A concise route to D-erythro-sphingosine from N-Boc-L-serine derivatives via sulfoxide or sulfone intermediates

Article abstract of DOI:10.1016/S0040-4039(01)02145-1

Sulfoxide and sulfone intermediates 7 and 15, respectively, were employed to synthesize synthons 3 and 4, which are readily converted to the naturally occurring (2S,3R,4(E))-sphingosine 1 and (2S,3R)-sphinganine 2.

Full text of DOI:10.1016/S0040-4039(01)02145-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 375–377
A concise route to
D
-erythro-sphingosine from N-Boc- -serine
L
derivatives via sulfoxide or sulfone intermediates
Jiong Chun, Guoqing Li, Hoe-Sup Byun and Robert Bittman*
Department of Chemistry and Biochemistry, Queens College of The City University of New York, Flushing, NY 11367-1597,
USA
Received 11 September 2001; accepted 30 October 2001
Abstract—Sulfoxide and sulfone intermediates 7 and 15, respectively, were employed to synthesize synthons 3 and 4, which are
readily converted to the naturally occurring (2S,3R,4(E))-sphingosine 1 and (2S,3R)-sphinganine 2. © 2002 Elsevier Science Ltd.
All rights reserved.
Sphingolipids have been implicated in a vast variety of
physiological functions but are not readily obtained
from natural sources in homogeneous form.1 Therefore,
there is a great demand for chemical methods that
provide sphingolipids in sufficient amounts and high
chiral purity for use in biological and biochemical
studies. Since the first report of the synthesis of racemic
sphingosine in 1951,2 many different methods have
been employed for the chemical synthesis of naturally
occurring (2S,3R)-sphingosine (1a, Chart 1)3 and sphin-
ganine (2).4 However, because of the need to generate
two stereogenic centers with high stereoselectivity, as
well as an (E)ꢀC(4)ꢀC(5) double bond, most of the
synthetic procedures are quite lengthy. An efficient
four steps (two of which take place in one pot, with no
intermediate being isolated) is reported here that
involves the use of b-keto-sulfoxide or sulfone interme-
diates for CꢀC bond formation. The latter have not
been previously used for the preparation of sphin-
golipids, even though the reactions of sulfur-containing
carbanions have been used extensively in organic syn-
thesis.5 Our method provides facile access to synthon 3
from
readily obtained in only three steps from
derivative 12. It has previously been shown that syn-
thons 3 and 4 afford naturally occurring -erythro-sph-
ingosine 1a and
-erythro-sphinganine (2).6,7
L
-serine methyl ester derivative 5; synthon 4 is
L
-serinal
D
D
synthetic route to
D
-erythro-sphingosine (1a) in only
The synthesis of 1a began with the reaction of L-serine-
derived N-Boc-oxazolidine methyl ester 58 with an alkyl
phenyl sulfoxide (6) (Scheme 1). Sulfoxides 6a,b were
prepared in high yield by the reaction of thiophenol
with (a) n-pentadecyl bromide or (b) n-heptyl bromide
in the presence of Li2CO3 in DMF, followed by brief
treatment of the resulting sulfide with MCPBA in
CH2Cl2 at −78°C.9 Nucleophilic addition of the anion
of sulfoxide 6a,b (2 equiv.) to ester 5 gave sulfoxide
intermediates 7a,b,10 which were not isolated. On heat-
ing in CCl4 overnight, 7a,b afforded enones 3a,b in 36
and 50% overall yield, respectively.11
OH
OH
2
R
3
C15H31-n
HO
HO
NH2
NH2
1a R = C13H27-n
1b R = C5H11-n
2
O
O
R
C15H31-n
O
O
N
N
Boc
Boc
b-Ketosulfoxide 8 was prepared in 70% yield from 5 by
using 2 equiv. of the carbanion of methyl phenyl sulfox-
ide (Scheme 1). Attempts to carry out the C-alkylation
of 8 with long-chain alkyl halides mediated by different
bases have not been successful. When a strong base
such as NaH or t-BuOK in THF was used, O-alkyl-
ation was the major reaction, providing enol ether 9.
4
3a,b
Chart 1.
* Corresponding author. Tel.: (718) 997-3279; fax: (718) 997-3349;
e-mail: robert bittman@qc.edu
–
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02145-1

