A tethered aminohydroxylation route to l-arabino-[2R,3S,4R] and l-xylo-[2R,3S,4S]-C18-phytosphingosines

Article abstract of DOI:10.1016/j.tetlet.2009.02.173

A concise and highly efficient synthesis of l-arabino-[2R,3S,4R] and l-xylo-[2R,3S,4S]-C₁₈-phytosphingosines has been achieved. The synthetic strategy features the Sharpless kinetic resolution and tethered aminohydroxylation as the key steps.

Full text of DOI:10.1016/j.tetlet.2009.02.173

Tetrahedron Letters 50 (2009) 3425–3427
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Tetrahedron Letters
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A tethered aminohydroxylation route to L-arabino-[2R,3S,4R]
and L-xylo-[2R,3S,4S]-C18-phytosphingosines
*
Abhishek Dubey, Pradeep Kumar
Organic Chemistry Division, National Chemical Laboratory, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise and highly efficient synthesis of L-arabino-[2R,3S,4R] and L-xylo-[2R,3S,4S]-C18-phytosphingo-
Received 14 January 2009
Revised 16 February 2009
Accepted 22 February 2009
Available online 26 February 2009
sines has been achieved. The synthetic strategy features the Sharpless kinetic resolution and tethered
aminohydroxylation as the key steps.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Sharpless asymmetric kinetic resolution
Tethered aminohydroxylation
Regioselectivity
Stereoselectivity
Phytosphingosine
Sphingolipids
Sphingolipids are structurally diverse constituents of mem-
branes in mammals, plants, fungi, yeast, and in some prokaryotic
organisms and viruses.1 They exhibit a wide range of biological
activities such as cell proliferation, differentiation, adhesion, and
signal transduction.2 Phytosphingosine exists in nature as one of
the molecular species of sphingolipids in microorganisms, plants,
and many mammalian tissues such as brain, hair, intestine,3
uterus,4 liver,5 skin,6 kidney,7 and in blood plasma8 (Fig. 1). It
was first isolated from mushrooms in 19119 and its structure
was elucidated by Oda10a and by Carter et al.10b In addition to its
structural function as long-chain base of sphingolipids in mem-
branes, phytosphingosine is a potential heat stress signal in yeast
cells11a,b and some of its derivatives exhibit important physiologi-
amino alcohols in a regio- and stereoselective manner. This meth-
od overcomes the problem of low regioselectivity mainly encoun-
tered during the asymmetric aminohydroxylation,14
a recent
discovery of Sharpless to introduce amine and alcohol functionality
in a single step in enantio- and stereoselective way. As a part of our
research interest in asymmetric synthesis of bioactive molecules
such as lactones15 and amino alcohols,16 we became interested in
developing a new and highly concise route to phytosphingosine.
Herein we report a highly efficient synthesis of
-xylo-phytosphingosines employing Sharpless kinetic resolution
and tethered aminohydroxylation as the key steps.
As illustrated in Scheme 1, the synthesis of -arabino-[2R,3S,4R]-
C18-phytosphingosine started from commercially available penta-
decanol 3. Compound was oxidized using DMSO-pivaloyl
L-arabino- and
L
L
cal activity.
a
- and b-galactosyl and glucosylphytoceramids are
3
highly potent against tumors.11c
Most synthetic studies have been focused primarily on the
preparation of ribo-phytosphingosines, the stereochemistry of the
C-2 position being either derived from the chiral pool materials,
particularly serine, or by asymmetric synthesis.12 Although several
procedures of the target compound have already been reported,
most of these methods suffer either from large number of steps,
low yields or from low stereo- or regioselectivity. Therefore, a prac-
tical, concise expeditious, and high yield synthesis of the target
molecule is still desirable. The tethered aminohydroxylation13
has recently emerged as a powerful method of preparing vicinal
OH
NH2
OH
NH2
OH
OH
13
13
OH
OH
2
1
L-arabino-[2R,3S,4R]-C18- L-xylo-[2R,3S,4S]-C18-
Phytosphingosine
Phytosphingosine
* Corresponding author. Tel.: +91 20 25902050; fax: +91 20 25902629.
