Asymmetric sulfur ylide based enantioselective synthesis of D-erythro-sphingosine

Article abstract of DOI:10.1039/b814882a

An asymmetric sulfur ylide reaction was employed to prepare an epoxide intermediate in a convergent manner. This epoxide was efficiently transformed into D-erythro-sphingosine.

Full text of DOI:10.1039/b814882a

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Asymmetric sulfur ylide based enantioselective synthesis of
D-erythro-sphingosine†
Jose´ Antonio Morales-Serna, Josep Llaveria, Yolanda D´ıaz, M. Isabel Matheu and Sergio Castillo´n*
Received 26th August 2008, Accepted 1st October 2008
First published as an Advance Article on the web 17th October 2008
DOI: 10.1039/b814882a
An asymmetric sulfur ylide reaction was employed to prepare
an epoxide intermediate in a convergent manner. This epoxide
was efficiently transformed into D-erythro-sphingosine.
compound and analogues in order to obtain glycosphingolipids.14
Since, pure sphingosine and its derivatives are available in a limited
amount from natural sources, many methods for their synthesis
have been developed by using amino acids, carbohydrates and
other building blocks as the starting materials.15,16 However, most
of the methods require multistep reactions that result in low total
yields. The key to cost-effective and efficient synthesis is the choice
of a proper starting material that requires minimal protection-
deprotection steps.
In the present study, we report a convenient and concise
route for the synthesis of D-erythro-sphingosine 1. Based on the
retrosynthetic analysis depicted in Scheme 1, compound 1 can be
generated from the corresponding epoxide 4 via an intramolecular
ring-opening to introduce the amino functionality at C-2. The
selectivity of the intermolecular opening is controlled by the
double bond and affords the 3-amino derivative. For synthesising
epoxide 4 we envisaged an asymmetric reaction between a chiral
sulfur ylide obtained from bromide 6 and aldehyde 5, which
can incorporate the nucleophile (X) for epoxide opening in its
structure.
Sphingolipids, named by Johann Ludwig Wilhelm Thudichum1
in 1884 after the Greek Sphinx due to their enigmatic function,
have emerged over the last several decades as a family of key
signalling molecules, and include sphingosine 1, ceramide 2, and
sphingosine-1-phosphate 3 (Fig. 1).2 Data indicate that these
lipids regulate fundamental and diverse cell processes such as
differentiation, migration, and apoptosis.3,4 Moreover, on the
organismal level, sphingolipids play roles in higher order physi-
ological processes including inflammation5 and vasculogenesis.6
Recent studies implicate sphingolipid involvement in many of
the most common human diseases including diabetes,7 cancers,8
infection by microorganisms,9 Alzheimer’s disease,10 heart disease
and an array of neurological syndromes.11
Fig. 1 Naturally occurring sphingolipids.
The basic structure of a sphingolipid consists of a long-chain
sphingoid base backbone linked to a fatty acid via an amide bond
with the 2-amino group and to a polar head group at the C-1 po-
sition via an ester bond. There are four sphingosine stereoisomers
with a wide range of biological activities.12,13 The isomer D-erythro
is the most common metabolite and has been meticulously studied.
We have recently reported efficient glycosylation protocols of this
Scheme 1 Retrosynthetic analysis of D-erythro-sphingosine.
The aldehyde 5 is readily prepared from the alcohol 7. Lipophilic
chain fragment 6 should be available from allyl bromide (8) and
alkene 9 by means of cross-metathesis (CM) in order to introduce
the required E-olefin moiety.
As shown in Scheme 2, the synthesis started with the protection
of hydroxyaldehyde 7 as a carbamate, since it is appropriate for
opening the epoxide in a subsequent step. Thus, aldehyde 10 for
Departamento de Qu´ımica Anal´ıtica y Qu´ımica Orga´nica, Universitat Rovira
i Virgili, C/Marcel.li Domingo s/n, 43007 Tarragona, Spain. E-mail: sergio.
castillon@urv.net; Fax: +34 977 558446; Tel: +34 977 559556
† Electronic supplementary information (ESI) available: Experimental
details and characterization data of all the new compounds. See DOI:
10.1039/b814882a
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Scheme 2 Protection of alcohol 7.
asymmetric sulfur ylide reaction was obtained in excellent yield by
reaction of hydroxyaldehyde 7 and benzyl isocyanate (1.5 equiv)
in the presence of Et3N, employing Et2O as the solvent.
