Stereoselective total synthesis of sphingolipids

Article abstract of DOI:10.1007/s12039-016-1175-0

A novel sphingosine, 1,2-diacetyl D-erythro-sphinganine having a characteristic almond flavour was isolated from the edible mushroom Grifola gargal. We have synthesized this sphinganine along with the three other sphingolipids, such as 1,2-diacetyl L-threo-sphinganine, D-erythro-sphinganine triacetate and L-threo-sphinganine triacetate using Garner aldehyde as the starting material involving the Grignard reaction and Mitsunobu inversion. The sphingolipids 1,2-diacetyl D-erythro-sphinganine and 1,2-diacetyl L-threo-sphinganine have been synthesized for the first time. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s12039-016-1175-0

J. Chem. Sci. Vol. 128, No. 11, November 2016, pp. 1789–1794. ꢀc Indian Academy of Sciences.
DOI 10.1007/s12039-016-1175-0
Stereoselective total synthesis of sphingolipids
∗
PARAMESH JANGILI, PERLA RAMESH and BISWANATH DAS
Natural Products Chemistry Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad,
Telangana 500 007, India
e-mail: biswanathdas@yahoo.com
MS received 13 July 2016; revised 9 September 2016; accepted 9 September 2016
Abstract. A novel sphingosine, 1,2-diacetyl D-erythro-sphinganine having a characteristic almond flavour
was isolated from the edible mushroom Grifola gargal. We have synthesized this sphinganine along with
the three other sphingolipids, such as 1,2-diacetyl L-threo-sphinganine, D-erythro-sphinganine triacetate
and L-threo-sphinganine triacetate using Garner aldehyde as the starting material involving the Grignard
reaction and Mitsunobu inversion. The sphingolipids 1,2-diacetyl D-erythro-sphinganine and 1,2-diacetyl
L-threo-sphinganine have been synthesized for the first time.
Keywords. 1,2-Diacetyl D-erythro-sphinganine; 1,2-diacetyl L-threo-sphinganine; D-erythro-sphinganine
triacetate; sphingolipids; total synthesis; Garner aldehyde.
1
. Introduction
and eaten by native people of southern Argentina and
Chile. The compound 4 suppresses the formation of
osteoclasts.
Sphingolipids are important structural and functional
components of essentially all eukaryotic cells and are
abundantly located in all plasma membranes as well as
in some intracellular organelles.1 They exist as struc-
tural components of cell membranes in animals, plants
and some microbial systems. Sphingosine 1 and sphin-
ganine (dihydrosphingosine) 2 (Figure 1) are naturally
occurring bioactive compounds (long-chain, aliphatic,
In continuation of our work carried out on the
7
synthesis of natural bioactive compounds, herein we
,2
describe an efficient stereoselective total synthesis
of naturally occurring sphingolipid 1,2-diacetyl D-
erythro-sphinganine (4) along with three other sphin-
golipids, such as 1,2-diacetyl L-threo-sphinganine (5)
3
(
(
C-3 epimer of 4), D-erythro-sphinganine triacetate
6) (triacetyl derivative of compound 2) and L-threo-
2-amino-1,3 diols). Dihydrosphingosines are biosyn-
thetic precursors of sphingolipids (e.g., ceramides, sph-
ingomyelin, cerebrosides and gangliosides), which play
important roles in biological pathways such as cell reg-
ulation and signal transduction. Sphingoid bases con-
tain two chiral centres, viz., at carbon atoms 2 and
sphinganine triacetate (7) (triacetyl derivative of com-
pound 3, safingol) (Figure 2). Our planned approach to
the synthesis of the target molecules was initiated from
Garner aldehyde (9) involving the Grignard reaction
and Mitsunobu inversion. To our knowledge, there are a
3. Natural sphingoid bases occur in the D-erythro
few reports towards the total synthesis of sphingolipids
8
(
2S, 3R) configuration, but other additional unnatural
6
5
and 7. However, synthesis of the sphingolipids 4 and
isomers have also been reported. Among the unnatu-
ral sphingoid bases L-threo-(2S, 3S) dihydrosphingo-
sine (safingol) 3 (Figure 1) is of particular interest due
to its medicinal importance. Safingol is an antineoplas-
are reported here for the first time.
