A concise approach towards the bicyclo[3.3.1]nonan-9-one core present in the phloroglucin natural product hyperforin

Article abstract of DOI:10.1016/j.tetlet.2007.12.065

An approach towards the bicyclo[3.3.1]nonan-9-one core present in the bioactive phloroglucin natural product hyperforin is delineated in which the key C8 stereogenic quaternary centre is appropriately installed.

Full text of DOI:10.1016/j.tetlet.2007.12.065

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1417–1420
A concise approach towards the bicyclo[3.3.1]nonan-9-one
core present in the phloroglucin natural product hyperforin
Goverdhan Mehta *, Mrinal K. Bera
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 25 October 2007; revised 2 December 2007; accepted 12 December 2007
Available online 14 January 2008
Abstract
An approach towards the bicyclo[3.3.1]nonan-9-one core present in the bioactive phloroglucin natural product hyperforin is deli-
neated in which the key C8 stereogenic quaternary centre is appropriately installed.
Ó 2007 Elsevier Ltd. All rights reserved.
A large number of polycyclic polyprenylated acyl phlor-
O
O
oglucinol derivatives (PPAPs) with varying levels of struc-
tural and stereochemical complexity, from diverse plant
sources, have surfaced in the recent chemical literature.1,2
Among the more prominent examples of this growing fam-
ily of natural products, based on the bicyclo[3.3.1]nonane
framework and generously substituted with prenyl append-
ages and a dense oxygenation pattern, are nemorosone
1,2d,h enervosanone 2,2v garcinol 32b and hyperforin 42c
to name a few. Besides their complex architecture and var-
ied functionalization, these pholoroglucinol based natural
products display wide range of biological activity including
enhanced in vitro choline acetyltransferase (ChAT) activity
in P10 rat septal neurons and cytotoxicity against several
human cancer cell lines and even antibacterial activity.1
Thus, it is hardly surprising that PPAPs have emerged as
challenging and much sought after targets for total synthe-
sis in recent years.3–6
O
OH
O
O
O
Nemorosone (1)
Enervosanone (2)
O
O
9
OH
OH
7
5
3
O
1
8
O
O
O
OH
OH
Hyperforin (4)
Garcinol (3)
From a structural perspective, the majority of natural
PPAPs (such as 1–3) embody a gem-dimethyl group at
C8 on the bicyclo[3.3.1]nonan-9-one framework and it is
mainly this type that has received attention from synthetic
chemists.3–5 However, there are other PPAPs including
hyperforin, which bear a stereogenic centre at C8 with a
methyl and a homoprenyl substitution at the quaternary
centre. This type of natural products poses greater syn-
thetic challenge compared to the C8 gem-dimethyl bearing
PPAPs. It is hardly surprising therefore that there has been
only one synthetic approach reported6 so far towards
hyperforin 4 but which does not address the crucial issue
of setting the C8 quaternary centre. Besides its architec-
tural novelty, hyperforin 4 is also exceptional for its bio-
activity responses, being a constituent of St. John’s wort
*
Corresponding author. Tel.: +91 8023600367; fax: +91 8023600283.
E-mail address: gm@orgchem.iisc.ernet.in (G. Mehta).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.065

1418
G. Mehta, M. K. Bera / Tetrahedron Letters 49 (2008) 1417–1420
(Hypericum perforatum), a widely used over the counter to
fight mild depression, anxiety and schizophrenia.7 Such
remarkable attributes associated with hyperforin 4 make
it a very tempting target for total synthesis. As part of
our ongoing interest in the synthesis of PPAPs,4 we were
attracted to hyperforin 4 and report here our preliminary
results that have resulted not only in the framework
construction but also provide a solution to the more
vexatious issue of setting-up the C8 quaternary centre.
