Total synthesis of nostodione A, a cyanobacterial metabolite

Article abstract of DOI:10.1021/ol303036j

The first total synthesis of the mitotic spindle poison nostodione A is described. The inherent oxidative sensitivity of indoles is utilized for a late introduction of a second carbonyl to the cyclopent[b]indole-2-one system. The tricyclic system is prepared from indole-3-acetic acid and O-silylated 4-ethynylphenol, using a stereoselective intramolecular reductive Heck cyclization as the key transformation.

Full text of DOI:10.1021/ol303036j

ORGANIC
LETTERS
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2012
Vol. 14, No. 24
6274–6277
Total Synthesis of Nostodione A,
a Cyanobacterial Metabolite
†
Andreas Ekebergh, Anna Borje, and Jerker Martensson*
‡
,†
€
˚
Department of Chemical and Biological Engineering/Organic Chemistry,
Chalmers University of Technology, SE-412 96 Gothenburg, Sweden, and
Dermatochemistry and Skin Allergy, Department of Chemistry and Molecular Biology,
University of Gothenburg, SE-412 96, Gothenburg, Sweden
jerker@chalmers.se
Received November 5, 2012
ABSTRACT
The first total synthesis of the mitotic spindle poison nostodione A is described. The inherent oxidative sensitivity of indoles is utilized for a late
introduction of a second carbonyl to the cyclopent[b]indole-2-one system. The tricyclic system is prepared from indole-3-acetic acid and
O-silylated 4-ethynylphenol, using a stereoselective intramolecular reductive Heck cyclization as the key transformation.
Nostodione A (1) belongs to a small family of alkaloids
characterized by a tricyclic cyclopent[b]indol-2(1H)-one
ring system appended by a benzyl or a benzylidene sub-
stituent at its 3 position (Figure 1). The molecular structure
was first reported in 1993 by Proteau et al. who assigned
this structure to a fragment obtained upon ozonolysis of
the reduced form of scytonemin (2),1 a natural UV screen-
ing alkaloid belonging to the same family as nostodione A.
In 1994, nostodione A was for the first time obtained
directly from a biological source when Kobayashi et al.
isolated it from the cyanobacterium Nostoc commune.2
These authors also showed that the alkaloid in solution
exists as a rapidly interconverting equilibrium mixture of
its E and Z isomers (Figure 1). Herein we report the first
total synthesis of the alkaloid nostodione A.
chymotrypsin-like proteasome activity in vitro.3 What
biological function it may serve in cyanobacteria has
yet to be elucidated. However, it has been proposed to
serve as a monomeric intermediate in the biosynthesis of
scytonemin.4 In addition to the biological activity shown
for nostodione A itself, the fusedtricyclicsystem cyclopent-
[b]indole on which it is based has been shown to be a
privileged scaffold able to provide a new class of selective
LXR agonists.5
As recounted by Jordan et al.,6 cyclopent[b]indoles have
been synthesized by numerous methods. Synthetic routes
to cyclopent[b]indol-2(1H)-ones and cyclopent[b]indol-
1,2(3H,4H)-diones on the other hand are rare. The tricyclic
ketones have been obtained in low to good yield by the
Fischer indole synthesis7 and by different ring-closing
Nostodione A has been shown to suppress mitotic
spindle formation in sea-urchin eggs2 and to inhibit
(4) Soule, T.; Palmer, K.; Gao, Q. J.; Potrafka, R. M.; Stout, V.;
Garcia-Pichel, F. BMC Genomics 2009, 10.
(5) Ratni, H.; Blum-Kaelin, D.;Dehmlow, H.;Hartman, P.;Jablonski,
P.; Masciadri, R.; Maugeais, C.; Patiny-Adam, A.; Panday, N.; Wright,
M. Bioorg. Med. Chem. Lett. 2009, 19, 1654.
† Chalmers University of Technology.
‡ University of Gothenburg.
(1) Proteau, P. J.; Gerwick, W. H.; Garciapichel, F.; Castenholz, R.
Experientia 1993, 49, 825.
(6) Jordan, J. A.; Gribble, G. W.; Badenock, J. C. Tetrahedron Lett.
2011, 52, 6772.
(7) Dashkevich, S. N. Khim. Geterotsikl. Soedin. 1978, 132.
(8) Dominguez, G.; Casarrubios, L.; Rodriguez-Noriega, J.; Perez-
Castells, J. Helv. Chim. Acta 2002, 85, 2856.
(2) Kobayashi, A.; Kajiyama, S. I.; Inawaka, K.; Kanzaki, H.;
Kawazu, K. Z. Naturforsch., C: J. Biosci. 1994, 49, 464.
(3) Shim, S. H.; Chlipala, G.; Orjala, J. J. Microbiol. Biotechnol. 2008,
18, 1655.
r
10.1021/ol303036j
Published on Web 12/10/2012
2012 American Chemical Society

