A concise synthesis of the bioactive meroterpenoid natural product (±)-liphagal, a potent PI3K inhibitor

Article abstract of DOI:10.1016/j.tetlet.2009.07.019

A short, diversity-oriented synthesis that follows a biomimetic route to the marine natural product liphagal, from a commercially available building block, is delineated.

Full text of DOI:10.1016/j.tetlet.2009.07.019

Tetrahedron Letters 50 (2009) 5260–5262
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Tetrahedron Letters
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A concise synthesis of the bioactive meroterpenoid natural product
( )-liphagal, a potent PI3K inhibitor
*
Goverdhan Mehta , Nachiket S. Likhite, C. S. Ananda Kumar
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 short, diversity-oriented synthesis that follows a biomimetic route to the marine natural product lipha-
gal, from a commercially available building block, is delineated.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 8 May 2009
Revised 23 June 2009
Accepted 3 July 2009
Available online 9 July 2009
Natural products from diverse marine resources have emerged
as a copious repository of molecular diversity and hold considerable
promise as a rich source of lead structures in drug discovery.1,2 As a
result, marine flora and fauna continue to be explored vigorously by
many natural product chemists in search of new structural entities
and unique biological activity.2 During a collaborative program to
screen marine invertebrate extracts using a fluorescent polarization
Interestingly, 1 was found to be about 10-fold more potent against
PI3K than its isoform PI3K
3 Additionally, in secondary in vitro
assays, liphagal was observed to be cytotoxic to LoVo (human
colon: IC50 0.58 M), CaCo (human colon: IC50 0.67 M), and
MDA-468 (human breast: IC50 1.58
M) tumor cell lines.3 These
impressive bioactivity profiles, particularly the inhibition of PI3K
have drawn widespread attention because phosphatidylinosi-
a
c.
l
l
l
a
assay against human PI3K
a
, Andersen et al., in 2006, reported the
tol-3-kinases (PI3Ks) are pivotal enzymes that control a wide array
of intracellular signaling cascades and thus regulate cell prolifera-
tion and survival, adhesion, chemotaxis, differentiation, glucose
transport, membrane trafficking, and neurite outgrowth amongst
isolation of a novel meroterpenoid named liphagal 1 from the
methanol extract of the sponge Aka coralliphaga, collected from
reefs in Prince Rupert Bay, Portsmouth, Dominica.3 The structure
and stereochemistry of liphagal 1 were elucidated on the basis of
extensive and complementary spectral analyses, particularly NMR
(HMQC, HMBC, and 1D NOESY) studies.3 Liphagal 1 represents the
first member of a new ‘liphagane’ type of meroterpenoid carbon
skeleton. A mixed biogenetic pathway for liphagal 1, emanating
from arylated farnesol 2 has been proposed3 and it accounts for
the AB rings of this natural product displaying a characteristic ses-
quiterpene-like architecture.
others.4 The PI3K
a isoform selectivity exhibited by liphagal 1,
compared to other first generation PI3K inhibitors such as wort-
mannin 3, the natural flavonoids quercetin 4a and myrecetin 4b,
and the synthetic analogue LY 294002 5, which have been de-
ployed extensively in recent years to probe the PI3K signaling
pathways, makes it a lead structure with added value to explore
therapeutic potential against cancer and inflammatory and auto-
immune disorders.4a,5 Mutations, translocations, and amplifica-
tions of PI3K genes have been observed in several manifestations
of human cancer and therefore this lipid kinase is a promising tar-
get for small-molecule inhibition and offers promising therapeutic
opportunities for the treatment of cancer.5
OH
14
HO
CHO
OH
18
CHO
15
HO
HO
D
22
5
C
O
O
1
O
O
OH
11 B
8
21
O
A
OH
R
4
MeO
O
H
HO
O
O
N
O
O
1 liphagal
2
H
O
O
OH
Liphagal 1 exhibited impressive biological activity including
OH
O
inhibitory activity against PI3K
a (phosphoinositide-3-kinase a)
4a quercetin (R = H)
4b myrecetin (R = OH)
5 LY 294002
3 wortmannin
with an IC50 of 100 nM in a primary fluorescent polarization assay.3
Thus, on account of both the structural novelty of its tetracyclic
skeleton, harboring a trans-fused 6,7-bicarbocyclic core with three
stereogenic centers, and its promising biological activity profile,
* 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.2009.07.019

G. Mehta et al. / Tetrahedron Letters 50 (2009) 5260–5262
5261
liphagal 1 holds appeal as a synthetic target for total synthesis to
deliver the natural product in quantities sufficient for detailed
therapeutic evaluation and to build diversity around its novel scaf-
fold. In this Letter, we disclose our approach to liphagal 1, which is
an outcome of our ongoing interest in the synthesis of related
meroterpenoids such as frondosins.6
OHC
MeO
OHC
OHC
HO
OMe
OMe
OMe
OMe
OMe
a
b
OMe HO
Br
12
13
14
c
The group of Andersen,3 while elucidating the structure of
liphagal 1, also reported a total synthesis of the natural product
mimicking a plausible biogenetic route. Our retrosynthetic strategy
toward liphagal was based on the proposed biogenetic pathway3
and hinged on a key C–C bond disconnection that mandated con-
necting a preformed benzofuran precursor 6 with a readily avail-
able monoterpenoid 7 to establish the crucial C–C bond and
access the framework 8. Further elaboration of 8 into 9 was envis-
aged to set up the furan polyene cationic cyclization cascade
(9?10) en route to the target (Scheme 1). The key furan precursor
6 was to be accessed from a readily available aromatic precursor
11.
