Stereoselective synthesis of cytotoxic anhydrophytosphingosine pachastrissamine [Jaspine B]

Article abstract of DOI:10.1021/jo0707838

(Chemical Equation Presented) A practical stereoselective synthesis of cytotoxic anhydrophytosphingosine pachastrissamine (jaspine B) was achieved in 48% overall yield from D-(-)-tartaric acid. Key features of the sequence include the diastereoselective f

Full text of DOI:10.1021/jo0707838

Stereoselective Synthesis of Cytotoxic
Anhydrophytosphingosine Pachastrissamine
[Jaspine B]
Kavirayani R. Prasad* and Appayee Chandrakumar
Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560012, India
prasad@orgchem.iisc.ernet.in
FIGURE 1. Bio-active anhydrophytosphingosine and sphingolipids.
ReceiVed April 15, 2007
treatment of arthritis, inflammation, obesity, and disorders of
lipid metabolism closely resembles the sphigolipid phyto-
sphingosine 3.4 The tri-substituted tetrahydrofuran structural
framework and the proven bioactivity of 1 prompted extensive
synthetic studies, resulting in a handful of approaches reported
very recently.5 Many of these syntheses relied on employing
either carbohydrates or serine as the chiral source. For example
Ramana et al.5a utilized D-glucose, whereas Du et al.5c employed
D-xylose as the source of chirality in their multistep synthesis
of 1. Research groups of Datta5d and Rao5e have independently
disclosed the synthesis of 1 from L-serine. Synthesis of 1 from
phytosphingosine 3 has also been reported by Lee et al.6a and
by van der Berg et al.6b In continuation of our successful efforts
in the stereoslective synthesis of bioactive oxygenated natural
products from chiral pool tartaric acid,7 herein we report a facile
stereoselective synthesis of pachastrissamine.
As shown in retrosynthesis (Scheme 1), we envisaged the
formation of 1, by reduction of the azide in 14, synthesis of
which was anticipated Via the intramolecular Williamson
etherification of the tosylate 13. The tosylate 13 can be obtained
from the 3,4-protected tetrol 9. γ-Hydroxybutyramide 7, derived
from the dimethylamide 5 obtained from tartaric acid, was
identified as the appropriate precursor for the synthesis of 9.
The synthetic sequence commenced with the controlled
addition of n-tetradecylmagnesium bromide (1.5 eq) to the bis-
dimethylamide 5, derived from D-(-)-tartaric acid,8 affording
the keto amide 6 in 86% yield.9 Stereoselective reduction of
the ketone in 6 with NaBH4 in presence of CeCl3·7H2O furnished
A practical stereoselective synthesis of cytotoxic anhydro-
phytosphingosine pachastrissamine (jaspine B) was achieved
in 48% overall yield from D-(-)-tartaric acid. Key features
of the sequence include the diastereoselective formation of
a tetrol with three contiguous chiral centers, which was
further elaborated to pachastrissamine. The synthetic route
is operationally simple, diastereoselective and is amenable
for the synthesis of a number of analogues of pachastrissa-
mine.
Tetrahydrofuran backbone is ubiquitous heterocyclic unit
found in a number of biologically active natural products.1
Recently, Kuroda et al. isolated pachastrissamine 1, a cytotoxic
anhydrophytosphingosine comprising a tetrahydrofuran back-
bone from the Okinawan marine sponge Pachastrissa sp (Figure
1).2 Subsequently, Ledroit et al. isolated the same compound
from marine sponge Jaspis sp. (hence the name jaspine B) and
another natural product jaspine A 2.3 1 was found to be
marginally active against the A5409 human lung carcinoma cell
line and at submicromolar level against HT29, MEL28, and
P388 cancer cell lines. Pachastrissamine possess three contigu-
ous stereogenic centers and is structurally similar to the open
chain sphingolipid D-ribo-phytosphingosine 3. It might be very
likely that 3 is the biosynthetic precursor to 1 and 2. Interest-
ingly, guggultetrol 4, a naturally occurring lipid isolated from
the gum-resin of the tree Commiphoru mukul (guggulu), known
in Ayurveda, the Indian traditional system of medicine, for the
(4) (a) Patil, V. D.; Nayak, U. R.; Dev, S. Tetrahedron 1973, 29, 1595.
