Toward a total synthesis of the novel polyketide natural product spiculoic acid A

Article abstract of DOI:10.1021/ol0521329

(Chemical Equation Presented) An enantioselective approach toward the recently isolated marine natural product, spiculoic acid A, conceptualized along the proposed biogenetic hypothesis, involving an intramolecular Diels-Alder reaction as the pivotal step

Full text of DOI:10.1021/ol0521329

ORGANIC
LETTERS
2005
Vol. 7, No. 25
5569-5572
Toward a Total Synthesis of the Novel
Polyketide Natural Product Spiculoic
Acid A
Goverdhan Mehta* and Uday Kumar Kundu
Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560012, India
gm@orgchem.iisc.ernet.in
Received September 4, 2005
ABSTRACT
An enantioselective approach toward the recently isolated marine natural product, spiculoic acid A, conceptualized along the proposed biogenetic
hypothesis, involving an intramolecular Diels Alder reaction as the pivotal step, is delineated. Access to a structurally embellished bicyclic
−
core of the natural product has been accomplished.
In 2004, Andersen and co-workers1 reported the isolation
of novel polyketide natural products spiculoic acids A (1)
and B (2) from the extracts of the Caribbean marine sponge
Plakortis angulospiculatus (Carter) collected from the reefs
off the coast of Dominica. Bicyclic hydrindane-based
structures 1 and 2 for these natural products were arrived at
on the basis of incisive high-field 2D NMR studies. It was
further shown that spiculoic acid A 1 exhibited in vitro
cytotoxicity against the human breast cancer MCF cell line
with an IC50 of 8 µg/mL. More recently, three more natural
products based on the spiculane skeleton, iso-3, nor-4, and
dinor-spiculoic acids A 5, have been isolated from sponge
Plakortis zyggompha, and 3 and 4 were shown to display
weak cytotoxicity against both tumor cell lines A549 (lung
carcinoma) and HT 29 (colon carcinoma).2 Absolute config-
uration of these spiculane natural products 1-5 has not been
determined and remains unknown. From biogenetic consid-
erations, spiculoic acid A 1 is an unusual and rare construct,
putatively incorporating four butyrate and a propionate unit
and involving a Diels-Alderase-mediated intramolecular [4
+ 2]-cycloaddition in a precursor such as 6 to generate its
highly embellished bicyclic structure (Scheme 1).1
The presence of six stereogenic centers, two vicinal
quaternary carbons, and a network of diverse and distributed
functionalities on its novel framework, together with its
bioactivity profile, makes spiculoic acid A 1 a challenging
and enticing synthetic objective that immediately engaged
our attention. In formulating a synthetic strategy toward 1,
(1) Huang, X. H.; Soest, R. V.; Roberge, M.; Andersen, R. J. Org. Lett.
2004, 6, 75.
(2) Berrue´, F.; Thomas, O. P.; Ferna´ndez, R.; Amade P. J. Nat. Prod.
2005, 68, 547.
10.1021/ol0521329 CCC: $30.25
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Scheme 1
Scheme 2
desymmetrization of the diacetate of the meso-2-methyl-1,3-
propanediol 15 (Scheme 3).5 Hydroxyl protection in 16 as
MOM ether and acetate hydrolysis yielded 17.4 Swern
oxidation in 17 and Horner-Wittig olefination furnished the
R,â-unsaturated ester 18.4 DIBAL-H reduction in 18 led to
the allylic alcohol 19 (Scheme 3). Sharpless epoxidation6 of
allylic alcohol 19 in the presence of the D-tartaric acid diethyl
ester was stereoselective (9:1) and afforded the epoxide 20
in a predictable manner with ample precedence.7
Regioselective epoxide opening in 20 with Et2CuLi led8
to the diol 21, and the primary hydroxyl group was
chemoselectively oxidized to the hydroxyl aldehyde 22
(Scheme 4). Horner-Wittig olefination in 22 with ethyl
2-(triphenylphosphoranylidene)butyrate introduced the ele-
ments of the second butyrate moiety in a stereoselective
manner to furnish 23.4 The free hydroxyl group in 23 was
now protected as the benzyl ether derivative 24. DIBAL-H
reduction in 24 gave the allylic alcohol 25, and the primary
hydroxyl group was now protected as the TBDPS derivative
26, in which the three hydroxyl groups were chemo-
differentiable through protective group manoeuvres (Scheme
4). Removal of the MOM protection in 26 led to 27, and
further PDC oxidation furnished the key aldehyde 28.
Our original plan was to elaborate the aldehyde 28 to gem-
dibromoalkene 29 and further to the alkyne 30 en route to
the pivotal fragment 8 (Scheme 5). However, several tactical
operations on 28 using PPh3-CBr4 reagent9 failed to deliver
the desired 29 and only led to the elimination of the OBn
recourse to the putative biogenetic pathway involving an
intramolecular Diels-Alder reaction as the pivotal step in
precursor 6 appeared to be most appealing. From a retrosyn-
thetic point of view, it was further reasoned that 6 could be
assembled from two building blocks 7 and 8 involving a
Suzuki or equivalent cross-coupling reaction (Scheme 1). In
this letter, we detail the travails toward speculoic acid A 1
that have so far led to the bicyclic hydrindane 9 (vide infra),
incorporating much of the framework and several key
stereochemical features present in the natural product.
Preparation of fragment 7 was fairly straightforward
and accomplished from diethyl malonate 10 (Scheme 2).
Sequential alkylation in 10 with ethyl bromide and di-
iodocarbene furnished 11.3,4 Base-mediated decarboxylative
elimination gave (E)-3-iodo-2-methyl-2-propenoic acid 12,
and further LAH reduction and oxidation of the resulting
allylic alcohol led to aldehyde 13. Wittig styrenylation on
13 delivered the desired 7 (3:2) along with the (Z)-isomer
14 from which it was easily separable (Scheme 2).4
(5) For a related example, see: Grisenti, P.; Ferraboschi, P.; Manzocchi,
A.; Santaniello, E. Tetrahedron 1992, 48, 3827.
For an enantioselective approach toward the synthesis of
the more challenging fragment 8, we selected (R)-mono-
acetate 16 (98% ee), readily prepared from the enzymatic
(6) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(7) (a) Wakabayashi, T.; Mori, K.; Kobayashi, S. J. Am. Chem. Soc.
2001, 123, 1372. (b) Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873.
(8) For examples of cuprate-mediated epoxide opening, see: (a) Nicolaou,
K. C.; Murphy, F.; Barluenga, S.; Ohshima, T.; Wei, H.; Xu, J.; Gray, D.
L. F.; Baudoin, O. J. Am. Chem. Soc. 2000, 122, 3830. (b) Horita, K.;
Tanaka, K.; Yonemitsu, O. Chem. Pharm. Bull. 1993, 41, 2044.
(3) Baker, R.; Castro, J. L. J. Chem. Soc., Perkin Trans. 1 1990, 47.
(4) All new compounds reported here were characterized on the basis
1
of their spectral data (IR, H and 13C NMR, and HRMS).
5570
Org. Lett., Vol. 7, No. 25, 2005

