A novel stereoselective synthesis of pachastrissamine (jaspine B) starting from 1-pentadecanol

Article abstract of DOI:10.1016/j.tetasy.2007.12.001

A novel stereoselective synthesis of pachastrissamine (jaspine B), starting from commercially available 1-pentadecanol is described. Sharpless asymmetric dihydroxylation and a chelation controlled vinyl Grignard reaction are the key steps in this synthetic strategy.

Full text of DOI:10.1016/j.tetasy.2007.12.001

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 209–215
A novel stereoselective synthesis of pachastrissamine (jaspine B)
starting from 1-pentadecanol
K. Venkatesan and K. V. Srinivasan*
Division of Organic Chemistry, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
Received 14 November 2007; accepted 4 December 2007
Available online 11 January 2008
Abstract—A novel stereoselective synthesis of pachastrissamine (jaspine B), starting from commercially available 1-pentadecanol is
described. Sharpless asymmetric dihydroxylation and a chelation controlled vinyl Grignard reaction are the key steps in this synthetic
strategy.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
displayed a remarkable bioactivity (IC50 = 0.24 lM)
against the A549 human lung carcinoma cell line using
the ATPlite assay and represented the most potent antican-
cer agent on this cell line yet isolated from the Jaspis
genus.1,3 Jaspine B represents the first example of an
anhydrophytosphingosine structural feature in a natural
product. Pachastrissamine possesses three contiguous ste-
reogenic centers and is structurally similar to the open
Pachastrissamine I (Fig. 1), a naturally occurring novel
anhydrophytosphingosine derivative, has recently been iso-
lated from the Okinawan marine sponge Pachastrissa sp.1
Another research group has reported the isolation of the
same natural product from a different marine sponge, Jas-
pis sp. and named it as jaspine B.2 Jaspine B hydrochloride
H
AcHN
OAc
C
OH
H2N
OH
HN
O
Jaspine A
14H29
III
C
14H29
O
O
C
14H29
Panchatrissamine
(Jaspine B) I
Diacetyl derivative
O
II
OH OH
OH NH2
OH
NH2
OH
C13H27
OH
H29C14
H
29C14
OH
Guggultetrol
OH
OH
D-erythro-sphingosine
D-ribo-phytosphingosine
VI
V
IV
HO
H
N
OH
O
VII
H2N
OH
Figure 1.
*
Corresponding author. Tel.: +91 20 25902098; fax: +91 20 25902629; e-mail: kv.srinivasan@ncl.res.in
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.12.001

210
K. Venkatesan, K. V. Srinivasan / Tetrahedron: Asymmetry 19 (2008) 209–215
chain sphingolipid D-ribo-phytosphingosine IV. Interest-
ingly, guggultetrol VI, a naturally occurring lipid isolated
from the gum-resin of the tree Commiphoru mukul (gug-
gulu), known in Ayurveda, the Indian traditional system
of medicine, for the treatment of arthritis, inflammation,
obesity, and disorders of lipid metabolism closely resem-
bles the sphigolipid phytosphingosine IV.4 The impressive
biological activity and the novel structural features encour-
aged us to undertake a stereoselective synthesis of this
interesting natural product. In the interest of evaluating
the biological and pharmacological properties of these
compounds, it was necessary to obtain sufficient quantities
by chemical synthesis. Most of the total syntheses known
for jaspine B derive the asymmetry from the chiral pool
of starting materials5,6 such as xylose, glucose, and Gar-
ner’s aldehyde. Even though the synthesis of jaspine B, as
reported by Overkleeft and co-workers5d involved only
three steps, the starting material D-ribo-phytosphingosine
itself has to be prepared from 3,4,6-tri-O-acetyl-D-galactal
in nine steps, and is thus highly expensive and less widely
available. Moreover, some of the literature methods for
the synthesis of jaspine B involve expensive catalysts such
as Grubb’s catalyst5b and unnatural (ꢀ)-diethyl tartrate.5e
H2N
OH
OH N3
Ref. 6b
OTs
H
29C14
C14H27
OH
O
16
(2S,3S,4S)-jaspine B
Ia
OH
OMOM OH
COOEt
H29C14
H
29C14
OH
AD
COOEt
OMOM
3
7
H29C14
OH
H29C14
1
2
Scheme 1. Retrosynthetic approach to (2S,3S,4S)-jaspine B I.
in alcohol 5 in 96% yield. Alcohol 5 was oxidized with
IBX to afford aldehyde 6. Due to the unstable nature of
aldehyde 6, it was immediately taken to the next step as
such without further purification (Scheme 2).
To the best of our knowledge, there has been no synthetic
report which describes asymmetric synthesis of jaspine B,
starting from 1-pentadecanol, which is achiral. However,
most recently two contemporary synthetic protocols for
the preparation of jaspine B starting from different achiral
starting materials have been reported.7 As a part of our
ongoing project for the asymmetric synthesis of biologi-
cally active compounds,8 we herein report a novel route
to the synthesis of jaspine B I, starting from the commer-
cially available, and inexpensive achiral starting material
1-pentadecanol 1, for the first time.
