A common and stereoselective strategy for the synthesis of N,O,O,O-tetra-acetyl d-ribo-(2S,3S,4R)-phytosphingosine and 2-epi-jaspine B

Article abstract of DOI:10.1016/j.tetlet.2011.07.032

A common and stereoselective strategy for the synthesis of N,O,O,O-tetra-acetyl d-ribo-(2S,3S,4R)-phytosphingosine and 2-epi-jaspine B was achieved by using Grignard addition on N-benzyl sugar lactamine and Wittig olefination as key steps.

Full text of DOI:10.1016/j.tetlet.2011.07.032

Tetrahedron Letters 52 (2011) 4861–4864
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A common and stereoselective strategy for the synthesis of N,O,O,O-tetra-acetyl
D-ribo-(2S,3S,4R)-phytosphingosine and 2-epi-jaspine B
⇑
G. Srinivas Rao, B. Venkateswara Rao
Organic Division III, Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A common and stereoselective strategy for the synthesis of N,O,O,O-tetra-acetyl D-ribo-(2S,3S,4R)-phyto-
Received 10 June 2011
Revised 5 July 2011
Accepted 9 July 2011
Available online 22 July 2011
sphingosine and 2-epi-jaspine B was achieved by using Grignard addition on N-benzyl sugar lactamine
and Wittig olefination as key steps.
Ó 2011 Elsevier Ltd. All rights reserved.
Sphingoids are long-chain amino-diol and -triol bases that form
the backbone and the characteristic structural unit of sphingoli-
pids, which are important membrane constituents and play a vital
role in cell regulation as well as signal transduction.1 Furthermore,
glycosphingolipids show important biological activities, such as
antitumor,2a antiviral,2b antifungal,2c and cytotoxic properties.2d
Phytosphingosines, one of the major classes of sphingoids, have
been isolated and identified either separately or as parts of sphin-
golipids from plants,3a marine organisms,3b,c fungi,3d yeasts3e and
even mammalian tissues3f–k of kidney,3g liver,3h uterus,3i intes-
tine,3j and skin.3k In addition to being base components of sphingo-
lipids in membranes, phytosphingosines themselves are found to
be bioactive lipids. For example, ribo-phytosphingosine 1 is a po-
tential heat stress signal in yeast cells.4 It has also been established
that various diastereomers of sphingosines exhibit different activ-
ities and metabolism.5 Some of its derivatives exhibit important
physiological activities.6 For instance KRN 7000 (Fig. 1) which is
a glucosphingolipid exhibits natural killer activity and strongly
inhibits tumor metastasis in mice.6b Since it is costly to isolate
these lipids from the natural sources, and also not possible to ob-
tain homogeneous material for biological studies, a great work
has been carried out for the synthesis of these compounds. Among
all the eight possible stereoisomers of phytosphingosine
cell lines. Later, Debitus and co-workers9 isolated the same com-
pound from a Vanuatuan marine sponge genus Jaspis and named
it as jaspine B 2a. This compound displayed remarkable bioactivity
(IC50 0.24 lM) against the A549 human lung carcinoma cell line
using the ATPlite assay and represented as the most potent anti-
cancer agent on this cell line. Delgado and co-workers reported
that the potency of cytotoxicity is dependent on the stereochemis-
try of the tetrahydrofuran moiety.10
The novel structural features and interesting biological activity
of pachastrissamine have prompted chemists to develop several
syntheses for jaspine B 2a and its isomers.11 Our group published
the first total synthesis of jaspine B 2a and its C2 epimer 2b.12a
We also published the synthesis of the C2 and C3 epimer 2c and
an enantiomer of jaspine B 2d and their biological activity in com-
parison to jaspine B 2a12b and 3-epi jaspine 2e.12c
In continuation of our efforts in this area, we envisaged a con-
cise, efficient, and common method for the synthesis of N,O,O,O-
tetra-acetyl ribo-(2S,3S,4R)-phytosphingosine 3 and 2-epi-jaspine
B 2b. The starting material for our approach is
an inexpensive sugar and possesses desired chirality. The retrosyn-
thetic analysis of N,O,O,O-tetra-acetyl -ribo-(2S,3S,4R)-phyto-
D-ribose, which is
D
sphingosine 3 and 2-epi-jaspine 2b is depicted in Scheme 1.
Compound 4 is a common intermediate for the synthesis of 3
and 2b and it can be obtained from compound 5 after appropriate
manipulations. The amino group can be introduced by nucleophilic
addition on ribosylamine 6 and the required lipid chain can be
introduced by Wittig olefination.
Earlier we explored stereoselective Grignard addition on chiral-
imines for the synthesis of polyhydroxylated pyrrolidines13 and
carbasugrs.14 In this report we expanded the utility of this sugari-
mine Grignard addition, for the synthesis of N,O,O,O-tetra-acetyl
ribo-phytosphingosine 3 and 2-epi-jaspine 2b.
(2S,3S,4R)-2-aminooctadecane-1,3,4-triol
1
with
D-ribo-stereo-
chemistry is the most common one. Owing to their interesting bio-
logical activities many synthetic approaches to enantiomerically
pure
D-ribo-phytosphingosine 1 have been reported in the
literature.7
Jaspine B, also known as pachastrissamine (2a, Fig. 1), is a cyclic
anhydro-phytosphingosine derivative, which was initially isolated
from a marine sponge Pachastrissa sp. (family Calthropellidae) in
2002 by Higa and co-workers,8 and found to have cytotoxicity at
a level of IC50 0.01
lg/mL against P388, A549, HT29, and MEL28
The starting material 5-O-tert-butyl dimethylsilyl-2,3-O-isopro-
pylidene-
D-ribofuranose 7, required for our synthesis was prepared
from
D
-ribose using our earlier procedure (Scheme 2).15 Reaction
⇑
Corresponding author. Tel./fax: +91 40 27193003.
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B. Venkateswara
on 7 with benzylamine gave ribosylamine 6. Treatment of the
crude ribosylamine 6 with vinylmagnesium bromide at ꢀ78 °C
Rao).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.032

