Synthetic studies towards the phloroglucin natural product hyperforin: construction of the fully prenylated bicyclic core

Article abstract of DOI:10.1016/j.tetlet.2009.03.041

An approach towards the highly functionalized bicyclo[3.3.1]nonan-9-one core of the complex PPAP-based natural product hyperforin, with the full complement of prenyl substituents in required stereo-disposition, is delineated.

Full text of DOI:10.1016/j.tetlet.2009.03.041

Tetrahedron Letters 50 (2009) 3519–3522
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Synthetic studies towards the phloroglucin natural product hyperforin:
construction of the fully prenylated bicyclic core
*
Goverdhan Mehta , Mrinal K. Bera
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An approach towards the highly functionalized bicyclo[3.3.1]nonan-9-one core of the complex PPAP-
based natural product hyperforin, with the full complement of prenyl substituents in required stereo-dis-
position, is delineated.
Received 12 January 2009
Revised 24 February 2009
Accepted 5 March 2009
Available online 13 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Hyperforin 1, the major bioactive constituent of Hypericum per-
foratum (St. John’s wort), belongs to a small, but rapidly growing
class of complex natural products commonly referred to as polycy-
clic polyprenylated acyl phloroglucinols (PPAPs).1,2c In structural
terms, PPAP natural products embody a highly oxygenated and
densely substituted bicyclo[3.3.1]nonan-9-one framework with
subtle stereochemical variations.1,2 A distinctive feature of the
PPAPs is the copious distribution of isoprenoid fragments on its
polyketide-derived core bicyclic structure and the wide-ranging
bioactivity profile exhibited by many members of this family.
Hyperforin 1 is a representative of an important sub-group (see
structures 1–4, Scheme 1) among PPAPs.
A remarkable feature of hyperforin 1 is its broad bioactivity pro-
file.3,4 While the ability of 1 as a reuptake inhibitor of various neu-
rotransmitters, and therefore as an antidepressant, is well
recognized,4a,d its activity against MRSA is also quite impressive.4e
The activity of 1 as an antiviral agent against HIV/AIDS and hepa-
titis C is also under investigation. Very recently, hyperforin and
its derivatives have been shown to exhibit antimalarial activity4f
against Plasmodium falciparum and inhibit human sirtuins SIRT1
and SIRT2.4g These exceptional and diverse bioactivity attributes3,4
make hyperforin 1 an interesting compound for generating thera-
peutic leads, probing biomolecular mechanisms and analogue
design.
O
O
9
9
OH
OH
7
5
7
3
5
3
1
1
O
O
O
O
Hyperforin (1)
Adhyperforin (2)
O
OH
O
OH
O
O
O
O
O
OH
OH
Furohyperforin (3)
Guttiferone A (4)
Scheme 1. Hyperforin and representative PPAPs.
towards hyperforin which has led to the first acquisition of its core
structure with the full complement of prenyl substituents with
requisite stereochemistry.
For reasons of structural complexity and biological activity,
hyperforin has emerged as a challenging and alluring target for to-
tal synthesis. Several synthetic approaches5 directed towards this
natural product, including our own,5a have appeared in the recent
literature. However, only limited progress5 towards this target
has been made so far, and to our knowledge, no total synthesis
has been achieved. In this Letter, we disclose further progress
The major challenge in the synthesis of 1 resides in the installa-
tion of a prenyl group at C-7 and a quaternary centre at C-8 bearing
a homoprenyl moiety on the bicyclo[3.3.1]nonane framework in a
well-defined stereochemical disposition. The retrosynthesis of 1 is
depicted in Scheme 2. Accordingly, bicyclic enone 5 was envisaged
as an advanced intermediate which could be accessed from the
pentaalkylated bicyclic dione 6. Bridged bicyclic system 6 was to
be realized following our previously tested, reconstructive aldol
strategy5a,6 from enol lactone 7. The enol lactone 7 can be readily
obtained from pentaalkylated cyclohexanone derivative 8 through
ester hydrolysis followed by enol lactonization. The cyclohexanone
* Corresponding author. Tel.: +91 8023600367; fax: +91 8023600283.