COOEt
a
H29C14
H29C14
OH
OH
2
1
OMOM O
O
c
b
d
H
29C14
OEt
OMOM
H
29C14
OEt
OH
OH
4
3
2. Results and discussion
OMOM
OMOM
The Sharpless asymmetric dihydroxylation can be envi-
sioned as a powerful tool offering considerable opportuni-
ties for synthetic manipulation.9 Sharpless asymmetric
dihydroxylation and a chelation controlled vinyl Grignard
reaction are the key steps of our synthetic strategy and are
shown in Scheme 1. We envisioned that azido diol 16 could
be prepared from terminal olefin 7, which in turn could be
prepared from diol 3 after suitable protection via a chela-
tion controlled vinyl Grignard reaction. Diol 3 itself could
be prepared by Sharpless asymmetric dihydroxylation of
an a,b-unsaturated olefin ester 2, which in turn could be
obtained from the commercially available 1-pentadecanol
1.
e
H29C14
H
29C14
O
OMOM
OMOM
6
5
Scheme 2. Synthesis of intermediate 6 (Sharpless dihydroxylation method
as a key step). Reagents and conditions: (a) (i) PCC, dry DCM, 0 °C, 3 h,
(ii) Ph3P@CHCO2Et, benzene, reflux, 4 h, 92%; (b) (DHQ)2PHAL,
K2CO3, K3[Fe(CN)]6, MeSO2NH2, OsO4 (0.1 M sol in toluene), t-
BuOH/H2O (1:1), 0 °C, 24 h, 88%; (c) MOMCl, dry DCM, DIPEA,
0 °C to rt, overnight, 96%; (d) DIBAL-H, dry DCM, ꢀ10 °C, 1 h, 96%; (e)
IBX, EtOAc, reflux, 3 h.
To create a third stereogenic center with the required
stereochemistry, a chelation controlled vinyl Grignard
reaction11 was performed (Scheme 3).
1-Pentadecanol 1 after subjection to oxidation with PCC,
followed by a Wittig olefin reaction, furnished trans-a,b-
unsaturated ester 2 in 92% yield. Olefin 2 was treated with
osmium tetroxide and potassium ferricyanide as a co-oxi-
dant in the presence of a (DHQ)2PHAL ligand under
asymmetric dihydroxylation (AD) conditions9 to give diol
3 in 88% yield and 97% ee.10 Treatment of the diol with
MOMCl in the presence of DIPEA gave the di MOM
derivative 4, which on reduction with DIBAL-H resulted
Thus, the crude aldehyde 6 was subjected to a vinylation
reaction using vinyl magnesium bromide in the presence
of MgBr2ꢁEt2O at ꢀ78 °C to furnish the syn-isomer (allylic
alcohol 7) in 89% yield with high diastereomeric excess
1
(de = >95%) as judged by H and 13C NMR spectroscopic
analysis.

K. Venkatesan, K. V. Srinivasan / Tetrahedron: Asymmetry 19 (2008) 209–215
211
cleavage12 followed by reduction with NaBH4 in MeOH to
afford terminal alcohol 11 in 82% yield, which was pro-
tected as the MOM ether using MOMCl to furnish
MOM-protected alcohol 12 in 94% yield and subsequently
the benzyl moiety of 12 was deprotected with 5% Pd/C in
methanol to give the secondary alcohol 13 in 96% yield.
The secondary alcohol 13 was tosylated using TsCl in the
presence of Et3N and subsequently a nucleophilic displace-
ment with sodium azide furnished the required azide 14 in
83% yield (Scheme 5).
OMOM
OMOM OH
a
H
29C14
H29C14
O
OMOM
OMOM
6
7
Scheme 3. Chelation controlled vinyl Grignard reaction. Reagents and
conditions: (a) vinyl magnesium bromide, MgBr2ꢁOEt2, dry THF, ꢀ78 °C,
45 min, 89%.
Allylic alcohol 7 was mesylated using MsCl in the presence
of Et3N after which nucleophilic displacement with sodium
azide furnished the terminal azide 9 in only 93% yield.
Also, the one-pot azide formation conducted in DMF med-
ium under the standard conditions (DMF/CCl4 (7:1), TPP,
NaN3, 75 °C, 12 h) resulted in no reaction (96% of 7 was
recovered from the reaction medium) as shown in Scheme
4.
Deprotection of the MOM groups followed by mono-tosyl-
ation furnished tosyl derivative 16. The spectral and anal-
ytical data of 16 are in conformity with the reported
data in the literature.6b Compound 16 was subjected to
cyclization and subsequent reduction, by employing the
literature procedure6b to furnish jaspine B I with all the
desired stereocenters (88% yield from 16, Scheme 6).
3. Conclusion
OMOM
In conclusion, a novel total synthesis of jaspine B, with
high enantioselectivity starting from an achiral molecule
has been developed, in which two of the stereogenic centers
were established by Sharpless asymmetric dihydroxylation,
and the third stereogenic center was established by a chela-
tion controlled vinyl Grignard reaction to afford jaspine B I
with the required stereochemistry.
N3
(93%)
H29C14
OMOM
a
b
9
7
OMOM N3
H
29C14
OMOM
8
4. Experimental
Scheme 4. Reagents and conditions: (a) (i) MsCl, dry CH2Cl2, Et3N, 0 °C,
3 h, (ii) NaN3, dry DMF, 65 °C, 12 h, 93%; (b) DMF/CCl4 (7:1), PPh3,
NaN3, 75 °C, 12 h.
