A short and efficient stereoselective synthesis of dihydrosphingosine triacetate

Article abstract of DOI:10.1016/S0957-4166(99)00578-9

A highly enantiocontrolled synthesis of D-(+)-erythro-dihydrosphingosine (sphinganine) triacetate is described using the Sharpless asymmetric dihydroxylation and the regiospecific nucleophilic opening of a cyclic sulfite as key steps. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00578-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4797–4802
A short and efficient stereoselective synthesis of
dihydrosphingosine triacetate
∗
Rodney A. Fernandes and Pradeep Kumar
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411 008, India
Received 9 November 1999; accepted 6 December 1999
Abstract
A highly enantiocontrolled synthesis of D-(+)-erythro-dihydrosphingosine (sphinganine) triacetate is described
using the Sharpless asymmetric dihydroxylation and the regiospecific nucleophilic opening of a cyclic sulfite as
key steps. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Sphingosine 1 and its biosynthetic precursor, dihydrosphingosine (sphinganine, 2) are most abundant
long chain aminoalcohols possessing generally 18 or 20 carbon atoms. Sphinganine is an intermediate in
the biosynthesis of sphingolipids such as ceramides, sphingomyelin, cerebrosides and gangliosides which
1
play important roles in cell regulation and signal transduction, with sphinganine itself found to be an
2
inhibitor of protein kinase C. Various methods for the synthesis of sphingosine 1, dihydrosphingosine
2
and their derivatives have been documented in the literature. One of them is based on the ring
3
opening of chiral epoxide with azide as the key step. The second major synthetic strategy utilises
carbohydrate precursors as chiral pool materials to establish the stereochemistry at C-2 and C-3. The
4
most explored methods reported so far are the stereoselective addition of an organometallic reagents
5
to chiral aldehydes derived particularly from L-serine. This approach leads to the carbon–carbon bond
formation (C-3 and C-4) and simultaneously sets the stereochemistry of the C-3 hydroxyl group in one
step. The other interesting synthetic methodologies involve the use of a variety of chiral precursors
6
to build up the structure by nucleophilic addition processes. Although several syntheses of the target
compound have already been published, each suffers either from low-yielding steps or from low stereo-
7
or regioselectivity. This is especially apparent in approaches based on the ammonolysis of epoxy alcohol
7
b,c,f
intermediates.
Therefore a practical, expeditious and high-yielding synthesis of the target molecule
8
is still desirable. In connection with our studies on the synthesis of some naturally occurring lactones
∗
Corresponding author. E-mail: tripathi@dalton.ncl.res.in
0
957-4166/99/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00578-9
tetasy 3212

4
798
R. A. Fernandes, P. Kumar / Tetrahedron: Asymmetry 10 (1999) 4797–4802
mainly by stereoselective transformation of diols via cyclic sulfates, we became interested in developing
a simple and concise route to dihydrosphingosine. Herein we report a new and highly enantiocontrolled
five step strategy for the synthesis of dihydrosphingosine as its triacetate derivative. The Sharpless
asymmetric dihydroxylation of an appropriate olefin 4 and the regiospecific nucleophilic opening of a
cyclic sulfite 6 were employed as key steps in the synthesis.