(b) Kumar, V.; Dev, S. Tetrahedron 1987, 43, 5948. (c) Kjaer, A.; Kjaer,
D.; Skrydstrup, T. Tetrahedron 1986, 42, 1439.
(5) (a) Ramana, C. V.; Giri, A. G.; Suryawanshi, S. B.; Gonnade, R. G.
Tetrahedron Lett. 2007, 48, 265. (b) Ribes, C.; Falomir, E.; Carda, M.;
Marco, J. A. Tetrahedron 2006, 62, 5421. (c) Du, Y.; Liu, J.; Linhardt, R.
J. J. Org. Chem. 2006, 71, 1251. (d) Bhaket, P.; Morris, K.; Stauffer, C.
S.; Datta, A. Org. Lett. 2005, 7, 875. (e) Sudhakar, N.; Kumar, A. R.;
Prabhakar, A.; Jagadeesh, B.; Rao, B. V. Tetrahedron Lett. 2005, 46, 325.
(6) (a) Lee, T.; Lee, S.; Kwak, Y. S.; Kim, D.; Kim, S. Org. Lett. 2007,
9, 429. (b) van den 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.
(7) (a) Prasad, K. R.; Anbarasan, P. Tetrahedron: Asymmetry 2005, 16,
3951. (b) Prasad, K. R.; Anbarasan, P. Tetrahedron Lett. 2006, 47, 1433.
(c) Prasad, K. R.; Anbarasan, P. Synlett 2006, 2087. (d) Prasad, K. R.;
Anbarasan, P. Tetrahedron: Asymmetry 2006, 17, 1146. (e) Prasad, K. R.;
Anbarasan, P. Tetrahedron 2006, 62, 8303. (f) Prasad, K. R.; Chandrakumar,
A.; Anbarasan, P. Tetrahedron: Asymmetry 2006, 17, 1979. (g) Prasad, K.
R.; Gholap, S. L. Synlett 2005, 2260. (h) Prasad, K. R.; Gholap, S. L. J.
Org. Chem. 2006, 71, 3643. (i) Prasad, K. R.; Anbarasan, P. Tetrahedron
2007, 63, 1089.
* Fax: +918023600529.
(1) Faul, M. M.; Huff, B. E. Chem. ReV. 2000, 100, 2407.
(2) Kuroda, I.; Musman, M.; Ohtani, I. I.; Ichiba, T.; Tanaka, J.; Gravalos,
D. G.; Higa, T. J. Nat. Prod. 2002, 65, 1505.
(3) Ledroit, V.; Debitus, C.; Lavaud, C.; Massiot, G. Tetrahedron Lett.
2003, 44, 225.
(8) (a) Toda, F.; Tanaka, K. J. Org. Chem. 1988, 53, 3607. (b) Seebach,
D.; Hidber, A. Org. Syn. Coll. 7, 447.
10.1021/jo0707838 CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/11/2007
6312
J. Org. Chem. 2007, 72, 6312-6315

SCHEME 1. Retrosynthesis for Pachastrissamine (Jaspine
B)
SCHEME 2. Stereoselective Synthesis of Pachastrissamine
a mixture of diastereomeric alcohols (dr ≈ 95:5 by NMR,10
7
being the major isomer) in 97% yield. Reaction of this mixture
of alcohols with excess 2,2-dimethoxypropane in presence of
p-toluenesulphonic acid in benzene followed by column puri-
fication resulted in pure R-hydroxy ester 8 in 86% yield.11
Reduction of the ester 8 with NaBH4 produced the diol 9 in
94% yield. Primary hydroxy group in 9 was protected as the
tert-butyldimethylsilylether in 92% yield, which on subsequent
tosylation furnished the tosylate 10 in 98% yield. SN2 displace-
ment of the tosylate in 10 with sodium azide furnished the azide
11 in 60% yield with desilylated azidohydrin 12 in 39%.
