A new modular indole synthesis. Construction of the highly strained CDEF parent tetracycle of nodulisporic acids A and B

Article abstract of DOI:10.1021/ol0606536

Construction of the highly strained CDEF parent tetracycle, a structural motif found only in the potent ectoparasiticidal agents (+)-nodulisporic acids A and B and related congeners, has been achieved via a new modular indole synthesis, exploiting a sequential Stille cross-coupling/Buchwald-Hartwig union/cyclization tactic. The new indole synthesis holds the promise of rapid assembly of diverse, highly substituted indoles possessing uncommon substitution patterns.

Full text of DOI:10.1021/ol0606536

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2167-2170
A New Modular Indole Synthesis.
Construction of the Highly Strained
CDEF Parent Tetracycle of Nodulisporic
Acids A and B
Amos B. Smith, III,* La´szlo´ Ku1rti, and Akin H. Davulcu
Department of Chemistry, Monell Chemical Senses Center and Laboratory for
Research on the Structure of Matter, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received March 16, 2006
ABSTRACT
Construction of the highly strained CDEF parent tetracycle, a structural motif found only in the potent ectoparasiticidal agents (
acids A and B and related congeners, has been achieved via a new modular indole synthesis, exploiting a sequential Stille cross-coupling/
Buchwald Hartwig union/cyclization tactic. The new indole synthesis holds the promise of rapid assembly of diverse, highly substituted
+)-nodulisporic
−
indoles possessing uncommon substitution patterns.
The nodulisporanes, a novel class of indole diterpene
alkaloids, display potent insecticidal properties, particularly
effective against flea and tick infestations in dogs and cats.1
Their mode of action, modulation of the invertebrate-specific
glutamate-gated chloride ion channels, ensures little or no
mammalian toxicity.2 Nodulisporic acid A [(+)-1] was first
reported by the Merck Research Laboratories in 1997 (Fig-
ure 1).3 Although exhibiting good in vitro and in vivo activ-
ity against fleas, the potency, stability, and pharmacoki-
netic profile were not optimal; Merck and Co. there-
fore launched a medicinal chemistry campaign to opti-
mize the profile of this lead compound. A chemical mu-
tagenesis program was also initiated to prepare a large
number (>1000) of analogues.4 To date, however, none of
the reported analogues exhibit more potency than (+)-1,
although some improvement in pharmacokinetic properties
has been achieved.
Intrigued by the architectural complexity, in conjunction
with the remarkable antiparasitic activity, we initiated a
synthetic program to devise a modular strategy that would
(3) Ondeyka, J. G.; Helms, G. L.; Hensens, O. D.; Goetz, M. A.; Zink,
D. L.; Tsipouras, A.; Shoop, W. L.; Slayton, L.; Dombrowski, A. W.;
Polishook, J. D.; Ostlind, D. A.; Tsou, N. N.; Ball, R. G.; Singh, S. B. J.
Am. Chem. Soc. 1997, 119, 8809-8816.
(4) Chakravarty, P. K.; Shih, T. L.; Colletti, S. L.; Ayer, M. B.; Snedden,
C.; Kuo, H.; Tyagarajan, S.; Gregory, L.; Zakson-Aiken, M.; Shoop, W.
L.; Schmatz, D. M.; Wyvratt, M.; Fisher, M. H.; Meinke, P. T. Bioorg.
Med. Chem. Lett. 2003, 13, 147-150.
(1) Sings, H.; Singh, S. The Alkaloids: Chemistry and Biology; Cordell,
G. A., Ed.; Elsevier Academic Press: San Diego, CA, 2003; Vol. 60, pp
51-163.
(2) Ludmerer, S. W.; Warren, V. A.; Williams, B. S.; Zheng, Y.; Hunt,
D. C.; Ayer, M. B.; Wallace, M. A.; Chaudhary, A. G.; Egan, M. A.;
Meinke, P. T.; Dean, D. C.; Garcia, M. L.; Cully, D. F.; Smith, M. M.
Biochemistry 2002, 41, 6548-6560.
10.1021/ol0606536 CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/20/2006

