Synthetic studies toward geranylated PPAP natural products oblongifolin A, oblongifolin D, and enervosanone

Article abstract of DOI:10.1016/j.tetlet.2012.06.045

A concise approach of general utility toward mono- and di-geranylated PPAP frameworks employing 'reconstructive aldol cyclization' as the key step is delineated.

Full text of DOI:10.1016/j.tetlet.2012.06.045

Tetrahedron Letters 53 (2012) 4538–4542
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Tetrahedron Letters
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Synthetic studies toward geranylated PPAP natural products oblongifolin A,
oblongifolin D, and enervosanone
Goverdhan Mehta a,b, , Manabendra Das a, Uday Kumar Kundu a
⇑
a Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
b School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise approach of general utility toward mono- and di-geranylated PPAP frameworks employing
‘reconstructive aldol cyclization’ as the key step is delineated.
Received 22 May 2012
Revised 7 June 2012
Accepted 9 June 2012
Available online 21 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
PPAP natural products
Geranylation
Michael addition
Aldol cyclization
The plant family Clusiaceae (Guttiferae), which in turn consists
of many genera and species, has been receiving attention for cen-
turies as they are mentioned in folk medicine for alleviating a vari-
ety of disorders. Recent investigations into the chemical
constituents of this family have revealed it to be a rich repository
of polycyclic polyprenylated acylphloroglucinol (PPAP) natural
products, a novel and growing group of complex natural products
embodying a bicyclo[3.3.1]nonane-2,4,9-trione core.1,2 A notable
feature of PPAPs is the presence of a dense and varied oxy-func-
tionalization pattern together with generous and strategic place-
ment of hydrophobic prenyl arms on its bicyclic nucleus. Indeed,
PPAPs are constituted through mixed biosynthesis involving the
polyketide and mevalonate pathways. Many PPAPs have been
shown to exhibit a very wide ranging bioactivity profile that in-
cludes anticancer, antibacterial, antidepressant, anti-HIV, antima-
larial, antiulcer, and anti-neurodegenerative among others.1,2
Prototypical examples of some prominent PPAP natural products
are clusianone 1, nemorosone 2, and hyperforin 3, all embodying
a bicyclo[3.3.1]nonane frame and each laced with 3 or 4 prenyl
substituents (Fig. 1). Considering their structural and bioactivity
attributes, it is natural that PPAPs have drawn considerable atten-
tion from the synthetic community world-wide1,3 as well as from
our group4 and two very recent reviews1b,c summarize the note-
worthy achievements in the arena.
stituents are present at C5, C7, or C8 positions, have surfaced re-
cently.2m–o Notable examples of such entities include mono-
geranylated oblongifolin A 42o and enervosanone 62m and di-ger-
anylated oblongifolin D 5.2o These geranylated PPAPs 4-(Fig. 1)
and many of their recently reported siblings also exhibit impres-
sive biological activity.5 Recent reports6 that a higher prenylated
moiety like the geranyl group with extended reach and conforma-
tional flexibility can provide enhanced affinity for biological mem-
branes and interactions with cellular targets in some bioactive
compounds6b,c have further kindled interest in geranylated PPAPs.
However, barring one report4f from our group outlining an Effen-
berger cyclization based approach to the C8-geranylated PPAP
framework, there have been no other endeavors targeted toward
geranylated PPAPs. We report here a tactical variant of our general
methodology4b,d toward PPAPS that provides convenient access to
the C5 and C7 mono-geranylated and C5, C7-di-geranylated core
present in natural products 4–6, respectively.
Following our earlier forays toward PPAPs, the present approach
toward geranylated bicyclo[3.3.1]nonane framework also ema-
nated from dimedone derived enol ether 7. The initial aim was to
install the geranyl substituents at the C5 and/or C7 position with
requisite relative stereochemistry required for oblongifolins A 4
and D 5.20 Geranylation of 7 with geranyl bromide proceeded
smoothly and led to geranylated enol ether 8. Hydrolysis to dime-
done derivative 9 with a reactive 1,3-dicarbonyl functionality lend
itself amenable toward implementing a quaternization protocol in
a stereocontrolled manner.7 Sequential Michael addition to methyl
acrylate and prenylation of 9 in a single pot operation led to the
installation of the quaternary center with requisite stereochemistry
A subclass of novel natural products representing an interesting
structural variant among PPAPs, wherein one or more geranyl sub-
⇑
Corresponding author. Tel.: +91 4023010785; fax: +91 4023012460.
E-mail addresses: gmsc@uohyd.ernet.in, gm@orgchem.iisc.ernet.in (G. Mehta).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.045

