Stereoselective synthesis of D-erythro- and L-threo-sphinganines via palladium-catalyzed equilibration and Suzuki coupling

Article abstract of DOI:10.1016/S0040-4039(02)02309-2

The Pd-catalyzed isomerization of 5-vinyloxazolines was utilized for the stereoselective synthesis of D-erythro- and L-threo-spinganine triacetate. A hydroboration/Suzuki coupling sequence was employed to elongate the hydrophobic chain.

Full text of DOI:10.1016/S0040-4039(02)02309-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9027–9029
Stereoselective synthesis of
D
-erythro- and
L
-threo-sphinganines
via palladium-catalyzed equilibration and Suzuki coupling
Gregory R. Cook* and Ketheeswaran Pararajasingham
Department of Chemistry, North Dakota State University, Fargo, ND, 58105-5516, USA
Received 2 October 2002; revised 14 October 2002; accepted 15 October 2002
Abstract—The Pd-catalyzed isomerization of 5-vinyloxazolines was utilized for the stereoselective synthesis of
D-erythro- and
L
-threo-spinganine triacetate. A hydroboration/Suzuki coupling sequence was employed to elongate the hydrophobic chain.
© 2002 Elsevier Science Ltd. All rights reserved.
Sphingolipids such as sphingosine 1 and the saturated
derivative sphinganine 2 are important constituents of
cellular membranes and play a critical role in many
physiological processes including modulation of
immune response, signaling and cell recognition.1 As
such, they have been the targets of intense interest for
synthetic chemists due to the lack of readily available
natural sources.2,3 Key to the preparation of these
compounds is the stereoselective construction of the
aminodiol portion of the molecule. We have recently
developed methodology for the synthesis of vicinal
aminoalcohols via a palladium-catalyzed isomerization
of 5-vinyloxazolines.4 We thought application of this
methodology to serine derivatives with the lipid chain
attached would offer a concise route to sphingolipids.
one face to the other. With unsubstituted vinyl deriva-
tives, allyl isomerization occurs readily and efficiently
via a p-s-p equilibration of the intermediate palladium
allyl complex, however, for the isomerization of more
substituted derivatives the issues are more complex
(Scheme 2). A p-s-p isomerization of a disubstituted
allyl complex would result in a change of olefin geome-
try concomitant with a change in the stereochemistry of
the oxazoline ring. Thus, this mechanism would allow
equilibration of 5 and 6 or 7 and 8, but would not allow
equilibration of all four stereoisomers. In order for all
isomers to equilibrate an alternative mechanism, nucle-
ophilic displacement by a second Pd atom, must occur.
As both mechanisms have established precedence in
Pd-catalyzed allylic substitution reactions,5 we exam-
ined this route for the synthesis of 1 with the anticipa-
tion that all four stereoisomers would equilibrate to the
favored trans, E isomer 7.
The results of our study and the preparation of
D
-ery-
thro- and
L-threo-sphinganine are presented in this
letter.
Model compounds 5, 6, 7, and 8, (R=CH2OTBS,
R%=n-Bu) were prepared from
L-serine and indepen-
dently subjected to the Pd-catalyzed equilibration con-
ditions. To our disappointment, we found no evidence
Our initial strategy for the synthesis of sphingolipids is
outlined in Scheme 1. We envisioned a Pd-catalyzed
ring-opening ring-closing sequence to afford the 5-vinyl-
oxazoline 3 with high stereoselectivity. The oxazolidi-
none 4 would derive from L-serine. The metal-catalyzed
diastereomeric equilibration of 3 would require the
isomerization of the intermediate Pd-allyl complex from
* Corresponding author. Tel.: 701-231-7413; fax: 701-231-1057;
e-mail: gregory.cook@ndsu.nodak.edu
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02309-2

