Total synthesis of cytotoxic sponge alkaloids hachijodines F and G

Article abstract of DOI:10.1016/S0040-4039(02)00379-9

The total synthesis of two cytotoxic sponge alkaloids hachijodines F (1) and G (2) via a common intermediate 3 is described.

Full text of DOI:10.1016/S0040-4039(02)00379-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2745–2747
Total synthesis of cytotoxic sponge alkaloids hachijodines
F and G
William R. F. Goundry, Victor Lee and Jack E. Baldwin*
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK
Received 16 January 2002; revised 15 February 2002; accepted 21 February 2002
Abstract—The total synthesis of two cytotoxic sponge alkaloids hachijodines F (1) and G (2) via a common intermediate 3 is
described. © 2002 Elsevier Science Ltd. All rights reserved.
Hachijodines F (1) and G (2) are 3-alkylpyridine alka-
loids recently isolated among other alkaloids from the
marine sponge of the genera Amphimedon.1 Both 1 and
2 were found to be cytotoxic towards P388 murine
leukaemia cells with IC50 at 1 mg/mL. The structures of
1 and 2 were established via NMR spectroscopy and
mass spectrometry. The relatively low abundance of 1
and 2 from the natural source (10.2×10−4% and 30.2×
10−4% yield, respectively) and their interesting biologi-
cal property prompt us to investigate their synthesis.
Herein we describe the successful total synthesis of 1
and 2.
The synthesis of 1 and 2 makes use of compound 3 as
a common intermediate. The preparation of 3 is shown
in Scheme 1. 5-Bromo-1-pentene 4 was treated with an
excess of lithiated 3-picoline2–5 (prepared from 3-picol-
ine and LDA) in THF and DMPU to give 56 in 70%
yield. Compound 5 was then subjected to the Lemieux–
Johnson oxidation7 to deliver aldehyde 6 in 73% yield.
Conversion of 6 to acetylene 3 was effected in 79% yield
with dimethyl(1-diazo-2-oxopropyl)phosphonate in
the presence of potassium carbonate and methanol8
(Scheme 1).
The synthesis of hachijodine F (1) commenced with the
selective monobromination9 of octane-1,8-diol 7 to give
8-bromooctan-1-ol 8 in 95% yield. Compound 8 was
converted to its tert-butyldiphenylsilyl ether 9 in 89%
yield with tert-butyldiphenylsilyl chloride and imida-
zole.10 Iodide 10 was obtained in 95% yield from 9 via
a Finkelstein reaction.11 Compound 10 was reacted
with the acetylide anion generated from 3 (3+nBuLi in
THF/DMPU) to deliver 11 in 48% yield.12 Deprotec-
tion of 11 was effected with ammonium fluoride in
methanol13 to afford alcohol 12 in 90% yield. Reaction
of 12 with p-toluenesulphonyl chloride and
triethylamine14,15 gave tosylate 13 in 67% yield. Com-
pound 13 was subjected to nucleophilic displacement
with N-methylhydroxylamine under the modified
Mukaiyama conditions16 to give hachijodine F (1) in
61% yield (Scheme 2).
N
OH
Hachijodine F (1)
N
N
OH
Hachijodine G (2)
N
3
N
Common intermediate
The synthesis of hachijodine G (2) began with the
selective protection of nonane-1,9-diol 14 with tert-
butyldiphenylsilyl chloride with Hunig’s base in N,N-
* Corresponding author. E-mail: j.e.baldwin@chem.ox.ac.uk
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00379-9

2746
W. R. F. Goundry et al. / Tetrahedron Letters 43 (2002) 2745–2747
i
ii
iii
O
Br
N
N
N
4
5
6
3
t
Scheme 1. Reagents and conditions: (i) LDA, DMPU, 3-picoline, THF, 70%; (ii) OsO4, NaIO4, BuOH, H2O, 73%; (iii) K2CO3,
MeOH,
, 79%.
ii
X
X
TBDPSO
iii
HO
9, X = Br
10, X = I
7, X = OH
8, X = Br
iv
i
OR
N
OH
vii
N
11, R = TBDPS
12, R = H
13, R = Ts
N
v
Hachijodine F (1)
vi
Scheme 2. Reagents and conditions: (i) HBr(aq.), toluene, reflux, 95%; (ii) TBDPSCl, imidazole, THF, 89%; (iii) NaI, acetone,
reflux, 95%; (iv) 3, nBuLi, DMPU, 48%; (v) NH4F, MeOH, 90%; (vi) TsCl, Et3N, CH2Cl2, 67%; (vii) Et4NI, Et3N, Me-
NHOH·HCl, DMPU, 61%.
1
dimethylformamide17 to give monoprotected diol 15
in 55% yield. Alcohol 15 was oxidised with 2-iodoxy-
benzoic acid (IBX)18–20 to aldehyde 16 in 83% yield.
Compound 16 was converted into cis-vinyl iodide 17
in 65% using the Stork and Zhao olefination proto-
col.21,22 Compound 17 was coupled to 3 using Alami’s
modified Sonogashira reaction23 to deliver 18 in 87%
yield. Compound 18 was deprotected with ammonium
fluoride in methanol13 to deliver alcohol 19 in 92%
yield. Compound 19 was converted to its tosylate 20
in 81% yield with p-toluenesulphonyl chloride and tri-
ethylamine.14,15 Compound 20 was treated with N-
methylhydroxylamine16 to give hachijodine G (2) in
46% yield (Scheme 3).
The H NMR data of hachijodines F (1) and G (2)
(in CDCl3 with traces of trifluoroacetic acid added)
are consistent with the literature data. In conclusion,
we have developed efficient routes to both hachijodi-
nes F (1) and G (2) using 3 as a common intermedi-
ate.
Acknowledgements
We thank Professor Nobuhiro Fusetani for providing
us with the spectra of hachijodines F (1) and G (2).
ii
iii
I
OR
OR
O
HO
OR
16, R = TBDPS
17, R = TBDPS
14, R = H
i
15, R = TBDPS
iv
OR
N
OH
vii
18, R = TBDPS
19, R = H
20, R = Ts
v
N
vi
Hachijodine G (2)
N
Scheme 3. Reagents and conditions: (i) iPr2NEt, DMF, TBDPSCl, 55%; (ii) IBX, DMSO, THF, 83%; (iii) NaN(TMS)2,
[Ph3PCH2I]+I−, THF, DMPU, 65%; (iv) Pd(PPh3)4, pyrrolidine, CuI, 3, 87%; (v) NH4F, MeOH, 92%; (vi) TsCl, Et3N, DCM, 81%;
(vii) Et4NI, Et3N, MeNHOH·HCl, DMPU, 46%.

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2747
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