Regioselective monodemethylation of commercially available
aldehyde 12 led to 13, which on selective bromination furnished
14. One-pot furan annulation7 of 14 was quite smooth and fur-
nished the requisite bromo-benzofuran 158 in fair yield, Scheme
2. Intermolecular displacement by the enolate anion generated
from 15, on geranyl bromide 16, was the key step in accessing
the carbon framework of the target. After a few exploratory exper-
iments using different bases and solvents, it was observed that the
contemplated intermolecular displacement could be effected in the
presence of potassium tert-butoxide in toluene to furnish the de-
sired product 17 in modest yield,8 Scheme 3.
Initially, a direct polyene cyclization of 17 was attempted but
was understandably unsuccessful, as the conjugating carbonyl
group in 17 significantly diminished the propensity of the furan
double bond toward participation in the polyene cyclization cas-
cade. It was therefore considered appropriate to first elaborate
the carbonyl group in 17 into a surrogate functionality of the C21
methyl group in the target, prior to implementing the projected
cationic cascade cyclization. Consequently, furanylketone 17 was
subjected to Wittig olefination to furnish the exomethylene com-
pound 18,8 Scheme 3.
O
O
OMe
OMe
OMe
H
O
O
OMe
Br
O
Br
15
Scheme 2. Reagents and conditions: (a) BBr3, CH2Cl2, 0 °C–rt, 16 h, 87%; (b) Br2,
AlCl3, CH2Cl2, 0 °C–rt, 5 h, 77%; (c) K2CO3, 2-chloroacetone, butane-2-one, reflux,
3 h, 76%.
OMe
OMe
MeO
MeO
Br
Br
O
O
a
+
O
O
Br
16
15
17
b
OMe
OMe
OMe
MeO
MeO
MeO
Br
Br
Br
O
O
O
d
c
H
20
18
19
Scheme 3. Reagents and conditions: (a) tBuOK, toluene, 0 °C, 2 h, 40% based on
recovered starting material; (b) Ph3P+CH3BrÀ, nBuLi, 0 °C, 30 min, 78%; (c) H2, 5%
Pd–CaCO3 poisoned with Pb, MeOH, rt, 30 min, 88%; (d) ClSO3H, 2-nitropropane,
À78 °C, 30 min, 40%.
Regioselective catalytic hydrogenation of the triene 18 pro-
ceeded uneventfully to furnish the desired product 19.8 The stage
was now set to implement the pivotal biomimetic cyclization as
per a general protocol,9 which has been adopted successfully by
Andersen’s group.3 Exposure of 19 to chlorosulfonic acid in 2-nitro-
propane led to the formation of tetracyclic 20 (1:2.5 mixture of
In a complementary sequence to 20, cyclogeranyl bromide 2110
was employed in an intermolecular displacement by the enolate
anion derived from the benzofuran 15 to furnish 22,8 Scheme 4.
This key C–C bond-forming reaction was somewhat better than
a
- and b-C8-methyl epimers, respectively).8 As expected, and in
OMe
OMe
MeO
MeO
Br
Br
keeping with the well-established polyene cyclization, the 6,7-ring
fusion had the desired trans stereochemistry.
