1-Deoxy-5-hydroxysphingolipids as new anticancer principles: An efficient procedure for stereoselective syntheses of 2-amino-3,5-diols

Article abstract of DOI:10.1021/ol050829o

(Chemical Equation Presented) Enantioselective preparation of the linear homoallylic alcohol I allows efficient formation of the 2-amino-3,5-diol moiety present in several biologically active compounds, including 1-deoxy-5- hydroxysphingosine analogue IV, which has exhibited excellent biological activity against colon cancer. The conversion of I into IV involves a sequence of enantioselective epoxidation of the O-tert-butoxycarbonyl derivative of I, followed by regioselective and stereospecific oxacyclization of II to introduce differentiated oxygens in III.

Full text of DOI:10.1021/ol050829o

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3155-3157
1-Deoxy-5-hydroxysphingolipids as New
Anticancer Principles: An Efficient
Procedure for Stereoselective Syntheses
of 2-Amino-3,5-diols
John M. Wiseman, Frank E. McDonald,* and Dennis C. Liotta
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
fmcdona@emory.edu
Received April 15, 2005
ABSTRACT
Enantioselective preparation of the linear homoallylic alcohol I allows efficient formation of the 2-amino-3,5-diol moiety present in several
biologically active compounds, including 1-deoxy-5-hydroxysphingosine analogue IV, which has exhibited excellent biological activity against
colon cancer. The conversion of I into IV involves a sequence of enantioselective epoxidation of the O-tert-butoxycarbonyl derivative of I,
followed by regioselective and stereospecific oxacyclization of II to introduce differentiated oxygens in III.
Sphingolipids are a diverse family of biomolecules that have
been shown to play a variety of important roles in the
chemistry of cellular membranes, as well as cell growth,
differentiation, and apoptosis.1 Thus sphingolipids have been
identified as a potentially new class of anticancer principles.
For instance, the parent D-erythro-(2S,3R)-sphingosine (1)
(Figure 1) has been shown to affect multiple signaling
pathways, including but not limited to potent inhibition of
protein kinase C dependent pathways for cell proliferation,2
as well as activation of caspase pathways for apoptosis.3 The
anticancer activity of sphingosine and other sphingolipids
has been demonstrated both in cell culture and in vivo,
particularly against colon cancer cell lines.4 However, in vivo
phosphorylation of the primary alcohol of sphingosine to
sphingosine 1-phosphate (S1P) is problematic, as S1P has
exhibited promitotic and antiapoptotic activity.5 Safingol
(2S,3S-sphinganine (2)) has been explored as an anticancer
lead, as this compound is less reactive with sphingosine
kinase despite the primary hydroxyl group, perhaps as a result
of the different C2,C3-amino alcohol stereochemistry.6 The
laboratories of Liotta and Merrill have developed a class of
(1) Merrill, A. H., Jr.; Sandhoff, K. Sphingolipids: Metabolism and Cell
Signaling. In Biochemistry of Lipids, Lipoprotein, and Membranes; Vance,
D. E., Vance, J. E., Eds.; Elsevier: New York, 2002; pp 373-407.
(2) (a) Hannun, Y. A.; Loomis, C. R.; Merrill, A. H., Jr.; Bell, R. M. J.
Biol. Chem. 1986, 261, 12604. (b) Smith, E. R.; Merrill, A. H.; Obeid, L,
M.; Hannun, Y. A. Methods Enzymol. 2000, 312, 361.
(3) (a) Obeid, L. M.; Linardic, C. M.; Karolak, L. A.; Hannun, Y. A.
Science 1993, 259, 1769. (b) Jan, M. S.; Liu, H. S.; Lin, Y. S. Biochem.
Biophys. Res. Commun. 1999, 264, 724.
(4) Symolon, H.; Schmelz, E. M.; Dillehay, D. L.; Merrill, A. H., Jr. J.
Nutr. 2004, 134, 1157.
(5) Spiegel, S.; Milstein, S. J. Biol. Chem. 2002, 277, 25851.
(6) (a) Buehrer, B. M.; Bell, R. M. J. Biol. Chem. 1992, 267, 3154. (b)
Kedderis, L. B.; Bozigian, H. P.; Kleeman, J. M.; Hall, R. L.; Palmer, T.
E.; Harrison, S. D. Fundam. Appl. Toxicol. 1995, 25, 201. (c) Schwartz, G.
K.; Ward, D.; Saltz, L.; Casper, E. S.; Speiss, T.; Mullen, E. Clin. Cancer
Res. 1997, 3, 343.
10.1021/ol050829o CCC: $30.25
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Published on Web 06/22/2005

