Synthesis of a versatile (S)-3-(hydroxymethyl)butane-1,2,4-triol building block and its application for the stereoselective synthesis of N-homoceramides

Article abstract of DOI:10.1021/ol052335x

(Chemical Equation Presented) A versatile (S)-3-(hydroxymethyl)butane-1,2, 4-triol building block has been synthesized starting from D-isoascorbic acid, a common food preservative. The key transformation in this approach was the introduction of branching

Full text of DOI:10.1021/ol052335x

ORGANIC
LETTERS
2005
Vol. 7, No. 26
5769-5772
Synthesis of a Versatile
(S)-3-(Hydroxymethyl)butane-1,2,4-triol
Building Block and its Application for
the Stereoselective Synthesis of
N-Homoceramides
Ulrik Hillaert and Serge Van Calenbergh*
Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences,
Ghent UniVersity, Harelbekestraat 72, B-9000 Ghent, Belgium
serge.Vancalenbergh@UGent.be
Received September 26, 2005
ABSTRACT
A versatile (S)-3-(hydroxymethyl)butane-1,2,4-triol building block has been synthesized starting from
D
-isoascorbic acid, a common food
preservative. The key transformation in this approach was the introduction of branching through a high yield and fully regioselective epoxide
opening. This flexible synthon has been elaborated to a new class of (dihydro-)N-homo(phyto)ceramides.
The development and availability of reliable and efficient
methods for the construction of chiral building blocks are
crucial for the synthesis of many pharmaceutical agents and
complex natural products. These chiral building blocks can
be derived from the chiral pool or by chemical/enzymatic
means from achiral or racemic starting material.
(S)-3-(Hydroxymethyl)butane-1,2,4-triol is a flexible, mul-
tivalent, scaffold with defined stereochemical features which
can be exploited by judicious selection of appropriate protect-
ing groups. Some examples of the synthetic potential of this
intermediate are summarized in Figure 1. Indeed, sugar deriv-
atives (S,S)-4-(hydroxymethyl)pyrrolidine-3-ol,1 the enanti-
omer of the common precursor of second-generation purine
phosphorylase inhibitors2 and oxetanocin A, a known anti-
bacterial, antitumoral, and antiviral natural product,3 are read-
ily accessible through a limited number of steps (A). More-
over, ceramide analogues with an inversed amide functional-
ity (B) could provide useful biochemical tools for assessment
of ceramide interaction with a myriad of clinically relevant
enzymes. Finally, simple elaboration of the other primary
alcohol (C4-OH) to the amide part (C) gives access to
(2) (a) Kotian, P. L.; Chand, P. Tetrahedron Lett. 2005, 46, 3327-3330.
(b) Makino, K.; Ichikawa, Y. Tetrahedron Lett. 1998, 39, 8245-8248. (c)
Evans, G. B.; Furneaux, R. H.; Lewandowicz, A.; Schramm, V. L.; Tyler,
P. C. J. Med. Chem. 2003, 46, 5271-5276.
(3) Selected examples: (a) Ichikawa, E.; Yamamura, S.; Kato, K.
Tetrahedron Lett. 1999, 40, 7285-7388. (b) Kikuchi, Y.; Kurata, H.;
Shigeru, N.; Yamamura, S. Tetrahedron Lett. 1997, 38, 4795-4798. (c)
Gumina, G.; Chu, C. K. Org. Lett. 2002, 4, 1147-1149. (d) Nishiyama,
S.; Yamamura, S.; Kato, K.; Takita, T. Tetrahedron Lett. 1988, 29, 4743-
4746.
(1) (a) Tyler, P. C.; Clinch, K. PCT Int. Appl. WO 2005033076, 2005.
(b) Karlsson, S.; Hogberg, H.-E. Tetrahedron: Asymmetry 2001, 12, 1977-
1982.
10.1021/ol052335x CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/25/2005