G. Mehta et al. / Tetrahedron Letters 53 (2012) 4538–4542
4539
O
O
O
OH
OH
OH
O
O
O
O
O
Ph
O
Ph
Hyperforin 3
Clusianone 1
Nemorosone 2
O
O
9
O
OH
OH
OH
5
7
2
O
O
O
O
O
O
OH
OH
OH
Oblongifolin D 5
Figure 1. Representative PPAP natural products.
Enervosanone 6
OH
Oblongifolin A 4
O
O
O
O
a
b
c
O
OEt
O
OEt
O
OR
8
7
9
10. R=Me
11. R=H
d
e
O
O
O
f
H
O-
O
O
O
O
O
13
12
OH
O
9
O
g
5
7
O
O
OH
14
15
Scheme 1. Reagents and conditions: (a) LDA, geranyl bromide, THF, À78 °C ? À5 °C, 12 h, 92%; (b)10% HCl, acetone–water (10:1), 25 °C, 12 h, 95%; (c) DBU (0.3 mole), THF,
methyl acrylate (1.1 equiv), 5 h, then prenyl bromide (1.1 equiv), 3 h, 67%; (d) KOH, MeOH–H2O (10:1), 65 °C, 4 h, 96%; (e) Ac2O–NaOAc, 140 °C, 3 h under N2, 81%; (f) DIBAL-H
(3 equiv), 0 °C, 2 h; (g) PCC, SiO2, DCM, 25 °C, 86% after 2-steps.
and delivered 10 (Scheme 1). 1,3-Stereoinduction by the pre-exist-
ing geranyl arm in 9, as observed in related cases by us earlier,4b,c
and the chosen sequence of the tandem Michael addition-alkylation
reactions secured the stereochemistry depicted in 10. Ester hydro-
lysis in 10 to acid 11 and enol-lactonization following a classical
protocol led to 12. A reconstructive aldol protocol in 12 was trig-

