The first total synthesis of the 6-hydroxy-4E-sphingenines

Article abstract of DOI:10.1016/S0040-4039(03)00390-3

Ceramides containing the 6-hydroxy-4E-sphingenines, previously unknown long-chain bases, have recently been found in human skin. A total synthesis of 6-hydroxy-4E-sphingenines has been achieved.

Full text of DOI:10.1016/S0040-4039(03)00390-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2983–2985
The first total synthesis of the 6-hydroxy-4E-sphingeninesꢀ
J. S. Yadav,* V. Geetha, A. Krishnam Raju, D. Gnaneshwar and S. Chandrasekhar
Organic Chemistry Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 11 December 2002; revised 30 January 2003; accepted 7 February 2003
Abstract—Ceramides containing the 6-hydroxy-4E-sphingenines, previously unknown long-chain bases, have recently been found
in human skin. A total synthesis of 6-hydroxy-4E-sphingenines has been achieved. © 2003 Elsevier Science Ltd. All rights
reserved.
Sphingolipids, e.g. 1 (e.g. ceramides, sphingomyelin,
gangliosides) constitute a broad class of biologically
important compounds. They are ubiquitous membrane
components of essentially all eukaryotic cells and are
abundantly located in all plasma membranes as well as
in some intracellular organelles (endoplasmic reticulum
(ER), golgi complex and mitochondria).1–4
Initially, propargyl alcohol was treated with dodecyl
bromide in liquid ammonia using lithium amide at
liquid ammonia temperature, to give compound 4 in
70% yield.8 Acetylenic alcohol 4 was reduced with 2
equiv. of LiAlH4 in refluxing THF to afford the trans-
allylic alcohol 5 in 95% yield.9
Ceramides containing the 6-hydroxy-4E-sphingenines 2
and 3, previously unknown long-chain bases, have
recently been found in human skin.5,6 They occur in the
stratum corneum, not as the free base, but as ceramides
(the N-acylated base). These 6-hydroxy sphingosines
ranged from 17 to 22 carbons in length, with 18–20
carbon species predominating.
Our group has been actively involved in the synthesis of
sphingosine7 and therefore stimulated by its biological
significance and activity, we were encouraged to initiate
studies directed towards the total synthesis of 6-
hydroxy-4E-sphingenines 2 (2-amino-(2S,3R,4E,6S)-4-
octadecene-1,3,6-triol) and 3 (2-amino-(2S,3R,4E,6R)-
4-octadecene-1,3,6-triol) for the first time. The retrosyn-
thetic analysis for 2 and 3 is as shown in Scheme 1.
Keywords: sphingolipids; 6-hydroxy-4E-sphingenines; Sharpless
asymmetric epoxidation; Garner aldehyde.
ꢀ IICT Communication No. 030125.
* Corresponding author. Fax: +91-40-2716-0512; e-mail: yadav@
iict.ap.nic.in
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00390-3

