Synthetic studies toward the PPAP natural products, prolifenones A and B and hyperforin: An Effenberger cyclization approach

Article abstract of DOI:10.1016/j.tetlet.2010.07.171

A synthetic approach toward the geranylated PPAP natural products, prolifenones A and B, employing Effenberger cyclization as the key step, is delineated. The efficacy of this approach is further expanded through access to an advanced precursor of hyperfo

Full text of DOI:10.1016/j.tetlet.2010.07.171

Tetrahedron Letters 51 (2010) 5302–5305
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthetic studies toward the PPAP natural products, prolifenones A and B
and hyperforin: an Effenberger cyclization approach
*
Goverdhan Mehta , Thangavel Dhanbal, 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:
A synthetic approach toward the geranylated PPAP natural products, prolifenones A and B, employing
Effenberger cyclization as the key step, is delineated. The efficacy of this approach is further expanded
through access to an advanced precursor of hyperforin.
Received 2 June 2010
Revised 19 July 2010
Accepted 30 July 2010
Available online 6 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Polycyclic polyprenylated acylphloroglucinols (PPAPs) are a
growing family of functionally complex natural products, all based
on a bicyclo[3.3.1]nonane-2,4,9-trione core, and occurring in the
plants and shrubs of the family Clusiaceae (Guttiferae), which in turn
is composed of many genera and species.1,2 PPAPs are notable for
their dense and varied functionalization pattern, mixed biosynthesis
based onthepolyketide andmevalonate pathways, andwide ranging
bioactivity profile.1,2 Clusianone (1), nemorosone (2), and hyperforin
(3), embodying a bicyclo[3.3.1]nonane framework, generously
substituted with prenyl groups and exhibiting impressive biological
activity are typical examples of PPAPs (Fig. 1).1a Considering these
attributes, it is hardly surprising that considerable synthetic efforts,3
including our own,4 have been directed toward this group of natural
products and there have been some noteworthy successes.
More recently, new structural variants among PPAPs, bearing
one or more geranyl substituents at different positions, have been
O
O
O
O
OH
OH
OH
OH
O
O
O
O
O
O
O
O
Ph
Ph
hyperforin (3)
clusianone (1)
nemorosone (2)
prolifenone-A(4)
O
O
O
O
OH
OH
OH
O
OH
O
O
O
O
O
O
O
OH
OH
OH
OH
prolifenone-B(5)
enervosanone (6)
oblongifolin-A (7)
oblongifolin-D (8)
Figure 1.
* Corresponding author. Tel.: +91 4023134848; fax: +91 4023012460.
E-mail address: gmsc@uohyd.ernet.in (G. Mehta).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.171

G. Mehta et al. / Tetrahedron Letters 51 (2010) 5302–5305
5303
unraveled. These include prolifenone A (4), prolifenone B (5),2n
enervosanone (6), oblongifolin A (7),2o and a di-geranylated oblon-
gifolin D (8) as significant examples (Fig. 1). These geranylated
PPAPs 4–8 are attractive targets for total synthesis endeavors, par-
ticularly as they display interesting bioactivities.2 However, no
synthetic report directed toward any member of this family has ap-
peared in the literature so far. As part of our ongoing interest in the
synthesis of PPAP natural products,4 we became interested in the
synthesis of these geranylated PPAPs and wanted to harness the
efficacy of the Effenberger5 cyclization (annulation) as the pivotal
reaction.3aa This choice was dictated by the presence of an enolic
1,3-dicarbonyl moiety in one of the C3 bridges of the bicy-
clo[3.3.1]nonane framework of the PPAPs 4–8, and the demon-
strated utility of the Effenberger cyclization protocol in the
synthesis of the important PPAP natural product clusianone
(1).3c,g,i,m
Among the prototypical geranylated PPAPs, prolifenones A (4)
and B (5) interested us as the setting-up of their C8 quaternary cen-
ter bearing a homogeranyl chain, in a stereoselective manner, was
considered a challenge worth pursuing. In this Letter, we report
our initial studies toward accessing the core structure of prolife-
nones 4 and 5, employing the Effenberger cyclization, and further
extension of this protocol in the context of the closely related PPAP,
hyperforin (3).