E-mail address: pk.tripathi@ncl.res.in (P. Kumar).
Figure 1. Structures of L-arabino-[2R,3S,4R]- and L-xylo-[2R,3S,4S]-C18-Phytosp-
hingosines.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.173

3426
A. Dubey, P. Kumar / Tetrahedron Letters 50 (2009) 3425–3427
OH
OH
OH
a
b
OH
13
13
13
13
O
3
4
6
5
(Erythro:threo)
96:4
OTBS
O
OTBS
OTBS
c
e
d
5
13
13
13
NH2
O
OH
7
8
O
9
OTBS
O
NH
OH
OAc
NH
NHAc
g
f
OH
h
OH
OAc
13
13
13
O
OAc
O
O
12
10
11
Tetraacetate derivative of
L-arabino-[2R,3S,4R]-C18-
Phytosphingosine
OH
OH
OAc
NHAc
b
c-h
OAc
13
13
13
O
6
OAc
13
14
Tetraacetate derivative of
L-
-[2 ,3 ,4 ]-C -Phytosphingosine
xyl o R S S
18
Scheme 1. Reagents and conditions: (a) (i) pivaloyl chloride, DMSO, Et3 N, -78 °C; (ii) vinyl bromide, Mg, ꢀ78 °C, 2 h, 88%; (b) (ꢀ)-DIPT, Ti(O-iPr)4, TBHP, dry DCM, molecular
sieves, 3 Å, ꢀ20 °C, 4 days, 49% for 5 and 46% for 6; (c) TBS-OTf, 2,6-lutidine, dry CH2Cl2, 15 min, ꢀ10 °C, 90%; (d) (CH3)3S+Iꢀ, n-BuLi, ꢀ20 °C, 75% (e) Cl3CCONCO, K2CO3,
i
CH2Cl2:CH3OH (1.5:1), 4 h, 90%; (f) NaOH, t-BuOCl, Pr2EtN, potassium osmate, 2.5 h, 66%; (g) TsOH (Cat.), MeOH (h) (i) K2CO3, methanol, rt, 6 h; (ii) Ac2O, pyridine, DMAP
(cat), overnight, 82%.
chloride17 to give the aldehyde, which on Grignard reaction with vi-
nyl magnesium bromide furnished the allylic alcohol 4 in 88% yield.
The treatment of 4 with titanium tetraisopropoxide and tert-butyl-
hydroperoxide in the presence of (ꢀ)-DIPT under Sharpless asym-
metric kinetic resolution conditions18 provided the epoxy alcohol
5 and chiral allylic alcohol 619 in 46% yield and 97% ee (determined
from the corresponding Mosher’s ester). The epoxide 5 was found
to be a mixture of erythro and threo (96:4) which was subsequently
convertedintotheirsilylderivativesby treatmentwith TBSOTfinthe
presence 2,6-lutidine. The required erythro isomer 720 could easily
be separated by column chromatography in 90% yield. Epoxide 7
was treated with excess of dimethylsulfonium methylide21 (gener-
ated from trimethylsulfonium iodide and n-BuLi) to furnish the
allylic alcohol 8 in 75% yield. Alcohol 8 was then reacted with tri-
chloroacetyl isocyanate in CH2Cl2 to give the corresponding isocya-
nate which on treatment with aq. K2CO3 and methanol furnished the
carbamate 9 in 90% yield. The carbamatewas converted into the oxa-
zolidinone derivative 10 by a tethered aminohydroxylation proto-
col13 using tert-butyl hypochlorite as the oxidant, potassium
osmate, NaOH, diisopropylethylamine, and propanol as the solvent.
