Efficient synthesis of key intermediate toward liphagal synthesis

Article abstract of DOI:10.1080/00397910903531920

Liphagal (A) is a very potent and selective inhibitor of PI3K (p110) and is under development for an oncolytic drug. We herein report the new and concise synthesis of key intermediates (7, 8), which have been used for liphagal synthesis and will be useful

Full text of DOI:10.1080/00397910903531920

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Efficient Synthesis of Key Intermediate
Toward Liphagal Synthesis
Vijaykumar Deore a , Manoj Kumar Lohar a , Ramswaroop Mundada a
, Abhijit Roychowdhury a , Ram Vishwakarma a & Sanjay Kumar a
a Department of Medicinal Chemistry , Piramal Life Sciences ,
Mumbai, India
Published online: 15 Dec 2010.
To cite this article: Vijaykumar Deore , Manoj Kumar Lohar , Ramswaroop Mundada , Abhijit
Roychowdhury , Ram Vishwakarma & Sanjay Kumar (2010) Efficient Synthesis of Key Intermediate
Toward Liphagal Synthesis, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 41:2, 177-183, DOI: 10.1080/00397910903531920
To link to this article: http://dx.doi.org/10.1080/00397910903531920
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Synthetic Communications1, 41: 177–183, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903531920
EFFICIENT SYNTHESIS OF KEY INTERMEDIATE
TOWARD LIPHAGAL SYNTHESIS
Vijaykumar Deore, Manoj Kumar Lohar,
Ramswaroop Mundada, Abhijit Roychowdhury,
Ram Vishwakarma, and Sanjay Kumar
Department of Medicinal Chemistry, Piramal Life Sciences, Mumbai, India
Liphagal (A) is a very potent and selective inhibitor of PI3Ka (p110a) and is under devel-
opment for an oncolytic drug. We herein report the new and concise synthesis of key inter-
mediates (7, 8), which have been used for liphagal synthesis and will be useful for
generating liphagal-based chemical entities for drug discovery purposes.
Keywords: Anticancer; isoform selective inhibitor; liphagal; natural product synthesis; PI3K
INTRODUCTION
Phosphatidylinositol-3-kinases (PI3Ks) are members of a family of lipid
kinases that regulate cellular metabolism and growth by phosphorylation of the
3-position of phosphatidylinositol diphosphate (PIP2) to phosphatidylinositol tri-
phosphate (PIP3). The PI3K signaling pathway is negatively regulated by phospha-
tase and tensin homolog (PTEN), which is most frequently mutated in human
cancer. This leads to amplification of signaling and as such is a promising target
for small-molecule inhibition, with potential therapeutic targets for anticancer drug
development.[1–5] Based on the primary structure and mechanism of action, PI3Ks
are divided into two major classes, class I and class II.[6,7] The class I PI3Ks are
further divided into class IA enzymes: p110a, p110b, and p110d, which are activated
by tyrosine kinase receptors, whereas the only member of class IB enzyme, p110c, is
activated by G-protein-coupled receptor. The class II PI3Ks, C2a, C2b, and C2c, are
characterized by the presence of a C2 domain at the C terminus. The recent studies
with isoform-specific small-molecule inhibitors helped to elucidate the distinct cellu-
lar function of different class I isoforms (p110a, p110b, p110d, and p110c). It has
been reported that inhibition of p110a is essential for affecting growth suppression
in malignant cell lines.[8] The other class I isoforms have their therapeutic potential
in other disease areas, namely, inflammation, autoimmune disease (p110d and
p110c), and thrombosis (p110b).[1,3,9–11] The isoform specific molecules capable
of attenuating PI3 K signaling should have significant therapeutic potential for
Received September 30, 2009.
Address correspondence to Sanjay Kumar, Department of Medicinal Chemistry, Piramal Life
Sciences, Mumbai 400 063, India. E-mail: Sanjay.kumar@piramal.com
177

