Rapid access to the Welwitindolinone alkaloid skeleton by cyclization of indolecarboxaldehyde substituted cyclohexanones

Article abstract of DOI:10.1021/ol051239t

(Chemical Equation Presented) A very rapid access to cyclohexanone-bridged indole systems was established by an acid-mediated ring closure of appropriately substituted indole aldehydes, which involved an apparent disproportionation of an aldol-like interm

Full text of DOI:10.1021/ol051239t

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4087-4089
Rapid Access to the Welwitindolinone
Alkaloid Skeleton by Cyclization of
Indolecarboxaldehyde Substituted
Cyclohexanones
Je´roˆme Baudoux, Alexander J. Blake, and Nigel S. Simpkins*
School of Chemistry, UniVersity of Nottingham, Nottingham U.K.
nigel.simpkins@nottingham.ac.uk
Received May 26, 2005
ABSTRACT
A very rapid access to cyclohexanone-bridged indole systems was established by an acid-mediated ring closure of appropriately substituted
indole aldehydes, which involved an apparent disproportionation of an aldol-like intermediate. One of the bridged indole intermediates was
further transformed into an oxindole having the essential skeleton of the Welwitindolinone alkaloids.
In 1994, Moore and co-workers described the isolation of a
family of unusual alkaloids from the blue-green algae
Hapalosiphon welwitschii and Westiella intricata Borzi,
including the structures of N-methylwelwitindolinone C
isothiocyanate 1 (also known as welwistatin), welwitindoli-
none A isonitrile 2, and a number of related structures,
including oxindole 3, which is epimeric at C-3 with respect
to welwistatin (Figure 1).1,2
Welwistatin has established biological activities, including
reversal of P-glycoprotein-mediated multiple-drug-resistance
(MDR), larvacidal activities, and microtubule effects that
result in inhibition of cancer cell proliferation.3,4 The isonitrile
2, which is a proposed biosynthetic precursor to welwistatin
(and welwitindolinones B and D), shows antifungal activity.
The interesting biological activities of these compounds,
combined with their fascinating and synthetically chal-
lenging structures, make them attractive targets for synthesis.
However, progress in this area has been surprisingly limited,
(1) Stratmann, K.; Moore, R. E.; Bonjouklian, R.; Deeter, J. B.; Patterson,
G. M. L.; Shaffer, S.; Smith, C. D.; Smitka, T. A. J. Am. Chem. Soc. 1994,
116, 9935.
Figure 1. Structures of 1-3.
(2) See also: Jimenez, J. I.; Huber, U.; Moore, R. E. J. Nat. Prod. 1999,
62, 569.
(3) Smith, C. D.; Zilfou, J. T.; Stratmann, K.; Patterson, G. M.; Moore,
R. E. Mol. Pharmacol. 1995, 47, 241.
with only Wood’s group describing substantive approaches
to both 1 and 2.5,6 The work to date has recently been
reviewed.7
(4) Zhang, X.; Smith, C. C. Mol. Pharmacol. 1996, 49, 288.
10.1021/ol051239t CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/25/2005

