A direct organocatalytic entry to sphingoids: Asymmetric synthesis of D-arabino- and L-ribo-phytosphingosine

Article abstract of DOI:10.1039/b515007h

The organocatalytic asymmetric synthesis of d-arabino- and l-ribo-phytosphingosine is described employing a diastereo- and enantioselective (S)-proline-catalyzed aldol reaction of 2,2-dimethyl-1,3-dioxan-5-one and pentadecanal as the key step. The Royal S

Full text of DOI:10.1039/b515007h

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A direct organocatalytic entry to sphingoids: asymmetric synthesis of
D-arabino- and L-ribo-phytosphingosine
ˇ
Dieter Enders,* Jir´ı Palecek and Christoph Grondal
ˇ
Received (in Cambridge, UK) 24th October 2005, Accepted 5th December 2005
First published as an Advance Article on the web 3rd January 2006
DOI: 10.1039/b515007h
equivalent 2,2-dimethyl-1,3-dioxan-5-one (3, dioxanone) and
pentadecanal (4) (Scheme 1).6–8
The organocatalytic asymmetric synthesis of D-arabino- and
L-ribo-phytosphingosine is described employing a diastereo-
and enantioselective (S)-proline-catalyzed aldol reaction of 2,2-
dimethyl-1,3-dioxan-5-one and pentadecanal as the key step.
After extensive optimization of the reaction conditions regard-
ing to yield as well as diastereo- and enantioselectivity (Table 1),
we were able to obtain the aldol product 5 with 49% yield and
Sphingoids are long-chain amino-diol and -triol bases that form
the backbone and the characteristic structural unit of sphingo-
lipids, which are important membrane constituents and play vital
roles in cell regulation as well as signal transduction.1
Furthermore, glycosphingolipids show important biological
activities, e.g. antitumor,2a antiviral,2b antifungal2c or cytotoxic
properties.2d Phytosphingosines, one of the major classes of
sphingoids, have been isolated and identified either separately or
as parts of sphingolipids found in plants,3a marine organisms,3b–c
fungi,3d yeasts3e and even mammalian tissues,3f–l for instance in the
kidney,3g liver,3h uterus,3i intestine,3j skin3k and blood plasma.3l
Due to the physiological importance of these compounds a large
number of syntheses have been reported, which usually involve
many steps and extensive protecting group strategies.4
Fig. 1 Structures of the title phytosphingosines 1 and 2.
We now wish to report a direct and flexible organocatalytic
approach to sphingoids demonstrated with the efficient asym-
metric synthesis of D-arabino- (1) and L-ribo-phytosphingosine (2)
(Fig. 1). Our novel approach to the title compounds 1 and 2
commences with a diastereo- and enantioselective (S)-proline-
catalyzed aldol reaction5 of the readily available dihydroxy acetone
Scheme 1 (S)-proline catalyzed aldol reaction as key step to sphingoids.
Institut fu¨r Organische Chemie, RWTH Aachen, Landoltveg 1, 52074
Aachen, Germany. E-mail: enders@rwth-aachen.de;
Fax: (+49)241 809 2127; Tel: (+49)241 809 4676
Scheme 2 Direct reductive amination of 5.
Table 1 Optimization of the (S)-proline-catalyzed asymmetric aldol reaction of dioxanone 3 with pentadecanal (4) to afford 5
Entry
Temp
Time/d
Ratio 3 : 4
(S)-proline (mol%)
Solvent
Yield (%)a
de (%)b
ee (%)c
1
2
3
4
5
6
7
8
rt
rt
rt
rt
rt
rt
rt
rt
rt
2 uC
rt
rt
rt
4
4
4
4
4
4
4
4
4
20
4
4
4
4
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
2 : 1
2 : 1
5 : 1
30
30
30
30
30
30
30
30
30
30
10
30
60
30
b
DMSO
DMF
CH3CN
THF
H2O
6
28
25
38
.99
.99
.99
.99
—
.99
.99
.99
.99
—
94
92
89
81
—
91
81
94
95
—
82
94
94
88
c
no reaction
36
neat
CH2Cl2
Pentane
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
40
28
9
49 (60)d
10
11
12
13
14
a
no reaction
37
49
50
53
.99
.99
.99
.99
rt
Yield of 5 isolated after flash chromatography on silica gel. Determined on crude 5 by 1H-NMR, 13C-NMR, GC and HPLC. Determined
d
by HPLC on a chiral stationary phase (Daicel IA, n-heptane : isopropanol 95 : 5, major isomer 11.2 min, minor isomer 10.7 min). Yield of
8 mmol experiment (see text).
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Chem. Commun., 2006, 655–657 | 655