O
O
a
+
O
O
OMe
OMe
OMe
MeO
MeO
MeO
Br
R
R
R
21
15
22
b
O
O
O
OMe
OMe
OMe
MeO
MeO
MeO
O
Br
Br
Br
FGI
H
H
O
O
O
10
9
8
7
d
c
base
OMe
OMe
OMe
OMe
R
H
20
+
23
24
O
O
X
OHC
Scheme 4. Reagents and conditions: (a) tBuOK, toluene, 0 °C, 2 h, 50% based on
recovered starting material; (b) Ph3P+CH3BrÀ, nBuLi, 0 °C, 30 min, 80%; (c) H2, 10%
Pd–C, ethyl acetate, rt, 10 min, 90%; (d) ClSO3H, 2-nitropropane, À78 °C, 30 min,
40%.
R
OH
11
6
Scheme 1. Retrosynthetic analysis.

5262
G. Mehta et al. / Tetrahedron Letters 50 (2009) 5260–5262
7. Landelle, H.; Godard, A. M.; Laduree, D.; Chenu, E.; Robba, M. Chem. Pharm. Bull.
OMe
OMe
OMe
1991, 39, 3057–3060.
MeO
MeO
MeO
8. All new compounds were fully characterized on the basis of IR, 1H NMR, 13C
NMR, and HRMS data. Spectral data of selected compounds are as follows:
Br
CHO
CHO
Compound 15: IR (neat): mmax 2924, 1680, 1551, 1461, 1212, 1036 cmÀ1 1H
;
O
O
O
NMR (300 MHz, CDCl3): d 7.45 (s, 1H), 7.05 (s, 1H), 3.92 (s, 3H), 3.91 (s, 3H),
2.61 (s, 3H); 13C NMR (75 MHz, CDCl3): d 187.89, 153.62, 151.53, 148.46,
148.11, 122.50, 112.43, 102.83, 100.42, 60.91, 56.29, 26.15; HRMS (ES): m/z
calcd for C12H11BrO4 (M+Na)+: 320.9738, found: 320.9733; compound 17: IR
a
+
H
H
(neat): mmax 2925, 1682, 1553, 1460, 1214, 1043 cmÀ1 1H NMR (300 MHz,
;
H
20
25
26
CDCl3): d 7.47 (s, 1H), 7.07 (s, 1H), 5.20 (t, J = 7.0 Hz, 1H), 5.07 (t, J = 6.3 Hz, 1H),
3.94 (s, 3H), 3.93 (s, 3H), 3.01 (t, J = 7.5 Hz, 2H), 2.47 (dd, J = 14.5, 7.3 Hz, 2H),
2.09–1.99 (m, 4H), 1.66 (s, 6H), 1.59 (s, 3H); 13C NMR (75 MHz, CDCl3): d
190.82, 153.97, 151.76, 148.61, 148.31, 136.73, 131.37, 124.24, 122.78, 122.43,
112.33, 103.09, 100.72, 61.19, 56.59, 39.66, 39.18, 26.66, 25.63, 22.73, 17.65,
16.05; HRMS (ES): m/z calcd for C22H27BrO4 (M+Na)+: 457.0990, found:
457.0992; compound 18: IR (neat): mmax 2922, 1613, 1578, 1460, 1211,
Scheme 5. Reagents and conditions: (a) (i) nBuLi, THF, À78 °C, 5 min; (ii) DMF,
À78 °C–rt, 1 h, 75%.
1045 cmÀ1 1H NMR (300 MHz, CDCl3): d 6.95 (s, 1H), 6.62 (s, 1H), 5.86 (s,
;
that with geranyl bromide described above, but only marginally.
Compound 22 embodying cyclogeranyl and benzofuran moieties
was subjected to Wittig olefination to furnish the exomethylene
product 23,8 which was reduced catalytically in a regioselective
manner to furnish 24.8 Chlorosulfonic acid-mediated furan–olefin
cyclization followed the desired course and afforded 20 as an epi-
meric mixture, which was found to be identical to that obtained
above from geranyl bromide and benzofuran 15.
