Biomimetic synthesis of marine sponge metabolite spiculoic acid A and establishment of the absolute configuration of the natural product

Article abstract of DOI:10.1039/b607035c

The synthesis of spiculoic acid A (1) using a biomimetic Diels-Alder reaction is described; comparison of the specific rotation of the natural and synthetic material revealed that the enantiomer of the natural product has been synthesized. The Royal Socie

Full text of DOI:10.1039/b607035c

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Biomimetic synthesis of marine sponge metabolite spiculoic acid A and
establishment of the absolute configuration of the natural product{
James E. D. Kirkham,a Victor Lee*a and Jack E. Baldwin*b
Received (in Cambridge, UK) 17th May 2006, Accepted 26th May 2006
First published as an Advance Article on the web 12th June 2006
DOI: 10.1039/b607035c
Andersen et al. have proposed that 1 is biosynthesized from 2
through an enzyme catalysed Diels–Alder reaction (Fig. 1).1,3 Our
continued interest in biomimetic chemistry4 prompted us to
examine the application of this proposed intramolecular Diels–
Alder reaction in the synthesis of 1.5 Herein we report the
successful execution of our synthetic plan and the establishment of
the absolute configuration of 1. During the course of our
investigation Mehta and Kundu disclosed a synthetic approach
to 1 and prepared a highly truncated analogue of the natural
product.6
The synthesis of spiculoic acid A (1) using a biomimetic Diels–
Alder reaction is described; comparison of the specific rotation
of the natural and synthetic material revealed that the
enantiomer of the natural product has been synthesized.
Spiculoic acid A (1) (Fig. 1) is a polyketide recently isolated from
the extracts of the Caribbean marine sponge Plakortis angulospi-
culatus by Andersen et al.1 Spiculoic acid A (1) was found to be
optically active and its structure and relative stereochemistries were
established based on a combination of NMR and mass spectro-
metry studies. Further activity assay showed that 1 is cytotoxic
towards the human breast cancer MCF-7 cell line (IC50 8 mg/mL).
At the time of its isolation and structure elucidation 1 was
considered to be unprecedented due to its spiculane carbon
skeleton. Six stereocentres reside within this relatively small bicyclic
core, two of which are quaternary and adjacent to each other. A
group of similar compounds were subsequently isolated from the
marine sponge Plakortis zyggompha.2
Realizing the potential sensitivity of 2 we elected to use 3 as its
surrogate. Since the absolute configuration of natural 1 was
unknown, we decided to use the chiral structure of 1 depicted in
Andersen’s publication as our synthetic target. The synthesis of 3
commenced with the conversion of Roche ester 4 into aldehyde 5
in an overall yield of 98% by protection of the primary alcohol
using imidazole and tert-butyldimethylsilyl chloride,7 followed by
reduction of the ester8 to primary alcohol and oxidation to
Fig. 1 Retrosynthetic analysis of spiculoic acid A (1).
aChemistry Research Laboratory, University of Oxford, 12 Mansfield
Road, Oxford, UK OX1 3TA. E-mail: victor.lee@chem.ox.ac.uk;
Fax: +44 (0)1865 285 002; Tel: +44 (0)1865 275 650
Scheme 1 Reagents and conditions: (i) (a) TBSCl, imidazole, THF; (b)
LiBH4, THF, reflux; (c) DMSO, (COCl)2, iPr2NEt, CH2Cl2, 278 uC, 98%
bChemistry Research Laboratory, University of Oxford, 12 Mansfield
Road, Oxford, UK OX1 3TA. E-mail: jack.baldwin@chem.ox.ac.uk;
Fax: +44 (0)1865 275 632; Tel: +44 (0)1865 275 671
i
over three steps; (ii) 6, nBu2BOTf, Pr2NEt, CH2Cl2, 278 uC, 89%; (iii)
LiBH4, MeOH, H2O, 73%; (iv) para-methoxybenzaldehyde dimethyl
acetal, pyridinium tosylate, CH2Cl2, 96%; (v) TBAF, THF, 100%; (vi)
IBX, THF, DMSO, 100%.
1
{ Electronic supplementary information (ESI) available: H, 13C, DEPT,
COSY, HSQC, NOESY and TOCSY NMR spectra for (2)-1. See DOI:
10.1039/b607035c
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 2863–2865 | 2863