2. Experimental
4
tic, antipsoriatic drug and a competitive inhibitor of
2.1 General
5
protein kinase C.
6
Recently, Choi et al., isolated a novel sphingosine, Infrared spectra were recorded on Perkin-Elmer RX1
,2-diacetyl D-erythro-sphinganine (4) (Figure 2), from FT-IR spectrophotometer. NMR spectra were recorded
1
the edible mushroom Grifola gargal, having a char- on Inova 500 MHz and Bruker 300 MHz spectrome-
acteristic almond flavour. This mushroom is collected ters using CDCl and CD OD as solvents and Me Si as
3
3
4
internal standard. The chemical shifts are expressed as δ
values in parts per million (ppm) and the coupling con-
stants (J) are given in hertz (Hz). ESIMS were recorded
with VG-Autospec micromass. Optical rotations were
∗
For correspondence
Part 86 in the series “Synthetic studies on natural products”
1789

1790
Paramesh Jangili et al.
Figure 1. Structures of sphingosine (1) and sphinganines (dihydro sphingosines) (2 and 3).
Figure 2. Structures of synthesized sphinganines (4−7).
measured with JASCO DIP 360 digit polarimeter. All (m, 4H); 1.62–1.55 (m, 2H); 1.49 (s, 12H); 1.45 (s, 3H);
13
reactions were monitored by thin-layer chromatography 1.25 (br. s, 26H); 0.88 (t, J = 6.8 Hz, 3H). C NMR
(
TLC) using silica gel F254 pre-coated plates. (125 MHz, CDCl ): 154.1; 94.2; 81.0; 72.9; 64.7; 62.3;
3
3
2
4.4; 32.7; 31.8; 29.6; 29.6; 29.5; 28.3; 26.4; 26.0; 24.2;
+
2.6; 14.0. ESIMS: m/z 442 [M+H] . Anal Calcd. for
2.2 tert-Butyl (S)-4-((S)-1-hydroxyhexadecyl)-2,
C H NO : C, 70.70; H, 11.64%. Found: C, 70.60; H,
26
51
4
2
-dimethyloxa zolidine-3-carboxylate (10)
1
1.68%.
To the solution of Garner aldehyde (9) (2.0 g, 8.72 mmol)
◦
in THF (10 mL), was added at −78 C pentadecyl mag-
2
.3 tert-Butyl ((2S,3S)-1,3-dihydroxyoctadecan-2-yl)
nesium bromide in THF (10 mL) which was prepared
from 1-bromopentadecane (7.58 mL, 26.16 mmol) and
carbamate (11)
Mg (0.847 g, 34.88 mmol) in the usual manner. The Compound 10 (2.8 g, 6.34 mmol) and pyridinium p-
◦
mixture was stirred at the same temperature (−78 C) toluene sulfonate (0.159 g, 0.634 mmol) were dissolved
for 1 hour and then gradually brought to r.t. The mix- in MeOH (10 mL) and stirred at r.t. for 2 h. The solvent
ture was then stirred overnight at r.t. to produce the was removed under reduced pressure. The residue was
mixture of diastereomers 10 and 10a. The reaction was purified by flash CC (silica gel, hexane/AcOEt, 7:3) to
quenched by the addition of aqueous saturated NH Cl give pure compound 11 (2.34 g, 92%) as a white solid.
