An efficient synthesis of D-erythro- and D-threo-sphingosine from D-glucose: Olefin cross-metathesis approach

Article abstract of DOI:10.1021/ol052320z

(Chemical Equation Presented) The D-erythro- and D-threo-sphingosine were synthesized via E-selective olefin cross-metathesis using a D-glucose-derived building block and long-chain terminal alkene.

Full text of DOI:10.1021/ol052320z

ORGANIC
LETTERS
2005
Vol. 7, No. 26
5805-5807
An Efficient Synthesis of
-threo-Sphingosine from
D
-erythro- and
-Glucose:
D
D
Olefin Cross-Metathesis Approach
Vinod D. Chaudhari, K. S. Ajish Kumar, and Dilip D. Dhavale*
Department of Chemistry, Garware Research Centre, UniVersity of Pune,
Pune - 411 007, India
ddd@chem.unipune.ernet.in
Received September 24, 2005
ABSTRACT
The
D-erythro- and
D-threo-sphingosine were synthesized via E-selective olefin cross-metathesis using a
D-glucose-derived building block and
long-chain terminal alkene.
Glycosphingolipids are commonly found in eukaryotic cell
membranes, plasma membranes, and some intracellular
organelles (endoplasmic reticulum, golgi complex, and
mitochondria).1 They play a crucial role in inter- and
intramolecular communication as well as in the regulation
of cell growth, differentiation, and programmed cell death.2
The backbone of sphingolipids consists of a base bearing a
long aliphatic chain and a polar 2-amino-1,3-diol headgroup.
Although a number of structurally related sphingoid base
structures are known, the most abundant sphingoid base in
nature is D-erythro-C18-sphingosine-(2S,3R,4E)-2-amino-
octadec-4-ene-1,3-diol, 1a (Figure 1), which is known to be
a promising protein kinase C inhibitor.3 Since the 1950s, a
plethora of asymmetric as well as chiron approaches have
been reported for 1a and its analogues4-6 wherein most of
the strategies utilize more traditional C-C double bond-
forming reactions such as olefination6 or stereoselective
reduction of triple bond. However, three recent reports on
D-erythro-sphingosine made use of E-selective cross-
metathesis (CM) olefination of two terminal alkene com-
pounds: one with a long chain and the other with an
2-amino-1,3-diol.5i-k The attractive features of CM olefina-
tion are (a) high E-selectivity with good yield in the product
formation and (b) the functional group tolerance and reason-
able stability of Grubb’s catalyst in the presence of amino-
diol functionality.5i-k,7 Although a number of long-chain
terminal alkenes are commercially available, the preparation
* Corresponding author. Fax: (+91) 20 25691728.
(1) (a) Thudichum, J. L. W. A Treatise on the Chemical Constitution of
the Brain; Archon Books, Hamden, CT, 1962. (b) Hakomori, S. J. Biol.
Chem. 1990, 5, 878. (c) Van Meer, G.; Buger, K. N. J. Trends Cell Biol.
1992, 2, 332.
(2) (a) Hannun, Y. A.; Obeid, L. M. Trends Biochem. Sci. 1995, 20, 73.
(b) Mathias, S.; Pena, L. A.; Kolesnick, R. N. Biochem. J. 1998, 335, 465.
(c) Birbes, H.; Bawab, S. E.; Obeid, L. M.; Hannun, Y. A. AdV. Enzyme
Regul. 2002, 42, 113.
Figure 1.
10.1021/ol052320z CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/19/2005

