Enantiodivergent synthesis of D- and L-erythro-sphingosines through Mannich-type reactions of N-benzyl-2,3-O-isopropylidene-D-glyceraldehyde nitrone

Article abstract of DOI:10.1021/jo060465t

The addition of a 2-silyloxy silylketene acetal to N-benzyl-2,3-O- isopropylidene-D-glyceraldehyde nitrone (Mannich-type reaction) can be stereocontrolled to give 2S,3S,4S and 2R,3R,4S adducts as major compounds, depending on whether the reaction is activated with zinc(II) triflate or tin-(IV) chloride, respectively. The corresponding major adducts were used for preparing diastereomeric polyhydroxy-β-aminoesters that were further converted into suitable orthogonally protected enantiomeric D- and L-erythro-sphingosines.

Full text of DOI:10.1021/jo060465t

reported during the past years. Of particular interest is the
addition of 2-silyloxy silylketene acetals B, because two adjacent
stereogenic centers are created simultaneously and R-silyloxy-
â-amino acids C are obtained6 (eq 1).
Enantiodivergent Synthesis of D- and
L-erythro-Sphingosines through
Mannich-Type Reactions of
N-Benzyl-2,3-O-isopropylidene-D-glyceraldehyde
Nitrone
Pedro Merino,* Pablo Jimenez, and Tomas Tejero
Laboratorio de Sintesis Asimetrica, Departamento de Quimica
Organica, Instituto de Ciencia de Materiales de Aragon,
UniVersidad de Zaragoza, CSIC, E-50009 Zaragoza,
Aragon, Spain
Among the CdN functionalities A that can be used in
Mannich-type reactions, nitrones offer some advantages. In
addition to their high reactive CdN bond, nitrones possess a
reactive oxygen atom, which allows the use of Lewis acids to
modulate the reactivity. In this respect, Mannich-type reactions
are rather suitable to be studied with nitrones, because those
processes need to be activated by a Lewis acid. We have already
reported6 the stereocontrolled addition of unsubstituted silyl
ketene acetals to D-glyceraldehyde-derived nitrone 1 en route
to a new class of nucleoside analogues. Nitrone 1 has demon-
strated to be an excellent equivalent of several chiral units
containing both amino and oxygen functionalities.7 On the basis
of these results, we describe herein the stereocontrolled addition
of a 2-silyloxy silylketene acetal to nitrone 1 en route to
pmerino@unizar.es
ReceiVed March 3, 2006
(2) For some recent and representative examples, see: (a) Akiyama, T.;
Suzuki, A.; Fuchibe, K. Synlett 2005, 1024-1026. (b) Jaber, N.; Assie,
M.; Fiaud, J.-C.; Collin, J. Tetrahedron 2004, 60, 3075-3084. (c) Bari, L.
D.; Guillarme, S.; Hermitage, S.; Howard, J. A.; Jay, D. A.; Pescitelli, G.;
Whiting, A.; Yufit, D. S. Synlett 2004, 708-710. (d) Jacobsen, M. F.;
Skrydstrup, T. J. Org. Chem. 2003, 68, 7112-7114. (e) Saaby, S.; Nakama,
K.; Lie, M. A.; Hazel, R. G.; Jorgensen, K. A. Chem.sEur. J. 2003, 9,
6145-6154. (f) Ishimaru, K.; Kojima, T. J. Org. Chem. 2003, 68, 4959-
4962. (g) Kobayashi, S.; Matsubara, R.; Nakamura, Y.; Kitagawa, H.;
Sugiura, M. J. Am. Chem. Soc. 2003, 125, 2507-2515. (h) Nagano, Y.;
Orita, A.; Otera, J. Tetrahedron 2003, 59, 5569-5578. (i) Ueno, M.; Ishitani,
H.; Kobayashi, S. Org. Lett. 2002, 4, 3395-3397. (j) Wenzel, A. G.;
Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964-12965. (k) Kobayashi,
S.; Kobayashi, J.; Ishiani, H.; Ueno, M. Chem.sEur. J. 2002, 8, 4185-
4190.
(3) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. Tetrahedron Lett. 2003,
44, 2817-2820. (b) Murahashi, S.-I.; Imada, Y.; Kawakami, T.; Harada,
K.; Yonemushi, Y.; Tomita, N. J. Am. Chem. Soc. 2002, 124, 2888-2889.