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Scheme 3 Diastereoselective reductive amination and ketone–amine conversion. Reagents and conditions: i, TBSOTf, 2,6-lutidine, CH2Cl2, 220 uC, 95%,
de > 99%; ii, BnNH2, NaBH(OAc)3, AcOH, CH2Cl2, 2 uC, 94%, de > 99%; iii, L-Selectride, THF, 278 uC, 93%, de > 99%; iv, MsCl, DMAP, CH2Cl2, 210
to 0 uC, 91%, de > 99%; v, NaN3, 18-crown-6, DMF, 100 uC, 80%, de > 99%; vi, LAH, THF, 0 uC, 98%, de > 99%.
excellent diastereo- and enantiomeric excesses (entry 9). The
optimization process was performed on small scale (1 mmol). To
our delight, after carrying out the optimized reaction
conditions on larger scale (8 mmol) we were able to obtain 5
with an increased yield of 60% and identical diastereo- and
enantioselectivity.{
Thus, the simple (S)-proline catalyzed aldol reaction of the
Scheme 4 Deprotection of 8 to D-arabino-phytosphingosine 1.
dioxanone 3 with pentadecanal directly delivered gram amounts of
The deprotection of the orthogonally triple protected phyto-
the selectively acetonide protected ketotriol precursor of the core
sphingosine 8 could be achieved by removal of the silyl- and
unit of phytosphingosines in excellent stereoisomeric purity. In
acetonide group in the presence of TBAF and TFA in THF. The
order to create stereoselectively the syn- and the anti-1,3-
remaining benzyl group was cleaved by hydrogenation on Pd/C to
aminoalcohol function of the stereotriad, we first envisaged a
afford the title D-arabino-phytosphingosine (1) in 99% yield
(Scheme 4).10
diastereoselective reductive amination of 5.
Initially, we investigated this reductive amination of 5 with
In summary, we have developed a direct and flexible entry to
BnNH2 and NaHB(OAc)3 in the presence of AcOH, but
phytosphingosines by an asymmetric organocatalytic aldol reac-
unfortunately we obtained only a 1 : 1 epimeric mixture of the
tion and subsequent diastereoselective ketone–amine conversion.
corresponding 1,3-aminoalcohol 6 in 72% yield (Scheme 2).
Our modular [C3 + Cn]-concept for the key aldol reaction should
Therefore we attempted the reductive amination with the
enable the introduction of different sidechains, which will greatly
corresponding TBS-protected aldol derivative 7, which can be
expand the potential of this strategy to sphingoids. For example,
easily obtained in excellent yield (95%) using TBSOTf and 2,6-
the class of sphingofungines11 should be directly accessible
lutidine.8b The anti-1,3-aminoalcohol 8 was obtained in almost
employing long chain a-oxygenated aldehydes, and this is currently
quantitative yield (94%) and virtually complete diastereoselectivity
being investigated in our laboratory.
(de > 99%). Thus, our 3-step organocatalytic protocol affords
This
work
was
supported
by
the
Deutsche
orthogonality and selectively protected D-arabino-phytosphingo-
sine of high diastereo- and enantiomeric purity. Needless to say,
that the corresponding enantiomer can be obtained using (R)-
proline instead of (S)-proline as the organocatalyst.
Forschungsgemeinschaft (SPP Organokatalyse) and the Fonds
der Chemischen Industrie (C. G. gives thanks for a Kekule´
fellowship). We thank BASF AG, Degussa AG, Bayer AG and
Wacker-Chemie for the donation of chemicals.
Because the direct and stereoselective reductive amination of 5
or 7 to afford the corresponding syn-1,3-aminoalcohol was not
possible, we decided to synthesize the syn-isomer via a substitution
reaction by inversion of the stereogenic centre. Therefore 7 was
first transformed to the corresponding anti-1,3-diol 9 by a highly
diastereoselective reduction with L-Selectride. The newly
generated secondary alcohol was then converted into the
mesylate 10 (91%) and subsequently into azide 11 (80%). The
substitution of the mesylate 10 by NaN3 in the presence of a crown
ether (18-c-6) proceeded with complete inversion of the stereogenic
centre (>99 : 1, determined by GC).
Notes and references
{ Unless otherwise stated, all chemicals are commercially available and
were used without further purification with the exception of pentadecanal
(4).6 All new compounds were fully characterized (IR, NMR, MS,
elemental analysis, optical rotation). 5: In a 25 mL round-bottomed flask
the dioxanone 3 (1 g, 7.7 mmol) and 30 mol% (S)-proline (0.27 g, 2.3 mmol)
were dissolved in chloroform (4 mL). The solution was stirred for 30 min
before 4 (1.7 g, 7.7 mmol) was added in one portion. The flask was flushed
with argon and stirred for 4 d. The reaction mixture was quenched with sat.
ammonium chloride solution (10 mL), extracted with diethyl ether (3 6
20 mL) and the combined organic phases were dried over MgSO4,
concentrated and purified by column chromatography (silica gel, methylene
chloride : diethyl ether, 9 : 1). The aldol product 5 was obtained as
Subsequent reduction of the azide 11 with LAH afforded the
syn-1,3-aminoalcohol 12 in virtually quantitative yield (Scheme 3).9
656 | Chem. Commun., 2006, 655–657
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colourless oil (1.64 g, 60%). [a]2D6 = 2111.8 (c = 1.1, CHCl3); Found: C,
71.0; H, 11.4. Calc. for C21H40O4: C, 70.7; H, 11.3.; IR (CHCl3) nmax/cm21
3540, 2925, 2855, 1741, 1463, 1378, 1223, 1092, 722; 1H-NMR
dH(400 MHz; CDCl3; Me4Si) 0.88 (3H, t, J 6.9 Hz, CH3), 1.28 (26H, m,
13 6 CH2), 1.44 (3H, s, CH3), 1.48 (3H, s, CH3), 2.97 (1H, br s, OH), 3.89
(1H, m, CH), 4.02 (1H, d, J 17.3 Hz, CH2), 4.09 (1H, dd, J 6.9 and 1.4 Hz,
CH), 4.27 (1H, dd, J 17.3 and 1.4 Hz, CH2); dC(100 MHz, CDCl3, Me4Si)
14.1 (CH3), 22.7 (CH2), 23.5 (CH3), 23.9 (CH3), 25.0 (CH2), 29.4 (CH2),
29.6 (3 6 CH2), 29.7 (2 6 CH2), 29.8 (3 6 CH2), 31.9 (CH2), 32.3 (CH2),
66.7 (CH2), 70.6 (CH), 76.0 (CH), 100.9 (C), 211.2 (CO); m/z (CI,
isobutane) 340 (M+ 2 16, 22), 339 (M+ 2 17, 100), 338 (8).
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