Double stereodifferentiation in asymmetric dihydroxylation: Application to the first diastereoselective synthesis of L-xylo-[2R,3S,4S]-C18-phytosphingosine

Article abstract of DOI:10.1016/S0040-4039(00)01851-7

The first diastereoselective synthesis of L-xylo-(2R,3S,4S)-C₁₈-phytosphingosine (1) has been achieved by double stereodifferentiation of enantiomerically enriched terminal olefin 14 using (DHQD)₂-PHAL ligand in an asymmetric dihydroxylation with a diastereomeric ratio of 83:17. This phytosphingosine was fully characterized by the physical and spectral data of the corresponding tetraacetate 21. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01851-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10309–10312
Double stereodifferentiation in asymmetric dihydroxylation:
application to the first diastereoselective synthesis of
L
-xylo-[2R,3S,4S]-C -phytosphingosine
1
8
Rodney A. Fernandes and Pradeep Kumar*
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune-411008, India
Received 10 August 2000; revised 28 August 2000; accepted 19 October 2000
Abstract
The first diastereoselective synthesis of L-xylo-(2R,3S,4S)-C -phytosphingosine (1) has been achieved
18
by double stereodifferentiation of enantiomerically enriched terminal olefin 14 using (DHQD) –PHAL
2
ligand in an asymmetric dihydroxylation with a diastereomeric ratio of 83:17. This phytosphingosine was
fully characterized by the physical and spectral data of the corresponding tetraacetate 21. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: asymmetric dihydroxylation; double stereodifferentiation; diastereoselective synthesis; sphingolipids; phy-
tosphingosines.
Although known for more than 100 years, the finding that defects in sphingolipid metabolism
leads to several inherited human diseases and that sphingolipids are involved in essentially all
1
aspects of cell regulation have led to an explosion of interest in sphingolipids; namely
sphingomyelins, gangliosides, cerebrosides and other complex cellular lipid homologues. These
have long-chain bases as the backbone, i.e. sphingosine, dihydrosphingosine and phytosphin-
gosine which are important membrane components playing vital roles in cell regulation and
2
signal transduction. Due to their varied biological activities, a great deal of effort has been
made towards the synthesis of sphingolipids.
Of the eight C -phytosphingosine isomers belonging to ribo-, arabino-, xylo-,and lyxo-
1
8
series, most synthetic studies have been focused primarily on the preparation of ribo- or
arabino-phytosphingosines, the stereochemistry of the C-2 position being either derived from the
3
chiral pool materials or by asymmetric synthesis. To our knowledge, only seven syntheses of
4
5
lyxo- or xylo-phytosphingosines either racemic or enantiomerically enriched have been
*
Corresponding author. Fax: +0091-20-5893614; e-mail: tripathi@dalton.ncl.res.in
NCL communication No. 6595.
†
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01851-7

10310
described to date. As part of our research program aimed at developing enantioselective
6
a,b
6c,d
syntheses of naturally occurring lactones
and amino alcohols,
Sharpless asymmetric
dihydroxylation and subsequent transformation of the diols formed via cyclic sulfites/sulfates
were envisaged as powerful tools offering considerable opportunities for synthetic manipula-
tions. Herein we report the first diastereoselective synthesis of L-xylo-(2R,3S,4S)-C -phytosph-
18
ingosine 1 by employing the Sharpless asymmetric dihydroxylation as the source of chirality.
The enantiomerically enriched terminal olefin 14 was prepared following the reaction steps as
shown in Scheme 1. The commercially available pentadecanol 9 was oxidized to the aldehyde
and subsequently treated with (ethoxycarbonylmethylene)triphenylphosphorane to give the
Wittig product 10. The dihydroxylation of olefin 10 under the Sharpless asymmetric dihydroxy-
7
8
20
D
lation conditions gave the diol 11 in 94% yield and 99% ee ([a] −10.13, c=1, CHCl ). The
3
dihydroxy protection as acetonide 12 followed by lithium aluminum hydride reduction of the
ester gave compound 13 in excellent yield. The primary alcohol was oxidized to the aldehyde
under the normal Swern oxidation conditions which on subsequent Wittig reaction furnished the
olefin 14.
Scheme 1. Reagents and conditions: (i) (a) P O , DMSO, CH Cl , Et N, 0°C. (b) Ph PꢀCHCO Et, THF, reflux, 12
2
5
2
2
3
3
2
h; (ii) (DHQ) –PHAL, OsO , MeSO NH , K Fe(CN) , K CO , t-BuOH:H O [1:1], 24 h., 0°C; (iii) 2,2-DMP,
2
4
2
2
3
6
2
3
2
(
−
CH ) CO, PTSA, rt, overnight; (iv) LiAlH , Et O, 0°C to rt, overnight; (v) (a) (COCl) , DMSO, CH Cl , Et N,
78°C. (b) Ph P CH I , NaHMDS, THF, 0°C to rt, 12 h
3 3
3 2 4 2 2 2 2 3
+
−
9
The concept of double diastereoselection was introduced for ever-increasing demand of
higher selectivity in stereoselective reactions. In asymmetric dihydroxylation of olefins also, the
stereoselective outcome of the reaction gets affected by the presence of pre-existing chiral
information in the substrate.

