Stereoselective total synthesis of pachastrissamine (jaspine B)

Article abstract of DOI:10.1016/j.tetlet.2007.12.014

A short total synthesis of the cytotoxic natural product pachastrissamine is described. The synthesis includes eight steps starting from Garner's aldehyde and proceeds in 20% overall yield. Pd(0)-mediated intramolecular cyclisation and Ru-mediated cross-metathesis are the key reactions in this sequence.

Full text of DOI:10.1016/j.tetlet.2007.12.014

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Tetrahedron Letters 49 (2008) 980–983
Stereoselective total synthesis of pachastrissamine (jaspine B)
Mikko Passiniemi, Ari M. P. Koskinen *
Laboratory of Organic Chemistry, Helsinki University of Technology, PO Box 6100, FIN-02015 HUT, Finland
Received 28 September 2007; revised 26 November 2007; accepted 5 December 2007
Available online 8 December 2007
Abstract
A short total synthesis of the cytotoxic natural product pachastrissamine is described. The synthesis includes eight steps starting from
Garner’s aldehyde and proceeds in 20% overall yield. Pd(0)-mediated intramolecular cyclisation and Ru-mediated cross-metathesis are
the key reactions in this sequence.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Natural products; Enantioselective synthesis; Pachastrissamine; Cross metathesis; Cyclization
Natural products remain a rich source of leads for new
drugs.1 The structural diversity of natural compounds out-
matches that of purely synthetic ones, and more closely
matches those of drug-like structures than, for example,
chemical libraries produced by combinatorial chemistry.2
These often astounding structures continue to provide
challenges for the development of new strategies for the
formation of structural skeleta, although sometimes the
sheer excitement of the endeavour of total synthesis has
motivated many groups in the search for new chemistry.3
Total synthesis is still an important tool for confirming
the absolute structure of a compound.4 Nature’s ways of
producing this structural diversity markedly differ from
current synthetic practices, and this has recurrently led to
endeavours in biomimetic synthesis,5 protecting group-free
strategies6 and organocatalysis.7
In 2002, pachastrissamine 1, an anhydrophytosphingo-
sine, was isolated from the marine sponge Pachastrissa
sp. (family Calthropellidae) found around the Okinawan
islands.8 Almost simultaneously a French group working
on the ethanolic extracts of a Vanuatuan marine sponge,
Jaspis sp.9 isolated two bioactive compounds, jaspines A
and B, the latter being identical to pachastrissamine. The
structure of pachastrissamine consists of a 14-carbon alkyl
chain attached to an all S (2S,3S,4S) configured 2-amino-3-
hydroxytetrahydrofuran ring (Fig. 1).
Fig. 1. Structures of pachastrissamine (jaspine B) 1 and jaspine A.
*
Corresponding author. Tel.: +358 9 451 2526; fax: +358 9 451 2538.
E-mail address: Ari.Koskinen@hut.fi (A. M. P. Koskinen).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.014

M. Passiniemi, A. M. P. Koskinen / Tetrahedron Letters 49 (2008) 980–983
981
The hydrochloride salt of pachastrissamine displayed
marked submicromolar cytotoxicity against the P388,
HT29 and MEL28 cell lines. It has proved to be the most
potent compound yet isolated from the genus Jaspis on
the A549 human lung carcinoma cell line (IC50 0.24 lM).
Recently, several total syntheses of pachastrissamine 1
have been reported.10
We have a long interest in the use of amino acids as
chiral adducts for the synthesis of nitrogen- containing
natural products.11 We envisioned that our previous
experience as well as new methodology could be used in
the synthesis of pachastrissamine 1. Retrosynthetically
(Scheme 1), 2 can be assembled via a cross-metathesis reac-
tion of the vinylic tetrahydrofuran derivative 3a and the
commercial 1-tetradecene. The tetrahydrofuran ring 3a
can be derived from a Pd-mediated intramolecular 1,5-ring
closure of the acyclic hydroxyalkene 4. This in turn can
easily be prepared from a stereoselective coupling of
Garner’s aldehyde 5 and vinylic iodide 6.
triple bond followed by TBS protection of the free alcohol
gave the vinyl iodide 6 (Scheme 2) in high yield (51% over
three steps) with a single purification process (Kugelrohr
distillation at <0.2 mmHg).
Iodide 6 was then coupled with Garner’s aldehyde (n-
BuLi in toluene). Without additives the anti/syn-selectivity
was 4:1. Better selectivities were achieved with either
HMPA (anti/syn 12:1) or DMPU (anti/syn up to 17:1) as
an additive. Yields varied between 55% with DMPU and
63% without any additives. Stereoisomers 10a and 10b were
easily separated by MPLC.
The anti-alcohol 10a (Scheme 3) was protected as the
benzyl ether 11 (NaH, in situ formed BnI in refluxing
THF).12 Removal of the TBS group (TBAF) followed by
acetylation of the free alcohol 12 gave acetate 13. Depro-
tection of the N,O-acetal with FeCl3 adsorbed on silica
gel13 provided the primary alcohol 414 in 94% yield. This
reaction could also be performed with 80% aqueous AcOH
at 55 °C,11b but depending on the scale, acetylation of the
primary alcohol becomes a problem. With the free alcohol
4 to hand the stage was set for the key cyclisation step.
Pd(0)-mediated intramolecular 1,5-cyclisation provided
Our synthesis commenced with the preparation of the
vinyl iodide 6. Iodination of propargyl alcohol 7 under
basic conditions in MeOH and diimide reduction of the
Scheme 1. Retrosynthesis of pachastrissamine, 1.
Scheme 2. Reagents and conditions: (a) I2, KOH, MeOH, (82%); (b) KO2CN@NCO2K, AcOH, MeOH, (65%); (c) TBSCl, imidazole, DMF (96%); (d) (i)
6, n-BuLi, additive (HMPA or DMPU), toluene, À78 °C, (ii) 5, toluene, À95 °C.

