A facile stereodivergent synthesis of threo- and erythro-N,N-dibenzyl sphingosines from (S)-N,N-dibenzyl-O-TBDMS-serinal

Article abstract of DOI:10.1016/S0957-4166(98)00231-6

The (L)-threo-N,N-dibenzyl sphingosine was prepared in two steps from the serinal derivative 1 by diastereoselective alkenylation with pentadec-1- enyl(ethyl)zinc and deblocking. (D)-erythro-N,N-Dibenzyl 'sphingosine was also prepared in two steps from 1

Full text of DOI:10.1016/S0957-4166(98)00231-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2493–2498
A facile stereodivergent synthesis of threo- and erythro-N,N-
dibenzyl sphingosines from (S)-N,N-dibenzyl-O-TBDMS-serinal
José M. Andrés and Rafael Pedrosa ∗
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Valladolid, Doctor Mergelina s/n, 47011-
Valladolid, Spain
Received 21 May 1998; accepted 10 June 1998
Abstract
The (L)-threo-N,N-dibenzyl sphingosine was prepared in two steps from the serinal derivative 1 by diastereo-
selective alkenylation with pentadec-1-enyl(ethyl)zincand deblocking. (D)-erythro-N,N-Dibenzyl sphingosine was
also prepared in two steps from 1 by a highly diastereoselective alkynylation with pentadecynyl magnesium
bromide and subsequent stereoselective LAH reduction. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
The fact that sphingosines or their derivatives exert important biological activities1 has attracted a lot
of synthetic attention.2 Some of the most interesting methods start from serine because this α-amino
acid bears a part of the chiral moiety present in the final product.3 Starting from these derivatives two
stereochemical aspects must be solved: the implantation of the trans double bond4 and the control of the
stereochemistry at C-3.5
Our recent report on the stereoselective syn-addition of diethylzinc to α-N,N-dibenzylamino-
aldehydes6 prompted us to prepare the (S)-serinal derivative 1 as a starting chiron capable of giving
different stereoisomers by tuning the nature of the organometallic used as the nucleophile,7 and now we
report here on the transformation of 1 into both threo- and erythro-N,N-dibenzyl sphingosines syn-3 and
anti-3 in two steps.
∗
Corresponding author.
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00231-6

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2. Results and discussion
(S)-N,N-Dibenzyl-O-TBDMS serinal 1 was prepared from (L)-N,N-dibenzyl methyl serinate in 74%
overall yield. Protection of the alcohol as TBDMS ether followed by reduction of the ester with
NaBH4–LiCl in THF–ethanol gave the corresponding monoprotected aminodiol which was submitted
to Swern oxidation affording the serinal derivative 1.7
The synthesis of (2S,3S,4E)-2-(N,N-dibenzyl)-4-octadecene-1,3-diol (L-threo-sphingosine) syn-3 was
achieved by syn-addition of pentadec-1-enyl(ethyl)zinc to 1 (Scheme 1). The mixed zinc derivative was
prepared as previously described8 by transmetallation with diethylzinc of the hydroboration product of
1-pentadecyne with dicyclohexylborane. The reaction of 1 with two equivalents of the zinc derivative
in toluene–heptane at 0°C for 4 h gave the protected sphingosines 2 in 57% yield as a mixture (4:1) of
epimers where the major diastereomer was syn-2 as demonstrated by 1H NMR analysis after separation
of the mixture by flash chromatography (silica gel, toluene:hexane=3:1). The final threo-N,N-dibenzyl
sphingosine (syn-3) was obtained in 78% yield from syn-2 by treatment with TBAF in THF at 0°C for 12
h.
An alternative method allowed the preparation of (D)-erythro-N,N-dibenzyl sphingosine (anti-3) from
the serinal derivative 1. The reaction of 1 with pentadecynyl magnesium bromide9 at 0°C for 45
min in diethyl ether yielded anti-4 as a single diastereomer in 82% yield after purification by flash
chromatography.