The high E-selectivity and the functional tolerance are attractive
features of cross-metathesis olefination in the synthesis of natural
products.17 In a recent synthesis of the sphingosines and phy-
tosphingosines, CM has been used as a carbon chain elongation
strategy.18 Therefore, we reasoned that a cross metathesis reaction
of allyl bromide 8 and alkene 9 in presence of Grubbs’19 catalyst
will provide the intermediate 620 with the correct configuration.
Substrate 8 was stirred with 4 equiv of olefin 9 and 0.02 equiv
of second generation Grubbs’ catalyst (B) in CH2Cl2 for 8 h at
reflux. The reaction proceeded smoothly, and the desired coupling
product 6 was obtained in 97% yield with an E : Z selectivity
of 52 : 1. The homocoupling product of 8 was not observed by
1H NMR. In this case the use of Ti(OiPr)4 or other additive
was not necessary to obtain excellent results. A decrease in the
selectivity (E : Z 11 : 1) and the yield (78%) was observed when the
first generation Grubbs’ catalyst (A) was employed under similar
conditions (Scheme 3).
Scheme 4 Synthesis of D-erythro-sphingosine.
Fig. 2 Ylide intermediate.
◦
tivity first by treatment with NaHMDS (1.5 equiv) at -15 C in
THF.25 Then, removal of the benzyl group employing Li (excess)
and EtNH2/t-BuOH at -78 ◦C gave 14 in 90% yield over two
steps.18d,26 Finally, alkaline hydrolysis of oxazolidinone 14 with
KOH at reflux for 2.5 h furnished D-erythro-◦sphingosine 1 in
quantitative yield. Synthetic 1 gave mp 72–74 C (lit18d mp 72–
75 ◦C), [a]D -1.6 (c 0.9 in CHCl3) (lit18d [a]D -1.6) (c1 in CHCl3)).
Scheme 3 Synthesis of 6 by cross-metathesis.
The key step is the synthesis of the epoxide 13 with control
of the configuration of the stereogenic centers at C-2 and C-3 by
using the stoichiometric sulfur ylide reaction, which is of particular
interest because of the valuable synthetic intermediates that have
been generated using this reaction.21 The sequence developed to
prepare epoxide 13 is summarized in Scheme 4. Sulfide 1122 was
selected as chiral auxiliary in order to prepare the corresponding
chiral sulfur ylide.21 Reaction of sulfide 11 (1 equiv) with allyl
bromide 6 (1.2 equiv) in CH2Cl2 and in the presence of AgBF4
(4 equiv) afforded the required sulfonium salt 12 in 80% yield.23
Subsequent treatment of the salt 12 with EtP2 base (1.1 equiv) and
the aldehyde 10 (1.1 equiv) furnished the desired epoxide 13 in
60% yield. Crucial to the success of the reaction were conditions
that favoured the formation of stabilized ylide 15 (Fig. 2), namely
employing the EtP2 base at -78 ◦C in CH2Cl2.
1
400 MHz H and 125 MHz 13C NMR spectroscopic data were
consistent with data reported for the synthetic product. The match
of optical rotation values indicate that the formation of the epoxide
13 was completely stereoselective.
In summary, D-erythro-sphingosine has been obtained in 42%
overall isolated yield and high enantioselectivity by using an
asymmetric sulfur ylide reaction between the sulfonium salt 12
and the aldehyde 10 as the key step.
Acknowledgements
The authors acknowledge the financial support of DGI CTQ2005-
03124 (Ministerio de Educacio´n y Ciencia, Spain). J. Llaveria and
J. A. Morales-Serna thanks DURSI (Generalitat de Catalunya)
and Fons Social Europeo for a fellowship.
