Stereoselective synthesis of safingol and its natural stereoisomer from d-glycals

Article abstract of DOI:10.1016/j.tetlet.2008.05.112

Efficient and convenient syntheses of (2S,3S)-safingol and its natural (2S,3R)-isomer have been developed from 3,4,6-tri-O-benzyl glycals. The key step is the one-pot reduction of an azide, saturation of the double bonds and debenzylation under catalytic hydrogenation.

Full text of DOI:10.1016/j.tetlet.2008.05.112

Tetrahedron Letters 49 (2008) 4728–4730
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of safingol and its natural stereoisomer from D-glycals
*
Hari Prasad Kokatla, Ram Sagar, Yashwant D. Vankar
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient and convenient syntheses of (2S,3S)-safingol and its natural (2S,3R)-isomer have been developed
from 3,4,6-tri-O-benzyl glycals. The key step is the one-pot reduction of an azide, saturation of the double
bonds and debenzylation under catalytic hydrogenation.
Received 27 March 2008
Revised 22 May 2008
Accepted 27 May 2008
Available online 13 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Sphingolipid
Safingol
Glycals
Wittig reaction
Catalytic hydrogenation
Sphingosine 1 and sphiganine (dihydrosphingosines) 3 are nat-
urally occurring (long-chain, aliphatic, 2-amino-1,3 diol) bioactive
compounds. Dihydrosphingosines are biosynthetic precursors of
sphingolipids (e.g., ceramides, sphingomyelin, cerebrosides and
gangliosides), which play important roles in biological pathways
such as cell regulation and signal transduction.1 Sphingoid bases
contain two chiral centres, viz. at carbon atoms 2 and 3. Natural
enhances the cytotoxic effect of the chemotherapeutic agent myto-
mycin (MMC: Cat. No. 47589) in gastric cancer cells promoting
drug induced apoptosis.5–7
Due to its promising biological activity, a number of syntheses
of safingol 2 and its stereoisomers have been reported in the
literature including methods based on an enantioselective Henry
reaction8 and ketone reduction,9 multistep synthesis from (Z)-2-
butene-1,4-diol,10 a chiral oxazolidinyl ester11 and resolution
based methods.12a–c One of the most recent syntheses of safingol
was reported by Lee et al.,13 which was based on palladium-cata-
lyzed oxazoline formation followed by cross metathesis. Another
sphingoid bases occur in the
three additional unnatural isomers have also been reported.2
Among the unnatural sphingoid bases -threo-(2S,3S) dihydrosp-
D-erythro (2S,3R) configuration, but
L
hingosine (safingol) 2 is of particular interest due to its medicinal
importance. Safingol is an antineoplastic, antipsoriatic drug3 and
a competitive inhibitor of protein kinase C.4 It is reported that
safingol inhibits enzymatic activity and 3H-phorbal dibutarate
recent report by Chattopadhyay et al.14 begins from a
D-mannitol
derived aldehyde and involves a diastereoselective step in which
the unrequired diastereomer is also obtained in a reasonable
amount. The above-mentioned stereoselective syntheses of safin-
binding of purified rat brain PKC (IC50 = 37.5
lM, 31 lM, respec-
tively). It also inhibits human PKC , the major overexpressed iso-
gol, except that from D
-mannitol,14 either employ a chiral ligand
a
enzyme in MCF-7 DOXR cells (IC50 = 40
lM). Further, safingol
or a chiral auxiliary, which itself may require a few steps for its
NH2
HO
NH2
NH2
HO
1
1
3
HO
1
(CH2)14CH3
3
3
(CH2)14CH3
(CH2)12CH3
2
2
2
OH
OH
OH
1
2
3
Sphingosine
Safingol
D-erythro-dihydro-
sphingosine
* Corresponding author. Tel.: +91 512 2597169; fax: +91 512 259 0007.