10311
With a view to exploiting the concept of double diastereoselection, the olefin 14 was subjected
to the Sharpless asymmetric dihydroxylation conditions. The results of double stereodifferentia-
tion are given in Table 1.
Table 1
10
Double stereodifferentiation in AD reaction of 14
Ligand
15a
15b
Yield
Diastereomeric mixture
2
0
(
(
DHQ) –PHAL
1
5
2
1
89%
92%
16 ([a] −17.3, c=1, CHCl3)
20
2
D
DHQD) –PHAL
17 ([a]D −19.5, c=1, CHCl3)
2
Thus, the diastereomeric ratio of 15a:15b in the case of (DHQ) -PHAL ligand was 1:2 whereas
2
a considerable enhancement in the diastereomeric ratio of 15a:15b (5:1) was observed with the
use of (DHQD) –PHAL ligand (Table 1). The poor diastereoselectivity observed in the former
2
case may be because of opposite influences of the chiral reagent and substrate (mismatched case)
while the latter could be regarded as matched case where the chirality information of the reagent
and the substrate probably act synergistically and therefore, a high degree of diastereoselection
was obtained. Mixture 17 was then converted into L-xylo-(2R,3S,4S)-C -phytosphingosine 1 as
18
its tetraacetate derivative 21 as shown in Scheme 2.
Scheme 2. Reagents and conditions: (i) Pivaloyl chloride, pyr, CH Cl , 0°C to rt, overnight; (ii) (a) MeSO Cl, pyr,
2
2
2
DMAP(cat.), CH Cl , 60°C, overnight. (b) LiN , DMF, 80°C, 12 h; (iii) LiAlH , Et O, 0°C to rt, overnight; (iv) (a)
2
2
3
4
2
6
N HCl, MeOH, rt, overnight. (b) Ac O, pyr, DMAP(cat.), CH Cl , rt, 12 h
2 2 2
Protection of the primary hydroxyl group of 17 was carried out using pivaloyl chloride and
pyridine at 0°C to give 18. The C-2 hydroxy was then converted into the azido functionality
through mesylation followed by the nucleophilic displacement with LiN to give 19 with
3
inversion of configuration at C-2. The protection of the primary hydroxyl group as a pivaloate
was advantageous over other protecting groups since both pivaloate deprotection and azide
reduction could be accomplished together under the same conditions. Thus the lithium alu-
minum hydride reduction of 19 gave the amino alcohol 20 in excellent yield. Deprotection of the

10312
acetonide was effected with 6N HCl in MeOH to give the hydrochloride salt of (2R,3S,4S)-2-
amino-1,3,4-trihydroxyoctadecane. This was subsequently acetylated using Ac O, pyridine and
2
catalytic amount of DMAP to give the tetraacetate 21 of L-xylo-(2R,3S,4S)-C -phytosphin-
18
gosine 1 (66% de) in 30% overall yield.
Similarly compound 16 was converted into the tetraacetate of
tosphingosine 4 (33% de) in 26% overall yield.
D
-lyxo-(2S,3S,4S)-C -phy-
18
In conclusion, the first diastereoselective synthesis of the L-xylo isomer of phytosphingosine
has been achieved through double stereodifferentiation using the Sharpless asymmetric dihy-
droxylation. The synthetic strategy described here has significant potential for further extension
to the syntheses of other lyxo- and xylo- isomers simply by changing the ligand and also to the
arabino- and ribo- isomers by employing the cis olefin for step 2 (Scheme 1). Currently, studies
are in progress in this direction.
Acknowledgements
R.A.F. thanks CSIR, New Delhi, for financial assistance. We are grateful to Dr. M. K.
Gurjar for his support and encouragement. This is NCL communication No. 6595.
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13
1
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.