A practical synthesis of D-erythro-sphingosine using a cross-metathesis approach

Article abstract of DOI:10.1039/b403568b

Starting from a vinylepoxide, a short and practical synthesis of D-erythro-sphingosine is described. The key transformations are a regioselective opening of the vinylepoxide and an E-selective cross-metathesis, affording the target molecule in 5 steps and 51% overall yield.

Full text of DOI:10.1039/b403568b

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A practical synthesis of D-erythro-sphingosine using
a cross-metathesis approach†
Staffan Torssell and Peter Somfai*
Organic Chemistry, KTH Chemistry, Royal Institute of Technology, S-100 44 Stockholm,
Sweden. E-mail: somfai@kth.se; Fax: +46 8 7912333; Tel: +46 8 7906960
Received 9th March 2004, Accepted 26th March 2004
First published as an Advance Article on the web 20th April 2004
Starting from a vinylepoxide, a short and practical synthesis of -erythro-sphingosine is described. The key
transformations are a regioselective opening of the vinylepoxide and an E-selective cross-metathesis, affording
the target molecule in 5 steps and 51% overall yield.
Introduction
Sphingolipids are constituents of cell membranes in all
eukaryotic cells and the recent discovery of their biologically
active metabolites e.g. sphingosine, ceramide and lysosphingo-
lipids has generated interest in the physiological role of these
molecules. -erythro-Sphingosine (1, Scheme 1) and related
compounds have been shown to inhibit protein kinase C, which
affects cell regulation and signal transduction, and exhibits
antitumor promoter activities in various mammalian cells. In
addition, these compounds may function as modulators of cell
function and possibly also as secondary messengers.1–3 Due to
the biological importance of 1 and its derivatives many syn-
thetic routes to enantiopure sphingolipids have been described
in the literature. Most of these utilize starting materials
from the chiral pool e.g. -serine or carbohydrates,4–8 while
asymmetric routes are more rare.9–12
Scheme 2 Synthesis of oxazolidinone 5. Reagents and conditions: a.
BnNCO, Et3N, Et2O, 60 ЊC, 98%; b. NaHMDS, THF, Ϫ15 ЊC, 88%.
by base-induced Payne rearrangement gave 3 in high yield
and excellent enantiomeric purity (>99% ee15), as described
previously.16–18 It was expected that intermolecular reaction of
3 with various nitrogen nucleophiles would, due to electronic
influences, result in a preferential ring-opening at the allylic
position.19 To circumvent this the C-2 amino functionality was
introduced through a two-step procedure. Alkyl isocyanates
have previously been used as nitrogen nucleophiles to give
regioselective attack at the C-2 position of epoxy alcohols.20,21
Consequently, when epoxy alcohol 3 was treated with benzyl
isocyanate and Et3N in a sealed tube benzyl carbamate 4 was
obtained in excellent yield. The subsequent intramolecular
ring-opening of 4 using NaH proceeded sluggishly and gave a
poor yield of oxazolidinone 5.20,21 Gratifyingly, when using
NaHMDS in THF at low temperature instead, 5 was obtained
in 88% yield.22
Scheme 1 Retrosynthetic analysis of -erythro-sphingosine.
Cross-metathesis and completion
We became interested in assembling 1 by using a cross-
metathesis reaction to introduce the required E-olefin moiety
(Scheme 1). Such a strategy would be convenient compared to
alternatives using more traditional C–C double bond forming
reactions, since the required catalyst is commercially available
and the metathesis usually proceeds with a low amount of
byproduct formation.13,14 The polar head group 5 should be
available from epoxide 3, which, in turn, is readily prepared
from divinylcarbinol (2). The realization of this strategy yields
a practical synthesis of 1 that is outlined below.
Due to the lipid chain and the hydrophilic head group,
compound 1 exhibits surfactant-like properties such as low
solubility in organic solvents at low temperature, and problems
with flash chromatography due to aggregation of the material
on the silica gel column.12 The late introduction of the aliphatic
chain by a cross-metathesis reaction overcomes many of these
problems and has advantages over several of the existing
strategies of 1 where the lipid chain is introduced at an early
stage of the synthetic route.
Compound 6 was synthesized by coupling allylic alcohol 5
with 1-pentadecene using Ru-catalysts A–C (Fig. 1 and Table 1).