4.1. General experimental
Solvents were purified and dried by standard procedures
prior to use; petroleum ether with boiling range 60–80 °C
was used for column chromatography. Optical rotations
were measured using sodium D line on a JASCO-P-1020-
Thus, allyl alcohol 7 was benzylated to give the terminal
olefin 10 in 87% yield. Olefin 10 was subjected to oxidative
OMOM OBn
OMOM OBn
a
7
b,c
OH
H
29C14
H29C14
OMOM
OMOM
11
10
OMOM OH
OMOM
OBn
OMOM
e
d
f
OMOM
OMOM
H
29C14
H
29C14
OMOM
OMOM
12
13
OMOM N3
H
29C14
OMOM
14
Scheme 5. Synthesis of intermediate 14. Reagents and conditions: (a) BnBr, NaH, THF, 0 °C, 4 h, 87%; (b) (i) OsO4 (0.1 M sol in toluene), t-BuOH/THF/
H2O (3:2:1), NMO, overnight, (ii) NaIO4, NaHCO3, water, rt, 3 h; (c) NaBH4, MeOH, 0 °C to rt, 1 h, 82% from 10; (d) MOMCl, dry DCM, DIPEA, 0 °C
to rt, 6 h, 94%; (e) H2/Pd–C, MeOH, rt, overnight, 96%; (f) (i) TsCl, dry CH2Cl2, Et3N, DMAP (cat.), 0 °C to rt, 3 h, (ii) NaN3, dry DMF, 95 °C, 14 h,
83%.

212
K. Venkatesan, K. V. Srinivasan / Tetrahedron: Asymmetry 19 (2008) 209–215
peaks), 31.9, 32.2, 60.1, 121.2, 149.6, 166.8. Anal. Calcd
for C19H36O2: C, 76.97; H, 12.24. Found: C, 76.88; H,
12.31.
H2N
OH
C14H29
OH N3
c
a
OR
14
H
29C14
O
OH
b
I
4.1.2. Synthesis of (2R,3S)-2,3-dihydroxyheptadecanoic acid
ethyl ester 3. To a mixture of K3[Fe(CN)]6 (15.99 g,
15
16
R = H
R = Ts
48.55 mmol),
K2CO3
(6.70 g,
48.55 mmol)
and
Scheme 6. Synthesis of (2S,3S,4S)-jaspine B I. Reagents and conditions:
(a) aq HCl, THF, 0 °C to rt, 5 h; (b) p-tosyl chloride, CH2Cl2, DMAP,
0 °C to rt, 4 h, 80% from 14; (c) Ref. 6b.
(DHQ)2PHAL (13.6 mg, 1 mol %), in t-BuOH–H2O (1:1,
80 mL) cooled to 0 °C, was added OsO4 as a 0.1 M solution
in toluene (0.70 mL, 0.4 mol %) followed by methanesul-
fonamide (1.54 g, 16.2 mmol). After stirring for 30 min at
0 °C, the (E)-a,b-unsaturated ester 2 (4.80 g, 16.19 mmol)
was added in one portion. The reaction mixture was stirred
at 0 °C for 24 h and then quenched with solid Na2SO3
(22 g). Stirring was continued for 60 min and the solution
was extracted with EtOAc (3 ꢂ 25 mL). The combined
organic phase was washed with brine, dried over Na2SO4,
and concentrated. The residue was purified by silica gel col-
umn chromatography using petroleum ether/EtOAc (3:2)
polarimeter under standard conditions. Infrared spectra
were recorded on Perkin Elmer FTIR spectrometer. Enan-
tiomeric excesses were measured using either chiral HPLC
or by comparison with the specific rotation. Elemental
analyses were carried out with a Carlo Erba CHNS–O
EA 1108 Elemental analyzer. All reactions requiring anhy-
drous conditions were performed under a positive pressure
of argon using oven-dried glassware (110 °C), which was
cooled under argon. Column chromatography was per-
formed using silica gel (100–200 mesh size and 230–400
mesh size for flash column chromatography) and TLC
was carried out using aluminum sheets precoated with sil-
ica gel 60F254 (Merck). All chemicals used were reagent
grade procured commercially and used without further
purification. 1H NMR and 13C NMR spectra were re-
corded on a Bruker Avance DPX 200/400 spectrometer
by using TMS as an internal standard. Infra red spectra
were recorded with ATI MATT-SON RS-1 FTIR spec-
trometer. MS analyses were performed on a Peseiex API
QSTAR Pulsar with an electrospray ionization mass spec-
trometer (LC–MS), using MeOH as a solvent (m/z, fragen-
tor 70 V).
to afford the diol 3 (4.71 g, 88%) as a colorless solid; mp
25
56–58 °C; ½aꢃD ¼ ꢀ7:1 (c 0.8, CHCl3). IR (CHCl3): 3400,
3133, 3020, 2927, 2855, 1732, 1515, 1466, 1389, 1215,
1
1030, 759, 670 cmꢀ1. H NMR (200 MHz, CDCl3): d 0.81
(t, J = 7.0 Hz, 3H), 1.18 (br s, 24H), 1.23 (t, J = 7.2 Hz,
3H), 1.49–1.57 (m, 2H), 2.0 (br s, 2H), 3.78 (dt, J = 7.1,
2.1 Hz, 1H), 4.01 (dd, J = 2.1 Hz, 1H), 4.17 (q,
J = 7.2 Hz, 2H). 13C NMR (50 MHz, CDCl3): d 14.1,
22.6, 25.7, 29.3, 29.5 (several overlapping peaks), 29.6,
31.9, 33.7, 61.9, 72.6, 73.1, 173.7. Anal. Calcd for
C19H38O4: C, 69.05; H, 11.59. Found: C, 69.12; H, 11.50.
