Nodulisporic acid A synthetic studies. 2. Construction of an eastern hemisphere subtarget.

Article abstract of DOI:10.1021/ol016888t

In this, the second of two Letters, we describe an effective assembly of (+)-4, an eastern hemisphere subtarget comprising the FGH rings of (+)-nodulisporic acid A (1) (17 steps, 9% overall yield). Central to the synthesis is a Koga three-component conjug

Full text of DOI:10.1021/ol016888t

ORGANIC
LETTERS
2001
Vol. 3, No. 24
3971-3974
Nodulisporic Acid A Synthetic Studies. 2.
Construction of an Eastern Hemisphere
Subtarget
Amos B. Smith, III,* Young Shin Cho, and Haruaki Ishiyama
Department of Chemistry, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received October 10, 2001
ABSTRACT
In this, the second of two Letters, we describe an effective assembly of (+)-4, an eastern hemisphere subtarget comprising the FGH rings of
(+)-nodulisporic acid A (1) (17 steps, 9% overall yield). Central to the synthesis is a Koga three-component conjugate addition−alkylation
sequence which secures the trans orientation of the vicinal quaternary methyl groups.
In 1997 the Merck group reported the isolation and structure
elucidation of (+)-nodulisporic acid A (1), a novel indole
terpene, which displays potent oral systemic activity against
fleas in dogs.1 Further study on the mechanism of action
demonstrated that nodulisporic acid A (1) acts as an
insecticide by selectively modulating the invertebrate-specific
glutamate-gated chloride ion channel.2 Efforts to identify the
key constituents of the nodulisporic acid A pharmacophore
revealed that even minor changes to the polycyclic core lead
to deleterious effects on the biological activity.3 However,
modifications of the C(8) side chain afforded several
nodulisporic acid A derivatives which exhibit enhanced
activity.4
(+)-Nodulisporic acid A (1) possesses an intriguing array
of architectural features including a highly substituted indole
core, nine stereogenic carbons, and an eight-ring fused array,
including the unique, highly strained five-membered â-
ketodihydropyrrole. Ring D, derived from isoprenylation of
the indole moiety, is unprecedented among the indole
mycotoxins.1 Also of interest vis a` vis the biogenetic origin
of (+)-nodulisporic acid is the reversal of the ring fusion of
the dihydropyran and cyclopentyl ring in the western
hemisphere compared to the janthitrems5 and shearinines.6
In the preceding Letter,7 we outlined our convergent
strategy for the construction of (+)-1, in conjunction with
an efficient synthesis of the western subtarget (-)-3, exploit-
(1) (a) 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. (b) 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.
(2) (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.
(4) Berger, R.; Shoop, W. L.; Pivnichny, J. V.; Warmke, L. M.; Zakson-
Aiken, M.; Owens, K. A.; deMontigny, P.; Schmatz, D. M.; Wyvratt, M.
J.; Fisher, M. H.; Meinke, P. T.; Colletti, S. L. Org. Lett. 2001, 3, 3715.
(5) de Jesus, A. E.; Steyn, P. S.; van Heerden, F. R.; Vleggaar, R. J.
Chem. Soc., Perkin Trans. 1 1984, 697.
(3) Meinke, P. T.; Ayer, M. B.; Colletti, S. L.; Li, C.; Lim, J.; Ok, D.;
Salva, S.; Schmatz, D. M.; Shih, T. L.; Shoop, W. L.; Warmke, L. M.;
Wyvratt, M. J.; Zakson-Aiken, M.; Fisher, M. H. Bioorg. Med. Chem. Lett.
2000, 10, 2371.
(6) Belofsky, G. N.; Gloer, J. B.; Wicklow, D. T.; Dowd, P. F.
Tetrahedron 1995, 51, 3959.
(7) Smith, A. B., III; Ishiyama, H.; Cho, Y. S.; Ohmoto, K. Org. Lett.
2001, 3, 3967.
10.1021/ol016888t CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/03/2001