4
2
5
−1
1
(
10 mL) and extracted with AcOEt. The organic layer [α] = + 16.2 (c = 2.5, CHCl ). IR õ (KBr)/cm :
D
3
max
was washed with 5% aqueous HCl (10 mL), water, 3430, 2975, 2855, 1690, 1360, 1255, 1175, 1060. H
brine and then dried over Na SO . The two diastere- NMR (500 MHz, CDCl ): 5.22 (d, J = 7.9 Hz, 1H);
2
4
3
omers 10 and 10a were separated by careful CC (sil- 4.01 (dd, J = 3.4, 11.4 Hz, 1H); 3.82 (d, J = 3.8 Hz,
ica gel, 100–200 mesh, 0–5% increasing amount of 1H); 3.76 (m, 1H); 3.53 (m, 1H); 2.54 (br. s, 2H); 1.56–
AcOEt in hexane) to produce two diastereomeric alco- 1.48 (m, 2H); 1.46 (s, 9H); 1.25 (br. s, 26H); 0.88 (t,
1
3
hols 10 and 10a in the ratio 9:1 (syn:anti, 9:1) with J = 6.7 Hz, 3H). C NMR (125 MHz, CDCl ): 156.1;
3
8
6% yield. The pure alcohol 10 (2.98 g) was obtained 79.6; 73.7; 62.3; 54.9; 34.2; 31.8; 29.6; 29.5; 29.3;
2
5
+
as a colorless oil. [α] = −32.2 (c =2.0, CHCl ). IR 28.3; 25.9; 22.6; 14.0. ESIMS: m/z 402 [M+H] . Anal
D
3
−1
õmax (KBr)/cm : 3440, 2925, 2855, 1701, 1366, 1258, Calcd. for C H NO : C, 68.78; H, 11.80%. Found: C,
23
47
4
1
1
175, 1061. H NMR (500 MHz, CDCl ): 4.10–3.49 68.90; H, 11.75%.
3

Total synthesis of sphingolipids
1791
2.4 (2S,3S)-2-((tert-Butoxycarbonyl)amino)-3-
2.6 L-threo-Sphinganine triacetate (7)
hydroxy octadecyl acetate (8)
To a solution of compound 5 (0.1 g, 0.26 mmol) in
To a solution of 1,3-diol 11 (2.2 g, 5.47 mmol) in dry CH Cl (5 mL), Et N (0.043 mL, 0.31 mmol) was
2
2
3
dry CH Cl (10 mL), Et N (0.76 mL, 5.47 mmol) was added, followed by Ac O (0.029 mL, 0.31 mmol) was
2
2
3
2
◦
added, followed by Ac O (0.51 mL, 5.47 mmol) was added at 0 C and the reaction mixture was allowed to
added at 0 C and the reaction mixture was allowed rise to r.t. After 2 h, the reaction mixture was washed
2
◦
to r.t. After completion of reaction (2 h), the reaction with brine (5 mL) and water (5 mL), dried over Na SO4
2
mixture was washed with brine (10 mL) and water and evaporated. The crude product was purified by
(
10 mL), dried over Na SO and evaporated. The crude silica gel CC (hexane/AcOEt, 9:1) to give L-threo-
2 4
product was purified by silica gel CC (hexane/AcOEt, sphinganine triacetate 7 (0.087 g, 79%) as a white solid.
2
4
−1
9
:1) to give pure monoacetyl ester 8 (1.87 g, 77%) [á] = −12.0 (c =0.5, CHCl ). IR õ (KBr)/cm :
D
3
max
2
5
as a white solid. [α] = +3.4 (c =0.6, CHCl ). IR 2925, 2855, 1740, 1655, 1543, 1460, 1370, 1235, 1048.