2. Results and discussion
The synthesis of the target molecule D-(+)-erythro-dihydrosphingosine triacetate started from pal-
mityl aldehyde 3 as illustrated in Scheme 1. Thus, treatment of 3 with (ethoxycarbonylmethyl-
ene)triphenylphosphorane in THF under reflux gave the Wittig product 4 in 87% yield. The dihydroxyla-
9
tion of olefin 4 using the well established Sharpless asymmetric dihydroxylation procedure gave the
1
0
20
diol 5 in excellent yield with 99% ee having [α]D =+8.6 (c 2, CHCl ). Diol 5 was then treated
3
with thionyl chloride to afford the cyclic sulfite 611 in 96% yield. The essential feature of our synthetic
strategy shown in Scheme 1 was based on the presumption that the nucleophilic opening of the cyclic
sulfite 6 would occur in a regiospecific manner at the α-carbon. It may be important to mention here
that the regiospecific opening of the cyclic sulfate has been applied successfully to the stereoselective
8
synthesis of some naturally occurring lactones. In this connection it was thought worthwhile to explore
the possibility of ring opening of the cyclic sulfite itself by a nucleophile in a regiospecific way. Indeed,
the cyclic sulfite 6 reacted with lithium azide with apparent complete selectivity for attack at C-2, the
α-position, to furnish the azido alcohol 7 in 68% yield. The carbonyl group must be responsible for
1
2
the increased reactivity of the α-position. The azido alcohol 7 on reduction with lithium aluminium
hydride followed by subsequent acetylation afforded the target molecule as triacetate 8 in 76% yield
2
0
23
4f
23
7e
having [α]D =+17.2 (c 0.2, CHCl ) [lit. [α] =+16.8 (c=1, CHCl ), [α] =+17.4 (c=1, CHCl ) ].
3
D
3
D
3
Scheme 1. (i) Ph
t-BuOH:H O (1:1), 0°C, 24 h (94%); (iii) SOCl
Et O (1:1), rt, 12 h (68%); (v) (a) LiAlH , Et O, 0°C to rt, overnight, (b) Ac
2
3
P_CHCO
2
Et, THF, reflux, 18 h (87%); (ii) (DHQD)
, CCl , reflux, 1.5 h (96%); (iv) (a) LiN
O, pyridine, rt, 18 h (76%)
2
–PHAL, K
3
Fe(CN)
6
, K
2
CO
3
, OsO
4
(cat), MeSO
2
NH
SO
2
,
:
2
2
4
3
, DMF, 100°C, 18 h, (b) 20% H
2
4
2
4
2

R. A. Fernandes, P. Kumar / Tetrahedron: Asymmetry 10 (1999) 4797–4802
4799
The physical constants for D-(+)-dihydrosphingosine triacetate obtained were in excellent agreement
4
f,7e
with the literature values.
3. Conclusion
In conclusion, we have demonstrated that the stereoselective synthesis of sphinganine triacetate can
be accomplished by the Sharpless asymmetric dihydroxylation and the subsequent regiospecific nucleo-
philic opening of the corresponding cyclic sulfite. Thus, the results described herein constitute a short,
high-yielding and efficient synthesis of the protected dihydrosphingosine. To the best of our knowledge,
this is the first asymmetric synthesis of sphinganine using Sharpless asymmetric dihydroxylation as the
source of chirality.
4. Experimental
4.1. General information
Solvents were purified and dried by standard procedures before use; petroleum ether of boiling range
0–80°C was used. Melting points are uncorrected. Optical rotations were measured using sodium D
6
line on a JASCO-181 digital polarimeter. Infrared spectra were recorded on an ATI MATTSON RS-1
1
13
FT-IR spectrometer. H NMR and C NMR were recorded on Bruker AC-200 and MSL-300 NMR
spectrometers, respectively. Mass spectra were obtained with a Finnigan MAT-1020 B-70 eV mass
spectrometer. Elemental analyses were carried on a Carlo Erba CHNS-O analyzer. Enantiomeric excess
was determined by chiral HPLC.
