From silphinenes to penifulvins: A biomimetic approach to penifulvins B and C

Article abstract of DOI:10.1021/ol902594b

(Figure presented) The biomimetic total synthesis of penifulvins B and C uses a mefa-photocycloaddition as a key step which gives rapid access to the fenestranetype carboskeleton with control of an onring quaternary stereocenter. The route Is concise, stereocontrolled, scaleable, and flexibile and requires only one protecting group.

Full text of DOI:10.1021/ol902594b

ORGANIC
LETTERS
2010
Vol. 12, No. 2
272-275
From Silphinenes to Penifulvins: A
Biomimetic Approach to Penifulvins B
and C
Tanja Gaich* and Johann Mulzer*
UniVersity of Vienna, Institute of Organic Chemistry, Wa¨hringerstrasse 38, A-1090
Vienna, Austria
tgaich@scripps.edu; johann.mulzer@uniVie.ac.at
Received November 9, 2009
ABSTRACT
The biomimetic total synthesis of penifulvins B and C uses a meta-photocycloaddition as a key step which gives rapid access to the fenestrane-
type carboskeleton with control of an onring quaternary stereocenter. The route is concise, stereocontrolled, scaleable, and flexibile and
requires only one protecting group.
Recently, Gloer et al. described the isolation of novel
sesquiterpenoids named penifulvin A, and B, C (1-3), as
well as 12-hydroxy-silphinen-15-oic acid 41 from the fungus
Penicillium griseofulVum (syn. P. patulum Bain.; P. urticae
bain.), which were obtained from white mycelia growth on
dead hardwood branches collected in Hawaiian forests.
Among these metabolites, 1 shows significant antiinsectan
activity in assays against the fall armyworm Spodoptera
frugiperda.2 The overall structures of 1-3 and 4 were
secured (except for the absolute configurations) by X-ray
Figure 1. Structures of penifulvins A-C and 12-hydroxysilphinene-
15-oic acid.
crystallographic analysis and revealed a highly complex
dioxa[5.5.5.6]fenestrane structure in which four rings share
a central quaternary carbon atom (Figure 1). 1 and 4 contain
five stereocenters, whereas 2 and 3 have six of them, three
of which are quaternary.
Due to this unusually dense array of stereogenic carbons,
these compounds represent attractive targets for total syn-
thesis. Recently, we disclosed the synthesis of penifulvin A
(1).3 Herein we wish to report two enantioselective total
syntheses of penifulvins B (2) and C (3) by means of a meta-
photocycloaddition4,5 (Scheme 1).
(1) (a) Penifulvin A: Shim, H. S.; Swenson, D. C.; Gloer, J. B; Dowd,
P. F; Wicklow, D. T. Org. Lett. 2006, 8, 1225–1228. (b) Penifulvins B and
C, 12-hydroxy-silphinen-15-oic acid: Shim, H. S.; Gloer, J. B.; Wicklow,
D. T J. Nat. Prod. 2006, 69, 1601–1605. In this paper also, penifulvins D
and E were described.
Our synthesis was guided by two major interests. First
we wanted to corroborate our biosynthetic hypothesis for
(2) 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.
(3) Gaich, T.; Mulzer, J. J. Am. Chem. Soc. 2009, 131, 452–453.
(4) (a) Bryce-Smith, D.; Gilbert, A.; Orger, B. H. Chem. Commun. 1966,
512–514. (b) Wilzbach, K. E.; Kaplan, L. J. Am. Chem. Soc. 1966, 88,
2066–2067. (c) Morrison, H. A.; Ferree, W. I., Jr. Chem. Commun. 1969,
268–269
.
10.1021/ol902594b  2010 American Chemical Society
Published on Web 12/09/2009