The reaction proceeded smoothly to furnish the protected aminoal-
cohol 1022 in 66% yield with complete regio- and excellent diastere-
oselectivity (syn:anti 12:1, determined from 1H NMR). The
diastereomeric mixture could easily be separated by column chro-
matography. The key step in the tethered aminohydroxylation as de-
picted in Figure 2 is the intramolecular addition of the RN@Os@O
fragment across the alkene leading to syn or anti relative stereo-
chemistry.13 In the conformation A, due to the presence of hydrogen
in the inside allylic position, the intramolecular approach of active
osmiumspeciestoalkenewouldbefavoredthusleadingtothemajor
syn-product. The presence of bulky group (R in B) may hinder the ap-
proach of the active osmium species to the alkene and thus the reac-
tion via conformation B leading to the anti- product is disfavored.
The compound 10 was desilylated using p-TSA and methanol to
give the alcohol 11 in 78% yield, which on hydrolysis with K2CO3 in
methanol furnished the crude aminoalcohol. Subsequent acylation
using Ac2O in the presence of pyridine and catalytic amount of
DMAP produced the tetraacetate derivative of phytosphingosine
1223 in 82% yield.
For the synthesis of L-xylo-[2R,3S,4S]-C18-phytosphingosine, the
allylic alcohol 6 obtained by the chiral resolution of 4 was sub-
jected to Sharpless asymmetric epoxidation to give the epoxide
13 in 75% yield as a single diastereomer, which was converted into
the tetraacetate derivative of L-xylo-[2R,3S,4S]-C18-phytosphingo-

A. Dubey, P. Kumar / Tetrahedron Letters 50 (2009) 3425–3427
3427
O
O
H
H
R
Favorable
H
N
H
Os
O
apporach
H
O
O
Hindered
apporach
O
H
O
O
H
N
Os
O
O
H
R
B
A
OTBS
disfavored
favored
syn
R =
anti
13
Figure 2. Proposed transition states for the syn/anti selectivity observed during the TA reaction.
Kobayashi, E.; Motoski, K.; Yamaguchi, Y.; Uchida, T.; Fukushima, H.; Koezuka,
Y. Oncol. Res. 1995, 7, 529.
sine 14 following the same sequence of reactions as described for
12 (Scheme 1).The physical and spectroscopic data of 14 were in
accordance with those described in literature.12b
12. (a) Fernandes, R. A.; Kumar, P. Tetrahedron Lett. 2000, 41, 10309; (b) Fernandes,
R. A.; Kumar, P. Synthesis 2003, 1, 129; (c) Kumar, P.; Naidu, S. V. Tetrahedron
Lett. 2003, 44, 1035; (d) Azuma, H.; Tamagaki, S.; Ogino, K. J. Org. Chem. 2000,
65, 3538; (e) Abraham, E.; Brock, E. A.; Candela-Lena, J. I.; Davis, S. G.; Georgiou,
M.; Nicholson, R. L.; Perkins, J. H.; Roberts, P. M.; Russell, A. J.; Sanchej-
Fernandez, E. M.; Scott, A. D.; Thomson, J. E. Org. Biomol. Chem. 2008, 6, 1665.
and references cited therein.
13. (a) Donohoe, T. J.; Johnson, P. D.; Helliwell, M.; Keenan, M. Chem. Commun.
2001, 3, 401; (b) Donohoe, T. J.; Johnson, P. D.; Cowley, A.; Keenan, M. J. Am.
Chem. Soc. 2002, 124, 12934; (c) Donohoe, T. J.; Johnson, P. D.; Pye, R. J. Org.
Biomol. Chem. 2003, 1, 2025; (d) Donohoe, T. J.; Johnson, P. D.; Pye, R. J.;
Keenam, M. Org. Lett. 2004, 6, 2583; (e) Donohoe, T. J.; Carole, J. R.; William, G.;
Johannes, K.; Emile, R. Org. Lett. 2007, 7, 1725.
