analyses showed a significant racemization (ca. 20%) of
product 8. Assuming that an intramolecular hydrogen bond-
ing interaction of the 1-O(H)‚‚‚HNBoc portion of serine
thiophenyl ester 7 may decrease the nucleophility of the
1-OH,10 DMAP was added and DMF was used as the solvent
to achieve a higher rate of silylation. Although significantly
improved, 2% racemization could not be avoided under these
reaction conditions. Finally, employing N-methyl morpholine
rather than triethylamine furnished the requisite silylated
product 8 in less than 30 min without racemization (ee
>99%).
Scheme 3 O-Functionalized Derivativesa
The subsequent cross-coupling of thiol ester 8 and boronic
acid 5 delivered peptidyl ketone 9 in high yield (94%). HPLC
analyses demonstrated that high enantiopurity (ee >99%)
was maintained and no E/Z isomerization of the R,â-
unsaturated ketone was observed throughout the course of
the reaction and the workup procedure.
a All starting material stereoprofiles were conserved in the
products
Following the reported method,16 selective phosphorylation
of the 1-OH group of 11 with P(OMe)3/CBr4/pyridine
followed by deprotection of the resulting phosphate ester with
a TMSBr-mediated cleavage gives sphingosine-1-phosphate
(S1P) in 62% yield.
In seeking a method for the asymmetric reduction of enone
9, desilylation of 9 (HCl in MeOH/H2O) generated the
alcohol 12, which was used to carry out a diastereoselective
chelation-controlled reduction of the ketone by using
Et2BOMe/NaBH4.11 The resulting N-protected R-amino
alcohol 11 was produced with very good anti selectivity
(anti:syn > 93:7). However, 1% racemization had occurred
during the desilylation of 9 with HCl and the racemization
was exacerbated by using TBAF for the desilylation. To
avoid racemization, the ketone reduction was performed
before the desilylation step. Excellent anti diastereoselective
reduction (>97:3)12 of 9 was observed by employing LiAl-
(tert-butoxy)3H in ethanol13 at -78 °C giving alcohol 10 in
96% yield. Subsequent desilylation of 10 produced diol 11
in 99% yield and >94% diastereomeric purity (1H NMR).
HPLC and LC-MS showed high enantiopurity for each of
the diastereomers (ee >99%).14 A simple recrystallization
from isopropyl ether/hexane (1:1) improved the diastereo-
meric purity of 11 to 99%. A final N-deprotection with TFA
yielded (-)-D-erythro-sphingosine15 in 90% yield without
epimerization.
In summary, a concise total synthesis (6 steps, 71% overall
yield from N-Boc-L-serine) of high enantiopurity (-)-D-
erythro-sphingosine and sphingosine-1-phosphate has been
achieved by using a key thiol ester and boronic acid cross-
coupling for the critical bond-forming step.17 This method
not only establishes a rapid, mild, and efficient synthesis of
sphingosine, but also provides a powerful tool for rapidly
building a family of sphingosine-related lipids. Future work
will demonstrate the versatility of the thiol ester-boronic
coupling for the construction of various amino acid-derived
sphingosine analogues.
Acknowledgment. The National Institutes of General
Medical Sciences, DHHS supported this investigation through
grant No. GM066153. We thank Dr. Paul Reider of Amgen
for his support of our work and Dr. Gary Allred of Synthonix
for providing boronic acids for our studies.
Extension of this synthesis of D-erythro-sphingosine will
give easy access to hundreds of sphingolipid related natural
products. Note, for example, that this mild cross-coupling
method shows a high tolerance for phosphate (Scheme 3,
13 f 14) and glycoside functionality (Scheme 3, 15 f 16)
attached to the 1-hydroxyl of the serine thiol ester.
Supporting Information Available: Complete descrip-
tion of experimental details and product characterization and
photocopies of spectra. This material is available free of
(10) Szabo, L.; Li, Y.; Polt, R. Tetrahedron Lett. 1991, 32, 585-588.
(11) Chen, K. M.; Hardtmann, G.; Prasad, K.; Repic, O.; Shapiro, M. J.
Tetrahedron Lett. 1987, 28, 155-158.
OL070991M
1
(12) Ratio was determined by H NMR.
(13) Hoffman, R. V.; Najib, M.; Cervantes-Lee, F. J. Org. Chem. 2002,
67, 1045-1056.
(14) LC-MS showed 4 isomers of 11 with the same mass weight based
on the synthetic route with a racemic mixture of 9.
(15) (-)-D-erythro-Sphingosine was characterized as its triacetate deriva-
tive. See the Supporting Information.
(16) (a) Szulc, Z. M.; Hannun, Y. A.; Bielawska, A. Tetrahedron Lett.
2000, 41, 7821-7824. (b) Murakami, T.; Furusawa, K.; Tamai, T.;
Yoshikaib, K.; Nishikawa, M. Bioorg. Med. Chem. Lett. 2005, 15, 1115-
1119.
(17) Yang, H.; Liebeskind, L. S. U.S. Prov. Patent Appl. 60/842,624,
September 6, 2006.
Org. Lett., Vol. 9, No. 16, 2007
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