Indole diterpenoid synthetic studies. Construction of the heptacyclic core of (-)-nodulisporic acid D

Article abstract of DOI:10.1021/ol0602912

Construction of the heptacyclic core of (-)-nodulisporic acid D, a representative member of a recently discovered class of architecturally complex, ectoparasiticidal indole alkaloids, has been achieved. The modular synthetic strategy comprises an expedien

Full text of DOI:10.1021/ol0602912

ORGANIC
LETTERS
2006
Vol. 8, No. 8
1669-1672
Indole Diterpenoid Synthetic Studies.
Construction of the Heptacyclic Core of
(−)-Nodulisporic Acid D
Amos B. Smith, III,* Akin H. Davulcu, and La´szlo´ Ku1rti
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 February 2, 2006
ABSTRACT
Construction of the heptacyclic core of (−)-nodulisporic acid D, a representative member of a recently discovered class of architecturally
complex, ectoparasiticidal indole alkaloids, has been achieved. The modular synthetic strategy comprises an expedient, stereocontrolled
synthesis of a tricyclic western hemisphere, in conjunction with union of an eastern hemisphere, exploiting the 2-substituted indole synthetic
protocol introduced and developed in our laboratory.
The nodulisporanes comprise an important class of indole
diterpene alkaloids, reported by the Merck Research Labo-
ratories, that are of contemporary interest due to their potent
insecticidal properties, particularly for the treatment of flea
and tick infestations in dogs and cats.1 The first member of
this class, (+)-nodulisporic acid A (1, Figure 1),2 a product
of the endophytic fungus Nodulisporium sp. (MF5954), was
found to be an effective systemic ectoparasiticidal agent,3
devoid of mammalian toxicity, resulting from the mode of
action which entails modulation of invertebrate-specific
glutamate-gated chloride ion channels. Interruption of the
chloride channel results in insect paralysis and ultimate death.
Although nodulisporic acid A (1) exhibited good in vitro
and in vivo activity against fleas, the potency and pharma-
cokinetic profile were not optimal. A medicinal chemistry
campaign was therefore undertaken. In parallel with tradi-
tional medicinal chemistry efforts, Merck scientists also
sought analogues and/or natural congeners of the parent
compound, both from the original producer as well as
variants derived by chemical mutagenesis. Nodulisporic acid
D [(-)-2], a diminutive form of nodulisporic acid A (1),
was isolated from the mutant strain Nodulisporium
ATCC74473. Structural assignment entailed comparison of
the 1H and 13C NMR data with that of (+)-nodulisporic acid
A and related analogues.4 Particularly noteworthy was the
absence of the isoprene unit that bridges the C26-N1
positions of the more complex nodulisporanes, as well as
the absence of the C24 hydroxyl group. The structural
assignment of 2 was fully corroborated by HMBC experi-
ments. From the biological perspective, nodulisporic acid D
(1) Sings, H.; Singh, S. In The Alkaloids: Chemistry and Biology;
Cordell, G. A., Ed.; Elsevier Academic Press: New York, 2003; Vol. 60,
p 51.
(2) 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.
(3) Ludmerer, S. W.; Warren, V. A.; Williams, B. S.; Zheng, Y. C.;
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.
(4) Singh, S. B.; Ondeyka, J. G.; Jayasuriya, H.; Zink, D. L.; Ha, S. N.;
Dahl-Roshak, A. M.; Greene, J.; Kim, J. A.; Smith, M. M.; Shoop, W.;
Tkacz, J. S. J. Nat. Prod. 2004, 67, 1496.
10.1021/ol0602912 CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/24/2006