4540
G. Mehta et al. / Tetrahedron Letters 53 (2012) 4538–4542
O
O
O
c
a
9
O
O
O
RO
16. R=Me
17. R=H
18
b
d
O
O
HO
O
e
O
OH
20
19
Scheme 2. Reagents and conditions: (a) DBU (0.5 equiv), THF, methyl acrylate (1.1 equiv), 5 h, then geranyl bromide (1.1 equiv), 3 h, 62%; (b) KOH, MeOH–H2O (10:1), 65 °C,
4 h, 82%; (c) Ac2O–NaOAc, 140 °C, 2 h under N2, 82%; (d) DIBAL-H (3 equiv), 0 °C, 1.5 h; (e) PCC, SiO2, DCM, 25 °C, 87% after 2-steps.
a
a
OMe
21
23
22
Scheme 3. Reagents and conditions: (a) DBU (0.5 equiv), THF, geranyl bromide, 25 °C, 5 h, then methyl acrylate (1.1 equiv), 2 h, 80%.
gered through DIBAL-H mediated reduction to the thermodynami-
cally controlled re-aldolization cyclized to a bicylco[3.3.1]nonane
framework bearing diol 14 through concurrent reduction of the by-
stander carbonyl group. PCC oxidation of the diol 14 smoothly
delivered the triketone 15 bearing the C5-prenyl and C7-geranyl
substituent pattern and in particular the C7-geranyl group in the
desired ‘endo’ stereochemistry required for oblongifolin A.
As we turned our attention to enversanone 6,2m it became clear
that the strategy that proved successful in the case of oblongifolins
A & D required tweaking in the case of 6 as the C7 prenyl substitu-
ent in this case was ‘exo’ disposed. An obvious solution toward this
end was to reverse the sequence of tandem Michael addition-alkyl-
ation in 21 to first mono geranylation and then Michael addition to
deliver 21 which would eventuate in ‘exo’ C7 prenyl substituent at
the end of the sequence (Scheme 3). When an attempt was made to
execute this tandem protocol on 9, it only delivered the gem-diger-
anylated 23 and not the required 22 perhaps due to the very reac-
tive nature of the 1,3-carbonyl moiety present in it (Scheme 3). Our
repeated failures to access 22 forced us to redesign our strategy.
For this purpose, dimedone derived enol ether 7 was readily preny-
lated to 24 and further enone transposition through reduction and
acid hydrolysis led to 25 (Scheme 4). Conjugate reduction in 25 led
to 26 (Scheme 4). A regio- and stereocontrolled geranylation in 26
could now be implemented under kinetically controlled conditions
to deliver mono-geranylated product 27. The anion derived from
27 readily underwent Michael addition to methyl acrylate to fur-
nish 28 and set-up the quaternary center in a stereocontrolled
manner through 1,3-stereoinduction. Acid hydrolysis of 28 and
enol-lactonization of the resultant carboxylic acid 29 delivered
30 (Scheme 4). DIBAL-H reduction of 30 triggered the reconstruc-
tive aldol cyclization to result in bicyclo[3.3.1]nonane framework
31 with ‘exo’ disposed C7 prenyl group. Oxidation of 31 led to
Build-up of the digeranylated framework present in oblongifo-
lin D was next on the agenda and the monogeranylated dimedone
9 served as the starting point. Quaternization in 9 was now imple-
mented through a tandem Michael addition of methyl acrylate and
alkylation with geranyl bromide in a single pot operation to furnish
16 (Scheme 2). Stereochemistry of 16 was again dictated by the
1,3-stereoinduction and the chosen sequence of the tandem Mi-
chael addition and alkylation. Ester hydrolysis in 16 to the acid
17 and enol-lactonization smoothly delivered the enol-lactone 18
(Scheme 2). Reconstructive aldolization in 18 though retro-aldol
and re-aldol steps, induced by DIBAL-H reduction of 18, led to
the dihydroxylated bicyclo[3.3.1]nonane framework 19 through
collateral carbonyl reduction. Bicyclic diol 19, apparently a mixture
of hydroxyl diastereomers, was oxidized by PCC to a single bicy-
clo[3.3.1]nona-2,6,9-trione 20 embodying the core structure of
oblongofolin D (Scheme 2). Interestingly, both 15 and 20 have gen-
erous substitution on their bicyclic framework for further evolu-
tion toward the targeted natural products.