E-mail address: vankar@iitk.ac.in (Y. D. Vankar).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.112

H. P. Kokatla et al. / Tetrahedron Letters 49 (2008) 4728–4730
4729
R2
OBn
O
OAc
R1
OAc
R1
R1
i (ref. 16)
ii
BnO
BnO
BnO
CHO
(CH2)10CH3
BnO
R2
R2
4: R1 = OBn, R2 = H
5: R1 = H, R2 = OBn
8: R1 = OBn, R2 = H (74%)
6: R1 = OBn, R2 = H (52%)
7: R1 = H, R2 = OBn (90%)
9: R1 = H, R2 = OBn (75%)
OH
R1
OMs
iii
BnO
(CH2)10CH3
iv
(CH2)10CH3
R2
R1
R2
10: R1 = OBn, R2 = H (97%)
11: R1 = H, R2 = OBn (96%)
12: R1 = OBn, R2=H (98%)
13: R1 = H, R2 = OBn (97%)
N3
NHAc
v
BnO
vi
AcO
(CH2)14CH3
(CH2)10CH3
R1
R1
R2
R2
14: R1 = OBn, R2 = H (75%)
15: R1 = H, R2 = OBn (73%)
2: R1= OAc, R2 = H (78%)
3: R1 = H, R2 = OAc (77%)
Scheme 1. Reagents and conditions: (i) HgSO4 (cat.), 0.02 N H2SO4,1,4-dioxane, 6 h (for compound 4); 8 h (for compound 5), then Ac2O, Et3N, 0 °C; (ii) C12H25PPhþ3 Brꢀ, n-BuLi,
dry THF, ꢀ78 °C; (iii) NaOMe (cat.), MeOH, rt, 1 h; (iv) MsCl, Et3N, 0 °C; (v) NaN3, DMF, 100 °C, 8 h; (vi) H2/Pd–C, MeOH (1% TFA); Ac2O, Et3N.
synthesis. Herein, we report a stereoselective synthesis, which
takes advantage of a chiral pool (carbohydrate based) starting
material to construct both the stereocenters of safingol and its dia-
stereomer in a good overall yield of 21% and 36%, respectively. Our
synthetic route uses simple reactions and involves the reduction of
an azide, double bonds and debenzylation in a single pot as the key
step.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.05.112.
References and notes
In continuation of our work on the functionalization of glycals15
towards biologically important molecules, we report a short and
efficient synthesis of safingol and its isomer from tri-O-benzyl
glycals.
1. Hannun, Y. A.; Bell, R. M. Science 1989, 243, 500.
2. Hoffman, R. V.; Tao, J. J. Org. Chem. 1998, 63, 3979.
3. USP Dictionary of USAN and International Drug Names; US Pharmacopeia:
Rockville, MD, 2000; p 636.
4. Schwartz, G. K.; Jiang, J.; Kelsen, D.; Albino, A. P. J. Natl. Cancer Inst. 1993, 85,
402.
The synthetic approach is outlined in Scheme 1. 3,4,6-Tri-O-
benzylated glycals 4 and 5 were subjected to Perlin hydrolysis16
followed by acetylation to afford trans-enals 6 and 7, respectively.
Wittig reaction of 6 and 7 with dodecyltriphenylphosphonium
bromide gave trans dienes 817 and 9,18 exclusively, in 74 and 75%
yields, respectively. Methanolysis of the acetates 8 and 9 with a
catalytic amount of sodium methoxide gave hydrolyzed products
1017 and 1118 in excellent yields. Conversion of the free hydroxyl
group to mesylates 1217 and 1318 followed by an SN2 displacement
with sodium azide gave the products 1417 and 1518 with complete
inversion of the configuration at C-2 and provided the desired threo
and erythro configurations, respectively. One-pot reduction of the
azide, saturation of the double bonds and deprotection of the
benzyl ether was carried out using catalytic hydrogenation with
10% Pd–C on 14 and 15 followed by acetylation to give the acetyl-
ated derivatives of safingol 2 and its diastereomer 3 in 78% and 77%
yields. The spectral data of these compounds were in good agree-
ment with the reported data of the respective natural
materials.19a,b
5. Sachs, C. W.; Safa, A. R.; Harrison, S. D.; Fine, R. L. J. Biol. Chem. 1995, 270, 26639.
6. Schwartz, G. K.; Haimovitz-Friedman, A.; Dhupar, K.; Ehleiter, D.; Maslak, P.;
Lawrence, L.; Loganzo, F.; Kelsen, D.; Fuks, Z.; Albino, A. P. J. Natl. Cancer Inst.
1995, 87, 1394.
7. Kedderis, L. B.; Bozigian, H. P.; Kleeman, J. M.; Hall, R. L.; Palmer, T. E.; Harrison,
S. D. Fundam. Appl. Toxicol. 1995, 25, 201.
8. Shibasaki, M.; Tokunaga, T.; Watanabe, S.; Suzuki, T.; Shibasaki, M. J. Org. Chem.
1995, 60, 7388.
9. Masui, M.; Shioiri, T. Tetrahedron Lett. 1998, 39, 5199.
10. Shibuya, H.; Kawashima, K.; Narita, N.; Ikeda, M.; Kitagawa, I. Chem. Pharm.
Bull. 1992, 40, 1154.