(c) Qian, C.; Wang, L. Tetrahedron 2000, 56, 7193-7197. (d) Kawakami,
T.; Ohtake, H.; Arakawa, H.; Okachi, T.; Imada, Y.; Murahashi, S.-I. Bull.
Chem. Soc. Jpn. 2000, 73, 2423-2444. (e) Ohtake, H.; Imada, Y.;
Murahashi, S.-I. J. Org. Chem. 1999, 64, 3790-3791. (f) Jost, S.; Gimbert,
Y.; Greene, A. E. J. Org. Chem. 1997, 62, 6672-6677. (g) DeGiorgis, F.;
Lombardo, M.; Trombini, C. Synthesis 1987, 1243-1245. (h) Kita, Y.;
Tamura, O.; Itoh, F.; Kishino, N.; Miki, T.; Kohno, M.; Tamura, Y. Chem.
Pharm. Bull. 1989, 37, 2002-2007.
(4) (a) Diez, E.; Prieto, A.; Simon, M.; Vazquez, J.; Alvarez, E.;
Fernandez, R.; Lassaletta, J. M. Synthesis 2006, 540-550. (b) Jacobsen,
M. F.; Ionita, L.; Skrydstrup T. J. Org. Chem. 2004, 69, 4792-4796. (c)
El-Kaim, L.; Grimaud, L.; Perroux, Y.; Tirla, C. J. Org. Chem. 2003, 68,
8733-8735. (d) Atlan, V.; Bienayme, H.; El-Kaim, L.; Majee, A. Chem.
Commun. 2000, 1585-1586. (e) Manabe, K.; Oyamada, H.; Sugita, K.;
Kobayashi, S. J. Org. Chem. 1999, 64, 8054-8057.
(5) (a) Ullah, E.; Rotzoll, S.; Schmidt, A.; Michalik, D.; Langer, P.
Tetrahedron Lett. 2005, 46, 8997-8999. (a) Ha, H.-J.; Ahn, Y.-G.; Lee,
G. S. Tetrahedron: Asymmetry 1999, 10, 2327-2336. (b) Ha, H. J.; Choi,
C. J.; Lee, W. K. Synth. Commun. 2002, 32, 1495-1500. (c) Saito, S.;
Uedo, E.; Kato, Y.; Murakami, Y.; Ishikawa, T. Synlett 1996, 1103-1104.
(6) Merino, P.; Alamo, E. M.; Bona, M.; Franco, S.; Merchan, F. L.;
Tejero, T.; Vieceli, O. Tetrahedron Lett. 2000, 41, 9239-9243.
(7) For an account, see: Merino, P.; Franco, S.; Merchan, F. L. Synlett
2000, 442-454.
The addition of a 2-silyloxy silylketene acetal to N-benzyl-
2,3-O-isopropylidene-D-glyceraldehyde nitrone (Mannich-
type reaction) can be stereocontrolled to give 2S,3S,4S and
2R,3R,4S adducts as major compounds, depending on
whether the reaction is activated with zinc(II) triflate or tin-
(IV) chloride, respectively. The corresponding major adducts
were used for preparing diastereomeric polyhydroxy-â-
aminoesters that were further converted into suitable or-
thogonally protected enantiomeric D- and L-erythro-sphin-
gosines.
Stereoselective nucleophilic additions of enolates to imines
and related compounds (the so-called Mannich-type reactions)
are used extensively for the asymmetric synthesis of a broad
range of â-amino carbonyl derivatives, which are useful as chiral
auxiliaries, ligands, and building blocks for the preparation of
various nitrogen-containing biologically active compounds.1
Several examples concerning the Lewis-acid promoted addition
of silylketene acetals to CdN double bonds A, including
imines,2 nitrones,3 hydrazones,4 and iminium salts,5 have been
* To whom correspondence should be addressed. Phone and fax: +34 976
762075.
(1) (a) Co´rdova, A. Acc. Chem. Res. 2004, 37, 102-112. (b) Arend,
M.; Westermann, B.; Rich, N. Angew. Chem., Int. Ed. 1998, 37, 1045-
1070. (c) Kleinman, E. F. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford. 1991; Vol. 2, pp 893-
951. (d) Arend, M.; Wang, X.; Wirth, T. In Organic Synthesis Highlights
V; Schmalz, H.-G., Ed.; Wiley-VCH Verlag: Weinheim, Germany, 2003;
pp 134-143. (e) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991-8035.
