Synthesis of a possible structure of pyrinodemin A

Article abstract of DOI:10.1016/S0040-4039(01)02117-7

An alternative possible structure of pyrinodemin A is synthesised. The ¹³C NMR of the synthetic product 3 is in better agreement with the literature data.

Full text of DOI:10.1016/S0040-4039(01)02117-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 327–329
Synthesis of a possible structure of pyrinodemin A
Stuart P. Romeril, Victor Lee, Timothy D. W. Claridge and Jack E. Baldwin*
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK
Received 14 September 2001; revised 23 October 2001; accepted 5 November 2001
Abstract—An alternative possible structure of pyrinodemin A is synthesised. The 13C NMR of the synthetic product 3 is in better
agreement with the literature data. © 2002 Elsevier Science Ltd. All rights reserved.
Pyrinodemin A is a cytotoxic alkaloid isolated from the
marine sponge Amphimedon sp. by Kobayashi et al.1 The
structure of pyrinodemin A was proposed as 1 based on
NMR and mass spectrometry studies. Both we2 and
others3 have recently synthesised structure 1 and con-
cluded the position of the double bond in the natural
product was incorrectly assigned between C16%ꢀC17%.
Both groups observed that in the 13C NMR spectrum of
synthetic 1, the olefinic carbons appeared as two signals
separated by 1 ppm. Both groups then prepared the
C15%ꢀC16% double bond isomer 2. The 13C NMR of 2 also
showed two separated signals for the olefinic carbons,
albeit now 0.4 ppm apart. In light of the differences
between the spectroscopic data of 2 and the literature
data, we concluded that 2 does not correspond to natural
pyrinodemin A.2 In contrast, Snider et al. concluded 2
is probably the correct structure of pyrinodemin A.3
In this paper, we present the synthesis of a third
structure, 3, and show that the 13C NMR data of 3 are
in better agreement with the literature data than either
1 or 2.
H
H
19'
17' 16'
12'
14'
N
N
O
H
20' 18'
13'
15'
N
1
H
H
19'
17'
14' 12'
13'
N
N
O
H
20' 18'
16' 15'
N
2
H
H
15' 14'
19'
12'
17'
N
N
O
16'
20'
18'
H
13'
N
3
* 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(01)02117-7