Our proposed approach in the context of the prolifenones 4 and
5 is displayed retrosynthetically (for 5) in Scheme 1 and hinged on
the key Effenberger cyclization5 on stereodefined 10 to furnish 9,
the penultimate precursor of the natural product, embodying the
requisite bicyclo[3.3.1]nonanone framework. The precursor 10
was to be accessed from farnesyl-derived methyl ketone 11
through the intermediacy of the dimedone derivative 12 and cyclo-
hexadione enol ether 13, Scheme 1.
The first task was to devise a convenient access to the dimedone
derivative 12 harboring the key C8 quaternary center. For this
purpose, commercial farnesol (14) was oxidized to farnesol in a
routine manner and addition of methyl lithium led to the homo-
farnesol 15, which on further oxidation delivered the farnesyl-de-
rived methyl ketone 11. Tandem Michael addition–Claisen
condensation in 11 with dimethyl malonate led to 16 which deliv-
ered, on further decarboxylation, the required dimedone derivative
126 embodying the C8 quaternary center and a homogeranyl chain,
Scheme 2.
OH
OH
a
14
15
b
O
OMe
MeO C
2
c
O
O
11
12
O
O
MeO C
2
8
O
O
d
16
Scheme 2. Reagents and conditions. (a) (i) MnO2, hexane, 0 °C to rt, 24 h, 82%; (ii)
MeLi, Et2O, À78 °C to 0 °C, 3 h, 89%; (b) MnO2, hexane, 0 °C to rt, 48 h, 68%; (c)
CH2(COOMe)2, NaOEt, EtOH, 60 °C, 12 h; (d) KOH, EtOH, 60 °C, 72 h, 64% (over two
steps).
prenyl bromide furnished a readily separable diastereomeric mix-
ture of 18 and 196 (1:1.1), among which the latter had the required
relative stereochemistry of the prenyl and the homogeranyl sub-
stituents, Scheme 3. The stereochemistry of 18 and 19 was settled
unambiguously through extensive 2D NMR analyses and the key
nOes are displayed on their respective structures. Enone transposi-
tion of the desired diastereomer 19 via DIBAL-H reduction and
acid-mediated elimination of ethanol furnished the transposed en-
one 20. Chemoselective reduction of the enone double bond in 20
was accomplished with NiCl2–NaBH4 to furnish 10,6 Scheme 3.
Cyclohexanone 10 was regioselectively transformed into its TBS–
enol ether 21 to set the stage for the contemplated Effenberger
annulation.
Exposure of 21 to malonyl chloride, essentially following Stol-
tz’s conditions,3aa and subsequent base hydrolysis furnished stere-
oselectively the bicyclo[3.3.1]nonanone scaffold 9, bearing the
enolic 1,3-dicarbonyl moiety, as a mixture of regioisomers, Scheme
The dimedone derivative 12 was readily transformed into the
ethyl enol ether 17 and kinetically controlled alkylation with
O
O
9
OH
5
OH
Effenberger
cyclization
7
Cl
O
1
8
O
O
O
O
H
O
Cl
9
10
5
O
OR
O
O
O
11
12
13
Scheme 1. Retrosynthetic analysis of prolifenone B (5) from farnesyl-derived methyl ketone 11.

5304
G. Mehta et al. / Tetrahedron Letters 51 (2010) 5302–5305
O
O
a
O
OEt
OTBS
O
12
17
Cl
Cl
O
b
22
Figure 2.
