Oxidative coupling as a biomimetic approach to the synthesis of scytonemin

Article abstract of DOI:10.1021/ol201812n

The first total synthesis of the dimeric alkaloid pigment scytonemin is described. The key transformations in its synthesis from 3-indole acetic acid are a Heck carbocyclization and a Suzuki-Miyaura cross-coupling, orchestrated in a stereospecific tandem

Full text of DOI:10.1021/ol201812n

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4458–4461
Oxidative Coupling as a Biomimetic
Approach to the Synthesis of Scytonemin
†
‡
‡
†
‡
Andreas Ekebergh, Isabella Karlsson, Rudi Mete, Ye Pan, 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, University of Gothenburg, SE-412 96
Gothenburg, Sweden
jerker@chalmers.se
Received July 6, 2011
ABSTRACT
The first total synthesis of the dimeric alkaloid pigment scytonemin is described. The key transformations in its synthesis from 3-indole acetic acid
are a Heck carbocyclization and a SuzukiꢀMiyaura cross-coupling, orchestrated in a stereospecific tandem fashion, followed by a
biosynthetically inspired oxidative dimerization. The tandem sequence generates a tetracyclic (E)-3-(arylidene)-3,4-dihydrocyclopenta[b]indol-
2(1H)-one that is subsequently dimerized into the unique homodimeric core structure of scytonemin.
The cyanobacterial dimeric alkaloid pigment scytone-
min (Figure 1) is characterized by a homodimeric core
structure that is unique among natural products and
composed of two 1,10 linked cyclopent[b]indole-2(1H)-
ones. This core in scytonemin is symmetrically appended
by 4-hydroxybenzylidene in the 3-position of the fused
tricyclic system. The parent skeleton comprising the eight
rings has been given the trivial name scytoneman by
Proteau et al. who, in 1993, were the first to elucidate the
chemical structure of the scytonemin pigment.1 Scytone-
min has been proposed to be formed biosynthetically by a
putative tyrosinase NpR1263 promoting an oxidative
dimerization of the R,β-unsaturated ketone (2) (Scheme 1).2
Figure 1. Structure of scytonemin. The scytoneman skeleton is
highlighted by bold lines.
The biosynthetic route to the reduced form of this mono-
meric precursor has been disclosed and shown to com-
mence from L-tryptophan and p-hydroxyphenylpyruvic
acid.3 In an alternative suggestion, nostodione A has been
put forward as the actual monomeric precursor, and the
putative tyrosinase NpR1263 to be essential for the bio-
synthesis of this monomer.4
† Chalmers University of Technology.
‡ University of Gothenburg.
(1) Proteau, P. J.; Gerwick, W. H.; Garcia-Pichel, F.; Castenholz, R.
Experientia 1993, 49, 825.
(2) Balskus, E. P.; Walsh, C. T. J. Am. Chem. Soc. 2008, 130, 15260.
(3) Balskus, E. P.; Walsh, C. T. J. Am. Chem. Soc. 2009, 131, 14648.
(4) Soule, T.; Palmer, K.; Gao, Q.; Potrafka, R. M.; Stout, V.;
Garcia-Pichel, F. BMC Genomics 2009, 10, 336.
r
10.1021/ol201812n
Published on Web 07/25/2011
2011 American Chemical Society