Reaction of 11 with tetra-butylammonium fluoride (TBAF)
produced the azidohydrin 12 in 88% yield. Primary alcohol in
12 was converted to the tosylate, which on subsequent reaction
with FeCl3·6H2O12 yielded the dihydroxy azido tosylate 13 in
94% yield for two steps. Reaction of 13 with K2CO3 in MeOH
afforded the tetrahydrofuran 14 in 97% yield. Hydrogenation
of 14 with Pd/C gave pachastrissamine 1 in 94% yield, the
spectral and physical data of which are in complete agreement
with that reported in literature2,6a (Scheme 2).
is operationally simple, highly diastereoselective, and applicable
for the access of different analogues of pachastrissamine.
Experimental Section
(4S,5S)-N,N,2,2-Tetramethyl-5-pentadecanoyl-1,3-dioxolane-
4-carboxamide (6). In an oven-dried two-neck 100 mL, round-
bottom flask equipped with a magnetic stir bar, rubber septum, and
argon inlet was placed 5 (1.71 g, 7.0 mmol) dissolved in THF (20
mL). The solution was cooled to -15 °C and tetradecylmagnesium
bromide (10.5 mmol, 21 mL of 0.5 M solution in THF) was added
slowly and stirred for 0.5 h at the same temperature. After the
reaction was complete (indicated by TLC), it was cautiously
quenched by addition of ice cold solution of saturated NH4Cl (20
mL). The reaction mixture was poured into water (25 mL) and
extracted with EtOAc (3 × 25 mL). The combined organic layers
were washed with brine (20 mL) and dried (Na2SO4). The residue
obtained after removal of the solvent was purified by silica gel
column chromatography to yield 6 (2.4 g, 86%) as white solid: Rf
0.6 (1:1 EtOAc:petroleum ether); mp 45-46 °C; [R]D -14 (c 2,
In summary, a facile and efficient stereoselective synthesis
of natural phytosphingosine pachastrissamine (jaspine B) was
achieved from D-(-)-tartaric acid. In the present sequence,
pachastrissamine was obtained in 48% overall yield from the
bis-dimethylamide derived from tartaric acid. The synthetic route
(9) Formation of minor amount (4%) of diketone resulting from the
addition of tetradecylmagnesium bromide to both amide groups is observed.
For an optimized synthesis of γ-oxo-amides by controlled addition of
Grignard reagents to 5, see: Prasad, K. R.; Chamdrakumar, A. Tetrahedron
2007, 63, 1798.
(10) Diastereomeric ratio of the product alcohol was estimated within
1
detectable limits by H NMR. Reduction with other reducing agents such
as NaBH4, K-selectride produced alcohols with varied selectivity. The
alcohols were inseparable at this stage. Formation of the major diastereomer
can be attributed to the addition of hydride either by a Cram/Felkin open
chain model or by a â-chelation, similar to that reported by Chikasita et al.
Chikashita, H.; Nikaya, T.; Uemura, H.; Itoh, K. Bull. Chem. Soc. Jpn.
1989, 62, 2121.
(11) The reaction proceeds through the intermediacy of trihydroxy ester
I, formed by the deprotection of the acetonide in alcohol 7, followed by
γ-hydroxy assisted amide hydrolysis. For related γ-hydroxy assisted hy-
CHCl3); IR (CHCl3): 2925, 1719, 1659, 1373, 1155, 864 cm-1
;
1H NMR (300 MHz, CDCl3) δ 5.12 (d, 1H, J ) 6 Hz), 4.78 (d,
1H, J ) 6 Hz), 3.13 (s, 3H), 2.97 (s, 3H), 2.72-2.53 (m, 2H),
1.59-1.55 (m, 2H), 1.41 (s, 6H), 1.23 (brs, 24H), 0.86 (t, 3H, J )
6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 209.5, 168.1, 112.0, 82.1,
74.9, 39.5, 37.0, 36.0, 31.9, 29.6, 29.5, 29.4, 29.3, 29.1, 26.3, 26.0,
23.0, 22.6, 14.1; Analysis calcd for C23H43NO4: C 69.48; H 10.90;
N 3.52. Found: C 69.28; H 10.67; N 3.67.