O
O
H
H
H
H
H
+
annulation of TBS–enol ether 21, could be converted directly into
the desired regioisomer 24 on exposure to trimethyl orthoformate
and p-toluenesulfonic acid in refluxing methanol. With the acqui-
sition of 24 with requisite C7 and C8 relative stereochemistry,
we had reached the penultimate stage in our synthesis of the pro-
lifenones 4 and 5, and the task that remained was the introduction
of the requisite C1 substituent. However, our initial efforts in this
direction through direct bridge-head substitution at C1, following
appropriate precedence,3m,p were consistently unsuccessful, how-
ever, some tactical modifications are being explored currently.
Having successfully demonstrated the preparation of the
prolifenone framework lacking the C1 substituent, we next ex-
plored the efficacy of the Effenberger cyclization in the related con-
text of hyperforin (3). Toward this objective, cyclohexanone 25,
recently reported by us,4e and having a preinstalled quaternary
center with a homoprenyl substituent, appeared to be a suitable
precursor. The TBS- protected enol ether 26 of 25, on exposure to
malonyl chloride underwent smooth and stereoselective Effenber-
ger cyclization to furnish the bicyclo[3.3.1]nonanone scaffold 27
bearing an enolic 1,3-dicarbonyl moiety, as a mixture of regioisom-
ers. The stereochemical outcome and malonyl group addition from
OEt
OEt
CH3
19
H
nOe
nOe
18
c
d
O
O
20
10
e
O
OH
f
7
8
OTBS
O
9
21
the
a-face once again mirror the observation made in the case of
the prolifenones (vide supra). Brief exposure of 27 to TMS-diazo-
h
g
nOe
O
O
a
H
O
OTBS
O
OMe
7
8
7
+
8
25
26
H
H
OMe
nOe
O
b
nOe
nOe
O
O
24
23
O
OH
c
Scheme 3. Reagents and conditions: (a) TiCl4, EtOH, 0 °C to rt, 1 h, 86%; (b) LDA,
prenyl bromide, À78 °C to 0 °C, 10 h, 92% (18:19 = 1:1.1); (c) (i) DIBAL-H, CH2Cl2,
0 °C, 30 min; (ii) concd HCl, acetone/H2O (20:1), 0 °C, 15 min, 63% (over 2 steps); (d)
NiCl2, NaBH4, MeOH, 0 °C to rt, 1 h, 97%; (e) TBSOTf, Et3N, DMAP, 0 °C to rt, 3 h, 93%;
(f) CH2(COCl)2, CH2Cl2, KOH, PTC, À20 °C, 24 h, 38%; (g) TMS-CHN2, Et2O, 0 °C, 1 h,
66% (23:24 = 1:1); (h) CH(OMe)3, PTSA, MeOH, reflux, 48 h, 45%.
OMe
O
28
27
d
+
O
O
OMe
OMe
e
3. The origin of the stereoselectivity during the Effenberger annu-
lation on 21 leading to 9 may be attributed to the stereoinductive
effect of the axial methyl group which hinders the b-face as shown
in structure 22 (Fig. 2). Exposure of 9 to TMS-diazomethane led to
two readily separable regioisomeric methyl enol ethers 23 and 24,6
Scheme 3. The two regioisomeric methyl enol ethers were differen-
tiated on the basis of 2D NMR studies, more notably through the
key nOes depicted on structures 23 and 24. It was further observed
that the regioisomeric mixture 9, obtained from the Effenberger
O
O
29
30
Scheme 4. Reagents and conditions: (a) TBSOTf, Et3N, DMAP, CH2Cl2, 0 °C, 3 h, 95%;
(b) CH2(COCl)2, KOH, CH2Cl2, H2O, À10 °C, 24 h; (c) TMS-CHN2, Et2O, 0 °C, 1 h, 25%
(over two steps) (28:29 = 1:1); (d) CH(OMe)3, PTSA, MeOH, 50 °C, 48 h, 66%; (e) LDA,
prenyl bromide, THF, À78 °C, 1 h, 61%.