11. (a) Villard, R.; Fotiadu, F.; Buono, G. Tetrahedron: Asymmetry 1998, 9, 607; (b)
Azumn, H.; Tamagaki, S.; Ogino, K. J. Org. Chem. 2000, 65, 3538.
12. (a) Grob, C. A.; Jenny, E. F.; Utzinger, H. Helv. Chim. Acta 1951, 34, 2249; (b)
Egerton, M. J.; Gregory, G. I.; Malkin, T. J. Chem. Soc. 1952, 2272; (c) Grob, C. A.;
Jenny, E. F. H. Helv. Chim. Acta 1952, 35, 2106; (d) Zhang, L. H.; Onici, D. C.;
Muller, R.; McCosar, B. H.; Popa, E. ARKIVOC 2005, 10, 285.
13. Tian, Y. S.; Joo, J. E.; Pham, V. T.; Ham, W. H.; Lee, K. Y. Arch. Pharm. Res. 2007,
30, 67.
14. Sharma, A.; Sunita, G.; Chattopadhyay, S. Tetrahedron Lett. 2007, 48, 633.
15. (a) Rawal, G. K.; Kumar, A.; Tawar, U.; Vankar, Y. D. Org. Lett. 2007, 9, 5171; (b)
Rawal, G. K.; Rani, S.; Madhusudanan, K. P.; Vankar, Y. D. Synthesis 2007, 294;
(c) Rawal, G. K.; Rani, S.; Kumar, A.; Vankar, Y. D. Tetrahedron Lett. 2007, 47,
9117; (d) Reddy, G. B.; Madhusudanan, K. P.; Vankar, Y. D. J. Org. Chem. 2004,
69, 2630; (e) Agarwal, A.; Rani, S.; Vankar, Y. D. J. Org. Chem. 2004, 69, 6137.
16. (a) Gonzalez, F.; Leasage, S.; Perlin, A. S. Carbohydr. Res. 1975, 42, 267; (b) Sagar,
R.; Pathak, R.; Shaw, A. K. Carbohydr. Res. 2004, 339, 2031; (c) Saquib, M.; Sagar,
R.; Shaw, A. K. Carbohydr. Res. 2006, 341, 1052.
In conclusion, relatively short syntheses of safingol and its
natural stereoisomer have been reported from
-galactal as chiral pools, respectively.
D-glucal and
D
17. Experimental data of selected compounds: (2R,3S,4E,6E)-1,3-bis(benzyloxy)-
octadeca-4,6-dien-2-yl acetate (8): To
phosphonium bromide (207 mg, 0.27 mmol) in THF (5 mL) was added
dropwise 1.6 solution of n-BuLi (0.26 mL, 0.42 mmol) in hexane at
a solution of dodecyltriphenyl-
Acknowledgement
a
M
ꢀ78 °C, and the mixture was stirred at this temperature for 20 min. A solution
of aldehyde 6 (100 mg, 0.27 mmol) in THF (5 mL) was added dropwise. The
reaction mixture was allowed to stir for an additional 30 min and warmed to
room temperature. It was then quenched with a saturated aqueous solution of
NH4Cl (5 mL) and extracted with EtOAc (3 ꢁ 15 mL). Usual workup followed by
purification by column chromatography (1:9 EtOAc–hexane) gave 8 (163 mg,
YDV thanks the Department of Science and Technology, New
Delhi, for financial support in the form of Ramanna Fellowship
(Grant No. SR/S1/RFOC-04/2006). HK and RS thank CSIR, New
Delhi, for senior research fellowships.

4730
H. P. Kokatla et al. / Tetrahedron Letters 49 (2008) 4728–4730
74%). ½a 2D8
ꢂ
+24.00 (c 1.00, CH2Cl2); IR (neat film) 3062, 2924, 1744, 1651, 1605,
1H NMR (400 MHz, CDCl3): d
J = 7.0, 10.7 Hz, 1H), 4.17 (dd, J = 3.9, 8.0 Hz, 1H), 4.42 (d, J = 11.7 Hz, 1H), 4.52
1495, 1455, 1371, 1235, 1071, 988, 845 cmꢀ1
;
(br s, 2H), 4.59 (d, J = 11.7 Hz, 1H), 4.86–4.89 (m, 1H), 5.51–5.60 (m, 2H), 6.02
(dd, J = 10.7, 11.2 Hz, 1H), 6.56 (dd, J = 11.2, 15.2 Hz, 1H), 7.25–7.35 (m, 10H);
13C NMR (100 MHz, CDCl3): d 14.1, 22.6, 27.8, 29.2, 29.3, 29.5, 29.5, 29.6, 29.6,
31.8, 38.5, 68.5, 70.6, 73.3, 78.9, 82.7, 126.9, 127.0, 127.6, 127.7, 127.8, 128.3,
128.4, 131.4, 134.7, 137.4, 137.6. HRMS calcd for C33H48O5S [M+Na]+ 579.3120,
found: 579.3123.