4.1.3. Synthesis of (2R,3S)-2,3-bis(methoxymethoxy)-hepta-
decanoic acid ethyl ester 4. To a CH2Cl2 solution of pro-
tected diol 3 (4.50 g, 13.62 mmol) was charged into a flame
dried RB flask under argon atmosphere. DIPEA (9.5 mL,
54.48 mmol) was charged slowly over 5 min at rt and then
3.20 mL of MOMCl (42.22 mmol, 3.1 equiv) was slowly
added to the reaction mixture at to 0 °C over a period of
10 min. The reaction was stirred at rt for about 12 h and
quenched with 20 mL of water. The organic layer was
separated, dried over anhyd Na2SO4 and concentrated in
vacuo. The residue obtained was purified by silica gel
column chromatography using petroleum ether/EtOAc
4.1.1. Synthesis of trans-2-heptadecenoic acid ethyl ester
2. To an ice cold solution of 1-pentadecanol 1 (8.0 g,
35 mmol) in dry CH2Cl2 was charged PCC (11.32 g,
52.5 mmol) and the reaction mixture was stirred at 0 °C
for 3 h. The organic solvent was evaporated in vacuo and
to the residue obtained was charged 100 mL of diethyl
ether, stirred at rt for 15 min and filtered through a short
neutral alumina bed. The organic solvent was dried over
anhyd Na2SO4 and concentrated in vacuo. The crude alde-
hyde (1-pentadecanal) obtained was used as such for the
next step without further purification.
(20:1) to give 5.47 g of 4 as a pale yellow liquid in
25
96% yield. ½aꢃD ¼ þ43:6 (c 1.0, CHCl3). IR (CHCl3):
2927, 2855, 1748, 1466, 1370, 1216, 1153, 1112, 1032,
759, 667 cmꢀ1 1H NMR (200 MHz, CDCl3): d 0.81 (t,
.
To a solution of (ethoxycarbonylmethylene)triphenyl-
phosphorane (14.67 g, 42.23 mmol) in dry benzene
(120 mL) was added a solution of the above aldehyde in
dry benzene (100 mL). The reaction mixture was refluxed
for 4 h. It was then concentrated and purified by silica
gel column chromatography using petroleum ether/EtOAc
(9.5:0.5) as eluent to afford the a,b-unsaturated olefin
(9.55 g, 92%) as a colorless oily liquid; IR (CHCl3): 3133,
3020, 2927, 2855, 1732, 1515, 1466, 1389, 1215, 1030,
J = 7.1 Hz, 3H), 1.18 (br s, 24H), 1.23 (t, J = 7.2 Hz,
3H), 1.55–1.59 (m, 2H), 3.28 (s, 3H), 3.34 (s, 3H), 3.83–
3.92 (m, 1H), 4.10–4.18 (m, 3H), 4.59 (d, J = 2.4 Hz,
2H), 4.66 (d, J = 3.2 Hz, 2H). 13C NMR (100 MHz,
CDCl3): d 14.1, 14.2, 22.7, 25.4, 29.3, 29.5, 29.6 (several
overlapped peaks), 30.9, 31.9, 55.7, 56.2, 60.9, 76.8, 78.4,
96.4, 96.5, 171.0. Anal. Calcd for C23H46O6: C, 65.99; H,
11.08. Found: C, 65.90; H, 11.15.
759, 670 cmꢀ1
.
1H NMR (200 MHz, CDCl3): d 0.81 (t,
4.1.4. Synthesis of (2S,3S)-2,3-bis(methoxymethoxy)hep-
tadecan-1-ol 5. To a solution of 4 (5.30 g, 12.66 mmol)
in dry CH2Cl2 (75 mL) at ꢀ10 °C was added dropwise DI-
BAL-H (19 mL, 18.98 mmol, 1.0 M solution in toluene)
through a syringe. The reaction mixture was allowed to
warm to room temperature over 1 h, then re-cooled to
J = 7.0 Hz, 3H), 1.18 (br s, 24H), 1.23 (t, J = 7.2 Hz,
3H), 1.33–1.42 (m, 2H), 2.06–2.17 (m, 2H), 4.06 (q,
J = 7.2 Hz, 2H), 5.69 (td, J = 15.1, 1.6 Hz, 1H), 6.88–
6.97 (m, 1H). 13C NMR (50 MHz, CDCl3): d 14.2, 14.3,
22.7, 28.0, 29.2, 29.4, 29.5, 29.6 (several overlapping

K. Venkatesan, K. V. Srinivasan / Tetrahedron: Asymmetry 19 (2008) 209–215
213
0 °C and treated with saturated solution of sodium/potas-
sium tartrate. The solid material was filtered through a
pad of Celite and concentrated in vacuo. Silica gel column
chromatography of the crude product (residue) using
was dissolved in 2 mL of DMF. To this, NaN3 (0.049 g,
0.745 mmol) was added and the reaction mixture was
heated to 65 °C under an argon atmosphere for about
12 h. Then, the reaction mixture was concentrated to half
of its volume in vacuo, the residue obtained was dissolved
in 10 mL of EtOAc and washed with brine solution. The
organic solvent was separated, dried over Na2SO4 and con-
centrated in vacuo. The crude product was then purified by
silica gel column chromatography using petroleum ether/
petroleum ether/EtOAc (10:3) as eluent gave alcohol 5
25
(4.58 g, 96%) as a colorless oil. ½aꢃD ¼ ꢀ10:5 (c 1.0,
CHCl3). IR (neat, mmax): 3300, 3019, 2957, 2928, 2856,
1463, 1378, 1261, 1216, 1099, 1026, 838, 759, 669 cmꢀ1
.