4.2. Ethyl trans-octadec-2-enoate 4
To a solution of (ethoxycarbonylmethylene)triphenylphosphorane (5.65 g, 16.22 mmol) in dry THF
(35 mL) was added dropwise a solution of hexadecanal (3 g, 12.47 mmol) in THF (5 mL) at room
temperature. The reaction mixture was refluxed for 18 h. The solvent was removed under reduced
pressure and the crude product was purified on a silica gel column using petroleum ether:EtOAc (9:1) as
−
1
eluent to give 4 (3.37 g, 87%) as a white solid. Mp 25–26°C; IR νmax/cm (neat) 2926, 2854, 1724, 1655,
1
1
466, 1367, 1310, 1178, 1128, 1045, 980, 721; H NMR (CDCl ) δ 0.86 (t, J=6.8 Hz, 3H), 1.15–1.30
3
(
m, 24H), 1.35 (t, J=7.2 Hz, 3H), 1.45 (m, 2H), 2.18 (ddt, J=6.98, Jallylic=1.46 Hz, 2H), 4.18 (q, J=7.2
Hz, 2H), 5.8 (dt, Jtrans=15.63, Jallylic=1.46 Hz, 1H), 6.97 (dt, J=6.98, Jtrans=15.63 Hz, 1H); 13C NMR
(
CDCl ) δ 14.2, 14.4, 22.8, 28.3, 29.3, 29.5–29.9, 32.1, 32.4, 60.1, 121.6, 149.3, 166.7; MS (EI), m/z
3
+
(%) 311 [M +1] (18.58), 265 (46.15), 264 (48.71), 222 (12.82), 213 (37.6), 155 (21.36), 127 (60), 101
(
64.53), 88 (47.43), 83 (56.4), 69 (60.25), 57 (86.32), 55 (100). Anal. calcd for C H O (310.50): C,
20
38
2
77.36; H, 12.33. Found: C, 77.68; H, 11.99.
4.3. Ethyl-(2S,3R)-2,3-dihydroxyoctadecanoate 5
To a mixture of K Fe(CN) (4.14 g, 12.6 mmol), K CO (1.74 g, 12.6 mmol) and (DHQD) –PHAL
3
6
2
3
2
(
33 mg, 42.4 µmol, 1 mol%) in t-BuOH:H O (1:1, 50 ml) cooled at 0°C was added osmium tetroxide
2
(170 µL, 0.1 M solution in toluene, 0.4 mol%) followed by methanesulfonamide (0.4 g, 4.2 mmol).

4
800
R. A. Fernandes, P. Kumar / Tetrahedron: Asymmetry 10 (1999) 4797–4802
After stirring for 5 min at 0°C, the olefin 4 (1.3 g, 4.2 mmol) was added in one portion. The reaction
mixture was stirred at 0°C for 24 h and then quenched with solid sodium sulfite (6 g). The stirring was
continued for an additional 45 min and then the solution was extracted with EtOAc (3×20 mL). The
combined organic phases were dried (Na SO ) and concentrated. Silica gel column chromatography of
2
4
the crude product using petroleum ether:EtOAc (3:2) as eluent gave 5 (1.355 g, 94%) as a white solid.
2
0
−1
Mp 65–66°C; [α]D =+8.6 (c 2, CHCl ); IR νmax/cm (CHCl ) 3400–3300, 3133, 3018, 2926, 2854,
3
3
1
1
732, 1460, 1401, 1215, 760, 667; H NMR (CDCl ) δ 0.89 (t, J=7.5 Hz, 3H), 1.15–1.30 (m, 26H), 1.33
3
(
t, J=7.5 Hz, 3H), 1.60 (m, 2H), 1.95 (d, J=8 Hz, 1H), 3.08 (d, J=4 Hz, 1H), 3.88 (m, 1H), 4.08 (dd, J=4,
3
2
6
1
Hz, 1H), 4.3 (q, J=7.5 Hz, 2H); 1 C NMR (CDCl ) δ 13.9, 14.0, 22.5, 25.8, 29.2, 29.5, 31.8, 33.6,
3
+
1.9, 72.5, 73.2, 173.5; MS (EI), m/z (%) 299 [M −OCH CH ] (0.5), 271 (0.9), 253 (1.3), 123 (3.6),
2
3
09 (7.6), 104 (100), 95 (15.20), 82 (17.85), 76 (32.14), 69 (14.3), 57 (14.20). Anal. calcd for C H O
4
20
40
(344.52): C, 69.72; H, 11.70. Found: C, 69.36; H, 12.08.
4.4. (4S,5R)-4-Ethoxycarbonyl-5-pentadecyl-1,3,2-dioxathiolane-2-oxide 6
A two necked round-bottomed flask equipped with a reflux condenser topped with a CaCl guard tube
2
and a rubber septum was charged with diol 5 (2.00 g, 5.8 mmol) and dry CCl (15 mL). Thionyl chloride
4
(1.043 g, 0.64 mL, 8.77 mmol) was added through a syringe and the reaction mixture was refluxed for
1
.5 h. After completion of reaction, the reaction mixture was cooled; water (5 mL) and CH Cl (20
2
2
mL) were added. The organic layer was separated and aqueous layer extracted with CH Cl (2×20 mL).
