The total synthesis of hyperpapuanone, hyperibone L, epi-clusianone and oblongifolin A

Article abstract of DOI:10.1038/nchem.1170

Polyprenylated polycyclic acylphloroglucines (PPAPs) are a family of natural products that possess a wide range of different important biological activities because of the relative position and configuration of four substituents that decorate one common c

Full text of DOI:10.1038/nchem.1170

ARTICLES
PUBLISHED ONLINE: 16 OCTOBER 2011 | DOI: 10.1038/NCHEM.1170
The total synthesis of hyperpapuanone,
hyperibone L, epi-clusianone and oblongifolin A
¨
Nicole Biber, Katrin Mows and Bernd Plietker
*
Polyprenylated polycyclic acylphloroglucines (PPAPs) are a family of natural products that possess a wide range of
different important biological activities because of the relative position and configuration of four substituents that
decorate one common central bicyclo[3.3.1]nonane-2,4,9-trione core. The rigid bicyclic framework with its lipophilic side
chains and its hydrophilic trione moiety represents a nature-derived lead structure that arranges the substituents (R1 to R4)
into a defined topographical orientation. As the substituents are responsible for the biological activities, the seven-step
synthetic approach presented here sets the stage for an iterative introduction of R1 to R4 and thus generates structurally
diverse trans-type B PPAPs. Four natural and one non-natural trans-type B PPAPs were prepared starting from
acetylacetone with overall yields that ranged from 6 to 22%. The concept of separating framework construction from
decorating transformations plus the minimization of protecting-group operations are the key issues for the realization of
our synthetic approach.
olyprenylated polycyclic acylphloroglucines (PPAPs) are a epi-clusianone (2)4,5, oblongifolin A (1)13, hyperibone L (3)14 and
family of natural products, of which more than 100 members hyperpapuanone (4)15. Furthermore, 4 was also prepared as its
P
have been discovered to date. Most of these were isolated C1–C5 regioisomer 5, which was a proposed revised structure for
from plants and trees from Clusiaceae (Guttiferae). This group of 4 (ref. 1). These natural products possess important biological
natural products spans a wide range of biological activities, and activities (Fig. 1). To date, detailed studies on the cellular inhibition
has antimicrobial, antioxidant, anticancer or antidepressant proper- pathways have been performed only with 2, which possesses anti-
ties1–15. It is surprising to find that this diverse biological activity is proliferative effects on various cancer cell lines through the inhi-
probably the consequence of the relative configuration and position bition of cysteine and serine proteases12. Although no in-depth
of substituents decorated around one common highly oxygenated bioactivity studies for 1 and 3 have been published so far, the struc-
and densely substituted bicyclo[3.3.1]nonane-2,4,9-trione core1. tural similarity of these compounds to 2 implies a similar bioactivity
This bicyclic framework can be regarded as a novel type of profile. Obviously, the aryl ketone moiety appears to be essential for
natural core structure that helps to arrange the corresponding sub- the inhibition of tumour cell replication.
stituents in the correct topographical orientation. The PPAPs are
Changing the substituent R4 from an aryl to an alkyl group
divided into three types (A, B and C) depending on the position causes a change in the bioactivity. Although 4 shows no activity
of the acyl group on the bicyclic core (Fig. 1)1. Apart from the pos- against cancer cell lines, it possesses a significant antimicrobial
ition of the acyl group the configuration of the C7-substituent R1 activity15. Similar studies carried out with epi-clusianone (2)
relative to the carbonyl bridge is another important issue. The C7 revealed an even broader antimicrobial activity10. From the available
group functions as a molecular anchor unit and thus directs the con- bioactivity data, it can be concluded that this natural product family
formation of the cyclohexanone moiety to be in a chair-like (for cis- might offer new perspectives for pharmaceutical research. However,
(or exo)-type PPAPs1) or in a boat-like conformation (for trans- (or as mentioned above, one of the main problems is the lack of efficient
endo)-type PPAPs1) (Fig. 1). This conformational change has a access to structurally diverse trans-type B PPAPs. This fact hampers
direct influence on the biological activity. In the case of, for their systematic exploration and can, to some extent, be attributed to
example, clusianone2–4 (a cis-type PPAP) the side-chain R1 is the small amounts of material available from natural resources.
