The first synthesis of the anhydrophytosphingosine pachastrissamine (jaspine B) from Garner's aldehyde

Article abstract of DOI:10.1016/j.tetlet.2004.11.035

The synthesis of the natural anhydrophytosphingosine pachastrissamine (jaspine B) 1a from Garner's aldehyde is described.

Full text of DOI:10.1016/j.tetlet.2004.11.035

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 325–327
The first synthesis of the anhydrophytosphingosine
pachastrissamine (jaspine B) from GarnerÕs aldehydeI
N. Sudhakar,a A. Ravi Kumar,a A. Prabhakar,b B. Jagadeeshb and B.Venkateswara Raoa,*
aOrganic Chemistry Division III, Indian Institute of Chemical Technology, Hyderabad 500007, India
bNuclear Magnetic Resonance Division, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 6 September 2004; revised 29 October 2004; accepted 5 November 2004
Available online 25 November 2004
Abstract—The synthesis of the natural anhydrophytosphingosine pachastrissamine (jaspine B) 1a from GarnerÕs aldehyde is
described.
Ó 2004 Elsevier Ltd. All rights reserved.
Pachastrissamine 1a, the first natural anhydrophyto-
sphingosine derivative was recently isolated from a
marine sponge, Pachastrissa sp. (family calthropellidae)
by Higa and co-workers1 and found to possess cyto-
toxicity at a level of IC50 0.01lg/mL against P388,
A549, HT29 and Mell 28 cell lines. Later Debitus and
co-workers2 isolated the same compound from a marine
sponge, genus jaspis, which is a main source of many
cytotoxic compounds such as jaspamides,3 jaspis-
amides,4 isomalabaricane,5 toyocamycin and 5-methoxy
carbonyltubercidine,6 and named as 1a.
Jaspine
B
1a displayed marked cytotoxicity
(IC50 = 0.24lM) against the A549 human lung carci-
noma cell line using the ATP lite assay. Jaspine B 1a
proved to be the most potent compound yet isolated
from the jaspis genus on this cell line, cf. pectenotoxin
II (IC50 > 10lM),8 bengamide Y (IC50 = 12.8lM),9
bengamide Z (IC50 = 10.5lM).10 The important biolog-
ical activity and the novel structural features of 1a
prompted us to undertake its total synthesis.
The convergent total synthesis of 1a started from the
GarnerÕs aldehyde.11 Stereoselective addition of vinyl-
magnesium bromide to 3 afforded a 6:1 mixture of allylic
alcohols 4 and 5, which were separated by column chro-
matography.12 The alcohol functionality of compound 4
was protected as itÕs O-benzyl ether to give 6. Oxidative
degradation of the alkene functionality with ozone affor-
ded the aldehyde, which then underwent Grignard addi-
tion using C14H29MgBr in THF to give compounds 7a
and 7b as an inseparable diastereomeric mixture (ratio
Jaspamides possess interesting biological activities
such as antiproliferative (cytotoxic and antimicrobial),
anthelminthic, insecticidal and ichthyototoxic activi-
ties.7
OR
RHN
OR
RHN
1
7:3 by H NMR), which was carried further as such
(Scheme 1).
C14H29
C14H29
O
O
Deprotection of the acetonide group in compound 7 was
achieved using 80% AcOH to give compounds 8a and
8b, which were converted into the O-silyl ethers 9a,b.
The hydroxyl groups in compounds 9a,b were converted
into mesylates, which were treated with TBAF to give
the five membered cyclic compounds 10 and 11 in a
7:3 ratio, which were easily separable by column chro-
matography. The confirmation of structures and assign-
ments for the tetrahydrofurans 10 and 11 was achieved
by detailed 1D and 2D NMR studies including DQF-
COSY and NOESY experiments. For 10 strong NOE
1b
2b
R = H
1a
2a
R = H
R = Ac
R = Ac
Keywords: Grignard reactions; Cyclization; Pachastrissamine (jas-
pine B).
q CDRI Communication No. 040913.
*
Corresponding author. Tel.: +91 040 27160123x2614; fax: +91 040
27160512; e-mail: venky@iict.res.in
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.035

