Enantioselective synthesis of lyxo-(2R,3R,4R)-C18-phytosphingosine using double stereodifferentiation

Article abstract of DOI:10.1016/S0957-4166(00)00106-3

lyxo-C₁₈-Phytosphingosine can be synthesized by the cis-dihydroxylation of an (E)-allylic trichloroacetamide obtained by an Overman rearrangement. A double stereodifferentiation using AD-mix-β and an enantiomerically enriched (S)-allylic trichloroacetamide allowed the first synthesis of lyxo-(2R,3R,4R)-C₁₈-phytosphingosine with high diastereoselectivity (de=94%) and excellent enantioselectivity (ee=93%). This sphingosine was fully characterized by the physical and spectral data of the corresponding tetraacetate. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00106-3

Tetrahedron: Asymmetry 11 (2000) 1585±1592
Enantioselective synthesis of lyxo-(2R,3R,4R)-C18-
phytosphingosine using double stereodi€erentiation1
Catherine Martin,* William Prunck, Michel Bortolussi and Robert Bloch*
 Â
Ã
Laboratoire des Carbocycles (Associe au CNRS), Institut de Chimie Moleculaire d'Orsay Bat. 420,
Â
Universite de Paris-Sud, 91405 Orsay France
Received 8 February 2000; accepted 17 March 2000
Abstract
lyxo-C18-Phytosphingosine can be synthesized by the cis-dihydroxylation of an (E)-allylic tri-
chloroacetamide obtained by an Overman rearrangement. A double stereodi€erentiation using AD-mix-b
and an enantiomerically enriched (S)-allylic trichloroacetamide allowed the ®rst synthesis of lyxo-
(2R,3R,4R)-C18-phytosphingosine with high diastereoselectivity (de=94%) and excellent enantioselectivity
(ee=93%). This sphingosine was fully characterized by the physical and spectral data of the corresponding
tetraacetate. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Sphingolipids constitute a class of widely ranging natural products in the membranes of
eukaryotic cells and in all plasma membranes. These compounds, as well as some of their
metabolites, are involved in a number of cellular events including cell growth, di€erentiation,
adhesion and neuronal repair. They have also been shown to play critical roles as secondary
messengers in cell signalling.2 Many physiological processes can be a€ected by these molecules;
however in many cases little is known about the precise function of individual sphingolipids in
vivo and furthermore several sphingolipids seem to have not only one but several functions.
Structurally, sphingolipids are formed from two di€erent units: a polar head group (carbohy-
drates) and a ceramide. The ceramide moiety consists of a sphingoid base (aminoalcohol) linked
through an amide bond to a fatty acid. d-erythro-Sphingosine 1 is the most common sphingoid
base found in the structure of sphingolipids of eukaryotic cells.3 In addition to 1, more than
60 other sphingoid base structures have been found in natural sphingolipids. Among them
C18-phytosphingosines 2±5 and their C16±C22 homologues have been isolated from plants, fungi,
* Corresponding author. Fax: +33(1)69156278.
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00106-3

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C. Martin et al. / Tetrahedron: Asymmetry 11 (2000) 1585±1592
human tissues4 and marine natural sources.5 Due to the variety of their biological activities, a
great deal of e€ort has been devoted recently towards the synthesis of sphingolipids and various
methods have been developed for their preparation.
2. Results and discussion
Previous synthetic studies have focused primarily on the preparation of ribo- or arabino-
phytospingosins, the stereochemistry of the C2 position being either derived from compounds of
the chiral pool6 or established by asymmetric synthesis.7 To our knowledge, only six syntheses of
lyxo- or xylo-phytosphingosines either racemic8 or enantiomerically enriched9 have been described
to date. We have recently reported the synthesis and the rearrangement of (Z)-allylic tri-
chloroacetimidates10 starting from the lactol 6, easily available in both enantiomeric forms, from
the corresponding lactones.11 The potential of this reaction is illustrated here by the enantio-
selective synthesis of lyxo-(2R,3R,4R)-C18-phytosphingosine. The success of this synthesis
depends on the excellent transfer of chirality observed during the rearrangement of allylic tri-
chloroacetimidates to (E)-allylic amides10 and on the diastereoselectivity of the cis-dihydroxylation
of these (E)-allylic amides.12 Our synthesis is depicted in Scheme 1.