(f) Burk, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221-3242.
10.1021/jo060465t CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/13/2006
J. Org. Chem. 2006, 71, 4685-4688
4685

TABLE 1. Addition of Silylketene Acetal 2 to Nitrone 1a
entry
Lewis acid
equiv
time (h)
3:4b
4a:4b:4c:4dc
(3S,4S)/(3R,4S)d
anti/syne
yieldf (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
TMSOTf
ZnBr2
ZnBr2
Et2AlCl
Et2AlCl
AlCl3
1.0
1.0
0.2
1.0
0.2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.2
1.0
1.0
0.2
3
3
3
3
6
3
3
3
3
3
3
2
2
3
3
3
100:0
100:0
100:0
0:100
0:100
30:70
0:100
60:40
100:0
100:0
90:10
100:0
100:0
75:25
70:30
70:30
92:1:1:6
89:2:3:6
86:2:4:8
94:0:3:3
90:2:5:3
88:3:6:3
98:0:2:0
81:1:14:4
81:4:10:5
98:0:2:0
95:1:4:0
97:0:3:0
97:0:3:0
35:47:6:12
7:85:3:5
20:72:3:5
93:7
92:8
90:10
97:3
90:10
94:6
100:0
95:5
91:9
100:0
99:1
100:0
100:0
41:59
10:90
23:77
93:7
91:9
88:12
94:6
92:8
91:9
98:2
82:18
85:15
98:2
96:4
97:3
97:3
82:18
92:8
92:8
80
76
78
68
35
60
55
66
80
84
86
89
86
82
84
30
SnCl2
Cu(OTf)2
Sc(OTf)3
Yb(OTf)3
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
g
g
SnCl4
SnCl4
SnCl4
g
g
a The reaction was carried out in dichloromethane at -78 °C. b Determined by NMR of the crude reaction mixture. c Determined by NMR after desilylation
of the reaction mixture, when necessary. d Referred to the diastereofacial selectivity, induced by the stereocenter at C-4. e Referred to the relative configuration
between the two newly formed stereocenters at C-2 and C-3. f Referred to isolated yields of 3 + 4. g The reaction was conducted in the presence of 4-Å
molecular sieves.
SCHEME 1. Mannich-Type Reaction between 1 and 2
polyhydroxy-â-amino acids. We further describe the use of the
obtained products for the enantiodivergent synthesis of orthogo-
nally protected D- and L-erythro-sphingosines.8
We studied the Mannich-type reaction of the readily available9
nitrone 1 and silyl ketene acetal 2.10 We chose derivative 2
because it is easily synthesized from methyl glycolate, it is
configurationally stable, and it bears two different silyl groups,
facilitating further elaborations. The corresponding Z-isomer
cannot be obtained with good stereoselectivity, and only an
unuseful derivative with two TBS groups (which would give
rise to nonorthogonally protected derivatives) can be prepared
in the Z configuration with good yields.
In a typical experimental procedure, nitrone 1 in dichlo-
romethane was stirred at -78 °C with silyl ketene acetal 2 and
in the presence of a Lewis acid. Yields, product distribution,
and Lewis acids are collected in Table 1. Depending on the
Lewis acid used to promote the reaction, O-silyl hydroxylamines
3 and free hydroxylamines 4 were obtained. The formation of
four diastereoisomers is possible on the addition of 2 to 1.
Whereas TMSOTf (entry 1) and Zn-derived Lewis acids (entries
2, 3, 9, 11-13) only afforded O-silyl hydroxylamines 3, the
rest of Lewis acids produced either free hydroxylamines (en-
tries 4, 5, 7, and 10) or mixtures of compounds (entries 6, 8,
14-16). From a synthetic point of view and to analyze the
stereoselectivity of the reaction, it was convenient to treat the
reaction mixture with citric acid in methanol to obtain free
hydroxylamines 4 (Scheme 1). Under these conditions, only
trimethylsilyl groups are removed. The addition reaction was
carried out with 1.0 equiv of Lewis acid, although catalytic
amounts can be used in those cases in which O-silylated
hydroxylamines are obtained (entries 3 and 13). On the other
hand, in those cases in which compounds 4 were the main
products of the reaction, the yield dropped considerably under
catalytic conditions (entries 5 and 16), presumably because the
Lewis acid promotes the desilylation and, consequently, the
catalyst is eliminated from the reaction mixture.
