Total synthesis of pachastrissamine (jaspine B) enantiomers from d-glucose

Article abstract of DOI:10.1016/j.tetlet.2006.11.048

Synthesis of both enantiomers of pachastrissamine is described from a common chiral template. The stereoselective construction of the central tetrahydrofuran units was based on the pseudodesymmetrization of a pentodialdo-1,4-furanose derivative taking adv

Full text of DOI:10.1016/j.tetlet.2006.11.048

Tetrahedron Letters 48 (2007) 265–268
Total synthesis of pachastrissamine (jaspine B) enantiomers
from D-glucose
C. V. Ramana,* Awadut G. Giri, Sharad B. Suryawanshi and Rajesh G. Gonnade
National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
Received 7 August 2006; revised 1 November 2006; accepted 8 November 2006
Available online 28 November 2006
Abstract—Synthesis of both enantiomers of pachastrissamine is described from a common chiral template. The stereoselective con-
struction of the central tetrahydrofuran units was based on the pseudodesymmetrization of a pentodialdo-1,4-furanose derivative
taking advantage of the latent symmetry present.
Ó 2006 Published by Elsevier Ltd.
Pachastrissamine (1, Fig. 1), isolated and characterized
by Higa and co-workers in 2002 from the Okinawa mar-
ine sponge Pachastrissa sp. (family Calthropellidae) is a
novel anhydrophytosphingosine with important bio-
activity.1 It was later (in 2003) isolated from another
marine sponge, genus Jaspis by Debitus and co-workers
and named as jaspine B.2 The structure of 1 and the all-
cis geometry of the THF ring was assigned by spectros-
copy, largely NMR, and the (2S,3S,4S) configuration of
the ring carbon atoms was determined on the basis of
(S)- and (R)-MTPA derivatization on the N-monoacet-
ylated pachastrissamine. This was reported to exhibit
promising cytotoxic activity in the submicromolar range
against P388, A549, HT29, and MEL28 (IC50 = 0.001
lg/mL) cell lines. Its simple structure and this promising
biological activity have stimulated substantial synthetic
work, culminating in several total syntheses.3–7 In this
letter we wish to report a chiral pool synthesis of both
1 and its antipode 2 starting from a single chiron.
As shown in Figure 1, our intended strategy exploited
the pseudosymmetry present in pentodialdo-1,4-fura-
nose 98 to derive enantiomeric azidoalkynes 3 and 4,
which upon alkylation and hydrogenation should result
C
H
C H
14 29
O
O
14 29
O
O
alkylation
alkylation
hydrogenation
hydrogenation
H N
OH
HO
NH
2
2
N
OBn
BnO
O
N
3
3
3
4
(+)-Pachastrissamine (1)
(−)-Pachastrissamine (2)
5
5
1
O
O
1
O
O
5
2
2
3
O
BnO
BnO
OH
HO
OBn
6
9
5
O
D-Glucose
O
TsO
O
+
O
H
O
HO
OBn
BnO
7
8
Figure 1. The key pseudodesymmetrization strategy for (+)- and (ꢀ)-pachastrissamine.
Keywords: Chiron approach; Pachastrissamine/jaspine B; Pentodialdo-1,4-furanose; Ohira–Bestmann reaction; Ring isomerization.
*
Corresponding author. Tel.: +91 20 25902577; fax: +91 20 25902629; e-mail: vr.chepuri@ncl.res.in
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.11.048