1H NMR (200 MHz, CDCl3): d 0.81 (t, J = 7.1 Hz, 3H),
1.18 (br s, 24H), 1.55–1.59 (m, 2H), 1.88 (br s, 1H), 3.34
(s, 3H), 3.37 (s, 3H), 3.59–3.67 (m, 4H), 4.61–4.72 (m,
4H). 13C NMR (50 MHz, CDCl3): d 14.1, 22.7, 25.8,
29.3, 29.5, 29.6 (several overlapping peaks), 30.4, 31.9,
55.8, 55.9, 62.7, 78.4, 82.4, 96.8, 97.7. Anal. Calcd for
C21H44O5: C, 66.98; H, 11.78. Found: C, 66.89; H, 11.87.
EtOAc (9.5:0.5) to afford 0.247 g of azide 9 as a pale yellow
25
oily compound (93%). ½aꢃD ¼ þ8:25 (c 0.15, CHCl3). IR
(neat): mmax 2959, 2927, 2855, 2103, 1262, 1216, 1150,
1
1098, 1027, 760, 669 cmꢀ1. H NMR (200 MHz, CDCl3):
d 0.81 (t, J = 7.1 Hz, 3H), 1.18 (br s, 24H), 1.45–1.57 (m,
2H), 3.30 (s, 3H), 3.33 (s, 3H), 3.47–3.55 (m, 1H), 3.73
(d, J = 4.6 Hz, 2H), 4.08 (t, J = 5.1 Hz, 1H), 4.51 (d,
J = 6.8 Hz, 1H), 4.60–4.70 (m, 3H), 5.69–5.74 (m, 2H).
13C NMR (100 MHz, CDCl3): d 14.1, 22.7, 25.5, 29.4,
29.6 (several overlapping peaks), 29.7, 30.7, 31.4, 31.9,
36.5, 52.3, 55.7, 55.8, 79.8, 94.3, 96.9, 127.0, 132.2, 162.5.
4.1.5. Synthesis of (3R,4S,5S)-4,5-bis(methoxymethoxy)-
nonadec-1-en-3-ol 7. A mixture of 4.10 g of alcohol 5
(10.89 mmol) and 4.57 g of IBX (16.34 mmol) in 40 mL
of EtOAc was refluxed for about 3 h. The reaction mixture
was filtered off and washed with excess of EtOAc. The sol-
vent was evaporated from the filtrate in vacuo to afford the
crude aldehyde 6 which was then, directly taken to the next
step without any further purification.
4.1.7. Synthesis of 1-(((3R,4R,5S)-4,5-bis(methoxymethoxy)-
nona-dec-1-en-3-yloxy)methyl)benzene 10. To the DMF
solution of the allyl alcohol 7 (3.80 g, 9.44 mmol) under
argon, 0.680 g of NaH (50% assay, 14.16 mmol) was added
slowly at 0 °C. The reaction mixture was then stirred at
room temperature for 30 min, after which it was again
cooled to 0 °C. To this was added slowly the DMF solution
of BnBr (1.3 mL of BnBr in 5 mL of DMF, 10.86 mmol),
tetra n-butylammonium iodide (0.348 g, 0.94 mmol) and
the stirring was further continued for 4 h at the same tem-
perature. The reaction mixture was quenched with the
addition of cold water at 0 °C and was concentrated to half
of its volume in vacuo. To this was charged diethyl ether
and the mixture was stirred well for 10 min. The organic
layer was separated, dried over Na2SO4 and concentrated
in vacuo. The crude product was then purified by silica
gel column chromatography using petroleum ether/EtOAc
The crude aldehyde 6 dissolved in CH2Cl2 under argon was
added via cannula to a stirred suspension of MgBr2ꢁEt2O at
0 °C. After stirring for 10 min, the flask was cooled to
ꢀ78 °C and vinyl magnesium bromide (11 mL,
10.89 mmol; purchased from Aldrich as 1.0 M solution in
THF) was added slowly at ꢀ78 °C and the reaction was
stirred further at this temperature for 45 min. The solvent
was then removed in vacuo, after which the residue was di-
luted with CH2Cl2 and allowed to warm to 0 °C. Then, the
reaction mixture was diluted with saturated aq NH4Cl and
extracted with CH2Cl2 (3 ꢂ 50 mL). The combined organic
layers were washed with brine, dried over Na2SO4, and
concentrated in vacuo. Silica gel column chromatography
of the crude product using petroleum ether/EtOAc (10:1)
(20:1) to afford 4.05 g of terminal olefin 10 in 87% of yield.
25
as eluent gave syn-isomer of the allylic alcohol 7 as a pale
½aꢃD ¼ ꢀ2:10 (c 0.80, CHCl3). IR (CHCl3): 3019, 2927,
25
yellow viscous oil (3.90 g, 89%). ½aꢃD ¼ þ1:85 (c 0.56,
2854, 1466, 1215, 1150, 1099, 1027, 927, 757, 669 cmꢀ1
.