The diastereoselectivities are reasonably good, with the
2S,3S,4S isomer 4a being the major product after desilylation.
Excellent diastereofacial inductions exerted by the dioxo-
lane ring (corresponding to a (4a + 4c)/(4b + 4d) ratio) were
obtained with SnCl2 (entry 7), Yb(OTf)3 (entry 10), and
Zn(OTf)2 (entry 11). In the last case, better results were obtained
when the reaction was conducted in the presence of molecular
sieves (entry 12). Moreover, the use of 20 mol % of Lewis acid
(entry 12) did not lead to loss of selectivity or chemical yield.
(8) For other recent approaches to erythro-sphingosines, see: (a) Masuda,
Y.; Mori, K. Eur. J. Org. Chem. 2005, 4789-4800. (b) Lim, H.-S.; Park,
J.-J.; Kwangseok, K.; Lee, M.-H.; Chung, S.-K. Bioorg. Med. Chem. Lett.
2004, 14, 2499-2503. (c) Raghavan, S.; Rajender, A. J. Org. Chem. 2003,
68, 7094-7097. (d) Lim, H.-S.; Oh, Y.-S.; Suh, P.-G.; Chung, S.-K. Bioorg.
Med. Chem. Lett. 2003, 13, 237-240. (e) Lee, J.-M.; Lim, H.-S.; Chung,
S.-K. Tetrahedron: Asymmetry 2002, 13, 343-347. (f) Murakami, T.;
Furusawa, K. Tetrahedron 2002, 58, 9257-9263. (g) Nakamura, T.;
Shiozaki, M. Tetrahedron 2001, 57, 9087-9092. (h) Duffin, G. R.; Ellames,
G. J.; Hartmann, S.; Herbert, J.; Smith, D. I. J. Chem. Soc., Perkin Trans.
1 2000, 2237-2242.
(9) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. Tetrahedron:
Asymmetry 1997, 8, 3489-3496.
(10) (a) Hamura, T.; Yamaguchi, H.; Kuriyama, Y.; Tanabe, M.;
Miyamoto, M.; Yasui, Y.; Matsumoto, T.; Suzuki, K. HelV. Chim. Acta
2002, 85, 3589-3604. (b) Hattori, K.; Yamamoto, H. Tetrahedron 1994,
50, 3099-3112. (c) Hattori, K.; Yamamoto, H. J. Org. Chem. 1993, 58,
5301-5303.
4686 J. Org. Chem., Vol. 71, No. 12, 2006

SCHEME 2. Synthesis of Sphingosines
Interestingly, when SnCl4 was used as Lewis acid (entry 14), a
dramatic change on the products distribution was observed, with
a slight reversal of the diastereofacial selectivity being found.
Moreover, such a reversal increased considerably by the addition
of molecular sieves to the reaction mixture (entry 15). Under
these conditions, the 3R,4S isomers were obtained preferentially,
with the stereofacial selectivity being 90:10. Unfortunately,
SnCl4 could not be used in a catalytic amount, due to the reasons
given above. In all cases, the two newly formed stereogenic
centers adopted an anti relative configuration corresponding to
2R,3R and 2S,3S isomers 4a and 4b, respectively. Because of
it, only those major compounds were fully characterized and
further used in the synthesis of sphingosines. The configurational
assignment of compounds 4a and 4b was established by
converting them into derivatives of known absolute configura-
tions, as will be subsequently discussed. The stereochemical
course of the reaction can be explained on the basis of alternative
mechanisms, as we have previously reported.11 According to
these findings, the reaction promoted by Lewis acids such as
Zn(OTf)2 is better described as a nucleophilic addition stepwise
process. On the other hand, the reaction promoted by Lewis
acids forming more covalent interactions with the nitrone oxygen
(such as SnCl4) could be assigned to a polar concerted 1,3-
dipolar cycloaddition.12
transformation of the dioxolane ring into a hydroxymethyl
group13 afforded the orthogonally protected D-erythro-sphin-
gosine 10 (61.5% overall yield from 4a, 6 steps). The con-
figurational assignment of compound 10 was made by its con-
version to N-Boc-D-erythro-sphingosine 11 and by a comparison
of the obtained product with that described in the literature,8c
as well as by deprotecting 11 to D-erythro-sphingosine 12 and
comparison of the obtained compound with an authentic sample.