To complete the synthesis (Scheme 4),24 epoxide 13 was con-
verted to oxazolidinone 14 with complete regio- and stereoselec-
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2008, 73, 1179–1385; (d) J. Jeon, M. Shin, J. W. Yoo, J. S. Oh, J. G. Bae,
S. H. Jung and Y. G. Kim, Tetrahedron Lett, 2007, 48, 1105–1108; (e) I.
Kumar and C. V. Rode, Tetrahedron: Asymmetry, 2007, 18, 1975–1980;
(f) H. J. Yoon, Y.-W. Kim, B. K. Lee, W. K. Lee, Y. Kim and H.-J. Ha,
Chem. Commun., 2007, 79–81; (g) D. Mormeneo, J. Casas, A. Llebaria
and A. Delgado, Org. Biomol. Chem., 2007, 5, 3769–3777; (h) H. Yang
and L. S. Liebeskind, Org. Lett., 2007, 9, 2993–2995; (i) D. Enders, J.
Palecek and C. Grondal, Chem. Commun., 2006, 655–657; (j) S. Kim,
S. Lee, T. Lee, H. Ko and D. Kim, J. Org. Chem., 2006, 71, 8661–8664;
(k) Y. Cai, C.-C. Ling and D. R. Bundle, Org. Biomol. Chem., 2006, 4,
1140–1146; (l) W. Desadee and T. Ishikawa, J. Org. Chem., 2005, 70,
9399–9406.
Notes and references
1 J. L. W. Thudichum, A treatise on the Chemical Constitution of the
Brain, Bailliere, Tindall and Cox, London, 1884.
2 M. Tani, M. Ito and Y. Igarashi, Cell. Signal., 2007, 19, 229–
237.
3 J. Riethmu¨ller, A. Riehle, H. Grassme´ and E. Gulbins, Biochim.
Biophys. Acta, 2006, 1758, 2139–2147.
4 C. F. Snook, J. A. Jones and Y. A. Hannun, Biochim. Biophys. Acta,
2006, 1761, 927–946.
5 M. El Alwani, B. X. Wu, L. M. Obeid and Y. A. Hannun, Pharmacol.
Ther., 2006, 112, 171–183.
6 K. M. Argraves, B. A. Wilkerson, W. S. Argraves, P. A. Fleming, L. M.
Obeid and C. J. Drake, J. Biol. Chem., 2004, 279, 50580–50590.
7 S. A. Summers and D. H. Nelson, Diabetes, 2005, 54, 591–602.
8 D. E. Modrak, D. V. Gold and D. M. Goldenberg, Mol. Cancer. Ther.,
2006, 5, 200–208.
17 For review, see: (a) R. W. Franck and M. Tsuji, Acc. Chem. Res., 2006,
39, 692–701; (b) J. Prunet, Curr. Top. Med. Chem., 2005, 5, 1559–1577;
(c) S. J. Cannon and S. Blechert, Angew. Chem Int. Ed., 2003, 42, 1900–
1923.
18 (a) T. Yamamoto, H. Hasegawa, T. Hakogi and S. Katsumura, Org.
Lett., 2006, 8, 5569–5572; (b) M. Lombardo, M. G. Capdevila, F. Pasi
and C. Tombini, Org. Lett., 2006, 8, 3303–3305; (c) V. D. Chaudhari, K.
S. A. Kumar and D. D. Dhavale, Org. Lett., 2005, 7, 5805–5807; (d) S.
Torssell and P. Somfai, Org. Biomol. Chem., 2004, 2, 1643–1646; (e) A.
N. Rai and A. Basu, Org. Lett., 2004, 6, 2861–2863; (f) O. V. Singh, D.
J. Kampf and H. Han, Tetrahderon Lett., 2004, 45, 7239–7242.
19 T. M. Trnka and R. H. Grubbs, Acc. Chem. Res., 2001, 34, 18–29.
20 S. Raucher, Tetrahedron Lett., 1977, 44, 3909–3912.
21 For a general review abaout asymetric sulfur ylide reaction see: (a) E.
M. McGarrigle, E. L. Myers, O. Illa, M. A. Shaw, S. L. Riches and V.
K. Aggarwal, Chem. Rev., 2007, 107, 5841–5883; (b) J. R. Fulton, V. K.
Aggarwal and J. de Vicente, Eur. J. Org. Chem., 2005, 1479–1492; (c) V.