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M. Passiniemi, A. M. P. Koskinen / Tetrahedron Letters 49 (2008) 980–983
Scheme 3. Reagents and conditions: (a) BnBr, TBAI, NaH, THF, 0 °C?reflux; (b) TBAF, CH2Cl2, rt (85% from 10a); (c) Ac2O, DMAP, Et3N, CH2Cl2,
rt (95%); (d) FeCl3–SiO2, CHCl3, rt (94%); (e) cat. Pd(PPh3)4, PPh3, THF, 55 °C (95%); (f) 15, 1-tetradecane, CH2Cl2, 40 °C (87%); (g) (i) H2 (g), Pd(OH)2,
MeOH/EtOAc (1:1), rt, (ii) HCl (g) MeOH/EtOAc (1:1) (76%).
the desired separable tetrahydrofuran diastereomers 3a and
3b in excellent yield (95%, 2:1 dr).15,16
References and notes
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Coupling of the alkyl chain to the furan derivative 3a
was effected using Grubbs’ cross-metathesis reaction.17
Cross- metathesis has been used in the synthesis of cera-
mide derivatives18 as well as in the synthesis of nucleic
acids.19 Reaction of 3a with Grubbs’ 2nd generation cata-
lyst 15 and an excess of 1-tetradecene (1000 mol %) pro-
vided the desired alkene 1420 in excellent yield (87%).
1
According to H NMR the alkene was produced only in
the E-configuration. Finally, hydrogenation (H2 gas with
Pd(OH)2 as the catalyst in (1:1) MeOH/EtOAc) effected
the removal of both the double bond and benzyl protecting
group. After filtration of the reaction mixture through a
pad of CeliteÒ, the solution was treated with HCl gas at
0 °C to cleave the Boc-protection to afford pachastris-
samine (jaspine B) 1 as the hydrochloride salt (76%).
In conclusion, we have described a total synthesis of the
cytotoxic natural product pachastrissamine 1 in eight steps
and 20% overall yield starting from Garner’s aldehyde. We
have demonstrated the utility of the Pd(0)-mediated intra-
molecular cyclisation in forming tetrahydrofuran rings and
cross-metathesis reaction in preparing the natural product.
Acknowledgements
This research was supported by the Helsinki University
of Technology and the Finnish Cultural Foundation (Art-
turi and Aina Helenius fund).

M. Passiniemi, A. M. P. Koskinen / Tetrahedron Letters 49 (2008) 980–983
983
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5.67 (tdd, J = 1.1, 9.3, 11.1 Hz, 1H), 5.84 (dddd, J = 0.8, 6.3, 7.2,
11.3 Hz, 1H), 7.31 (m, 5H). 13C NMR (100 MHz, CDCl3) ppm: 20.9,
28.3, 54.8, 60.0, 62.3, 71.0, 75.8, 79.5, 127.8, 128.0, 128.5, 129.1, 132.0,
137.5, 155.7, 170.8. HRMS calcd for (C20H29NO6Na) [M+Na]
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J = 7.3, 8.6 Hz, 1H), 4.02 (dd, J = 7.2, 8.5 Hz, 1H), 4.02 (m, 1H), 4.38
(m, 1H), 4.52 (d, J = 11.7 Hz, 1H), 4.65 (d, J = 11.7 Hz, 1H), 5.03 (br
d, J = 7.7 Hz, 1H), 5.29 (ddd, J = 1.1, 1.7, 10.3 Hz, 1H), 5.40 (ddd,
J = 1.3, 1.6, 17.2 Hz, 1H), 6.03 (ddd, J = 7.0, 10.3, 17.2 Hz, 1H), 7.36
(m, 5H). 13C NMR (100 MHz, CDCl3) d 28.3, 52.8, 70.8, 73.6, 79.63,
79.67, 82.3, 118.2, 127.8, 128.0, 128.5, 134.2, 137.6, 155.5. HRMS
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1H), 3.95 (t, J = 4.7 Hz, 1H), 3.99 (dd, J = 7.7, 8.2 Hz, 1H), 4.32 (dd,
J = 4.2, 7.7 Hz, 1H), 4.36 (m, 1H), 4.51 (d, J = 11.7 Hz, 1H), 4.66 (d,
J = 11.7 Hz, 1H), 5.04 (d, J = 7.7 Hz, 1H), 5.65 (tdd, J = 1.1, 7.7,
15.5 Hz, 1H), 5.80 (td, J = 6.7, 15.4 Hz, 1H), 7.33 (m, 5H). 13C NMR
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30.04, 30.1, 32.3, 32.8, 53.4, 70.9, 74.1, 80.0, 80.3, 83.0, 125.9, 128.2,
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3.95 (dd, J = 3.1, 11.2 Hz, 1H), 4.34 (d, J = 11.7 Hz, 1H), 4.42 (dd,
J = 5.2, 8.7 Hz, 1H), 4.58 (dd, J = 5.9, 12.5 Hz, 1H), 4.61 (d,
J = 11.9 Hz, 1H), 4.68 (dd, J = 7.5, 13.2 Hz, 1H), 5.22 (br s, 1H),