View Article Online
aldehyde 5 using Swern’s conditions9 (Scheme 1). Evans’ aldol
condensation10 of 5 and oxazolidinone 611 delivered secondary
alcohol 7 in 89% yield. Reductive removal of the chiral auxiliary
was effected with lithium borohydride in wet methanol12 to afford
diol 8 in 73% yield. Diol 8 was converted into para-methoxy-
benzylidene acetal 9 in 96% yield using para-methoxybenzaldehyde
dimethyl acetal and a catalytic amount of pyridinium tosylate.13
This was followed by removal of the TBS group with TBAF to
afford primary alcohol 10 in quantitative yield, which was oxidized
to aldehyde 11, again in quantitative yield, using iodoxybenzoic
acid (IBX).14
Wittig olefination of aldehyde 11 with stabilized ylide 1215 gave
ester 13 in 77% yield (Scheme 2). The E stereochemistry of the
double bond in 13 was confirmed by NOE studies. Ester 13 was
reduced to alcohol 14 with lithium aluminium hydride16 in 99%
yield, which was oxidized to unsaturated aldehyde 15 by
iodoxybenzoic acid (IBX) in quantitative yield. Treating aldehyde
15 with ylide 12 delivered the doubly conjugated ester 16 in 65%
yield. Again, the geometry of the newly formed double bond was
confirmed to be E by NOE experiment. Ester 16 was reduced to
alcohol 17 in 96% yield, which was followed by oxidation to
aldehyde 18 in 100% yield.
Aldehyde 18 was subjected to a Julia/Kocienski olefination17
with benzylsulfone 1918 using lithium bis(trimethylsilyl)amide as
base to give E,E,E triene 20 in 82% yield (Scheme 3). Reductive
cleavage of the para-methoxybenzylidene acetal was effected with
diisobutylaluminium hydride13 to give primary alcohol 21 in 82%
Scheme 3 Reagents and conditions: (i) 19, LiN(TMS)2, THF, 82%; (ii)
DIBAL, CH2Cl2, 82%; (iii) IBX, DMSO, THF, 80%; (iv) 23, toluene,
100 uC, 25%.
yield, which was oxidized to aldehyde 22 in 80% yield with IBX.
The final Wittig olefination in our synthesis was conducted by
heating a mixture of aldehyde 22 with ylide 23. Gratifyingly, this
delivered bicyclic structure 24 directly in 25% yield. Presumably the
desired Wittig reaction took place to afford 3, which underwent a
Diels–Alder reaction in situ to give 24. We also isolated a 5–20%
yield of an a,b-unsaturated aldehyde, which was formed by the
E1cB elimination of para-methoxybenzyl alcohol from 22.
The final stage of the synthesis of 1 began with removal of the
para-methoxybenzyl protecting group from 24 with 2,3-dichloro-
5,6-dicyanobenzoquinone (DDQ) under buffered conditions19 to
afford secondary alcohol 25, which was found to co-elute with the
para-methoxybenzaldehyde formed in the DDQ deprotection
during flash chromatography (Scheme 4). Therefore, this partially
purified mixture was subjected to
a catalytic amount of
tetrakis(triphenylphosphine)palladium(0) in the presence of excess
morpholine20 to remove the allyl ester. This delivered free acid 26
in a combined yield of 94% over two steps after chromatographic
Scheme 2 Reagents and conditions: (i) 12, toluene, 100 uC; (ii) LiAlH4,
THF, 0 uC; (iii) IBX, DMSO, THF.
2864 | Chem. Commun., 2006, 2863–2865
This journal is ß The Royal Society of Chemistry 2006