G. Mehta et al. / Tetrahedron Letters 53 (2012) 4538–4542
4541
O
a
b
c
7
O
O
OEt
24
25
26
d
g
e
O
O
O
O
OR
O
H
28. R=Me
29. R=H
27
f
h
O
O
i
O
O
OH
HO
30
31
32
Scheme 4. Reagents and conditions: (a) LDA, prenyl bromide, THF, À78 °C ? À5 °C, 12 h, 77%; (b) DIBAL-H, THF, 0 °C, 2 h and then 50% HCl, acetone–water (3:1), 25 °C,
30 min, 67% after two steps; (c) K-selectride, THF, À55 °C, 4 h, 87%; (d) LDA, geranyl bromide, THF, À78 °C, 91%; (e) KtOBu, THF, methyl acrylate (1.1 equiv), 0.5 h, 75%; (f)
KOH, MeOH–H2O (10:1), 25 °C, 8 h, 87%; (g) Ac2O–NaOAc, 120 °C, 4 h under N2, 67%; (h) DIBAL-H (3 equiv), 0 °C, 2 h, 82%; (i) PCC, SiO2, DCM, 25 °C, 95%.
Ressler, E. T.; Basile, M. J.; Weinstein, I. B.; Kennelly, E. J. J. Nat. Prod. 2005, 68,
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the desired bicyclo[3.3.1]nonan-3-9-dione 32 for further
elaboration.
In summary, we have advanced the utility of a general ‘recon-
structive aldol cyclization’ based approach to PPAPs and report
here the first synthesis of the geranylated bicyclo[3.3.1]nonane
core present in oblongifolins A and D and enversanone.
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Acknowledgments
G.M. thanks CSIR, India for the award of Bhatnagar Fellowship.
M.D. and U.K.K. thank CSIR and JNCASR, Bangalore for the award of
Research Fellowship and post-doctoral fellowship, respectively.
This research was carried out at the Indian Institute of Science,
Bangalore. G.M. also acknowledges the current research support
from Eli Lilly and Jubilant Bhartia Foundations at the University
of Hyderabad.
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7. All new compounds were characterized on the basis of their spectroscopic data
(IR, 1H, 13C, MS). Spectral data for some of the key compounds are as follows: 15:
IR (neat) 1742, 1715, 1702 cmÀ1 1H NMR (300 MHz, CDCl3) d 5.16–5.12 (m, 1H),
;
5.7–5.03 (m, 1H), 4.94–4.91 (m, 1H), 3.4 (s, 1H), 2.45–2.36 (m, 5H), 2.10–1.94
(m, 6H), 1.68–1.58 (cluster of s, 15H), 1.48–1.41 (m, 1H), 1.32 (s, 3H), 0.83 (s,
3H); 13C NMR (75 MHz, CDCl3) d 209.6, 206.1, 204.3, 136.8, 135.7, 131.5, 124.0,
121.5, 117.33, 78.6, 63.4, 61.4, 40.0, 37.6, 36.2, 32.1, 31.1, 27.2, 26.7, 25.9, 25.7,
22.3, 20.0, 17.7, 17.6, 15.9; HRMS(ES): m/z Calcd for C26H38O3 (M+Na): 421.2719.
Found: 421.2724. 20: IR (neat) 1739, 1714, 1702 cmÀ1 1H NMR (300 MHz,
;
CDCl3) d 5.17–5.12 (m, 1H), 5.05–5.03 ((m, 1H), 4.96–4.92 (m, 1H), 3.4 (s, 1H),
2.58–2.38 (m, 5H), 2.19–1.95 (m, 12H), 1.66–1.58 (cluster of s, 18H), 1.31, (s,
3H), 0.83 (s, 3H);); 13C NMR (75 MHz, CDCl3) d 209.4, 205.9, 204.1, 139.3 (2c),
136.9, 131.5, 124.1, 121.6, 119.3, 117.2, 78.8, 63.5, 61.2, 57.90, 39.9 (2C), 37.6,
37.4, 36.2, 32.1, 30.8, 27.0, 26.7, 26.6, 25.9, 25.6, 22.4, 19.9, 17.6, 16.1; m/z Calcd
for
C
31H46O3 (M+Na): 489.3345. Found: 489.3354; 31: IR (neat) 1725,
1702 cmÀ1
;
1H NMR (300 MHz, CDCl3) d 5.22(t, 1H), 5.08 (br s, 3H), 2.88 (s,
1H), 2.77–2.50 (m, 2H), 2.24–1.80 (m, 12H), 1.71 (s, 3H), 1.67 (s, 3H), 1.60 (br s,
9H), 1.42–1.22 (m, 1H), 1.06 (s, 3H), 0.84 (s, 3H); 13C NMR (75 MHz, CDCl3) d
210.4, 208.4, 138.1, 133.09, 131.4, 124.2, 122.7, 119.4, 79.3, 49.4, 45.5, 42.6,
42.4, 40.1, 39.5, 35.2, 29.8, 29.5, 26.7 (2C), 25.8, 25.7, 21.2, 17.9, 17.7, 16.2; m/z
Calcd for C26H40O2 (M+Na): 407.2926. Found: 407.2931.