For our synthetic approach towards hyperforin 4, it was
considered prudent to identify a starting material in which
the key C8 quaternary centre was pre-installed. Towards
this end, the racemic cyclohexane-1,3-dione derivative 5
was identified as the synthon but as it was not reported
in the literature, a straightforward multi-gram access from
commercially available citral 6 via the homogeranyl ketone
7 was devised, Scheme 1. This involved a tandem Michael
reaction–Claisen condensation of 7 with diethyl malonate
to deliver 8 and further decarboxylation delivered the
requisite 5.8
One-pot tandem Michael addition to methyl acrylate
and prenylation of 1,3-diketone 5 in the presence of DBU
led to a readily separable mixture of diastereomers 98 and
10 (1:1.2),8 Scheme 2. Each of the two diastereomers 9
and 10 was further processed to deliver the desired
bicyclo[3.3.1]nonan-9-one framework through an enol-
lactonization and retro-aldol/aldol cyclization protocol.
Diasteromer 9 was hydrolyzed to carboxylic acid 11 and
further elaborated to enol-lactone 12.8 At this stage, it was
felt useful to introduce an additional prenyl unit that would
eventuate at the C3 position in hyperforin 4. This was
a, b
O
O
7
6
c
CH(CO2Et)2
OEt
EtOOC
O
O
O
E
O
O
O
O
O
EtOOC
a
d
+
E
O
O
O
O
O
8
5
5
9
10
Scheme 1. Reagents and conditions: (a) MeLi, Et2O, 0 °C, 3 h, 82%; (b)
MnO2, hexane, rt, 12 h, 72%; (c) CH2(COOEt)2, NaOEt, EtOH, 60 °C,
12 h; (d) KOH, EtOH, 60 °C, 72 h, 58% (over two steps).
Scheme 2. Reagents and conditions: (a) (i) Methyl acrylate, DBU, THF,
rt, 3 h; (ii) Me2C@CHCH2Br, DBU, THF, rt, 3 h, 48% (over two steps)
[9:10 = 1:1.2; E ꢀ CO2Me].
O
O
O
O
a
c
b
CO2Me
CO2H
O
O
O
O
O
O
13
9
11
12
d
O
OH
O
O
HO
O
O
O
O
O
OH
HO
14
Scheme 3. Reagents and conditions: (a) concd HCl, acetone, H2O, 50 °C, 12 h, 88%; (b) NaOAc, Ac2O, 140 °C, 1 h, 75%; (c) LDA, Me2C@CHCH2Br,
À78 °C, 1 h, 51%; (d) DIBAL-H, DCM, 0 °C, 2 h, 54%.

G. Mehta, M. K. Bera / Tetrahedron Letters 49 (2008) 1417–1420
1419
readily realized through kinetic deprotonation of 12 and a
prenyl bromide quench to furnish 13 through 1,3-stereoin-
duction attributable to the pre-existing bridgehead prenyl
group, Scheme 3. Chemoselective DIBAL-H reduction of
the lactone moiety in 13 initiated the thermodynamically
controlled retro-aldol and re-aldolization cascade to fur-
nish the desired bicyclo[3.3.1]nonan-9-one scaffold 148 as
shown in Scheme 3. This was a very satisfying outcome
as in 14 we not only had the correctly installed C8 stereo-
genic centre but also adequate functionality in the two
bridges for further elaboration to the target structure 4.
Next, attention was turned to diastereomer 10 and this
was subjected to the same protocol as 9 as depicted in
Scheme 4 to generate the bicyclo[3.3.1]nonan-9-one frame-
work. Thus, ester hydrolysis in 10 delivered acid 15, which
was transformed to enol-lactone 16.8 Regio- and stereo-
selective kinetic prenylation in 16 led to 17. DIBAL-H
reduction of 17 triggered the retro-aldol/re-aldolization
cascade and led to the anticipated bicyclo[3.3.1]nonan-9-
one derivative 188 quite smoothly in which the homoprenyl
chain at C8 was in the exo-position. Acetylation in 18 was
regioselective and furnished the crystalline monoacetate 19,
Scheme 4. A single crystal X-ray structure determination9
secured its formulation, and by extrapolation, the dia-
stereomeric bicyclo[3.3.1]nonan-9-one derivative 14. The
exo-orientation of the homoprenyl group in 18 was not
an entirely unwelcome outcome as this stereochemical
arrangement is also found in Nature and lends flexibility
to our overall synthetic approach, which can be exploited
in other contexts.10
In summary, we have delineated a concise and promis-
ing synthetic strategy towards the acquisition of the poly-
prenylated bicyclo[3.3.1]nonan-9-one core present in the
phloroglucin natural product hyperforin in which the key
C8 quaternary centre bearing a methyl and homoprenyl
group could be installed.
