Investigation into the absolute stereochemistry of the marine sponge alkaloid pyrinodemin A

Article abstract of DOI:10.1016/j.tetlet.2003.08.097

The absolute configuration of the marine sponge alkaloid pyrinodemin A is established by organic synthesis.

Full text of DOI:10.1016/j.tetlet.2003.08.097

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7757–7761
Investigation into the absolute stereochemistry of the marine
sponge alkaloid pyrinodemin A
Stuart P. Romeril, Victor Lee,* Jack E. Baldwin,* Timothy D. W. Claridge and Barbara Odell
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK
Received 21 July 2003; revised 12 August 2003; accepted 21 August 2003
Abstract—The absolute configuration of the marine sponge alkaloid pyrinodemin A is established by organic synthesis.
© 2003 Elsevier Ltd. All rights reserved.
Pyrinodemin A is a bis-3-alkylpyridine alkaloid isolated
from the Okinawan marine sponge Amphimedon sp. by
Kobayashi et al.1 The compound is chiral ([h]2D5=−9)
and cytotoxic towards murine leukaemia L1210 and
KB epidermoid carcinoma cells. The structure and rel-
ative stereochemistry of pyrinodemin A was proposed
as 1 based on a combination of NMR spectroscopy
and electron impact mass spectrometry studies. The
interesting structure of pyrinodemin A has attracted
the attention of two research groups. Both our group
and the Snider group have achieved the synthesis of
racemic 1 and discovered that the spectroscopic data
of synthetic 1 did not correspond to pyrinodemin A.2,3
In the 13C NMR spectrum of synthetic 1 the olefinic
carbons (C16% and C17%) were observed as two clearly
resolved signals (Dl=1.1 ppm) whereas in the natural
product only one signal was attributed to the olefinic
carbons. In an attempt to clarify the actual structure
of pyrinodemin A, both groups have separately sug-
gested and synthesised the C15%ꢀC16% double bond iso-
mer 2 as an alternative structure of the natural
product. It was observed by both groups that the
spectroscopic data of racemic 2 was also not consis-
tent with the published data of natural pyrinodemin
A. Hence we concluded that 2 was not the real struc-
ture of pyrinodemin A.2 In contrast the Snider group
advocated that 2 was probably the correct structure of
pyrinodemin A.3
* Corresponding authors. E-mail: victor.lee@chem.ox.ac.uk; jack.baldwin@chem.ox.ac.uk
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.097

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S. P. Romeril et al. / Tetrahedron Letters 44 (2003) 7757–7761
We subsequently prepared the corresponding C14%ꢀC15%
double bond isomer 3 in racemic form and found the
1H and 13C NMR data matched the published results
(Dl=0.02 ppm).4 However the lack of an authentic
sample for comparison made it difficult to solve this
problem solely by organic synthesis. Therefore we con-
sidered 3 as a possible candidate for the true structure
of pyrinodemin A.
could be derived from aldehyde 15 which in turn could
be synthesised from chiral epoxide 7 (Scheme 2).
The commercially available but-3-en-1-ol 4 was pro-
tected as it tert-butyldiphenylsilyl ether 5 in 99% yield.5
The double bond in 5 was oxidised with MCPBA to
give epoxide 6 in 98% yield.6 Epoxide 6 was subjected
to Jacobsen’s hydrolytic kinetic resolution to give stere-
ochemically pure (ee>95%) epoxide 7 in 47% yield.7,8
The choice of this particular enantiomer is purely arbi-
trary. Reaction of 7 with lithium trimethylsilylacetylide
in the presence of boron trifluoride–THF complex9
afforded a 94% yield of secondary alcohol 8. The
terminal trimethylsilyl group was removed by potas-
sium carbonate in methanol10 to deliver acetylene 9 in
89% yield. Alcohol 9 was converted into bis-silyl ether
10 in 98% yield with tert-butyldiphenylsilyl triflate and
2,6-lutidine.11 The terminal acetylene 10 was treated
with n-butyllithium followed by the addition of 1,7-
dibromoheptane in the presence of DMPU to furnish
compound 11 in 81% yield. Semi-hydrogenation of 11
with Lindlar catalyst in the presence of quinoline gave
alkene 12 in 99% yield.12 Reaction of 12 with lithiated
3-picoline delivered compound 13 in 76% yield.13 Selec-
tive deprotection of the primary silyl ether in 13 was
effected with HF·pyridine14 to afford alcohol 14 in 85%
yield. Alcohol 14 was oxidised with IBX15–17 to alde-
hyde 15 in 88% yield (Scheme 3).
Herein we report the asymmetric synthesis of 3 thus
establishing
the
absolute
stereochemistry
of
pyrinodemin A. Although the precise location of the
double bond in pyrinodemin A is not known, we are
confident that the sign and the magnitude of the specific
rotation of this natural product is primarily due to the
asymmetric central core and the exact position of the
double bond in the side chain of the molecule does not
have any significant effect on its specific rotation.
We envisaged that an asymmetric synthesis of
pyrinodemin A could be achieved by introducing a
stereodirecting group in the nitrone precursor. We
chose a secondary alcohol as the chiral inducing group
because it could also act as a reference point for
establishing the absolute configuration of the cycloaddi-
tion (Scheme 1). We were optimistic that even if the
cycloaddition generated a mixture of diastereoisomers,
separation of these compounds would still enable us to
execute our plan. Based on this analysis, nitrone 17
Scheme 1.
Scheme 2.

