Biomimetic synthesis of polycyclic polyprenylated acylphloroglucinol natural products isolated from hypericum papuanum

Article abstract of DOI:10.1021/ol101380a

(Equation Presented). Biomimetic syntheses of three polycylic polyprenylated acylphloroglucinol natural products isolated from Hypericum papuanum, ialibinone A, ialibinone B, and hyperguinone B, have been accomplished by selective oxidative cyclizations o

Full text of DOI:10.1021/ol101380a

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3532-3535
Biomimetic Synthesis of Polycyclic
Polyprenylated Acylphloroglucinol
Natural Products Isolated from
Hypericum papuanum
Jonathan H. George,* Micha D. Hesse, Jack E. Baldwin,† and Robert
M. Adlington†
School of Chemistry & Physics, UniVersity of Adelaide, North Terrace,
Adelaide SA 5005, Australia
jonathan.george@adelaide.edu.au
Received June 15, 2010
ABSTRACT
Biomimetic syntheses of three polycylic polyprenylated acylphloroglucinol natural products isolated from Hypericum papuanum, ialibinone A,
ialibinone B, and hyperguinone B, have been accomplished by selective oxidative cyclizations of the proposed biosynthetic precursor 5,
which was synthesized from phloroglucinol in three steps.
Polycyclic polyprenylated acylphloroglucinols (PPAPs) are
a large family of natural products isolated from a wide range
of plant species.1 Many PPAPs have been shown to exhibit
potent biological activities and are therefore highly attractive
targets for synthesis.2 They are biosynthetically derived from
simpler monocyclic polyprenylated acylphloroglucinols, with
the mechanism generally thought to involve cationic or
radical cyclizations by reaction between the prenyl or prenyl-
derived side chains and the electron-rich phloroglucinol core.
Most PPAPs feature a bicyclo[3.3.1]nonane-2,4,9-trione core
adorned with prenyl and/or geranyl side chains, such as
garsubellin A3 and hyperforin, the presumed active com-
pound in the antidepressant St. John’s wort.4 A smaller group
of PPAPs possess a bicyclo[3.2.1]octane-2,4,8-trione core,
such as ialibinone A (1).5 Many PPAP natural products have
densely functionalized, highly oxygenated structures as a
result of secondary cyclizations and oxidations and are
therefore very challenging synthetic targets. We were
interested in investigating some biomimetic cascade reaction
approaches to PPAP natural products and decided to focus
on the relatively simple family of compounds isolated from
the leaves of Hypericum papuanum,5a a plant used in
traditional medicine in Papua New Guinea. Several unique
PPAP natural products have been isolated from this plant,
including ialibinones A (1) and B (2)5a (Figure 1), which
both contain a bicyclo[3.2.1]octane core and were found
† Department of Chemistry, University of Oxford.
(1) For a review of PPAP natural products, see: Singh, I. P.; Bharate,
S. B. Nat. Prod. Rep. 2006, 23, 558.
(4) Mennini, T.; Gobbi, M. Life Sci. 2004, 75, 1021.
(5) (a) Winkelmann, K.; Heilmann, J.; Zerbe, O.; Rali, T.; Sticher, O.
J. Nat. Prod. 2000, 63, 104. (b) Winkelmann, K.; Heilmann, J.; Zerbe, O.;
Rali, T.; Sticher, O. J. Nat. Prod. 2001, 64, 701. (c) Winkelmann, K.;
Heilmann, J.; Zerbe, O.; Rali, T.; Sticher, O. HelV. Chim. Acta 2001, 84,
3380.
(2) For a review of the synthesis of PPAP natural products, see: Ciochina,
R.; Grossman, R. B. Chem. ReV. 2006, 106, 3963.
(3) Fukuyama, Y.; Minami, H.; Kuwayama, A. Phytochemistry 1998,
49, 853.
10.1021/ol101380a  2010 American Chemical Society
Published on Web 06/30/2010