With the key precursor 20 in hand, albeit as a mixture of epi-
mers, the bromine substituent was transformed into an aldehyde
group by metal exchange and DMF-mediated formylation to fur-
nish a conveniently separable (HPLC) mixture of tetracyclic alde-
hydes 25 and 26,8 Scheme 5. The resulting liphagal dimethyl
ether 25 and the 8-epi-liphagal dimethyl ether 26 were found to
be spectroscopically identical with the reported compounds.3,11
1H), 5.22–5.18 (m, 2H), 5.10 (t, J = 6.3 Hz, 1H), 3.90 (s, 6H), 2.48–2.43 (m, 2H),
2.34–2.27 (m, 2H), 2.08–1.98 (m, 4H), 1.69 (s, 3H), 1.61 (s, 6H); 13C NMR
(75 MHz, CDCl3): d 157.77, 150.76, 147.11, 145.41, 136.89, 136.01, 131.32,
124.56, 124.34, 123.37, 113.17, 102.86, 102.46, 99.87, 61.13, 56.77, 39.69,
33.18, 27.26, 26.75, 25.64, 17.65, 16.10; HRMS (ES): m/z calcd for C23H29BrO3
(M+Na+: 455.1198, found: 455.1186; compound 19: IR (neat):
m
max 2927, 1460,
1211, 1045 cmÀ1
;
1H NMR (300 MHz, CDCl3): d 6.93 (s, 1H), 6.34 (s, 1H), 5.15–
5.07 (m, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.02–2.91 (m, 1H), 2.08–1.75 (m, 8H),
1.68 (s, 3H), 1.60 (s, 3H), 1.58 (s, 3H), 1.33 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3):
d 165.24, 150.50, 146.85, 144.28, 135.63, 131.30, 124.42, 124.38,
123.85, 102.25, 101.30, 99.80, 61.13, 56.83, 39.71, 35.48, 33.14, 26.70, 25.66,
25.51, 19.06, 17.67, 16.04; HRMS (ES): m/z calcd for C23H31BrO3 (M+Na)+:
457.1354, found: 457.1351; compound 22: IR (neat): mmax 2937, 1687, 1458,
1337, 1214, 1043 cmÀ1 1H NMR (300 MHz, CDCl3): d 7.48 (s, 1H), 7.07 (s, 1H),
;
3.94 (s, 3H), 3.93 (s, 3H), 3.05–2.99 (m, 2H), 2.45 (t, J = 8.55 Hz, 2H), 1.95 (t,
J = 6.0 Hz, 2H), 1.69 (s, 3H), 1.62–1.57 (m, 2H), 1.48–1.42 (m, 2H), 1.06 (s, 6H);
13C NMR (75 MHz, CDCl3): d 191.26, 153.87, 151.71, 148.51, 148.26, 135.79,
128.52, 122.80, 112.37, 102.97, 100.72, 61.19, 56.52, 39.92, 39.82, 35.12, 32.83,
28.54, 23.21, 19.92, 19.48; HRMS (ES): m/z calcd for C22H27BrO4 (M+H)+:
435.1172, found: 435.1183; compound 23: IR (neat): mmax 2927, 1461, 1339,
Since the
natural product liphagal
a-epimer 25 has already been deprotected to give the
1212, 1046 cmÀ1 1H NMR (300 MHz, CDCl3): d 6.96 (s, 1H), 6.67 (s, 1H), 5.83 (s,
;
1
through boron triiodide-mediated
demethylation,3 our acquisition of the tetracyclic dimethyl ether
25 constitutes a formal synthesis of the natural product.
1H), 5.23 (s, 1H), 3.90 (s, 6H), 2.50–2.44 (m, 2H), 2.30–2.24 (m, 2H), 1.95 (t,
J = 6.0 Hz, 2H), 1.69 (s, 3H), 1.62–1.54 (m, 2H), 1.47–1.41 (m, 2H), 1.05 (s, 6H);
13C NMR (75 MHz, CDCl3): d 157.78, 150.71, 147.04, 138.08, 136.65, 127.86,
124.52, 112.70, 102.84, 102.22, 61.16, 56.67, 39.86, 35.05, 35.02, 33.59, 32.82,
28.69, 28.65, 20.03, 19.52; HRMS (ES): m/z calcd for C23H29BrO3 (M+H)+:
433.1379, found: 433.1365; compound 24: IR (neat): mmax 2936, 1458, 1212,
In conclusion, a short (nine linear steps from a commercial
starting material), scalable, and diversity-oriented approach to
the bioactive marine natural product liphagal has been described.
1045, 1000 cmÀ1 1H NMR (300 MHz, CDCl3): d 6.92 (s, 1H), 6.37 (s, 1H), 3.89 (s,
;
3H), 3.88 (s, 3H), 2.98–2.92 (s, 1H), 1.97–1.83 (m, 4H), 1.56–1.50 (m, 6H), 1.42–
1.25 (m, 6H), 0.95 (s, 6H); 13C NMR (75 MHz, CDCl3): d 165.04, 150.46, 146.76,
144.20, 136.96, 127.17, 124.38, 102.09, 101.49, 99.78, 61.14, 56.77, 39.89,
35.69, 34.94, 34.36, 32.78, 28.62, 28.59, 26.19, 19.77, 19.54, 18.98; HRMS (ES):
m/z calcd for C23H31BrO3 (M+H)+: 435.1536, found: 435.1529; compound 25: IR
Acknowledgments
G.M. thanks CSIR for the award of Bhatnagar Fellowship and a
research grant. This research was also facilitated through research
support from the Chemical Biology Unit of JNCASR, Bangalore. We
thank Dr. Ganesh Pandey, NCL, Pune for extending help to access
preparative HPLC.