(4S,5R)-N,N,2,2-Tetramethyl-5-((S)-1-hydroxylpentadecyl)-
1,3-dioxolane-4-carboxamide (7). To a solution of 6 (2.0 g, 5
mmol) in methanol (25 mL) cooled to -15 °C was added CeCl3·
7H2O (3.72 g, 10 mmol), and the mixture was stirred for 15 min.
NaBH4 (0.38 g, 10 mmol) was then added portion wise at -15 °C
and stirred at the same temperature for 2 h. After the reaction was
complete (TLC), it was quenched by the addition of water (1 mL).
Most of the volatiles were removed under reduced pressure. The
solid thus obtained was triturated with diethyl ether (10 mL). The
suspension was filtered through a short pad of Celite, and the Celite
drolysis of butyramides (a) Martin, R. B.; Hedrick, R.; Parcell, A. J. Org.
Chem. 1964, 29, 158. (b) Hauser, C. R.; Adams, T. C., Jr. J. Org. Chem.
1977, 42, 3029. (c) Vedejs, E.; Kruger, A. W. J. Org. Chem. 1999, 64,
4790.
(12) For FeCl3 mediated deprotection of acetals see: (a) Sen, S. E.;
Roach, S. L.; Boggs, J. K.; Ewing, G. J.; Magrath, J. J. Org. Chem. 1997,
62, 6684. (b) Prasad, K. R.; Chandrakumar, A. Tetrahedron: Asymmetry
2005, 16, 1897. (c) Reference 7.
J. Org. Chem, Vol. 72, No. 16, 2007 6313

pad was washed with diethyl ether (25 mL). The ethereal layers
were combined and evaporation of solvent followed by silica gel
column chromatography of the resultant crude residue afforded the
alcohol 7 (1.94 g, 97%) (dr ∼95 : 5) as a white solid: Rf 0.4 (1:1
EtOAc:petroleum ether); mp 42-44 °C; [R]D +10 (c 1.5, CHCl3);
IR (CHCl3): 3447, 2924, 2854, 1653, 1380, 1069 cm-1; 1H NMR
(300 MHz, CDCl3) δ 4.60-4.53 (m, 2H), 3.66-3.58 (m, 1H), 3.15
(s, 3H), 2.97 (s, 3H), 2.05 (d, 1H, J ) 9.3 Hz), 1.54-1.26 (m,
26H), 1.45 (s, 3H), 1.39 (s, 3H), 0.88 (t, 3H, J ) 6.9 Hz); 13C
NMR (75 MHz, CDCl3) δ 168.9, 110.1, 80.2, 74.2, 70.0, 37.0, 35.7,
34.8, 31.9, 29.7, 29.6, 29.5, 29.3, 26.8, 26.1, 25.8, 22.7, 14.1;
Analysis calcd for C23H45NO4: C 69.13; H 11.35; N 3.51. Found:
C 69.00; H 11.21; N 3.49.
(S)-methyl 2-hydroxy-2-((4S,5S)-2,2-dimethyl-5-tetradecyl-
1,3-dioxolan-4-yl)acetate (8). To a solution of 7 (0.9 g, 2.3 mmol)
in benzene (10 mL), p-toluenesulphonic acid (0.64 g, 3.38 mmol)
and 2,2-dimethoxypropane (0.5 mL, 4.5 mmol) were added and
refluxed for 12 h. The reaction mixture was cooled to room
temperature, and K2CO3 (0.75 g) was added. After stirring for 15
min, it was filtered through a short pad of Celite, and the Celite
pad was washed with diethyl ether (20 mL). Evaporation of solvent
followed by silica gel column chromatography of the resultant
residue gave 8 (0.76 g, 86%) as a colorless oil: Rf 0.6 (3:7 EtOAc:
petroleum ether); [R]D -29 (c 1.2, CHCl3); IR (neat): 3508, 2925,
1750, 1466, 1131, 899 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.15-
4.07 (m, 2H), 3.88-3.80 (m, 1H), 3.84 (s, 3H), 3.00 (d, 1H, J )
9.0 Hz), 1.68-1.18 (m, 26H), 1.40 (s, 6H), 0.88 (t, 3H, J ) 6.9
Hz); 13C NMR (75 MHz, CDCl3) δ 172.9, 109.1, 81.4, 76.4, 68.8,
52.7, 32.6, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 27.0, 26.5, 26.0, 22.6,
14.1; HRMS for C22H42O5 + Na calcd: 409.2930; found: 409.2920.
