Total synthesis of ( - )-Penifulvin A, an insecticide with a dioxafenestrane skeleton

Full text of DOI:10.1021/ja8083048

Published on Web 12/19/2008
Total Synthesis of (-)-Penifulvin A, an Insecticide with a Dioxafenestrane
Skeleton
Tanja Gaich* and Johann Mulzer*
UniVersity of Vienna, Institute of Organic Chemistry, Wa¨hringer Strasse 38, 1090 Wien, Austria
Received October 28, 2008; E-mail: tanja.gaich@univie.ac.at; johann.mulzer@univie.ac.at
The fall armyworm (Spodoptera frugiperda) is native to the
tropical regions of the western hemisphere from the United States
to Argentina, and its larvae cause enormous damage by consuming
foliage of a variety of field crops, including barley, buckwheat,
cotton, corn, oat, rice, sugar cane, soybean, tobacco, wheat, and
others.1 In Florida, for example, the fall armyworm is the most
significant pest of corn. As resistance to pesticides has been noted
and is expected to become increasingly problematic from year to
year, a way out of this dilemma would be the introduction of new
environmentally benign pesticides. In this respect we were intrigued
Figure 1. Structures of Penifulvins A-E.
by a recent paper2 in which Gloer and co-workers described a novel
sesquiterpenoid named penifulvin A (1), isolated from the fungus
Scheme 1. Retrosynthetic Overview
Penicillium griseofulVum (syn. P. patulum Bain.; P. urticae bain).
This metabolite, which belongs to a larger family of penifulvins
A-E (Figure 1),3 not only shows significant insecticidal activity
in assays against the fall armyworm but also appeared, due to its
unusual and complex molecular architecture, an attractive target
for total synthesis. Furthermore, for procuring larger quantities,
acquiring SAR data and elucidating the full bioprofile of the
compound, a rational nonbiological access was of importance.
The overall structure of 1, which has been secured by X-ray
crystallographic analysis,2 reveals a complex oxa-fenestrane4
structure in which four rings share a central quaternary carbon.
Additionally there are two more quaternary carbons, a γ- and a
δ-lactone sharing the acylal center, and a total of five stereogenic
centers congested on a 15 carbon skeleton. This ring system, whose
absolute configuration is unknown, has not been described previ-
ously in literature. Herein we report the first total synthesis of
racemic and optically active 1 from inexpensive o-tolylacetic acid
(2) (Scheme 1).
Scheme 2. Preparation of Photocyclization Precursors 3a and 3ba
For our key transformation, we focused on Wender’s marvelous
photoinduced cyclization of arene olefins5 such as 3a (optically
active) and 3b (racemic) (Scheme 3), both readily available from
2 (Scheme 2). Racemic carboxylic acid 3b was obtained from the
alkylation of the dianion. The stereogenic center in 3a was
introduced via Myers’ alkylation6 in 95% ee leading to amide 5 in
two steps. As 5 undergoes racemization on basic hydrolysis, it was
reduced to the alcohol.
The photoreaction of 3a,b (Scheme 3) starts with a formal [3
+ 2] cycloaddition to generate exciplex E which undergoes 1,3-
bond formation to deliver the allylic regioisomers 6 and 7 (6a:
7a ) 55:45; 6b:7b ) 46:54). The stereochemical course of the
addition is controlled by the stereogenic center in compound 3.
According to the A1,3-strain model7 steric interactions between
the aromatic methyl and the R group are minimized. This effect
strongly disfavors conformations such as syn-3, so that anti-3
can be assumed to be the preferred conformation in the
photocyclization.
a Reagents and conditions: (a) 2 LDA, -78 °C, THF, 5-bromo-2-methyl-
2-pentene (4); (b) (R,R)-N-MPE, DIC, DMAP, DCM; (c) LiCl (6 equiv)
LDA, 4, THF, rt, 24 h; (d) LDA, BH3NH3, THF. (R,R)-N-MPE ) (R,R)-
N-methylpseudoephedrine, DIC ) diisopropyl carbodiimide, DMAP )
dimethylaminopyridine, DCM ) dichloromethane, LDA ) lithium diiso-
propyl amide.
6a was reduced under Birch-like conditions (Scheme 4) to give
triquinanyl alcohol 8, which was oxidized to carboxylic acid 9.