E-mail address: gm@orgchem.iisc.ernet.in (G. Mehta).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.041

3520
G. Mehta, M. K. Bera / Tetrahedron Letters 50 (2009) 3519–3522
O
O
O
OH
O
O
O
O
5
6
Hyperforin 1
O
CO2Me
O
O
O
O
O
10
9
8
7
Scheme 2. Retrosynthetic strategy towards hyperforin 1.
derivative 8 in which the C-7 and C-8 stereogenic centres are duly
installed was to be accessed from cyclohexanone derivative 9.
Lastly, 9 was to be elaborated from the versatile building block
10, Scheme 2.
MeO2C
a
b
Thus, the recently reported cyclohexa-1,3-dione derivative 105
was elaborated to the ethyl enol ether 11 and further LDA-pro-
moted prenylation under kinetically controlled conditions led to
a readily separable mixture of diastereomers 12 and 13 (1.2:1),
Scheme 3.7 Among these two diastereomers, 13 had the requisite
C-7 and C-8 relative stereochemistry in the context of the target
structure 1. The prenylated enol ether derivative 13 was reduced
with DIBAL-H and the resulting mixture of epimeric allylic alco-
hols, on exposure to aqueous acid, led to the desired eliminative
unmasking of the carbonyl group to deliver the enone 14, Scheme
3. Chemoselective reduction of the conjugated double bond in 14
with nickel boride8 was successfully implemented to afford the
key precursor 9.
O
O
O
16
15
9
c
O
O
f
d
O
O
O
R
18
19,
, R = OH
6
17
e
R = O
O
O
O
Scheme 4. Reagents and conditions: (a) LDA, prenyl bromide, THF, À78 °C, 4 h, 73%;
(b) tBuOK, CH2@CHCO2Me, C6H6, rt, 15 min, 65%; (c) (i) KOH, MeOH, H2O, 60 °C,
89%; (ii) NaOAc, Ac2O, 140 °C, 1 h, 69%; (d) DIBAL-H, CH2Cl2, 0 °C, 2 h, 64%; (e) PCC,
CH2Cl2, rt, 1 h, 87%; (f) LDA, prenyl bromide, THF, À78 °C, 1 h, 73%.
a
b
O
OEt
OEt
12
10
11
+
O
O
d
c
a
b
O
O
OEt
O
OEt
O
13
9
14
12
20
21
Scheme 3. Reagents and conditions: (a) TiCl4, EtOH, 0 °C–rt, 1 h, 83%; (b) LDA,
prenyl bromide, À78 °C to 0 °C, 10 h, 92% (12:13 = 1.2:1); (c) (i) DIBAL-H, CH2Cl2,
0 °C, 30 min; (ii) concd HCl, acetone–H2O (20:1), 0 °C, 15 min, 68% (over 2 steps);
(d) NiCl2, NaBH4, MeOH, 0 °C–rt, 1 h, 97%.
Scheme 5. Reagents and conditions: (a) (i) DIBAL-H, CH2Cl2, 0 °C, 30 min; (ii) concd
HCl, acetone–H2O (20:1), 0 °C, 15 min, 71% (over 2 steps); (b) NiCl2, NaBH4, MeOH,
0 °C–rt, 1 h, 92%.

G. Mehta, M. K. Bera / Tetrahedron Letters 50 (2009) 3519–3522
3521
CO2Me
a
b
c
21
O
O
O
O
22
23
24
d
O
O
O
f
e
O
HO
O
27
26
25
Scheme 6. Reagents and conditions: (a) LDA, prenyl bromide, THF, À78 °C, 4 h, 69%; (b) tBuOK, CH2@CHCO2Me, C6H6, rt, 15 min, 74%; (c) (i) KOH, MeOH, H2O, 60 °C, 2 h, 83%;
(ii) NaOAc, Ac2O, 140 °C, 1 h, 68%; (d) DIBAL-H, CH2Cl2, 0 °C, 2 h, 62%; (e) PCC, CH2Cl2, rt, 1 h, 91%; (f) LDA, prenyl bromide, THF, À78 °C, 1 h, 70%.