(neat): mmax 2932, 1693, 1606, 1463, 1239, 1054 cmÀ1 1H NMR (400 MHz,
;
CDCl3): d 10.56 (s, 1H), 7.47 (s, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 3.37–3.28 (m, 1H),
2.57–2.53 (m, 1H), 2.21–2.13 (m, 1H), 1.88–1.82 (m, 1H), 1.73–1.64 (m, 1H),
1.61–1.49 (m, 5H), 1.46 (d, J = 7.2 Hz, 3H), 1.37 (s, 3H), 1.30–1.22 (m, 2H), 0.99
(s, 3H), 0.96 (s, 3H); 13C NMR (100 MHz, CDCl3): d 188.43, 158.86, 149.49,
147.90, 146.34, 125.27, 124.58, 114.80, 113.09, 62.81, 57.29, 53.46, 41.87,
40.31, 39.46, 34.80, 34.77, 33.51, 33.26, 24.04, 22.11, 21.97, 20.20, 18.89; HRMS
(ES): m/z calcd for C24H32O4 (M+Na)+: 407.2198, found: 407.2189; compound
References and notes
26: IR (neat): mmax 2934, 1694, 1463, 1241, 1053 cmÀ1 1H NMR (300 MHz,
;
1. For a recent review, see: Blunt, J. W.; Copp, B. R.; Hu, W.-P.; Munro, M. H. G.;
Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2008, 25, 35–94 and references
cited therein.
2. For reviews on marine natural products as drugs, see: (a) Molinski, T. F.;
Dalisay, D. S.; Lievens, S. L.; Saludes, J. P. Nat. Rev. Drug Disc. 2009, 8, 69–85; (b)
Marris, E. Nature 2006, 443, 904–905; (c) Newman, D. J.; Cragg, G. M. J. Nat.
Prod. 2004, 67, 1216–1238.
3. Marion, F.; Williams, D. E.; Patrick, D. O.; Hollander, I.; Mallon, R.; Kim, S. C.;
Roll, D. M.; Feldberg, L.; Soest, R. V.; Andersen, R. J. Org. Lett. 2006, 8, 321–324.
4. For recent reviews, see: (a) Sundstrom, T. J.; Anderson, A. C.; Wright, D. L. Org.
Biomol. Chem. 2009, 7, 840–850; (b) Hennessy, B. T.; Smith, D. L.; Ram, P. T.; Lu,
Y.; Mills, G. B. Nat. Rev. Drug Disc. 2005, 4, 988–1004.
CDCl3): d 10.57 (s, 1H), 7.42 (s, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 3.36–3.27 (m, 1H),
2.53–2.48 (m, 1H), 1.95–1.46 (m, 9H), 1.42 (d, J = 6.9 Hz, 3H), 1.41 (s, 3H), 1.29–
1.20 (m, 1H), 0.99 (s, 3H), 0.96 (s, 3H); 13C NMR (75 MHz, CDCl3): d 188.28,
157.65, 149.30, 148.03, 146.22, 125.28, 124.06, 115.08, 112.56, 62.79, 57.28,
50.35, 42.01, 40.35, 39.20, 35.79, 34.56, 33.72, 31.19, 22.83, 22.35, 20.45, 18.97,
18.72; HRMS (ES): m/z calcd for C24H32O4 (M+Na)+: 407.2198, found: 407.2189.
9. (a) Ishihara, K.; Ishibashi, H.; Yamamoto, H. J. Am. Chem. Soc. 2002, 124, 3647–
3655; (b) Barrero, A. F.; Altarejos, J.; Alvarez-Manzaneda, E. J.; Ramos, J. M.;
Salido, S. J. Org. Chem. 1996, 61, 2215–2218.
10. Crombie, B. S.; Smith, C.; Varnavas, C. Z.; Wallace, T. W. J. Chem. Soc., Perkin
Trans. 1 2001, 206–215.
11. The stereochemistry of 25 and 26 and of the precursor 20 followed from the
earlier work of Andersen.3
5. Bader, A. G.; Kang, S.; Zhao, L.; Vogt, P. K. Nat. Rev. Cancer 2005, 5, 921–929.
6. Mehta, G.; Likhite, N. S. Tetrahedron Lett. 2008, 49, 7113–7116.