2
2
The combined organic layers were washed with saturated NaHCO (20 mL) and brine (30 mL), dried
3
(
Na SO ) and passed through a pad of silica gel. The filtrate was concentrated and the crude product was
2 4
purified on a silica gel column using petroleum ether:EtOAc (9:1) as eluent to give 6 (2.176 g, 96%) as
2
0
−1
a colorless oil. [α]D =+79.21 (c 2, CHCl ); IR νmax/cm (neat) 3131, 3024, 2925, 2854, 1741, 1461,
3
1
1
397, 1278, 1215, 1032, 758; H NMR (CDCl ) δ 0.88 (t, J=7 Hz, 3H), 1.15–1.30 (m, 26H), 1.34 (t, J=7
3
Hz, 3H), 1.8–1.95 (m, 2H), 4.30–4.34 (dq, J=7, 2 Hz, 2H), 4.50 (d, J=7.5 Hz, 0.5H), 4.6–4.68 (m, 0.5H),
5
2
8
3
.05 (d, J=7 Hz, 0.5H), 5.09–5.17 (m, 0.5H); 13C NMR (CDCl ) δ 13.73, 13.8, 22.43, 24.99, 25.39,
3
8.81, 29.11–29.15, 31.71, 32.29, 34.73, 62.13, 62.84 (diastereomeric), 80.08, 81.36 (diastereomeric),
+
+
2.41, 86.58 (diastereomeric), 167.00; MS (EI), m/z (%) 390 [M ] (0.5), 345 [M −OCH CH ] (1.28),
2
3
+
+
26 [M −SO ] (3.85), 325 [M −HSO ] (3.8), 317 (3.85), 2.53 (15.4), 233 (14.10), 157 (6.41), 130
2
2
(
19.23), 109 (52.56), 95 (96), 83 (96), 69 (97.43), 57 (100), 55 (96). Anal. calcd for C H O S (390.57):
20 38 5
C, 61.50; H, 9.80; S, 8.20. Found: C, 61.42; H, 9.74; S, 8.12.
4.5. Ethyl-(2R,3R)-2-azido-3-hydroxyoctadecanoate 7
To a solution of cyclic sulfite 6 (0.5 g, 1.28 mmol) in dry DMF (10 mL) was added LiN (0.125 g, 2.56
3
mmol) under argon. The reaction mixture was stirred at 100°C for 18 h under argon. The solvent was
removed under reduced pressure, to the residue was added 20% aqueous H SO :Et O (1:1, 10 mL) and
2
4
2
the mixture was stirred at room temperature for 12 h. Excess NaHCO was added to it and the reaction
3
mixture was stirred for 20 min and then extracted with ether (3×20 mL). The organic layer was separated
and passed through a Celite and silica gel bed. Removal of solvent afforded the crude product as a dark
yellow oil which was purified on a silica gel column using petroleum ether:EtOAc (3:1) as eluent to give
−1
7
3
(
4
(0.321 g, 68%) as a colorless low-melting solid. [α]D20=−4.85 (c 2, CHCl ); IR νmax/cm (CHCl3)
3
1
476, 2922, 2853, 2109, 1741, 1460, 1373, 1263, 1191, 1119, 1095, 1028; H NMR (CDCl ) δ 0.88
3
t, J=7 Hz, 3H), 1.15–1.30 (m, 26H), 1.36 (t, J=7 Hz, 3H), 1.62 (m, 2H), 2.23 (m, 1H), 3.22 (m, 1H),
.14 (dd, J=6, 8 Hz, 1H), 4.34 (q, J=7 Hz, 2H); 13C NMR (CDCl ) δ 13.76, 13.80, 22.46, 29.18–29.51,
3

R. A. Fernandes, P. Kumar / Tetrahedron: Asymmetry 10 (1999) 4797–4802
4801
+
+
3
2
1.77, 61.20, 71.00, 72.5, 170.0; MS (EI), m/z (%) 369 [M ] (2.6), 367 (10.52), 341 [M −N ] (1.31),
2
68 (9.87), 253 (20), 241 (26.31), 167 (6.58), 154 (15.13), 111 (44.08), 104 (40.8), 97 (93.42), 83 (100),
7
1 (81.58), 55 (44.08), 57 (75.65). Anal. calcd for C H N O (369.53): C, 65.00; H, 10.64; N, 11.37.