Ozonolytic cleavage of the double bond generated the nonisolable
dialdehyde 10 which immediately cyclized to lactol 11.8 Oxidation
gave 1, whose spectral data were in full accord with those of an
authentic sample (see Supporting Information). The optical rotation
of our material was [R]D20 ) -127 (c 0.35, CHCl3) compared to a
The synthesis was completed in different ways for the racemic
and the optically active series (Scheme 4). Thus, the optically active
regioisomers 6a and 7a were separated by chromatography, and
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452 J. AM. CHEM. SOC. 2009, 131, 452–453
10.1021/ja8083048 CCC: $40.75
2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Photocyclization of 3a,ba
In the racemic series, the mixture of 6b and 7b was carried
through the sequence without separation. Thus, reduction of this
mixture under Birch-like conditions was directly followed by
ozonolysis and oxidation, and rac-1 was finally obtained in pure
form by column chromatography and crystallization. Compound
rac-12 was not isolated.
In conclusion we have disclosed a concise synthesis of penifulvin
A in racemic and optically active form from o-tolylacetic acid in
altogether 5 steps (14% overall yield) and 8 steps (8% overall yield),
respectively. Apart from the photocyclization which leads to readily
separable regioisomers, the synthesis is stereo- and regiocontrolled,
does not require protecting groups or purification of intermediates,
and is scalable. Precursor 2 can be modified by introducing
substituents onto the aromatic ring and/or the aliphatic side chain,
so that a variety of analogues, among them penifulvins B-E, should
be available for performing SAR tests in the insecticidal role.
Acknowledgment. We thank Hanspeter Ka¨hlig, Susanne Fels-
inger, and Lothar Brecker for NMR analysis; Gerald Wagner for
assistance; Professor J. B. Gloer, Iowa State University, for fruitful
discussions and a generous sample of 1; and the Austrian Science
Fund (FWF) for financial support.
a Conditions: hν, pentane, 22 °C, 2 h (Series a: R ) CH2OH, optically
active, 70% yield. Series b: R ) CO2H, racemic, 62% yield).
Scheme 4. Completion of the Synthesisa
Supporting Information Available: Detailed experimental proce-
dures and characterization of new compounds and comparison NMR
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
(1) See for instance: Capinera, J. L. Fall armyworm. Homepage of the
University of Florida Institute of Agriculture and Consumer Services,
Division of Plant Industry, and University of Florida Institute of Food and
Agricultural Sciences, Department of Entymology and Nematology, July
1999 (http://creatures.ifas.ufl.edu/field/fall_armyworm.htm).
(2) Shim, H. S.; Swenson, D. C.; Gloer, J. B.; Dowd, P. F.; Wicklow, D. T.
Org. Lett. 2006, 8, 1225–1228.
(3) Shim, H. S.; Gloer, J. B.; Wicklow, D. T. J. Nat. Prod. 2006, 69, 1601–
1605.
(4) For a review on fenestranes, see: Keese, R. Chem. ReV. 2006, 106, 4787–
4808.
(5) Wender, P. A.; Ternansy, R. J. Tetrahedron Lett. 1985, 26, 2625–2628.
See also: Wender, P A.; Ternansky, R.; DeLong, M.; Singh, S.; Olivero,
A.; Rice, K. Pure Appl. Chem. 1990, 62, 1597–602. Wender, P. A.; Siggel,
L.; Nuss, J. M. ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5 (Paquette, L. A., Ed), pp
654-673. (c) Morrison, H.; Ferrie, W. I., Jr. J. Chem. Soc. D 1969, 268–
269. Mattay, J. J. Photochem. 1987, 37, 167–183. Chappell, D.; Russell,
A. T. Org. Biomol.Chem. 2006, 4, 4409–4430.
a Reagents and conditions: (a) EtNH2, Li, THF, -78 °C, 7 h; (b) IBX,
DMSO, 22 °C, 20 min, then NaClO2, 2-methyl-2-butene, tert-BuOH,
NaH2PO4, 1 h; (c) O3, DCM, -78 °C, 2 min, then thiourea, 22 °C, 40 min;
(d) PDC (4 equiv), DCM, 22 °C, 20 min, then AcOH (20 equiv), 20 min.
IBX ) 2-iodoxybenzoic acid, DMSO ) dimethylsulfoxide, DCM )
dichloromethane, PDC ) pyridinium chlorochromate.
(6) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.;
Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496–6511.
(7) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841–60.
(8) Lactol 11 was formed as a mixture of anomers.
20
(9) The rotation of [R]D )-3.5 (c 0.17, MeOH), reported for 1 in ref 2 is
wrong. We corrected the value by measuring an authentic sample, which
was kindly provided by Professor J. B. Gloer.
value of [R]D20 ) -133 (c 0.50, CHCl3) of the authentic sample.9,10
This result also confirms the absolute configuration (1S, 4R, 7S,
8S, 9R) of 1.
(10) The enantiomeric excess of our synthetic sample of 1 was determined via
the chiral 1H NMR shift reagent ([Eu(hfc)3] to be >90%.
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