Nodulisporic acid A synthetic studies. 1. Overall strategy and construction of a western hemisphere subtarget.

Article abstract of DOI:10.1021/ol0168871

In this, the first of two Letters, we outline our overall strategy for the construction of (+)-nodulisporic acid A (1), a representative member of a new class of indole diterpenes. In addition, we describe the efficient assembly of (-)-6, an advanced western hemisphere subtarget, comprising the ABC rings of (+)-nodulisporic acid A (1). The synthesis proceeded in 9% overall yield (longest linear sequence, 11 steps), exploiting a Shibasaki-Mori tandem transmetalation-cyclization to construct ring B. [reaction: see text]

Full text of DOI:10.1021/ol0168871

ORGANIC
LETTERS
2001
Vol. 3, No. 24
3967-3970
Nodulisporic Acid A Synthetic Studies. 1.
Overall Strategy and Construction of a
Western Hemisphere Subtarget
Amos B. Smith, III,* Haruaki Ishiyama, Young Shin Cho, and Kazuyuki Ohmoto
Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received October 10, 2001
ABSTRACT
In this, the first of two Letters, we outline our overall strategy for the construction of (+)-nodulisporic acid A (1), a representative member of
a new class of indole diterpenes. In addition, we describe the efficient assembly of (−)-6, an advanced western hemisphere subtarget, comprising
the ABC rings of (+)-nodulisporic acid A (1). The synthesis proceeded in 9% overall yield (longest linear sequence, 11 steps), exploiting a
Shibasaki−Mori tandem transmetalation−cyclization to construct ring B.
(+)-Nodulisporic acid A (1, Figure 1), a novel insecticide
recently isolated by Ondeyka and co-workers from the
fermentation extract of the fungus Nodulisporium sp.1
possesses unique architecture as deduced initially from
spectroscopic evidence, including the Dunkel computerized
2D INADEQUATE protocol.2 The relative stereochemistry
was subsequently confirmed by single-crystal X-ray diffrac-
tion analysis of the p-bromobenzoate methyl ester derivative
(2, Figure 1); the absolute stereochemistry was established
by the advanced Mosher ester method.3
Nodulisporic acid A (1) proved to be a potent insecticide,
discovered while screening the natural product extract against
the larvae of the blowfly (Lucilia seracata; LC50 of 0.3
(1) 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.
Figure 1.
Am. Chem. Soc. 1997, 119, 8809.
(2) (a) Dunkel, R.; Mayne, C. L.; Curtis, J.; Pugmire, R. J.; Grant, D.
M. J. Magn. Reson. 1990, 90, 290. (b) Dunkel, R.; Mayne, C. L.; Pugmire,
R. J.; Grant, D. M. Anal. Chem. 1992, 64, 3133. (c) Dunkel, R.; Mayne, C.
L.; Foster, M. P.; Ireland, C. M.; Li, D.; Owen, N. L.; Pugmire, R. J.; Grant,
D. M. Anal. Chem. 1992, 64, 3150.
(3) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092.
ppm).1 Further study revealed that (+)-1 has an LC50 of 0.5
ppm against Aedas aegypti (the larvae of the mosquito) and
is more active than paraherquamide (LC50 of 50 ppm in both
10.1021/ol0168871 CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/03/2001