S. P. Romeril et al. / Tetrahedron Letters 44 (2003) 7757–7761
7759
Scheme 3. Reagents and conditions: (i) TBDPSCl, imidazole, THF, 99%; (ii) MCPBA, DCM, 98%; (iii) (R,R)-(salen)Co(III)·OAc,
THF, H2O (0.55 equiv.), 47%; (iv) trimethylsilylacetylene, n-BuLi, BF3·THF, 94%; (v) K2CO3, MeOH, 89%; (vi) TBDPSOTf,
2,6-lutidine, 98%; (vii) n-BuLi, DMPU, Br(CH2)7Br, THF, 81%; (viii) Lindlar catalyst, H2, quinoline, benzene, 99%; (ix)
3-picoline, LDA, DMPU, THF, 76%; (x) HF·pyridine, THF, 85%; (xi) IBX, DMSO, THF, 88%.
Aldehyde 15 was condensed with known hydroxyl-
amine 162 to afford nitrone 17 in 62% yield. Thermal
cyclisation of nitrone 17 in benzene under reflux deliv-
ered an inseparable mixture of 18 and 19 in a combined
yield of 82%. The mixture of 18 and 19 was deprotected
with ammonium fluoride in methanol18 to give alcohols
20 (59% yield) and 21 (30% yield) which could be
separated by flash chromatography (Scheme 4).
The relative configurations of 20 and 21 were deter-
mined by 1D DPFGSE-NOESY studies19 using H-18 as
the reference point. For the major diastereoisomer 20, a
significant NOE enhancement for H-17b was observed
when H-18 was irradiated while the signal enhancement
for H-17a was relatively small. This implied that H-17a
is on the opposite face of the ring with respect to H-18.
Irradiation of H-16 led to NOE enhancement for H-17a
and H-20. The signal for H-16 was enhanced when
H-15 was irradiated. The results demonstrated that
H-15, H-16, H-17a, H-20 are on the same face of the
molecule. Hence the absolute stereochemistry of 20 is
(15S,16S,18S,20R). In the minor product 21, irradia-
tion of H-18 led to NOE enhancement for H-16 and
H-20. The signal for H-16 was also enhanced when
either H-20 or H-15 was irradiated. NOE enhancement
was observed for H-20 and H-18 when H-19b was
irradiated. Hence all these protons are located on the
same face of the molecule and the absolute stereochem-
istry of 21 is assigned as (15R,16R,18S,20S) (Fig. 1).
The major alcohol 20 was converted into its thiocar-
bonate derivative 22 in 93% yield using phenyl
chlorothionoformate20 with 4-(1-pyrrolidino)pyridine.21
Scheme 4. Reagents and conditions: (i) 16, Na2SO4, DCM,
62%; (ii) benzene, heat, 82% (18+19); (iii) NH4F, MeOH,
70°C, chromatographic separation, 59% for 20; 30% for 21.

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S. P. Romeril et al. / Tetrahedron Letters 44 (2003) 7757–7761
Figure 2. Absolute configuration of pyrinodemin A central
core.
alkaloids, pyrinodemins B–D, have also been isolated
from the same sponge extract.23 Although their specific
rotations have not been reported, it is likely that
pyrinodemins B–D will have the same absolute stereo-
chemistry as pyrinodemin A.
Figure 1.
Barton’s deoxygenation of 22 with tris(trimethylsil-
yl)silane and AIBN afford (−)-3 in 69% yield.22 The H
1
and 13C NMR data of (−)-3 were consistent with racemic
3 we had previously prepared. Similarly the minor
compound 21 was transformed into thiocarbonate 23 in
92% yield and reduced to (+)-3 in 65% yield (Scheme 5).
Acknowledgements
We thank the States of Jersey Education Committee for
a scholarship (to S.P.R.), Professor Eric Jacobsen for his
technical advice on hydrolytic kinetic resolution and for
providing us a pre-print of Ref. 8.
The specific rotations of (−)-3 and (+)-3 are [h]2D4=−5.1
(c 1.0 CHCl3) and [h]2D3=+5.5 (c 0.9 CHCl3), respectively
{cf. literature value of natural pyrinodemin A [h]2D5=−9
(c 1.0 CHCl3)}. The enantiomeric excesses of (−)-3 and
(+)-3 were determined to be 83% and 95% respectively
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