Addition of tetradecylmagnesium bromide to enantiomerically enriched lactol 6 a€orded the
1
diol 7 with excellent diastereoselectivity (de=90% as shown by H NMR).13 After protection of
the primary hydroxy group as a t-butyldiphenylsilyl ether 8, a retro Diels±Alder reaction, initiated
by microwaves,14 led quantitatively to the (Z)-allylic alcohol 9. Microwaves were particularly
useful for this cycloreversion since a quantitative yield was obtained within a few minutes (150ꢀC,
30 min) while under heating (150ꢀC, oil bath) the reaction proceeded to only 15% conversion
after 30 minutes.

C. Martin et al. / Tetrahedron: Asymmetry 11 (2000) 1585±1592
1587
Scheme 1. Reagents and conditions: (i) C14H29MgBr, THF, 80%; (ii) TBDPSiCl, imidazole, DMF, 70%; (iii) micro-
waves, 100%; (iv) CCl3CN, DBU, CH2Cl2; (v) xylenes, 140ꢀC, 7 h, 81% for the two steps; (vi) AD-mix-b, 1%
K2OsO2(OH)4, CH3SO2NH2, H2O/tBuOH 1/1, 4 h, 80%; (vii) (a) nBu4NF, THF, 4 h; (b) NaOH, H2O/C2H5OH 1/1,
100ꢀC, 16 h, 67% for the two steps; (viii) (CH3CO)2O, pyridine, DMAP (10 mol%), CH2Cl2, 6 h, 74%
Alcohol 9 was then reacted with trichloroacetonitrile in the presence of DBU to give the
unstable trichloroacetimidate 10 which, without any puri®cation, was thermally rearranged
(re¯uxing xylenes)15 into the (E)-allylic trichloroacetamide 11. The enantiomeric purity of
compound 11 (ee=93%), determined by chiral HPLC (chiralcel OD-H column, hexane/iPrOH
99.5/0.5, 0.5 mL min^1), suggests that the thermal transposition occurred with a total transfer of
chirality. The next critical step was the diastereoselective dihydroxylation of the (E)-allylic amide
11. Two main factors are likely to in¯uence the stereochemical outcome of the osmium tetroxide
dihydroxylation of the (E)-ole®n 11: (a) the con®guration and the substitution of the ole®nic
double bond; and (b) the conformation of the stereogenic centre next to this double bond.
Sharpless16 and Kishi17 have rationalized the stereochemical results arising from these two factors
using empirical models which, in our case, can be represented by Fig. 1 and Fig. 2. Our experi-
mental results are shown in Table 1.
The relative and absolute con®gurations of the major stereomer 12 have been established
after its total deprotection to the (2R,3R,4R)-enantiomer of the known lyxo-(2S,3S,4S)-C18-
phytosphingosine and its chemical transformation to the corresponding tetraacetate 13.18 As
shown in Table 1, the (S)-con®guration of the stereogenic centre has only a small e€ect on the
diastereoselectivity of the dihydroxylation (entries 1 and 2). However the stereochemical outcome
of the dihydroxylation of (S)-11 using OsO4, NMO is in agreement with Kishi's empirical model

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C. Martin et al. / Tetrahedron: Asymmetry 11 (2000) 1585±1592
Figure 1. Empirical mnemonic device according to Sharpless16
Figure 2. Reactant like empirical model according to Kishi17
Table 1
Dihydroxylation of ole®n 11

C. Martin et al. / Tetrahedron: Asymmetry 11 (2000) 1585±1592
1589
(Fig. 2) so that the reagent approaches the face of the substrate which is also predicted by
Sharpless's model for the reaction of (S)-11 with AD-mix-b (Fig. 1). Thus, a double stereo-
di€erentiation should occur for the reaction between (S)-11 and AD-mix-b (matched pair).