With the acquisition of the cyclohexanone derivative 9, the cru-
cial issue of setting up the C-5 quaternary centre with appropriate
stereochemistry was addressed. LDA-promoted prenylation of 9
was regioselective and furnished the tetraalkylated cyclohexanone
15, Scheme 4 without any perceptible formation of diprenylated
product. Michael addition of the anion derived from 15 to methyl
acrylate was stereoselective, directed through the 1,3-stereoinduc-
tion effect of the pre-existing C-7 prenyl group, and installed the
key quaternary centre to furnish pentaalkylated cyclohexanone
derivative 167 as a single diastereomer. Such 1,3-stereoinductions
have been observed by us in related systems and the stereochem-
ical outcome has been firmly established on the basis of X-ray and
NMR studies.5a,6a,b Setting up of this C-5 quaternary centre was
crucial and it ensured that the stereochemistry of the C-7 prenyl
and the C-8 methyl group would be cis to each other and that they
would be exo disposed on the bicyclic framework as was required
for the synthesis of hyperforin.
Base-promoted hydrolysis of the ester group in 16 proceeded
smoothly and the resulting carboxylic acid was readily elaborated
to the bicyclic enol lactone 17 in a routine manner. Access to enol
lactone 17 set the stage for executing the key retro-aldol/re-aldol
reaction cascade.6 Thus, reduction of enol lactone 17 with DIBAL-
H triggered the structural reconstitution and delivered the bicy-
clo[3.3.1]nonan-9-one derivative 18 as a mixture of C-2 hydroxy
epimers. The epimeric mixture 18 was routinely oxidized with
PCC to afford the bicyclic diketone 197 having the key substitution
of the hyperforin core. In the bicyclo[3.3.1]nonan-9-one derivative
19, the stereogenic centres at C-5, C-7 and C-8 were appropriately
positioned and the placement of the carbonyl functionalities at C-2
and C-9 as handles for further transformation towards the target
was important. The next task was to install the C-3 prenyl side
chain by exploiting the C-2 carbonyl functionality in 19. Thus,
LDA-promoted prenylation of bicyclic dione 19 was executed un-
der kinetically controlled conditions to furnish bicyclic dione
derivative 67 embodying the full complement of prenyl substitu-
ents on the bicyclic core as required in the target structure.
It was considered appropriate to implement the synthetic pro-
tocol outlined above on the diastereomer 12 to create stereochem-
ical diversity on the PPAP framework. Towards this end, prenylated
ethyl enol ether 12 was reduced with DIBAL-H to a mixture of
epimeric allylic alcohols which on acid hydrolysis furnished
cyclohexenone derivative 20. The enone double bond was reduced
chemoselectively with nickel boride8 to the ring saturated cyclo-
hexanone 21,7 Scheme 5.
Access to cyclohexanone derivative 21 enabled the tandem pre-
nylation and Michael addition with full stereo- and regiocontrol.
Thus, LDA-mediated prenylation of 21 delivered epimeric monopr-
enylated 22 regioselectively. Michael addition of the anion derived
from 22 to methyl acrylate proceeded as contemplated, to set up
the C-5 quaternary centre in 237 in a stereoselective fashion,
Scheme 6.
Hydrolysis of 23 to the carboxylic acid and conversion to enol
lactone 24 set the stage for executing the retro-aldol/re-aldol cas-
cade.6 Thus, enol lactone 24 was exposed to DIBAL-H to initiate the
desired structural rearrangement leading to bicyclo[3.3.1]nonan-
9-one derivative 25 as a mixture of C-2 epimeric hydroxy com-
pounds. PCC oxidation of 25 readily furnished bicyclic dicarbonyl
compound 26.7 LDA-promoted prenylation of 26 under kinetically
controlled conditions led to the prenylated products 27, Scheme 6.
Once again it was possible to arrive at the basic PPAP core with full
complement of prenyl groups. Interestingly, the stereochemical
architecture in 27 with the C-7 and C-8 prenyl arms disposed cis
and exo has not been encountered in Nature and is a useful dem-
onstration of how total synthesis can facilitate creation of un-nat-
ural diversity around complex natural products.