The initial coupling attempts under standard conditions14
using catalyst A or B resulted in no reaction or required
prolonged reaction times, giving 6 in moderate yield and E : Z
selectivity (Table 1, entries 1–3). When using toluene23 as
solvent homodimer 7 precipitated as a white solid and thereby
shifted the equilibrium toward 7 (entry 4). This could be
resolved by addition of Ti(OiPr)4 to the reaction mixture and 6
was isolated in 52% yield (78% based on recovered starting
material) with 16 : 1 E : Z selectivity (entry 7). The E : Z isomers
Results and discussion
Synthesis of oxazolidinone 5
The synthesis of oxazolidinone 5 starts from commercially
available 2 (Scheme 2). Sharpless epoxidation of 2 followed
† Electronic supplementary information (ESI) available: spectroscopic
data for compounds 1 and 4–8. See http://www.rsc.org/suppdata/ob/b4/
b403568b/
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 4 3 – 1 6 4 6
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Table 1 Cross-metathesis
Entry
Catalyst (mol%)
Conditionsa
Product (Yield %b)
E : Z
1
2
A (5)
B (5)
B (5)
B (10)
40 ЊC, 43 h
rt, 3 d
40 ЊC, 24 h
50 ЊC, 1.5 h
No reaction
6 (35)
6 (49)
6 (7)
7 (57)
6 (7)
6 (30)
6 (52)
6 (53)
6 (59)
N.A.
14 : 1
5 : 1
12 : 1
E
N.A.
N.A.
16 : 1
13 : 1
17 : 1
3
4c
5d
6d
7d
8
A (5)
40 ЊC, 40 h
40 ЊC, 22 h
40 ЊC, 45 min
rt, 48 h
B (10)
B (10)
C (10)
C (10)
9
40 ЊC, 1.5 h
a 2 equiv. 1-pentadecene in CH2Cl2. b Isolated yield. c 2 equiv. of 1- pentadecene in PhMe d 2 equiv. Ti(OiPr)4 was added prior to the catalyst.
approach, has been developed. The required stereochemistry
was introduced via a regioselective epoxide opening while the
aliphatic chain of 1 was introduced with a highly E-selective
cross-metathesis in the presence of Grubbs’ phosphine free
catalyst C. Two quantitative deprotection steps completed
the synthetic route, furnishing 1 in 51% yield over five steps. The
strategy is flexible and would permit the synthesis of sphingo-
lipids with different aliphatic chains by using other olefins in the
Fig. 1 Ru-catalysts used in the cross-metathesis reaction.
cross-metathesis reaction.
were easily separated by flash chromatography. The need for
Ti(OiPr)4 could be explained by the heteroatom density in 5,
Experimental
as Ru catalyst B can form inactive chelates with Lewis-basic
sites in the substrate.23 The presence of Ti(OiPr)4 decreases
For general experimental procedures see ref 12.
the amount of Ru-substrate chelates and increases the amount
of desired product.24–26 When employing Grubbs’ phosphine-
free 3-bromopyridine catalyst C27 (Fig. 1) the yield and E : Z
selectivity were increased to 59% (82% based on recovered
starting material) and 17 : 1 respectivly (Table 1, entry 9).
Catalyst C was easily made from the commercially available B
and has shown increased reactivity in various cross-metathesis
reactions.28–30
((2R,3R)-3-Vinyloxiran-2-yl)methyl benzylcarbamate (4)
To a solution of ((2R,3R)-3-vinyloxiran-2-yl)methanol18 (509
mg, 5.08 mmol) in Et2O (20 cm3) was added freshly distilled
Et3N (1.42 cm3, 10.16 mmol) followed by BnNCO (0.94 cm3,
7.62 mmol). The resultant mixture was heated to 60 ЊC in a
sealed tube for 17 h, cooled to rt and quenched with sat. NH4Cl
(15 cm3). The phases were separated and the aqueous layer was
extracted twice with CH2Cl2. The combined organic phases
were dried over MgSO4 and concentrated in vacuo. Flash
Removal of the benzyl group in 6 with sodium in liquid
ammonia gave oxazolidinone 8 which was then hydrolyzed with
KOH to afford -erythro-sphingosine (1) in quantitative yield
over two steps (Scheme 3). Analytical data of 1 were in good
agreement with literature data.4–12
chromatography (CH2Cl2
CH2Cl2 + 1% MeOH) of the
residue gave 4 (1.161 g, 98%) as a low melting white solid:
δH(400 (MHz; CDCl3) 3.14 (1 H, m), 3.29 (1 H, d, J 6.6), 4.01
(1 H, dd, J 12.2 and 6.0), 4.39 (2 H, d, J 6.0), 4.46 (1 H, dd,
J 12.2 and 3.1), 5.08 (1 H, br s), 5.31–5.34 (1 H, m), 5.63–5.48
(2 H, m) and 7.26–7.37 (5 H, m); δC(100 (MHz; CDCl3) 45.2,
56.4, 57.5, 64.8, 120.3, 127.6, 127.7, 128.8, 134.5, 138.4
and 156.1; [α]2D0 +26.2 (c 0.39 in CHCl CHCl3) [lit.21 [α]2D0 +25.7
(c 0.39 in CHCl3)].