266
C. V. Ramana et al. / Tetrahedron Letters 48 (2007) 265–268
in the synthesis of 1 and 2, respectively.9 We anticipated
that the two enantiomeric furan systems 5 and 6 could
be fashioned efficiently by employing selective Ohira–
Bestmann alkynylation at either end of 9. The Ohira–
Bestmann alkynylation at C(5) is a direct proposition,
whereas for the Ohira–Bestmann alkynylation at C(1),
we were interested in the acid mediated ring isomeriza-
tion of 8.
reductive deketalization12 of the resulting alkyne 1213
using excess triethylsilane in the presence of BF3ÆEt2O.
The spectral data of 6 were comparable with its antipode
5.14
Once we had easy access to enantiomeric alkynols 5 and
6, the stage was set for the synthesis of the mirror iso-
mers of pachastrissamine. Thus, alkynols 5 and 6 were
transformed to the corresponding azidoalkynes 3 and
4 by treatment with Tf2O in pyridine followed by react-
ing the intermediate triflates with LiN3 in DMF. The
spectral and analytical data of compounds 3 and 4 were
in agreement with the proposed structures.15 After
examining a set of bases and reaction conditions, we
concluded that the alkylation of azidoalkynes 3, 4 with
1-bromododecane was facile using n-BuLi in THF-
HMPA and the alkylated products 13 and 14 were
obtained in 61% and 57% yields, respectively.16 Hydro-
genolysis of 13 and 14 was effected by refluxing in meth-
anol in the presence of ammonium formate and cat. 10%
Pd/C. The requisite pachastrissamine enantiomers were
characterized either after chromatographic purification
or as their diacetates 15 and 16, respectively (Scheme
2). The spectral and analytical data of the 1 and its diac-
etate 1517 were in agreement with the reported values
and the structure of 15 was further established by single
crystal X-ray analysis (Fig. 2).18–20
Prior to the discussion on the synthesis of enantiomeric
alkynols 5 and 6, it is pertinent to mention that while
our work was in progress furanoaldehyde 7 was pre-
pared and used by Linhardt and co-workers5 for the
synthesis of natural pachastrissamine (1). The synthesis
of alkynol 5 started with reduction of the easily available
dialdofuranose 9 (prepared from D-glucose following
the literature procedure, Scheme 1) with NaBH4.10
Tosylation of 10 using p-TsCl in pyridine followed by
acid mediated acetonide deprotection with concomitant
2,5-ring closure gave dimethylacetal 11 in a good yield.
The following acetal hydrolysis reaction proceeded with
2 N sulfuric acid in acetic acid and the resulting alde-
hyde 7 was subjected to Ohira–Bestmann alkynylation
under standard conditions.11
Alkynol 6 was prepared in two steps from 9 by first sub-
jecting it to the Ohira–Bestmann alkynylation and then
O
O
O
TsO
O
HO
b)
O
O
O
ref 8
a)
D-Glucose
93%
O
O
89%
O
BnO
BnO
BnO
8
9
10
c)
81%
OMe
OMe
O
O
O
e)
d)
O
67%
81%
HO
OBn
HO
OBn
11
HO
OBn
5
7
O
O
O
e)
O
O
O
f)
82%
91%
O
O
BnO
OH
BnO
BnO
9
12
6
Scheme 1. Reagents and conditions: (a) NaBH4, MeOH, 0 °C, 2 h; (b) p-TsCl, pyridine, DMAP, CH2Cl2, 5 h; (c) PTSA, methanol, reflux, 6 h; (d)
2 N, H2SO4, 50% AcOH, 9 °C, 2 h; (e) (MeO)2P(@O)C(@N2)COCH3, methanol, K2CO3, rt, 7–9 h; (f) BF2ÆEt2O, Et3SiH, CH2Cl2, ꢀ20 °C ꢀ rt, 6 h.
Figure 2. ORTEP structure of compound 15.