View Article Online
Fig. 3 Absolute configuration of natural spiculoic acid A (1).
Scheme 4 Reagents and conditions: (i) DDQ, CH2Cl2, pH 7 buffer; (ii)
(PPh3)4Pd, morpholine, 94% over two steps; (iii) IBX, EtOAc, 70 uC, 45%.
Fig. 4 Speculated absolute configurations of iso- (27), nor- (28) and
dinor-spiculoic acids A (29).
We thank Hoffmann-La Roche for partial support of this work.
Notes and references
1 X.-H. Huang, R. van Soest, M. Roberge and R. J. Andersen, Org. Lett.,
2004, 6, 75–78.
2 F. Berrue´, O. P. Thomas, R. Ferna´ndez and P. Amade, J. Nat. Prod.,
2005, 68, 547–549.
Fig. 2 Selected NOESY correlations of (2)-1.
3 (a) E. M. Stocking and R. M. Williams, Angew. Chem., Int. Ed., 2003,
42, 3078–3115; (b) H. Oikawa and T. Tokiwano, Nat. Prod. Rep., 2004,
21, 321–352; (c) H. Oikawa, Bull. Chem. Soc. Jpn., 2005, 78, 537–554.
4 J. E. Moses and R. M. Adlington, Chem. Commun., 2005, 5945–5952.
5 K. Takao, R. Munakata and K. Tadano, Chem. Rev., 2005, 105,
4779–4807.
6 G. Mehta and U. K. Kundu, Org. Lett., 2005, 7, 5569–5572.
7 N. Tsukada, T. Shimada, Y. S. Gyoung, N. Asao and Y. Yamamoto,
J. Org. Chem., 1995, 60, 143–148.
8 K. Mori and K. Koseki, Tetrahedron, 1988, 44, 6013–6020.
9 J. M. Minguez, S.-Y. Kim, K. A. Giuliano, R. Balachandran,
C. Madiraju, B. W. Day and D. P. Curran, Bioorg. Med. Chem.,
2003, 11, 3335–3357.
10 D. A. Evans, J. V. Nelson, E. Vogel and T. R. Taber, J. Am. Chem.
Soc., 1981, 103, 3099–3111.
11 M. A. Brimble, Aust. J. Chem., 1990, 43, 1035–1046.
12 T. D. Penning, S. W. Djuric, R. A. Haack, V. J. Kalish, J. M. Miyashiro,
B. W. Rowell and S. S. Yu, Synth. Commun., 1990, 20, 307–312.
13 Z. H. Peng and K. A. Woerpel, J. Am. Chem. Soc., 2003, 125,
6018–6019.
14 (a) M. Frigerio and M. Santagostino, Tetrahedron Lett., 1994, 35,
8019–8022; (b) M. Frigerio, M. Santagostino, S. Sputore and
G. Palmisano, J. Org. Chem., 1995, 60, 7272–7276; (c) M. Frigerio,
M. Santagostino and S. Sputore, J. Org. Chem., 1999, 64, 4537–4538.
15 S. E. Sen and G. J. Ewing, J. Org. Chem., 1997, 62, 3529–3536.
16 R. Stu¨rmer and R. W. Hoffmann, Chem. Ber., 1994, 127, 2519–2526.
17 (a) P. R. Blakemore, W. J. Cole, P. J. Kocienski and A. Morley, Synlett,
1998, 26–29; (b) P. R. Blakemore, J. Chem. Soc., Perkin Trans. 1, 2002,
2563–2585.
purification. Finally, oxidation of 26 with IBX in hot ethyl
acetate21 gave spiculoic acid A (1) in 45% yield.
Extensive spectroscopic studies were conducted on compounds
24, 25, 26 and 1 to confirm their structures and relative
stereochemistries. Analysis of the spectroscopic data for synthetic
1 gave an H-5/H-9 coupling constant of 11.8 Hz, indicating that
both protons are axial and that the [4.3.0] bicycle is trans. NOESY
studies indicated that the correct relative stereochemistry has been
achieved via the Diels–Alder reaction (Fig. 2). The absolute
stereochemistry of 1 was established through knowledge of the
1
absolute configuration of the C-6 and C-8 stereocentres. The H
and 13C NMR spectra of synthetic 1 were indistinguishable from
those of the natural product.
22
The specific rotation of synthetic 1 ([a]D = 297, c = 0.16,
CH2Cl2) is comparable in magnitude to that of natural 1 ([a]D
=
+110, c = 0.1, CH2Cl2),1 but of opposite sign. Therefore, we
conclude that the absolute configuration of natural spiculoic acid
A (1) is as depicted in Fig. 3.
In summary, we have demonstrated the application of a
biomimetic strategy to the synthesis of spiculoic acid A (1) and
through our synthesis have established the absolute configuration
of the natural product. Analogues iso- (27), nor- (28) and dinor-
(29) spiculoic acids A (Fig. 4), recently isolated from the marine
sponge Plakortis zyggompha,2 all possess specific rotations that are
positive and large in value. Therefore, it is tempting to imply that
the absolute configurations of these compounds are identical to
that of (+)-1.
18 H. Hilpert and B. Wirz, Tetrahedron, 2001, 57, 681–694.
19 P. Wipf and T. H. Graham, J. Am. Chem. Soc., 2004, 126, 15346–15347.
20 S. Friedrich-Bochnitschek, H. Waldmann and H. Kunz, J. Org. Chem.,
1989, 54, 751–756.
21 J. D. More and N. S. Finney, Org. Lett., 2002, 4, 3001–3003.
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 2863–2865 | 2865