of a suitable 2-amino-1,3-diol with terminal double bond and
optimization of coupling conditions are the challenges in the
successful implementation of this strategy to target mol-
ecules. As a part of our interest in the synthesis of amino
sugars,8 we thought of exploiting the CM reaction with
D-ribo- and D-xylo-configurated 3-azido-5,6-ene derivatives
with 1-pentadecene, as a crucial step, in the synthesis of
D-erythro- and D-threo-sphingosine 1a and 1b, respectively.
Our results are reported herein.
Scheme 1. Synthesis of D-erythro- and D-threo-Sphingosine
As shown in Scheme 1, the requisite 3-azido-3,5,6-
trideoxy-1,2-O-isopropylidene-R-D-ribo-hexofuran-5-ene 2a
was obtained in five steps as per known procedure from
D-glucose in 79% yield,9 while 3-azido-3,5,6-trideoxy-1,2-
O-isopropylidene-R-D-xylo-hexofuran-5-ene 2b was derived
from D-allose following the same reaction sequence.10 In
general, the presence of an azide functionality in a molecule
precludes CM olefination, leading to either failure or poor
yield of the product.5j,k,7c,11 Despite these reports, we checked
(3) (a) Karlsson, K.-A. Trends Pharmacol. Sci. 1991, 12, 265. (b)
Hannun, Y.; Bell, R. M. Science 1989, 243, 500. (c) Hannun, Y. Science
1996, 274, 1855. (d) Kolter, T.; Sandhoff, K. Angew. Chem., Int. Ed. 1999,
38, 1532. (e) Vankar, Y. D.; Schmidt, R. R. Chem. Soc. ReV. 2000, 29,
201. (f) Brodesser, S.; Sawatzki, P.; Kolter, T. Eur. J. Org. Chem. 2003,
2021.
(4) For recent reviews of sphingosine/ceramide, see: (a) Liao, J.; Tao,
J.; Lin, G.; Liu, D. Tetrahedron 2005, 61, 4715. (b) Curfman, C.; Liotta,
D. Methods Enzymol. 1999, 311, 391. (c) Koskinen, P. M.; Koskinen, A.
M. P. Synthesis 1998, 1075.
the feasibility of the CM reaction with 2a and 2b. Thus, use
of first-generation Grubb’s catalyst A in the individual
reactions of 2a and 2b with 1-nonene did not provide cross-
coupled products, while the same reactions with 10 mol %
Grubb’s catalyst B (second generation) with 1-nonene as well
as 1-pentadecene afforded the cross-coupled products 3a/
3b and 4a/4b, respectively, in good yields with complete
E-stereoselectivity12 (Scheme 1, Table 1).
(5) For some recent syntheses of sphingosine/ceramide see: (a) Olofsson,
B.; Somfai, P. J. Org. Chem. 2003, 68, 2514. (b) Jeong, I.-Y.; Lee, J. H.;
Lee, B. W.; Kim, J. H.; Park, K. H. Bull. Korean Chem. Soc. 2003, 24,
617. (c) Milne, J. E.; Jarowicki, K.; Kocienski, P. J.; Alonso, J. Chem.
Commun. 2002, 426. (d) Lees, W. J.; Gargano, J. M. Tetrahedron Lett.
2001, 42, 5845. (e) Duclos, R. I. Chem. Phys. Lipids 2001, 111, 111. (f)
Lee, J.-M.; Lim, H.-S.; Chung, S.-K. Tetrahedron: Asymmetry 2002, 13,
343. (g) Bittman, R.; Chun, J.; Li, G.; Byun, H.-S. Tetrahedron Lett. 2002,
43, 375. (h) Schmidt, R. R.; Zimmermann, P. Angew. Chem., Int. Ed. 1986,
25, 725. For a cross-metathesis approach to sphingosines, see: (i) Torssell,
S.; Somfai, P. Org. Biomol. Chem. 2004, 2, 1643. (j) Rai, A. N.; Basu, A.
Org. Lett. 2004, 6, 2861. (k) Rai, A. N.; Basu, A. J. Org. Chem. 2005, 70,
8228.
(6) For Wittig olefination, both E and Z isomers were observed. See:
(a) Gigg, J.; Gigg, R.; Warren, C. D. J. Chem. Soc. 1966, 1872. (b) Reist,
E. J.; Christie, P. H. J. Org. Chem. 1970, 35, 4127. (c) Gigg, R.; Conant,
R. J. Chem. Soc., Perkin Trans. 1 1977, 2006. (d) Kiso, M.; Nakamura,
A.; Tomita, Y.; Hasegawa, A. Carbohydr. Res. 1986, 158, 101. (e) Schmidt,
R. R.; Zimmermann, P. Tetrahedron Lett. 1986, 27, 481. (f) Zimmermann,
P.; Schmidt, R. R. Liebigs. Ann. Chem. 1988, 663. (g) Ohashi, K.;
Yamagiwa, Y.; Kamikawa, T.; Kates, M. Tetrahedron Lett. 1988, 29, 1185.
(h) Sugawara, T.; Narisada, M. Carbohydr. Res. 1989, 194, 125. (i) Hirata,
N.; Yamagiwa, Y.; Kamikawa, T. J. Chem. Soc., Perkin Trans. 1 1991,
2279.
(7) (a) Chatterjee, A. K.; Choi, T.-L.; Sander, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360. (b) Connon, S. J.; Blechert, S. Angew.
Chem., Int. Ed. 2003, 42, 1900. (c) Kanemitsu, T.; Seeberger, P. H. Org.
Lett. 2003, 5, 4541. (d) Nolen, E. G.; Kurish, A. J.; Potter, J. M.; Donahue,
L. A.; Orlando, M. D. Org. Lett. 2005, 7, 3383. (e) Grubbs, R. H. Handbook
of Metathesis; Wiley-VCH: Weinheim, Germany, 2003; Vol. 2, Chapter
2. (f) Formentin, P.; Gimeno, N.; Steinke, J. H. G.; Vilar, R. J. Org. Chem.
2005, 70, 8235.
(8) (a) Dhavale, D. D.; Markad, S. D.; Karanjule, N. S.; Prakashareddy,
J. J. Org. Chem. 2004, 69, 4760. (b) Karanjule, N. S.; Markad, S. D.;
Sharma, T.; Sabharwal, S. G.; Puranik, V. G.; Dhavale, D. D. J. Org. Chem.
2005, 70, 1356 and references therein.
Table 1. Study of Cross Metathesis Reactions
sub-
entry strate
catalyst reaction
product
alkenea
(mol %) conditions (% yield)b
1
2
3
4
5
6
2a
2b
2a
2b
2a
2b
1-nonene
1-nonene
1-nonene
1-nonene
A (20) 30 °C, 72 h no reactionc
A (20) 30 °C, 72 h no reactionc
B (10) 30 °C, 15 h 3a, 83
B (10) 30 °C, 14 h 3b, 86
1-pentadecene B (10) 30 °C, 16 h 4a, 85
1-pentadecene B (10) 30 °C, 15 h 4b, 87
a 1-Nonene and 1-pentadecene (2.0 equiv) in CH2Cl2. b Isolated yield.
c Starting compound (65-75%) was isolated.
In an attempt to synthesize the natural sphingosine 1a,
the cross-coupled product 4a was treated with TFA-water
to afford an anomeric mixture of hemiacetal that on sodium
periodate cleavage and subsequent reaction with LAH
(9) (a) Gruner, S. A. W.; Keri, G.; Schwab, R.; Venetianer, A.; Kessler,
H. Org. Lett. 2001, 3, 3722. (b) Gurjar, M. K.; Patil, V. J.; Pawar, S. M.
Indian J. Chem. 1987, 26B, 1115.
(10) For synthesis of 2b by other methods, see: (a) Fernandez, J. M.
G.; Mellet, C. O.; Blanco, J. L. J.; Fuentes, J. J. Org. Chem. 1994, 59,
5565. (b) Calvo-Flores, F. G.; Garcia-Mendoza, P.; Hernandez, F.; Isac-
Garcia, J.; Santoyo-Gonzalez, F. J. Org. Chem. 1997, 62, 3944. (c) Santoyo-
Gonzalez, F.; Garcia-Calvo-Flores, F.; Garcia-Mendoza, P.; Hernandez-
Mateo, F.; Isac-Garcia, J.; Perez-Alvarez, M. D. Chem. Commun. 1995,
461.
(11) (a) Barrett, A. G.; Beall, J. C.; Braddock, D. C.; Flack, K.; Gibson,
V. C.; Salter, M. M. J. Org. Chem. 2000, 65, 6508. (b) Randl, S.; Blechert,
S. J. Org. Chem 2003, 68, 8879.
(12) Under our experimental conditions, the 1H NMR spectrum of crude
products 3a and 4a did not show any additional signals either due to
Z-isomer or the self-coupled products. However, in the case of 3b and 4b,
the 1H NMR spectrum of crude showed a trace amount of (<4%) self-
coupled products.
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Org. Lett., Vol. 7, No. 26, 2005