oriented in a cis fashion to give the preferred conformation shown
A variety of natural products show similar core structures and
in Fig. 1. Inversion of the C7 stereochemistry leads to epi-clusia- differ only in their substitution pattern. The PPAPs might be
none4,5 (2) (a trans-type PPAP) with its boat-like conformation. regarded as an impressive example of nature’s structural diversity.
Although both natural products show a similar bioactivity
profile2–12, epi-clusianone (2) is significantly less cytotoxic4.
Results and discussion
From a chemical aspect, in particular the densely substituted Retrosynthesis. At the outset of our synthetic studies, we thought
central core and the remarkable structure–activity relationship that
clear separation of the framework (that is, the
a
have attracted the attention of synthetic chemists within the past bicyclo[3.3.1]nonatrione core) construction and decoration (the
five years. As a consequence, elegant and short total syntheses introduction of the corresponding substituents R1 to R4) could set
towards cis-type PPAPs have been developed16–26. However, an effi- the basis for a conceptually unprecedented and general approach
cient approach towards trans-type PPAPs is underdeveloped.
towards trans-type B PPAPs. A strict realization of this concept
Herein, we report a general modular and practical total synthesis would allow for a variety of substitution patterns without
of trans-type B PPAPs that allows the preparation, starting from changing the entire synthetic strategy and offers the chance of a
acetylacetone (6), of a set of natural products in just seven steps future bioactivity-directed synthesis of defined PPAP libraries.
with overall yields that range from 6 to 22%. To exemplify the Furthermore, a special emphasis was placed on the practicability
versatility of our approach, we synthesized four natural products, of the synthesis. Using
a combination of well-established
Institut fu¨r Organische Chemie, Universita¨t Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany. e-mail: bernd.plietker@oc.uni-stuttgart.de
*
938
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1170
ARTICLES
This work
trans
cis
O
O
O
O
R3
R3
O
7
O
O
O
Ph
O
R4
O
R1
HO
HO
R1
7
HO
R4
R2
R2
HO
HO
O
O
HO
Hyperibone L (3)
Oblongifolin A (1)
No synthesis reported
No synthesis reported
O
Inhibition of human tumour cell replication
Inhibition of tubulin assembly
O
O
O
R3
5
R3
7
O
O
O
O
O
R1
O
Ph
R1
O
O
HO
HO
1
R2
R2
7
R4
R4
HO
HO
Hyperpapuanone (4)
Total synthesis reported
• Selected antimicrobial activity against
Bacillus cereus
epi-Clusianone (2)
No synthesis reported
• Anti-HIV activity
• Low cytotoxicity
Staphylococcus epidermidis
Micrococcus luteus
• Inhibition of human tumour cell replication
• Antispasmodic activity
• Vascorelaxant activity
O
O
O
R3
R3
• Antianaphylactic activity
O
O
• Selected antimicrobial activity against:
Leishmania amazonensis (leishmaniasis)
Staphylococcus aureus
Staphylococcus mutans (dental caries)
Trypanosoma cruzi (Chagas disease)
7
O
O
O
O
R4
R1
R1
R4
HO
R2
R2
7
HO
HO
regio-Hyperpapuanone (5)
No synthesis reported
Total synthesis reported
Figure 1 | Classification of PPAPs and total syntheses accomplished. Total syntheses of cis-type A and B PPAPs like, for example, garsubellin A (refs 16,17),
nemoroson20,23, ent-hyperforin22, clusianone18–21,24, plukentione25 and hyperibone K (ref. 26) have been achieved. HIV ¼ human immunodeficiency virus.