D
3
−1
1
õmax (KBr)/cm : 3350, 2917, 2850, 1743, 1685, 1531,
1
H NMR (500 MHz, CDCl ): 5.64 (d, J = 9.3 Hz, 1H);
3
1
367, 1232, 1173, 1049. H NMR (300 MHz, CDCl ): 5.06 (m, 1H); 4.39 (m, 1H); 4.07–4.01 (m, 2H); 2.05
3
4
.91 (d, J = 8.0 Hz, 1H); 4.28–4.17 (m, 1H); 4.06 (s, 3H); 2.02 (s, 3H); 1.99 (s, 3H); 1.62-1.54 (m, 2H);
13
(
(
(
dd, J = 6.1, 11.0 Hz, 1H); 3.79 (m, 1H); 3.69–3.58 1.24 (br. s, 26H); 0.87 (t, J = 6.7 Hz, 3H). C NMR
m, 1H); 2.32 (br. s, 1H); 2.08 (s, 3H); 1.55–1.48 (125 MHz, CDCl ): 170.7; 170.4; 170.0; 72.4; 63.3;
3
m, 2H); 1.45 (s, 9H); 1.25 (s, 26H); 0.88 (t, J = 7.0 50.0; 31.9; 31.2; 29.6; 29.6; 29.5; 29.3; 29.2; 25.1; 23.2;
13
+
Hz, 3H). C NMR (75 MHz, CDCl ): 171.2; 156.0; 22.6; 20.9; 20.7; 14.1. ESI MS: m/z 428 [M+H] . Anal
3
79.6; 70.1; 63.4; 52.7; 33.7; 31.9; 29.7; 29.6; 29.5; Calcd. for C H NO : C, 67.41; H, 10.61%. Found: C,
24
45
5
2
9.3; 28.3; 25.6; 22.7; 20.9; 14.1. ESI MS: m/z 466 67.25; H, 10.57%.
+
[
M+Na] . Anal Calcd. for C H NO : C, 67.68; H,
25
49
5
11.13%. Found: C, 67.83; H, 11.09%.
2.7 (2S,3R)-2-((tert-Butoxycarbonyl)amino)
octadecane-1,3-diyl diacetate (12)
2.5 1,2-Diacetyl L-threo-sphinganine (5)
The monoacetyl ester 8 (1.0 g, 2.25 mmol) was dis-
solved in anhydrous THF (20 mL), AcOH (0.257 mL,
To a solution of compound 8 (0.3 g, 0.68 mmol) in
4
.50 mmol) and PPh (1.18 g, 4.50 mmol) were added
CH Cl (5 mL) excess trifluoroacetic acid (TFA) was
3
2
2
◦
at 0 C. To the reaction mixture, a solution of diiso-
propyl azodicarboxylate (0.88 mL, 4.50 mmol) in anhy-
drous THF (10 mL) was added. The solution was stirred
at r.t. and after 2 h the reaction was quenched by the
added dropwise and stirred at r.t. for 1 h. The reac-
tion mixture was dried on the rotary evaporator to
remove the excess TFA. The resulting residue (unpro-
tected amine) was dissolved in CH Cl (5 mL) and
2
2
addition of water (10 mL), and extracted with Et O (30
basified to pH 8 with aq. NaHCO followed by the
2
3
mL). After phase separation the organic phase was dried
addition of the acetyl chloride (0.053 mL, 0.75 mmol).