(reduction of azide and aldehyde functionality in one pot)
afforded D-erythro-sphingosine 1a as waxy solid (Scheme
1). The reaction sequence was repeated for 4b as above to
get D-threo-sphingosine 1b. Owing to the instability of 1a,b
toward crystallization and chromatographic purification, the
sphingosines 1a,b were individually treated with benzyl-
chloroformate and sodium bicarbonate in methanol-water
to give N-Cbz-protected D-erythro-sphingosine 1c and D-
threo-sphingosine 1d, respectively. The spectroscopic ana-
lytical data for 1c was found to be in consonance with that
reported,13 while 1d was characterized independently.
In conclusion, our work illustrates the efficiency of the
E-selective CM olefination methodology in the synthesis of
D-erythro- and D-threo-sphingosine 1a and 1b, respectively.
The four-step synthesis from 2a and 2b gives corresponding
1a in 65.4% and 1b 65.2% in overall yield. The cross-
metathesis products 3a and 3b could also be used in the
synthesis of short-chain ceramides.14 The easy availability
of starting materials and reagents, a few high-yielding steps,
and compatibility of Grubb’s catalyst (second generation)
with sugar azides make our approach versatile for the syn-
thesis of different types of sphingosine analogues and lipids.
Acknowledgment. We thank the Department of Science
and Technology, New Delhi, India, for financial support
(Grant No. SP/S1/G23-2000). We are grateful to Prof. M.
S. Wadia for helpful discussion.
Supporting Information Available: Detailed experi-
1
mental procedures and copies of H and 13C NMR spectra
of compounds 3a, 3b, 4a, 4b, 1c, and 1d. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL052320Z
(14) (a) Garner, P.; Park, J. M.; Malecki, E. J. Org. Chem. 1988, 53,
4395. (b) Van Overmeire, I.; Boldin, S. A.; Dumont, F.; Van Calenbergh,
S.; Slegers, G.; De Keukeleire, D.; Futerman, A. H.; Herdewijn, P. J. Med.
Chem. 1999, 42, 2697 and references therein.
(13) Boutin, R. H.; Rapoport, H. J. Org. Chem. 1986, 51, 5320.
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