In summary, the preparation of bicyclic dione 6 with appropri-
ate positioning of all four prenyl/homoprenyl side arms, with cor-
rect stereochemistry at C-5, C-7 and C-8, and placement of the C-2
and C-9 carbonyl functionalities for further elaboration, reflects the
furthest advance so far towards the target natural product and sets
the stage for completion of the synthesis of hyperforin.
Acknowledgements
One of us, M.K.B., thanks UGC for the award of a Research Fel-
lowship. G.M. thanks CSIR for the award of Bhatnagar Fellowship.
This research was also supported by JNCASR through its chemical
biology programme.
References and notes
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3522
G. Mehta, M. K. Bera / Tetrahedron Letters 50 (2009) 3519–3522
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C18H30
O
(M+Na): 285.2194, found: 285.2189. 16: IR (neat): mmax 1741,
;
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2.54 (1/2ABq, J = 10.5 Hz, 1H), 2.27–2.12 (m, 6H), 1.98–1.89 (m, 6H), 1.72 (s,
3H), 1.70 (s, 3H), 1.68 (s, 3H), 1.61 (s, 3H), 1.59 (s, 6H), 1.44–1.38 (m, 4H), 0.73
(s, 3H); 13C NMR (100 MHz, CDCl3): d 215.36, 173.82, 134.31, 132.57, 131.61,
124.22, 123.20, 119.32, 51.68, 50.96, 49.97, 41.22, 41.05, 38.93, 38.29, 32.14,
31.03, 28.69, 27.81, 26.04, 25.86, 25.67, 22.01, 19.33, 17.97, 17.91, 17.62;
HRMS (ES): m/z calcd for C27H44O3 (M+Na): 439.3188, found: 439.3185. 19: IR
(neat): mmax 1723, 1700 cmÀ1 1H NMR (400 MHz, CDCl3): d 5.22–5.18 (m, 1H),
;
5.07–5.03 (m, 2H), 3.19 (s, 1H), 2.75–2.68 (m, 1H), 2.57–2.55 (m, 1H), 2.26–
2.08 (m, 6H), 1.95–1.81 (m, 3H), 1.73 (s, 3H), 1.71 (s, 3H), 1.67 (s, 3H), 1.64 (s,
3H), 1.62 (s, 3H), 1.58 (s, 3H), 1.31–1.16 (m, 2H), 0.91–0.80 (m, 2H), 0.83 (s,
3H); 13C NMR (100 MHz, CDCl3): d 210.87, 208.12, 134.50, 133.08, 131.91,
123.97, 122.71, 119.35, 75.10, 49.18, 48.47, 42.71, 42.62, 39.75, 38.86, 35.37,
29.76, 29.46, 26.04, 25.85, 25.69, 22.67, 21.48, 18.19, 17.93, 17.59; HRMS (ES):
m/z calcd for C26H40O2 (M+Na): 407.2926, found: 407.2922. 6: IR (neat): mmax
1724, 1696 cmÀ1 1H NMR (400 MHz, CDCl3): d 5.22–5.18 (m, 1H), 5.08–5.01
;
(m, 3H), 3.22 (s, 1H), 2.73–2.69 (m, 1H), 2.51–2.49 (m, 1H), 2.24–2.02 (m, 7H),
1.88–1.84 (m, 2H), 1.73 (s, 6H), 1.69 (s, 3H), 1.67 (s, 3H), 1.63 (s, 3H), 1.58 (s,
6H), 1.57 (s, 3H), 1.31–1.12 (m, 3H), 0.89–0.79 (m, 2H), 0.82 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 210.62, 208.11, 134.38, 133.90, 133.00, 131.95, 123.98,
122.79, 120.94, 119.53, 75.64, 50.25, 48.84, 48.26, 42.52, 42.46, 38.93, 37.09,
35.47, 29.81, 29.25, 27.83, 26.06, 25.89, 25.85, 25.69, 21.42, 18.45, 17.97,
17.91, 17.61; HRMS (ES): m/z calcd for C31H48O2 (M+Na): 475.3552, found:
3. For
a recent review on the bioactivity of hyperforin, see: Medina, M. A.;
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4877 and references cited therein.