The reaction was monitored by TLC. Upon comple-
tion (2.5 h), the reaction mixture was diluted with sat-
(
1
(
1
Na SO ), concentrated and purified by CC to give pure
2 4
25
2 (0.843 g, 77%) as a colorless oil. [α] = + 12.1
D
−1
c = 0.3, CHCl ). IR õ
(KBr)/cm : 2925, 2854,
746, 1723, 1368, 1236, 1171. H NMR (300 MHz,
urated aqueous NH Cl. The phases were separated and
3
max
4
1
the aqueous layer was extracted with CH Cl . The com-
2
2
CDCl ): 5.02 (m, 1H); 4.92 (dd, J = 6.2, 12.5 Hz, 1H);
bined organic extracts were washed with brine, dried
3
4
1
3
7
2
4
1
.09-3.99 (m, 2H); 2.06 (s, 6H); 1.67-1.57 (m, 2H);
(
5
Na SO ) and purified by CC to afford pure compound
2 4
24
.45 (s, 9H); 1.25 (br. s, 26H); 0.88 (t, J = 6.8 Hz,
(0.187 g, 72%) as a white solid. [á] = + 2.8
D
13
−1
H). C NMR (75 MHz, CDCl ): 170.8; 168.6; 151.3;
(
2
c = 0.4, CHCl ). IR õ
(KBr)/cm : 3300, 2945,
840, 1725, 1645, 1540, 1435, 1365, 1061. H NMR
3
3
max
1
9.9; 72.3; 62.9; 51.2; 31.9; 31.2; 29.6; 29.6; 29.5; 29.4;
9.3; 28.3; 25.0; 22.6; 21.0; 20.8; 14.1. ESI MS: m/z
(
1
1
500 MHz, CDCl ): 4.24 (dd, J = 4.0, 10.0 Hz,
3
+
86 [M+H] . Anal Calcd. for C H NO : C, 66.77; H,
H); 4.18–4.02 (m, 2H); 3.68 (m, 1H); 2.62 (br. s,
H); 2.09 (s, 3H); 2.02 (s, 3H); 1.45 (m, 1H); 1.25
27 51
6
0.58%. Found: C, 66.85; H, 10.54%.
13
(
s, 27H); 0.88 (t, J = 6.9 Hz, 3H). C NMR (125
MHz, CDCl ): 171.6; 170.4; 69.7; 63.4; 51.5; 33.7;
3
2.8 D-erythro-Sphinganine triacetate (6)
3
1
1.9; 29.6; 29.5; 29.5; 29.3; 25.7; 23.3; 22.7; 20.9;
+
4.1. ESI MS: m/z 386 [M+H] . Anal Calcd. for To a solution of compound 12 (0.8 g, 1.64 mmol) in
C H NO : C, 68.53; H, 11.24%. Found: C, 68.62; CH Cl (5 mL), excess trifluoroacetic acid was added
22
43
4
2
2
H, 11.21%.
dropwise and stirred at r.t. for 1 h. The reaction mixture

1792
Paramesh Jangili et al.
was dried on the rotary evaporator to remove the excess 2:8) to give pure 1,2-diacetyl D-erythro-sphinganine 4
2
5
TFA. The resulting residue (unprotected amine) was (0.088 g, 79%) as a white solid. [α] = + 6.2 (c =0.25,
D
−
1
dissolved in CH Cl (8 mL) and basified to pH 8 with CH OH). IR õ (KBr)/cm : 3279, 2918, 2850, 1739,
2
2
3
max
1
aq. NaHCO followed by the addition of the acetyl chlo- 1650, 1555, 1465, 1341, 1221. H NMR (500 MHz,
3
ride (0.128 mL, 1.80 mmol). The reaction was moni- CDCl ): 5.98 (d, J = 7.9 Hz, 1H); 4.33 (dd, J = 11.6,
3
tored by TLC. Upon completion (2.5 h), the reaction 6.4 Hz, 1H); 4.18 (dd, J = 11.6, 3.2 Hz, 1H); 4.11
mixture was diluted with saturated aqueous NH Cl. (m, 1H); 3.63 (m, 1H); 2.06 (s, 3H); 2.00 (s, 3H); 1.47
4
The phases were separated and the aqueous layer was (m, 2H); 1.24 (br. s, 26H); 0.86 (t, J = 6.8 Hz, 3H).
13
extracted with CH Cl . The combined organic extracts
C NMR (125 MHz, CDCl ): 171.3; 170.3; 72.6; 63.1;
3
2
2
were washed with brine, dried (Na SO ) and purified 52.9; 34.0; 31.9; 29.6; 29.6; 29.5; 29.3; 25.9; 23.3; 22.7;
2
4
+
by CC to afford pure D-erythro-sphinganine triacetate 20.9; 14.1. ESI MS: m/z 386 [M+H] . Anal Calcd. for
2
4
6
1
1
(0.507 g, 72%) as a white solid. [á] = + 12.7 (c = C H NO : C, 68.53; H, 11.24%. Found: C, 68.70; H,
−
3 max
D
22 43
4
1
.1, CHCl ). IR õ
(KBr)/cm : 2935, 2840, 1729,
11.21%.
