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.
(6) Shindy, H. A.; El-Maghraby, M. A.; Eissa, F. M. Dyes Pigm.
2002, 52, 79–87.
(7) (a) Rives, A.; Delaine, T.; Legentil, L.; Delfourne, E. Tetrahedron
Focus turned toward assembling the coupling part-
ners 3c and (R)-4c to assess the viability of the proposed
ꢀ
Lett. 2010, 50, 1128–1130. (b) Rives, A.; Le Calve, B.; Delaine, T.;
Legentil, L.; Kiss, R.; Delfourne, E. Eur. J. Med. Chem. 2010, 45, 343–
351.
(8) Previous syntheses of pyrrolo[2,3-f]indoles (B) rely on classical
indolization reactions, see: JappꢀMurray: (a) Yamashkin, S. A. Khim.
Geterotsikl. Soedin. 1995, 55–57. Fischer:(b) Park, I.-K.; Suh, S.-E.;
Lim, B.-Y.; Cho, C.-G. Org. Lett. 2009, 11, 5454–5456. Leimgruberꢀ
Batcho:(c) Berlin, A.; Bradamante, S.; Ferraccioli, R.; Pagani, G. A.;
(10) Gold(III): (a) Arcadi, A.; Bianchi, G.; Marinelli, F. Synthesis
2004, 4, 610–618. (b) Alfonsi, M.; Arcadi, A.; Aschi, M.; Bianchi, G.;
Marinelli, F. J. Org. Chem. 2005, 70, 2265–2273. (c) Kuwano, R.;
Kashiwabara, M. Org. Lett. 2006, 8, 2653–2655. (d) Zhang, Y.; Donahue,
J. P.; Li, C.-J. Org. Lett. 2007, 9, 627–630. (e) Ambrogio, I.; Arcadi, A.;
Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett 2007, 11, 1775–1779. (f)
Miyazaki, Y.; Kobayashi, S. J. Comb. Chem. 2008, 10, 355–357. (g)
Fukuoka, S.; Naito, T.; Sekiguchi, H.; Somete, T.; Mori, A. Hetero-
cycles 2008, 76, 819–826. (h) Dash, J.; Shirude, P. S.; Balasubrama-
nian, S. Chem. Commun. 2008, 26, 3055–3057. (i) Majumdar, K. C.;
Samanta, S.; Chattopadhyay, B. Tetrahedron Lett. 2008, 49, 7213–7216.
(j) Nakajima, R.; Ogino, T.; Yokoshima, S.; Fukuyama, T. J. Am. Chem.
Soc. 2010, 132, 1236–1237. (k) Hashmi, A. S. K.; Ramamurthi, T. D.;
Rominger, F. Adv. Synth. Catal. 2010, 352, 971–975. (l) Capelli, L.;
Manini, P.; Pezzella, A.; d’Ischia, M. Org. Biomol. Chem. 2010, 8, 4243–
4245. (m) Xu, M.; Hou, Q.; Wang, S.; Wang, H.; Yao, Z.-J. Synthesis
2011, 4, 626–634.
ꢁ
Sannicolo, F. J. Chem. Soc. Chem. Commun. 1987, 1176–1177. Bischler:
(d) Prasad, G. K. B.; Burchat, A.; Weeratunga, G.; Watts, I.; Dmitrienko,
G. I. Tetrahedron Lett. 1991, 32, 5035–5038. Madelung:(e) Chen, H. Z.;
Jin, Y. D.; Xu, R. S.; Peng, B. X.; Desseyn, H.; Janssens, J.; Heremans,
P.; Borghs, G.; Geise, H. J. Synth. Met. 2003, 139, 529–534. The
Rh(I)-catalyzed hydroamination of ortho- alkynylaniline furnishes
the pyrrolo[2,3-f]indole heterocyclic system in poor yield (20%):
(f) Clentsmith, G. K. B.; Field, L. D.; Messerle, B. A.; Shasha, A.;
Turner, P. Tetrahedron Lett. 2009, 50, 1469–1471.
(9) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689–
6690. (b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998,
63, 7652–7662. For the use of achiral and racemic propargylic alcohols
in the Larock indolization:(c) McCarroll, A. J.; Bradshaw, T. D.;
Westwell, A. D.; Matthews, C. S.; Stevens, M. F. G. J. Med. Chem.
2006, 50, 1707–1710. (d) Djakovitch, L.; Dufaud, V.; Zaidi, R. Adv.
Synth. Catal. 2006, 348, 715–724.
(11) Gold(I): Wang, C.; Widom, J.; Petronijevic, F.; Burnett, J. C.;
Nuss, J. E.; Bavari, S.; Gussio, R.; Wipf, P. Heterocycles 2009, 79, 487–
520.
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