Treatment of anti-4 with LAH in THF at 0°C quantitatively removed the TBDMS protecting group
leading to the propargyl amino diol anti-5 in 80% yield after purification. However, when a mixture of
anti-4 and LAH was refluxed in THF for 6 h, a concomitant deprotection and reduction of the triple
bond led to a mixture of (D)-erythro-N,N-dibenzyl sphingosine (anti-3 and anti-5). Separation by flash
chromatography allowed anti-3 to be isolated in 62% yield and anti-5 to be recovered in 17% yield,
which was available for recycling.3c
The stereochemistry of the final products, syn-3 and anti-3, was determined by 1H NMR spectroscopy.
To this end, syn-3 and anti-3 were transformed into the dioxane derivatives cis-6 and trans-6 respectively
by reaction with 2,2-dimethoxypropane (acetone, cat. TsOH, 8 h, reflux). The coupling constant10
(
1,3J=4.1 Hz) between H-4 (m, δ=4.43) and H-5 (m, δ=2.39) in cis-6 showed a cis relationship of these
protons, and consequently for the substituents at C-4 and C-5. However, the trans relationship for H-4
(dd, δ=4.36) and H-5 (m, δ=2.82) was deduced from their coupling constant10 (1,3J=9.8 Hz) in trans-6.
The synthesis of N,N-dibenzyl-sphingosines presented here has several advantages. The stereochem-
istry at C-2 is introduced directly from L-serine. This stereocenter is then used to induce the stereochem-
istry at C-3. All four stereoisomeric N,N-dibenzyl sphingosines can be prepared in two steps and high
yield by a single synthetic strategy depending only on the choice of starting amino aldehyde (D or L) and
the alkylating agent.
3. Experimental
3.1. General
The reactions were carried out in oven-dried glassware, under an argon atmosphere, and using
anhydrous solvents. Diethylzinc, as a 1 M solution in heptane, and borane–methyl sulfide complex were
purchased from Aldrich. The 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were registered on
a Bruker AC 300 or Bruker AMX 300, using TMS as the internal standard. IR spectra were recorded on

J. M. Andrés, R. Pedrosa / Tetrahedron: Asymmetry 9 (1998) 2493–2498
2495
Scheme 1.
a Philips PU 9706 spectrometer, as a film or by KBr dispersion. Optical rotations were measured on a
Perkin–Elmer 241 polarimeter in a 1 dm cell.
3.2. Reaction of 1 with pentadec-1-enyl(ethyl)zinc
Cyclohexene (0.41 ml, 4 mmol) was added under Ar at 0°C to a stirred 1 M solution of borane–methyl
sulfide complex (0.20 ml, 2 mmol) in toluene (2 ml). After 3 h at 0°C, 1-pentadecyne (417 mg, 0.53 ml,
2 mmol) was added, and the mixture was stirred at r.t. for 1 h. Then, the solution was cooled to −78°C
and Et2Zn 1 M solution in heptane (2.1 ml, 2.1 mmol) was added to it. The mixture was then placed
in an ice-bath and the chiral aldehyde 1 (383 mg, 1 mmol) in toluene (4 ml) was added. The mixture
was stirred for 4 h, after which it was treated with saturated aq. NH4Cl solution (30 ml) to quench the
reaction. The mixture was then extracted with ether (2×20 ml) and the combined extracts were washed
with brine, dried (Na2SO4) and evaporated under reduced pressure. Purification of the residue by flash-

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chromatography (silica gel, toluene:hexane=3:1) afforded syn-2 (274 mg, 0.46 mmol; 46%) and anti-2
(66 mg, 0.11 mmol; 11%).
3.3. (2S,3S,4E)-2-(N,N-Dibenzylamino)-1-O-(tert-butyldimethylsilyl)-4-octadecene-1,3-diol (syn-2)
Colorless oil. [α]D23=+45.4 (c 1.15, CHCl3). IR (film): 3400, 2910, 1450, 1250, 1090, 970, 835, 750,
1
700 cm−1. H NMR δ: 0.09 and 0.11 (2s, 6H); 0.88 (t, 3H, J=7.0 Hz); 0.96 (s, 9H); 1.25 (br s, 22H);
1.98 (m, 2H); 2.63 (m, 1H); 3.68 (d, 2H, J=13.2 Hz); 3.78 (dd, 1H, J1=11.2 Hz, J2=6.8 Hz); 3.86 (dd, 1H,
J1=11.2 Hz, J2=3.1 Hz); 3.97 (m, 1H); 4.00 (d, 2H, J=13.2 Hz); 4.35 (br s, 1H); 5.18 (dd, 1H, J1=15.3
Hz, J2=8.0 Hz); 5.68 (dt, 1H, J1=15.3 Hz, J2=6.8 Hz); 7.20–7.40 (m, 10H). 13C NMR δ: −5.7; −5.6;
14.11; 8.1; 22.7; 25.9; 29.1; 29.2; 29.3; 29.5; 29.6; 29.7; 31.9; 32.3; 54.5; 59.6; 63.3; 68.6; 127.1; 128.4;
129.1; 129.9; 135.3; 139.2.