Figure 2. General structures of O1-homoceramides (1) and
N-(dihydro)homo(phyto)ceramides (2-5).
Recently, our group reported an expedient route for the
synthesis of D-erythro-O1-homoceramides8 (Figure 2; 1). An
alternative synthetic procedure for this class of non-natural
ceramide analogues was later proposed by Ogino and co-
workers.9 The authors found that several representatives
exhibited considerable apoptotic activities. Recently, Schmidt
and co-workers10 presented the synthesis of O1-homosphin-
gosine phosphonate starting from D-galactose.
Figure 1. Synthetic potential of key intermediate (S)-3-(hydroxy-
methyl)butane-1,2,4-triol: (A) (aza)sugar derivatives; (B) ceramides
and phytoceramides with an inversed amide functionality; (C)
PDMP homologues; (D) N-(dihydro)homo(phyto)ceramides.
Epoxide synthon 6 (Scheme 1), prepared from D-isoascor-
D-threo-PDMP homologues4 (D-threo-1-phenyl-2-amino de-
canoyl-3-morpholinopropanol), an inhibitor of glucosyl ce-
ramide synthase which is a potential target in the treatment
of cancer.5
bic acid as previously described,11 provided the stereochem-
Scheme 1. Synthesis of Key Intermediate 8
Here, we wish to demonstrate the usefulness of the (S)-3-
(hydroxymethyl)butane-1,2,4-triol scaffold in preparing a novel
class of homoceramide analogues (Figure 1; D), which con-
tain an additional methylene group between the N-acyl chain
and C2 (Figure 2; 2-4). Interestingly, our procedure seemed
also convenient for the synthesis of N-homophytoceramide
(5), which can serve as a key intermediate for the synthesis
of R-galactosyl-N-homoceramide. This latter compound
represents a homologue of R-galactosylceramide, a poten-
tially useful agent for the treatment of autoimmune diseases.6
Homologation is a classical tool in medicinal chemistry
to alter biological properties of endogenous compounds.
Salbutamol, for instance, a widely7 used bronchodilator with
agonistic properties for â2-receptors, consists of a 4-hydroxy-
3-hydroxymethylphenyl moiety instead of the catechol ring,
which is present in (nor)adrenaline.
(4) Abe, A.; Wild, S. R.; Lee, L.; Shayman, J. A. Curr. Drug Metab.
2001, 2, 331-338.
(5) (a) Radin, N. S. Bioorg. Med. Chem. 2003, 11, 2123-2142. (b)
Reynolds, C. P.; Maurer, B. J.; Kolesnick, R. N. Cancer Lett. 2004, 206,
169-180.
(6) Representative reviews: (a) Van Kaer, L. Nat. Immunol. 2005, 5,
31-42. (b) Yamamura, T.; Miyamoto, K.; Illes, Z.; Pal, E.; Araki, M.;
Miyake, S. Curr. Top. Med. Chem. 2004, 4, 561-567.
(7) Salbutamol is the representative for treatment of asthma and chronic
obstructive pulmonary disease (COPD) in the WHO Essential Medicines
Library (EMLib); http://mednet3.who.int/EMLib.
ical and structural features required for our synthetic
approach. Since epoxide opening is often hampered by
(8) De Jonghe, S.; Lamote, I.; Venkataraman, K.; Boldin, S. A.; Hillaert,
U.; Rozenski, J.; Hendrix, C.; Busson, R.; De Keukeleire, D.; Van
Calenbergh, S.; Futerman, A. H.; Herdewijn, P. J. Org. Chem. 2002, 67,
988-996.
5770
Org. Lett., Vol. 7, No. 26, 2005