C. V. Ramana et al. / Tetrahedron Letters 48 (2007) 265–268
267
C12H25
C
14H29
O
3
O
13
O
O
C
14H29
O
O
a)
b)
c)
d)
5
6
81%
67%
61%
91%
N3
OBn
N3
OBn
OBn
H2N
OH
AcHN
OAc
1
15
C12H25
C14H29
O
O
C14H29
a)
b)
c)
d)
85%
69%
57%
94%
N3
OBn
N3
H2N
OH
AcHN
OAc
16
4
14
2
Scheme 2. Reagents and conditions: (a) (i) Tf2O, pyridine, CH2Cl2, 0 °C, 6 h; (ii) LiN3, DMF, rt, 12 h; (b) n-BuLi, THF:HMPA (7:1), C12H25Br, ꢀ78
to ꢀ40 °C, 1 h; (c) 10% Pd/C, ammonium formate, MeOH, reflux, 10 h; (d) Ac2O, Et3N, DMAP, CH2Cl2, rt, 6 h.
10. (a) Horton, D.; Swanson, F. O. Carbohydr. Res. 1970, 14,
159–171; (b) Patil, N. T.; John, S.; Sabharwal, S. G.;
Dhavale, D. D. Bioorg. Med. Chem. 2002, 10, 2155–2160.
11. (a) Ohira, S. Synth. Commun. 1989, 19, 561–564; (b) Roth,
In summary, we have reported a simple chiral pool strat-
egy for the synthesis of both enantiomers of pachastriss-
amine starting with D-glucose. The synthesis is
sufficiently flexible to allow substitution or variation in
the length of the side chain to synthesize analogues.
G. J.; Liepold, B.; Muller, S. G.; Bestmann, H. J. Synlett
¨
1996, 521–522.
12. (a) Bennek, J. A.; Gray, G. R. J. Org. Chem. 1987, 52,
892–897; (b) Murty, K. V. S. N.; Vasella, A. Helv. Chim.
Acta 2001, 84, 939–963.
Acknowledgements
13. Tronchet, J. M. J.; Gonzalez, A.; Zumwald, J. B. Helv.
Chim. Acta 1974, 57, 1505–1510.
We thank Mukund K. Gurjar for encouragement and
the Department of Science and Technology (New
Delhi), for the project grant (SR/FTP/CSA-02/2002)
under the ‘Fast Track Proposals for Young Scientists’.
AGG thanks UGC (New Delhi), S.B.S. thanks CSIR
(New Delhi), for the financial assistance in the form
of research fellowships.
25
14. Spectral data of 5. ½aꢁD ꢀ57.9 (c 1, CHCl3). IR (CHCl3) m:
3403, 3290, 3065, 2942, 2120, 1598, 1496, 1218, 1069, 754,
1
698, 666 cmꢀ1. H NMR (200 MHz, CDCl3) d: 2.15 (br s,
1H), 2.57 (d, J = 2.3 Hz, 1H), 3.67 (dd, J = 2.2, 9.8 Hz,
1H), 3.91 (dd, J = 2.3, 4.7 Hz, 1H), 4.18 (dd, J = 4.7,
9.8 Hz, 1H), 4.32–4.34 (dt, J = 2.3, 4.7 Hz, 1H), 4.64 (d,
J = 11.9 Hz, 1H), 4.77 (dd, J = 2.2, 4.7 Hz, 1H), 4.78 (d,
J = 11.9 Hz, 1H), 7.27–7.38 (m, 5H). 13C NMR
(50 MHz, CDCl3) d: 70.6 (d), 72.7 (t), 73.1 (t), 75.5 (d),
76.4 (d), 78.9 (s), 84.9 (d), 127.8 (d), 127.9 (d), 128.5 (d),
137.5 (s) ppm. ESI-MS: m/z 219.1 (23%, [M+1]+),
236.2 (38%, [M+NH4]+), 241.2 (100%, [M+Na]+), 257.1
(18%, [M+K]+). Anal. calcd for C13H14O3: C, 71.54; H,
References and notes
1. Kuroda, I.; Musman, M.; Ohtani, I. I.; Ichiba, T.; Tanaka,
J.; Gravalos, D. G.; Higa, T. J. Nat. Prod. 2002, 65, 1505–
1506.
2. Ledroit, V.; Debitus, C.; Lavaud, C.; Massiot, G. Tetra-
hedron Lett. 2003, 44, 225–228.
3. Sudhakar, N.; Kumar, A. R.; Prabhakar, A.; Jagadeesh,
B.; Rao, B. V. Tetrahedron Lett. 2005, 46, 325–327.
4. Bhaket, P.; Morris, K.; Stauffer, C. S.; Datta, A. Org. Lett.
2005, 7, 875–876.
5. Du, Y.; Liu, J.; Linhardt, R. J. J. Org. Chem. 2006, 71,
1251–1253.
6. 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.
7. Ribes, C.; Falomir, E.; Carda, M.; Marco, J. A. Tetra-
hedron 2006, 62, 5421–5425.
8. (a) Defaye, J.; Ratovelomanana, V. Carbohydr. Res. 1971,
17, 57–65; (b) Defaye, J.; Horton, D.; Muesser, M.
Carbohydr. Res. 1971, 20, 305–318; (c) Yu, H.-W.; Zhang,
H.-Y.; Yang, Z.-J.; Min, J.-M.; Ma, L.-T.; Zhang, L.-H.
Pure Appl. Chem. 1998, 70, 435–438.
9. For earlier pseudodesymmetrization approaches employ-
ing sugar chirons, see: (a) Hoffmann, H. M. R.; Dunkel,
R.; Mentzel, M.; Reuter, H.; Stark, C. B. W. Chem. Eur. J.
2001, 7, 4772–4789; (b) Boulineau, F. P.; Wei, A. Org.
Lett. 2004, 6, 119–121; (c) Boulineau, F. P.; Wei, A. J.
Org. Chem. 2004, 69, 3391–3399.
25
6.47. Found: C, 71.44; H, 6.59. Spectral data of 6. ½aꢁD 56
(c 0.9, CHCl3). ESI-MS: m/z 241.3 (100%, [M+Na]+),
257.3 (24%, [M+K]+); Anal. calcd for C13H14O3: C, 71.54;
H, 6.47. Found: C, 71.49; H, 6.39.
25
15. Spectral data of 3. ½aꢁD ꢀ69 (c 1.3, CHCl3). IR (CHCl3) m:
3304, 3020, 2125, 2110, 1603, 1585, 1216, 759, 698,
638 cmꢀ1
.
1H NMR (200 MHz, CDCl3) d: 2.64 (d,
J = 2.3 Hz, 1H), 3.92–4.04 (m, 3H), 4.16 (br dd, J = 5.0,
6.1 Hz, 1H), 4.71 (dd, J = 2.3, 6.1 Hz, 1H), 4.74 (d,
J = 11.8 Hz, 1H), 4.83 (d, J = 11.8 Hz, 1H), 7.31–7.46 (m,
5H). 13C NMR (50 MHz, CDCl3) d: 59.9 (d), 69.4 (t), 69.7
(d), 73.2 (t), 76.9 (d), 78.8 (s) 79.4 (d), 127.9 (d), 128.0 (d),
128.5 (d), 137.0 (s). Anal. calcd for C13H13N3O2: C, 64.19;
H, 5.39, N, 17.27. Found: C, 64.29; H, 5.21, N, 17.18.
25
Spectral data of 4. ½aꢁD 70.1 (c 1.3, CHCl3). ESI-MS: m/z
267.3 (27%), 283.4 (40%, [M+K]+). Anal. calcd for
C13H13N3O2: C, 64.19; H, 5.39, N, 17.27. Found: C,
64.01; H, 5.61, N, 17.24.
16. Weaving, R.; Roulland, E.; Monneret, C.; Florent, J.-C.
Tetrahedron Lett. 2003, 44, 2579–2581.
25
17. Spectral data of 15. Mp: 110 °C; ½aꢁD ꢀ34.6 (c 1, CHCl3),
25
lit.7 {½aꢁD ꢀ28.4 (c 1, CHCl3)}. IR (CHCl3) m: 3019, 2927,
2855, 1743, 1676, 1550, 1467, 1374, 1215, 1049, 757 cmꢀ1
.
1H NMR (200 MHz, CDCl3) d: 0.86 (t, J = 6.8 Hz, 3H),
1.23 (br s, 24H), 1.40–1.48 (m, 2H), 1.97 (s, 3H), 2.15 (s,
3H), 3.58 (dd, J = 7.9, 8.6 Hz, 1H), 3.85–3.93 (m, 1H), 4.06