E€ectively, in this case, a good diastereomeric excess was observed (entry 3), which could be
further increased (de=94%) by the use of a larger quantity of catalyst (entry 4).
Direct basic hydrolysis of the trichloroacetamide 12 gave only poor yields of the deprotected
aminotriol, and the phytosphingosine 3 was best obtained by basic hydrolysis (KOH, H2O/C2H5OH
1/1, 100ꢀC, 15 h) of the oxazolidinone formed by the reaction of the silylated alcohol 12 with
tetrabutylammonium ¯uoride in THF.19 The aminotriol 3 was then easily peracylated to a€ord
the tetraacetate 13.
The absolute (2R,3R,4R)-con®guration of 3, arising from its mode of formation, was con®rmed
by the sign of its speci®c rotation which was opposite to the sign of rotation of the known
(2S,3S,4S)-enantiomer.9 The relative con®guration of the three asymmetric carbons was established
1
by comparison of the H and 13C NMR spectra of the corresponding tetraacetate 13 with the
spectra of the known C16 analogue6h and of the very recently reported C18 enantiomer.9c
In conclusion, we have described in this paper an alternative route to enantiomerically enriched
lyxo-phytosphingosines which could also be adapted to the synthesis of the xylo-enantiomers and
which compares favourably with the existing methods.
3. Experimental
3.1. General
NMR spectra were recorded on a Bruker AM250 or AC200 spectrometer with tetramethylsilane
as an internal standard. Optical rotations were measured on a Perkin±Elmer 241 polarimeter.
Mass spectra were obtained with a GC±MS R.10-10 or a Finnigan MAT 95S spectrometer.
Microwaves experiments were performed using a single mode reactor Prolabo Synthewave 402.
Melting points are reported without correction. Elemental analyses were performed by the analytical
centre of Gif/Yvette. All reactions were carried out under an inert atmosphere of argon and
monitored by thin-layer chromatography (TLC). TLC was performed on Merck silica gel 60F-
254 precoated on glass.
3.2. (1S,2S,3R,4R,10R)-2-Hydroxymethyl-3-(10-hydroxypentadecyl)-7-oxabicyclo[2.2.1]hept-5-
ene 7
To a stirred solution of tetradecylmagnesium bromide (40 mmol) in THF (50 mL) was added at
0ꢀC 1.54 g (10 mmol) of lactol 6. The reaction mixture was allowed to reach room temperature
and stirred for 4 h. After addition of a saturated ammonium chloride solution (50 mL), the
organic layer was separated and the aqueous phase was extracted with dichloromethane (3Â40
mL). The combined organic layers were dried (MgSO4), concentrated and the residue puri®ed by
¯ash chromatography on silica gel (eluent: ether) to a€ord 2.82 g (80%) of a mixture of 7 (95%)
0
1
and its (1S,2S,3R,4R,1 S)-diastereomer (5%). The spectral data for 7 follow. H NMR (250
MHz, CDCl3) ꢀ: 0.94 (t, J=7.0 Hz, 3H), 1.20±1.60 (m, 26H), 1.92 (m, 1H), 1.80 (dd, J=8.6, 1.7
Hz, 1H), 3.80±4.10 (m, 5H), 5.0 (s, 1H), 5.11 (s, 1H), 6.49 (m, 2H).