(S)-3-Benzyl-4-((R)-1-hydroxyallyl)oxazolidin-2-one (5)
Scheme 3 Deprotection of 1. Reagents and conditions: a. 1 M KOH,
H2O : EtOH 1 : 1, 100 ЊC, 100%; b. Na, NH3(l), Ϫ78 ЊC, 100%.
To a stirred solution of urethane 4 (1.022 g, 4.38 mmol) in THF
(50 cm3) at Ϫ15 ЊC was added dropwise NaHMDS (6.57 cm3,
6.57 mmol, 1 M in THF). The resultant mixture was slowly
allowed to reach 0 ЊC (5 h) and then quenched by addition
of sat. NH4Cl (20 cm3). The phases were separated and the
aqueous layer was extracted twice with Et2O, dried over MgSO4
Conclusions
In conclusion, an efficient and practical route for the synthesis
of -erythro-sphingosine (1), based on a cross-metathesis
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 4 3 – 1 6 4 6
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and then concentrated in vacuo. Flash chromatography
(pentane : EtOAc 3 : 2) of the residue gave 5 (899 mg, 88%) as a
colorless oil. νmax(film)/cmϪ1 3216, 1745, 1265 and 739; δH(400
MHz; CDCl3) 2.20 (1 H, d, J 3.5), 3.70 (1 H, ddd, J 9.2, 6.2 and
2.6), 4.15 (1 H, t, J 8.8), 4.25 (1 H, dd, J 8.8 and 6.3), 4.36 (1 H,
A-part of ABq, J 15.2), 4.37 (1 H, s), 4.73 (1 H, B-part of ABq,
J 15.2), 5.28 (1 H, dd, J 10.6 and 1.3), 5.41 (1 H, dd, J 17.2 and
1.3), 5.66 (1 H, ddd, J 17.2, 10.6 and 4.9) and 7.32–7.37 (5 H,
m); δC(100 MHz; CDCl3) 46.8, 58.4, 62.4, 69.2, 118.2, 128.2,
128.3, 129.2, 134.6, 136.3 and 159.3; [α]2D0 +4.7 (c 1.04 in
CHCl3); m/z (FAB+) 234.1134 (M + H) C13H16NO3 requires
234.1130).
(S)-4-((R,E )-1-Hydroxyhexadec-2-enyl)oxazolidin-2-one (8)
To a solution of Na (excess) in freshly distilled NH3 (45 cm3) at
Ϫ78 ЊC was cannulated oxazolidinone 6 (558 mg, 1.34 mmol) in
Et2O (10 cm3). The resultant blue solution was stirred at Ϫ78 ЊC
for 4 h and then carefully quenched with sat. NH4Cl. The
NH3was then slowly evaporated under a stream of N2. The
phases were separated and the aqueous layer was extracted
three times with EtOAc, dried over MgSO4 and concentrated in
vacuo to give 8 (437 mg, 100%) as a white solid: mp 71–72 ЊC
(lit.32 73–74 ЊC); δH(400 MHz; CDCl3) 0.81 (3 H, t, J 6.8),
1.20–1.37 (22 H, m), 2.04 (2 H, q, J 7.0), 2.92 (1 H, br s), 3.86
(1 H, m), 4.12 (1 H, m), 4.33 (1 H, dd, J 8.8 and 5.2), 4.39 (1 H,
t, J 8.8), 5.37 (1 H, ddt, J 15.4, 6.8 and 1.2), 5.83 (1 H, ddt, 15.4,
6.8 and 0.8) and 6.11 (1 H, s); δC(100 (MHz; CDCl3) 14.2, 22.8,
29.1, 29.4, 29.5, 29.6, 29.74, 29.79, 29.81, 32.1, 32.5, 56.4, 66.4,
73.3, 126.3, 126.6, 136.6 and 160.5; [α]2D0 Ϫ1.3 (c 1.75 in CHCl3)
[lit.32 [α]2D0 Ϫ 0.8 (c 2.0 in CHCl3)].