In both cases, the physical and spectroscopic properties of the
obtained compounds were fully consistent with those reported.
Following the same reaction sequence illustrated in Scheme
2, the major compound 4b, obtained when SnCl4 was used as
a promoter, was transformed into the enantiomeric protected
L-erythro-sphingosine ent-10 (see Supporting Information).
Complete deprotection of this compound afforded pure
L-erythro-sphingosine ent-12, which served to further confirm
the configurational assignments previously made.
In conclusion, we have achieved a stereodivergent Mannich-
type reaction between nitrone 1 and R-alkoxysilyl ketene acetal
2, which provided efficient routes to enantiomerically pure
polyhydroxy-â-amino acids. In addition, further elaboration of
these compounds allowed us to apply that diastereodivergent
approach to the enantiodivergent preparation of orthogonally
protected D- and L-erythro-sphingosines 10 and ent-10 in 53.1
and 40.5% overall yields (7 steps from nitrone 1), respectively,
thus showing a high efficiency relative to prior syntheses.8
Compounds 10 and ent-10 are of synthetic utility for the
preparation of more complex compounds such as ceramides,8a,14
glycosphingolipids,8h,15 or phosphorylated derivatives.8b,d At
Compound 4a was readily transformed into protected â-amino-
R-hydroxy ester 5 in a very efficient way by catalytic hydro-
genation in the presence of Boc2O. Compound 5 was reduced
to aldehyde 6, which was used in the next step without further
purification. A Schlosser modification of the Wittig condensation
between 6 and phosphorane 7 afforded alkene 8 in 88% isolated
yield and as an only E-isomer. The well-known two-step
(13) For examples of the equivalence between the dioxolane ring and
the hydroxymethyl group, see: Chiacchio, U.; Borrello, L.; Iannazzo, D.;
Merino, P.; Piperno, A.; Rescifina, A.; Richichi, B.; Romeo, G. Tetrahe-
dron: Asymmetry 2003, 14, 2419-2425 and references therein.
(14) Yin, J.; Liu, H.; Pidgeon, C. Bioorg. Med. Chem. Lett. 1998, 8,
179-182.
(11) Merino, P.; Mates, J. A. ARKIVOC 2001, part xi, BT181-D.
(12) Recent studies based on NMR data of the corresponding complexes
have demonstrated that nitrones act as monodentate ligands with Lewis
acids: Merino, P.; Tejero, T. Unpublished results. See also ref 7.
J. Org. Chem, Vol. 71, No. 12, 2006 4687

9.57 (d, 1H, J ) 2.9 Hz)) which was taken up in MeOH (15 mL),
cooled to 0 °C, and treated with NaBH4 (56 mg, 1.5 mmol). After
stirring at 0 °C for 1 h, the reaction mixture was treated with
saturated aq NaHCO3 (25 mL) and EtOAc (30 mL). The organic
layer was separated, and the aqueous layer was extracted with
EtOAc (2 × 15 mL). The combined organic extracts were dried
(MgSO4), filtered, washed with brine (25 mL), and evaporated under
reduced pressure. The crude product was purified by radial
chromatography (hexane/EtOAc, 75:25) to give pure 10 (0.269 g,
76% from 8) as an oil: [R]22D -7.7 (c 0.5, CHCl3); 1H NMR (400
MHz, CDCl3) δH 0.08 (s, 6H), 0.79-0.96 (m, 12H), 1.17-1.41
(m, 22H), 1.44 (s, 9H), 2.01-2.14 (m, 2H), 2.77 (br s, 1H), 3.57-
3.70 (m, 1H), 3.77 (dd, 1H, J ) 5.7, 11.0 Hz), 3.96 (dd, 1H, J )
1.1, 11.0 Hz), 4.40 (d, 1H, J ) 6.1 Hz), 4.90 (d, 1H, J ) 8.1 Hz),
5.48 (m, 1H), 5.73-5.88 (m, 1H). 13C NMR (100 MHz, CDCl3)
δC -4.1, 14.3, 18.0, 22.9, 25.0, 28.6, 29.2, 29.3, 29.3, 29.7, 29.7,
30.4, 31.1, 32.7, 56.8, 64.9, 72.9, 76.6, 77.0, 77.4, 80.9, 131.1,
133.5, 156.4. Anal. Calcd for C29H59NO4Si: C, 67.78; H, 11.57;
N, 2.73. Found: C, 67.89; H, 11.77; N, 2.53.