Scheme 1. Proposed Biosynthetic Origin of Ialibinones A and
B, Hyperguinone B, and Hyperpapuanone from 5
Figure 1. Representative PPAP natural products from H. papuanum.
to exhibit antibacterial activity against Bacillus cereus,
Staphylococcus epidermidis, and Micrococcus luteus.
Hyperguinone B (3)5b is a bicyclic compound featuring a
2,2-dimethyl-2H-pyran ring, while hyperpapuanone (4)5b
and papuaforins A-E5b all contain the more common
bicyclo[3.3.1]nonane core.
separated by careful flash chromatography on silica gel
or alternatively by selective extraction from basic aqueous
solutions.
Ialibinones A (1) and B (2) and hyperguinone B (3) are
presumably all derived from a common monocyclic precursor
5 by various oxidative cyclizations (Scheme 1). Similarly,
hyperpapuanone (4) might arise via prenylation of the C-1
prenyl group of 5, followed by an electrophilic cyclization
of the resultant carbocation intermediate to form the C(5)-C(8)
bond. Although 5 has not itself been isolated as a natural
product, its biosynthesis by diprenylation of a 1-methyl-3-
acylphloroglucinol derivative is likely. Ialibinones A (1) and
B (2), hyperguinone B (3), and related PPAP natural products
from Hypericum papuanum were all isolated in optically
active form. This optical activity presumably derives from
an asymmetric prenylation of the 1-methyl-3-acylphloroglu-
cinol precursor, catalyzed by an aromatic prenyl transferase
enzyme. The aim of this project was therefore to synthesize
the proposed common intermediate 5 in racemic form and
then to investigate oxidative cyclizations of this compound
with a view to racemic synthesis of complex PPAP natural
product structures.
Scheme 2. Synthesis of Key Biomimetic Intermediate 5
The synthesis of the proposed biosynthetic intermediate
5 commenced with a Friedel-Crafts reaction of anhydrous
phloroglucinol (6) with isobutyryl chloride and AlCl3 in
nitrobenzene, which gave (2-methylpropionyl)phloroglu-
cinol6 (7) in 83% yield (Scheme 2). Prenylation of 7 with
prenyl bromide in aqueous KOH7 gave a mixture of the
desired m-diprenylacylphloroglucinol 8 (39%), together
with the gem-diprenylated acylphloroglucinol 9 (30%,
mixture of four tautomeric forms) and the triprenylated
acylphloroglucinol 10 (10%). These products could be
C-Methylation of 8 was then carried out by treatment with
NaOMe and MeI in MeOH to give 5 in 78% yield. Both 5
and 8 are unstable with respect to aerial oxidation, with 8
giving the R-hop acid cohumulone8 in quantitaive yield and
(6) Crombie, L.; Jones, R. C. F.; Palmer, C. J. J. Chem. Soc., Perkin
Trans. 1 1987, 317.
(7) Xiao, L.; Tan, W.; Li, Y. Synth. Commun. 1998, 28, 2861.
Org. Lett., Vol. 12, No. 15, 2010
3533

5 giving a complex mixture of products. In solution, 5 exists
as a 3:1 mixture of two tautomeric forms, 5 and 5a. However,
crystallization of 5 from hexane gave colorless crystals of
5, and X-ray studies confirmed the structure9 and proved
that methylation had occurred at C-1. With 5 in hand, the
proposed biomimetic oxidative cyclizations were investi-
gated. In the first instance, treatment of 5 with PhI(OAc)2 in
THF gave a 1:1 mixture of (()-ialibinones A ((()-1) and B
((()-2) in combined yield of 58% (Scheme 3). Several
alternative oxidizing systems (such as Mn(OAc)3/Cu(OAc)2
and CAN) were investigated, but all gave inferior results.10
of 13 would give tertiary carbocation 14 and then (()-1 and
(()-2 by loss of a proton.11
The resultant 1:1 mixture of (()-ialibinones A and B could
1
be separated by HPLC to give materials with H and 13C
spectroscopic data identical to those previously reported.5a
This is the first synthesis of ialibinones A and B, although
an approach to the 6-5-5 ring system has been reported,12
and structurally related semisynthetic products of hop
constituents have also been described.13 Ialibinones A and
B both exist as a 1.8:1 mixture of enol tautomers (the major
tautomer is shown). The 1H NMR spectra of these tautomers
all show resonances at around 18 ppm in CDCl3, indicating
complete enolization. The first 5-exo-trig radical cyclization
(11 f 12) clearly proceeds with a high degree of stereo-
control, which could be explained by invoking a chairlike
transition state for this reaction. Alternatively, this first radical
cyclization could be nonstereoselective but reversible, with
only the cis adduct 12 being aligned for a second radical
cyclization onto the C(5) prenyl group. The second 5-exo-
trig cyclization is not stereoselective.
Scheme 3. Biomimetic Synthesis of Ialibinones A and B
Treatment of 5 with PhI(OAc)2 in the presence of TEMPO
gave (()-hyperguinone B ((()-3) in 73% yield (Scheme 4).
This reaction presumably proceeds via a selective hydride
abstraction by the in situ generated TEMPO cation to
generate the o-quinone methide intermediate 15, which
undergoes a 6π-electrocyclization to give the 2,2-dimethyl-
2H-pyran ring of 3. The selectivity of this process is
noteworthy, as 5 contains two prenyl groups that could
potentially be oxidized and three phenolic oxygen atoms
which could cyclize to form a 2,2-dimethyl-2H-pyran ring.
However, hyperguinone B is the only observable reaction
product, formed as a 3:1 mixture of enol tautomers.
Scheme 4. Synthesis of Hyperguinone B
The reaction presumably proceeds via initial single-electron
oxidation of 5 to give the stabilized R-keto radical intermedi-
ate 11, with the radical character centered at C-5. A
stereoselective 5-exo-trig cyclization of this radical onto the
pendant C-1 prenyl group would then give tertiary radical
12, which could undergo a second 5-exo-trig cyclization onto
the C-5 prenyl group to give tertiary radical 13 (as a mixture
of C-10 epimers). Finally, a further single-electron oxidation
(8) (a) Hoek, A. C.; Hermans-Lokkerbol, A. C. J.; Verpoorte, R.
Phytochem. Anal. 2001, 12, 53. (b) For oxidation of deoxyhumulone to
humulone under aerobic conditions, see: Fung, S. Y.; Zuurbier, K. W. M.;
Paniego, N. B.; Scheffer, J. J. C.; Verpoorte, R. J. Phytochemistry 1997,
44, 1047.
The same oxidative conditions of PhI(OAc)2 and TEMPO
were used to selectively oxidize the triprenylated acylphlo-
(9) Crystallographic data for the structure of 5 have been deposited with
the Cambridge Crystallographic Data Centre (CCDC 780154). Copies of
this data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif.
(11) For a similar radical cyclization cascade reaction in the synthesis
of tricycloillicinone, see: (a) Pettus, T. R. R.; Chen, X.; Danishefsky, S. J.
J. Am. Chem. Soc. 1998, 120, 12684. (b) Pettus, T. R. R.; Inoue, M.; Chen,
X.; Danishefsky, S. J. J. Am. Chem. Soc. 2000, 122, 6160. (c) Lei, X.; Dai,
M.; Hua, Z.; Danishefsky, S. J. Tetrahedron Lett. 2008, 49, 6383.
(10) For related radical cyclizations of dearomatized phloroglucinols
using Mn(OAc)3, see: Mitasev, B.; Porco, J. A. Org. Lett. 2009, 11, 2285.
3534
Org. Lett., Vol. 12, No. 15, 2010