1
646, 1540, 1462, 1360, 1239, 1061. H NMR (500
MHz, CDCl ): 5.90 (d, J = 9.0 Hz, 1H); 4.90 (m,
3
3
. Results and Discussion
1
4
3
H); 4.38 (m, 1H); 4.25 (dd, J = 6.1, 11.5 Hz, 1H);
.06 (d, J = 4.0, 11.7 Hz, 1H); 2.07 (s, 3H); 2.06 (s,
H,); 2.00 (s, 3H); 1.60 (m, 2H); 1.24 (br. s, 26H,); 0.88
The retrosynthetic analysis (Scheme 1) indicates that
the 1,2-diacetyl D-erythro-sphinganine 4 can be syn-
thesized from the D-erythro-sphinganine triacetate 6,
which can be prepared from the monoacetyl ester 8.
On the other hand, L-threo-sphinganine triacetate 7 can
be prepared from its diacetyl compound 5, which can
also be prepared from the same monoacetyl ester 8. The
monoacetyl compound 8 can in turn, be prepared from
the Garner aldehyde 9.
1
3
(
1
t, J = 7.0 Hz, 3H). C NMR (125 MHz, CDCl ):
3
70.9; 170.9; 169.7; 74.0; 62.5; 50.5; 31.9; 31.4; 29.6;
2
9.6; 29.5; 29.4; 29.3; 25.3; 22.6; 20.9; 20.8; 14.1. ESI
+
MS: m/z 428 [M+H] . Anal Calcd. for C H NO : C,
24
45
5
6
7.41; H, 10.61%. Found: C, 67.30; H, 10.64%.
2.9 N-((2S,3R)-1,3-Dihydroxyoctadecan-2-yl)
acetamide (13)
The present synthesis was initiated by treatment of
the Garner aldehyde 9 with 1-bromo pentadecane and
To a solution of triacetate 6 (0.4 g, 0.935 mmol) in
◦
Mg in THF at −78 C and the mixture was brought to
absolute MeOH (6 mL) was added anhydrous Na CO
2
3
r.t. to produce the diastereomeric alcohols 10 and 10a
(
1
0.118 g, 1.12 mmol). The mixture was stirred at r.t. for
h. Then, the solution was filtered, the solvent evapo-
rated and the solid residue was purified over silica gel
eluent, CH Cl with increasing amount of MeOH) to
(Scheme 2). The stereochemistry of the two diastere-
omers 10 and 10a were assigned by following Buono’s
9
method. According to this method, syn alcohol is major
(
2
2
25
product compared to anti-alcohol. This stereochemistry
is further confirmed by subsequent conversion to the
target molecules. The two diastereomers were separated
by careful CC (silica gel 100–200 mesh, 0–5% increas-
ing amount of AcOEt in hexane), which produced 10
and 10a in the ratio 9:1 (syn:anti, 9:1) with 86% yield.
Due to less amount of minor diastereomer 10a, we
have synthesized 1,2-diacetyl D-erythro-sphinganine
give 1,3-diol 13 (0.263 g, 82%) as a white solid. [α] =
D
−1
+
6.6 (c = 0.2, CH OH). IR õ (KBr)/cm : 3400,
3
max
1
2
940, 2835, 1650, 1548, 1430, 1362, 1061. H NMR
(
500 MHz, CD OD): 3.86 (m, 1H); 3.72–3.64 (m, 2H);
3
3
2
.59 (m, 1H); 1.97 (s, 3H); 1.52 (m, 2H); 1.28 (br. s,
13
6H); 0.89 (t, 3H, J = 7.0 Hz). C NMR (125 MHz,
CD OD): 173.4; 72.3; 62.1; 57.0; 34.8; 33.1; 30.8; 30.5;
3
2
6.8; 23.7; 22.8; 14.4. ESI MS: m/z 344 [M+H]+. Anal
(4) and D-erythro-sphinganine triacetate (6) from major
Calcd. for C H NO : C, 69.92; H, 12.03%. Found: C,
20
41
3
diastereomer 10.
