Enantioselective synthesis of sphingadienines and aromatic ceramide analogs

Article abstract of DOI:10.1021/ol202064j

A new approach to the synthesis of sphingoid bases has been developed. The strategy is based on Sonogashira coupling of a chiral acetylenic carbamate that can be prepared in enantiomerically enriched form from 2,3-epoxy-4-pentyn-1-ol, which is readily acc

Full text of DOI:10.1021/ol202064j

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5184–5187
Enantioselective Synthesis
of Sphingadienines and Aromatic
Ceramide Analogs‡
´
Marıa Moreno, Caterina Murruzzu, and Antoni Riera*
´
Unitat de Recerca en Sıntesi Asimetrica (URSA-PCB), Institute for Research in
Biomedicine (IRB) and Departament de Quımica Organica, Universitat de Barcelona,
ꢀ
´
ꢀ
c/Baldiri Reixac, 10, E-08028 Barcelona, Spain
antoni.riera@irbbarcelona.org
Received July 29, 2011
ABSTRACT
A new approach to the synthesis of sphingoid bases has been developed. The strategy is based on Sonogashira coupling of a chiral acetylenic
carbamate that can be prepared in enantiomerically enriched form from 2,3-epoxy-4-pentyn-1-ol, which is readily accessible by Sharpless
asymmetric epoxidation. Several N-Boc-sphingadienines and aromatic ceramide analogs have been synthesized.
Glycosphingolipids are constituents of eukaryotic cell
membranes1 and play important roles in many physiolo-
gical processes.2 The basic components of these lipids are
called sphingosines and have a characteristic 2-amino-1,3-
diol fragment with a 2S,3R (D-erythro) configuration3
(Figure 1). Ceramides are fatty acid sphingosine amides
and have been implicated in the regulation of cell growth
and differentiation, inflammation, and apoptosis.4 Cera-
mides have been implicated in many physiological events.5
The C(4)ÀC(5) trans double bond in the sphingoid base
may be crucial for the biological activities of ceramides.
Sphingosines are potent inhibitors of protein Kinase C.6
There is growing interest in the development of sphingo-
sine analogs. For instance, sphingosines with aromatic
substituents in the side chain7 are stronger sphingosine
kinase inhibitors relative to their corresponding parent
compounds.8 Sphingadienines, which have two double
bonds in the hydrocarbon chain, are less abundant sphin-
goid bases.9 Over the past few years, ceramide analogs with
(6) (a) Merrill, A. H., Jr.; Nimkar, S.; Menaldino, D.; Hannun, Y. A.;
Loomis, C.; Bell, R. M.; Tyagi, S. R.; Lambeth, J. D.; Stevens, V. L.;
Hunter, R..; et al. Biochemistry (N. Y.) 1989, 28, 3138–3145. (b) De
Jonghe, S.; Van Overmeire, I.; Poulton, S.; Hendrix, C.; Busson, R.; Van
Calenbergh, S.; De Keukeleire, D.; Spiegel, S.; Herdewijn, P. Bioorg.
Med. Chem. Lett. 1999, 9, 3175–3180.
(7) (a) Chandrasekhar, S.; Saritha, B.; Jagadeshwar, V.; Prakash,
S. J. Tetrahedron: Asymmetry 2006, 17, 1380–1386. (b) Murakami, T.;
Furusawa, K.; Tamai, T.; Yoshikai, K.; Nishikawa, M. Bioorg. Med.
Chem. Lett. 2005, 15, 1115–1119. (c) Lim, H.; Park, J.; Ko, K.; Lee, M.;
Chung, S. Bioorg. Med. Chem. Lett. 2004, 14, 2499–2503.
(8) Van Overmeire, I.; Boldin, S. A.; Venkataraman, K.; Zisling, R.;
De Jonghe, S.; Van Calenbergh, S.; De Keukeleire, D.; Futerman, A. H.;
Herdewijn, P. J. Med. Chem. 2000, 43, 4189–4199.
‡
ꢁ
Dedicated to Prof. Rafael Suau (Universidad de Malaga), in memoriam.
(1) (a) Sweely, C. In Biochemistry of Lipids, Lipoproteins and Mem-
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(b) Miller-Pedraza, H. Chem. Rev. 2000, 100, 4663–4682.
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C. A.; Sullards, M. C.; Liotta, D. C.; Merrill, A. H., Jr. J. Lipid Res. 2008,
49, 1621–1639.
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1993, 25, 43–64. (b) Jarvis, W. D.; Grant, S.; Kolesnick, R. N. Clin.
Cancer Res. 1996, 2, 1–6. (c) Dickson, R. C. Annu. Rev. Biochem. 1998,
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Menaldino, D. S.; Bushnev, A.; Sun, A.; Liotta, D. C.; Symolon, H.; Desai,
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r
10.1021/ol202064j
Published on Web 09/02/2011
2011 American Chemical Society