4862
G. Srinivas Rao, B. Venkateswara Rao / Tetrahedron Letters 52 (2011) 4861–4864
OH
O
OH
O
NH2 OH
C14H29
C25H51
OH
H2N
OH
HO
HO
HN
O
HO
OH
C14H29
2a
O
C14H29
1
D-ribo -phytosphingosine
Jaspine B
OH
KRN-7000
H2N
OH
H2N
OH
H2N
OH
H2N
OH
C14H29
2b
C14H29
enantiomer of
C14H29
O
O
C14H29
2e
O
O
2- epi-Jaspine B
C2 and C3 epimer
3-epi-Jaspine B
2d
Jaspine B
of jaspineB 2c
Figure 1. Structures of
D-ribo-(2S,3S,4R)-phytosphingosine, KRN 7000, jaspine B, and its isomers.
OAc NHAc
OAc
C14H29
TBSO
NHBn
OAc
3
O
NHBn
OH NHBn
OH
TBSO
C12H25
HO
O
O
H2N
OH
O
O
OH
4
5
6
C14H29
O
2b
Scheme 1. Retrosynthetic analysis of N,O,O,O-tetra-acetyl
D-ribo-phytosphingosine 3 and 2-epi-jaspine B 2b.
TBSO
TBSO
NHBn
O
NBnCbz
O
NHBn
OH
TBSO
TBSO
a
b
c
HO
HO
O
O
O
O
O
O
O
O
8
6
7
5
O
O
TBSO
HO
HO
HO
TBSO
HO
NBnCbz
OH
BnN
O
BnN
O
d
f
g
e
O
O
O
O
O
O
11
9
10
O
BnN
O
OAc NHAc
OAc
OH NHBn
OH
h
i
C12H25
C14H29
C12H25
OAc
O
O
OH
3
4
12
Scheme 2. Synthesis of N,O,O,O-tetra-acetyl
D
-ribo-phytosphingosine 3. Reagents and conditions: (a) BnNH2, MeOH, reflux; (b) vinylmegnesium bromide, THF, ꢀ78 °C, 2 h,
72%; (c) Cbz-Cl, NaHCO3, MeOH, 1 h, 98%; (d) (i) O3, CH2Cl2, ꢀ78 °C, 30 min and DMS, (ii) NaBH4, MeOH, 1 h (85% for two steps); (e) NaH, THF, 30 min, 92%; (f) TBAF, THF, 2 h,
96%; (g) (i) NaIO4, CH2Cl2, H2O, rt, 4 h, (ii) C13H27Ph3P+Brꢀ, n-BuLi, THF, 1 h (90% for two steps); (h) 6 N HCl, EtOH, reflux, 6 h, 94%; (i) (i) H2, Pd/C, MeOH, 6 h, (ii) (Ac)2O, N(Et)3,
CH2Cl2, 6 h (85% for two steps).
gave exclusively 5 as a single isomer. The absolute configuration of
the newly generated stereo center was not confirmed at this stage,
but as per our earlier observation it should give the erythro-iso-
mer.14 The formation of erythro-isomer can be explained via seven
membered transition state A16 or Felkin-Anh model B (Fig. 2). In
fact the formation of erythro-isomer shows that chelation between
sugarimine and isopropylidene group has not taken place due to
steric strain.
The amino functionality in 5 was converted into carbamate
with CbzCl to give 8. Oxidative degradation of the alkene function-
ality in 8 with ozone afforded the aldehyde, which on treatment
with NaBH4 in MeOH gave alcohol 9. In order to protect the pri-
mary hydroxyl group, compound 9 was treated with sodium hy-
dride to give the cyclic carbamate 10. Deprotection of silylether
in 10 with TBAF gave diol 11. The diol functionality of compound
11 was oxidatively cleaved to aldehyde using NaIO4 in CH2Cl2/