70.04; H, 12.00%.
The acetonide group of alcohol 10 was deprotected
by treatment with PPTS in MeOH to form diol 11 with
2.10 1,2-Diacetyl D-erythro-sphinganine (4)
10
9
2% yield (Scheme 3). The 1,3-diol 11 was mono
To a solution of 1,3-diol 13 (0.1 g, 0.29 mmol) in dry protected of its primary hydroxyl group as acetyl ester
CH Cl (4 mL), Et N (0.04 mL, 0.29 mmol) was added, 8 by treatment with Ac O and Et N in CH Cl with
2
2
3
2
3
2
2
11
followed by Ac O (0.027 mL, 0.29 mmol) was added 77% yield. The mono acetyl ester 8 was converted
at 0 C and the reaction mixture was allowed to rise to to 1,2-diacetyl L-threo-sphinganine 5 by following two
2
◦
r.t. After completion of reaction (2 h), the reaction mix- steps: i) Boc group was deprotected from 8 by using
ture was washed with brine (5 mL) and water (5 mL), excess TFA in CH
Cl ; ii) unprotected amine was con-
2
2
dried over Na SO and evaporated. The crude product verted to N-acylated amine on treatment with acetyl
2
4
12
was purified by silica gel CC using (AcOEt/hexane, chloride, aq.NaHCO in CH Cl with 72% yield.
3
2
2

Total synthesis of sphingolipids
1793
Scheme 1. Retrosynthetic analysis of sphingolipids.
Scheme 2. Grignard reaction on Garner aldehyde.
◦
Scheme 3. (a) PPTS/MeOH, r.t., 2 h, 92%. (b) Ac2O, Et3N, CH2Cl2, 0 C-r.t.,
2
h, 77%. (c) i) TFA/CH2Cl2, r.t., 1 h. ii) Acetyl chloride, NaHCO3, CH2Cl2-
◦
H2O, r.t., 2.5 h, 72% (Over two steps). (d) Ac2O, Et3N, CH2Cl2, 0 C-r.t., 2 h,
79%.
◦
Scheme 4. (a) PPh3, AcOH, DIAD, THF, 0 C-r.t., 4 h, 77%. (b) i) TFA/
CH2Cl2, r.t., 1 h. ii) AcCl, NaHCO3, CH2Cl2-H2O, r.t., 2.5 h, 73% (Over two
◦
steps). (c) Na2CO3/MeOH, r.t., 1 h, 82%. (d) Ac2O, Et3N, CH2Cl2, 0 C-r.t.,
2
h, 79%.
1
,2-Diacetyl L-threo-sphinganine 5 was converted to L-
The mono acetyl ester 8 was subjected to Mitsunobu
threo-sphinganine triacetate 7 by treatment with Ac O inversion by using triphenyl phosphine (PPh ), AcOH
2
3
and Et N in CH Cl with 79% yield.
and diisopropyl azodicarboxylate (DIAD) in dry THF
3
2
2

1794
Paramesh Jangili et al.