CHCl3). IR (neat): mmax 3450, 3019, 2927, 2855, 1466,
1H NMR (200 MHz, CDCl3): d 0.81 (t, J = 7.1 Hz, 3H),
1.18 (br s, 24H), 1.45–1.57 (m, 2H), 3.23 (s, 3H), 3.34 (s,
3H), 3.49 (m, 2H), 3.92–4.00 (m, 1H), 4.27 (d,
J = 10.5 Hz, 1H), 4.42–4.53 (m, 1H), 4.57 (d, J = 2.1 Hz,
1H), 4.60 (s, 2H), 4.67 (d, J = 6.9 Hz, 1H), 4.84 (d,
J = 10.5 Hz, 1H), 5.26 (d, J = 3.8 Hz, 1H), 5.70–5.88 (m,
1H), 7.24 (br s, 5H). 13C NMR (50 MHz, CDCl3): d 14.1,
22.7, 25.3, 29.3, 29.6 (several overlapping peaks), 29.7,
31.1, 31.9, 55.8, 56.2, 70.6, 78.4, 80.5, 81.0, 96.9, 98.4,
118.8, 127.5, 127.7, 127.9, 128.3, 135.4, 138.2. Anal. Calcd
for C30H52O5: C, 73.13; H, 10.64. Found: C, 73.22; H,
10.73.
1378, 1216, 1030, 761, 669 cmꢀ1 1H NMR (200 MHz,
.
CDCl3): d 0.81 (t, J = 7.1 Hz, 3H), 1.18 (br s, 24H),
1.55–1.59 (m, 2H), 1.8 (br s, 1H), 3.06 (dd, J = 4.4 Hz,
1H), 3.33 (s, 3H), 3.37 (s, 3H), 3.58–3.66 (m, 1H), 4.21–
4.28 (m, 1H), 4.61–4.76 (m, 4H), 5.13 (td, J = 1.6,
10.3 Hz, 1H), 5.30 (td, J = 1.53, 11 Hz, 1H), 5.81–5.97
(m, 1H). 13C NMR (50 MHz, CDCl3): d 14.1, 22.7, 25.7,
29.3, 29.5 (several overlapping peaks), 29.6, 30.9, 31.9,
55.9, 56.3, 71.8, 78.4, 83.7, 96.7, 98.5, 116.3, 137.7. LC–
MS (ESI-TOF) m/z: 425.04 (M+Na).
4.1.6. Synthesis of trans-(4S,5S)-1-azido-4,5-bis-(methoxy-
methoxy)-2-nonadecene 9. To the CH2Cl2 solution of 7
(250 mg, 0.621 mmol) under argon, Et3N (0.18 mL,
1.24 mmol) was added slowly at rt. The reaction flask
was cooled to 0 °C and mesyl chloride (0.06 mL,
0.714 mmol) was added. The reaction mixture was stirred
at 10 °C for about 2 h and quenched with 2 mL of water.
The organic solvent was separated, dried over anhyd
Na2SO4, concentrated in vacuo and the residue obtained
4.1.8. Synthesis of (2R,3R,4S)-2-(benzyloxy)-3,4-bis-(meth-
oxymethoxy)-octadecan-1-ol 11. The oxidative cleavage of
the terminal olefin 10 (3.50 g, 7.08 mmol) was performed
using standard conditions12 to afford the crude aldehyde
(3.01 g) as a pale yellow liquid. IR (CHCl3): 2925, 2854,
1732, 1455, 1377, 1212, 1151, 1102, 1029, 918, 734,
698 cmꢀ1. The crude aldehyde obtained was used as such
in the next step without further purification.

214
K. Venkatesan, K. V. Srinivasan / Tetrahedron: Asymmetry 19 (2008) 209–215
To the methanolic solution of the above crude aldehyde,
NaBH4 (250 mg, 7.08 mmol) was added at 0 °C. The reac-
tion mixture was further stirred at rt for 1 h and was con-
centrated to half of its volume in vacuo. Then, the reaction
mixture was quenched with brine solution and the product
was extracted with diethyl ether (3 ꢂ 25 mL). The com-
bined organic phases were dried over Na2SO4 and concen-
trated to give the crude alcohol, which was then purified by
silica gel column chromatography using petroleum ether/
29.3, 29.6 (several overlapping peaks), 29.7, 30.6, 31.9,
55.4, 55.9, 56.2, 69.7, 70.0, 78.3, 80.1, 96.6, 97.0, 98.4.
LC–MS (ESI-TOF) m/z: 473.21 (M+Na).
4.1.11. Synthesis of (2S,3S,4S)-2-azido-1,3,4-tris-(methoxy-
methoxy)-octadecane 14. To a solution of 13 (0.550 g,
1.22 mmol) in dry CH2Cl2 (4 mL) at 0 °C were added
Et3N (0.2 mL, 1.47 mmol), p-tosyl chloride (254 mg,
1.33 mmol), and DMAP (3 mg, 2 mol %). The reaction
mixture was stirred at room temperature for 3 h and then
poured into DCM/H2O mixture. The organic phase was
separated and the aqueous phase extracted with DCM
(3 ꢂ 10 mL). The combined organic phase was washed
with water, brine, dried over Na2SO4, and concentrated
to a white solid, which was dissolved in dry DMF
(3 mL). To this, NaN3 (0.099 g, 1.52 mmol) was added
and the reaction mixture was heated to 95 °C under an
argon atmosphere for about 14 h, and then cooled to room
temperature. The reaction mixture was concentrated to
half of its volume in vacuo. The residue obtained was dis-
solved in 8 mL of EtOAc and washed with brine solution.