178
V. DEORE ET AL.
Figure 1. PI3 kinase inhibitors (A–F).
treatment of various diseases such as inflammation, autoimmune diseases, cardiovascu-
lar diseases, and cancer.[3,4] There are several PI3k inhibitors under active development
(Fig. 1), namely wortmannin (B), LY294002 (C), a synthetic analog of the flavanoid
quercetin (D), siphonodictyal B (E), and frondosin B (F), that have been described in
patent literature.[12–14] All reported advance molecules (B–F) are pan-PI3K inhibitors
and have also been reported to inhibit other kinases (AKT, mTOR, etc.). Liphagal
(A) is the only molecule that has been reported not only as a selective PI3K inhibitor
but also has shown selectivity among the various isoforms (P110a, p110b, p110c,
p110d). It significantly inhibits p110a at low concentrations. It was reported to be
10-fold more active toward the a-isoform of PI3 K than the c-isoform.[15]
Liphagal was isolated from the marine sponge Aka coralliphaga, and its syn-
thesis[15,16] and structural elucidation have been reported.[15] The total synthesis of
liphagal involves starting with 2,4,5-trimethoxy benzaldehyde to get the key inter-
mediate (E)-7-bromo-2-(6,10-dimethylundeca-5,9-dien-2-yl)-5,6-dimethoxybenzo-
furan (7) in 12 steps, which on treatment with chlorosulfonic acid yielded cyclic
compound (8). The cyclic intermediate (8) on formylation followed by deprotection
with BI3 in two steps resulted in liphagal (A). Thus, the total synthesis of liphagal
was a 15-step transformation. Since liphagal is the only known isoform selective
PI3 K inhibitor, Andersen’s paper[15] is of prime scientific importance in the drug dis-
covery program. Typically, for a medicinal chemistry program, a large number of
new chemical entities (NCEs) are synthesized to generate a lead compound. For such
a purpose, starting with a 15-step synthesis and then subsequently generating NCEs
is unrealistic. The task in hand was to synthesize the key intermediate (7) in the few-
est possible steps. We devised a synthetic scheme where intermediate 7 could be
synthesized in six steps starting from readily available and cost-effective starting

KEY INTERMEDIATE TOWARD LIPHAGAL SYNTHESIS
179
material 2,4,5-trimethoxy benzaldehyde. For the purpose of synthesizing NCEs,
intermediate 7 or 8 would be a suitable starting point where the bromo group can
be used for the diversification. These modifications will subsequently lead to
liphagal-based novel molecules as PI3 K inhibitors.
RESULTS AND DISCUSSION
We started with trimethoxy benzaldehyde, which on reaction with BBr3 at
room temperature yielded 2-hydroxy-4,5-dimethoxy benzaldehyde (2). Compound
2, on treatment with bromine acetic acid, yielded 3-bromo-2-hydroxy-4,5-dimethoxy
benzaldehyde (3); both compounds 2 and 3 have been synthesized as per literature
procedure.[15] Compound 3, on treatment with chloroacetone and potassium car-
bonate in dimethyl formamide (DMF), yielded 2-acetyl-7-bromo-5,6-dimethoxy
benzofuran (4).
The challenge at this stage was to do a geranylation at the carbonyl carbon. At
first, we started with geranyl bromide and converted it to geranylmagnesium bromide
and reacted the same with the ketone compound 4. Under many different reaction
conditions, this Grignard yielded no significant amount of the desired products.
Resorting to an alternative route, we thought of executing a SN2 reaction on the
methyl functionality of the acetyl group. Thus, we treated compound 4 with NaH
and then subsequently reacted it with geranyl bromide for 15 min. This gave us a mix-
ture of both mono- and digeranyl product (data not shown). On further optimization,
we realized that attenuating the quantity of NaH can help to push the reaction toward
monogeranylation to yield compound 5. We also observed that geranyl chloride
yielded more desired monogeranyl product (5) than geranyl bromide. Treatment of
7-bromo-2-gernoyl-5,6-dimethoxybenzofuran (5) with methyl magnesium bromide
yielded tertiary hydroxyl compound 6 in decent yields. The hydroxyl group of com-
pound 6 was further reduced by treatment with ZnI and NaCNBH3 in dichloroethane
at 80 ꢀC to yield the key intermediate 7. The intermediate 8 was synthesized from
intermediate 7 by cyclization using chlorosulfonic acid at ꢁ78 ꢀC as per published
procedure.[15] The bromo- and dimethoxy functionality of intermediates 7 and 8
will serve as a tool for developing new compounds of therapeutic importance and
will be published subsequently. Also, intermediate 8 can be converted to liphagal
on treatment with BuLi, DMF, and BI3 using the literature procedure.[15]
In conclusion, we report an efficient and facile method for the synthesis of key
intermediates 7 and 8 of liphagal. The concise synthesis of these intermediates will
make liphagal-based NCE synthesis more practical in a pharmaceutical setup. The
intermediates are also designed in such a fashion so that there are points of diversi-
fication, a critical aspect for NCE generation toward drug discovery.
EXPERIMENTAL
Material and Method
2,4,5-Trimethoxy benzaldehyde, chloroacetone, geranyl chloride=bromide,
sodium cyanoborohydride, and methylmagnesium bromide were purchased from
Sigma-Aldrich, USA. All other solvents and reagents were analytical grade and were