9028
G. R. Cook, K. Pararajasingham / Tetrahedron Letters 43 (2002) 9027–9029
Scheme 2.
for the Pd-displacement mechanism with these sub-
strates after exploring a large variety of catalysts, lig-
ands, and solvents. Oxazolines 5 or 6 were readily
equilibrated to a near equal mixture (1.3:1), and 7 or 8
equilibrated to give the thermodynamically favored 7
(99:1), however, there was no equilibration of 5 or 6
with 7 or 8. Thus, the direct preparation of sphingosi-
nes with the lipid chain attached was not attainable. We
therefore focused our efforts toward utilizing an unsub-
stituted substrate that avoids the problem of olefin
isomers, and explored methods to elongate the aliphatic
chain after isomerization. We have previously shown
that chain extension of 5-vinyloxazolines could be
alcohol onto the BOC group with the assistance of
sodium hydride followed by acylation gave 11 with the
same isomer ratio. Treatment with a palladium(0) cata-
lyst in acetonitrile provided predominantly the trans-
oxazoline 12 in 90% isolated yield. Contrary to
aminoalcohol 10, the oxazoline diastereomers were
readily separated by silica gel chromatography to
afford the pure trans diastereomer. The minor
diastereomer could be recycled simply by subjecting it
once again to the conditions of the Pd-catalyzed iso-
merization to offer the same 91:9 mixture of trans to cis
oxazolines. Accordingly, efficiency in the preparation of
the trans isomer could be improved, particularly when
carrying out the chemistry on larger scale.
accomplished by
a hydroboration/Suzuki coupling
sequence4c and we pursued this avenue toward the
synthesis of sphinganines.
Completion of the synthesis is outlined in Scheme 4.
Hydroboration of trans-12 with 9-BBN was followed
by Suzuki coupling with Z-1-bromo-1-tridecene9 to
afford the extended oxazoline 13. Hydrogenation of the
olefin and hydrolysis under acidic conditions afforded
The synthesis of both
nine began with the protected
D
-erythro- and
L-threo-sphinga-
L
-serine derivative 9
(Scheme 3). Diisobutylaluminum hydride reduction fol-
lowed by the addition of vinylmagnesium bromide
afforded the aminoalcohol derivative 106 as a mixture
of diastereomers (syn:anti, 60:40).7,8 Cyclization of the
D
-erythro-sphinganine, which was converted into the
known triacetate derivative 1410 for ease of purification
and characterization. The -threo-isomer was readily
L
obtained from cis-12 by the analogous synthetic
sequence. As cis-12 was attained in only small amounts
in the Pd-catalyzed isomerization reaction, a prepara-
tion from the trans isomer was developed. Partial
hydrolysis of trans-12 afforded the N-benzoylaminodiol
derivative. The primary alcohol was reprotected with
TBSCl and imidazole. Finally the cis-12 oxazoline ring
was formed in quantitative yield by activation of the
secondary alcohol as the mesylate and SN2 displace-
ment by the amide carbonyl.
In conclusion, we have demonstrated the facile synthe-
sis of both D-erythro- and L-threo-sphinganine from the
same intermediate 5-vinyloxazoline prepared via a Pd-
catalyzed isomerization and subsequent Suzuki cou-
pling. Access to the
would be attainable in an analogous fashion starting
from -serine.
L-erythro- and D-threo-isomers
Scheme 3. Reagents and conditions: (a) DIBAL-H, Tol,
−78°C (82%); (b) vinylmagnesium bromide, THF (59%); (c)
NaH, THF, PhCOCl (60%); (d) Pd(PPh3)4, CH3CN (90%).
D

G. R. Cook, K. Pararajasingham / Tetrahedron Letters 43 (2002) 9027–9029
9029
Scheme 4. Reagents and conditions: (a) 9-BBN, THF, Pd(PPh3)4, Z-1-bromo-tridecene, NaOH, THF (62%); (b) H2, Pd/C, EtOAc
(89%); (c) 2N HCl, THF, NaOH (59%); (d) Ac2O, pyr. (58%); (e) 2N HCl, THF (77%); (f) TBSCl, imidazole (70%); (g) MeSO2Cl,
Et3N (99%); (h) 9-BBN, THF, Pd(PPh3)4, Z-1-bromo-tridecene, NaOH, THF (52%); (i) H2, Pd/C, EtOAc (86%); (j) 2N HCl,
THF, NaOH (66%); (k) Ac2O, pyr. (71%).
Acknowledgements
10, 4797–4802; (g) Villard, R.; Fotiadu, F.; Buono, G.
Tetrahedron: Asymmetry 1998, 9, 607–611; (h) Hoffman,
R. V.; Tao, J. J. Org. Chem. 1998, 63, 3979–3985.
4. (a) Cook, G. R.; Shanker, P. S. Tetrahedron Lett. 1998,
39, 3405–3408; (b) Cook, G. R.; Shanker, P. S.; Peterson,
S. L. Org. Lett. 1999, 1, 615–617; (c) Cook, G. R.;
Shanker, P. S. J. Org. Chem. 2001, 66, 6818–6822.
5. Granberg, K. L.; Ba¨ckvall, J.-E. J. Am. Chem. Soc. 1992,
114, 6858–6863.
We are grateful to the National Science Foundation
(CAREER Award 9875013) for financial support of
this work.
References
6. All compounds displayed satisfactory spectroscopic
(NMR, IR) and analytical data (combustion analysis or
HRMS) consistent with their structure.
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1
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