roglucinol 10 to the bicyclic compound 16, which is a close
analogue of the natural product machuone14 (Scheme 5).
Scheme 6. Electrophilic Cyclizations of 5 with I2
Scheme 5. Synthesis of 16 from 10
In summary, a series of oxidative cyclization reactions of
monocyclic polyprenylated acylphloroglucinols have been
investigated. By adopting a biomimetic approach and syn-
thesizing the proposed biosynthetic intermediate 5, a group
of highly diverse polycyclic ring systems has been accessed.
Oxidative radical cyclization of 5 with PhI(OAc)2 gave (()-
ialibinones A ((()-1) and B ((()-2) via a selective radical
cascade reaction to install the bicyclo[3.2.1]octane ring
system. Synthesis of (()-hyperguinone B ((()-3) was carried
out by oxidation of 5 with PhI(OAc)2 and TEMPO, and
treatment of gem-diprenylated acylphloroglucinol 8 with I2
gave a compound with a bicyclo[3.3.1]nonane core (17).
Further studies on oxidative cyclizations of more complex
polyprenylated acylphloroglucinols are underway in these
laboratories and will be reported in due course.
Attempts to carry out electrophilic oxidative cyclizations
of 5 to give PPAPs with bicyclo[3.3.1]nonane 2,4,9-trione
cores (which are common to most PPAP natural products)
were unsuccessful with reagents such as I2 and m-CPBA.
This is hardly surprising, since 5 contains two distinct prenyl
groups of similar reactivity toward electrophiles and three
enol groups which could react intramolecularly with any
intermediate iodonium ions or epoxides via either C or O
cyclization modes. In general, complex mixtures of oxygen
heterocycles were formed. However, reaction of the gem-
diprenylated acylphloroglucinol 9 under standard iodolac-
tonization conditions generated 17 in 28% yield as a single
diastereomer,15 together with 18 in 40% yield (Scheme 6).
Tri-iodide 17 features a bicyclo[3.3.1]nonane core fused to
a tetrahydrofuran (relative stereochemistry assigned by
observation of key NOEs) and is thus similar in structure to
complex PPAP natural products such as garsubellin A.
Acknowledgment. We thank Dr. Barbara Odell (Univer-
sity of Oxford) for NMR studies and Dr. Amber Thompson
(University of Oxford) for crystallographic studies.
(12) Srikrishna, A.; Beeraiah, B.; Gowri, V. Tetrahedron 2009, 65, 2649.
(13) John, G. D.; Shannon, P. V. R. J. Chem. Soc., Perkin Trans. 1
1978, 1633.
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 1-3, 5, 7-9, and
16-18. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) Monache, F. D.; Monache, G. D.; Gacs-Baitz, E. Phytochemistry
1991, 30, 2003.
(15) For related electrophilic cyclizations of monocyclic polyprenylated
acylphloroglucinols, see: (a) Raikar, S. B.; Nuhant, P.; Delpech, B.;
Marazano, C. Eur. J. Org. Chem. 2008, 1358. (b) Tsukano, C.; Siegel, D. R.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2007, 46, 8840.
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