180
V. DEORE ET AL.
used without any further purification. 1H and 13C NMR was recorded on Bruker 300
(BBO) and Bruker 500 (TXI). The mass spectra (MS) and high-resolution mass spec-
tra (HRMS) were recorded on ESI-QTOF (Bruker Daltonics microTOFQ).
2-Hydroxy-4,5-dimethoxybenzaldehyde (2)
BBr3 (1,0 M in CH2Cl2, 20 mmol) was added to a solution of 2,4,5-trimethox-
ybenzaldehyde (1) (4.2 g, 20 mmol) in CH2Cl2 (100 mL) at 0 ꢀC. The resulting dark
mixture was stirred at rt for 16 h. Water (250 mL) was then added, and the mixture
was stirred for 30 min. The aqueous phase was extracted with CH2Cl2 (3 ꢂ 200 mL).
The organic phase was dried over Na2SO4, filtered, and evaporated under reduced
pressure. Chromatography of the residue on silica gel (CH2Cl2) afforded the phenol
1
(3.2 g) in 88% yield. H NMR (500 MHz, DMSOd6): d 10.76 (s, 1H), 10.03 (s, 1H),
7.14 (s, 1H), 6.56 (s, 1H), 3.83 (s, 3H), 3.73 (s, 3H) ppm. MS m=z [M ꢁ H]ꢁ m=z 181.
3-Bromo-2-hydroxy-4,5-dimethoxybenzaldehyde (3)
Bromine (0.8 mL, 15.3 mmol) was added at rt to a solution of the phenol
(2.76 g, 15.2 mmol) and NaOAc (1.9 g, 23 mmol) in AcOH (100 mL). The resulting
yellow solution was stirred for 2 h. The solvent was removed under vacuum, and
the residue was poured into an aqueous solution of NaHCO3. The aqueous phase
was extracted with EtOAc. The combined EtOAc layers were washed with brine
(25 mL), dried over anhydrous Na2SO4, and filtered, and the solvent was removed
under pressure. Chromatography of the residue on silica gel (3:7 EtOAc=hexanes)
1
afforded the bromophenol 3 in 54% yields. H NMR (300 MHz, CDCl3): d 11.60
(s,1H), 9.78 (s,1H), 7.05 (s,1H), 4.02 (s,3H), 3.91 (s,3H) ppm. MS m=z [M þ Na]þ
m=z 283.
1-(7-Bromo-5,6-dimethoxybenzofuran-2-yl)ethanone (4)
3-Bromo-2-hydroxy-4,5-dimethoxybenzaldehyde (5 g, 19.23 mmol) is added to
a solution of potassium carbonate (3.2 g, 23 mmol) and DMF (50 ml). Chloroacetone
(95%, 2.25 g, 23 mmol) is then added dropwise, while stirring, over a period of
30 min. The mixture was stirred and heated at 100 ꢀC for 4 h, cooled to rt, and fil-
tered. The filtrate was evaporated, and the residue was column chromatographed
(2% MeOH=CHCl3) to furnish the desired product in 60% yield. 1H NMR
(300 MHz, CDCl3): d 7.47 (s, 1H), 7.07 (s, 1H), 3.94 (s, 3H), 3.83 (s, 3H) 2.62 (s,
3H) ppm. MS m=z [M þH]þm=z 299.
1-(7-Bromo-5,6-dimethoxybenzofuran-2-yl)-5,9-dimethyldeca-
4,8-dien-1-one (5)
(7-Bromo-5,6-dimethoxybenzofuran-2-yl)ethanone (4) (500 mg, 1.67 mmol)
was added to dry DMF (15 mL) in a nitrogen atmosphere. The reaction flask was
cooled to 0 ꢀC, and sodium hydride (47 mg, 1.17 mmol) was added. After 15 min, ger-
anyl bromide (254 mg, 1.17 mmol) was added, and the mixture was stirred at rt for
1 h. The solvent was removed under vacuum, and the residue was subjected to