((R)-1-((4S,5S)-2,2-dimethyl-5-tetradecyl-1,3-dioxolan-4-yl)-
ethane-1,2-diol (9). In a single-neck round-bottom flask equipped
with magnetic stir bar and guard tube was placed a solution of 8
(0.68 g, 1.75 mmol) in MeOH (10 mL). NaBH4 (0.13 g, 3.5 mmol)
was then introduced portion wise at 0 °C. The reaction mixture
was slowly warmed up to room temperature and stirred for 3 h at
the same temperature. After the reaction was complete (TLC), most
of the methanol was removed under reduced pressure and water
(20 mL) was added to the reaction mixture and extracted with
EtOAc (3 × 15 mL). The combined organic layers were washed
with brine (15 mL) and dried over Na2SO4. Evaporation of solvent
followed by silica gel column chromatography of the crude residue
furnished 9 (0.59 g, 94%) as a white solid: Rf 0.3 (1:1 EtOAc:
petroleum ether); mp 48-49 °C; [R]D -31.2 (c 0.8, CHCl3); IR
(CHCl3): 3414, 2924, 2854, 1467, 1216, 1038, 689 cm-1; 1H NMR
(300 MHz, CDCl3) δ 4.07-4.00 (m, 1H), 3.70-3.63 (m, 4H), 2.66
(brs, 1H), 2.48 (brs, 1H), 1.58-1.19 (m, 26H), 1.41 (s, 6H), 0.88
(t, 3H, J ) 6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 108.1, 82.0,
77.2, 69.5, 65.3, 32.8, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 27.4, 26.8,
26.0, 22.7, 14.1; Analysis calcd for C21H42O4: C 70.34; H 11.81.
Found: C 69.98; H 11.56.
26.0,25.8, 22.7, 18.2, 14.1, -5.4, -5.5; HRMS for C27H56O4Si +
Na calcd: 495.3846; found: 495.3860.
To a solution of the silyl ether obtained above (0.59 g, 1.3 mmol)
in CH2Cl2 (10 mL) was added DMAP (0.31 g, 2.5 mmol) and
p-toluenesulphonyl chloride (0.36 g, 1.9 mmol) at room temperature,
and the mixture was stirred for 4 h at the same temperature. It was
then poured into water (10 mL) and extracted with diethyl ether (3
× 10 mL). The combined organic layers were washed with brine
(15 mL) and dried (Na2SO4). Evaporation of solvent followed by
silica gel column chromatography of the crude residue afforded
10 (0.80 g, 98%) as a colorless oil: Rf 0.7 (1:9 EtOAc: petroleum
ether); [R]D -16.6 (c 0.6, CHCl3); IR (neat): 2926, 2855, 1371,
1
1096, 835 cm-1; H NMR (300 MHz, CDCl3) δ 7.78 (d, 2H, J )
7.8 Hz), 7.30 (d, 2H, J ) 7.8 Hz), 4.40-4.35 (m, 1H), 3.85-3.67
(m, 4H), 2.41 (s, 3H), 1.59-1.20 (m, 26H), 1.29 (s, 3H), 1.16 (s,
3H), 0.86 (t, 3H, J ) 6.9 Hz), 0.82 (s, 9H), 0.00 (s, 3H), -0.01 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 144.7, 133.9, 129.7, 127.9,
108.6, 79.4, 78.2, 76.3, 61.7, 32.6, 31.9, 29.7, 29.6, 29.5, 29.4, 27.3,
26.4, 25.9, 25.7, 22.7, 21.6, 18.2, 14.1, -5.6; HRMS for C34H62O6-
SSi + Na calcd: 649.3934; found: 649.3962.