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C. Martin et al. / Tetrahedron: Asymmetry 11 (2000) 1585±1592
3.3. (1S,2S,3R,4R,10R)-2-(t-Butyldiphenylsilyloxymethyl)-3-(10-hydroxypentadecyl)-7-oxabicyclo-
[2.2.1]hept-5-ene 8
To a stirred solution of t-butyldiphenylsilyl chloride (2.45 g, 8.9 mmol) and imidazole (1.26 g,
18.6 mmol) in dimethylformamide (5 mL) was added slowly at room temperature a solution of diol
7 (2.62 g, 7.44 mmol) in dimethylformamide (10 mL). The mixture was stirred for 1.5 h and diethyl
ether (100 mL) was added. The organic phase was washed with water (3Â20 mL) and dried over
MgSO4. The solvent was removed under reduced pressure and the residue was puri®ed by ¯ash
chromatography on silica gel (pentane/ether, 50/40) to give 3.08 g (70%) of 8 as a colourless oil.
20
1
‰ꢁŠD +20.8 (c 1.0, CH3OH); H NMR (200 MHz, CDCl3) ꢀ: 0.89 (t, J=7.0 Hz, 3H), 1.08 (s, 9H),
1.10±1.45 (m, 26H), 1.69 (dd, J=8.6, 1.7 Hz, 1H), 1.87 (m, 1H), 2.93 (d, J=3.2 Hz, 1H), 3.65 (m,
1H), 3.92 (m, 2H), 4.95 (s, 1H), 5.04 (s, 1H), 6.39 (m, 2H), 7.40 (m, 6H), 7.70 (m, 4H); 13C NMR
(63 MHz, CDCl3) ꢀ: 14.1, 19.2, 22.6, 26.5, 29.3, 29.6, 31.9, 37.9, 43.1, 43.5, 63.7, 68.7, 79.1, 79.9,
127.7, 129.7, 133.3, 134.8, 134.9, 135.5, 136.9; CIMS (NH3) m/z (relative intensity) 608 (MNH+4,
48), 591 (MH+, 100). Anal. calcd for C38H58O3Si: C, 77.23; H, 9.90. Found: C, 77.16; H, 9.93.
3.4. (4R,2Z)-1-(t-Butyldiphenylsilyloxy-2-octadecen-4-ol 9
Compound 8 (3 g, 5.1 mmol) was placed in a Pyrex open tube allowing the evaporation of
furan and was irradiated for 30 minutes in a microwave oven at 150ꢀC. After cooling to room
temperature, 2.65 g (100%) of pure unsaturated alcohol 9 was obtained. ‰ꢁŠ2D0+7.8 (c 1.05,
1
CH3OH); H NMR (250 MHz, CDCl3) ꢀ: 0.92 (t, J=6.8 Hz, 3H), 1.10 (s, 9H), 1.20±1.40 (m,
24H), 1.40±1.60 (m, 2H), 4.10±4.40 (m, 3H), 5.46 (dd, J=11.1, 11.1 Hz, 1H), 5.70 (dt, J=11.1, 5.5
Hz, 1H), 7.45 (m, 6H), 7.70 (m, 4H); 13C NMR (63 MHz, CDCl3) ꢀ: 14.6, 19.5, 23.1, 25.7, 27.2,
29.8, 30.0, 37.5, 60.7, 68.1, 128.1, 130.2, 130.6, 134.6, 135.9, 136.0; CIMS (NH3) m/z (relative
intensity) 540 (MNH+4, 3), 523 (MH+, 17), 522 (M+, 28), 506 (54), 505 (100). Anal. calcd for
C34H54O2Si: C, 78.10; H, 10.41. Found: C, 78.32; H, 10.23.
3.5. (2S,3E)-1-t-Butyldiphenylsilyloxy-2-trichloroacetylamino-3-octadecene 11
To a stirred solution of alcohol 9 (2.30 g, 4.4 mmol) in dichloromethane (70 mL) were added
successively at ^5ꢀC diazabicycloundecene (1 g, 6.6 mmol) and trichloroacetonitrile (1.14 g, 7.9
mmol). The solution was stirred at ^5ꢀC for an additional 1 h and the reaction mixture was
quenched by addition of saturated aqueous solution of ammonium chloride (30 mL). After
decantation, the organic phase was ®ltered on sodium sulfate and silica gel. The solvent was
removed under reduced pressure to give crude acetimidate 10 which without any puri®cation was
dissolved in xylenes (100 mL). The solution was re¯uxed for 7 h and the solvents were removed
under reduced pressure. The residue was puri®ed by ¯ash chromatography on silica gel (pentane/
ether, 90/10) to give 2.38 g (81% from 9) of the trichloroacetamide 11 as a colourless oil.