regioselectivity issues involving the use of hazardous cyanide1b
or additional synthetic steps implicated in allylic transforma-
tions,3b we opted to use 1,3-dithiane12 to introduce branching.
Hence, tritylation followed by reduction of the ester and
subsequent epoxide opening with 2-lithio-1,3-dithiane13
produced intermediate 1,3-diol 7 with complete regioselec-
tivity (47% yield in six steps from D-isoascorbic acid).
Protection of 1,3-diol 7 with di-tert-butylsilyl ditriflate
followed by dithiane deprotection with MeI under alkaline
conditions and final reduction of the unmasked aldehyde with
NaBH4 gave access to 8 (75% from 7, 36% from D-
isoascorbic acid in nine steps), which represents a unique
intermediate from which each of the primary alcohols can
selectively be addressed for further modification.
Scheme 3. Synthesis of d-ribo-N-Homophytoceramide 5
Access to D-ribo-N-homophytoceramide 5 is outlined in
Schemes 2 and 3. Mesylation of intermediate 8 followed by
Scheme 2. Synthesis of Azido Intermediate 10
subsequent acylation of the primary amine with palmitoyl
chloride afforded silyl-protected intermediate 13 (39%). Final
desilylation with TBAF furnished D-ribo-N-homophytoce-
ramide 5 (62%).
Since the presence of azides in Wittig olefination has led
to controversial results,16 we opted to transform the azide to
a phthalimide in a two-step sequence involving reduction of
9 under Staudinger conditions followed by phthalimide
protection of the thus formed primary amine, thereby
affording intermediate 14 in good yield (Scheme 4; 88%).
azide introduction and trityl removal yielded alcohol 9 in
good yield (83%). Subsequent periodinane oxidation and
addition of tetradecylmagnesium chloride to the thus formed
aldehyde furnished protected azido-N-homophytosphingosine
10 (40%) as a single diastereomeric form.
Assignment of the erythro configuration was achieved by
converting intermediate 10 to the 3,4-isopropylidene-
protected triol 11 in a two-step sequence entailing silyl
deprotection and dioxolane formation (Scheme 3; 51%) and
Scheme 4. Synthesis of Z-Alkene Intermediate 15
1
subsequent comparison of H NMR data with similarly
protected natural D-ribo-azidophytosphingosine 12.14,15
Azide reduction under Staudinger conditions following
TBDMS protection of the secondary alcohol in 10 and
(9) (a) Shikata, K.; Niiro, H.; Azuma, H.; Tachibana, T.; Ogino, K.
Bioorg. Med. Chem. Lett. 2003, 13, 613-616. (b) Shikata, K.; Niiro, H.;
Azuma, H.; Ogino, K.; Tachibana, T. Bioorg. Med. Chem. 2003, 11, 2723-
2728.
(10) Tarnowski, A.; Retz, O.; Bar, T.; Schmidt, R. R. Eur. J. Org. Chem.
2005, 6, 1129-1141.
(11) (a) Dunigan, J.; Weigel, L. O. J. Org. Chem. 1991, 56, 6225-2557.
(b) Ikunaka, M.; Matsumoto, J.; Fujima, Y.; Hirayama, Y. Org. Proc. Res.
DeV. 2002, 6, 49. (c) Ziegler, F. E.; Belema, M. J. Org. Chem. 1994, 59,
7962.
(12) For a review on the role of 1,3-dithianes in natural product synthesis,
see: Yus, M.; Na´jera, C.; Foubelo, F. Tetrahedron 2003, 59, 6147-6212.
(13) Paquette, L. A.; Boulet, S. L. Synthesis 2002, 888-894.
(14) (a) Compound 12 has been prepared according to literature
procedures starting from commercially available D-ribo-phytosphingosine
(ref 15). (b) Both 11 (3J3,4 ) 5.57 Hz) and 12 (3J3,4 ) 5.38 Hz) exhibit a
comparable vicinal coupling constant, thereby indicating a cis-relationship
of the ring substituents (standard sphingolipid numbering is used for clarity
reasons).
Subsequent oxidation of the primary alcohol with Dess-
Martin periodinane yielded the intermediate aldehyde. Al-
(16) Selected examples: (a) Nugent, T. C.; Hudlicky, T. J. Org. Chem.
1998, 63, 510-520. (b) Timmer, M. S. M.; Verdoes, M.; Sliedregt, L. A.
J. M.; van der Marel, G. A.; van Boom, J. H.; Overkleeft, H. S. J. Org.
Chem. 2003, 68, 9406-9411. (c) Hudlicky, T.; Nugent, T. J. Org. Chem.
1994, 59, 7944-7946.
(15) Schmidt, R. R.; Maier, T. Carbohydr. Res. 1998, 174, 169-179.
Org. Lett., Vol. 7, No. 26, 2005
5771

after two recrystallizations, isomerically pure (E)-N-homoce-
ramide 3 (38%). Finally, hydrogenation of the Z-double bond
in 2 gave access to dihydro-N-homoceramide 4 (84%).
Scheme 5. Access to (Dihydro)-N-homoceramides 2-4
In summary, we have reported an expedient route toward
a versatile (S)-3-(hydroxymethyl)butane-1,2,4-triol scaffold
starting from D-isoascorbic acid, a common food preservative.
The key transformation in this approach was the introduction
of branching through a high yield and fully regioselective
2-lithio-1,3-dithiane epoxide opening. On the basis of this
flexible synthon, we report the first synthesis of (dihydro)-
N-homoceramides 2-4. In addition, a fully stereoselective
Grignard reaction gave access to D-ribo-N-homophytocera-
mide 5, which will be utilized in a further study toward the
elaboration of its R-galactosyl derivative.
Acknowledgment. We wish to thank S. Goormans for
kindly providing a sample of compound 12. S.V.C. is
indebted to the “Fonds voor Wetenschappelijk Onderzoek-
Vlaanderen” for financial support (“krediet aan navorser”).
though reaction conditions specifically addressed the E-iso-
mer, Schlosser-Wittig olefination surprisingly only produced
Z-isomer 15. Hydrazine-mediated phthalimide deprotection
followed by acylation with palmitoyl chloride and silyl
deprotection with TBAF furnished (Z)-N-homoceramide 2
(Scheme 5; 59%). Photoinduced double bond isomerization
in the presence of diphenyl disulfide as sensitizer produced,
Supporting Information Available: Full experimental
1
details and copies of H and 13C spectra are available. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL052335X
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Org. Lett., Vol. 7, No. 26, 2005