assays) but less active than ivermectin, which displays an
LC50 of 0.02 and 0.045 ppb, respectively.1 Importantly,
nodulisporic acid A was shown by the Merck group to
possess potent oral activity in dogs for the control of fleas.4
Subsequent research on the mechanism of action suggests
that the insecticidal activity of (+)-1 arises via modulation
of the glutamate-gated chloride channels,5 vital to insect
neurotransmission. Interruption of the glutamate-gated chlo-
ride channels results in insect paralysis and death. Since
glutamate-gated chloride channels are not found in mammals,
nodulisporic acid A (1) holds considerable promise as a
systemic insecticidal agent. Interestingly, despite the resem-
blance between nodulisporic acid A (1) and other complex
indole tremorgens, such as janthitrem G6a and the shearinines,6b
lolitrems,6c,d paspalitrems,6e and penitrems,6f (+)-1 does not
possess tremorgenic activity, presumably due to the lack of
the C(9) axial hydroxyl group, as is known for the simple
indole diterpenes paspline and paspalicine.7 Currently, (+)-
nodulisporic acid A (1) is under development by the Animal
Health Division at Merck & Co.
further elaboration, that embodies the ABC western hemi-
sphere rings of (+)-nodulisporic acid A (1). In the following
Letter,9 we describe an effective synthesis of the eastern
hemisphere lactone 7.
From the retrosynthetic perspective, initial scission be-
tween C(2′′) and C(3′′) and removal of the five-membered-
ring isoprenyl moiety reveals indole 5 (Scheme 1), which,
Scheme 1
More recently (1999), Hensens and co-workers at Merck
disclosed the isolation and structure determination of two
fermentation congeners, nodulisporic acid A1 (3, Figure 1)
and A2 (4, Figure 1), which exhibit similar biological
profiles;8 nodulisporic acid A1 (3) has an LD50 of 0.4-1.5
ppm against Lucilia seracata, similar to that of (+)-1, while
nodulisporic acid A2 (4) was slightly less active with an LD50
of 0.8-2.2 ppm.
Although nodulisporic acid A (1) resembles other indole
diterpenes,6 the unprecedented N1-C26 bridge with a readily
epimerizable isoprenyl side chain, the A ring dihydropyran,
and the cyclopentyl ring possessing a labile secondary
benzylic hydroxyl conspire to make (+)-nodulisporic acid
A (1) a most formidable synthetic target. Intrigued by the
architectural complexity and the outstanding antiparasitic
activity, we recently mounted an investigation with a view
toward both total synthesis and analogue preparation. In this
the first of two Letters,9 we disclose our overall synthetic
strategy in conjunction with an efficient assembly of tricyclic
aniline (-)-6, complete with appropriate functionality for
in turn, is envisioned to arise via union of the western
hemisphere 6 with the eastern hemisphere 7, exploiting an
indole ring synthetic protocol10 that proved highly effective
in our recent total synthesis of (-)-penitrem D.10d For 6, the
cyclopentane ring was expected to arise via a palladium-
catalyzed tandem transmetalation-cyclization of 8.11 Asym-
metric addition of SAMP hydrazone 912 to aldehyde 10 in
turn would provide, after removal of the chiral auxiliary and
hydroxyl protection (TESCl), the requisite precursor for enol
triflate 8.
(4) Shoop, W. L.; Gregory, L. M.; Zakson-Aiken, M.; Michael, B. F.;
Haines, H. W.; Ondeyka, J. G.; Meinke, P. T.; Schmatz, D. M. J. Parasitol.
2001, 87, 419.
(5) (a) Smith, M. M.; Warren, V. A.; Thomas, B. S.; Brochu, R. M.;
Ertel, E. A.; Rohrer, S.; Schaeffer, J.; Schmatz, D.; Petuch, B. R.; Tang, Y.
S.; Meinke, P. T.; Kaczorowski, G. J.; Cohen, C. J. Biochemistry 2000, 39,
5543 (b) Kane, N. S.; Hirschberg, B.; Qian, S.; Hunt, D.; Thomas, B.;
Brochu, R.; Ludmerer, S. W.; Zheng, Y.; Smith, M.; Arena, J. P.; Cohen,
C. J.; Schmatz, D.; Warmke, J.; Cully, D. F. Proc. Natl. Acad. Sci. U.S.A.
2000, 97, 13949.
(6) (a) de Jesus, A. E.; Steyn, P. S.; van Heerden, F. R.; Vleggaar, R. J.
Chem. Soc., Perkin Trans. 1 1984, 697. (b) Belofsky, G. N.; Gloer, J. B.;
Wicklow, D. T.; Dowd, P. F. Tetrahedron 1995, 51, 3959. (c) Gallagher,
R. T.; Hawkes, A. D.; Steyn, P. S.; Vleggaar, R. J. Chem. Soc., Chem.
Commun. 1984, 614. (d) Ede, R. M.; Miles, C. O.; Meagher, L. P.; Munday,
S. C.; Wilkins, A. L. J. Agric. Food Chem. 1994, 42, 231 and references
therein. (e) Dorner, J. W.; Cole, R. J.; Cox, R. H.; Cunfer, B. M. J. Agric.
Food Chem. 1984, 32, 1069 and references therein. (f) de Jesus, A. E.;
Steyn, P. S.; van Heerden, F. R.; Vleggaar, R.; Wessels, P. L. J. Chem.
Soc., Perkin Trans. 1 1983, 1857 and references therein.
Assembly of western hemisphere (-)-6 began with com-
mercially available 3-amino-4-methylbenzyl alcohol 11
(10) (a) Smith, A. B., III; Visnick, M. Tetrahedron Lett. 1985, 26, 3757.
(b) Smith, A. B., III; Visnick, M.; Haseltine, J. N.; Sprengeler, P. A.
Tetrahedron 1986, 42, 2957. (c) Smith, A. B., III; Kanoh, N.; Minakawa,
N.; Rainier, J. D.; Blase, F. R.; Hartz, R. A. Org. Lett. 1999, 1, 1263. (d)
Smith, A. B., III; Kanoh, N.; Ishiyama, H.; Hartz, R. A. J. Am. Chem. Soc.
2000, 122, 11254.
(7) Dorner, J. W.; Cole, R. J.; Cox, R. H.; Cunfer, B. M. J. Agric. Food
Chem. 1984, 32, 1069.
(8) Hensens, O. D.; Ondeyka, J. G.; Dombrowski, A. W.; Ostlind, D.
A.; Zink, D. L. Tetraheron Lett. 1999, 40, 5455.
(9) Smith, A. B., III; Cho, Y. S.; Ishiyama, H. Org. Lett. 2001, 3, 3971.
(11) Mori, M.; Kaneta, N.; Shibasaki, M. J. Org. Chem. 1991, 56, 3486.
(12) (a) Enders, D.; Zamponi, A.; Raabe, G.; Runsink, J. Synthesis 1993,
725. (b) Enders, D.; Whitehouse, D. L. Synthesis 1996, 621.
3968
Org. Lett., Vol. 3, No. 24, 2001