Thus, our synthetic sequence toward scytonemin com-
menced with a standard transformation of 3-indole
acetic acid (4) into its corresponding Weinreb amide (5)
(Scheme 2),10 which was subsequently iodinated in the
2-position using molecular iodine and silver triflate.11
Careful addition of silver triflate and use of slightly less
than 1 equiv of iodine were crucial to avoid formation of a
diiodinated product, which in our hands was impossible to
separate from the desired product. Treatment of the
iodinated Weinreb amide 6 with preformed trimethylsily-
lethynyl lithium gave the alkynyl ketone 7. This ketone was
converted into its corresponding acetal (8) by the proce-
dure reported by Tsunoda et al.12 Accordingly, 1,2-bis-
(trimethylsiloxy)ethane was used as the acetalizing agent
and trimethylsilyl trifluoromethanesulfonate as the cata-
lyst. Of several screened conditions these were the only
ones that effected satisfactory acetal formation. The for-
mation of the tricyclic cyclopent[b]indole-2-one skeleton
and the exocyclic double bond with correct stereochemis-
try was accomplished by a tandem HeckꢀSuzukiꢀMiyaura
reaction. Effective use of the tandem sequence of Heck
carbocyclization of five-membered rings and Suzukiꢀ
Miyaura coupling in stereoselective formation of substi-
tuted exocyclic double bonds has recently been reported in
the literature.9,13 We chose to follow a protocol described
by Littke et al.14,15 It has been successfully applied to both
SuzukiꢀMiyaura and Heck-type cross couplings sepa-
rately but, to the best of our knowledge, not in tandem
reactions. Consequently, the alkynyl iodoindole 8 was
treated with an arylboronic acid in the presence of cesium
carbonate and a catalytic amount of palladium and tri-
tert-butylphosphine. It was discovered that the conditions
of this domino reaction needed careful tuning to favor the
desired reaction pathway. Using phenylboronic acid in
excess (1.5 equiv of PhB(OH)2 and 2.5 equiv of Cs2CO3)
yielded the cyclized product 9a exclusively, while the same
excess of 4-methoxyboronic acid produced a significant
amount of the undesired 2-(4-methoxyphenyl)-indole to-
gether with the wanted product 9b. The electron-rich
boronic acid increased the rate of reaction for the inter-
molecular Suzuki coupling to the degree where it success-
fully competed with the intramolecular Heck cyclization.
Decreasing the excess of boronic acid and base (1.1 equiv
of MeOPhB(OH)2 and 1.8 equiv of Cs2CO3) suppressed
the unwanted cross coupling but had an unfortunate effect
on the overall conversion. Further screening and evalua-
tion of reaction conditions to circumvent this problem are
Scheme 1. Retrosynthetic Analysis of Scytonemin
The biological role of scytonemin has been ascertained
to be as a UV-absorbing pigment to protect important
cellular components in the cyanobacteria against harmful
UV radiation.5 Its critical biological importance for the
cyanobacterial survival is highlighted by the facts that the
pigment is found in more than 300 species of cyanobacteria
and that the scytonemin biosynthetic gene cluster is highly
conserved across several studied cyanobacterial lineages.6
Scytonemin received attention when it was reported to
be the first characterized small molecule inhibitor of polo-
like kinase 1 and to inhibit other cell cycle regulatory
kinases as well.7 In compliance with these observations,
it has been shown to possess both anti-inflammatory and
antiproliferative properties.8 Scytonemin has therefore
been proposed to serve as a new pharmacophore that
could be used in the development of a chemically new class
of therapeutically useful drugs.
In a project aimed at exploring the photochemistry and
photophysics of scytonemin we need access to derivatives
of both the dimeric form as well as its monomeric pre-
cursor. Our plan to prepare these compounds takes its
starting point in the molecular symmetry and the prospect
of stereospecific formation of the exocyclic double bond;
see Scheme 1. Initial disconnection of the C1ꢀC10 bond
generates the monomeric precursor (2). Inspired by the
proposed biosynthetic route to scytonemin, and attracted
by the possibility to couple two identical moieties without
the need ofprior installation of any functional group lostin
the subsequent coupling, we set out to complete the syn-
thesis of the scytoneman skeleton by an oxidative coupling
of two identical halves. Further disconnection of two cis-
vinylic bonds at the exocyclic double bond produces an
alkynyl haloindole (3). This intermediate was expected to
participate in a palladium-mediated syn-addition of the
indolyl group and an aryl group to the triple bond, to
create both the fused tricyclic skeleton and the exocyclic
double bond with the correct stereochemistry in a single
operation.9 The final disconnection, which corresponds to
an acyl substitution, generates the commercially available
3-indole acetic acid (4).
(8) Stevenson, C. S.; Capper, E. A.; Roshak, A. K.; Marquez, B.;
Grace, K.; Gerwick, W. H.; Jacobs, R. S.; Marshall, L. A. Inflammation
Res. 2002, 51, 112.
(9) Arthuis, M.; Pontikis, R.; Florent, J. C. Tetrahedron Lett. 2007,
48, 6397.
(10) Duval, E.; Cuny, G. D. Tetrahedron Lett. 2004, 45, 5411.
(11) Baran, P. S.; Shenvi, R. A. J. Am. Chem. Soc. 2006, 128, 14028.
(12) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21,
1357.
(13) Cheung, W. S.; Patch, R. J.; Player, M. R. J. Org. Chem. 2005,
70, 3741.
(5) Cockell, C. S.; Knowland, J. Biol. Rev. Cambridge Philos. Soc.
1999, 74, 311.
(6) Sorrels, C. M.; Proteau, P. J.; Gerwick, W. H. Appl. Environ.
Microbiol. 2009, 75, 4861.
(14) Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10.
(15) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
4020.
(7) Stevenson, C. S.; Capper, E. A.; Roshak, A. K.; Marquez, B.;
Eichman, C.; Jackson, J. R.; Mattern, M.; Gerwick, W. H.; Jacobs,
R. S.; Marshall, L. A. J. Pharmacol. Exp. Ther. 2002, 303, 858.
Org. Lett., Vol. 13, No. 16, 2011
4459