Acknowledgements
One of us, M.K.B., thanks UGC for the award of a
research fellowship. We thank the CCD facility at IISc
for the single crystal X-ray diffraction data.
References and notes
1. Review Ciochina, R.; Grossman, R. B. Chem. Rev. 2006, 106, 3963–
3986.
2. Selected references: (a) Karanjgoakar, C. G.; Rama Rao, A. V.;
Venkataraman, K.; Palmer, K. J. Tetrahedron Lett. 1973, 14, 4977–
4980; (b) Krishnamurthy, N.; Lewis, Y. S.; Ravindranath, B.
Tetrahedron Lett. 1981, 22, 793–796; (c) Baystrov, N. S.; Chernov,
B. K.; Dobrynin, V. N.; Kolosov, M. N. Tetrahedron Lett. 1975, 16,
2791–2794; (d) de Oliveira, C. M. A.; Porto, M. A.; Brittich, V.;
Venkato, I.; Marsaioli, A. J. Tetrahedron Lett. 1996, 37, 6427–6430;
(e) Fukuyama, Y.; Kuwayama, A.; Minami, H. Chem. Pharm. Bull.
1997, 45, 947–949; (f) Fukuyama, Y.; Minami, H.; Kuwayama, A.
Phytochemistry 1998, 49, 853–857; (g) de Oliveira, C. M. A.; Porto, A.
L. M.; Bittrich, V.; Marsaioli, A. J. Phytochemistry 1999, 50, 1073–
1079; (h) Cuesta-Rubio, O.; Velez-Castro, H.; Frontana-Uribe, B. A.;
O
O
a
CO2Me
CO2H
O
O
´
Cardenas, J. Phytochemistry 2001, 57, 279–283; (i) Shan, M. D.; Hu,
10
15
L. H.; Chen, Z. L. J. Nat. Prod. 2001, 64, 127–130; (j) Winkelmann,
K.; Heilmann, J.; Zerbe, O.; Rali, T.; Sticher, O. J. Nat. Prod. 2001,
b
´
64, 701–706; (k) Cuesta-Rubio, O.; Frontana-Uribe, B. A.; Ramırez-
ˇ
´
Apan, T.; Cardenas, J. Z. Naturforsch. 2002, 57c, 372; (l) Savikin-
Fodulovic´, K.; Aljancˇic´, I.; Vajs, V.; Menkovic´, N.; Macura, S.;
´
´
Gojgic, G.; Milosavljevic, S. J. Nat. Prod. 2003, 66, 1236–1238; (m)
Wu, J.; Cheng, X.-F.; Harrison, L. J.; Goh, S.-H.; Sim, K.-Y.
Tetrahedron Lett. 2004, 45, 9657–9659; (n) Verotta, L.; Lovaglio, E.;
Sterner, O.; Appendino, G.; Bombardelli, E. J. Org. Chem. 2004, 69,
7869–7874; (o) Weng, J.-R.; Tsao, L.-T.; Wang, J.-P.; Wu, R.-R.; Lin,
C.-N. J. Nat. Prod. 2004, 67, 1796–1799; (p) Wu, C.-C.; Weng, J.-R.;
Won, S.-J.; Lin, C.-N. J. Nat. Prod. 2005, 68, 1125–1127; (q) Gartner,
O
O
c
O
O
O
O
17
16
M.; Muller, T.; Simon, J. C.; Giannis, A.; Sleeman, J. P. ChemBio-
¨
d
Chem 2005, 6, 171–177; (r) Herath, K.; Jayasuriya, H.; Ondeyka, J.