G. Mehta et al. / Tetrahedron Letters 51 (2010) 5302–5305
5305
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diate in quest for the natural product hyperforin, Scheme 4. The
present approach to 30, only requiring further introduction of the
C1 and C3 substituents, should pave the way for developing a short
synthesis of hyperforin.
In conclusion, we have demonstrated the utility of an Effenber-
ger cyclization-based approach in the stereoselective synthesis of
the penultimate precursor of the geranylated PPAPs, prolifenones
A and B. The efficacy of this tactic has been further demonstrated
through a short access to an advanced intermediate of hyperforin.
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6. All new compounds reported here are racemic and characterized on the basis of
spectroscopic data (IR, 1H, 13C NMR and HRMS). Compound 12: IR (neat): mmax
Acknowledgments
1588, 1576 cmÀ1 1H NMR (300 MHz, CDCl3): d 5.06–5.02 (m, 2H), 3.34 (s, 2H),
.
2.60 (1/2ABq, J = 14 Hz, 2H), 2.48 (1/2ABq, J = 14 Hz, 2H), 2.05–1.93 (m, 6H), 1.67
(s, 3H), 1.58 (s, 3H), 1.57 (s, 3H), 1.42–1.22 (m, 2H), 0.98 (s, 3H). 13C NMR
(75 MHz, CDCl3): d 203.76 (2C), 135.99, 131.45, 124.11, 123.01, 57.51, 52.46,
44.64, 41.17, 39.58, 33.59, 26.57, 25.66, 25.05, 22.19, 17.65, 15.92. HRMS (ES):
m/z calcd for C18H28O2Na (M+Na): 299.1987, found: 299.1985. Compound 19: IR
D.T. thanks JNCASR for the award of a post-doctoral fellowship.
M.K.M. thanks CSIR for the award of a research fellowship. G.M. is
thankful to CSIR for the award of a Bhatnagar Fellowship.
(neat): mmax 1660, 1614 cmÀ1 1H NMR (300 MHz, CDCl3): d 5.25 (s, 1H), 5.20–
.
5.16 (m, 1H), 5.07–5.03 (m, 2H), 3.76 (q, J = 6.9 Hz, 2H), 2.37–1.93 (m, 12H), 1.68
(s, 6H), 1.60 (s, 6H), 1.57 (s, 3H), 1.43–1.41 (m, 1H), 1.36 (t, J = 7.2 Hz, 3H), 0.98
(s, 3H). 13C NMR (75 MHz, CDCl3): d 202.05, 174.00, 135.31, 131.65, 131.37,
124.24, 123.91, 123.22, 100.80, 64.04, 55.32, 40.32, 39.64, 39.59, 37.83, 26.63,
25.78, 25.68, 24.56, 22.26, 22.16, 17.80, 17.67, 15.92, 14.15. HRMS (ES): m/z
calcd for C25H40O2 (M+H): 373.3106, found: 373.3114. Compound 10: IR (neat):
References and notes
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mmax 1716, 1450 cmÀ1 1H NMR (300 MHz, CDCl3): d 5.12–5.06 (m, 3H), 2.38–
.
2.18 (m, 5H), 2.12–1.96 (m, 8H), 1.71 (s, 3H), 1.68 (s, 3H), 1.61 (s, 3H), 1.59 (s,
6H), 1.23–1.54 (m, 2H), 0.81 (s, 3H). 13C NMR (75 MHz, CDCl3): d 212.73, 135.27,
132.62, 131.37, 124.23, 124.01, 123.36, 52.52, 42.70, 41.35, 40.93, 40.84, 39.66,
27.45, 27.27, 26.65, 25.84, 25.68, 21.75, 20.05, 17.88, 17.67, 15.94. HRMS (ES):
m/z calcd for C23H38ONa (M+Na): 353.2820, found: 353.2814. Compound 23: IR
´
ˇ ´
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(neat): mmax 1737, 1659, 1599 cmÀ1 1H NMR (400 MHz, CDCl3): d 5.73(s, 1H),
.