enhanced antitumor activity have been proposed as a
potential new class of chemotherapeutic agents.10
sphingosine analogs and sphingadienines using this ap-
proach (Figure 2).
Figure 1. Biologically important sphingolipids.
Figure 2. Retrosynthetic analysis of sphingadienines and aro-
matic sphingosine analogs.
Most synthetic approaches to sphingoid alkaloids11À14
are based on the diastereoselective addition of organome-
tallic nucleophiles to Garner’s aldehyde or equivalent
compounds, which entail forming the C3ÀC4 bond or
ring closing metathesis (forming the C4ÀC5 bond). Con-
trariwise, we envisioned that a novel and convenient route
to these compounds would be through coupling of aryl or
vinyl halides to the acetylenic carbamates I to form the
C5ÀC6 bond. To date, few precedents of alkyne-amino-
diol synthons have been described.15 Adequately protected
compounds I would be accessible from the known acet-
ylenic epoxy alcohol 1, which can be prepared in any
configuration by Sharpless asymmetric epoxidation of
the commercially available (E)-2-penten-4-yn-1-ol. Herein
we describe the enantioselective synthesis of aromatic
We obtained the epoxy alcohol 116 by Sharpless
epoxidation17 of commercial (E)-2-penten-4-yn-1-ol in
moderate yield and 90% ee. Treatment of this compound
with benzoyl isocyanate afforded, somewhat surprisingly,
benzoate 2 in good yield.18 In this case, the carbamate
formation, the intramolecular epoxide ring opening, and
the subsequent trans-acylation took place in a one-pot
reaction (Scheme 1). Benzoate 2 is a very convenient chiral
aminodiol synthon, since both chiral centers are clearly
defined and all functional protecting groups would be
easily deprotected by simple hydrolysis.
Scheme 1. Preparation of the Acetylenic Carbamate 2, Key
Intermediate of Our Approach
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Koskinen, P. M.; Koskinen, A. M. P. Synthesis 1998, 1075–1091. (d)
Byun, H. S.; Bittman, R. Phospholipids Handb. 1993, 97–140.
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Hirono, R.; Furusawa, K. Tetrahedron 2005, 61, 9233–9241. (b) Kang,
J.; Garg, H.; Sigano, D. M.; Francella, N.; Blumenthal, R.; Marquez,
V. E. Bioorg. Med. Chem. 2009, 17, 1498–1505. (c) Yang, H.; Liebeskind,
L. S. Org. Lett. 2007, 9, 2993–2995.
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K. S. A.; Dhavale, D. D. Org. Lett. 2005, 7, 5805–5807. (b) Nakamura,
T.; Shiozaki, M. Tetrahedron Lett. 1999, 40, 9063–9064.
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Biomol. Chem. 2004, 2, 1643–1646. (b) Righi, G.; Ciambrone, S.;
D’Achille, C.; Leonelli, A.; Bonini, C. Tetrahedron 2006, 62, 11821–
11826. (c) Llaveria, J.; Diaz, Y.; Matheu, M. I.; Castillon, S. Org. Lett.
2009, 11, 205–208. (d) Morales-Serna, J. A.; Llaveria, J.; Diaz, Y.;
Matheu, M. I.; Castillon, S. Org. Biomol. Chem. 2008, 6, 4502–4504. (e)
Sa-Ei, K.; Montgomery, J. Tetrahedron 2009, 65, 6707–6711.
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Futerman, A. H.; Van Calenbergh, S. Bioorg. Med. Chem. 2006, 14,
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S. Y.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765–5780. (b)
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Org. Lett., Vol. 13, No. 19, 2011
5185