ing a Shibasaki-Mori transmetalation-cyclization.8 Herein,
we present an effective synthesis of eastern hemisphere 4,
highlighted by the tandem installation of a vinyl moiety and
the C(3) quaternary methyl group exploiting a Koga three-
component conjugate addition-alkylation protocol (Scheme
1).9 Further disconnection of 5 leads to diol 6, previously
Scheme 2
Scheme 1
with high efficiency. The configurations of the newly
generated stereocenters were determined by single-crystal
X-ray analysis of diol (-)-9a. Although diols (-)-9a and
(+)-9b were appropriately functionalized for the eastern
hemisphere construction, the overall length of this route [23
steps from (-)-Wieland-Miesher ketone] was not amenable
to large-scale production. We therefore sought a more
efficient strategy.
In redesigning the synthesis with (+)-4 as the target, we
recognized an opportunity for the tandem generation of the
stereogenic centers at C(3) and C(12) (Scheme 3). Toward
prepared during the Smith-O˜ mura synthesis of (+)-pyri-
Scheme 3
pyropene A.10
Initially, we investigated a route to the eastern subtarget
(+)-4, beginning with lactone (+)-7 (Scheme 2). Tricyclic
lactone (+)-7, designed as a common building block for
construction of a variety of indole tremorgens,11 was derived
from (-)-Wieland-Miesher ketone (16 steps; 8% overall
yield).11b A three-step sequence then furnished individual
acetals (+)-8a and -8b.11c Reductive alkylation via a method
developed in our laboratory12 in the 1980s followed by
stereoselective reduction of the ketone10 led to the dia-
stereoselective generation of the C(7) and C(8) stereocenters
(8) Mori, M.; Kaneta, N.; Shibasaki, M. J. Org. Chem. 1991, 56, 3486.
(9) Kogen, H.; Tomioka, K.; Hashimoto, S.; Koga, K. Tetrahedron 1981,
37, 3951.
(10) Nagamitsu, T.; Sunazuka, T.; Obata, R.; Tomoda, H.; Tanaka, H.;
Harigaya, Y.; O˜ mura, S.; Smith, A. B., III. J. Org. Chem. 1995, 60, 8126.
(11) (a) Smith, A. B., III; Nolen, E. G., Jr.; Shirai, R.; Blase, F. R.;
Ohta, M.; Chida, N.; Hartz, R. A.; Fitch, D. M.; Clark, W. M.; Sprengeler,
P. A. J. Org. Chem. 1995, 60, 7837. (b) Smith, A. B., III; Hartz, R. A.;
Spoors, P. G.; Rainier, J. D. Isr. J. Chem. 1997, 37, 69. (c) Smith, A. B.,
III; Kanoh, N.; Ishiyama, H.; Hartz, R. A. J. Am. Chem. Soc. 2000, 122,
11254.
this end, Koga reported that addition of vinyl Grignard
reagent to an R,â-unsaturated imine (e.g., 10), possessing a
stereogenic center R to the nitrogen, afforded an intermediate
(12) Smith, A. B., III; Mewshaw, R. J. Org. Chem. 1984, 49, 3685.
3972
Org. Lett., Vol. 3, No. 24, 2001