326
N. Sudhakar et al. / Tetrahedron Letters 46 (2005) 325–327
OBn
OH
OH
CHO
NBoc
a
b
+
O
NBoc
O
NBoc
O
O
NBoc
6
5
4
3
OBn
OBn
C14H29
R1
C14H29
R1
e
c
d
O
NBoc
R2
HO
NHBoc
R2
8a R1 = H, R2 = OH
8b R1 = OH, R2 = H
7a R1 = H, R2 = OH
7b R1 = OH, R2 = H
(ratio of 7a and 7b is 7:3)
BocNH
+
OBn
OBn
BocNH
OBn
C14H29
f
R1
R2
C14H29
O
TBSO
NHBoc
C14H29
O
9a R1 = H, R2 = OH
9b R1 = OH, R2 = H
11
10
Scheme 1. Reagents and conditions: (a) vinylmagnesium bromide, THF, 0°C–rt, 12h, (b) BnBr, THF, NaH (60% w/w), 0°C–rt, 12h, 92%, (c) (i) O3,
DCM, ꢁ78°C, 1h, (CH3)2S, (ii) C14H29MgBr, THF, 12h, rt (83% for two steps), (d) 80% AcOH, 0°C–rt, 12h, 91%, (e) TBDMS-Cl, imidazole, dry
DCM, DMAP, 0°C–rt, 12h, 86%, (f) (i) MsCl, Et3N, DCM, 0°C–rt, 2h, (ii) TBAF, THF, rt, 2h, 88% (overall yield 28.3% for compound 10 and
12.1% for compound 11), (7:3 diastereoisomeric mixture for 10 and 11).
cross peaks were observed between NH–H10, H2–H4
and H5–H6, whereas for 11 the NOE cross peaks be-
tween NH–H10, H2–H5, H3–H5 and H4–H6 confirmed
the structures as shown in Figure 1.
electrospray analysis: m/z 300 (M++1ꢁCF3COOH) and
for the diacetate derivative were identical with the re-
ported values.1,2
Compound 11 was also converted into the C-2 epimer of
1a as itÕs TFA salt 1b and the di-acetate derivative 2b
was prepared using the same strategy (Scheme 3). The
spectral data of diacetate 2b is matched with the C-12
side chain derivative, which was synthesized earlier.13
Compound 1b is also reported as synthetic derivative
of phytosphingosine.14
The O-benzyl ether in compound 10 was cleaved under
Na/liq. NH3 conditions to afford alcohol 12. Compound
12 on treatment with 50% TFA–DCM gave the target
molecule pachastrissamine (jaspine B) 1a as itÕs TFA salt
(Scheme 2).
The diacetate derivative of pachastrissamine 2a was syn-
thesized from compound 1a using Et3N and Ac2O. The
In conclusion we have developed a strategy for the
synthesis of pachastrissamine (jaspine B) 1a and its di-
acetate derivative 2a from GarnerÕs aldehyde. The C-2
epimer of pachastrissamine (jaspine B) was also
synthesized.
25
D
1H NMR of the TFA salt of 1a [itÕs optical rotation ½aꢀ
25
+17.1 (c 0.4, EtOH)], {lit.1 ½aꢀ +18 (c 0.1, EtOH)} and
D
H
H
H
H
6
BocNH
6
BocNH
O-CH2-Ph
O-CH2-Ph
2
1
3
3
2
1
H
1
1
4
H
4
H
1. Spectral data
5
C13H27
O
O
H
H
11
5
H
11
C13H27
1.1. TFA salt of 1b
10
11
25
½aꢀ +14.46 (c 1.5, EtOH); (1H NMR, 300MHz,
D
Figure 1. NOEs observed in compounds 10 and 11.
CD3OD): d 0.89 (t, 3H, J = 7.3Hz), 1.22–1.39 (m,
BocHN
OH
TFAH2N
OH
AcHN
OAc
a
c
b
10
C14H29
C14H29
TFA salt of 1a
O
C14H29
O
O
12
2a
Scheme 2. Reagents and conditions: (a) Na/liq. NH3, THF, ꢁ78°C, 30min, 96%, (b) 50% TFA–DCM, rt, 6h, 87%, (c) Et3N, Ac2O, DCM, 0°C–rt,
4h, 94% (overall yield for 2a is 22.3%).