4, and (3) alkynylation of a suitable derivative of the
commercially available indol-3-ylacetic acid 5.
Scheme 1. Retrosynthetic Analysis of Nostodione A
The characteristic 1,2-diketone motif of nostodione
A was assumed to be possible to form with high selectivity
by DDQ-mediated oxidation at the 1 position of the
cyclopent[b]indol-2(1H)-one skeleton via a Yonemitsu
oxidation.13 During this oxidation the electron-rich indole
system substituted with an alkyl group in the C3 position
has been suggested to undergo efficient DDQ-mediated
dehydrogenation forming a vinylogous iminium cation. In
an aqueous environment this R,β-unsaturated iminium
system is readily attacked in the β-position by water and
the formed alcohol is subsequently oxidized by a second
equivalent of DDQ to the corresponding ketone.
In conformity with the majority of the reported routes to
the cyclopent[b]indol-2(1H)-one skeleton, our strategy for
the synthesis of nostodione A is based on the formation of
the five-membered ring annulated to the indole system.
This was expected to be accomplished by ring closure of an
arylethynyl haloindole via a palladium-mediated syn-addi-
tion to the triple bond of the indolyl group and a hydrogen
in an intramolecular reductive Heck cyclization. The inter-
vening syn-carbo-palladation not only strongly favors
the formation of a five-membered ring but also, concur-
rently with the ring-closure, stereospecifically delivers the
Z configuration of the excocyclic double bond. The reac-
tion has previously been successfully applied to the stereo-
selective construction of medium sized rings with exocyclic
double bonds.14À16
Figure 1. Structures of nostodione A (1) and scytonemin (2). The
tricyclic cyclopent[b]indol-2(1H)-one ring system with the
appended benzylidene substituent is highlighted.
strategies for the formation of the five-membered ring
annulated to the indole system.6,8À11
Our interest in the cyclopent[b]indol-2-one and -1,2-
dione skeleton originates from our efforts to prepare a
series of scytonemin derivatives for photophysical mea-
surements, to disclose its mode of action as a UV screening
compound. Within this campaign we need access to both
mono- and dimeric structures of cyclopent[b]indol-2-one
and, if possible, to derivatives with both E and Z config-
uration around the exocyclic carbonÀcarbon double bond
present in both nostodione A and scytonemin. To date,
our recent publication on the synthesis of scytonemin,
based on an E selective tandem HeckÀSuzukiÀMiyaura
reaction, constitutes the only report on the syntheses of
cyclopent[b]indol-2(1H)-ones with an exocyclic carbonÀ
carbon double bond in their 3 position.12 The route to
nostodioneA describedherein isthe offspring of continued
search for different methods to add functionalities and
substituents at position 1 of the cyclopent[b]indol-2(1H)-
one skeleton and to install the exocyclic double bond at the
3 position stereoselectively.
Accordingly, our synthetic endeavor toward nostodione
A began with the syntheses of the two building blocks 8
and 9 (Scheme 2). The terminal alkyne 8 was prepared in
two steps from the 4-ethynylphenol 7,17 and the Weinreb
amide 9 was prepared from indol-3-acetic acid according
to our previously reported procedure.12 The two building
blocks were merged effectively by treating the terminal
alkyne 8 with butyl lithium and reacting the formed
acetylide with the Weinreb amide 9. The formed ketone
Accordingly, the assembly of nostodione A was in-
tended to be accomplished by three major operations: (1)
late introduction of the 1,2-diketone motif by selective
oxidation of a complete nostodione A skeleton 3 (Scheme 1),
(2) stereospecific ring closure of a 3-arylethynyl-2-haloindole
(9) Franceschetti, L.; Garzon-Aburbeh, A.; Mahmoud, M. R.; Natalini,
B.; Pellicciari, R. Tetrahedron Lett. 1993, 34, 3185.
(10) Salim, M.; Capretta, A. Tetrahedron 2000, 56, 8063.
(11) Tang, Q.; Chen, X.; Tiwari, B.; Chi, Y. R. Org. Lett. 2012, 14,
1922.
€
(12) Ekebergh, A.; Karlsson, I.; Mete, R.; Pan, Y.; Borje, A.;
˚
Martensson, J. Org. Lett. 2011, 13, 4458.
(13) Oikawa, Y.; Yonemitsu, O. J. Org. Chem. 1977, 42, 1213.
(14) Wang, X.; Liu, L. Y.; Chang, W. X.; Li, J. Eur. J. Org. Chem.
2010, 5391.
(15) Donets, P. A.; Van der Eycken, E. V. Org. Lett. 2007, 9, 3017.
(16) Tietze, L. F.; Schimpf, R. Chem. Ber. 1994, 127, 2235.
(17) Hirose, T.; Matsuda, K. Chem. Commun. 2009, 5832.
Org. Lett., Vol. 14, No. 24, 2012
6275