G.; Guan, Z.; Borris, R. P.; Stijfhoorn, E.; Stevenson, D.; Wang, J.;
Sharma, N.; Macnaul, K.; Menke, J. G.; Ali, A.; Schulman, M. J.;
Singh, S. B. J. Nat. Prod. 2005, 68, 617–619; (s) Baggett, S.; Protiva,
P.; Mazzola, E. P.; Yang, H.; Ressler, E. T.; Basile, M. J.; Weinstein,
I. B.; Kennelly, E. J. J. Nat. Prod. 2005, 68, 354–360; (t) Massoit, G.;
Long, C.; David, B.; Serrano, M. J.; Daubie, F.; Alby, F.; Ausseil, F.;
Knibiehler, M.; Moretti, C.; Hoffmann, J. S.; Cazaux, C.; Lavaud, C.
J. Nat. Prod. 2005, 68, 979–984; (u) Hernandez, I. M.; Fernandez, M.
C.; Cuesta-Rubio, O.; Piccinelli, A. N.; Rastrelli, L. J. Nat. Prod.
2005, 68, 931–934; (v) Taher, M.; Idris, M. S.; Ahmad, F.; Arbain, D.
Phytochemistry 2005, 66, 723–726; (w) Cao, S.; Brodie, P. J.; Miller, J.
S.; Ratovoson, F.; Birkinshaw, C.; Randrianasolo, S.; Rakotobe, E.;
Rasamison, V. E.; Kingston, D. G. I. J. Nat. Prod. 2007, 70, 686–688.
3. For synthetic studies toward garsubellin A and related natural
products see: (a) Nicolaou, K. C.; Pfefferkorn, J. A.; Kim, S.; Wei, H.
OH
O
OH
O
HO
RO
18
R = H (18)
R = Ac (
e
)
19
Scheme 4. Reagents and conditions: (a) concd HCl, acetone, H2O, 50 °C,
12 h, 80%; (b) NaOAc, Ac2O, 140 °C, 1 h, 69%; (c) LDA,
Me2C@CHCH2Br, À78 °C, 1 h, 53%; (d) DIBAL-H, DCM, 0 °C, 2 h,
50%; (e) Ac2O, Et3N, DMAP, DCM, rt, 1 h, 89%.

1420
G. Mehta, M. K. Bera / Tetrahedron Letters 49 (2008) 1417–1420
X. J. Am. Chem. Soc. 1999, 121, 4724–4725; (b) Usuda, H.; Kanai,
(75 MHz, CDCl3): d 215.5, 135.1, 133.9, 131.9, 131.8, 124.5, 121.5,
118.7, 78.4, 74.4, 66.3, 52.1, 41.9, 41.1, 40.7, 37.2, 34.9, 30.9, 26.1,
25.9, 25.7, 25.5, 21.6, 17.9 (2C), 17.6. HRMS (ES): m/z calculated for
M.; Shibasaki, M. Org. Lett. 2002, 4, 859–862; (c) Usuda, H.; Kanai,
M.; Shibasaki, M. Tetrahedron Lett. 2002, 43, 3621–3624; (d)
Spessard, S. J.; Stoltz, B. M. Org. Lett. 2002, 4, 1943–1946; (e)
Young, D. G. J.; Zeng, D. J. Org. Chem. 2002, 67, 3134–3137; (f)
Kraus, G. A.; Nguyen, T. H.; Jeon, I. Tetrahedron Lett. 2003, 44,
659–661; (g) Takagi, R.; Nerio, T.; Miwa, Y.; Matsumura, S.;
Ohkata, K. Tetrahedron Lett. 2004, 45, 7401–7405; (h) Shimizu, Y.;
Kuramochi, A.; Usuda, H.; Kanai, M.; Shibasaki, M. Tetrahedron
Lett. 2007, 48, 4173–4177.
C
26H42O3H: 403.3212 (M+H)+, found: 403.3218. 16: IR (neat): mmax
1768, 1716, 1679 cmÀ1 1H NMR (300 MHz, CDCl3): d 5.44 (1H, s),
;
5.09–5.04 (1H, m), 4.99–4.94 (1H, m), 2.84–2.15 (6H, m), 2.00–1.93
(4H, m), 1.68 (6H, s), 1.59 (3H, s), 1.57 (3H, s), 1.43–1.37 (2H, m),
0.99 (3H, s); 13C NMR (75 MHz, CDCl3): d 208.9, 168.1, 148.6, 136.5,
132.1, 123.6, 117.5, 117.2, 48.8, 48.2, 42.6, 36.5, 33.8, 28.6, 27.4, 25.9,
25.6, 24.9, 23.1, 17.9, 17.6; HRMS (ES): m/z calculated for
4. (a) Mehta, G.; Bera, M. K. Tetrahedron Lett. 2004, 45, 1113–1116; (b)
Mehta, G.; Bera, M. K. Tetrahedron Lett. 2006, 47, 689–692.