easy-to-operate methodologies and a minimization of protecting identical conditions independent of the structure of the starting
group operations, only
a
small number of synthetic material. A regioselective 1,2-addition28 of methyllithium to the
transformations may be necessary, which thus increases both the diesters 9 and 10 gave rise to the corresponding methyl ketones,
practicability and the efficiency of the total synthesis. A brief
retrosynthetic analysis is sketched in Fig. 2. With regard to the
O
framework construction, the Dieckmann reaction of a densely
substituted cyclohexanone III and a tandem Michael addition–
Knoevenagel condensation to give a cyclohexenone IV are key
R3
O
R1
O
R2
steps
that
would
allow
quick
access
to
the
HO
R4
O
O
I
O
bicyclo[3.3.1]nonatrione core II. Neither transformation had been
used for the construction of strained bicyclic ring systems, so they
needed to be elaborated within this synthetic context. The
iterative framework decorations via nucleophilic substitutions
using alkylating, allylating or acylating conditions allow for a
regioselective generation of the correct substitution pattern in
which the C7 stereocentre orchestrates the trajectory of the
incoming electrophiles to set up the stereogenic centres with the
correct relative configuration (Fig. 2).
R3
VI
7
O
R1
a-Methylenation
R2
HO
Dieckmann
condensation
C-acylation
Allylation
II
Framework
construction
O
Framework
decoration
O
R1
V
O
R3
R2
RO2C
Michael addition–
Synthesis. Acetylacetone (6) serves as a common starting material
and was allylated in the first step using sodium hydride (NaH)
and the corresponding allylating agent R1–X (Fig. 3). This early
stage of the synthesis represents our first diversification point
(Fig. 3) and paves the way for the total synthesis of oblongifolin A
(1), which possesses a geranyl side chain, and the total synthesis
of the C7-prenylated compounds 2–5. We subjected the
corresponding allylation products directly to a deacylating aldol-type
a-methylenation using potassium carbonate (K2CO3) in an aqueous
formalin solution27. The a,b-unsaturated ketones 7 and 8 were
Knoevenagel condensation
Alkylation
Cuprate addition
Alkylation
R1
O
O
III
R2
RO2C
R1
IV
obtained in good yields starting from 6 and were employed in a Figure 2 | Retrosynthetic analysis. As the trans-type B PPAPs differ
subsequent tandem Michael addition–Knoevenagel condensation to mainly in the arrangement of the substituents R1 to R4, the retrosynthetic
give the cyclohexenone cores 9 and 10 in 86% and 89% yield, approach was designed to separate the steps that build the core structure
respectively. Both a-methylenation and ring-forming condensation (framework construction) from those that introduce the substituents
are framework-constructing operations and were performed under (framework decoration).
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1170
ARTICLES
O
O
6
i
51%
i
60%
R1a
=
=
O
O
R1b
R1b
7
R1a
ii
8
86%
ii
89%
O
O
O
O
O
O
MeO
OMe
MeO
OMe
R1b
R1a
10
9
iii, iv
59% over two steps
iii, iv
62% over two steps
iii, iv
63% over two steps
R2a
=
=
O
O
O
O
O
O
O
O
O
R2a
R2b
R2a
MeO
MeO
MeO
R2b
Me
R1b 11
R1a
R1a
12
13
v
95%
v
97%
v
96%
O
O
O
O
O
O
O
O
O
R2a
R2b
R2a
MeO
MeO
MeO
MeO
HO
16
R1a
14
15
R1b
R1a
R3a
=
=
vi
77%
vi
90%
vi
86%
vii
81%
R3b
Me
O
O
O
O
O
O
O
O
O
O
O
O
R2b
R3a
R2a