(S)-3-Benzyl-4-((R,E )-1-hydroxyhexadec-2-enyl)oxazolidin-2)-
one (6)
Typical cross-metathesis protocol. To a solution of allylic
alcohol 5 (34.8 mg, 0.15 mmol) in CH2Cl2 (1.0 cm3) was added
1-pentadecene (43.6 mm3, 0.30 mmol). To the resultant mixture
at reflux was added catalyst C28(13.2 mg, 0.015 mmol) in
CH2Cl2 (0.5 cm3) and the resulant mixture was stirred at reflux
for 1.5 h and then cooled to rt. The solvent was evaporated
to give a brown residue with 17.4 : 1 E : Z selectivity (crude
NMR). Flash chromatography (pentane : EtOAc 4 : 1) of the
residue gave isomerically pure 6 (36.5 mg, 59%) as a white solid
and recovered 5 (8 mg, 23%).
D-erythro-Sphingosine (1)
Oxazolidinone 8 (425.8 mg, 1.31 mmol) in 1 M KOH (20 cm3,
H2O : EtOH 1 : 1) was heated to reflux for 2.5 h, cooled to rt
and then 2 M NaOH (10 cm3) was added. The mixture was
extracted with EtOAc (3 × 20 cm3) and the combined organic
layers were dried over MgSO4 and concentrated in vacuo giving
1 (390.1 mg, 100%) as a white solid: mp 72–75 ЊC (lit.7 mp
70 ЊC, lit.12 mp 73–75 ЊC); δH(500 (MHz; CDCl3) 0.87 (3 H, t,
J 6.9), 1.25–1.38 (22 H, m), 2.05 (2 H, q, J 7.0), 2.27 (4 H, br s),
2.85 (1 H, m), 3.63 (1 H, dd, J 10.9 and 5.8), 3.67 (1 H, dd,
J 10.9 and 4.6), 4.04 (1 H, t, J 6.3), 5.47 (1 H, dd, J 15.4 and 7.2)
and 5.75 (1 H, dt, J 15.4 and 6.7); δC(100 (MHz; CDCl3) 14.3,
22.8, 29.3, 29.4, 29.5, 29.6, 29.76, 29.80, 29.82, 32.1, 32.5, 56.3,
64.2, 75.8, 129.4 and 134.9; [α]2D0 Ϫ1.6 (c 1.0, CHCl3) [lit.7 [α]2D0
Ϫ1.2 (c 1.74 in CHCl3), lit.8 [α]2D0 Ϫ1.5 (c 0.52, CHCl3)].
Typical cross-metathesis protocol using Ti(OiPr)4. To a solu-
tion of allylic alcohol 5 (827 mg, 3.55 mmol) in CH2Cl2(20 cm3)
was added Ti(OiPr)4 (2.10 cm3, 7.09 mmol) and the resultant
mixture was refluxed for 30 min. To the mixture was then added
1-pentadecene (1.040 cm3, 7.09 mmol) and catalyst B (301 mg,
0.35 mmol) in CH2Cl2 (10 cm3) and the resultant mixture was
refluxed for 45 min and then cooled to rt. The solvent volume
was reduced to approx. 4 cm3 and the resultant mixture
was subjected to flash chromatography (pentane : EtOAc 4 : 1)
to give 6 (E : Z 16 : 1) as a white solid and recovered 5 (280 mg,
34%). The E : Z-isomers were separated with a second flash
chromatography (pentane : EtOAc 4 : 1) to give isomerically
pure 6 (761 mg, 52%): mp 54–56 ЊC (lit.31 mp 56–57 ЊC); δH(400
(MHz; CDCl3) 0.88 (3 H, t, J 6.9), 1.27 (22 H, m), 2.01 (2 H, q,
J 7.3), 2.06 (1 H, s), 3.66 (1 H, ddd, J 9.1, 6.2 and 2.9), 4.17
(1 H, t, J 8.8), 4.25 (1 H, dd, J 8.8 and 6.3), 4.28 (1 H, s), 4.33
(1 H, A-part of ABq, J 15.2), 4.74 (1 H, B-part of ABq, J 15.2),
5.27 (1 H, dd, J 15.5 and 6.1), 5.79 (1 H, ddt, J 15.4, 6.9 and 1.2)
and 7.31–7.36 (5 H, m); δC(125 (MHz; CDCl3) 14.3, 22.8, 29.1,
29.3, 29.5, 29.6, 29.71, 29.78, 29.80, 29.81, 32.1, 32.5, 46.8, 58.7,
62.8, 69.7, 69.8, 126.22, 126.24, 128.2, 128.3, 129.1, 135.65,
135.68, 135.72, 136.4 and 159.3; [α]2D0 Ϫ12.5 (c 1.07 in CHCl3)
[lit.31 [α]2D0 Ϫ11.8 (c 1.07 in CHCl3)]; m/z (FAB+) 416.3174
(M + H. C26H42NO3 requires 416.3165).
Acknowledgements
This work was supported financially by AstraZeneca,
Södertälje, and the Swedish Research Council.
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