((S)-2-Azido-2-((4S,5S)-2,2-dimethyl-5-tetradecyl-1,3-dioxolan-
4-yl)ethoxy)(tert-butyl)dimethylsilane (11). To a solution of 10
(0.44 g, 0.7 mmol) in DMF (10 mL) was added NaN3 (0.09 g, 1.4
mmol) and was heated to 100 °C and stirred at the same temperature
for 12 h (CAUTION: Care should be taken when manipulating
sodium azide due to its toxicity and explosive nature). The reaction
mixture was cooled to room temperature and poured into water
(20 mL). It was then extracted with diethyl ether (3 × 10 mL),
and the combined organic layers was washed with brine (15 mL)
and dried over Na2SO4. Evaporation of solvent followed by silica
gel column chromatography of the crude residue afforded 11 (0.21
g, 60%) as a colorless oil and 12 (0.10 g, 39%). Compound 11: Rf
0.7 (1:9 EtOAc: petroleum ether); [R]D -9.4 (c 1.8, CHCl3); IR
1
(neat): 2927, 2855, 2099, 1464, 1256, 1101, 838, 777 cm-1; H
NMR (300 MHz, CDCl3) δ 4.01-3.93 (m, 2H), 3.73 (dd, 1H, J )
10.5, 7.2 Hz), 3.57 (t, 1H, J ) 7.2 Hz), 3.49-3.43 (m, 1H), 1.73-
1.26 (m, 26H), 1.26 (s, 6H), 0.92 (s, 9H), 0.88 (t, 3H, J ) 6.9 Hz),
0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 109.0,
79.8, 78.7, 65.3, 64.3, 34.0, 31.9, 29.7, 29.6, 29.5, 29.4, 27.4, 27.0,
26.1, 25.8, 22.7, 18.2, 14.1, -5.4; HRMS for C27H55 N3O3Si + Na
calcd: 520.3910; found: 520.3911.
(S)-2-Azido-2-((4S,5S)-2,2-dimethyl-5-tetradecyl-1,3-dioxolan-
4-yl)ethanol (12). To a solution of 11 (0.20 g, 0.4 mmol) in THF
(2.5 mL) was added TBAF (0.8 mL of 1 M solution in THF, 0.8
mmol) at 0 °C and stirred at room temperature for 1 h. It was then
poured into water (10 mL) and extracted with EtOAc (3 × 10 mL).
The combined organic layers were washed with brine (10 mL) and
dried over Na2SO4. Evaporation of solvent followed by silica gel
column chromatography of the crude residue afforded 12 (0.14 g,
88%) as a colorless oil: Rf 0.4 (2:8 EtOAc: petroleum ether); [R]D
-15 (c 0.4, CHCl3); IR (neat): 3446, 2925, 2854, 2103, 1219, 1070,
1
877 cm-1; H NMR (400 MHz, CDCl3) δ 3.98-3.96 (m, 1H),
3.89-3.87 (m, 1H), 3.77-3.74 (m, 1H), 3.67 (t, 1H, J ) 7.2 Hz),
3.57-3.54 (m, 1H), 2.25 (t, 1H, J ) 6.0 Hz), 1.67-1.26 (m, 26H),
1.40 (s, 6H), 0.88 (t, 3H, J ) 6.4 Hz); 13C NMR (75 MHz, CDCl3)
δ 109.3, 80.1, 79.6, 64.8, 63.1, 33.9, 31.9, 29.7, 29.6, 29.5, 29.4,
27.4, 26.9, 26.1, 22.7, 14.1; HRMS for C21H41 N3O3 + Na calcd:
406.3046; found: 406.3027.
