compounds was obtained. Use of the phosphine-free catalyst
B13 did not provide any improvement, and a 36% yield of 7
was obtained with the catalyst C.14,15 However, the mass
balance of the reaction was also very low, and extensive
efforts to increase the yield by variations in concentration,
olefin ratios, solvent, temperature, and catalyst loading were
unsuccessful. The failure of cross-metathesis reactions in the
presence of azide-containing molecules is precedented.16-18
Reaction of the phosphine ligands with the azide and/or
metal-mediated nitrene processes are possible complications
that can arise under these conditions.
In an effort to increase the yield of this critical olefin
metathesis step, the azide was reduced to the amine and
protected as the Fmoc carbamate 9. The carbamate 9
undergoes cross metathesis reactions in the presence of A
with a variety of alkenes to provide the products shown in
Figure 1 in high yields. Reaction of 9 with pentadecene
We chose diethyl tartrate as the starting material for the
five-carbon building block I, as both enantiomers are readily
available, allowing entry into both natural and ent-sphin-
golipids.6 The (-)-D-tartrate diester was converted to the
known azidotriol 2 in three steps using reported procedures.7-9
Selective benzoylation of 2 was accomplished via the
stannylene ketal intermediate.10 Silylation of the remaining
primary alcohol followed by installation of the p-methoxy-
benxyl ether afforded the differentially protected intermediate
4.11 Deacylation followed by oxidation with the Dess-Martin
periodinane proceeded smoothly to provide the aldehyde 5.
The requisite fifth carbon of the core building block 6 was
installed via Wittig methylenation.12
Scheme 2
Scheme 1
With building block 6 in hand, its cross-metathesis
reactivity with 1-pentadecene was examined. Exposure of 6
to 5 equiv of pentadecene in the presence of 20 mol % of
the Grubbs generation II catalyst (A) did not provide any of
cross-coupled product 7, and an intractable mixture of
provides 10 with the natural ceramide backbone. The use of
nonene as the coupling partner produced 11, a precursor to
a known short chain ceramide analogue.19 The product 12
is an alkene thiol derivative that can undergo facile conjuga-
tion to a variety of protein or polymeric carriers and gold
surfaces or nanoparticles.20
(5) During the preparation of this manuscript, we became aware of a
report by Torssell and Somfai describing a cross metathesis approach to
sphingosines using a different five-carbon building block. See: Torssell,
S.; Somfai, P. Org. Biomol. Chem. 2004, 2, 1643-1646. A patent (WO
03/101937) by Rich and Bundle refers to olefin cross metathesis reactions
of similar structures, but reduction to practice is not disclosed in the patent.
(6) An alternative and very efficient route to the natural enantiomer of
building block I that starts with 1,2-O-isopropylidene-R-D-glucofuranose
has been reported by Rich and Bundle (WO 03/101937) and has also been
used in their synthesis of thio-linked GM3: Rich, J. R.; Bundle, D. R. Org
Lett. 2004, 6, 897-900.
We have prepared the natural product ceramide in four
steps from the coupling product 10. The Fmoc group was
(7) Mori, K.; Kinsho, T. Liebigs Ann. Chem. 1991, 1309-1315.
(8) Metz, K.; Honda, M.; Komori, T. Liebigs Ann. Chem. 1993, 55-60.
(9) He, L.; Byun, H.-S.; Bittman, R. Tetrahedron Lett. 1998, 39, 2071-
2074.
(10) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643-663.
(11) Rai, A. N.; Basu, A. Tetrahedron Lett. 2003, 44, 2267-2269.
(12) During their synthesis of sphingolipids, Nugent and Hudlicky noted
that reaction of azido aldehydes with Wittig reagents also resulted in reaction
of the ylide at the azide functionality. See: Nugent, T.; Hudlicky, T. J.
Org. Chem. 1998, 63, 510-520. We have found that careful addition of
the ylide to the aldehyde at -78 °C results in clean olefination, while higher
temperatures give rise to products derived from both olefination and reaction
at the azide.
Figure 1.
2862
Org. Lett., Vol. 6, No. 17, 2004
Rai, Anand Narain