in conjunction with recent progress that has led to the
synthesis of the heptacyclic core (vide infra).
From the retrosynthetic perspective, late-stage Horner-
Wadsworth-Emmons reaction between heptacyclic aldehyde
4 and known phosphonate 58 would install the requisite
dienoate side chain (Scheme 1). Advanced aldehyde 4 in
Scheme 1. Retrosynthetic Analysis for Nodulisporic Acid D
Figure 1. Nodulisporic acids A (1), D (2), and F (3); nodulisporic
acid numbering.
(2) proved to be 62-fold less active than nodulisporic acid
A (1) in an ex vivo flea assay (LD90 ) 92.6 and 1.5 µM,
respectively) and >4000-fold lower in potency in an in vitro
competitive binding assay (IC50 > 1.0 µM). Biosynthetically,
2 is significant as the gateway intermediate for the genesis
of advanced nodulisporic acids (D f A).4
Intrigued by the architectural complexities and the biologi-
cal activities of the nodulisporanes, in conjunction with our
long-standing interest in the indole diterpenoid class of
natural products,5 we recently embarked on a program aimed
at the total synthesis of key members of this class. Our
ultimate goal is to devise a convergent, modular synthetic
strategy that will permit access not only to the nodulisporic
acids but also to an array of unnatural analogues not easily
accessible by chemical modification of the naturally produced
congeners.
The cornerstone of our initial synthetic strategy was
anticipated to entail the 2-substituted indole synthesis that
we introduced in 1986 and subsequently developed.6 The
successful application of this tactic for the total synthesis of
(+)-nodulisporic acid F (3), the simplest and first member
of the nodulisporic acid family of alkaloids to succumb to
synthesis, was disclosed in the preceding Letter.7 Herein, we
present a synthetic strategy for (-)-nodulisporic acid D (2),
turn was expected to arise from 6 via hydrogenolytic removal
of the benzyl group, followed by oxidation of the resulting
primary alcohol. The corresponding heptacyclic indole 6
would then arise via regioselective intramolecular carbon
alkylation of 7, as exploited to great advantage first in our
total synthesis of (-)-21-isopentenylpaxilline,9 and later for
(+)-nodulisporic acid F.7 Union of the western and eastern
hemispheres, the cornerstone of the synthetic strategy, would
(5) For representative studies, see: (a) Smith, A. B., III; Mewshaw, R.
E. J. Am. Chem. Soc. 1985, 107, 1796. (b) Mewshaw, R. E.; Taylor, M.
D.; Smith, A. B., III. J. Org. Chem. 1989, 54, 3449. (c) Smith, A. B., III;
Sunazuka, T.; Leenay, T. L.; Kingery-Wood, J. J. Am. Chem. Soc. 1990,
112, 8197. (d) Smith, A. B., III; Kingery-Wood, J.; Leenay, T. L.; Nolen,
E. G., Jr.; Sunazuka, T. J. Am. Chem. Soc. 1992, 114, 1438. (e) Smith, A.
B., III; Kanoh, N.; Minakawa, N.; Rainier, J. D.; Blase, F. R.; Hartz, R. A.
Org. Lett. 1999, 1, 1263. (f) Smith, A. B., III; Kanoh, N.; Ishiyama, H.;
Hartz, R. A. J. Am. Chem. Soc. 2000, 114, 1438.
(6) Smith, A. B., III; Visnick, M.; Haseltine, J. N.; Sprengler, P. A.
Tetrahedron 1986, 42, 2957.
(7) Smith, A. B., III; Davulcu, A. H.; Ku¨rti, L. Org. Lett. 2006, 8, 1665.
(8) Evans, D. A.; Miller, S. J.; Ennis, M. D. J. Org. Chem. 1993, 58,
471.
(9) Smith, A. B., III; Cui, H. Org. Lett. 2003, 5, 587.
1670
Org. Lett., Vol. 8, No. 8, 2006