20
1
‰ꢁŠD +4.2 (c 1.7, MeOH); H NMR (250 MHz, CDCl3) ꢀ: 0.89 (t, J=6.8 Hz, 3H), 1.07 (s, 9H),
1.10±1.45 (m, 24H), 2.05 (m, 2H), 3.72 (dd, J=10.2, 3.7 Hz, 1H), 3.83 (dd, J=10.2, 3.7 Hz, 1H),
4.46 (m, 1H), 5.47 (dd, J=15.5, 6.2 Hz, 1H), 5.73 (dt, J=15.5, 5.7 Hz, 1H), 7.40 (m, 6H), 7.70 (m,
4H); 13C NMR (63 MHz, CDCl3) ꢀ: 14.1, 19.2, 22.7, 26.7, 28.9, 29.1, 29.3, 29.5, 29.6, 29.7, 31.9,
32.3, 54.2, 65.5, 92.9, 125.5, 127.8, 129.9, 132.6, 134.3, 135.5, 161.0; CIMS (NH3) m/z (relative
intensity) 683, 685, 687, 689 (MNH+4, 98, 100, 37, 9), 666, 668, 670, 672 (MH+, 74, 93, 34, 6).
Anal. calcd for C36H54Cl3NO2Si: C, 64.93; H, 8.18; N, 2.10. Found: C, 65.07; H, 8.31; N, 2.14.

C. Martin et al. / Tetrahedron: Asymmetry 11 (2000) 1585±1592
1591
3.6. (2R,3R,4R)-1-t-Butyldiphenylsilyloxy-2-trichloroacetylamino-3,4-octadecanediol 12
To a mixture of tert-butylalcohol (5 mL) and water (5 mL) was added AD-mix-b (1.4 g),
K2OsO2(OH)4 (3.6 mg, 0.01 mmol) and MeSO2NH2 (95 mg, 1 mmol). The solution was cooled to
0ꢀC, ole®n 11 (665 mg, 1 mmol) was added and the reaction mixture was stirred at room
temperature for 4 h, quenched with sodium sul®te (1.5 g) and extracted with dichloromethane
(6Â20 mL). The organic phase was dried over magnesium sulfate and the solvents were removed
under reduced pressure. The residue was puri®ed by ¯ash chromatography on silica gel (ether) to
20
1
a€ord 560 mg (80%) of 12 as a colourless oil. ‰ꢁŠ ^3.7 (c 0.83, CH3OH); H NMR (250 MHz,
D
CDCl3) ꢀ: 0.89 (t, J=6.8 Hz, 3H), 1.09 (s, 9H), 1.15±1.50 (m, 26H), 2.35 (d, J=14 Hz, 1H), 3.12
(d, J=5 Hz, 1H), 3.65 (m, 2H), 3.82 (m, 2H), 4.24 (d, J=13 Hz, 1H), 7.40 (m, 6H), 7.70 (m, 4H);
13C NMR (63 MHz, CDCl3) ꢀ: 14.1, 19.2, 22.7, 26.8, 28.9, 29.3, 29.4, 31.9, 32.8, 54.3, 61.8, 69.7,
71.6, 92.9, 127.9, 130.1, 132.0, 132.3, 135.4, 135.5, 163.2; CIMS (NH3) m/z (relative intensity) 717,
719, 721, 723 (MNH4+, 46, 48, 37, 15), 700, 702, 704, 706 (MH+, 49, 51, 31, 15). Anal. calcd for
C36H56Cl3NO4Si: C, 61.78; H, 8.07; H, 2.0. Found: C, 61.67; H, 8.12; N, 1.91.