tert-Butyl (2S,3R,E)-1,3-Dihydroxyoctadec-4-en-2-ylcarbam-
ate 11. A solution of 10 (50 mg, 0.1 mmol) in THF (5 mL) was
treated with a 1.0 M anhydrous solution of Bu4NF in THF (0.15
mL, 0.15 mmol) at ambient temperature. After 1 h of stirring, the
reaction mixture was diluted with saturated aq NaHCO3 (15 mL)
and extracted with EtOAc (2 × 15 mL). The combined organic
extracts were washed with brine, dried (MgSO4), filtered, and
evaporated under reduced pressure to give a crude product that was
purified by radial chromatography (hexane/EtOAc, 80:20) to give
pure 11 (36 mg, 92%) as a white solid: mp 64-66 °C; [R]25D -1
(c 0.12, CHCl3) [lit.10g [R]24D -1.4 (c 1.0, CHCl3)]; 1H NMR (400
MHz, CDCl3) δH 0.90 (t, 3H, J ) 6.6 Hz), 1.12-1.42 (m, 22H),
1.46 (s, 9H), 2.00-2.15 (m, 2H), 2.60 (br s, 2H), 3.56-3.63 (m,
2H), 3.78 (dd, 1H, J ) 11.0, 3.6 Hz), 4.30 (t, 1H, J ) 4.2 Hz),
5.26 (br s, 1H), 5.50 (ddt, 1H, J ) 0.9, 5.2, 15.8 Hz), 5.80 (dd,
1H, J ) 5.4, 15.8 Hz). 13C NMR (100 MHz, CDCl3) δC 14.0, 22.9,
28.5, 29.1, 29.2, 29.3, 29.4, 29.6(2C), 32.0, 32.3,55.9, 62.6, 75.0,
79.8, 128.9, 134.0,156.5. Anal. Calcd for C23H45NO4: C, 69.13;
H, 11.35; N, 3.51. Found: C, 69.27; H, 11.18; N, 3.39.
present, we are studying Mannich-type reactions of 2-silyloxy
silyl ketene acetals with other chiral nonracemic nitrones.
Experimental Section
General Methods. For general experimental information see,
ref 16. Nitrone 19 and silyl ketene acetal 210 were prepared as
described.
Reaction between Nitrone 1 and Silyl Ketene Acetal 2. A 50-
mL round-bottomed flask was charged, under an argon atmosphere,
with 3-Å activated molecular sieves (200 mg), nitrone 1 (0.587 g,
2.5 mmol), and anhydrous dichloromethane (15 mL). The resulting
mixture was cooled to 0 °C, and then a solution of the corresponding
Lewis acid (see Table 1) in anhydrous dichloromethane (5 mL)
was added dropwise. After 10 min of stirring, the mixture was
cooled to -78 °C, and a solution of silyl ketene acetal 2 (1.39 g,
5 mmol) in dichloromethane (5 mL) was added slowly over 10
min. When the reaction was finished (see Table 1), aq saturated
NaHCO3 (10 mL) was added under vigorous stirring, and the
reaction mixture was allowed to reach room temperature. The
organic phase was separated, and the aqueous one was extracted
with EtOAc (2 × 15 mL). The combined organic extracts were
filtered through a pad of Celite, washed with brine (40 mL), dried
over anhydrous MgSO4, and concentrated under reduced pressure.
The crude product was purified by silica gel chromatography
(hexane/EtOAc, 95:5) to yield the pure products (data for com-
pounds 3 and 4: see Supporting Information).