20
39
3
3
Found: C, 64.89; H, 10.80; N, 11.65.
4.6. (2S,3R)-2-Acetamido-1,3-diacetoxyoctadecane 8
To a stirred suspension of LiAlH (25 mg. 0.66 mmol) in dry Et O (8 mL) at 0°C was added dropwise
4
2
a solution of 7 (100 mg, 0.27 mmol) in Et O (5 mL) through a syringe. The reaction mixture was
2
subsequently warmed to room temperature and stirred overnight. It was next hydrolysed with water (1
mL) and filtered through Celite. The Celite bed was washed with MeOH (3×20 mL). The total filtrate was
concentrated to an off white solid which was subsequently acetylated with Ac O (0.5 mL) and pyridine
2
(1 mL). After stirring for 18 h, the solvent was stripped off under reduced pressure and the residue was
purified on a silica gel column using petroleum ether:EtOAc (1:1) as eluent to give the triacetate 8 (88
mg, 76%) as a white solid. It was further recrystallised from petroleum ether/EtOAc. Mp 96–98°C (lit.
7
e
4f
7a
20
4f
9
7–98°C, 95–97°C, 89–91°C; [α] =+17.2 (c 0.2, CHCl ) [lit. +16.8 (c=1, CHCl ), +17.4 (c=1,
D
3
3
7
e
−1
1
CHCl ) ]; IR νmax/cm (CHCl ) 3291, 2913, 2847, 1730, 1646, 1537, 1368, 1233, 1036; H NMR
3
3
(
2
(
CDCl ) δ 0.84 (t, J=6.5 Hz, 3 H), 1.14–1.23 (m, 26H), 1.50–1.60 (m, 2H), 1.97 (s, 3H), 2.00 (s, 3H),
3
.02 (s, 3H), 3.99–4.21 (m, 2H), 4.33–4.37 (m, 1H), 4.98–5.01 (m, 1H), 5.77–5.80 (d, J=8 Hz, 1H); MS
+
EI), m/z (%) 427 [M ] (1.31), 354 (3.94), 308 (2.63), 307 (5.26), 295 (6.58), 294 (35.53), 188 (6.58),
145 (7.9), 144 (56.58), 102 (27.63), 85 (81.6), 84 (100).
Acknowledgements
RAF thanks CSIR, New Delhi, for financial assistance. We are grateful to Dr. T. Ravindranathan for
his support and encouragement. This is NCL communication no. 6581.
References
1
2
3
4
. Hannun, Y. A.; Bell, R. M. Science 1989, 243, 500–507.
. Schwartz, G. K.; Jiang, J.; Kelsen, D.; Albino, A. P. J. Nat. Cancer Inst. 1993, 85, 402–407.
. Sibuya, A.; Kawashima, K.; Ikeda, M.; Kitawaga, I. Tetrahedron Lett. 1989, 30, 7205–7208.
. (a) Kumar, P.; Schmidt, R. R. Synthesis 1998, 33–35. (b) Schmidt, R. R. In Synthesis in Lipid Chemistry; Tyman, J. H. P., Ed.;
Royal Society of Chemistry: Cambridge, UK; 1996, pp. 93–118 and references cited therein. (c) Murakami, T.; Hato, M. J.
Chem. Soc., Perkin Trans. 1 1996, 823–827. (d) Li, Y.-L.; Wu, Y.-L. Liebigs Ann. Chem. 1996, 2079–2082. (e) Schmidt, R.