Scheme 2. Synthetic Route to Nostodione A
a Measured by NMR integration. b Measured by NMR integration on crude product directly after workup.
described by Backvall and co-workers.20 The crude prod-
€
turned out to be unstable, vide infra, and was therefore
immediately masked as a racemic alcohol 10 by a sodium
borohydride reduction.
uct was obtained as an isomeric mixture in which the
excess of Z-configuration was much lower than in the
precursor 11a. It was found that ketone 12a spontaneously
isomerized to essentially pure E-isomer when kept in
solution. The change in stereochemistry was determined
by 1D-NOESY experiments. Saturating the ortho-protons
of the para-substituted aryl ring gave an enhanced NÀH
proton signal for the E isomer. This oxidation protocol
could also be applied to the free phenol 11b, albeit here
the reaction progressed sluggishly and was characterized
by premature precipitation of the catalyst. This can be
explained by the competitive interaction of the phenol
with the catalyst.20 The free phenol of ketone 12b could
at this stage be reprotected in high yield with triisopropyl-
silyl chloride. Thus, the total yield of ketone 12a from 10
is 63%.
Subjecting alcohol 10 to standard reductive Heck con-
ditions gave the wanted cyclization with high stereoselec-
tivity in a total yield of 78%. One-dimensional NOESY
experiments were performed to establish the stereochem-
istry around the exocyclic double bond. A distinct signal
due to the nuclear Overhauser effect between the vinylic
and the NÀH proton was observed for the Z isomers.
Unfortunately, the majority of the product was isolated
without the phenolic silyl group, a protective group which
proved necessary for the upcoming Yonemitsu oxidation.
Thus, the deprotected ring-closed product 11b had to be
reprotected at a later stage. The excision is believed to stem
from residual water, mainly from the formic acid, together
with the high polarity of the solvent. Similar reaction
conditions have been successfully applied to purposely
cleave off phenolic silyl groups.18 Changing the solvent
fromDMF tothe less polarTHF gavelesssilyl excision but
did on the other hand give substantially lower yield.
Next, the allylic alcohol 11a was converted into ketone
12a in very high yield by utilizing the ruthenium based
Shvo catalyst (14)19 in an Oppenauer type oxidation, as
Finally, ketone 12a was successfully transformed to
dione 13 using the oxidation protocol developed by
Yonemitsu et al. Subsequent flouride ion based silyl
excision produced the target molecule nostodione A (1)
in excellent yield.
As briefly pointed out above, the initial fusion of the
terminal alkyne 8 and Weinreb amide 9 yielded an unstable
(18) Jiang, Z. Y.; Wang, Y. G. Tetrahedron Lett. 2003, 44, 3859.
(19) Shvo, Y.; Blum, Y. Isr. J. Chem. 1984, 24, 144.
€
(20) Almeida, M. L. S.; Beller, M.; Wang, G.-Z.; Backvall, J.-E.
Chem.;Eur. J. 1996, 2, 1533.
6276
Org. Lett., Vol. 14, No. 24, 2012