R2a
R3a
R2a
R3a
R3b
MeO
MeO
MeO
17
33%
OH
18
72%
19
78%
20
84%
R1b
R1a
R1a
R1a
ix
viii
viii
O
viii
viii
51%
O
O
O
OH
HO
O
O
HO
O
O
HO
O
O
O
O
O
HO
O
O
1
4
2
3
5
6% overall yield
21% overall yield
22% overall yield
22% overall yield
14% overall yield
Figure 3 | Total synthesis of oblongifolin A (1), hyperpapuanone (4), epi-clusianone (2), hyperibone L (3) and regio-hyperpapuanone (5). i, NaH
(1.1 equiv.), R1X (1.5 equiv.), ethanol, 0 8C to room temperature (r.t.), 15 h, then K2CO3, formaldehyde, r.t., 5 h; ii, methylmagnesium chloride (2.0 equiv.),
dimethyl 1,3-acetonedicarboxylate (1.0 equiv.), methanol, 0 to 60 8C, 15 h; iii, NaH (1.1 equiv.), methyllithium (2.3 equiv.), THF, 0 8C, 5 h; iv, NaH (1.1 equiv.),
18-crown-6 (0.1 equiv.), R2X (1.5–2.5 equiv.), THF, 0 8C to r.t., 15 h; v, lithium chloride (2.02 equiv.), CuI (2.0 equiv.), methylmagnesium bromide (2.0 equiv.),
Me3SiCl (2.0 equiv.), THF, –78 8C, 5 h; vi, KO-t-amylate (2.0 equiv.), 1,3-dimesitylimidazolin-2-ylidene hexafluorophosphate (0.1 equiv.), Bu4N[Fe(CO)3(NO)]
(0.1 equiv.), 2-methyl-3-butene-2-yl methylcarbonate (2.0 equiv.), THF/methyl-t-butyl ether, 0 to 80 8C, 20 h; vii, KH (1.1 equiv.), 18-crown-6 (0.1 equiv.),
MeI (2.0 equiv.), dimethoxyethane, 0 8C to r.t., 15 h; viii, KO-t-Bu (2.0 equiv.), R4–C(¼O)CN (3.3 equiv.), THF, 0 to 35 8C, 24 h; ix, same as viii, but 0 8C to
r.t. and additional basic work-up with K2CO3, methanol.
940
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1170
ARTICLES
c
a
B–
+
O
R3
R2
R1
R3
R2
O
O
Na
R2
O
O
R2
O
O
O
O
R1
OMe
O
MeO
O
B–
OMe
O
OMe
R1
R1
+
R2
O
O
b
R3
R3
+
R3
O
HO
R1
R1
+
R3
HO
R2
R2
O
Met
R2
O
O
R1
O
R1
R1
O
O
OR
MeO2C
+
R3
Figure 4 | Stereochemical rationale for the allylations and Dieckmann condensation. a, The stereoselective course of the allylation of cyclohexenones 9 and 10
is directed mainly by the axially oriented substituent R1, which shields the bottom face of the almost planar enolate. b, For the allylation of cyclohexanones 14–16 the
trajectory of the incoming electrophile is directed by the axially oriented methyl and carboxylate groups. c, The resulting cyclohexenones 17–20 have to flip from a
chair-like to a boat-like confirmation for the Dieckmann condensation to take place. Red arrows indicate the potential trajectories for approach of electrophiles or
bases rather than electron movement. Where there are two possibilities, curved lines represent steric repulsion that leads to one trajectory being favoured.
a
Hyperpapuanone 4
regio-Hyperpapuanone 5
b
O
O
O
O
O
O
HO
HO
O
OMe
O
O
21
O-methyl hyperibone L
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
ppm
Figure 5 | Structural confirmation of hyperpapuanone (4). a, X-ray structure of O-methyl hyperibone L (21). b, 1H NMR data for hyperpapuanone (4) and
regio-hyperpapuanone (5). Hyperibone L (3) and regio-hyperpapuanone (5) differ only in the acyl group. The structural confirmation of hyperibone L (3) by
X-ray crystallography of its corresponding O-methyl ether 21 confirms indirectly the structure of hyperpapuanone (4). The correct three-dimensional
assembly of three of the four substituents found both in 5 and 3 plus a direct comparison of the 1H NMR spectra of hyperpapuanone 4 and its regioisomer 5
with the reported spectra of the isolated natural products confirm the structure originally proposed15.
