 6.7 Hz, 1 H,
6-H), 7.29–7.35 (m, 10 H, 2 O–CH2–C6H5) ppm.
Dibenzyl (3S,4R,5E)-(3-Amino-4-O-benzyloxymethyl-4-hydroxynon-
5-en-1-yl)phosphonate (52): A solution of 49b (33 mg, 59 µmol) in
tetrahydrofuran (8 mL) was diluted with water (1 mL), tri-
phenylphosphane (54 mg, 0.2 mmol) was added and then stirred at
50 °C for 16 h and left to cool. After evaporation in vacuo the
residue was extracted three times with CHCl3. The solution was
then evaporated under reduced pressure and purified by flash
chromatography (CHCl3/methanol, 19:1). Compound 52 (23 mg,
43 µmol, 73%) was furnished as a yellow oil. TLC (toluene/acetone,
9:1): Rf = 0.59. [α]D = –73.4 (c = 0.44, CHCl3). 1H NMR
[21] A. Schick, T. Kolter, A. Giannis, K. Sandhoff, Tetrahedron
1995, 51, 11207–11218.
3
(250 MHz, CDCl3): δ = 0.85–0.90 (t, J8,9 = 7.4 Hz, 3 H, 9-H),
[22]
[23]
[24]
T. Hakogi, Y. Monden, M. Taichi, S. Iwama, S. Fujii, K. Ikeda,
S. Katsumura, J. Org. Chem.2002, 67, 4839–4846.
X. Lu, H.-S. Byun, R. Bittman, J. Org. Chem. 2004, 69, 5433–
5438.
R. R. Schmidt, P. Zimmermann, Tetrahedron Lett. 1986, 27,
481–484.
1.31–2.09 (m, 3J7,8 Ϸ 3J8,9 = 7.4 Hz, 8 H, 1-, 2-, 7-, 8-H), 2.72–2.79
3
3
3
(br. m, J3,4 = 5.1 Hz, 1 H, 3-H), 3.81–3.87 (m, J3,4 = 5.1, J4,5
=
8.3, 4J4,6 Ͻ 1.0 Hz, 1 H, 4-H), 4.46–4.78 (m, 2J1Јa,1Јb = 6.8, J2Јa,2Јb
2
= 11.9 Hz, 4 H, O–C(1Ј)H2–O–C(2Ј)H2–C6H5), 4.91–5.09 (m, 4 H,
3
3
4
2 O–CH2–C6H5), 5.22–5.31 (br. m, J4,5 = 8.3, J5,6 = 15.5, J5,7
Ͻ
4
3
3
1.0 Hz, 1 H, 5-H), 5.63–5.74 (ddt, J4,6 Ͻ 1.0, J5,6 = 15.5, J6,7
=
[25] R. R. Schmidt, P. Zimmermann, Liebigs Ann. Chem. 1988,
663–667.
[26] O. T. Schmidt, Methods Carbohydr. Chem. 1963, 2, 318–325.
[27] O. Mitsunobu, M. Wada, T. Sano, J. Am. Chem. Soc. 1972, 94,
679–680.
6.6 Hz, 1 H, 6-H), 7.28–7.35 (m, 15 H, O–CH2–O–CH2–C6H5, 2
O–CH2–C6H5) ppm. MALDI-MS (positive mode, Matrix DHB,
THF): m/z = 538 [M + H]+.
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This work was supported by the Deutsche Forschungsgemeinschaft
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Received: September 22, 2003
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