ketone. To understand and possibly circumvent the degra-
dation, the more accessible and stable4-ethynylanisole was
Scheme 4. Alternative Oxidation of Allylic Alcohol 11a
Scheme 3. Oxidative Rearrangement of Model Compound 15
used in a model reaction. When the formed ketone 15
(Scheme 3) was left as a solid in air, complete conversion to
the spiro oxo-indoline 16 was observed within a week. This
oxidative rearrangement can be ascribed to the well estab-
lished auto-oxidative sensitivity of indoles, where chemical
modification occurs at the 2 and 3 position.21 The corre-
sponding alcohol did however not show any sign of
degradation, an alteration in reactivity we cannot explain.
Having been forced to mask the ketone formed in the
alkynylation as an alcohol, we devoted some effort trying
to efficiently reoxidize it after its cyclization. Allylic alco-
hols have been oxidized by DDQ22 under conditions
similar to those employed in the Yonemitsu oxidation. It
was therefore envisioned that these oxidations could be
executed in a tandem fashion to give dione 13 in a one-pot
procedure. However, all our attempts resulted in either
rapid degradation or no reaction at all. In the same spirit,
attempts were made to sequentially perform the reductive
Heck cyclization and a palladium catalyzed oxidation of
the formed allylic alcohols 11a and b in the same reaction
vessel. To this end a stoichiometric amount of bromome-
sitylene as a hydrideacceptor23 wasaddedwhenalmostfull
conversion was reached in the Heck cyclization, but oxida-
tion of the allylic alcohol was never observed. The oxida-
tion of allylic alcohol 11a was therefore performed as a
separate synthetic operation.
effectively. The light driven reaction can be explained
either as a photochemical [1,3] hydride shift, as described
by Peijnenburg and Buck,24 or as being catalyzed by
hydrochloric acid released from the photochemical oxida-
tion of chloroform.25 Interestingly, the rearrangement prod-
uct 17 is a phenol protected counterpart of the last estab-
lished intermediate in the biosynthesis of scytonemin.26
In summary, we report on the first total synthesis of the
alkaloid nostodione A. Its fused tricyclic indole core was
constructed in good yield by an intramolecular reductive
Heck cyclization of an alkynol appended indole. The ring
closure occurred with excellent ring-size selectivity and
with concurrent highly stereoselective formation of an
exocyclic double bond. Two consecutive oxidations trans-
formed the ring closedproduct to the protectednostodione
A. First, the allylic alcohol was converted to an R,
β-unsaturatedketone in excellent yield employingthe Shvo
catalyst. Next, the second carbonyl was introduced in good
yield using DDQ in the presence of water via a Yonemitsu
oxidation. Facile cleavage of the phenolic silyl group then
completed the total synthesis.
It was found that the R,β-unsaturated ketone 12a
could be regenerated by a rearrangement of the allylic
alcohol 11a followed by DDQ-mediated dehydrogena-
tion (Scheme 4). Alcohol 11a rearranged when irradiated
with UV-light in chloroform. In acetone, p-toluenesulphonic
acid induced the same rearrangement, although less
Acknowledgment. Financial support from The Swedish
Research Council is gratefully acknowledged. The work
was performed within the Centre for Skin Research
(SkinResQU) at Chalmers and University of Gothenburg.
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra are
supplied for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(21) Witkop, B.; Patrick, J. B.; Rosenblum, M. J. Am. Chem. Soc.
1951, 73.
(22) Walker, D.; Hiebert, J. D. Chem. Rev. 1967, 67, 153.
(23) Tamaru, Y.; Inoue, K.; Yamada, Y.; Yoshida, Z. Tetrahedron
Lett. 1981, 22, 1801.
(26) Balskus, E. P.; Walsh, C. T. J. Am. Chem. Soc. 2009, 131, 14648.
(24) Peijnenburg, W. J. G. M.; Buck, H. M. Tetrahedron 1988, 44,
4927.
(25) Baskerville, C.; Hamor, W. A. J. Ind. Eng. Chem. 1912, 4, 571.
The authors declare no competing financial interest.
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