3.4. (2S,3R,4E)-2-(N,N-Dibenzylamino)-1-O-(tert-butyldimethylsilyl)-4-octadecene-1,3-diol (anti-2)
Colorless oil. [α]D23=−5.8 (c 0.65, CHCl3). IR (film): 3400, 2910, 2840, 1450, 1250, 1070, 830, 740,
1
690 cm−1. H NMR δ: 0.09 and 0.11 (2s, 6H); 0.88 (t, 3H, J=7.0 Hz); 0.92 (s, 9H); 1.25 (br s, 22H);
2.05 (m, 2H); 2.85 (m, 1H); 3.66 (d, 2H, J=13.6 Hz); 3.88 (d, 2H, J=13.6 Hz); 3.90 (dd, 1H, J1=10.4 Hz,
J2=6.1 Hz); 4.00 (dd, 1H, J1=10.4 Hz, J2=5.8 Hz); 4.26 (m, 1H); 5.48 (dd, 1H, J1=15.3 Hz, J2=6.8 Hz);
5.72 (dt, 1H, J1=15.3 Hz, J2=6.6 Hz); 7.20–7.40 (m, 10H). 13C NMR δ: −5.6; 14.1; 18.1; 22.7; 25.9;
27.5; 29.2; 29.4; 29.7; 31.9; 32.4; 55.3; 61.7; 72.3; 127.0; 128.2; 128.9; 131.3; 132.4; 140.0. MS (m/z,
%): 593.75 (M+, 0.63), 430 (33), 354 (100), 262 (15), 222 (17), 181 (34), 132 (29), 91 (77).
3.5. (2S,3S,4E)-2-(N,N-Dibenzylamino)-4-octadecene-1,3-diol (syn-3)
Tetrabutylammonium fluoride (142 mg, 0.45 mmol) in THF (0.5 ml) was slowly added to a solution
of syn-2 (178 mg, 0.3 mmol) in THF (3 ml) at 0°C. The mixture was stirred overnight at 0°C, and the
reaction was quenched by the addition of water (3 ml). The aqueous phase was extracted with ether
(3×10 ml), and the combined organic extracts were washed with brine, dried (Na2SO4), concentrated
and flash-chromatographed (ethyl acetate:hexane=1:2) to yield syn-3 (112 mg, 0.23 mmol; 78%) as a
pure compound.
Colorless solid, m.p. 60–61°C (from hexane). [α]D23=+19.4 (c 1, CHCl3). IR (film): 3370, 2900, 2830,
1440, 955, 750, 690 cm−1. 1H NMR δ: 0.88 (t, 3H, J=7.0 Hz); 1.24 (br s, 22H); 1.99 (m, 2H); 2.73 (m,
1H); 3.48 (br s, 2H); 3.70 (m, 2H); 3.72 (d, 2H, J=13.1 Hz); 3.95 (d, 2H, J=13.1 Hz); 4.07 (m, 1H); 5.30
(dd, 1H, J1=15.3 Hz, J2=8.1 Hz); 5.73 (dt, 1H, J1=15.3 Hz, J2=6.8 Hz); 7.20–7.35 (m, 10H). 13C NMR
δ: 14.1; 22.6; 29.0; 29.2; 29.3; 29.4; 29.5; 29.6; 31.9; 32.2; 54.2; 59.2; 63.2; 71.0; 127.2; 128.4; 129.2;
130.2; 135.4; 139.0. MS (m/z, %): 479.75 (M+, 0.79), 240 (100), 181 (43), 148 (14), 91 (80), 70 (20).