KEY INTERMEDIATE TOWARD LIPHAGAL SYNTHESIS
181
column chromatography by using 2% MeOH=CHCl3 as an eluent to afford compound
5 in 30% yield. 1H NMR (300 MHz, CDCl3): d 7.49 (s, 1H), 7.09 (s, 1H), 5.24–5.19 (t,
1H), 5.09–5.07 (t, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.05–3.00 (t, 2H), 2.52–2.45 (q, 2H),
2.08–2.00 (m, 4H), 1.68 (s, 6H), 1.60 (s, 3H). 13C NMR (125 MHz, CDCl3): d 190.92,
153.88, 151.70, 148.45, 136.75, 131.45, 124.20, 122.78, 122.38, 112.47, 102.89, 100.76,
100.01, 61.24, 56.51, 39.67, 39.16, 29.71, 26.63, 25.69, 22.69, 17.69, 16.08. HRMS [M
þH]þ m=z 435.1165 (C22H28BrO4, calcd. 435.1148).
2-(7-Bromo-5,6-dimethoxybenzofuran-2-yl)-6,10-dimethylundeca-
5,9-dien-2-ol (6)
A solution of ketone 5 (2.0 g, 4.60 mmol) in anhydrous THF (50 mL) was
cooled to 0 ꢀC, and methylmagnesium bromide (3.0 M in Et2O, 3.4 mL, 10.2 mmol)
was added via syringe. The reaction mixture was stirred for 30 min at 0 ꢀC and
quenched with 1 N HCl. The solution was diluted with ethyl acetate (50 mL) and
washed with H2O, saturated NaHCO3, and brine (30 mL each). The organic layer
was dried over anhydrous Na2SO4 and filtered, and the solvent was removed under
reduced pressure. Column chromatography on silica (10% ethylacetate=hexane) gave
1
1.7 g (82%) of the desired product. H NMR (300 MHz, CDCl3): d 6.96 (s,1H), 6.58
(s, 1H), 5.14–5.06 (m, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 1.94–2.03(m, 9H), 1.68 (s, 3H),
1.62 (s, 3H), 1.59 (s, 3H), 1.54 (s, 3H) 13C NMR (75 MHz, CDCl3): d 163.33, 150.25,
146.52, 144.25, 135.74, 131.06, 123.76, 123.47, 123.12, 101.82, 101.73, 99.60, 72.0,
60.74, 56.24, 40.81, 39.19, 26.70, 26.13, 25.26, 22.45, 17.25, 15.62. HRMS [M
þH]þ m=z 473.127 (C23H31BrNaO4 calcd. 473.1298).
7-Bromo-2-(6,10-dimethylundecA-5,9-dien-2-yl)-5,6-dimethoxybenzo
Furan (7)
Compound 6 (1.6 g, 3.54 mmol) was dissolved in anhydrous 1,2-dichloroethane
(50 mL), and zinc iodide (1.7 g, 5.32 mmol) was added in a single portion, followed
by sodium cyanoborohydride (1.6 g, 25 mmol). The resultant solution was heated
to reflux with vigorous stirring for 2 h. The reaction was cooled to rt and poured into
H2O (50 mL). The layers were separated, and the aqueous layer was extracted with
CH2Cl2 (2 ꢂ 25 mL). The combined organic layers were washed with brine (40 mL),
dried over anhydrous Na2SO4, and filtered, and the solvent was removed under
pressure. Column chromatography on silica (5% ethylacetate=hexane) yielded 1.3 g
1
(85%) of 7. H NMR (500 MHz, CDCl3): d 6.92 (s, 1H), 6.34 (s, 1H), 5.14–5.08
(m, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 2.98–2.94 (m, 1H), 2.06–1.81 (m, 8H), 1.71 (s,
3H), 1.67 (s, 3H), 1.57 (s, 3H), 1.32 (d, 3H, J ¼ 6 Hz). 13C NMR (125 MHz, CDCl3):
d 165.22, 150.42, 146.71, 144.09, 135.62, 131.36, 124.41, 124.34, 123.83, 101.97,
101.31, 61.17, 56.73, 39.71, 35.42, 33.09, 29.71, 26.66, 25.70, 25.49, 19.08, 17.70,
16.05. MS [M þH]þm=z 435.2 (C23H31BrO3, calcd. 434.15).
Synthesis of Compound 8
Chlorosulfonic acid (0.27 mL, 2 mmol) was added to a solution of benzofuran 7
(218 mg, 0.5 mmol) in nitropropane (25 mL), at ꢁ 78 ꢀC. The resulting mixture was