(2S,3S,4S)-2-Azido-3,4-dihydroxyoctadecyl-4-methylbenzene-
sulfonate (13). To a solution of 12 (0.20 g, 0.5 mmol) in CH2Cl2
(2 mL) was added Et3N (0.2 mL) and p-toluenesulphonyl chloride
(0.15 g, 0.8 mmol) at 0 °C and stirred at room temperature for 4 h.
The reaction mixture was quenched by addition of water (10 mL),
extracted with diethyl ether (3 × 10 mL) and dried (Na2SO4).
Residue obtained after evaporation of the solvent was used as such
without further purification in the next step.
((R)-1-((4R,5S)-2,2-dimethyl-5-tetradecyl-1,3-dioxolan-4-yl)-
2-O-tert-butyldimethylsilyl-1-O-p-toluenesulphonyl-ethane-1,2-
diol (10). To a solution of 9 (0.55 g, 1.55 mmol) in DMF (2 mL)
was added imidazole (0.16 g, 2.32 mmol) and TBDMSCl (0.36 g,
2.32 mmol) at room temperature and stirred for 12 h. The reaction
mixture was then poured into water (10 mL) and extracted with
diethyl ether (3 × 10 mL). The combined organic layers were
washed with brine (10 mL) and dried (Na2SO4). Evaporation of
solvent followed by silica gel column chromatography of the crude
residue afforded the silyl ether (0.68 g, 92%) as a colorless oil: Rf
0.6 (1:9 EtOAc/ petroleum ether); [R]D -18.6 (c 1.5, CHCl3); IR
1
(neat): 3495, 2927, 1464, 1256, 1109, 837, 777 cm-1; H NMR
(300 MHz, CDCl3) δ 4.04-3.97 (m, 1H), 3.74-3.55 (m, 4H), 2.36
(brs, 1H), 1.56-1.25 (m, 26H), 1.47 (s, 6H), 0.88 (t, 3H, J ) 6.9
Hz), 0.89 (s, 9H), 0.07 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 108.6,
80.2, 77.0, 70.1, 64.6, 33.0, 31.9, 29.7, 29.6, 29.5, 29.4, 27.4, 26.9,
To a solution of the crude tosylate (obtained above) in CH2Cl2
(10 mL) was added FeCl3·6H2O (0.49 g, 1.8 mmol) at room
6314 J. Org. Chem., Vol. 72, No. 16, 2007

temperature. The resulting yellow colored suspension was stirred
for 8 h at room temperature. After the reaction was complete
(monitored by TLC), it was quenched by the addition of saturated
solution of NaHCO3. It was then extracted with EtOAc (3 × 10
mL), and the combined organic layers were washed with brine (15
mL) and dried over Na2SO4. Evaporation of solvent followed by
silica gel column chromatography of the residue afforded 13 (0.24
g, 94% for two steps) as a white solid: Rf 0.5 (4:6 EtOAc:petroleum
ether); mp 63-64 °C; [R]D +15 (c 0.4, CHCl3); IR (CHCl3): 3374,
δ 82.1, 72.5, 68.5, 63.7, 31.9, 29.7, 29.66, 29.6, 29.5, 29.4, 28.9,
26.1, 22.7, 14.1; Analysis calcd for C18H35N3O2: C 66.42; H 10.84;
N 12.91. Found: C 66.53; H 10.69; N 12.79.
