Total synthesis of the photoprotecting dipyrrolobenzoquinone (+)-terreusinone

Article abstract of DOI:10.1021/ol2027398

The first synthesis of (+)-terreusinone 1, a dipyrrolobenzoquinone with a potent UV-A protecting capability, is described. Key transformations include a one-pot Larock indolization-Sonogashira coupling reaction and the hydroamination of an unsubstituted o

Full text of DOI:10.1021/ol2027398

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6444–6447
Total Synthesis of the Photoprotecting
Dipyrrolobenzoquinone (þ)-Terreusinone
Christy Wang and Jonathan Sperry*
School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland,
New Zealand
j.sperry@auckland.ac.nz
Received October 12, 2011
ABSTRACT
The first synthesis of (þ)-terreusinone 1, a dipyrrolobenzoquinone with a potent UV-A protecting capability, is described. Key transformations
include a one-pot Larock indolizationꢀSonogashira coupling reaction and the hydroamination of an unsubstituted ortho-alkynylaniline catalyzed
by a cationic gold(I) complex. The synthesis proceeds in eight steps from commercially available starting materials, confirming the structure and
absolute configuration of the natural product.
Terreusinone (1) is a dipyrrolobenzoquinone isolated
from the algicolous marine fungus Aspergillus terreus in 2003
(Scheme 1).1 Terreusinone contains a pyrrolo[2,3-f]indole-
Scheme 1. Terreusinone (1) and Heterocyclic Motifs A and B
4,8-dione ring system (A) that is unique among natural
products. Moreover, terreusinone was shown to exhibit
significant UV-A protecting properties, implying 1 may serve
to protect the host organism from the harmful effects of solar
UV radiation.2 Significantly, the UV-A protecting capability
of 1 (ED50 ≈ 200 μm) is stronger than that of oxybenzone
(ED50 = 350 μm), a compound widely used in sunscreens,
suggesting 1 (and analogues thereof) may have potential
dermatological and biomedical applications.
The configuration of the stereocenters at C10/C100 in 1
were assigned as (R).1 A short time later, subjecting 1 to a
desymmetrizing microbial oxidation further confirmed the
C2-symmetrical structure 1.3
Successful syntheses of compounds bearing the dipyrro-
lobenzoquinone A include the flash vacuum pyrolysis of a
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Garcia-Pichel, F. Nat. Rev. Microbiol. 2011, 9, 791–802.
(3) Li, X.; Lee, S. M.; Choi, H. D.; Kang, J. S.; Son, B. W. Chem.
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€
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r
10.1021/ol2027398
Published on Web 11/14/2011
2011 American Chemical Society

diketopiperazine,4 the reaction of a series of activated meth-
ylene derivatives with 3,6-diamino-2,5-dibromobenzoquinones5
or p-chloranil,6 and the reaction of 1,2-amino alcohols
with indoloquinones followed byacid mediatedcyclization
and oxidation.7 These methods require harsh conditions,4ꢀ7
afford heavily substituted products,5,6 or proceed in a
nonregioselectivemanner.7 Furthermore, due to the nature
of the substrates involved, none of these methods can be
applied to the synthesis of dipyrrolobenzoquinones with
chiral substituents on the heterocyclic ring(s), as observed in
1. Broadly speaking, the simplest synthesis of dipyrroloben-
zoquinones of type A is via the oxidation of its benzenoid
derivative, pyrrolo[2,3-f]indole B (Scheme 1). Much like
dipyrrolobenzoquinones A, the literature syntheses of pyr-
roloindoles B possess narrow scope and none have incor-
porated chiral substituents onto the heterocyclic core.8
Unfortunately, despite attempting a plethora of reaction
conditions and various combinations of 3aꢀb/4aꢀd,
no pyrroloindole 2 was ever observed (Scheme 2).
Although the full details are not discussed herein, knowl-
edge of this failed approach is necessary when considering
the modified, ultimately successful synthesis of (þ)-1
detailed henceforth.
A new retrosynthesis of terreusinone 1was devised where-
by the two heterocyclic rings would be installed in separate
synthetic steps (Scheme 3). In this revised route, the synthe-
sis of 1 would conclude with the late stage oxidative
demethylation of pyrroloindole 2 which will in turn be
constructed by a gold-catalyzed10,11 hydroamination of
ortho-alkynylaniline 5. In keeping with the original propo-
sal, the highly substituted indole 5 would be constructed
using a Larock indolization. At this planning stage, it was
apparent that the modified catalytic system12 that facilitates
the use of aryl bromides13 in the Larock indolization may
also promote Sonogashira coupling.14 Accordingly, 5 could
be assembled by a novel one-pot Larock indolizationꢀ
Sonogashira coupling reaction between the dibromide 3c
and 2 equiv of the silylated propargylic alcohol (R)-4c,15
followed by reduction (Scheme 3).
Scheme 2. Failed Double Larock Indolization Approach
Scheme 3. Revised Approach to (þ)-Terreusinone
As alluded to in the above, the aim was to construct
terreusinone 1 by the late stage oxidative demethylation of
the pyrroloindole 2 (Scheme 2). The palladium-catalyzed
reaction between ortho-haloanilines and terminal alkynes
(Larock indolization) is a highly reputable procedure for
constructing 2-substituted indoles,9 and as such, we en-
visaged that pyrroloindole 2 be constructed using a double
Larock indolization of a halogenated 1,4-dianiline (3a or 3b)
with the chiral, secondary propargylic alcohols (R)-4aꢀd.
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Focus turned toward assembling the coupling part-
ners 3c and (R)-4c to assess the viability of the proposed
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Samanta, S.; Chattopadhyay, B. Tetrahedron Lett. 2008, 49, 7213–7216.
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Rh(I)-catalyzed hydroamination of ortho- alkynylaniline furnishes
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Org. Lett., Vol. 13, No. 24, 2011
6445