G. Srinivas Rao, B. Venkateswara Rao / Tetrahedron Letters 52 (2011) 4861–4864
4863
M
M
HO
NBn
H
TBSO
O
NBn
TBSO
BnN
H
O
HO
Nu
H
O
O
Nu
TBSO
OH
O
O
A
B
Figure 2. Seven-membered transition state (A) and Felkin Anh Model (B).
References and notes
BocHN
HO
BocHN
AcHN
OH
C14H29
OH
C14H29
a
b
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4
O
OH
14
13
TFA.H2N
OH
OAc
C14H29
d
c
C14H29
TFA salt of 2b
O
O
15
Scheme 3. Synthesis of TFA salt of 2-epi-jaspine B 2b. Reagents and conditions: (a)
(i) H2, Pd/C, MeOH, 6 h, (ii) (Boc)2O, Et3N, CH2Cl2, 2 h (95% over two steps); (b) (i)
TsCl, Et3N, DMAP, CH2Cl2, 86%; (c) TFA, CH2Cl2, 2 h; 89%; (d) (Ac)2O, Et3N, CH2Cl2,
4 h, 94%.
H2O, which was carried to the next step without any purification.
Wittig reaction on crude aldehyde with C13H27PPhþBrꢀ gave 12.
3
Global deprotection of carbamate and acetonide in 12 with 6 N
HCl in EtOH under reflux conditions gave 4. Hydrogenation of 4
gave the D-ribo-phytosphingosine 1. For the sake of characteriza-
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tosphingosine 3,17 by treating with acetic anhydride and Et3N,
whose physical properties are in good agreement with the reported
values.18
7. For a review of PHS synthesis prior to 2002, see: (a) Howell, A. R.; Ndakala, A. J.
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To convert the compound 4 into 2-epi-jaspine B 2b the follow-
ing reactions were carried out (Scheme 3). Hydrogenation of com-
pound 4 using Pd/C in MeOH followed by treatment of the
resultant amino functionality with (Boc)2O afforded carbamate
13. Regioselective tosylation of the primary hydroxy group of 13
prompted spontaneous cyclization to give the tetrahydrofuran
derivative 14.11b Deprotection of the Boc group in 14 with TFA/
CH2Cl2 provided the desired 2-epi-jaspine B 2b as TFA salt19a and
TFA salt of 2b on acetylation with acetic anhydride in the presence
of excess Et3N gave the acetyl derivative 15.19b The physical prop-
erties of the TFA salt of 2-epi-jaspine B 2b13a and its diacetative
derivative 1512b were in good agreement with the reported values.
In conclusion we have successfully demonstrated a general
strategy for the synthesis of N,O,O,O-tetra-acetyl
D-ribo-phyto-
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15 by using stereoselective vinyl Grignard on ribosylamine. Appli-
cation of this strategy to make some more analogs of phytosphin-
gosine and jaspine B are in progress.
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Acknowledgments
G.S.R. thanks CSIR, New Delhi for research fellowship. The
authors also thank Dr. J. S. Yadav for his constant support and
encouragement. We also thank DST (SR/S1/OC-14/2007), New Del-
hi, for financial assistance.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.07.032.