then entail reaction of 9, available from known lactone (+)-
10, with the N-silylated dianion derived from aniline 8. To
construct aniline 8, we envisioned a reaction sequence
involving an Enders SAMP hydrazone protocol10 to secure
the stereogenicity at C23, followed by a tandem Stille cross-
coupling/cyclization11 sequence to generate the tricycle (i.e.,
the C17-C18 σ-bond).12
We turned next to the critical tandem Stille ring closure.
After extensive experimentation, the conditions first put forth
by Kelly14 for intramolecular biaryl cross-couplings [e.g.,
Pd(PPh3)4, Me3SnSnMe3, LiCl, 1,4-dioxane] achieved the
envisioned tandem sequence (i.e., conversion to the aryl
stannane followed by ring closure); tricycle (-)-16 was
obtained in 96% yield. Removal of the phthalimide protecting
group (H2NNH2, EtOH; 93% yield) completed the construc-
tion of aniline (-)-8 in five steps and 40% overall yield from
bromide 12.
We initiated the synthetic venture with construction of
western hemisphere 8 (Scheme 2), beginning with the
To secure the absolute configuration of (-)-8, the corre-
sponding 3-bromophthalimide derivative (-)-17 was pre-
pared (see Supporting Information). X-ray crystallographic
analysis, exploiting the anomalous dispersion tactic, con-
firmed both the connectivity and the absolute stereochemistry
(Figure 2), thereby demonstrating that the C23 configuration,
Scheme 2. Preparation of the Western Hemisphere Subtarget
Figure 2. ORTEP representation of phthalimide (-)-17.
was in accord with that predicted by the Enders SAMP
hydrazone model.10
Union of (-)-8 with lactone (-)-9 next entailed treatment
of the N-silylated dianion derived from the in situ generated
N-trimethylsilyl-(-)-8 with (-)-9 [available in two steps
from known lactone (+)-10 (Scheme 3)]; ketoaniline (+)-
18 was produced in 94% yield.
metalation of known SAMP hydrazone (+)-1112 (t-BuLi,
THF, -78 °C), followed by alkylation with benzylic bromide
12 at -105 °C, to deliver adduct (+)-13 as a single
diastereomer in 72% yield, after thermal equilibration of the
initially formed mixture of (E)- and (Z)-hydrazone adducts
From the perspective of the scope of our 2-substituted
indole synthetic protocol, construction of (+)-18 represents
an interesting example, given the three potential sites for
deprotonation (e.g., the allylic hydrogen at C23 and the
benzylic hydrogens at C14 and C24) present in (-)-8. Aniline
(-)-8 also contains an embedded styryl motif, which holds
the potential for anionic polymerization under the reaction
conditions.15 Not surprisingly, our first attempts to generate
the N-silylated dianion derived from (-)-8 proved difficult.
However, careful purification of (-)-8, preferably via
recrystallization of phthalimide (-)-16, in conjunction with
rigorous exclusion of O2 during dianion generation, led
successfully to ketoaniline (+)-18 upon exposure to (-)-9.
The failure of ketoaniline (+)-18 to undergo the anticipated
indolization (as observed in simpler systems)5 was again
attributed to steric effects exerted by the adjacent C3
1
[ca. predominantly (Z)-hydrazone by H NMR]. Exposure
of (+)-13 to ozone, followed by reductive workup, effected
oxidative removal of the SAMP auxiliary to furnish ketone
(-)-14 in 74% yield and with g98% enantiomeric excess
(ee).13 Subsequent kinetic enolization (LiHMDS, THF, -78
°C) and, in turn, reaction with the Comins’ reagent [N-(5-
chloro-2-pyridyl)triflimide] effected conversion to enol tri-
flate (+)-15 in 82% yield.
(10) (a) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D.
Tetrahedron 2002, 58, 2253. (b) Enders, D.; Eichenauer, H. Angew. Chem.,
Int. Ed. Engl. 1976, 15, 549.
(11) Farina, V.; Krishnamurthy, V.; Scott, W. J. In The Stille Reaction;
John Wiley and Sons: New York, 1998; p 20.
(12) For a similar sequence see: Smith, A. B., III; Ishiyama, H.; Cho,
Y. S.; Ohmoto, K. Org. Lett. 2001, 3, 3967.
(13) The enantiomeric excess was determined by reverse-phase HPLC
employing a chiral column. See Supporting Information.
(14) Kelly, T. R.; Li, Q.; Bhushan, A. Tetrahedron Lett. 1990, 31, 161.
(15) The alkyllithium-initiated anionic polymerization of styrenes is well-
known; see: Wakefield, B. J. The Chemistry of Organolithium Compounds;
Pergamon: Oxford, 1974. Indeed, 5-vinyl-2-methylaniline undergoes facile
anionic polymerization upon exposure to s-BuLi.
Org. Lett., Vol. 8, No. 8, 2006
1671