N. Sudhakar et al. / Tetrahedron Letters 46 (2005) 325–327
NHBoc OH
327
OH
NH2TFA
NHAc
OAc
c
a
b
11
C14H29
C14H29
TFA salt of 1b
O
C14H29
O
O
13
2b
Scheme 3. Reagents and conditions: (a) Na/liq. NH3, THF, ꢁ78°C, 30min, 96%, (b) 50% TFA–DCM, rt, 6h, 89%, (c) Et3N, Ac2O, DCM, 0°C–rt,
4h, 94% (overall yield for 2b is 9.8%).
22H), 1.41–1.67 (m, 4H), 3.64–3.75 (m, 3H), 3.98–4.04
(m, 1H), 4.10–4.17 (m, 1H); 13C NMR (CD3OD,
125MHz): d 85.20, 74.33, 69.36, 53.65, 34.02, 32.95,
30.67, 30.65, 30.59, 30.55, 30.35, 26.76, 23.61, 14.34;
electrospray analysis: m/z 300 (M++1ꢁCF3COOH).
Acknowledgements
N. Sudhakar and A. Ravi Kumar thank UGC and
CSIR, New Delhi, respectively, for the research fellow-
ship (S.R.F). The authors also thank Dr. J. S. Yadav,
the late Dr. A. K. Singh and Dr. A. C. Kunwar for their
support and encouragement. We also thank Professor
Higa, Japan, for sending the spectral data of
pachastrissamine.
1.2. Compound 10
25
½aꢀ +1.08 (c 1.1, CHCl3); (1H NMR, 500MHz, CDCl3):
D
d 0.88 (t, 3H, J = 6.85Hz), 1.26 (br s, 24H), 1.44 (br s,
9H, CH3-Boc), 1.62 (m, 2H, H-5), 3.61 (dd, 1H,
References and notes
0
0
J1;1 ¼ 8:3Hz,
J1 2 ¼ 7:2Hz,
H-10),
1H, J3,4 = 4.5Hz, J4,CH2 = 6.4Hz, H-4), 3.91 (dd,
3.80
(dt,
1. Kuroda, I.; Musman, M.; Ohtani, I. I.; Ichiba, T.; Tanaka,
J.; Gravalos, D. G.; Higa, T. J. Nat. Prod. 2002, 65, 1505–
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2. Ledroit, V.; Debitus, C.; Lavaud, C.; Massiot, G. Tetra-
hedron Lett. 2003, 44, 225–228.
3. Bubb, M. R.; Senderowicz, A. M. J.; Sausville, E. A.;
Duncan, K. L. K.; Korn, E. D. J. Biol. Chem. 1994, 269,
14869–14871.
4. Kobayashi, J.; Murata, O.; Shigemori, H. J. Nat. Prod.
1993, 56, 787–791.
0
1H, J1;1 ¼ 8:3Hz, J1,2 = 7.7Hz, H-1), 3.95 (dd, 1H,
J3,4 = 4.5Hz,
J2,3 = 6.0Hz,
H-3),
4.35
(dddd,
0
J1,2 = 6.7Hz, J1 2 ¼ 7:4Hz, J2,3 = 6.2Hz, JNH,2 = 7.2Hz,
H-2), 4.58 (s, 2H, H-6), 5.0 (d, 1H, J = 8.3Hz, NH),
7.30-7.40 (m, 5H, phenyl); 13C NMR (75MHz, CDCl3):
d 155.55, 137.79, 128.47, 127.91, 81.90, 79.56, 79.14,
74.24, 70.56, 53.21, 31.89, 29.63, 29.56, 29.30, 28.37,
26.33, 22.63, 14.01; FABMS: m/z 490 (M++1).
5. Zabriskie, T. M.; Ireland, C. M. J. Nat. Prod. 1989, 52,
1353–1356.
6. Zampella, A.; Giannini, C.; Debitus, C.; Roussakis, C.;
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7. Sugiyama, S.; Honda, M.; Komori, T. Liebigs Ann. Chem.
1990, 1069–1078.
8. OÕConnell, P. W.; Tsien, S. H. Arch. Biochem. Biophys.
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12. (a) Garner, P.; Park, J. M. J. Org. Chem. 1988, 53, 2979–
2984; (b) Ojima; Vidal, E. S. J. Org. Chem. 1998, 63, 7999–
8003.
13. Sugiyama, S.; Honda, M.; Komori, T. Liebigs Ann. Chem.
1990, 1069–1078.
1.3. Compound 11
25
D
1
½aꢀ +5.1 (c 1, CHCl3); H NMR (500MHz, CDCl3):
d 0.88 (t, 3H, J = 6.9Hz), 1.26 (br s, 24H), 1.45 (br s,
9H, CH3-Boc), 1.47 (m, 2H, H-5), 3.57 (dd,
1H, J1;1 ¼ 8:7Hz, J1 ;2 ¼ 7:4Hz, H-10), 3.66 (dd, 1H,
0
0
J3,4 = 4.3Hz,
1H, J3,4 = 4.3Hz, J4,CH2 = 6.3Hz, H-4), 4.10 (dd, 1H,
J2,3 = 6.2Hz,
H-3),
3.83
(dt,
0
J1;1 ¼ 8:7Hz, J1,2 = 6.7Hz, H-1), 4.22 (dddd,
0
J1,2 = 6.7Hz, J1 ;2 ¼ 7:4Hz, J2,3 = 6.2Hz, JNH,2
=
7.2Hz, H-2), 4.53 (s, 2H, H-6), 5.10 (d, 1H, J = 7.2Hz,
NH), 7.28–7.40 (m, 5H, phenyl); 13C NMR (75MHz,
CDCl3): d 155.64, 137.51, 128.48, 127.99, 127.90,
82.50, 81.58, 79.58, 72.24, 71.12, 51.54, 33.92, 31.90,
29.64, 29.54, 29.32, 28.37, 25.72, 22.65, 14.05; FABMS:
m/z 490 (M++1).
14. Jo, S. Y.; Kim, H. C.; Jeon, D. J.; Kim, H. R. Heterocycles
2001, 55, 1127–1132.