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C. V. Ramana et al. / Tetrahedron Letters 48 (2007) 265–268
(dd, J = 8.1, 8.6 Hz, 1H), 4.80 (dq, J = 5.4, 8.0 Hz, 1H),
5.37 (dd, J = 3.4, 5.5 Hz, 1H), 5.61 (d, J = 8.2 Hz, 1H). 13
for crystal structure solution and refinement, University of
C
Gottingen, Germany, 1997)19 was used for structure
solution and full-matrix least-squares refinement on F2.
Hydrogen atoms were included in the refinement as per the
riding model.
NMR (50 MHz, CDCl3) d: 14.1 (q), 20.6 (q), 22.6 (t) 23.1
(q), 26.0 (t), 29.3 (2t), 29.4 (t), 29.5 (2t), 29.6 (2t), 31.9 (t),
51.3 (d), 69.9 (t), 73.5 (d), 81.20 (d). ESI-MS: m/z 384.2
(82%, [M+1]+), 406.3 (100%, [M+Na]+). Spectral data of
19. Sheldrick, G. M. SHELX-97 Program for Crystal Structure
Solution and Refinement; University of Gottingen:
Germany, 1997.
25
16. Mp: 108 °C; ½aꢁD 29 (c 1, CHCl3). ESI-MS: m/z 384.4
(23%, [M+1]+), 406 (100%, [M+Na]+), 422.3 (20% [M+K]+).
18. X-ray intensity data was collected on a Bruker SMART
APEX CCD diffractometer with graphite-monochroma-
20. The crystallographic data has been deposited with the
Cambridge Crystallographic Data Centre as deposition
No. CCDC 617243 (15). Copies of the data can be
obtained, free of charge, on application to the CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44 (1223)
336033; e-mail: deposit@ccdc.cam.ac.uk].
˚
tized (MoKa = 0.71073 A) radiation at room temperature.
All the data were corrected for Lorentzian, polarization,
and absorption effects using Bruker’s SAINT and SADABS
programs. SHELX-97 (G.M. Sheldrick, SHELX-97 program