which yielded the 1,2-disubstituted cyclohexanecarboxalde-
hyde 11 after methylation and acidic hydrolysis.9 We
anticipated that aldehyde 12 could be prepared from imine
5 via a similar protocol.
steps). The relative stereochemistry at C(7) and C(8) was
secured by single-crystal X-ray analysis.
Imine (+)-5 (Scheme 5), substrate for the Koga three-
component conjugate addition-alkylation, was then prepared
The second-generation synthesis of (+)-4 began with (+)-
Wieland-Miesher ketone (13), available in >99% ee via
the method of Fu¨rst (Scheme 4).13 Chemoselective trans-
Scheme 5
Scheme 4
by condensation of aldehyde (+)-17 with L-tert-leucine tert-
butyl ester18 in 94% yield. Addition of vinylmagnesium
bromide to (+)-5, followed by quenching the resulting anion
with methyl iodide in the presence of HMPA, afforded, after
hydrolysis, aldehyde (+)-18 in 59% yield.9 Subsequent
oxidation of the aldehyde to the carboxylic acid and
esterification with trimethylsilyldiazomethane19 then led to
methyl ester (+)-19. Contrary to the expectation based on
the Koga precedent,9 the undesired stereochemistry at C(12)
was obtained, as determined by single-crystal X-ray analysis.
Importantly, the C(3) quaternary center, vicinal to the C(4)
quaternary center, possessed the requisite stereochemistry for
(+)-nodulisporic acid A (1).
ketalization followed by Kirk-Petrow (phenylthio)methyl-
ation14 led to enone (+)-14. Reductive alkylation utilizing
aqueous formaldehyde and Sc(OTf)3 catalyst15 afforded
â-hydroxyketone (-)-15. Noteworthy, this reaction in aque-
ous media proceeded in higher yield [(1) Li/NH3, THF;
TMSCl, Et3N; (2) Sc(OTf)3, aqueous HCHO, THF, 75%
yield for two steps] compared to our earlier one-pot
anhydrous protocol [Li/NH3, THF; TMSCl, Et3N; HCHO(g),
42% yield].12 Stereoselective reduction of (-)-15 with
tetramethylammonium triacetoxyborohydride furnished trans
diol (-)-6, an intermediate in our (+)-pyripyropene A total
synthesis.10 Ketal hydrolysis [2 N HCl, THF] and disilylation
[TBSOTf, 2,6-lutidine, CH2Cl2] then furnished (-)-16 in
85% for the two steps. Sulfonylation with the Comins reagent
[N-(5-chloro-2-pyridyl)triflimide]16 next led to the requisite
enol triflate, which in turn underwent palladium-catalyzed
carbonylation17 to produce aldehyde (+)-17 (86% yield, two
The stereochemical issue at C(12) was easily corrected
via ozonolysis and epimerization to afford aldehyde (+)-
20, precursor to the targeted γ-lactone (Scheme 6).20 Reduc-
(18) Anderson, G. W.; Callahan, F. M. J. Am. Chem. Soc. 1960, 82,
3359.
(19) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1981,
29, 1475.
(20) The structure of (+)-20 was assigned by a 2D NOESY NMR
experiment. Full analysis of the data is shown in the Supporting Information.
(13) Gutzwiller, J.; Buchschacher, P.; Fu¨rst, A. Synthesis, 1977, 167.
(14) Kirk, D. N.; Petrow, V. J. Chem. Soc. 1962, 1091.
(15) Kobayashi, S. Chem. Lett. 1991, 2187.
(16) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(17) (a) Scott, W. J.; Crisp, G. T.; Stille, J. K. J. Am. Chem. Soc. 1984,
106, 4630. (b) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1985,
26, 1109.
Org. Lett., Vol. 3, No. 24, 2001
3973

In summary, we have developed an effective synthesis of
(+)-4, the eastern hemisphere FGH subtarget of (+)-
nodulisporic acid A (1), via the Koga three-component
conjugate addition-alkylation protocol. The synthesis pro-
ceeded in 17 steps and 9% overall yield. Studies directed
toward the union of the eastern and western hemispheres
[(+)-4 and (-)-3] and final elaboration to (+)-nodulisporic
acid A (1) will be reported in due course.
Scheme 6
Acknowledgment. Financial support was provided by the
National Institutes of Health (National Institute of General
Medical Sciences) through Grant GM-29028 and by Merck
Research Laboratories. We also thank Dr. G. Furst, Dr. R.
K. Kohli, and Dr. P. J. Carroll, Directors of the University
of Pennsylvania Spectroscopic Facilities, for assistance in
obtaining NMR spectra, high-resolution mass spectra, and
X-ray analysis, respectively.
Supporting Information Available: Spectroscopic and
analytical data for compounds 4, 5, 6, 9a, 9b, 15, 16, 17,
18, 19, and 20 and selected experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
tion of the aldehyde and treatment of the resulting alcohol
with TsOH [benzene, at reflux]21 then furnished the eastern
hemisphere γ-lactone (+)-4 in 65% for the two steps.
(21) Smith, A. B., III; Visnick, M.; Haseltine, J. N.; Sprengeler, P. A.
Tetrahedron 1986, 42, 2957.
OL016888T
3974
Org. Lett., Vol. 3, No. 24, 2001