3.7. (2R,3R,4R)-2-Aminooctadecane-1,3,4-triol 3
To a solution of compound 12 (140 mg, 0.2 mmol) in dry THF (5 mL) was added 400 ml (0.4
mmol) of a 1 M solution of tetrabutylammonium ¯uoride in THF. The solution was stirred for 4
h at room temperature. The solvent was removed under reduced pressure and to the residue was
added a solution of NaOH (400 mg) in a mixture of water (2.5 mL) and ethanol (2.5 mL). The
reaction mixture was stirred at 100ꢀC for 16 h, cooled to room temperature and poured into
water (15 mL). The aqueous phase was extracted with ether (10Â15 mL). The organic phase was
dried over magnesium sulfate and the solvent was removed under reduced pressure. Chromatography
of the residue on silica gel (CH2Cl2/MeOH/NH4OH, 4/1/0.1) gave 43 mg (67%) of triol 3 as a
white powder. ‰ꢁŠ2D0+7.7, (c 1.4, pyridine) [lit.,9c ‰ꢁŠD20^7.8 (c 0.46, pyridine), lit.,6a ‰ꢁŠD20^7.1 (c 0.4,
pyridine) for enantiomer]; mp 95±96ꢀC [lit.,6a mp 96±98ꢀC for enantiomer].
3.8. (2R,3R,4R)-2-Acetamino-1,3,4-triacetoxyoctadecane 13
To a solution of 32 mg (0.1 mmol) of triol 3 in dichloromethane (10 mL) were added acetic
anhydride (1 mL), pyridine (1 mL) and DMAP (5 mg). The reaction mixture was stirred for
6 h and water (15 mL) was added. After decantation, the aqueous phase was extracted with
dichloromethane (3Â10 mL). The organic phase was washed with 20 mL of water and dried over
magnesium sulfate. The solvent and excess of reagents were removed under reduced pressure
(10^2 torr) and the residue was puri®ed by chromatography on silica gel (CH3CO2Et/pentane,
65/35) to a€ord 36 mg (74%) of the tetraacetate 13 as a colourless solid. ‰ꢁŠ2D0+4.3 (c 0.5, CHCl3)
[lit.,9c ‰ꢁŠ2D0^3.1 (c 1.1, CHCl3) for the enantiomer]; mp 74ꢀC; IR 3430, 3372, 1740, 1685 cm^1;
1H NMR (250 MHz, CDCl3) ꢀ: 0.88 (t, J=6.7 Hz, 3H), 1.25 (m, 24H), 1.50 (m, 2H), 1.98 (s, 3H),
2.07 (s, 3H), 2.10 (s, 3H), 2.13 (s, 3H), 3.96 (dd, J=11.7, 3.2 Hz, 1H), 4.24 (dd, J=11.7, 4.5 Hz,
1H), 4.54 (m, 1H), 5.09 (m, 2H), 5.71 (d, J=9.7 Hz, 1H); 13C NMR (63 MHz, CDCl3) ꢀ:
14.1, 20.7, 20.8, 21.0, 22.7, 23.3, 25.2, 29.4, 29.5, 29.7, 30.9, 31.9, 47.4, 63.1, 71.2, 71.9, 169.6,
170.3, 170.6, 170.8; CIMS (NH3) m/z (relative intensity) 486 (MH+, 100), 485 (M+, 8), 426 (7),
144 (12). Anal. calcd for C26H47O7N: C, 64.30; H, 9.75; N, 2.88. Found: C, 64.19; H, 9.71; N,
2.55.

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C. Martin et al. / Tetrahedron: Asymmetry 11 (2000) 1585±1592
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18. The relative con®guration of the minor isomer 14 (racemic) has also been determined after its transformation to
1
the tetraacetate of the C18-xylo-phytosphingosine (þ)-5 and comparison of its H and 13C NMR spectra with the
spectra of the known C16 analogue, Ref. 6(h).
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