Anal. calcd for C32H49NO2: C, 80.11; H, 10.29; N, 2.92. Found: C, 80.06; H, 10.18; N, 3.25.
3.6. Reaction of 1 with pentadec-1-ynyl magnesium bromide
1-Pentadecyne (375 mg, 1.8 mmol) was dissolved in 2 ml of ether and added to a previously prepared
solution of 1 M EtMgBr in ether (2 ml, 2 mmol) after which the solution was refluxed for 2.5 h. Then, the
reagent was placed in an ice-bath and aminoaldehyde 1 (517 mg, 1.35 mmol) in ether (6 ml) was added
dropwise. After 45 min at 0°C, the reaction was complete and was quenched with saturated NH4Cl
solution (10 ml). The mixture was extracted with ether (2×10 ml), the combined organic layers were

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2497
washed with brine, dried over anhydrous Na2SO4 and the solvents evaporated under vacuum. After flash-
chromatography (silica gel, hexane:ethyl acetate=15:1) anti-4 (657 mg, 1.11 mmol; 82%) was obtained
as a pure compound.
3.7. (2S,3R)-2-(N,N-Dibenzylamino)-1-O-(tert-butyldimethylsilyl)-4-octadecyne-1,3-diol (anti-4)
Colorless oil. [α]D23=+5.3 (c 1.1, CHCl3). IR (film): 3420, 2920, 2840, 2220 (weak), 1450, 1250,
1090, 830, 770, 740, 690 cm−1. 1H NMR δ: 0.11 and 0.12 (2s, 6H); 0.88 (t, 3H, J=6.9 Hz); 0.95 (s, 9H);
1.25 (br s, 20H); 1.43 (m, 2H); 2.17 (td, 2H, J1=6.9 Hz, J2=2.0 Hz); 3.04 (m, 1H); 3.68 (d, 2H, J=13.1
Hz); 3.83 (dd, 1H, J1=10.4 Hz, J2=6.4 Hz); 3.90 (m, 1H); 4.11 (dd, 1H, J1=10.4 Hz, J2=6.9 Hz); 4.20 (d,
2H, J=13.1 Hz); 4.35 (brs, 1H); 7.20–7.35 (m, 10H). 13C NMR δ: −5.51; 14.1; 18.1; 18.8; 22.7; 25.9;
28.5; 28.9; 29.1; 29.3; 29.5; 29.6; 31.9; 55.3; 60.2; 61.3; 80.0; 86.6; 127.1; 128.3; 129.2; 139.6. MS (m/z,
%): 591.30 (M+, 0.09), 416 (7), 354 (100), 91 (45). Anal. calcd for C38H61NO2Si: C, 77.10; H, 10.39; N,
2.37. Found: C, 76.54; H, 10.18; N, 2.58.
3.8. LAH reduction of anti-4
To a stirred solution of 93 mg (2.45 mmol, 3.5 equiv.) of LiAlH4 in 6 ml of THF at 0°C was added
415 mg (0.7 mmol, 1 equiv.) of anti-4 in 4 ml of THF. After refluxing for 6 h, the reaction was cooled
and quenched with 0.1 ml of H2O, 0.1 ml of 15% NaOH and 0.3 ml of H2O. The solids were removed by
filtration and washed with ether. The combined organic extracts were dried over anhydrous MgSO4 and
evaporated to yield 334 mg of crude product (a 77:23 mixture of anti-3 and anti-5 by 1H NMR analysis).
Flash-chromatography (silica gel, hexane:ethyl acetate=4:1) gave 206 mg of anti-3 (62%) and 53 mg of
anti-5 (17%).