permit construction of not only the naturally occurring
nodulisporic acids but also, importantly, congeners not
readily available from the natural products.
Scheme 1. First-Generation Retrosynthetic Analysis
Although we were able to extend the Fischer indole
sequence to tetracyclic indole 16 (Scheme 2), possessing the
requisite 2-isopropenyl substituent10 found in nodulisporic
acids A and B, all attempts to employ hydrazones derived
from five-membered ketones such as 1,3-cyclopentanedione
or cyclopentanone (17 or 18, respectively) furnished none
of the desired tetracycles (19 or 20).
Figure 1. Representative nodulisporic acid congeners.
From the outset, we recognized the challenge of the
inherent strain of the central CDEF core of 1 and 2. To
accommodate this structural feature, we envisioned a late-
stage construction of the D-ring employing advanced hep-
tacycle 5 (Scheme 1), the latter expected to arise via union
of western hemisphere (-)-65 with eastern hemisphere
(+)-7,6 exploiting the indole synthetic protocol developed
and employed for related indole diterpene syntheses in our
laboratory.7
However, en route to both (-)-nodulisporic acid D (3)
and heptacycle 5, the considerable instability of the
C(24) hydroxyl group, in conjunction with both the propen-
sity of the C(18)-C(19) olefin to migration and the C(2′)
center to epimerization, became apparent. Successful elabo-
ration of ring D would thus demand extremely mild condi-
tions.
Figure 2. Reported approaches to the CDE tricycle.
Examination of the literature for viable tactics to elaborate
the requisite CDE core of the nodulisporic acids revealed
only two scenarios, one involving the addition of oxalyl
chloride to a highly electron-rich indole (8; Figure 2)8 and
the second being a classic Fischer indole synthesis employing
hydrazone 10.9
That the corresponding five-membered systems (19 and
20) would possess significant bond angle distortion (i.e., ring
strain) was clearly apparent upon examination of the single-
crystal X-ray structure of 16.
(8) Black, D. S. C.; Bowyer, M. C.; Catalano, M. M.; Ivory, A. J.;
Keller, P. A.; Kumar, N.; Nugent, S. J. Tetrahedron 1994, 50, 10497-
10508.
(9) van Wijngaarden, I.; Hamminga, D.; van Hes, R.; Standaar, P. J.;
Tipker, J.; Tulp, M. T. M.; Mol, F.; Olivier, B.; de Jonge, A. J. Med. Chem.
1993, 36, 3693-3699.
(10) O’Connor, J. M.; Stallman, B. J.; Clark, W. G.; Shu, A. Y. L.;
Spada, R. E.; Stevenson, T. M.; Dieck, H. A. J. Org. Chem. 1983, 48,
807-809.
(5) Smith, A. B., III.; Ishiyama, H.; Cho, Y. S.; Ohmoto, K. Org. Lett.
2001, 3, 3967-3970.
(6) Smith, A. B., III.; Cho, Y. S.; Ishiyama, H. Org. Lett. 2001, 3, 3971-
3974.
(7) (a) Smith, A. B., III.; Visnick, M.; Haseltine, J. N.; Sprengeler, P.
A. Tetrahedron 1986, 42, 2957-2969. (b) Smith, A. B., III.; Cui, H. Org.
Lett. 2003, 5, 587-590. (c) Smith, A. B., III.; Kanoh, N.; Ishiyama, H.;
Hartz, R. A. J. Am. Chem. Soc. 2000, 122, 11254-11255.
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Org. Lett., Vol. 8, No. 10, 2006