one-pot Larock indolizationꢀSonogashira coupling reac-
tion and the synthesis of dibromide 3c was the initial task.
Although commercially available 2-methoxy-4-nitroani-
line 6 underwent successful dibromination with NBS in
sulfuric acid, the undesired 1,2-dibromide 9 was isolated as
the sole product in poor yield, as determined by NOE
experiments (Scheme 4).17 In light of this disappointing
result, a two-step dibromination was considered. Thus, the
known bromide 716 underwent successful bromination (NBS,
H2SO4), affording dibromides 3c and 9, again heavily
favoring the undesired regioisomer 9 (93:7) (Scheme 4).
However, acetylation of bromide 7 gave 8 that, upon
exposure to the conditions used previously (NBS, H2SO4),
underwent bromination with concomitant acetate hydro-
lysis, giving bromides 3c and 9, pleasingly favoring regio-
isomer 3c in a 2:1 ratio (Scheme 4).
Scheme 5. Synthesis of (R)-4c
Upon subjecting dibromide 3c and an excess of (R)-4c to
Senanayake’s modified Larock indolization conditions,12a
both the Larock indolization and Sonogashira coupling
successfully occurred, furnishing indole 12 in 26% yield
(Scheme 6). 1H and 13C NMR spectroscopy showed only
one diastereomer of 12 was present,17 indicating the stereo-
chemical integrity in (R)-4c had been retained in the
product. The desired regiochemical outcome of the Larock
indolization was confirmed by NOE studies.17,19 Despite
the poor yield of this step, it did accomplish the formation
of three key bonds (2 ꢁ CꢀC, 1 ꢁ CꢀN) in a single
operation. Moreover, there are limited examples of
Larock indolizations with ortho-bromoanilines12 and
copper-free Sonogashira couplings14 with aryl bromides,
so achieving both of these transformations in a single step
represents a significant accomplishment. Extending the
utility of this reaction as a novel one-pot synthesis of
alkynyl indoles is currently under investigation in our
laboratory.
Racemic propargylic alcohol (()-4a was subjected to
kinetic resolution (Novozyme 435, vinyl acetate)18 fol-
lowed by silylation, delivering (R)-4c (Scheme 5). The
enantiomeric excess of (R)-4a showed a slight improvement
Scheme 4. Synthesis of Dibromide 3c
(96%) against the literature value (93%),18 determined by
Mosher’s ester analysis.17
Scheme 6. One-Pot Larock IndolizationꢀSonogashira Cou-
pling
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Farina, V.; Senanayake, C. H. Org. Lett. 2004, 6, 4129–4132. (b)
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J. D.; Boger, D. L. J. Am. Chem. Soc. 2010, 132, 7776–7783. (c)Cui, X.; Li,
J.; Fu, Y.; Liu, L.; Guo, Q.-X. Tetrahedron Lett. 2008, 49, 3458–3462. (d)
Batail, N.; Dufaud, V.; Djakovitch, L. Tetrahedron Lett. 2011, 52, 1916–
1918.
(13) As the synthesis of aromatic bromides is generally more facile
than that of iodides, dibromide 3c was chosen over the diiodide.
(14) For examples of the Sonogashira reaction of aryl bromides
under copper-free conditions, see: (a) Hundertmark, T.; Littke, A. F.;
Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729–1731. (b) Eckhardt,
M.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 13642–13643. (c) Cheng, J.;
Sun, Y.; Wang, F.; Guo, M.; Xu, J.-H.; Pan, Y.; Zhang, Z. J. Org. Chem.
2004, 69, 5428–5432. (d) Li, J.-H.; Liang, Y.; Xie, Y.-X. J. Org. Chem.
2005, 70, 4393–4396. (e) Shirakawa, E.; Kitabata, T.; Otsuka, H.;
Tsuchimoto, T. Tetrahedron 2005, 61, 9878–9885. (f) Keddie, D. J.;
Fairfull-Smith, K. E.; Bottle, S. E. Org. Biomol. Chem. 2008, 6, 3135–
3143. (g) Lipshutz, B. H.; Chung, D. W.; Rich, B. Org. Lett. 2008, 10,
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(15) Model studies indicated that triisopropylsilyl protected alkynol
4c was the best substrate for the Larock indolization.
(16) Tietze, L. F.; Looft, J.; Feuerstein, T. Eur. J. Org. Chem. 2003,
2749–2755.
(17) See Supporting Information for full details.
(18) Raminelli, C.; Comasseto, J. V.; Andrade, L. H.; Porto, A. L. M.
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(19) There is only one example of a Larock indolization proceeding
with complete reversal in regioselectivity: Nishikawa, T.; Wada, K.;
Isobe, M. Biosci. Biotechnol. Biochem. 2002, 66, 2273–2278.
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Org. Lett., Vol. 13, No. 24, 2011