4864
G. Srinivas Rao, B. Venkateswara Rao / Tetrahedron Letters 52 (2011) 4861–4864
Chem. 2010, 75, 3831; (r) Yoshimitsu, Y.; Inuki, S.; Oishi, S.; Fujii, N.; Ohno, H. J.
NMR (CDCl3, 300 MHz): d 6.00 (d, 1H, J = 9.4 Hz), 5.04 (dd, 1H, J = 3.0 and
8.3 Hz), 4.83–4.91 (m, 1H), 4.40 (m, 1H), 4.22 (dd, 1H, J = 4.7 and 11.5 Hz), 3.94
(dd, 1H, J = 3.0 and 11.5 Hz), 2.01 (s, 3H), 1.99 (s, 6H), 1.96 (s, 3H), 1.76 (m, 1H),
1.51 (m, 1H), 1.05–1.31 (m, 24H), 0.80 (t, 3H, J = 6.6 Hz); 13C NMR (CDCl3,
75 MHz): d 171.1, 170.8, 170.0, 169.7, 72.9, 71.9, 62.8, 47.6, 31.9, 29.6, 29.5,
29.4, 29.3, 29.3, 28.1, 25.5, 23.3, 22.6, 21.0, 20.7, 14.1; ESIMS m/z: 486 [M+H]+;
HRMS (ESI): calcd for C26H48NO7 [M+H]+ 486.3430, found 486.3441.
Org. Chem. 2010, 75, 3843; (s) Urano, H.; Enomoto, M.; Kuwahara, S. Biosci.,
Biotechnol., Biochem. 2010, 74, 152; (t) Salma, Y.; Ballereau, S.; Maaliki, C.;
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While preparing our manuscript the following publications appeared (w)
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18. Shirota, O.; Nakanishi, K.; Berova, N. Tetrahedron 1999, 55, 13643.
19. (a) Spectral data of compound of 2a as TFA salt: ½a D26
ꢁ
+16.2 (c 1.1, EtOH),{lit.12a
½ ꢁ +14.46 (c 1.5, EtOH)}; IR m ;
a 2D5 max: 2920, 2851, 1669, 1209, 1147 cmꢀ1 1H
12. (a) Sudhakar, N.; Kumar, A. R.; Prabhakar, A.; Jagadeesh, B.; Rao, B. V.
Tetrahedron Lett. 2005, 46, 325; (b) Chitra, C. J.; Sudhakar, N.; Kumar, A. R.; Rao,
B. V.; Roy, S.; Benerjee, R. Synthesis 2010, 115; (c) Rao, G. S.; Sudhakar, N.; Rao,
B. V.; Basha, S. J. Tetrahedron: Asymmetry 1963, 2010, 21.
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21, 2314; (b) Chandrasekhar, B.; Rao, B. V. Tetrahedron: Asymmetry 2009, 20,
1217; (c) Chandrasekhar, B.; Madhan, A.; Rao, B. V. Tetrahedron 2007, 63, 8746;
(d) Madhan, A.; Rao, B. V. Tetrahedron Lett. 2003, 44, 5641.
NMR (CD3OD, 300 MHz): d 4.14 (m, 1H), 4.03 (t, 3H, J = 5.7 Hz), 3.65–3.80 (m,
3H), 1.17–1.70 (m, 26H), 0.89 (t, 3H, J = 6.8 Hz); 13C NMR (CD3OD, 75 MHz): d
85.3, 74.4, 69.4, 53.7, 47.9, 34.1, 33.1, 30.8, 30.7, 30.6, 30.5, 26.9, 23.7, 14.4;
ESIMS m/z: 300 (M++1ꢀCF3COOH); HRMS (ESI): calcd for C18H38NO2 [M+H]+
300.2902, found 300.2902.
(b) Spectral data of compound 15: ½a D26
ꢁ
ꢀ15.1 (c 1.2, CHCl3), {lit.11b a 2D2
½ ꢁ ꢀ15.4
(c 1.0, CHCl3)}; IR
mmax: 3298, 2920, 2851, 1740, 1658, 1557, 1376, 1232,
1072 cmꢀ1 1H NMR (CDCl3, 300 MHz): d 5.68 (br d, 1H, J = 7.7 Hz), 4.66 (m,
;
14. Rao, J. P.; Rao, B. V.; Swarnalatha, J. L. Tetrahedron Lett. 2010, 51, 3083.
15. Kumar, D. N.; Rao, B. V.; Ramanjaneyulu, G. S. Tetrahedron: Asymmetry 2005, 6,
1611.
1H), 4.18 (t, 1H, J = 7.7 Hz), 3.84–3.90 (m, 1H), 3.52 (t, 1H, J = 8.5 Hz), 2.14 (s,
3H), 2.02 (s, 3H), 1.49–1.68 (m, 2H), 1.15–1.47 (m, 26H), 0.88 ((t, 1H,
J = 6.6 Hz); 13C NMR (CDCl3, 75 MHz): d 170.1, 169.9, 84.0, 76.7, 69.7, 49.9, 33.5,
31.9, 29.6, 29.5, 29.5, 29.4, 29.3, 25.5, 23.2, 22.7, 21.0, 14.1; ESIMS m/z: 406
(M+Na)+; HRMS (ESI): calcd for C22H41NO4Na [M+Na]+ 406.2933, found
406.2933.
16. Mekki, B.; Singh, G.; Wightman, R. H. Tetrahedron Lett. 1991, 32, 5143.
17. Spectral data of compound 3: ½a D26
ꢁ
+ 23.1 (c 0.62, CHCl3); {lit.18
1.1, CHCl3)}; IR m ;
½
a 2D0
ꢁ
+21.9 (c
max: 2924, 2854, 1741, 1659, 1543, 1370, 1221, 1044 cmꢀ1 1H