We became interested in the synthesis of these compounds
(especially 1) via bridged indole intermediates, such as 4,
as part of project examining bridgehead metalation chem-
istry.8 We believed that key intermediates, such as 4 (where
X is a protected alcohol or ketone function), would be
available by strategic disconnection at either bond a or bond
b, the forward reactions involving either intramolecular eno-
late arylation of 5 or aldol-type reaction of 6 (Scheme 1).
bridged structures, methylene-bridged product 9 and diketone
10, in roughly equal amounts.
This unexpected but pleasing result was confirmed by
detailed spectroscopic analysis of both compounds, the
structure of indole 9 also being secured by subsequent X-ray
crystallographic analysis (Figure 2).
Scheme 1
After our initial efforts to cyclize ketone 5 (X ) H) and
similar structures (obtained through indole Michael addition
to appropriate enones) proved unsuccessful, we turned instead
to the synthesis and reactions of indole aldehydes of structure
6. Similar intermediates have been accessed previously by
Deng and Konopelski, who utilized an indole-lead partner
in a key coupling process with an elaborated cyclohexanone.6a
Figure 2. ORTEP drawing of indole 9.
The reaction can be rationalized by invoking initial aldol
condensation to give 11, followed by dehydration to give
12 (both of these steps might be expected to be reversible).
Hydride transfer from C* of 11 to the corresponding position
in the extended iminium species 12 effects disproportionation
of 11, leading to the observed products (Scheme 3).
Palladium-catalyzed coupling of cyclohexanone with bro-
moindole 7, under conditions based on those described by
Buchwald,9 gave a product ketone, which on subsequent
Vilsmeier-Hack formylation then gave indole 8 ()6 where
X ) H and R ) Me) (Scheme 2).10 Attempted aldol-type
ring closure of 8 by reaction with bases ranging from
Ca(OH)2 to LDA gave no sign of the desired product. In
contrast, exposure to acidic conditions gave rise to two
Scheme 3
Scheme 2 a
Although this was a very exciting result, the formation of
two products was clearly problematic, and we sought
(5) (a) Wood, J. L.; Holubec, A. A.; Stoltz, B. M.; Weiss, M. M.; Dixon,
J. A.; Doan, B. D.; Shamji, M. F.; Chen, J. M.; Heffron, T. P. J. Am. Chem.
Soc. 1999, 121, 6326. (b) Ready, J. M.; Reisman, S. E.; Hirata, M.; Weiss,
M. M.; Tamaki, K.; Ovaska, T. V.; Wood, J. L. Angew. Chem., Int. Ed.
2004, 43, 1270.
(6) For other synthetic efforts, see: (a) Deng, H. B.; Konopelski, J. P.
Org. Lett. 2001, 3, 3001. (b) Jung, M. E.; Slowinski, F. Tetrahedron Lett.
2001, 42, 6835. (c) Lopez-Alvarado, P.; Garcia-Granda, S.; Alvarez-Rua,
C.; Avendano, C. Eur. J. Org. Chem. 2002, 1702.
(7) Avendano, C.; Mene´ndez, J. C. Curr. Org. Synth. 2004, 1, 65.
(8) (a) Blake, A. J.; Giblin, G. M. P.; Kirk, D. T.; Simpkins, N. S.;
Wilson, C. Chem. Commun. 2001, 2668. (b) Giblin, G. M. P.; Kirk, D. T.;
Mitchell, L.; Simpkins, N. S. Org. Lett. 2003, 5, 1673.
a Reagents: (a) cyclohexanone, Pd(OAc)2 (1 mol %), K3PO4 (2.3
equiv), (2-biphenyl)dicyclohexylphosphine (2.5 mol %), THF, 100
°C (sealed tube), 24 h, 51-73%; (b) POCl3, DMF, 0 °C, then KOH
(aq) 75%; (c) p-TsOH (0.5 equiv) THF, 50 °C, 24 h, 60% (9:10
ca. 1:1).
(9) (a) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360. (b) For a relevant review, see: Culkin, D. A.; Hartwig,
J. F. Acc. Chem. Res. 2003, 36, 234.
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Org. Lett., Vol. 7, No. 19, 2005

modified conditions that would give just one product. We
expected that iminium 12 might be intercepted by alternative
nucleophiles and that inclusion of an appropriate reaction
partner would therefore preclude intermolecular hydride
transfer from 11. Satisfyingly, repeating the PTSA cyclization
reaction of 8 in the presence of a powerful external source
of hydride, namely, Et3SiH (2.4 equiv), resulted in the
formation of 9 as the sole product in 92% yield.11 Conversely,
running the reaction in the presence of a hydride acceptor
(DDQ) gave only the diketone 10, although in a more modest
45% yield.
We were able to unequivocally establish the structure of
the product 13 by X-ray crystallography. The C-3 stereo-
chemistry presumably arises by least hindered protonation
from the convex face of the bridged system and makes 13 a
relative of the minor alkaloid 3, rather than welwistatin 1,
which is epimeric at this center.12
In summary, the new cyclization chemistry described here
gives extremely short access (three steps) to the bridged
framework of the Welwitindolinone alkaloids, and the
products synthesized appear to be suitable for further
manipulation toward the natural products and their close
analogues.13,14
Of key interest was the conversion of our indole structures
into the corresponding oxindoles, which are more closely
related to natural products, such as 1 and 3. To this end,
Acknowledgment. We thank the Engineering and Physi-
cal Sciences Research Council (EPSRC) for a Fellowship
to J.B., and also for funding for an X-ray diffractometer.
t
exposure of indole 9 to NBS in 95% BuOH at room
temperature gave rise to a single oxindole product 13 in 52%
yield (Figure 3).6a,12
Supporting Information Available: Description of ex-
perimental procedures described, and characterization data
for new compounds, including CIF X-ray data for compounds
9 and 13. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL051239T
(10) This result contrasts with one described by Deng and Konopelski
in ref 6a, in which a similar substrate underwent cyclohexanone (rather
than indole) formylation.
(11) (a) Appleton, J. E.; Dack, K. N.; Green, A. D.; Steele, J. Tetrahedron
Lett. 1993, 34, 1529. (b) Mahadevan, A.; Sard, H.; Gonzalez, M.; McKew,
J. C. Tetrahedron Lett. 2003, 44, 4589.
(12) Effective C-3 epimerization under has not been possible to date
(e.g., using protic conditions, NaOMe-MeOH).
(13) Further preliminary work has demonstrated that the new cyclization
is viable starting with keto aldehyde 6, where X ) OPMB. We have also
shown that bridgehead silylation of ketone 9 is possible.
(14) While our manuscript was under review, an intramolecular arylation
approach to similar bridged indoles appeared. See: MacKay, J. A.; Bishop,
R. L.; Rawal, V. H. Org. Lett. 2005, 7, 3421.
Figure 3. Schematic and ORTEP of product 13.
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