3.9. (2S,3R)-2-(N,N-Dibenzylamino)-4-octadecyne-1,3-diol (anti-5)
Colorless oil. [α]D23=−38.1 (c 1, CHCl3). IR (film): 3350, 2890, 2830, 2220, 1450, 1020, 900, 730,
1
690 cm−1. H NMR δ: 0.89 (t, 3H, J=7.0 Hz); 1.25 (m, 20H); 1.48 (m, 2H); 2.22 (td, 2H, J1=7.1 Hz,
J2=2.0 Hz); 3.04 (m, 1H); 3.79 (d, 2H, J=13.3 Hz); 3.85 (dd, 1H, J1=11.0 Hz, J2=6.0 Hz); 3.94 (dd, 1H,
J1=11.0 Hz, J2=7.7 Hz); 4.02 (d, 2H, J=13.3 Hz); 4.52 (dt, 1H, J1=6.0 Hz, J2=2.0 Hz); 7.20–7.40 (m,
10H). 13C NMR δ: 14.1; 18.8; 22.6; 28.5; 29.0; 29.1; 29.3; 29.5; 29.6; 31.9; 54.6; 59.6; 60.6; 62.0; 79.9;
87.4; 127.2; 128.4; 129.1; 139.2. MS (m/z, %): 477.30 (M+, 0.50), 446 (2), 282 (2), 240 (100), 181 (6),
91 (99).
3.10. (2S,3R,4E)-2-(N,N-Dibenzylamino)-4-octadecene-1,3-diol (anti-3)
Colorless oil. [α]D23=−47.0 (c 1.1, CHCl3). IR (film): 3360, 2920, 2850, 1450, 1025, 970, 745, 695
1
cm−1. H NMR δ: 0.88 (t, 3H, J=6.9 Hz); 1.26 (m, 22H); 2.50 (br s, 2H); 2.79 (m, 1H); 3.71 (d, 2H,
J=13.5 Hz); 3.76 (m, 1H); 3.78 (d, 2H, J=13.5 Hz); 3.87 (dd, 1H, J1=11.0 Hz, J2=7.0 Hz); 4.37 (t, 1H,
J=6.8 Hz); 5.48 (dd, 1H, J1=15.4 Hz, J2=7.2 Hz); 5.71 (dt, 1H, J1=15.4 Hz, J2=6.6 Hz); 7.20–7.40 (m,
10H). 13C NMR δ: 29.1; 29.3; 29.5; 29.7; 31.9; 32.3; 54.4; 59.2; 62.3; 72.3; 127.1; 128.3; 128.9; 131.8
(C-5); 133.2; 139.5.

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3.11. (2S,3S,4E)-2-(N,N-Dibenzylamino)-1,3-O-isopropylidene-4-octadecene-1,3-diol (cis-6)
Colorless oil. 1H NMR δ: 0.81 (t, 3H, J=6.2 Hz); 1.19 (m, 22H); 1.35 (s, 3H); 1.38 (s, 3H); 2.11 (m,
2H); 2.39 (m, 1H); 3.55 (d, 2H, J=14.4 Hz); 3.85 (dd, 1H, J1=12.8 Hz, J2=3.7 Hz); 4.22 (m, 3H); 4.43
(m, 1H); 5.61 (dt, 1H, J1=15.5 Hz, J2=6.5 Hz); 5.83 (dd, 1H, J=15.5 Hz, J=6.4 Hz); 7.10–7.40 (m, 10H).
3.12. (2S,3R,4E)-2-(N,N-Dibenzylamino)-1,3-O-isopropylidene-4-octadecene-1,3-diol (trans-6)
Colorless oil. 1H NMR δ: 0.89 (t, 3H, J=6.9 Hz); 1.28 (m, 22H); 1.35 (s, 3H); 1.46 (s, 3H); 2.15 (m,
2H); 2.82 (m, 1H); 3.64 (d, 2H, J=13.9 Hz); 3.86 (dd, 1H, J1=11.8 Hz, J2=5.7 Hz); 3.89 (d, 2H, J=13.9
Hz); 3.96 (dd, 1H, J1=11.8 Hz, J2=8.3 Hz); 4.36 (dd, 1H, J1=9.8 Hz, J2=7.8 Hz); 5.41 (dd, 1H, J1=15.4
Hz, J2=7.8 Hz); 5.87 (dt, 1H, J1=15.4 Hz, J2=6.6 Hz); 7.20–7.40 (m, 10H).
Acknowledgements
We thank the Spanish DGICYT (Project PB95-707) and the Junta de Castilla y León (Project VA42/97)
for the financial support of this work.
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