which represent the starting materials for diversification 2 (Fig. 3). cyclohexenones 11–13 in hand, the addition of methyl copper in
a-Allylation or methylation led to cyclohexenones 11–13 in good the presence of lithium chloride and trimethylsilyl chloride
overall yields with
a
high level of control of the relative (Me3SiCl) allowed a 1,4-methylation29 to yield the corresponding
stereochemistry in favour of the desired trans-diastereoisomers. The cyclohexanones 14–16 in 95–97% yield, which then were subjected
high level of stereoinduction can be rationalized by assuming a to a-methylation using NaH and methyl iodide (MeI). Fortunately,
pseudo-axial orientation of the substituent R1 within the the new C–C bond was formed with a high preference for the
deprotonated cyclohexenone (Fig. 4a). With the functionalized desired diastereoisomer in which both exocyclic carbonyl groups are
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1170
ARTICLES
10. Almeida, L. S. B. et al. Antimicrobial activity of Rheedia brasiliensis and
7-epiclusianone against Streptococcus mutans. Phytomedicine 15, 886–891 (2008).
11. Alves, T. M. et al. Biological activities of 7-epiclusianone. J. Nat. Prod. 62,
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Soc. 128, 1048–1049 (2006).
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yielding bridgehead and diketone substitutions by regioselective lithiation of enol ether
derivatives of bicyclo[3.3.1]nonane-2,4,9-triones. Org. Lett. 8, 5283–5285 (2006).
19. Qi, J. & Porco, J. A. Rapid access to polyprenylated phloroglucinols via alkylative
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oriented in a cis-fashion towards each other (Fig. 4b). Unfortunately,
using standard allylating agents instead of MeI led to an undesired
O-allylation. The desired C-allylation product was accessible only via
an Fe-catalysed allylic substitution developed recently by our group as
a methodological spin-off project30–32. Fortunately, by employing this
methodology the desired products 17–19 were obtained in good
yields and acceptable diastereoselectivities. With these materials
available we approached the Dieckmann condensation to the strained
central bicyclo[3.3.1]nonatrione core. To achieve the desired C–C
bond formation, the cyclohexanone ring has to flip from the
thermodynamically more stable chair-like into the more reactive
boat-like conformation, which orientates the reactive centres in close
proximity towards each other (Fig. 4c). This transformation was
achieved using potassium tert-butoxide (KO-t-Bu) in tetrahydrofuran
(THF) under mild conditions. Trapping of the intermediate enolate
using acyl cyanides led to the formation of the C-acylated natural
products 2–5 as a mixture of tautomers in good isolated and overall
yields (Fig. 3). Only for the total synthesis of oblongifolin A 1 was an
additional deprotection step necessary. Subjecting the crude aryl bis-
acetate to a basic work-up led to the formation of the desired natural
product 1. Double-bond isomerization or retro-Dieckmann-type ring
openings/deacylations were not observed.
21. Nuhant, P., David, M., Pouplin, T., Delpech, B. & Marazano, C. a,a′-Annulation
of 2,6-prenyl-substituted cyclohexanone derivatives with malonyl chloride:
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22. Shimizu, Y., Shi, S., Usuda, H., Kanai, M. & Shibasaki, M. Catalytic asymmetric
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23. Simpkins, N. S., Taylor, J. D., Weller, M. D. & Hayes, C. J. Synthesis of nemorosone
via a difficult bridgehead substitution reaction. Synlett 4, 639–643 (2010).
24. Garnsey, M. R., Lim, D., Yost, J. M. & Coltart, D. M. Development of a strategy
for the asymmetric synthesis of polycyclic polyprenylated acylphloroglucinols
via N-amino cyclic carbamate hydrazones: application to the total synthesis of
(þ)-clusianone. Org. Lett. 12, 5234–5237 (2010).