376
J. Chun et al. / Tetrahedron Letters 43 (2002) 375–377
O
O
O
R1
R
PhS(O)R (6),
CCl4
O
OCH3
Boc
O
N
N
S(O)Ph
Boc
Boc
O
LDA,
-78 °C -rt
N
reflux
3a R = C13H27-n
(36%, two steps, one pot, from 5)
3b R = C5H11-n
6a R = C15H31-n
6b R = C7H15-n
7a R1 = C14H29-n
7b R1 = C6H13-n
5
(50%, two steps, one pot, from 5)
n-C14H29
O
O
S
O
O
LDA
n-C14H29I
S
Ph
Ph
O
O
N
N
PhS(O)Me,
-78 °C
NaH or t-BuOK,
THF
Boc
Boc
(major)
9
8 (70%)
Scheme 1. Synthesis of sphingosine 1a via sulfoxide 6 and enone 3.
When a relatively weak base such as Cs2CO3 or K2CO3
in DMF or DBU in benzene was used, the yield of 7a
was low.
As depicted in Scheme 3, the preparation of synthon 4
began with N-Boc-oxazolidine
-serinal 12.8 Reaction
L
of methyl ester 5 with 2 equiv. of the anion of n-pen-
tadecyl phenyl sulfone (13)14 gave a low yield of b-keto-
sulfone 15; furthermore, it was difficult to separate
product 15 from starting sulfone 13. Therefore, sulfone
intermediate 14 was prepared by addition of the anion
of sulfone 13 to aldehyde 12. Oxidation of alcohol 14
(PCC, rt) provided b-ketosulfone 15 in 82% yield.15
Aluminum amalgam16 was used to effect the desulfonyl-
The synthesis of sphingosine from 3a was completed in
two steps. Diastereoselective reduction of 3a (NaBH4,
CeCl3, MeOH, −15°C) provided alcohol 10 in 72% yield
(Scheme 2).6,12 Hydrolysis of 10 (1 M HCl, dioxane,
100°C) afforded
D
-erythro-sphingosine (1a), which was
characterized as the triacetate derivative 11.13
OH
OAc
NaBH4
Ac2O
Py
1 M HCl
R
R
3a
1a
AcO
O
N
NHAc
CeCl3,
MeOH,
dioxane,
100 °C
10 R = C13H27-n
Boc
11
-15 °C
(72%)
Scheme 2. Conversion of enone 3a to sphingosine 1a.
O
OH
O
O
RSO2Ph (13)
R1
R1
Al(Hg)
aq. THF
PCC
H
R
O
O
O
O
N
N
SO2Ph
N
SO2Ph
Boc
n-BuLi, THF
-78°C
N
CH2Cl2
Boc
Boc
Boc
R = C15H31-n
12
15 (82% from 14)
(70% from 16)
R1 = C14H29-n
14 (50%)
R1 = C14H29-n
4 R = C15H31-n (85%)
see ref 6
R2
O
SO2Ph
O
n-C14H29
I
2
MeSO2Ph
O
5
N
DBU, C6H6
Boc
16 (71%)
n-BuLi,
THF, -78°C
O
N
Boc
3a R2 = C13H27-n
1a
Scheme 3. Synthesis of ketone 4, a precursor of 1a and 2, via b-ketosulfone 15.