isomerization. To secure the structure of (-)-7, C(7,13) diol
(-)-19, a highly crystalline compound, was prepared and
subjected to single-crystal X-ray analysis (Figure 3).
Scheme 3. Fragment Coupling; Access to the Heptacycle
(-)-6
Figure 3. ORTEP representation of diol (-)-19.
To complete construction of the heptacyclic core of
nodulisporic acid D (2), methanesulfonate (-)-20 was
prepared [MsCl, DMAP]. Execution of the annulation
conditions developed and optimized in conjunction with our
total synthesis of (+)-nodulisporic acid F [e.g., t-BuMgCl,
PhMe, Zn(OTf)2 (10 equiv), 110 °C] proceeded with high
regioselectivity, albeit at first furnishing the heptacyclic core
(-)-6 in only modest yield (<30%). Pleasingly, decreasing
the amount of Zn(OTf)2 to 1.0 equiv delivered (-)-6 in 72%
yield, with g20:1 regioselectivity favoring the desired C3
isomer. That the heptacyclic core of nodulisporic acid D
1
[(-)-6] was in hand was secured by detailed H NMR and
13C NMR analysis, with particular emphasis directed toward
the correspondence of the chemical shifts and J values
observed for the C13 methylene of (-)-6, compared to the
values reported for nodulisporic acid D.
In summary, we have implemented a convergent synthetic
approach, culminating in an expedient preparation of (-)-6,
the heptacyclic core of (-)-nodulisporic acid D (2). Current
efforts are focused on completion of the total synthesis of
(-)-nodulisporic acid D and related congeners.
quaternary center (nodulisporic acid numbering), which
presumably attenuates the rate of heteroatom-Peterson
olefination relative to thermodynamically driven intra-
molecular N f O silyl migration. This result was not a major
issue, as early work in our laboratory demonstrated that such
ketoanilines readily undergo acid-promoted cyclodehydration
to the corresponding indole.7 In the case at hand, however,
all attempts to achieve the acid-promoted cyclodehydration
of ketoaniline (+)-18 (e.g., PhH, PPTS, reflux; CHCl3, SiO2,
23 °C) led not only to indolization but also to concomitant
migration of the trisubstituted ∆18,19 olefin to furnish the
isomeric tetrasubstituted ∆18,23 olefin. This propensity for
acid-induced bond migration was not completely surprising.
In the original isolation paper, exposure to TFA led to a
similar outcome. The exceptional sensitivity, however, to
extremely mild acids was unexpected. Similar attempts to
effect the requisite indolization without olefin isomerization
employing Lewis acids [e.g., Sc(OTf)3, TMSOTf, MgBr2‚
Et2O] or dehydrating agents [e.g., TiCl4, MgSO4, Burgess
reagent] also met with failure. Success was eventually
achieved upon treatment with 1,1,1-trifluoroethanol at reflux
(6 h); the yield of (-)-7 was 98%! Selection of this reaction
protocol was based upon the conjecture that the weakly acidic
(pKa ≈ 13), highly polar (ꢀ ) 26.5) nature of 1,1,1-
trifluoroethanol might drive the dehydration without olefin
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
(stipend support of A.H.D.). We also 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. Finally, we are indebted
to Dr. P. T. Meinke and the Merck Research Laboratories
for providing generous financial support of this research
program, and for a sample of natural (-)-nodulisporic acid
D.
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.
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