0.87 (t, J = 6.3 Hz, 3H), 1.25–1.37 (br s, 18H), 2.02 (s, 3H), 2.14–2.17 (m, 2H),
3.64 (dd, J = 3.4, 10.7 Hz, 1H), 3.70 (dd, J = 5.6, 10.7 Hz, 1H), 4.06 (t, J = 6.1 Hz,
1H), 4.35 (d, J = 11.7 Hz, 1H), 4.47 (d, J = 11.9 Hz, 1H), 4.52 (d, J = 12.2 Hz, 1H),
4.56 (d, J = 11.9 Hz, 1H), 5.09 (dd, J = 2.6, 6.5 Hz, 1H), 5.50–5.57 (m, 2H), 5.97 (t,
J = 11 Hz, 1H), 6.5–6.4 (dd, J = 11.2, 15.1 Hz, 1H), 7.25–7.33 (m, 10H); 13C NMR
(100 MHz, CDCl3): d 14.1, 21.1, 22.6, 27.8, 29.1, 29.2, 29.3, 29.5, 29.6, 29.6, 31.8,
32.6, 68.3, 70.3, 70.4, 73.1, 73.6, 78.4, 126.6, 127.3, 127.5, 127.6, 127.6, 128.2,
128.3, 128.9, 129.1, 130.4, 133.8, 135.2, 138.0, 138.1, 173.5; HRMS calcd for
(2S,3S,4E,6E)-2-Azidooctadeca-4,6-diene-1,3-diyl)bis-(oxy)bis(methylene)diben-
zene (14): To a solution of mesylate 12 (290 mg, 0.52 mmol) in dry DMF was
added NaN3 (203 mg, 3.1 mmol) and the mixture stirred at 100 °C for 8 h. DMF
was removed under reduced pressure, and the reaction mixture washed with
H2O and the aqueous phase was extracted with EtOAc (3 ꢁ 15 mL). Usual
workup and purification by column chromatography gave 14 (196 mg, 75%)
C
34H48O4 [M+Na]+ 543.3450, found: 543.3455.
(2R,3S,4E,6E)-1,3-Bis(benzyloxy)octadeca-4,6-dien-2-ol (10): Compound
8
(350 mg, 0.67 mmol) was dissolved in dry MeOH (15 mL) and a catalytic
amount of NaOMe was added and the reaction mixture was allowed to stir for
1 h at room temperature. The reaction mixture was concentrated in vacuo and
passed through Amberlite-120 (H+). The crude product was purified by silica
gel column chromatography (hexane–EtOAc = 9:1) to give 10 in quantitative
½
a 2D8
ꢂ
ꢀ12.00 (c 0.05, CH2Cl2); IR (neat film) 3028, 2924, 2853, 2096, 1652, 1606,
1495, 1454, 1364, 1262, 1101, 1027, 989 cmꢀ1 1H NMR (400 MHz, CDCl3): d
.