5. For total syntheses of garsubellin A and related natural products, see:
(a) Kuramochi, A.; Usuda, H.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2005, 127, 14200–14201; (b) Siegel, D. R.; Danishefsky, S.
J. J. Am. Chem. Soc. 2006, 128, 1048–1049; (c) Rodeschini, V.;
Ahmad, N. M.; Simpkins, N. S. Org. Lett. 2006, 8, 5283–5285; (d)
Nuhant, P.; David, M.; Pouplin, T.; Delpech, B.; Marazano, C. Org.
Lett. 2007, 9, 287–289; (e) Ahmad, N. M.; Rodeschini, V.; Simpkins,
N. S.; Ward, S. E.; Blake, A. J. J. Org. Chem. 2007, 72, 4803–4815.
6. Nicolaou, K. C.; Carenzi, G. E. A.; Jeso, V. Angew. Chem., Int. Ed.
2005, 44, 3895–3899.
C
21H30O3Na: 353.2093 (M+Na)+, found: 353.2095; 18: IR (thin
film): mmax 3451, 1697 cmÀ1; 1H NMR (300 MHz, CDCl3): d 5.13–5.06
(3H, m), 3.92 (1H, br s), 3.79–3.75 (1H, m), 2.42–2.35 (3H, m), 2.17–
2.13 (3H, m), 2.02–1.85 (6H, m), 1.72 (3H, s), 1.70 (3H, s), 1.65 (6H,
s), 1.62 (3H, s), 1.58 (3H, s), 1.54–1.15 (3H, m), 1.09 (3H, s); 13C
NMR (75 MHz, CDCl3): d 215.2, 135.1, 133.9, 131.2, 124.6, 121.4,
118.7, 78.7, 74.9, 66.9, 52.1, 42.1, 41.0, 40.4, 35.2, 35.0, 30.9, 30.2,
26.1, 25.9, 25.7, 23.9, 22.7, 17.9 (2C), 17.6; HRMS (ES): m/z
calculated for C26H42O3Na: 425.3032 (M+Na)+, found: 425.3048.
9. Single crystal X-ray diffraction data on 19 were collected on a Bruker
AXS SMART APEX CCD diffractometer at 292 K. The X-ray
generator was operated at 50 KV and 35 mA using MoKa radiation.
The data were collected with an x scan width of 0.3°. A total of 606
frames per set were collected using SMART in three different settings
of u (0°, 90° and 180°) keeping the sample at a detector distance of
6.062 cm and the 2h value fixed at À25°. The data were reduced by
SAINTPLUS; an empirical absorption correction was applied using
the package SADABS, and XPREP was used to determine the space
group. The structures were solved using SIR92 and refined using
SHELXL97. Crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre, CCDC-664808. Crystal
data for compound 19: C28H44O4, M = 444.63, monoclinic, space
7. Adam, P.; Arigoni, D.; Bacher, A.; Eisenreich, W. J. Med. Chem.
2002, 45, 4786–4793.