K. Aggarwal and C. L. Winn, Acc. Chem. Res., 2004, 37, 611–620;
(d) V. K. Aggarwal and J. Richarson, Chem. Commun., 2003, 2644–
2651; (e) A.-H. Li, L.-X. Dai and V. K. Aggarwal, Chem. Rev., 1997,
97, 2341–2372.
22 V. K. Aggarwal, G. Fang, C. G. Kokotos, J. Richardson and M. G.
Unthank, Tetrahedron, 2006, 62, 11297–11303.
23 V. K. Aggarwal, I. Bae, H.-Y. Lee, J. Richardson and D. T. Williams,
Angew. Chem. Int. Ed., 2003, 42, 3274–3278.
24 B. Olofsson and P. Somfai, J. Org. Chem., 2003, 68, 2514–2517.
25 (a) S. P. Bew, S. D. Bull, S. G. Davies, E. D. Savory and D. J. Waltkin,
Tetrahedron, 2002, 58, 9387–9401; (b) W. R. Roush and M. A. Adam,
J. Org. Chem., 1985, 50, 3752–3757; (c) B. Bernet and A. Vasella,
Tetrahedron Lett., 1983, 24, 5491–5494.
26 R. Julina, T. Herzig, B. Bernet and A. Vasella, Helv. Chim. Acta, 1986,
69, 368–373.
9 L. J. Heung, Ch. Luberto and M. Del Poeta, Infect. Immun., 2006, 74,
28–39.
10 S. Zhou, H. Zhou, P. J. Walian and B. K. Jap, Biochemistry, 2007, 46,
2553–2563.
11 T. Kolter and K. Sandhoff, Biochim. Biophys. Acta, 2006, 1758, 2057–
2079.
12 A. H. Jr. Merril, S. Nimkar, D. Menaldino, Y. A. Hannun, C. Loomis,
R. M. Bell, S. R. Tyahi, J. D. Lambeth, V. L. Stevens, R. Hunter and
D. C. Liotta, Biochemistry, 1989, 28, 3138–3145.
13 C. W. Sachs, L. M. Ballas, S. W. Mascarella, A. R. Safa, A. H. Lewin, C.
Loomis, F. I. Carroll, R. M. Bell and R. L. Fine, Biochem. Pharmacol.,
1996, 52, 603–612.
14 (a) J. A. Morales-Serna, O. Boutureira, Y. D´ıaz, M. I. Matheu and
S. Castillo´n, Org. Biomol. Chem., 2008, 6, 443–445; (b) O. Boutureira,
J. A. Morales-Serna, Y. D´ıaz, M. I. Matheu and S. Castillo´n, Eur. J.
Org. Chem., 2008, 1851–1854; (c) J. A. Morales-Serna, Y. D´ıaz, M. I.
Matheu and S. Castillo´n, Org. Biomol. Chem., 2008, 6, 3831–3836.
15 For reviews, see: (a) J. Liao, J. Tao, G. Lin and D. Liu, Tetrahedron,
2005, 61, 4715–4733; (b) A. H. Jr. Merrill and Y. A. Hannun, Methods
Enzymol., 2000, 311, 91–479; (c) P. M. Koskinen and A. M. P. Koskinen,
Synthesis, 1998, 1075–1091.
16 For recent synthesis of sphingosines see: (a) E. Abraham, E. A. Brock,
J. I. Candela-Lena, S. G. Davies, M. Georgiu, R. L. Nicholson, J. H.
Perkins, P. M. Roberts, A. J. Russel, E. M. Sa´nchez-Ferna´ndez, P. M.
Scott, A. A. D. Smith and J. E. Thomson, Org. Biomol. Chem., 2008, 6,
1655–1673; (b) Y. Niu, X. Cao and X. S. Ye, Helv. Chim. Acta, 2008, 91,
746–752; (c) S. Kim, N. Lee, S. Lee, T. Lee and Y. M. Lee, J. Org. Chem.,
4504 | Org. Biomol. Chem., 2008, 6, 4502–4504
This journal is
The Royal Society of Chemistry 2008
©