to obtain 1,3-diacetyl compound 12 with 77% yield13 References
(
Scheme 4). 1,3-Diacetyl compound 12 was converted
1
2
. Hakomori S 1990 J. Biol. Chem. 265 18713
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to D-erythro-sphinganine triacetate 6 by following two
steps: i) Boc group was deprotected from 12 by using
excess TFA in CH Cl ; ii) unprotected amine was con-
verted to N-acylated amine on treatment with AcCl,
aq. NaHCO in CH Cl with 73% yield. D-erythro-
sphinganine triacetate 6 was converted to 1,3-diol 13
2
332
2
2
3. Mer J N and Hakomori S 1983 In Hand book of Lipid
Research Vol. 3, Sphingolipid Biochemistry D J Hanahan
(Ed.) (New York: Plenum Press)
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14
by treatment with Na CO in MeOH at r.t. with 82%
2
3
5
yield. The 1,3-diol 13 was mono protected of its pri-
mary hydroxyl group as acetyl ester by treatment with
Ac O and Et N in CH Cl to produce 1,2-diacetyl D-
6. Choi J-H, Yoshida M, Suzuki T, Harada E, Kawade M,
Yazawa K, Nishimoto S, Hirai H and Kawagishi H 2013
Tetrahedron 69 8609
7. (a) Paramesh J, Kumar C G, Poornachandra Y and Das
B 2015 Synthesis 47 653; (b) Bhunia N and Das B
2
3
2
2
erythro-sphinganine 4 with 79% yield. The physical
1
13
(optical rotation) and the spectral ( H and C NMR and
MS) properties of 4 were found to be identical to those
2
015 Synthesis 47 1499; (c) Lingaiah M, Kumar C G,
Poornachandra Y and Das B 2015 Tetrahedron Lett.
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Acta 98 509; (e) Srilatha M and Das B 2015 Helv. Chim.
Acta 98 267; (f) Reddy N S and Das B 2015 Helv.
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4
. Conclusions
In conclusion, we have described the stereoselective
total synthesis of naturally occurring sphingolipid
8. (a) Shibuya H, Kawashima K, Ikeda M and Kitagawa
I 1989 Tetrahedron Lett. 30 7205; (b) Cook G R and
Pararajasingham K 2002 Tetrahedron Lett. 43 9027;
1,2-diacetyl D-erythro-sphinganine (4) along with
(
4
c) Mori K and Umemura T 1981 Tetrahedron Lett. 22
433; (d) Umemura T and Mori K 1987 Agric. Biol.
three other sphingolipids, namely, 1,2-diacetyl L-
threo-sphinganine (5) (C-3 epimer of 4), D-erythro-
sphinganine triacetate (6) (triacetyl derivative of
compound 2) and L-threo-sphinganine triacetate (7)
Chem. 51 1973; (e) Ravinder M, Narendar T R, Sunday
O O, Ramesh V and Rao V J 2012 Arkivoc vi 421;
(f) Azuma H, Tamagaki S and Ogino K 2000 J. Org.
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R C and Howell A R 2002 Org. Lett. 4 1719
. Villard R, Fotiadu F and Buono G 1998 Tetrahedron:
Asymmetry 9 607
(
triacetyl derivative of compound 3, Safingol). Synthe-
sis of 1,2-Diacetyl D-erythro-sphinganine (4) and 1,
-diacetyl L-threo-sphinganine (5) are reported here for
9
2
the first time.
1
0. Lin S, Yang Z-Q, Kwok B H B, Koldobskiy M, Crews
C M and Danishefsky S J 2004 J. Am. Chem. Soc.
1
26 6347
Supplementary information (SI)
1
1
1
1. Yadav J S, Aravind S, Kumar G M and Reddy B V S
1
13
All the copies of H NMR and C NMR are given in the
supporting information. Supplementary Information is
available at www.ias.ac.in/chemsci.
2012 Tetrahedron Lett. 53 6163
2. Mina J G, Mosely J A, Ali H Z, Denny P W and Steel
P G 2011 Org. Biomol. Chem. 9 1823
3. Wallner A, Mang H, Glueck S M, Steinreiber A, Mayer
S F and Faber K 2003 Tetrahedron: Asymmetry 14
2427
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Acknowledgments
1
The authors thank CSIR and UGC, New Delhi for grant
of fellowships and financial assistance.