tert-Butyl (2S,3S,4R,E)-2-(tert-Butyldimethylsiloxy)-1,2-dihy-
droxynonadec-4-en-2-ylcarbamate 9. A solution of alkene 8 (0.4
g, 0.69 mmol) in MeOH (30 mL) was treated with p-toluenesulfonic
acid monohydrate (19 mg, 0.1 mmol), and the resulting solution
was heated at 50 °C for 4 h, at which time saturated aq NaHCO3
(39 mL) was added. The resulting mixture was extracted with ethyl
acetate (2 × 30 mL); the combined organic extracts were dried
(MgSO4), filtered, washed with brine (25 mL), and evaporated under
reduced pressure. The obtained crude diol 9 was pure enough to
be used in the next step without further purification. 1Η NMR (400
MHz, CDCl3) δH 0.08 (s, 6H), 0.82-0.94 (m, 12H), 1.16-1.41
(m, 22H), 1.44 (s, 9H), 1.99-2.13 (m, 2H), 3.03 (br s, 1H), 3.30
(br s, 1H), 3.53-3.71 (m, 2H), 3.76 (dd, 1H, J ) 3.1, 7.6 Hz),
3.84-3.94 (m, 1H), 4.13-4.21 (m, 1H), 4.94 (d, 1H, J ) 6.3 Hz),
5.46 (dd, 1H, J ) 6.3, 14.7 Hz), 5.81 (dt, 1H, J ) 6.6, 14.7 Hz).
13C NMR (100 MHz, CDCl3) δC -4.0, 15.2, 19.2, 23.9, 26.6, 29.5
(2C), 30.2, 30.3, 30.4(2C), 30.5, 30.6 (2C), 30.7, 32.4, 33.0, 33.3,
56.6, 64.3, 72.8, 74.5, 81.5, 132.3, 135.0, 156.7.
(2S,3R,E)-2-Amino-1,3-dihydroxy-4-octadecene (D-erythro-
sphingosine) 12. A solution of 11 (25 mg, 0.063 mmol) in TFA/
H2O (3:1 v/v, 2 mL) was stirred at ambient temperature for 12 h,
at which time 33% aq ammonia was added until pH ) 8-9, and
the resulting reaction mixture was extracted with CHCl3 (2 × 5
mL). The combined organic extracts were dried (MgSO4), filtered,
and evaporated under reduced pressure to give a residue that was
recrystallized from CHCl3/Et2O/hexane 1:1:4 to afford pure D-
erythro-sphingosine 12 (11 mg, 58%) as a white solid. The physical
and spectroscopic data of this material were identical to both the
literature data10e and those obtained from an authentic sample.
tert-Butyl (2S,3R,E)-2-(tert-Butyldimethylsiloxy)-1-hydroxy-
octadec-4-en-2-ylcarbamate 10. The diol 9 (obtained from 8, as
described above) was dissolved in CH2Cl2 (20 mL) and added to a
vigorously stirred suspension, previously formed with chromato-
graphic grade silica gel (1.5 g), aq solution of 0.65 M NaIO4 (1.5
mL), and CH2Cl2 (15 mL). The reaction mixture was stirred for 45
min and filtered. The silica gel was washed with CH2Cl2 (2 × 10
mL), and the filtrate was evaporated under reduced pressure to
afford the crude aldehyde (0.05 (s, 6H), 0.81-0.95 (m, 12H), 1.16-
1.43 (m, 22H), 1.45 (s, 9H), 2.03-2.15 (m, 2H), 4.19-4.30 (m,
1H), 4.42-4.49 (m, 1H), 5.29-5.48 (m, 2H), 5.88-6.02 (m, 1H),
Acknowledgment. This study was supported by the Min-
isterio de Educacion y Ciencia (MEC), FEDER Program
(Madrid, Spain, project CTQ2004-0421), and the Gobierno de
Arago´n (Zaragoza, Spain). P.J. thanks MEC for a FPU predoc-
toral grant. We thank C. Gentillini, B. Dayde, and S. Franco
for exploratory work.
Supporting Information Available: Experimental procedures
for the preparation of ent-10 and L-erythro-sphingosine from 4b,
characterization of the intermediate products, and 1H and 13C NMR
spectra of products. This material is available free of charge via
the Internet at http://pubs.acs.org.
(15) (a) Tsunoda, H.; Ogawa, S. Liebigs Ann. Chem. 1995, 267-277.
(b) Shibuya, M.; Kurosu, M.; Minagawa, K.; Katayama, S.; Kitagawa, I.
Chem. Pharm. Bull. 1993, 41, 1534-1544.
(16) Chiacchio, U.; Rescifina, A.; Saita, M. G.; Iannazzo, D.; Romeo,
G.; Mates, J. A.; Tejero, T.; Merino, P. J. Org. Chem. 2005, 70, 8991-
9001.
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