14. (a) Li, G.; Chang, H. T.; Sharpless, K. B. Angew. Chem., Int. Ed. 1996, 35, 451; (b)
Brien, P. O. Angew. Chem., Int. Ed. 1999, 38, 326. and references cited therein.
15. (a) Kandula, S. V.; Kumar, P. Tetrahedron Lett. 2003, 44, 6149; (b) Kumar, P.;
Naidu, S. V.; Gupta, P. J. Org. Chem. 2005, 70, 2843; (c) Kumar, P.; Naidu, S. V. J.
Org. Chem. 2005, 70, 4207; (d) Kumar, P.; Naidu, S. V. J. Org. Chem. 2006, 71,
3935; (e) Kumar, P.; Gupta, P.; Naidu, S. V. Chem. Eur. J. 2006, 12, 1397; (f)
Gupta, P.; Kumar, P. Eur. J. Org. Chem. 2008, 1195. and references cited therein.
16. (a) Fernandes, R. A.; Kumar, P. Eur. J. Org. Chem. 2000, 3447; (b) Kandula, S. V.;
Kumar, P. Tetrahedron Lett. 2003, 44, 1957; (c) Kondekar, N. B.; Subba Rao, K. V.;
Kumar, P. Tetrahedron Lett. 2004, 45, 5477; (d) Kumar, P.; Bodas, M. S. J. Org.
Chem. 2005, 70, 360; (e) Pandey, S. K.; Pandey, M.; Kumar, P. Tetrahedron Lett.
2008, 49, 2397. and references cited therein.
In conclusion, we have achieved a concise synthesis of both
L-arabino- and L-xylo-phytosphingosines using tethered amin-
ohydroxylation and Sharpless kinetic resolution as the key steps
and as a source of chirality. The tethered aminohydroxylation
was used to introduce the amino functionality in a highly diaste-
reoselective manner. The generality of the method shown has sig-
nificant potential of its further extension to the other isomers of
phytosphingosine and related analogues. Currently studies are in
progress to this direction.
Acknowledgments
A.D. thanks CSIR, New Delhi for the award of Senior Research
Fellowship. Financial support for funding of the project (Grant
No. SR/S1/OC-40/2003) from Department of Science & Technology,
New Delhi is gratefully acknowledged. This is NCL Communication
No. 6712.
17. Dubey, A.; Kandula, S. R. V.; Kumar, P. Synth. Commun. 2008, 38, 746.
18. Martin, V. S.; Woodard, S. S.; Katuski, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B.
J. Am. Chem. Soc. 1981, 103, 6237.
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ꢁ
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d 0.89 (t, J = 6.1 Hz, 3H), 1.26 (m, 24H), 1.54 (m, 2H), 1.69
(br s, 1H), 4.11 (m, 1H), 5.08–5.26 (m, 2H), 5.78–5.95 (m, 1H); 13C
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d
36.9, 62.6, 73.0, 114.2, 141.3; Anal. Calcd for C17H34O (254.45): C, 80.24;
H, 13.47. Found: C, 79.95; H, 13.73.
20. Spectral data of 7: ½a D25
ꢁ
ꢀ4.1 (c 1.0, CHCl3); 1H NMR (200 MHz, CDCl3): d 0.07 (s,
3H), 0.12 (s, 3H), 0.84–0.93 (m, 12H), 1.26 (s, 24 H), 1.49–1.53 (m, 2H), 2.55 (q,
J = 2.72, 5.12, 1H), 2.75–2.83 (m, 1H), 2.87–2.97 (m, 1H), 3.19–3.33 (m, 1H); 13C
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ꢁ
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ꢁ
ꢀ25.95 (c 1.5, CHCl3); lit.12d a 2D0
½ ꢁ ꢀ25.1 (c
1.5, CHCl3); 1H NMR (200 MHz, CDCl3): 0.86 (t, J = 6 Hz, 3H), 1.2–1.3 (m, 24 H),
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