5.10–5.02 (m, 2H), 4.97–4.95 (m, 1H), 3.76 (s, 3H), 3.15 (br s, 1H), 3.10(s, 1H),
2.26–1.86 (m, 8H), 1.72–1.53 (m, 4H), 1.68 (s, 3H), 1.66 (s, 3H), 1.63 (s, 3H), 1.61
(s, 3H), 1.55 (s, 3H), 1.17–1.09 (m, 1H), 0.92 (s, 3H). 13C NMR (100 MHz, CDCl3): d
206.38, 195.64, 175.57, 135.28, 133.37, 131.40, 124.19, 123.88, 122.15, 105.96,
61.44, 61.06, 56.61, 44.57, 39.68, 38.92, 38.56, 33.55, 28.09, 26.66, 25.78, 25.68,
21.51, 17.88, 17.68, 17.49, 15.89. HRMS (ES): m/z calcd for C27H40O3Na (M+Na):
435.2875, found: 435.2864. Compound 24: IR (neat): mmax 1739, 1657,
1606 cmÀ1 1H NMR (400 MHz, CDCl3): d 5.68 (s, 1H), 5.12–5.07 (m, 2H), 4.96
.
(m, 1H), 3.77 (s, 3H), 3.13 (d, J = 4 Hz, 1H), 3.10 (s, 1H), 2.46–2.38 (m, 1H), 2.19–
2.15 (m, 1H), 2.09–2.04 (m, 3H), 1.98–1.95 (m, 2H), 1.88–1.85 (m, 1H), 1.73–1.70
(m, 3H), 1.69 (s, 3H), 1.68 (s, 3H), 1.67 (s, 3H), 1.60 (s, 3H), 1.57 (s, 3H), 1.51–1.52
(m, 1H), 1.35–1.31 (m, 1H), 0.88 (s, 3H). 13C NMR (100 MHz, CDCl3): d 206.58,
194.09, 175.53, 135.33, 133.21, 131.22, 124.41, 124.02, 122.33, 105.43, 69.41,
56.85, 53.04, 45.71, 39.73, 39.58, 38.47, 32.05, 27.50, 26.72, 25.80, 25.67, 21.49,
17.90, 17.66, 17.51, 15.95. HRMS (ES): m/z calcd for
435.2875, found: 435.2878. Compound 28: IR (Neat): mmax 1737, 1660,
1599 cmÀ1 1H NMR (300 MHz, CDCl3): d 5.74 (s, 1H), 5.05–4.95 (m, 2H), 3.77
C27H40O3Na (M+Na):
.
(s, 3H), 3.15 (s, 1H), 3.10 (s, 1H), 2.21–2.15 (m, 4H), 1.89–1.84 (m, 1H), 1.69 (s,
3H), 1.65 (s, 3H), 1.63 (s, 3H), 1.54 (s, 3H), 1.23–1.06 (m, 3H), 0.91 (s, 3H), 0.89–
0.84 (m, 1H). 13C NMR (75 MHz, CDCl3): d 206.43, 195.68, 175.60, 133.39,
131.70, 124.00, 122.12, 105.95, 61.39, 61.04, 56.65, 44.54, 38.92, 38.54, 33.52,
28.06, 25.79, 25.73, 21.61, 17.90, 17.58, 17.47. HRMS (ES): m/z calcd for
3. Lead references for synthetic approaches and total syntheses of PPAP natural
ptoducts: (a) Shimizu, Y.; Shi, S. L.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew.
Chem., Int. Ed. 2010, 49, 1103–1106; (b) Abe, M.; Saito, A.; Nakada, M.
Tetrahedron Lett. 2010, 51, 1298–1302; (c) Tolon, B.; Delpech, B.; Marazano, C.