Scheme 2. Synthetic Route to Scytoneman-2,20-dione and Scytonemin
currently being undertaken. Acid catalyzed acetal hydro-
lysis and fluoride induced desilylation completed the
synthesis of the monomers 11a and 11b.
better yield compared to equimolar amounts. Of the
screened oxidants, ferric chloride showed the most poten-
tial. Slightly more than 2 equiv of LDA combined with 2
equiv of FeCl3 with respect to the monomer gave the
highest yield (Table 1, entry 5). Reducing the reagents to
1 equiv each decreased the yield by 16% (Table 1, entry 4).
On the other hand a cleaner reaction where the unreacted
monomer could be recovered quantitatively was obtained.
Employing the iron based conditions on the scytonemin
precursor 11b afforded its dimeric counterpart 12b in
higher yield than that obtained for the monomer 11a used
in the small prescreening study. This agrees with a recent
report showing that enolates conjugated with electron-rich
aromatic groups increase the efficiency of iron mediated
couplings, while electron-deficient aromatic groups sup-
press the reactivity.13
The last carbonꢀcarbon bond required to complete the
scytoneman skeleton is part of a 1,4-carbonyl moiety.
There are ample examples in the literature of successful
assembly of this structural element by oxidative coupling
of carbonyl enolates.16ꢀ18 Often oxidative coupling of
enolates entails copper or iron, in the form of different
salts, similar to enzymatic coupling conditions.16 Hyper-
valent iodine reagents are also employed to accomplish the
oxidative coupling of enolates.17 To find appropriate re-
action conditions for the oxidative coupling, the more
accessible monomer11a together witha small set of diverse
coupling reagents were selected for screening. Thus, the
monomer 11a was treated with LDA to give the corre-
sponding lithium enolate, which was subsequently treated
with an appropriate oxidant (Table 1). Cuprous triflate
showed poor reactivity giving the monomer back, whereas
cupric chloride consumed the monomer but without pro-
ducing the wanted product. The hypervalent iodine de-
monstrated very potent reactivity with polymerization as a
possible side reaction. In accordance with the mechanism
Table 1. Screening of Reaction Conditions for Oxidative Cou-
pling of the Unsaturated Ketones 12a and 12ba
R
oxidant
(equiv)
LDA
yield
(%)
time
(h)
entry
(compda)
(equiv)
for oxidative coupling with hypervalent iodine reagents
proposed by Kita et al.,19 it was found that about 0.5 equiv
of the oxidant in combination with 1 equiv of LDA gave a
1
2
3
4
5
6
H (12a)
H (12a)
H (12a)
H (12a)
H (12a)
OMe (12b)
CuOTf (2.4)
CuCl2 (1.2)
PhI(OAc)2 (0.6)
FeCl3 (1.1)
FeCl3 (2.2)
FeCl3 (2.2)
2
traceb
0
70
0.7
2
1.1
1.1
1.1
2.1
2.1
25
40
24
24
24
(16) DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc.
2008, 130, 11546.
(17) Kim, J. W.; Lee, J. J.; Lee, S. H.; Ahn, K. H. Synth. Commun.
56
70
1998, 28, 1287.
a See Scheme 2, step 8. General conditions: THF, ꢀ78 °C to rt.
(18) Krygowski, E. S.; Murphy-Benenato, K.; Shair, M. D. Angew.
Chem., Int. Ed. 2008, 47, 1680.
(19) Kita, Y.; Yakura, T.; Tohma, H.; Kikuchi, K.; Tamura, Y.
CuOTf was added as a MeCN solution. CuCl2 and FeCl3 were added as
DMF solutions. b Trace quantity could be observed by LC/MS.
Tetrahedron Lett. 1989, 30, 1119.
4460
Org. Lett., Vol. 13, No. 16, 2011