good yield, which in turn were readily reduced with
L-Selectride to cycloalkanones 30 and 31, respectively
(Scheme 3). Exposure of 31 to methanolic HCl afforded the
corresponding tetracyclic indole 39 in good yield.
Scheme 2. Application of the Fischer Indole Synthesis
Scheme 3. Stille Cross-Coupling/Buchwald-Hartwig
Union/Cyclization Tactica
Undaunted, we explored a number of alternative protocols
to introduce ring D, employing model systems 21-24 (Figure
3); the approaches included: (a) metal carbene N-H
insertion (21); (b) intramolecular nucleophilic displacement
(22); (c) Dieckmann condensation (23); and (d) intramo-
lecular Heck carbonylation (24). None of these tactics proved
successful, thus providing additional testimony to the inherent
ring strain of the CDE tricyclic core of the nodulisporic acids.
Figure 3. Prospective tactics for CDE tricycle construction.
a The X-ray crystal structure images above, 38 and 39, were
generated from the PDB files using Jmol Viewer Version 10.
We turned next to a transition-metal-catalyzed approach
(e.g., ketone arylation11 or Stille cross-coupling) envisioning
intermediates such as 15. We of course recognized that
conversion to the indole would, at best, be difficult employ-
ing thermodynamic conditions. To this end, reaction of
2-iodo-cycloalkenones12 (26 and 27) with indoline 2513
furnished the corresponding cycloalkenones 28 and 29 in
However, similar treatment of the five-membered congener
30 proved ineffective even upon extended exposure to a
variety of acids, solvents, and temperature regiments; only
decomposition occurred.
Fully convinced that 38 could not be generated employing
thermodynamic conditions, we converted enones 28 and 29
to the corresponding enol triflates 33 and 34, respectively;
removal of the Boc group set the stage for an intramolecular
Buchwald-Hartwig cyclization between an enol triflate and
a secondary amine (35 and 36).14 Initial efforts to achieve
the requisite C-N bond formation employing Pd2(dba)3/
(11) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360-1370.
(12) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B. W.
Tetrahedron Lett. 1992, 33, 917-918.
(13) Diep, V.; Dannenberg, J. J.; Franck, R. W. J. Org. Chem. 2003,
68, 7907-7910.
Org. Lett., Vol. 8, No. 10, 2006
2169

xantphos in toluene proved disappointing. Presumably strong
bases (e.g., LiHMDS, NaOt-Bu) are not compatible with the
enol triflate moiety.
Scheme 5. General Scheme for Construction of Diverse
Indoles
After considerable experimentation, conversion of 36 to
39 was achieved via treatment with 2.5 mol % of Pd2(dba)3
and 7.5 mol % of xantphos in THF at reflux, employing
Cs2CO3 as a mild base (Scheme 3). These conditions,
however, did not yield 38 when employed with 35. On the
other hand, when the kinetically derived enol triflate 37 was
prepared from 30 and reacted, tetracycle 38 was obtained in
high yield. Alternatively, increasing both the catalyst and
the ligand loading 4-fold [10 mol % of Pd2(dba)3 and 30
mol % of xantphos] furnished 38 from 35 in 55% yield. The
structures of both tetracycles 38 and 39 were secured by
single-crystal X-ray crystallography (Scheme 3). Not surpris-
ingly, considerable bond angle distortion was observed in
38 (see Supporting Information).
To demonstrate that the new modular indole synthesis
would prove suitable for construction of highly strained
indoles, as found in the CDEF core of nodulisporic acids
(+)-1 and (+)-2, (+)-estrone was converted to enol triflate
(+)-40 (see Supporting Information) and subjected to the
Buchwald-Hartwig conditions; heptacycle (+)-41 was iso-
lated in 55% yield (Scheme 4).
Scheme 4. Preparation of a Highly Substituted and Strained
Indole Derived from (+)-Estrone
In summary, a new, modular synthesis of indoles has been
developed exploiting a Stille cross-coupling/Buchwald-
Hartwig union/cyclization tactic. The reaction conditions are
mild, and as such, the new synthesis holds great promise
for the ready access of structurally diverse indoles.
Acknowledgment. Financial support was provided by the
National Institutes of Health (National Institute of General
Medical Sciences) through Grant GM-29028 and by the
Bristol-Myers Squibb Pharmaceutical Research Institute (for
stipend support of A.H.D.). We are also grateful to Eli Lilly
and Company for the graduate fellowship to L.K. and to Dr.
P. T. Meinke and the Merck Research Laboratories for
generous financial support of this research program. Finally,
we thank Dr. G. Furst, Dr. R. K. Kohli, and Dr. P. Carroll
for assistance in obtaining NMR spectra, high-resolution
mass spectra, and X-ray crystallographic data, respectively.
An overview of the modular indole protocol is presented
in Scheme 5; indoles 49 and 50 were prepared via path A,
and indole 51 was prepared via path B. Particularly note-
worthy is the regiochemical outcome for 50 and 51.
Supporting Information Available: Spectroscopic and
analytical data for all new compounds, as well as selected
experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) To the best of our knowledge, there has been no report of a Pd-
catalyzed intramolecular C-N bond forming reaction between an enol
triflate and a secondary amine.
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