0.87 (t, J = 6.6 Hz, 3H), 1.25–1.38 (br s, 18H), 2.14–2.19 (m, 2H), 3.55–3.63 (m,
3H), 4.04 (dd, J = 11.7, 10.0 Hz, 1H), 4.37 (d, J = 9.5 Hz, 1H), 4.47–4.54 (m, 2H),
4.60 (d, J = 11.7 Hz, 1H), 5.50–5.59 (m, 2H), 6.01 (dd, J = 10.9, 11.0 Hz, 1H), 6.56
(dd, J = 11.2, 15.1, 1H), 7.25–7.38 (m, 10H); 13C NMR (100 MHz, CDCl3): d 14.1,
22.6, 27.8, 29.2, 29.3, 29.5, 29.6, 31.8, 64.8, 69.6, 70.3, 70.4, 73.4, 79.5, 127.2,
127.6, 127.7, 127.8, 128.3, 128.4, 128.5 130.4, 134.4, 137.7, 137.9; HRMS calcd
yield. ½a 2D8
ꢂ
+0.40 (c 2.25, CH2Cl2); IR (neat film) 3458, 3087, 2923, 1654, 1606,
1495, 1454, 1363, 1257, 1092, 1027, 989 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d
0.85 (t, J = 6.6 Hz, 3H), 1.27–1.25 (br s, 18H), 2.15–2.20 (m, 2H), 2.36 (br s, 1H)
3.56 (dd,J = 5.8, 9.7 Hz, 1H), 3.61 (dd, J = 3.6, 9.7 Hz, 1H), 3.92–3.95 (m, 2H),
4.38 (d, J = 11.7 Hz, 1H), 4.50–4.53 (br s, 2H), 4.59 (d, J = 11.7 Hz, 1H), 5.3–5.4
(dd, J = 7.8, 10.7 Hz, 1H), 5.61 (dd, J = 7.8, 15.6 Hz, 1H), 6.04 (dd, J = 10.7,
11.2 Hz, 1H), 6.56 (dd, J = 11.2, 15.6 Hz, 1H), 7.2–7.3 (m, 10H); 13C NMR
(100 MHz, CDCl3): d 14.0, 22.6, 27.8, 29.1, 29.2, 29.5, 29.6, 29.6, 31.8, 32.6, 70.2,
70.4, 70.5, 70.6, 73.2, 80.4, 126.7, 127.4, 127.5, 127.6, 127.6, 127.7, 127.9, 128.3,
for C32H45N3O2 [M+Na]+ 526.3409, found: 526.3406. N,O,O-Triacetyl-
L-threo-
dihydrosphingosine (2): A mixture of olefin 14 (150 mg, 0.29 mmol) and Pd/C
(10% content, 50 mg) in MeOH (20 mL, containing 1% of TFA) was stirred for
28 h at room temperature under a H2 atmosphere (5 atm). The catalyst was
filtered, and the filtrate was concentrated in vacuo to give crude safingol. This
crude product was acetylated using Ac2O, Et3N to give acetylated safingol,
which was purified on a short silica gel column using EtOAc–hexane (4:6) as
128.9, 130.3, 133.8, 135.5, 136.5, 138.0, 138.1; HRMS calcd for
C32H46O3
[M+Na]+ 501.3345, found: 501.3343.
(2R,3S,4E,6E)-1,3-Bis(benzyloxy)octadeca-4,6-dien-2-yl methanesulfonate (12):
A solution of alcohol 10 (280 mg, 0.58 mmol) in dry CH2Cl2 (10 mL), and Et3N
(70 mg, 0.69 mmol) was cooled to 0 °C. Subsequently, mesyl chloride (79 mg,
0.69 mmol) was added and the reaction mixture was allowed to warm to room
temperature. After 30 min, the reaction mixture was washed with brine
(10 mL) and water (10 mL), dried over MgSO4 and evaporated. The crude
product was purified by silica gel column chromatography using
eluent to furnish the target compound 2 (70 mg, 78%) as a white solid; ½a D28
ꢂ
ꢀ10.40 (c 1.05, CH2Cl2); IR (neat film) 3299, 2924, 2853, 1744, 1658, 1543,
1462, 1371, 1233, 1044 cmꢀ1 1H NMR (400 MHz, CDCl3): d 0.85 (t, J = 6.6 Hz,
;
3H), 1.22 (br s, 26H), 1.52 (m, 2H), 1.99 (s, 3H), 2.03 (s, 3H), 2.05 (s, 3H), 4.00–
4.01 (m, 2H), 4.38 (m, 1 H), 5.04 (m, 1H), 5.63 (d, J = 9.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d 14.1, 20.7, 20.9, 22.6, 23.2, 25.1, 29.2, 29.3, 29.3, 29.5, 29.6,
29.6, 29.6, 31.2, 31.8, 50.0, 63.3, 72.4, 169.9, 170.4, 170.7; HRMS calcd for
(hexane:EtOAc = 8:2) to give 12 (317 mg, 98%): ½a D28
ꢂ
+14.70 (c 1.15, CH2Cl2);
C
24H45NO5 [M+H]+ 428.3298, found: 428.3370.
IR (neat film) 3063, 2924, 1656, 1606, 1496, 1454, 1360, 1206, 1099, 1027,
18. See Supplementary data for additional spectral data.
19. (a) Fernandes, R. A.; Pradeep, K. Tetrahedron: Asymmetry 1999, 10, 4797; (b)
Azuma, H.; Tamagaki, S.; Ogino, K. J. Org. Chem. 2000, 65, 3538.
970 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 0.87 (t, J = 6.5 Hz, 3H), 1.25–1.38 (br s,
18H), 2.14–2.18 (m, 2H), 2.90 (s, 3H) 3.66 (dd, J = 4.4, 10.5 Hz, 1H), 3.74 (dd,