Scytoneman-2,20-dione 13 was obtained directly from
the corresponding reduced dimer 12a by oxidation with
DDQ. To obtain scytonemin, the methoxy functionalities
of 12b had to be converted into its corresponding hydroxyl
groups before oxidation. Employing standard Lewis acidic
demethylating conditions afforded the wanted conversion
into tetrahydroscytonemin 12c, albeit with a moderate
decay of the substrate. Utilizing the oxidizing properties
of DDQ in the last synthetic procedure provided scytone-
min (1). Interestingly, reversing the order of the two last
synthetic operations, and thus demethylating the methoxy
scytonemin analogue, yielded no product at all. It has
previously been reported that scytonemin is sensitive
toward alkaline and Brønsted acidic conditions,20 a list
which now can be supplemented with Lewis acidic condi-
tions. The sensitivity to basic conditions impeded our initial
plan to use a silyl protective group on the phenolic oxygen
and then remove both this and the vinylic TMS group at
the same time in a final global deprotection. Despite several
attempts, we failed to develop reaction conditions strong
enough to enforce excision of the vinylic TMS group but
mild enough not to cause decomposition of scytonemin or
its tetrahydro analogue.
In summary, we have completed the synthesis of the
cyanobacterial alkaloid scytonemin. The parent struc-
ture, the scytoneman skeleton, was assembled by a
ferric chloride induced oxidative coupling of two iden-
tical fragments. This tetracyclic fragment was effec-
tively constructed stereospecifically, with respect to the
exocyclic double bond, by a tandem HeckꢀSuzukiꢀ
Miyaura cyclization as a key reaction. The synthetic
route is flexible and allows for effective synthesis of
numerous scytonemin analogues. We anticipate that
this could pave the way for the scytoneman skeleton
as a lead structure in the development of new anti-
inflammatory and anticancer drugs and potentially
also new UV stabilizers.
Acknowledgment. We thank the Swedish Research
Council and the Centre for Skin Research at University
of Gothenburg for financial support.
Supporting Information Available. Experimental pro-
cedures are supplied for all compounds, characterization
data and NMR-spectra are supplied for key compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Garcia-Pichel, F.; Castenholz, R. W. J. Phycol. 1991, 27, 395.
Org. Lett., Vol. 13, No. 16, 2011
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