475.3549. 21: IR (neat): mmax 1717 cmÀ1 1H NMR (300 MHz, CDCl3): d 5.15–
;
5.05 (m, 2H), 2.52–2.19 (m, 4H), 2.07–1.79 (m, 7H), 1.72 (s, 3H), 1.68 (s, 3H),
1.62 (s, 3H), 1.60 (s, 3H), 1.30–1.11 (m, 2H), 1.04 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 212.27, 132.60, 131.63, 124.38, 123.60, 51.80, 46.07, 40.99, 40.09,
34.35, 26.98, 26.57, 26.20, 25.81, 25.66, 21.79, 17.85, 17.52; HRMS (ES): m/z
calcd for C18H30
O
(M+Na): 285.2194, found: 285.2191. 23: IR (neat): mmax
1741, 1703 cmÀ1
;
1H NMR (400 MHz, CDCl3): d 5.09–5.02 (m, 3H), 3.65 (s, 3H),
2.28–2.11 (m, 7H), 1.97–1.90 (m, 2H), 1.81–1.61 (m, 4H), 1.72 (s, 3H), 1.69 (s,
3H), 1.67 (s, 3H), 1.59 (s, 9H), 1.51–1.44 (m, 2H), 1.10–1.06 (m, 2H), 1.03 (s,
3H); 13C NMR (100 MHz, CDCl3): d 214.80, 173.88, 134.27, 132.53, 131.68,
124.44, 123.62, 119.43, 51.68, 50.92, 49.48, 44.15, 41.20, 38.27, 32.22, 32.06,
31.35, 28.73, 27.86, 26.31, 26.00, 25.85, 25.68, 21.72, 17.99, 17.88, 17.49;
HRMS (ES): m/z calcd for C27H44O3 (M+Na): 439.3188, found: 439.3189. 26: IR
(neat): mmax 1724, 1699 cmÀ1 1H NMR (400 MHz, CDCl3): d 5.21–5.18 (m, 1H),
;
6. (a) Mehta, G.; Bera, M. K. Tetrahedron Lett. 2006, 47, 689–692; (b) Mehta, G.;
Bera, M. K.; Chatterjee, S. Tetrahedron Lett. 2008, 49, 1121–1124; See also:
Usuda, H.; Kanai, M.; Shibasaki, M. Org. Lett. 2002, 4, 859–862.
5.08–5.04 (m, 2H), 3.22 (s, 1H), 2.73–2.66 (m, 1H), 2.57–2.53 (m, 1H), 2.22–
2.03 (m, 7H), 1.99–1.92 (m, 1H), 1.85–1.79 (m, 3H), 1.72 (s, 6H), 1.68 (s, 3H),
1.62 (s, 3H), 1.60 (s, 3H), 1.57 (s, 3H), 1.20–1.12 (m, 2H), 1.07 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 210.84, 209.25, 134.46, 133.07, 132.22, 123.79, 122.95,
119.34, 73.92, 48.96, 48.09, 44.21, 42.17, 39.58, 35.26, 32.81, 29.89, 28.92,
26.06, 25.86, 25.69, 23.62, 21.23, 17.93, 17.89, 17.53; HRMS (ES): m/z calcd for
C26H40O2 (M+Na): 407.2926, found: 407.2926.
7. All new compounds were fully characterized on the basis of their IR, 1H NMR,
13C NMR and mass spectral data. Selected spectral data for key compounds: 9:
IR (neat): mmax 1715 cmÀ1 1H NMR (300 MHz, CDCl3): d 5.13–5.06 (m, 2H),
;
2.38–2.19 (m, 5H), 2.07–1.87 (m, 4H), 1.72 (s, 3H), 1.69 (s, 3H), 1.61 (s, 6H),
1.56–1.41 (m, 2H), 1.34–1.22 (m, 2H), 0.82 (s, 3H); 13C NMR (75 MHz, CDCl3): d
8. Gheorghe, A.; Schulte, M.; Reiser, O. J. Org. Chem. 2006, 71, 2173–2177.