The organic solvent was separated, dried over Na2SO4 and
concentrated in vacuo to furnish crude azide 14, which was
then purified by column chromatography over silica gel
EtOAc (7:1) to afford 2.89 g of pure alcohol 11 as a pale
25
yellow oily liquid (82% yield for two steps). ½aꢃD ¼ ꢀ15:5
(c 2.0, CHCl3). IR (CHCl3): 3459, 3018, 2926, 2854,
1466, 1455, 1215, 1150, 1101, 1027, 919, 758, 668 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d 0.81 (t, J = 7.1 Hz, 3H),
1.18 (br s, 24H), 1.51–1.60 (m, 2H), 3.30 (s, 3H), 3.36 (s,
3H), 3.59–3.77 (m, 5H), 4.51–4.73 (m, 6H), 7.26 (br s,
5H). 13C NMR (100 MHz, CDCl3): d 14.1, 22.7, 25.2,
29.3, 29.5, 29.6 (several overlapping peaks) 29.7, 30.7,
31.9, 55.9, 56.2, 60.8, 72.9, 78.4, 79.1, 79.3, 96.9, 98.8,
128.0, 128.4, 138.0. LC–MS (ESI-TOF) m/z: 518.86
(M+Na).
4.1.9. Synthesis of 1-(((2R,3 R,4S)-1,3,4-tris(methoxymeth-
oxy)-octadecan-2-yloxy)methyl)benzene 12. To the CH2Cl2
solution containing 11 (1 g, 2.0 mmol) under an argon
atmosphere, DIPEA (0.70 mL, 4.0 mmol) was charged at
rt and then MOMCl (1.8 mL, 2.2 mmol) was added to the
reaction mixture at 0 °C. The reaction mixture was stirred
at rt for about 6 h and quenched with 0.5 mL of cold water.
The organic layer was separated, dried over anhyd Na2SO4
and concentrated in vacuo. The residue obtained was puri-
fied by silica gel column chromatography using petroleum
using petroleum ether/EtOAc (9:1) as eluent to give 14 as
25
a yellow oil (0.482 g, 83%). ½aꢃD ¼ þ7 (c 0.5, CHCl3); IR
(CHCl3): 2927, 2103, 1519, 1030, 910, 756, 669, 625 cmꢀ1
.
1H NMR (200 MHz, CDCl3): d 0.81 (t, J = 7.2 Hz, 3H),
1.19 (br s, 24H), 1.52–1.61 (m, 2H), 3.32 (s, 6H), 3.37 (s,
3H), 3.60–3.92 (m, 5H), 4.60–4.75 (m, 6H). 13C NMR
(200 MHz, CDCl3): d 14.1, 22.7, 25.7, 29.3, 29.6 (several
overlapping peaks), 29.7, 30.6, 31.9, 55.4, 55.9, 56.2, 67.1,
69.7, 78.3, 80.1, 96.6, 97.0, 98.4. Anal. Calcd for
C24H49N3O6: C, 60.60; H, 10.38; N, 8.83. Found: C,
60.52; H, 10.44; N, 8.90.
ether/EtOAc (9:1) to give 1.02 g of 12 as a colorless oily
25
liquid in 94% yield. ½aꢃD ¼ þ5 (c 0.5, CHCl3). IR (CHCl3):
2925, 2854, 1466, 1261, 1213, 1151, 1106, 1034, 919, 801,
698, 734 cmꢀ1 1H NMR (200 MHz, CDCl3): d 0.81 (t,
.
J = 6.9 Hz, 3H), 1.10–1.26 (m, 24H), 1.45–1.48 (m, 2H),
3.30 (s, 6H), 3.34 (s, 3H), 3.60–3.76 (m, 5H), 4.52–4.84
(m, 8H), 7.16–7.33 (m, 5H). 13C NMR (100 MHz, CDCl3):
d 14.1, 22.7, 25.5, 29.3, 29.6 (several overlapping peaks),
29.8, 30.9, 31.9, 55.3, 55.9, 56.2, 67.6, 73.1, 77.9, 78.6,
96.6, 96.8, 98.5, 127.6, 128.0, 128.3, 138.4. LC–MS (ESI-
TOF) m/z: 562.83 (M+Na).
4.1.12. Synthesis of (2S,3S,4S)-2-azido-3,4-bis-(dihydroxy)-
octadecyl-4-methylbenzenesulfonate 16. To a solution of
14 (0.470 g, 0.99 mmol) in THF (4 mL) was added 10%
aq HCl (4 mL) at 10 °C and stirred at room temperature
for 5 h. The reaction mixture was quenched by the addition
of saturated solution of NaHCO3 and extracted with ethyl
acetate (3 ꢂ 10 mL). The organic layer was separated,
dried over Na2SO4 and concentrated in vacuo to afford
the crude azidotriol 15 as a residue. The residue obtained
was used as such without further purification in the next
step.