and stereoselective introduction of the required functional
groups onto the alkene carbons. Compound 6 was easily
prepared by application of enantioselective crotyl transfer
methodology pioneered by Nokami.11 Acid-catalyzed reaction
of the branched crotyl-menthol reagent 7 with tetradecanal
(8) provided only the trans alkene 6 with high enantio-
selectivity for the chiral alcohol.12 As each enantiomer of 7
can be prepared in two steps from the corresponding
enantiomer of menthol, both 6 and its enantiomer were easily
synthesized by this method.
The original plan was to convert the tert-butyl carbonate
derivative of 9 into the iodocarbonate 10 (Scheme 2), which
Scheme 2. Formation of Iodocarbonate 10 and Attempted
Azide Substitutions
Figure 1. Representative aminodiol natural products and 1-deoxy-
5-hydroxysphingolipid analogues.
1-deoxy-5-hydroxysphingosine analogues 3 and 4,7 with the
C2,C3-amino alcohol stereochemistry of safingol but with
the primary hydroxyl group of sphingosine moved to the C5-
position to maintain similar lipophilicity while further
decreasing opportunity for phosphorylation of hydroxyl
substituents. Interestingly, the 2-amino-3,5-diol of compound
3 is structurally identical to a substructure of the fungal toxin
fumonisin B1 (5).8
The aminodiol substructures of 1-deoxy-5-hydroxysphin-
ganine analogues 3 and 4, as well as fumonisins structurally
related to 5, have been previously prepared from L-alanine
via R-aminoketone7 or R-aminoaldehyde9 synthetic interme-
diates. Unfortunately such R-aminocarbonyl compounds are
notoriously prone to epimerization of the chiral center.10 This
was a serious impediment to reproducible gram-scale pro-
duction of 3 and 4 via the cross-aldol reaction of tetra-
decanal with the kinetic enolate derived from an R-amino-
methyl ketone arising from L-alanine.7 Thus, we were
encouraged to explore a substantially different synthetic
protocol in which the possibility of epimerization of chiral
centers would be unlikely or impossible.
proceeded with good yield and high stereoselectivity for the
1,3-syn cyclic carbonate.13 We had anticipated that 10 would
then undergo azide substitution of the secondary iodide with
inversion of configuration at C2, which would have given
the three heteroatom substituents at C2, C3, and C5 with
all-syn stereochemistry corresponding to target compound
4. Unfortunately attempted substitution of 10 with azide
nucleophiles14 under a variety of conditions gave the
elimination product 11 and only traces of the azidocarbonate
15 (successfully prepared later, as shown in Scheme 3).
Although azide substitution could be achieved from 11 by
We envisioned that the enantioselective preparation of the
linear homoallylic alcohol 6 (Scheme 1) might provide a
simple starting point for the preparation of 3 and 4, and the
chiral hydroxyl group of 6 would offer opportunity for regio-
(7) Menaldino, D. S.; Bushnev, A.; Sun, A.; Liotta, D. C.; Symolon, H.;
Desai, K.; Dillehay, D. L.; Peng, Q.; Wang, E.; Allegood, J.; Trotman-
Pruett, S.; Sullards, M. C.; Merrill, A. H., Jr. Pharmacol. Res. 2003, 47,
373.
(8) (a) Merrill, A. H. Jr.; Liotta, D. C.; Riley, R. T. Trends Cell Biol.
1996, 6, 218. (b) Desai, K.; Sullards, M. C.; Allegood, J.; Wang, E.;
Schmelz, E. M.; Hartl, M.; Humpf, H.-U.; Liotta, D. C.; Peng, Q.; Merrill,
A. H., Jr. Biochim. Biophys. Acta 2002, 1585, 188.
Scheme 1. Enantioselective Synthesis of Linear Homoallylic
Alcohol 6
(9) (a) Shi, Y.; Peng, L. F.; Kishi, Y. J. Org. Chem. 1997, 62, 5666. (b)
Gurjar, M. K.; Rajendran, V.; Rao, B. V. Tetrahedron Lett. 1998, 39, 3803.
(10) Myers, A. G.; Kung, D. W.; Zhong, B. J. Am. Chem. Soc. 2000,
122, 3236.
(11) Nokami, J.; Ohga, M.; Nakamoto, H.; Matsubara, T.; Hussain, I.;
Kataoka, K. J. Am. Chem. Soc. 2001, 123, 9168.
(12) Determined by Mosher ester analysis (Supporting Information).
(13) (a) Bartlett, P. A.; Meadows, J. D.; Brown, E. G.; Morimoto, A.;
Jernstedt, K. K. J. Org. Chem. 1982, 47, 4013. (b) Duan, J. J. W.; Smith,
A. B. J. Org. Chem. 1993, 58, 3703.
(14) (a) Wang, Y.-F.; Izawa, T.; Kobayashi, S.; Ohno, M. J. Am. Chem.
Soc. 1982, 104, 6465. (b) Davies, S. G.; Ichihara, O. Tetrahedron Lett.
1999, 40, 9313.
3156
Org. Lett., Vol. 7, No. 15, 2005