Structural confirmation of hyperpapuanone (4). Fortunately, we
were able to obtain, by X-ray crystallography, the structure of
hyperibone L (3) in its O-methylated form (Fig. 5), which proved
that the C7 stereocentre had the correct relative configuration. As
hyperibone L (3) and regio-hyperpapuanone (5) differ only in the
acyl group R4, X-ray crystallography might also serve as proof for
1
the structure of 5. A H NMR spectroscopy comparison (Fig. 5)
of 4 and 5 with the reported data15 supports that the structure
proposed originally for 4 is correct.
25. Zhang, Q., Mitasev, B., Qi, J. & Porco, J. A. Jr Total synthesis of plukenetione A.
J. Am. Chem. Soc. 132, 14212–14215 (2010).
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assignment of hyperibone K. J. Am. Chem. Soc. 132, 13642–13644 (2010).
28. Huckin, S. N. & Weiler, L. C-Acetylation of ketones. Can. J. Chem. 52,
1379–1380 (1974).
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episilicine. J. Org. Chem. 75, 178–189 (2010).
Summary
Herein we report a short, high-yielding synthetic approach towards
trans-type B PPAPs. The concept of a strict separation between frame-
work construction and framework decoration proved to be the key for
the successful synthesis of four natural and one non-natural product,
which differ in their substituents R1 to R4. With this synthetic
approach in hand, future work will concentrate on the elaboration
of an enantioselective version, as well as an extension towards the
total synthesis of trans-types A and C PPAPs. Hopefully, this work
and the creation of a library of trans-type PPAP analogues will set
the stage for in-depth studies of the structure–activity relationships.
30. Plietker, B. A highly regioselective salt-free iron-catalyzed allylic alkylation.
Angew. Chem. Int. Ed. 45, 1469–1473 (2006).
31. Plietker, B., Dieskau, A., Mo¨ws, K. & Jatsch, A. Ligand dependant mechanistic
dichotomy in iron-catalyzed allylic substitutions – s-allyl- vs. p-allyl
mechanism. Angew. Chem. Int. Ed. 47, 198–201 (2008).
Received 10 May 2011; accepted 12 September 2011;
published online 16 October 2011
32. Holzwarth, M., Dieskau, A., Tabassam, M. & Plietker, B. Preformed p-allyl iron
complexes as potent, well-defined catalysts for the allylic substitution. Angew.
Chem. Int. Ed. 48, 7251–7255 (2009).
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Acknowledgements
Dedicated to Barry M. Trost on the occasion of his 70th birthday. The authors
thank the Deutsche Forschungsgemeinschaft, the Deutsche Krebshilfe e.V.,
the Landesgraduiertenstiftung Baden-Wu¨rttemberg (PhD grant for N.B.) and the
Studienstiftung des deutschen Volkes (PhD grant for K.M.) for financial support.
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Author contributions
N.B. prepared the natural products 1–5. K.M. was involved in model studies towards the
synthesis of O-methyl hyperibone and crystallized this compound (see Supplementary
Information). B.P. designed the study, analysed the data and wrote the paper. All the
authors discussed the results and commented on the manuscript.
7. Neves, J. S. et al. Antianaphylactic properties of 7-epiclusianone, a tetraprenylated
benzophenone isolated from Garcinia brasiliensis. Planta Med. 73, 644–649 (2007).
8. Cruz, A. J., Lemos, V. S., dos Santos, M. H., Nagem, T. J. & Cortes, S. F. Vascular Additional information
effects of 7-epiclusianone, a prenylated benzophenone from Rheedia
gardneriana, on the rat aorta. Phytomedicine 13, 442–445 (2006).
9. Pereira, I. O. et al. Leishmanicidal activity of benzophenones and extracts from
Garcinia brasiliensis Mart. fruits. Phytomedicine 17, 339–345 (2010).
The authors declare no competing financial interests. Supplementary information and
chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at http://www.
nature.com/reprints. Correspondence and requests for materials should be addressed to B.P.
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