Scheme 3
Scheme 4
protection and formation of an R,â-unsaturated aldehyde.
28 needed to be elaborated to a (E,E)-1,3-diene to setup the
Diels-Alder reaction, keeping in mind the stereochemical
imprint of the target structure. Toward this end, aldehyde
28 was subjected to Horner-Wittig olefination to deliver
the R,â-unsaturated (E)-ester 31 and further reduced with
DIBAL-H to the allylic alcohol 32 (Scheme 6). Dess-Martin
oxidation11 of 32 led to the unsaturated aldehyde 33, and
repeat of the Horner-Wittig olefination delivered the (E,E)-
1,3-diene ester 34 (Scheme 6). In 34, the elements for an
IMDA reaction were in place, albeit in an inverse electron
demand sense and in a complex stereochemical environment.
When 34 was heated in o-dichlorobenzene in the presence
of BHT,12 a smooth [4 + 2]-cycloaddition occurred and a
single bicyclic product 9 was obtained.4 The stereostructure
of 9 was delineated on the basis of incisive analyses of its
spectral characteristics, particularly the COSY and nOe data.
Frustrated in the efforts to access 8, we decided to settle for
a lesser objective and ventured to demonstrate the viability
of the IMDA reaction10 to access the basic carbocyclic
framework and some of the stereochemical features present
in spiculoic acid A. For this purpose, the aldehyde group in
Scheme 5
(9) (a) Kobayashi, S.; Mori, K.; Wakabayashi, T.; Yasuda, S.; Handa,
K. J. Org. Chem. 2001, 66, 5580. (b) Mandal, A. K. Org. Lett. 2002, 4,
2043.
(10) For a recent review, see: Nicolaou, K. C.; Snyder, S. A.; Montagnon,
T.; Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668.
(11) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
Org. Lett., Vol. 7, No. 25, 2005
5571

Scheme 6
The stereochemical outcome of the IMDA reaction in 34,
natural product spiculoic acid A 1, which is patterned along
the proposed biogenetic hypothesis. Retrosynthesis on 1
identified two key fragments 7 and 8, and while the former
was assembled quite uneventfully, the latter presented
considerable problems necessitating a deviation to a model
study. These endeavors have culminated in the synthesis of
a much embellished hydrindane, endowed with much of the
stereochemical features of the natural product, and have laid
the foundation for further efforts toward the total synthesis
of spiculoic acids 1-5.
leading to a cis-hydrindane derivative, was not completely
along the anticipated lines but can be reconciled in terms of
the preferred exo transition state depicted in 35 (Scheme 6).
The important consequence of the key IMDA reaction in 34
was the establishment of five (as in 9) of the six stereogenic
centers of the target natural product 1 and this was a very
encouraging sign. Thus, the stage is now set for the stereo-
electronic retuning of the diene and dienophilic components
for a normal electron demand IMDA reaction to generate
the desired stereochemistry. In summary, we have delineated
an enantioselective approach toward the novel polyketide
Acknowledgment. U.K.K. thanks JNCASR for the award
of a postdoctoral fellowship. G.M. thanks CSIR, India, for
research support and the award of the Bhatnagar Fellowship.
We thank Mr. Atsuya Hirano and Mr. Tan Nakagawa,
Amano Enzyme Co., Japan, for a generous gift of Lipase
PS-D.
Chart 1. 1H-1H COSY (a) and nOe (b) Correlations in (-)-9
Supporting Information Available: Spectroscopic data
as well as copies of the spectra of the key compounds are
provided. This material is available free of charge via the
Internet at http://pub.acs.org.
OL0521329
(12) Motozaki, T.; Sawamura, K.; Suzaki, A.; Yoshida, K.; Ueki, T.;
Ohara, A.; Munakata, R.; Takao, K.-i.; Tadano, K.-i. Org. Lett. 2005, 7,
2261.
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