We also conducted the same series of transformations from
the enantiomer of 9, beginning with Shi epoxidation, which
afforded 17 (Scheme 4), the diastereomer of 13. With
Scheme 3. Stereoselective Synthesis of 4
Scheme 4. Stereoselective Synthesis of 3
samples of both diastereomers 13 and 17 in hand, which
1
exhibit differentiable H and 13C NMR characteristics, we
could unambiguously verify stereochemical and constitu-
tional purity of these intermediates. Lewis acid oxacyclization
of the epoxycarbonate 17 provided the cyclic carbonate 18
with 1,3-anti relationship of the C3 and C5 oxygen substit-
uents.19 The remaining steps of mesylate activation, azide
substitution to 19, carbonate methanolysis, and azide hy-
drogenation occurred uneventfully to provide the aminodiol
diastereomer 3.
In conclusion, we have demonstrated a new synthetic
sequence that is robust and highly stereo- and regioselective
for the preparation of 2-amino-3,5-diol substructures, applied
herein to the efficient synthesis of 1-deoxy-5-hydroxy-
sphingolipid analogues. The dichotomy of substitution versus
elimination for a secondary electrophilic substrate bearing
mesylate 15 versus iodide 10 was unexpected and may merit
further study. We note that this synthetic procedure is
potentially useful for other natural product types bearing
similar aminodiol substructures, including fumonisins.
radical substitution conditions,15 the mixture of azide dia-
stereomers obtained was considered impractical for efficient
large-scale synthesis.
However, a solution favoring substitution over elimination
was found merely by changing the leaving group at C2.
Specifically, Shi enantioselective epoxidation of 9 catalyzed
by ketone 12 with hydrogen peroxide as the stoichiometric
oxidant16,17 was followed by Lewis acid promoted intra-
molecular oxacyclization18 of the epoxycarbonate 13 (Scheme
3), to provide the cyclic carbonate 14 bearing the secondary
alcohol at C2 and 1,3-syn relationship of the C3 and C5
oxygen substituents.19 The derived C2-mesylate 15 then
underwent efficient substitution with sodium azide to provide
azidocarbonate 16 as a single isomer, and the elimination
side product 11 was not observed. The target aminodiol 4
was prepared on gram-scale by basic methanolysis of the
cyclic carbonate of 16, followed by catalytic hydrogenation
of the azide.
Acknowledgment. We thank the National Institutes of
Health (CA-87525) for support of this research. We also
acknowledge use of shared instrumentation provided by
grants from the National Institutes of Health, National
Science Foundation, and the Georgia Research Alliance
(NMR spectroscopy, mass spectrometry), as well as the
University Research Committee of Emory University (po-
larimeter).
(15) Ollivier, C.; Renaud, P. J. Am. Chem. Soc. 2001, 123, 4717.
(16) (a) Shu, L.; Shi, Y. Tetrahedron 2001, 57, 5213. (b) Shi, Y. Acc.
Chem. Res. 2004, 37, 488.
(17) The use of Oxone as the stoichiometric oxidant provided epoxy-
carbonate 13 with higher stereoselectivity (dr 19:1), but then two or three
recycles with additional Shi chiral ketone catalyst 12 were generally required
for complete conversion of substrates 9 and ent-9.
(18) (a) McDonald, F. E.; Bravo, F.; Wang, X.; Wei, X.; Toganoh, M.;
Rodriguez, J. R.; Do, B.; Neiwert, W. A.; Hardcastle, K. I. J. Org. Chem.
2002, 67, 2515. (b) Valentine, J. C.; McDonald, F. E.; Neiwert, W. A.;
Hardcastle, K. I. J. Am. Chem. Soc. 2005, 127, 4586.
(19) In preparations of each diastereomer 14 and 18, trace amounts of
the other diastereomer were isolated (arising from the minor enantiomers
generated in either the crotyl transfer or epoxidation step) and were separated
by silica gel chromatography, so that cyclization of each epoxy carbonate
13 and 17 afforded the major cyclic carbonates 14 and 18 respectively, in
enantio- and diastereomerically pure form.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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