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J. S. Yada6 et al. / Tetrahedron Letters 44 (2003) 2983–2985
synthesised using (−)-DET in the Sharpless asymmetric
epoxidation reaction (Scheme 2). A preparation of the
(S)-Garner aldehyde 10 was achieved starting from
The E-allyl alcohol 5 was subjected to the Sharpless
asymmetric epoxidation protocol.10 Accordingly, treat-
ment of 5 with (+)-DET, titanium tetraisopropoxide
and TBHP in dry CH2Cl2 at −30°C gave the epoxy
alcohol 6a. The optical rotation was found to be −25.6
(c 1.15, CHCl3).11 The epoxy alcohol 6a was converted
to epoxy chloride 7a using triphenylphosphine and
NaHCO3 in refluxing CCl4. The key-step was the execu-
tion of the earlier approach for the preparation of the
chiral propargyl alcohol from chiral 2,3-epoxy chloride
7a using LDA or LiNH2 in liquid ammonia. Accord-
ingly 7a was subjected to our reaction conditions,12 in
liquid ammonia using lithium amide to afford the chiral
propargyl alcohol 8a. The structure of compound 8a
L
-serine by the procedure reported in literature.13
After the successful completion of the syntheses of the
two fragments 9a and 10, our next aim was to couple
together the fragments. Lithium acetylide additions to
the Garner aldehyde proceed with high selectivity in the
Felkin–Anh sense.14 Of particular relevance is the
demonstration by Jurczak and co-workers15 that TBS-
protected pentadecyne behaves in a similar manner
with high selectivity. Thus the TBS protected pentade-
cyne 9a was lithiated using n-BuLi and treated with 2.1
equiv. of HMPT at −78°C followed by Garner aldehyde
10 to afford a 20:1 mixture of compounds in favour of
1
was confirmed by its H NMR spectrum, which gave a
signal at 2.4 ppm as a doublet for one proton corre-
sponding to the newly arisen acetylenic proton (Scheme
2).
1
11a in 87% yield.14,16 The H NMR spectrum of com-
pound 11a showed the absence of the terminal
acetylenic proton at 2.3 ppm of compound 9a and the
presence of peaks between 3.90 and 4.40 ppm corre-
sponding to five protons (-NCH, CH2O, CHOH and
CHOTBS).
The secondary hydroxyl functionality of compound 8a
was protected as its TBDMS ether using 2 equiv. of
imidazole, a catalytic amount of DMAP and 1.2 equiv.
of TBDMS-Cl in anhyd. CH2Cl2 at 0°C to afford
compound 9a in 95% yield. In a similar manner 9b was
The deprotection of the Boc, acetonide and TBS groups
of compound 11a to yield the alkynic amino triol 12a
was achieved by using 1N HCl:THF (1:1) under reflux
conditions for 16 h.17 Our final aim was to convert the
triple bond to a trans double bond and this was
1
achieved using LiAlH4 in THF at 0°C. The H NMR
spectrum of compound 218 showed resonances at 5.5
and 5.7 ppm as two double doublets corresponding to
the olefinic protons, which was consistent with its
FABMS m/z 316 (M+1) (Scheme 3).
Scheme 2.
Scheme 3.

J. S. Yada6 et al. / Tetrahedron Letters 44 (2003) 2983–2985
2985
Synthesis of the other diastereomer 3 was achieved by
coupling 9b with 10 and a similar procedure for the rest
of the steps as shown in Scheme 3.
13. (a) Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361;
(b) Jurczak, J.; Golebiowski, A. Chem. Rev. 1989, 89,
149; (c) Garner, P.; Ramakanth, S. J. Org. Chem. 1986,
51, 2609.
Thus, a total synthesis of the 6-hydroxy-4E-sphingeni-
nes was achieved for the first time. Further work on the
synthesis of other analogues of the 6-hydroxy-4E-sph-
ingenines utilizing the above method is in progress.
Their biological evaluation and the absolute stereo-
chemistry of the synthetic samples in comparison with
the natural products will be reported in due course.
14. (a) Herold, P. Helv. Chim. Acta 1988, 71, 354; (b) Van
Brunt, M. P.; Standaert, R. F. Org. Lett. 2000, 2, 705.
15. Gruza, H.; Kiciak, K.; Kraninski, A.; Jurczak, J. Tetra-
hedron: Asymmetry 1997, 8, 2627.
16. No effort was made to characterize 11a% and 11b%, which
were minor constituents.
17. Garner, P.; Park, J. M.; Malecki, E. J. Org. Chem. 1988,
53, 4395.
18. Spectral data for selected compounds:
Compound 8a (colourless solid): [h]D=−1.8 (c 1.6,
CHCl3). mp 36.0–36.5°C. 1H NMR (CDCl3, 200 MHz): l
0.9 (t, J=4.4 Hz, 3H), 1.22–1.78 (m, 22H), 2.40 (d,
J=3.6 Hz, 1H), 4.25 (m, 1H).
Acknowledgements
V.G. thanks the CSIR, New Delhi, for a research
fellowship.
Compound 8b: [h]D=+1.3 (c 1.05, CHCl3).
Compound 11a (viscous liquid): [h]D=−40.5 (c 1.45,
1
CHCl3). H NMR (CDCl3, 200 MHz): l 0.05 (s, 6H), 0.9
(s, 12H), 1.22–1.75 (m, 37H), 3.90–4.19 (m, 3H), 4.30 (bt,
1H), 4.44 (bs, 1H). 13C NMR (CDCl3, 50 MHz): l −5.1
and −4.5 [(CH3)2-Si], 14.0 (C-18), 18.1, 22.6, 25.1, 25.2,
25.7, 28.3, 29.1, 29.2, 29.4, 29.5, 31.8, 38.5 (C-7), 62.3
(C-6), 62.8 (C-2), 63.5 (C-3), 64.7 (C-1), 81.9, 82.0 (C-2),
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