Scheme 2
Scheme 4
(Scheme 2). Hydroxyl protection followed by regioselective
iodination with benzyltrimethylammonium dichloroiodate
(BTMA‚ICl2)13 afforded amine 12. Protection of the amino
group as the phthalimide, hydrolytic removal of the TBS
group, and oxidation of the resulting hydroxyl led to aldehyde
10 in 64% overall yield for the three steps.
Continuing with the synthesis, treatment of the Enders
SAMP hydrazone (+)-9,12 derived from known ketone 13,14
with t-BuLi at -78 °C in THF, followed by addition of
aldehyde 10 at -100 °C, afforded a diastereomeric mixture
of â-hydroxyhydrazones (11:2) in a combined yield of 84%;
separation via flash chromatography provided (-)-15 in 71%
yield (Scheme 3). Ozonolysis then afforded â-hydroxyketone
(-)-16.
Protection of the secondary hydroxyl in (-)-16 (TESOTf,
2,6-lutidine), followed by formation of the enol triflate with
the Comins reagent [N-(5-chloro-2-pyridyl)triflimide],18 pro-
vided vinyl triflate (+)-8 in 69% for the two steps (Scheme
5). The Shibasaki-Mori protocol11 for tandem transmetala-
Scheme 5
Scheme 3
The relative configurations of the newly generated ste-
reocenters were assigned by conversion of (-)-16 to the
corresponding acetonide (-)-17 (catecholborane;15 2,2-
methoxypropane, PPTS); NOESY spectral data revealed the
23R*/24S* relative configurations (Scheme 4).16 The absolute
configuration of (-)-16 was then assigned by advanced
Mosher ester analysis.3,17 The pertinent data from the
Kakisawa test of (-)-16 are illustrated in Scheme 4.
tion-cyclization (i.e., conversion of the vinyl triflate to the
vinylstannane and subsequent cyclization with aryl iodide)
(17) The minor product i was identified as below by Mosher ester analysis
and NOESY experiment of its acetonide derivative.
(13) Kajigaeshi, S.; Kakinami, T.; Yamasaki, H.; Fujisaki, S.; Okamoto,
T. Bull. Chem. Soc. Jpn. 1988, 61, 600.
(14) Magnus, P.; Mansley, T. E. Tetrahedron Lett. 1999, 40, 6909.
(15) Evans, D. A.; Chapman, K. T. Tetrahedron Lett. 1986, 27, 5939.
(16) Analysis of NOESY spectral data is shown in the Supporting
Information.
Org. Lett., Vol. 3, No. 24, 2001
3969

then furnished (-)-18. Unmasking the aniline moiety with
hydrazine completed the synthesis of western hemisphere
(-)-6.19
Studies to unite the western and eastern subtargets and
complete the total synthesis of (+)-nodulisporic acid A (1)
are currently ongoing in our laboratory.
In summary, we have designed and executed an efficient
synthesis of (-)-6, a western subtarget for (+)-nodulisporic
acid A (1), by exploiting an asymmetric aldol reaction
utilizing a SAMP hydrazone followed by a Shibasaki-Mori
tandem transmetalation-cyclization. The synthesis proceeded
in 11 steps and 9% overall yield. Importantly, the synthesis
of (-)-6 is highly competitive, compared to the recent
synthesis by Magnus et al. of a racemic ABC model.14
Acknowledgment. Financial support was provided by the
National Institutes of Health (National Institute of General
Medical Sciences) through Grant GM-29028 and by the
Merck Research Laboratories. We also thank Dr. G. Furst
and Dr. R. K. Kohli, Directors of the University of
Pennsylvania Spectroscopic Facilities, for assistance in
obtaining NMR spectra and high-resolution mass spectra,
respectively.
(18) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(19) We also observed as much as 27% of a reduced product, ii.
Supporting Information Available: Spectroscopic and
analytical data for compounds 6, 8, 9, 10, 12, 15, 16, 17,
and 18 and selected experimental procedures. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0168871
3970
Org. Lett., Vol. 3, No. 24, 2001