R.; Bar, T.; Wild, R. Synthesis 1995, 868–876. (f) Wild, R.; Schimdt, R. R. Liebigs Ann. Chem. 1995, 755–764. (g) Hirata,
N.; Yamagiwa, Y.; Kamikawa, T. J. Chem. Soc., Perkin Trans. 1 1991, 2279–2280.
5
. (a) Villard, R.; Fotiadu, F.; Buono, G. Tetrahedron: Asymmetry 1998, 9, 607–611. (b) Dondoni, A.; Perrone, D.; Turturici,
E. J. Chem. Soc., Perkin Trans. 1 1997, 2389–2393. (c) Williams, L.; Zhang, Z.; Shao, F.; Carroll, P.; Joullie, M. M.
Tetrahedron 1996, 52, 11673–11694. (d) Soai, K.; Takahashi, K. J. Chem. Soc., Perkin Trans. 1 1994, 1257–1258. (e)
Herold, P. Helv. Chim. Acta 1988, 71, 354–362. (f) Nimkar, S.; Menaldino, D.; Merrill, A. H.; Liotta, D. Tetrahedron Lett.
1
988, 29, 3037–3040. (g) Garner, P.; Park, J. M.; Malecki, E. J. J. Org. Chem. 1988, 53, 4395–4398.
6
7
. (a) Spanu, P.; Rassu, G.; Pinna, L.; Battistini, L.; Casiraghi, G. Tetrahedron: Asymmetry 1997, 8, 3237–3243. (b) Davis, F.
A.; Reddy, G. V. Tetrahedron Lett. 1996, 37, 4349–4352. (c) Katsumura, S.; Yamamoto, N.; Fukuda, E.; Iwama, S. Chem.
Lett. 1995, 393–394 and references cited therein.
. (a) Bongini, A.; Cardillo, G.; Orena, M.; Sandri, S.; Tomasini, C. J. Chem. Soc., Perkin Trans. 1 1986, 1339–1344. (b) Mori,
K.; Umemura, T. Tetrahedron Lett. 1982, 23, 3391–3394. (c) Mori, K.; Umemura, T. Tetrahedron Lett. 1981, 22, 4433–4436.
(d) Reist, E. J.; Christie, P. H. J. Org. Chem. 1970, 35, 3521–3524, 4127–4128. (e) Carter, H. E.; Shapiro, D. J. Am. Chem.

4
802
R. A. Fernandes, P. Kumar / Tetrahedron: Asymmetry 10 (1999) 4797–4802
Soc. 1953, 75, 5131–5132. (f) Jenny, E. F.; Grob, C. A. Helv. Chim. Acta 1953, 36, 1936–1944. (g) Grob, C. A.; Jenny, E.
F.; Utzinger, H. Helv. Chim. Acta 1951, 34, 2249–2254.
8
. (a) Pais, G. C. G.; Fernandes, R. A.; Kumar, P. Tetrahedron 1999, 55, 13445–13450. (b) Fernandes, R. A.; Kumar, P.
Tetrahedron: Asymmetry 1999, 10, 4349–4356. (c) Kumar, P.; Saravanan, K. Tetrahedron 1998, 54, 2161–2168.
. (a) Tietze, L. F.; Golitzer, J. Synthesis 1998, 873–878. (b) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996,
9
3
5, 448–451. (c) Torii, S.; Liu, P.; Bhuvaneswari, N.; Amatore, C.; Jutand, A. J. Org. Chem. 1996, 61, 3055–3060. (d) For
a review on asymmetric dihydroxylation, see: Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94,
483–2547.
2
1
0. For the measurement of enantiomeric excess, the diol 5 was converted into its dibenzoate 9. The enantiomeric purity of
the dibenzoate 9 was estimated to be in excess of 99% by HPLC using Lichrocart 250-4 (4mm ID×25cm) HPLC-Cartridge
(
R.R.-Whelk-01), 10% iPrOH in hexane, 1 mL/min.
1
1
1. For a review on cyclic sulfites and sulfates, see: Lohray, B. B. Synthesis 1992, 1035–1052.
2. Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic Chemistry, 3rd ed.; Harper & Row: New York, 1987;
p. 321 and references cited therein.