8. All new compounds reported here are racemic and were fully
characterized on the basis of their IR, 1H NMR, 13C NMR and
mass spectral data. Selected spectral data for key compounds: 5: IR
(neat): mmax 1594 cmÀ1 1H NMR (300 MHz, CDCl3): d 5.06–5.02
;
(1H, m), 3.34 (2H, s), 2.63–2.46 (4H, m), 2.04–1.93 (2H, m), 1.67 (3H,
s), 1.59 (3H, s), 1.33–1.26 (2H, m), 0.99 (3H, s). 13C NMR (75 MHz,
CDCl3): d 203.7 (2C), 132.4, 123.2, 57.5, 52.5 (2C), 41.2, 33.6, 25.6,
25.0, 22.3, 17.6. HRMS (ES): m/z calculated for C13H20O2Na:
231.1361 (M+Na)+, found: 231.1356. 9: IR (neat): mmax 1741,
˚
˚
group P21/c, a = 24.474(6) A, b = 6.2143(17) A, c = 18.784(5),
1693 cmÀ1
;
1H NMR (300 MHz, CDCl3): d 5.03–4.98 (1H, m),
b = 90.957(5)°, V = 2856.3(13) A , Z = 4,
q ,
calcd = 1.034 g cmÀ3
3
˚
4.91–4.86 (1H, m), 3.65 (3H, s), 2.59 (4H, s), 2.45 (2H, d, J = 7.2 Hz),
2.21–2.15 (2H, m), 2.09–2.03 (2H, m), 1.96–1.88 (2H, m), 1.66 (6H, s),
1.61 (3H, s), 1.57 (3H, s), 1.16–1.10 (2H, m), 1.01 (3H, s). 13C NMR
(75 MHz, CDCl3): d 208.9 (2C), 173.4, 136.2, 132.3, 123.1, 117.2, 67.9,
51.6, 50.1 (2C), 40.5, 35.1, 33.2, 29.1, 27.4, 25.9, 25.8, 25.6, 22.2, 17.5
F(000) = 976, l = 0.067 mmÀ1, T = 291 K, number of l.s. para-
meters = 298, R = 0.0852, Rw = 0.2466, GOF = 1.041 for 2862
reflections with I > 2r(I). An ORTEP diagram of 19, drawn at 30%
ellipsoidal probability, is shown below:
(2C). HRMS (ES): m/z calculated for
C
22H34O4Na: 385.2355
(M+Na)+, found: 385.2354. 10: IR (neat): mmax 1741, 1693 cmÀ1
;
1H
NMR (300 MHz, CDCl3): d 5.06–5.02 (1H, m), 4.89–4.85 (1H, m),
3.65 (3H, s), 2.70 (2H, 1/2ABq, J = 14.4 Hz), 2.47–2.42 (4H, m), 2.23–
2.16 (2H, m), 2.11–2.04 (2H, m), 1.99–1.88 (2H, m), 1.67 (6H, s), 1.59
(6H, s), 1.35–1.29 (2H, m), 0.87 (3H, s); 13C NMR (75 MHz, CDCl3):
d 209.0 (2C), 173.4, 136.5, 132.2, 123.4, 116.9, 68.2, 51.6, 49.9 (2C),
42.4, 36.1, 33.2, 29.3, 26.6, 25.9, 25.6, 24.9, 22.2, 18.0, 17.6; HRMS
(ES): m/z calculated for C22H34O4Na: 385.2355 (M+Na)+, found:
385.2366; 12: IR (neat): mmax 1768, 1716 cmÀ1 1H NMR (300 MHz,
;
CDCl3): d 5.45(1H, s), 5.04–4.96 (2H, m), 2.66–2.31 (6H, m), 2.01–
1.81 (4H, m), 1.69 (3H, s), 1.66 (3H, s), 1.58 (3H, s), 1.56 (3H, s), 1.35–
1.27 (2H, m), 1.14 (3H, s). 13C NMR (75 MHz, CDCl3): d 209.1,
168.2, 148.6, 136.5, 132.1, 123.5, 117.6, 117.1, 49.1, 48.8, 43.3, 36.1,
33.7, 28.5, 27.5, 25.8, 25.5, 25.2, 23.1, 17.9, 17.6. HRMS (ES): m/z
calculated for C21H30O3Na: 353.2093 (M+Na)+, found: 353.2094. 14:
IR (neat): mmax 3442, 1695 cmÀ1 1H NMR (300 MHz, CDCl3): d
;
5.17–5.06 (3H, m), 3.96 (1H, br s), 3.80–3.72 (1H, m), 2.45–2.36 (2H,
m), 2.19–1.76 (12H, m), 1.73 (3H, s), 1.70 (3H, s), 1.69 (3H, s), 1.66
(3H, s), 1.62 (6H, s), 1.51–1.43 (2H, m), 1.11 (3H, s); 13C NMR
10. Mehta, G.; Bera, M. K.; Chatterjee, S. Tetrahedron Lett. 2008, 49,
1121–1124.