Pachastrissamine (Jaspine B) (1). To a solution of 14 (32 mg,
0.1 mmol) in MeOH (1 mL) and CH2Cl2 (0.5 mL) was added 10%
Pd/C (16 mg). The reaction mixture was stirred for 3 h under H2
balloon at room temperature. The reaction mixture was then filtered
through a short pad of Celite and the Celite pad was washed with
CH2Cl2/MeOH (1:1, 10 mL). Evaporation of solvent followed by
silica gel column chromatography of the crude residue with CH2-
Cl2/MeOH (9:1) containing 1% NH4OH as an eluent gave pachas-
trissamine (Jaspine B) (28 mg, 94%) as a white solid: Rf 0.2 (1:9
MeOH:CHCl3 containing 1% NH4OH); mp 96-97 °C (lit6a mp
96.6-97.2 °C); [R]D +17.5 (c 0.4, EtOH), (lit2 [R]D +18 (c 0.1,
EtOH); IR (CHCl3): 3289, 2921, 1467, 1036, 721 cm-1; 1H NMR
(400 MHz, CDCl3) δ 3.95-3.91 (m, 1H), 3.88-3.86 (m, 1H),
3.76-3.71 (m, 1H), 3.53-3.50 (m, 1H), 1.96 (brs, 3H),1.71-1.62
(m, 2H), 1.43-1.25 (m, 24H), 0.88 (t, 3H, J ) 7.2 Hz); 13C NMR
(100 MHz, CD3OD) δ 84.3, 70.9, 68.9, 54.4, 33.1, 30.9, 30.8, 30.74,
30.71, 30.69, 30.5, 29.7, 27.2, 23.7, 14.1; HRMS for C18H37 NO2
+ H calcd: 300.2902; found: 300.2901.
1
2920, 2101, 1467, 1190, 1178, 814 cm-1; H NMR (300 MHz,
CDCl3) δ 7.83 (d, 2H, J ) 8.4 Hz), 7.37 (d, 2H, J ) 8.4 Hz), 4.44
(dd, 1H, J ) 11.1, 3.0 Hz), 4.31-4.19 (m, 1H), 3.78-3.73 (m,
2H), 3.37 (m, 1H), 2.46 (s, 3H), 1.59-1.19 (m, 26H), 0.88 (t, 3H,
J ) 6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 145.3, 132.4, 130.0,
128.0, 71.6, 70.0, 69.8, 61.6, 34.0, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3,
25.6, 22.7, 21.7, 14.1; Analysis calcd for C25H43N3O5S: C 60.33;
H 8.71; N 8.44; S 6.44. Found: C 60.29; H 8.66; N 8.49; S 6.68.
(2S,3S,4S)-4-Azido-2-tetradecyl-tetrahydrofuran-3-ol (14). To
a solution of 13 (0.12 g, 0.24 mmol) in MeOH (2 mL) was added
K2CO3 (0.07 g, 0.50 mmol) at 0 °C and allowed to warm to room
temperature and stirred for 4 h. The volatiles were removed under
reduced pressure and the solid thus obtained was triturated with
diethyl ether (10 mL) and filtered through a short pad of Celite.
The Celite pad was washed with diethyl ether (20 mL). Evaporation
of solvent followed by silica gel column chromatography of the
crude residue obtained gave 14 (0.08 g, 97%) as a white solid: Rf
0.6 (1:6 EtOAc:petroleum ether); mp 99-100 °C (lit6a mp 99.4-
100.1 °C); [R]D +17 (c 1.0, CHCl3), lit6a [R]D +16.7 (c 1.0, CHCl3);
Acknowledgment. We thank Department of Science and
Technology (DST), New Delhi for funding of this project. One
of us (A.C.) thanks Council of Scientific and Industrial Research
(CSIR), New Delhi for a research fellowship.
Supporting Information Available: General experimental
procedures and spectroscopic data for the compounds and copies
of 1H NMR, 13C NMR spectra are provided. This material is
available free of charge via the Internet at http://pubs.acs.org
1
IR (CHCl3): 3333, 2917, 2849, 2104, 1469, 1019, 720 cm-1; H
NMR (400 MHz, CDCl3) δ 4.21-4.19 (m, 1H), 4.14-4.01 (m,
1H), 3.97 (dd, 1H, J ) 9.2, 7.6 Hz), 3.85 (dd, 1H, J ) 9.2, 6.8
Hz), 3.76 (m, 1H), 2.10 (brs, 1H), 1.66-1.59 (m, 2H), 1.43-1.25
(m, 24H), 0.88 (t, 3H, J ) 7.2 Hz); 13C NMR (100 MHz, CDCl3)
JO0707838
J. Org. Chem, Vol. 72, No. 16, 2007 6315