328
S. P. Romeril et al. / Tetrahedron Letters 43 (2002) 327–329
The synthesis of 3 commenced with the selective
monobromination4 of pentane-1,5-diol 4 with hydro-
bromic acid and toluene to give 5-bromopentan-1-ol 5 in
60% yield. Compound 5 was protected as its tert-
butyldiphenylsilyl ether 6 in 96% yield with tert-
butyldiphenylsilyl chloride and imidazole in THF.5 6 was
then subjected to SN2 displacement with lithium acetylide
ethylenediamine complex6 in DMSO/THF to deliver
terminal acetylene 7 in 84% yield. Deprotonation of
acetylene 7 with n-butyllithium in THF/DMPU7 fol-
lowed by addition of 1-chloro-6-iodohexane gave 8 in
85% yield. Alkene 9 was obtained in 83% yield by
semi-hydrogenation of 8 with Lindlar catalyst in benzene
and quinoline.8 Reaction of alkene 9 with lithiated
3-picoline in THF and DMPU gave 10 in 79% yield.9
Deprotection of 10 was effected with ammonium fluoride
in methanol to deliver alcohol 11 in 95% yield.10 Alcohol
11 was oxidised with 2-iodoxybenzoic acid (IBX) in
DMSO/THF to aldehyde 12 in 93% yield.11–13 Aldehyde
12 was condensed with hydroxylamine hydrochloride in
the presence of sodium acetate in methanol to give oxime
13 in 90% yield.14 Reduction of 13 with sodium
cyanoborohydride in methanol at pH 3 gave hydroxyl-
amine 14 (Scheme 1).
olefinic singlet was resolved into two singlets at 129.91
and 129.93 ppm (Dl 0.02, exponential line broadening
0.50 Hz, referenced to CDCl3 at 77.16 ppm15). We also
noticed that the signal distribution between 20 and 40
ppm appeared to be a better match with the literature
spectrum than the two compounds that we had previ-
ously prepared.
We emphasise here that it would be hasty to conclude
that 3 is the correct structure of natural pyrinodemin A.
It is likely that the corresponding C13%ꢀC14% and
C12%ꢀC13% double bond position isomers would have
spectroscopic properties very similar to 3. Hence, an
unambiguous solution to the pyrinodemin A structural
problem is not immediately available unless more inten-
sive studies are conducted with the natural product.
However, the work presented in this paper has set one
end of the limit to where the double bond could reside
in the natural product. In future if pyrinodemin A is
isolated again from nature then the spectroscopic data
of 3 can be used as a reference standard for natural
product chemists. Another unresolved issue is the abso-
lute configuration of natural pyrinodemin A. We are
currently working on the asymmetric synthesis of struc-
ture 3 and hope to shed light on this matter.
14 was condensed with aldehyde 152 to afford nitrone 16
in 79% yield over two steps. Thermal cyclisation of
nitrone 16 at high dilution delivered 3 in 87% yield
(Scheme 2).
Acknowledgements
In the 50.3 MHz 13C NMR of 3, the olefinic carbon
resonances appeared as one signal. However, in the high
field 13C spectrum of 3 (125.73 MHz), the apparent
We thank the States of Jersey Education Committee for
financial support (to S.P.R.).
c
b
TBDPSO
TBDPSO
Br
HO
a
X
7
6
4, X = OH
5, X = Br
d
e
Cl
TBDPSO
TBDPSO
Cl
9
8
f
O
h
RO
12
N
N
10, R = TBDPS
11, R = H
g
i
j
HON
HON
H
N
14
13
N
Scheme 1. (a) HBr (aq.), toluene, reflux, 60%; (b) TBDPSCl, imidazole, THF, 96%; (c) lithium acetylide ethylenediamine complex,
DMSO, THF, 84%; (d) (1) nBuLi, THF, DMPU, (2) Cl(CH2)6I, 85%; (e) Lindlar catalyst, H2, quinoline, benzene, 83%; (f)
3-picoline, LDA, DMPU, THF, 79%; (g) NH4F, MeOH, 95%; (h) IBX, DMSO, THF, 93%; (i) NH2OH·HCl, MeOH, NaOAc,
90%; (j) NaCNBH3, MeOH, pH 3.

S. P. Romeril et al. / Tetrahedron Letters 43 (2002) 327–329
329
O
+
HON
H
N
N
15
14
(a)
+
N
_
O
N
N
16
(b)
N
H
H
19'
17' 15' 14' 12'
N
O
H
20' 18'
16'
13'
N
3
Scheme 2. (a) Anhydrous Na2SO4, dichloromethane, 79%; (b) benzene, heat, 87%.
References
9. Davies-Coleman, M. T.; Faulkner, D. J.; Dubouwchik,
G. M.; Roth, G. P.; Polson, C.; Fairchild, C. J. Org.
Chem. 1993, 58, 5925–5930.
10. Zhang, W.; Robins, M. J. Tetrahedron Lett. 1992, 33,
1177–1180.
1. Tsuda, M.; Hirano, K.; Kubota, T.; Kobayashi, J. Tetra-
hedron Lett. 1999, 40, 4819–4820.
2. Baldwin, J. E.; Romeril, S. P.; Lee, V.; Claridge, T. D.
W. Org. Lett. 2001, 3, 1145–1148.
3. Snider, B. B.; Shi, B. Tetrahedron Lett. 2001, 42, 1639–
1642.
11. Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994,
35, 8019–8022.
12. Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano,
G. J. Org. Chem. 1995, 60, 7272–7276.
13. Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem.
1999, 64, 4537–4538.
14. Holmes, A. B.; Smith, A. L.; Williams, S. F.; Hughes, L.
R.; Lidert, Z.; Switenbank, C. J. Org. Chem. 1991, 56,
1393–1405.
15. Gottlied, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem.
1997, 62, 7512–7515.
4. Chong, J. M.; Heuft, M. A.; Rabbat, P. J. Org. Chem.
2000, 65, 5837–5838.
5. Hall, D. P.; Deslongchamps, P. J. Org. Chem. 1995, 60,
7796–7814.
6. Smith, W. N.; Beumel, O. F. Synthesis 1974, 441–442.
7. Poulain, S.; Noiret, N.; Nugier-Chavin, C.; Patin, H.
Liebigs Ann. 1997, 35–40.
8. Lindlar, H.; Dubuis, R. Org. Syn. Coll. Vol. V 880–883.