Preparation of the long-chain (E)-vinyl iodides 4 from
the corresponding aldehydes via the Takai reaction has
been described.19 However, in our hands, the yields were
moderate and the reaction was not completely stereoselec-
tive. Conversely, hydrozirconation of the acetylenes 3
using Schwartz’s reagent20 followed by iodine treatment
afforded the (E)-vinyl iodides 4 in high yield with full
stereoselectivity (Scheme 2).
sphingadienines have been thus prepared in five steps
(8À14% overall yield) from epoxy alcohol 1.
Scheme 3. Functional Group Manipulation of the Enynes 5 and
Subsequent Reduction To Afford the N-Boc-Protected Sphin-
gadienines 9
Scheme 2. Preparation of the (E)-Vinyl Iodides 4
The Sonogashira coupling21 of carbamate 2 using either
vinyl iodide 4a or 4b, or using aryl iodides proceeded
in good yields under the standard reaction conditions
(Table 1).
We also prepared several aromatic analogs of ceramides
using an analogous sequence. First, N-Boc-protection of
the aromatic carbamates 6 gave N-Boc carbamates 10 in
excellent yields. Subsequent basic hydrolysis afforded the
N-Boc protected aminodiols 11. Then, Red-Al reduction
of the triple bond in compounds 11 afforded the allyl
alcohols 12 in moderate yields. Finally, acid deprotection
of the tert-butoxycarbamate, followed by amide formation
with n-alkyl p-nitrophenyl octanoate (PNPO), yielded the
desired ceramide analogs 13 (Scheme 4). These ceramide
analogs have been thus prepared in seven steps (7À18%
overall yield) from epoxy alcohol 1.
Table 1. Sonogashira Reactions of the Carbamate 2
entry
R-I
product.
yield
1
2
3
4
5
6
C
13H25-I (4a)
5a
5b
6a
6b
6c
6d
75%
75%
82%
80%
84%
80%
C9H17-I (4b)
Ph
MeO-Ph-I
tBu-Ph-I
n-C7H15-Ph-I
Scheme 4. Transformation of Aromatic Carbamates 6 into the
Aromatic Ceramide Analogs 13a
The functional group protection scheme of the enynes 5
was easily changed by treatment with Boc2O and subse-
quent chemoselective basic hydrolysis (using lithium
hydroxide) to afford the N-Boc-enynes 8. Gratifyingly,
these enynes were converted into the corresponding N-
Boc-sphingadienines 9 by Red-Al (sodium bis(2-meth-
oxyethoxy)aluminum hydride)22 reduction of the pro-
pargylic triple bond (Scheme 3). Deprotection of the Boc
group, however, proved to be difficult, and to date we have
not been able to perform it in a reasonable yield. The Boc-
(19) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408–7410.
(20) Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1996, 26, 8115–
8116.
(21) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
a PNPO = para-nitrophenyl octanoate.
ꢁ
1975, 16, 4467–4470. (b) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107,
874–922.
(22) Machacek, J.; Casensky, B.; Abrham, K. Collect. Czech. Chem.
Commun. 1973, 38, 343–349.
In summary, N-Boc-protected sphingadienines and sev-
eral aromatic analogs of ceramides have been synthesized
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Org. Lett., Vol. 13, No. 19, 2011

from a common acetylenic precursor in a very straightfor-
ward way. Our approach has two main advantages: first, all
the chiral centers are defined in the key intermediate, and
second, the acetylenic coupling offers high synthetic versa-
tility for the preparation of structurally diverse derivatives.
support. M.M. and C.M. thank MICINN and CIRIT
(Generalitat de Catalunya), respectively, for predoctoral
fellowships.
Supporting Information Available. Experimental pro-
cedures and characterization data for compounds 1À2,
4À13; 1H /13C NMR spectra of compounds 2 and 5À13.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank MICINN (CTQ2008-
00763/BQU) of Spain, the IRB Barcelona, and the
Generalitat de Catalunya (2009SGR 00901) for financial
Org. Lett., Vol. 13, No. 19, 2011
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