Nitro group reduction in 12 followed by TBAF-
mediated silyl ether cleavage delivered the ortho-alkynyl-
aniline 5, setting the scene for the key hydroamination
(Scheme 7).
Scheme 7. Total Synthesis of (þ)-Terreusinone 1
Various acid metal-based catalytic systems are known to
catalyze the hydroamination of unsubstituted ortho-alky-
nylanilines toindoles.20 However, the field of gold catalysis
has increased exponentiallyoverthe pastfew years21 and in
contrast to many of the aforementioned methods,20 the
catalysts involved are typically air- and moisture-stable
and reactionscan be performedinanopen flask under mild
conditions. Initial attempts to effect the desired transfor-
mation of 5 to 2 with all of the gold(III)10 and gold(I)11
catalysts reported to facilitate the synthesis of indoles from
ortho-alkynylanilines failed, primarily due to the insta-
bility of the substrate 5. In a final attempt, we turned to
Echavarren’s cationic gold(I) complex22 (acetonitrile)-
[(2-biphenyl)di-tert-butylphosphine]gold(I) hexafluoroan-
timonate 13. Upon exposing 5 to 12 mol % of complex 13
in toluene at 60 °C, pyrroloindole 2 was isolated in
excellent yield after 30 min (Scheme 7). This result demon-
strates a novel application of complex 13, extending its
utility in organic synthesis.22
ꢀ
Upon oxidation of 2 with Fremy’s salt under buffered
conditions, (þ)-terreusinone 1 was obtained in good yield.
The NMR spectroscopic data17 and optical rotation
{[R]2D1þ43.7 (c 0.16, MeOH); lit.,1 [R]Dþ47 (c 0.3, MeOH)}
of synthetic 1 were in excellent agreement with the litera-
ture,1 confirming the structure and absolute configuration
of the natural product. Unfortunately, we were unable to
establish contact with the authors of the isolation report1
and obtain an authentic sample of natural (þ)-1.
(21) Recent reviews: (a) Toste, F. D. Beil. J. Org. Chem. 2011, 7, 553–
554 and ensuing references. (b) Rudolph, M.; Hashmi, A. S. K. Chem.
Commun. 2011, 47, 6536–6544. (c) Shapiro, N. D.; Toste, F. D. Synlett
2010, 5, 675–691. (d) Gagosz, F. Tetrahedron 2009, 65, 1757 and ensuing
references. (e) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed.
2006, 45, 7896–7936.
In conclusion, this report describes the first synthesis of
the photoprotecting dipyrrolobenzoquinone natural pro-
duct (þ)-terreusinone. This synthesis is noteworthy for a
one-pot Larock indolizationꢀSonogashira coupling reac-
tion and the hydroamination of a delicate, unsubstituted
ortho-alkynylaniline 5 catalyzed by Echavarren’s cationic
gold(I) complex 13. The overall route proceeds in eight
steps, furnishing sufficient quantities of (þ)-1 that allows
further study of its photoprotecting properties, details of
which shall be reported in due course.
ꢀ
~
ꢀ
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Acknowledgment. We thank the Royal Society of
New Zealand Marsden Fund for supporting this work.
Supporting Information Available. Experimental pro-
cedures and NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 24, 2011
6447