J. Chun et al. / Tetrahedron Letters 43 (2002) 375–377
377
ation of b-ketosulfone 15, affording ketone 4 (85% yield),
6. Tao, J.; Hoffman, R. V. J. Org. Chem. 1998, 63, 3979–3985.
7. Koskinen, A. M. P.; Koskinen, P. M. Synlett 1993, 501–502.
which has been used to prepare enone 3a and sphinganine
2.6
8.
L
-Oxazolidine methyl ester 5 and aldehyde 12, which are
commercially available, are readily prepared from -serine:
Garner, P.; Park, J. M. Org. Synth. 1991, 70, 18–28.
L
Scheme 3 also shows that direct addition of the carbanion
derived from 2 equiv. of methyl phenyl sulfone to ester
5 gave sulfone 16,17 which was alkylated with n-tetra-
decyl iodide, providing an alternative route to b-ketosul-
fone intermediate 15.
9. Dodson, R. M.; Srinivasan, V.; Sharma, K. S.; Sauers, R.
F. J. Org. Chem. 1972, 37, 2367–2372.
10. For the formation of an b-ketosulfoxide by reaction of an
ester with an b-sulfinyl carbanion, see: Corey, E. J.;
Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1345–1353.
11. Experimental procedures for the preparation of enones
(−)-3a,b. 3a: To a solution of diisopropylamine (470 mL,
3.3 mmol) in 4 mL of dry THF was added 1.3 mL (3.3 mmol)
of n-BuLi (a 2.5 M solution in hexane,) at −15°C under
N2. After the mixture was stirred for 30 min, a solution of
phenyl sulfoxide 6a (1.0 g, 3.0 mmol) in 5 mL of THF was
addeddropwise. After30minat−15°C, thereactionmixture
was brought to −78°C and a solution of ester 5 (389 mg,
1.5 mmol) in 5 mL of THF was added slowly. The reaction
mixture was stirred at −78°C for 2 h and allowed to warm
to room temperature overnight, then quenched with satu-
rated aqueous NH4Cl solution (10 mL). The product was
extracted with EtOAc, washed with brine, and dried
(MgSO4). Concentration gave crude b-ketosulfoxide 7a,
which was dissolved in 25 mL of CCl4 and heated at reflux
for 12 h. Concentration and purification by flash chro-
matography (hexane/EtOAc, 4:1, Rf 0.80) gave 236 mg
(36%, two steps) of 3a as a colorless oil; [h]2D5 −30.0° (c 0.85,
CHCl3) (lit.6 [h]D25 −27.3° (c 0.54, CHCl3); lit.3e [h]2D0 −21.0°
(c 0.85, CHCl3)). 3b: This compound was prepared by the
procedure described above in 50% yield (two steps from
ester 5); [h]2D5 −7.4° (c 1.5, CHCl3).
In summary, the sphingoid base of the naturally occur-
ring lipids 1 and 2 has been conveniently synthesized
from the commercially available
L-serine-derived syn-
thons 5 and 12 by employing b-keto-sulfoxide and
sulfone intermediates 7 and 15. The S configuration of
the stereocenter at C-2 in products 1 and 2 is derived from
the configuration at C-2 of
reduction of enone 3 provides the requisite R configura-
tion at C-3 of -erythro-sphingosine (1), as demonstrated
L-serine. Diastereoselective
D
by the agreement of the specific rotation of triacetate
derivative 11 with literature values.13 This practical
method can be applied to the construction of sphingoid
bases containing a modified aliphatic chain.18 This
approach is well suited to the preparation of isotopically
labeled sphingoid bases derived from commercially avail-
able labeled serine.19
Acknowledgements
This work was supported by National Institutes of
Health Grant HL 16660.
12. For an example of stereoselective sulfoxide-mediated reduc-
tion of a ketone in a chiral N-Boc-oxazolidine derivative
with DIBAL-H, see: Khiar, N.; Singh, K.; Garc´ıa, M.;
Mart´ın-Lomas, M. Tetrahedron Lett. 1999, 40, 5779–5782.
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13. Triacetyl
D-erythro-sphingosine (−)-11 was obtained as a
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1
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Chem. 2000, 65, 7627–7633 and references cited therein);
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