4.1.10. Synthesis of (2R,3S,4S)-1,3,4-tris(methoxymethoxy)-
octa-2-decanol 13. To a solution of 12 (0.760 g, 1.41
mmol) in MeOH (10 mL) were added a catalytic amount
of 5% Pd/C and the reaction mixture was stirred at room
temperature under a hydrogen atmosphere (1 atm balloon
pressure) for 12 h. The reaction mixture was then filtered
through a pad of Celite and the solvent was removed under
reduced pressure to give the crude product, which was then
purified by column chromatography over silica gel using
To a solution of the above crude azidotriol 15 in CH2Cl2
(5 mL) was added Et3N (0.3 mL) and p-toluenesulphonyl
chloride (0.188 g, 0.99 mmol) at 0 °C and stirred at room
temperature for 4 h. The reaction mixture was quenched
by the addition of water (5 mL), extracted with ethyl ace-
tate (3 ꢂ 10 mL). The combined organic phases were dried
over Na2SO4 and concentrated to give the product, which
was then purified by silica gel column chromatography
using EtOAc/petroleum ether (3.5:6.5) to afford 0.393 g
petroleum ether/EtOAc (8:2) as eluent to give 13 (0.608 g,
25
96%) as a pale yellow oil. ½aꢃD ¼ ꢀ2:3 (c 1.6, CHCl3). IR
(CHCl3): 3400, 3019, 2926, 1519, 1031, 909, 758, 669,
625 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d 0.82 (t,
J = 6.9 Hz, 3H), 1.19 (br s, 24H), 1.54–1.59 (m, 2H), 2.10
(br s, 1H), 3.32 (br s, 6H), 3.37 (s, 3H), 3.56–3.60 (m,
2H), 3.64–3.69 (m, 2H), 3.88–3.93 (m, 1H), 4.61 (d,
J = 5.2 Hz, 2H), 4.64–4.75 (m, 3H), 4.82 (d, J = 6.5 Hz,
1H). 13C NMR (100 MHz, CDCl3): d 14.1, 22.7, 25.7,
of pure tosylated derivative 16 as a white solid (80% yield
25
for two steps). Mp 64–65 °C; ½aꢃD ¼ þ14 (c 0.45, CHCl3)
25
{lit.6b ½aꢃD ¼ þ15 (c 0.4, CHCl3)}; The spectral and analyt-
ical data were in good agreement with that of reported in
the literature.6b Anal. Calcd for C25H43N3O5S: C, 60.33;

K. Venkatesan, K. V. Srinivasan / Tetrahedron: Asymmetry 19 (2008) 209–215
215
2005, 7, 875–876; (c) Du, Y.; Liu, J.; Linhardt, R. J. J. Org.
Chem. 2006, 71, 1251–1253; (d) Van Tien Berg, R. J. B. H. N.;
Boltje, T. J.; Verhagen, C. P.; Litjens, R. E. J. N.; Van Der
Marel, G. A.; Overkleeft, H. S. J. Org. Chem. 2006, 71, 836–
839; (e) Ribes, C.; Falomir, E.; Carda, M.; Marco, J. A.
Tetrahedron 2006, 62, 5421–5425; (f) Chandrasekhar, S.;
Tiwari, B.; Prakash, S. J. ARKIVOC 2006, 11, 155–161; (g)
Liu, J.; Du, Y.; Dong, X.; Meng, S.; Xiao, J.; Cheng, L.
Carbohydr. Res. 2006, 341, 2653–2657.
H, 8.71; N, 8.44; S, 6.44. Found: C, 60.39; H, 8.78; N, 8.38;
S, 6.37.
4.1.13. Synthesis of pachastrissamine (jaspine B) I. The
spectral and analytical data of I are in good conformity
25
with the reported values.5e ½aꢃD ¼ þ17:7 (c 0.40, EtOH)
[lit.1 +18 (c 0.1, EtOH)]; amorphous solid; IR (CHCl3):
1
3350, 2926, 1469, 1030, 726 cmꢀ1; H NMR (200 MHz,
CD3OD) d 0.87 (t, J = 7.2 Hz, 3H), 1.25–1.39 (m, 24H),
1.57–1.66 (m, 2H), 2.10 (br s, 3H), 3.49–3.53 (m, 1H),
3.63–3.67 (m, 1H), 3.69–3.75 (m, 1H), 3.84–3.88 (m, 1H),
3.89–3.94 (m, 1H). 13C NMR (100 MHz, CD3OD) d 14.1,
22.7, 25.7, 29.3, 29.6 (several overlapping peaks), 29.7,
30.6, 31.9, 54.4, 71.8, 72.3, 83.2. Anal. Calcd for
C18H37NO2: C, 72.19; H, 12.45; N, 4.68. Found: C,
72.26; H, 12.51; N, 4.62.
6. (a) Ramana, C. V.; Giri, A. G.; Suryawanshi, S. B.; Gonnade,
R. G. Tetrahedron Lett. 2007, 48, 265–268; (b) Prasad, K. R.;
Chandrakumar, A. J. Org. Chem. 2007, 72, 6312–6315; (c)
Lee, T.; Lee, S.; Kwak, Y. S.; Kim, D.; Kim, S. Org. Lett.
´
´
2007, 9, 429–432; (d) Genisson, Y.; Lamande, L.; Salma, Y.;
´
Andrieu-Abadie, N.; Andre, C.; Baltas, M. Tetrahedron:
Asymmetry 2007, 18, 857–864; (e) Reddy, L. V. R.; Reddy, P.
V.; Shaw, A. K. Tetrahedron: Asymmetry 2007, 18, 542–546.
7. (a) Yakura, T.; Sato, S.; Yoshimoto, Y. Chem. Pharm. Bull.
2007, 55, 1284–1286; (b) Abraham, E.; Lena, J. I. C.; Davies,
S. G.; Georgiou, M.; Nicholson, R. L.; Roberts, P. M.;
Russell, A. J.; Ferna’ndez, E. M. S.; Smith, A. D.; Thomson,
J. E. Tetrahedron: Asymmetry 2007, 18, 2510–2513.
8. (a) Siddiqui, S. A.; Narkhede, U. C.; Lahoti, R. J.; Sriniva-
san, K. V. Synlett 2006, 1771–1773; (b) Siddiqui, S. A.;
Srinivasan, K. V. Tetrahedron: Asymmetry 2007, 18, 2099–
2103.
Acknowledgment
K.V. thanks UGC, New Delhi for providing a Research
Fellowship.
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