ARKIVOC 2009, 13, 252–264; (d) Barabé, F.; Bétournay, G.; Bellavance, G.;
Barriault, L. Org. Lett. 2009, 11, 4236–4238; (e) Couladouros, E. A.; Dakanali, M.;
Demadis, K. D.; Vidali, V. P. Org. Lett. 2009, 11, 4430–4433; (f) Kraus, G. A.; Jeon,
I. Tetrahedron Lett. 2008, 49, 286–288; (g) Nuhant, P.; David, M.; Pouplin, T.;
Delpech, B.; Marazano, C. Org. Lett. 2007, 9, 287–289; (h) Takagi, R.; Inoue, Y.;
Ohkata, K. J. Org. Chem. 2008, 73, 9320–9325; (i) Ahmad, N. M.; Rodeschini, V.;
Simpkins, N. S.; Ward, S. E.; Wilson, C. Org. Biomol. Chem. 2007, 5, 1924–1934; (j)
Tsukano, C.; Siegel, D. R.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2007, 46, 8840–
8844; (k) Qi, J.; Porco, J. A., Jr. J. Am. Chem. Soc. 2007, 129, 12682–12683; (m)
Rodeschini, V.; Simpkins, N. S.; Wilson, C. J. Org. Chem. 2007, 72, 4265–4267; (n)
Abe, M.; Nakada, M. Tetrahedron Lett. 2007, 48, 4873–4877; (o) Abe, M.; Nakada,
M. Tetrahedron Lett. 2006, 47, 6347–6351; (p) Siegel, D. R.; Danishefsky, S. J. J.
C
22H33O3 (M+H): 345.2429, found: 345.2427. Compound 29: IR (Neat): mmax
1737, 1654, 1604 cmÀ1 1H NMR (300 MHz, CDCl3): d 5.68 (s, 1H), 5.11–4.96 (m,
.
2H), 3.77 (s, 3H), 3.13 (br s, 1H), 3.09 (s, 1H), 2.44–2.40 (m, 1H), 2.16–2.06 (m,
3H), 1.88–1.78 (m, 1H), 1.68 (s, 9H), 1.56 (s, 3H), 1.35–1.25 (m, 2H), 0.88 (s, 3H),
0.89–0.85 (m, 2H). 13C NMR (75 MHz, CDCl3): d 206.66, 194.14, 175.57, 133.24,
131.78, 124.18, 122.30, 105.43, 69.37, 56.87, 53.03, 45.71, 39.56, 38.47, 32.03,
27.49, 25.81, 25.73, 21.60, 17.93, 17.65, 17.48. HRMS (ES): m/z calcd for
C
22H33O3 (M+H): 345.2429, found: 345.2427. Coumpound 30: IR (Neat): mmax
1732, 1656, 1598 cmÀ1 1H NMR (400 MHz, CDCl3): d 5.71 (s, 1H), 5.09–5.06 (m,
.
1H), 4.98–4.95 (m, 2H), 3.74 (s, 3H), 3.14 (s, 1H), 2.48–2.34 (m, 3H), 2.17–2.11
(m, 1H), 1.95–1.84 (m, 1H), 1.69 (s, 3H), 1.67 (s, 3H), 1.65 (s, 3H), 1.64 (s, 3H),
1.60 (s, 3H), 1.56 (s, 3H), 1.54–1.38 (m, 2H), 1.29–1.18 (m, 2H), 0.85 (s, 3H),
0.89–0.81 (m, 2H). 13C NMR (100 MHz, CDCl3): d 207.05, 193.84, 177.39, 133.66,
133.12, 131.67, 124.28, 122.49, 119.36, 106.23, 70.39, 56.83, 56.74, 45.88, 40.71,
39.20, 38.49, 29.63, 27.59, 25.87, 25.82, 25.72, 21.71, 17.95, 17.89, 17.67, 17.60.
HRMS (ES): m/z calcd for C27H40O3Na (M+Na): 435.2875, found: 435.2871.