Scheme 1. meta-Photocycloaddition as a Key Step for the
Formation of the Carbocyclic Core of the Penifulvins
Scheme 3. Stereochemical Implications of the
meta-Photocycloaddition
the oxidative formation of the dioxa[5.5.5.6]fenestrane
structure type (e.g., 3) from the well-known silphinene carbon
skeleton (4) (Scheme 2).6
Scheme 2. Biomimetic Oxidative Cyclization Cascade
As penifulvins B and C are epimers regarding the C-6
quaternary carbon center, they provide us with a second
interesting opportunity, the testing of the suprafacial selectiv-
ity of the meta-photocycloaddition, which is the key trans-
formation in our synthesis (Scheme 3). If we postulate that
the photoreaction forms two σ-bonds (C1-C8 and C2-C6)
to generate an exciplex E1 first, the C1-C8 bond might be
reopened in the next step to form a highly stabilized
cyclohexadienyl-tert-alkyl-diradical species E2 which un-
dergoes 1,2-rotation to E3 and recloses the C1-C8 bond to
E4. It thus depends on the relative rates of C7-C9/C7-C11
ring closure (formation of a highly strained cyclopropyl
system) vs C1-C8 ring opening (considerable strain release)
whether regioisomers 9/10 alone or additionally 11/12 are
obtained. Direct ring closures of E2 and E3 are unlikely due
to high ring strain. Similarly, a C1-C7 or C1-C11
combination in E2/E3 would create a highly strained cy-
clobutane ring. Another issue is the equilibrium between the
two potentially reactive conformers 8a/8b. The A1,3-strain7
between the 5-R-group and the 7-Me 8b is strongly disfa-
vored, so 8a may be assumed as the preferred conformer,
which directs the cycloaddition onto the top-face of the
benzenoid ring.
We thus prepared the trisubstituted E/Z-isomers 15 (for
2) and 5 (for 3) via Myers alkylation8 (Scheme 4) and
submitted them to photocyclization. To our delight, the
photoreaction proceeded exclusively with suprafacial stere-
ochemistry (Scheme 5). Hence 19 and 6 were formed from
the irradiation of Z-isomer 5, and 17 and 18 were formed
from E-isomer 15. Both cyclizations proceeded via exo
transition states.9 The synthesis was completed by separation
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Org. Lett., Vol. 12, No. 2, 2010
273

Scheme 4. Synthesis of the meta-Photocycloaddition Precursors
15 and 5 of Penifulvins B and C
Scheme 6. Completion of the Synthesis of 2
of the regioisomeric pairs (17/18 and 19/6), which could be
re-equilibrated via a thermal vinylcyclopropane-cyclopentene
rearrarrangement10 so that no material was lost. Next the
cyclopropane ring in 18 was opened regioselectively under
Birch-type conditions, and the primary alcohol was oxidized
to carboxylic acid 20 (Scheme 6). Ozonolytic cleavage of
the double bond converted 20 via a nonisolable dialdehyde
into the hemiacylal 21. Further oxidation to lactone 22 and
Scheme 5. meta-Photocycloaddition of 15 and 5
Scheme 7. Completion of the Synthesis of 3
274
Org. Lett., Vol. 12, No. 2, 2010

removal of the protective group furnished penifulvin B (2).
An analogous sequence was used to transform 6 into 3
(Scheme 7). All analytical data of our synthetic samples of
2 and 3 matched those reported by Gloer.1b
Although all intermediates could be isolated and character-
ized, their ultimate purification proved difficult and was thus
postponed to 22/25, which were shown to be diastereomeri-
cally pure with respect to the crucial quaternary center at
C6.
In conclusion, we have developed the first enantioselective
total syntheses of penifulvins B and C (2 and 3). Both
syntheses, which confirm the absolute configurations tenta-
tively assigned previously,1b use only one protecting group
and are concise, requiring 10 steps for 2 and 13 steps for 3,
respectively. The endgame supports our biosynthetic hy-
pothesis, in which the silphinene carbon skeleton is converted
into the dioxa[5.5.5.6]fenestrane ring system in a cascade
oxidation. Additionally our findings exponentiate the syn-
thetic value of the meta-photocycloaddition, because due to
its suprafacial stereochemistry with respect to the olefin
component the challenging problem of synthesizing stereo-
genic on-ring quaternary carbon centers11 is reduced to
selectively generating trisubstituted E/Z double bonds.12
Acknowledgment. We thank Hanspeter Ka¨hlig, Susanne
Felsinger, and Lothar Brecker, all at University of Vienna,
for NMR analysis
Supporting Information Available: Experimental data
and analytical characterization for all new compounds
provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL902594B
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