182
V. DEORE ET AL.
Scheme 1. Reagent and conditions: (a) DCM, BBr3, rt; (b) Br2, acetic acid; (c) chloroacetone, K2CO3,
DMF; (d) geranyl chloride, NaH, DMF, 60 ꢀC; (e) CH3MgBr; (f) ZnI, NaBH3CN, DCE, 80 ꢀC; (g) nitro-
propane, ClSO3H, ꢁ78 ꢀC, 30 min.
allowed to stir at ꢁ 78 ꢀC for 30 min. An aqueous solution of NaHCO3 was then
added, and the aqueous phase was extracted with EtOAc. The EtOAc layer was
dried over Na2SO4, filtered, and evaporated under reduced pressure. Chromato-
graphy of the residue on silica gel (3:97 EtOAc=hexanes) afforded the tetracyclic
1
compound 8 (93 mg) in 40% yield. H NMR (300 MHz, CDCl3): d 7.10 (s, 1H),
3.92 (s, 3H), 3.90 (s, 3H), 3.34–3.32 (m, 1H), 2.56–2.53 (m, 1H), 1.94–1.77 (m,
3H), 1.75–1.69 (m, 2H), 1.55–1.46 (m, 2H), 1.43 (s, 3H), 1.42–1.39 (m, 2H),
1.35–1.30 (m, 2H), 1.28 (s, 3H), 1.01 (s, 3H), 0.98 (s, 3H). 13C NMR (75 MHz,
CDCl3) d 151.36, 138.87, 134.88, 133.07, 126.50, 106.32, 63.44, 59.48, 52.40, 47.01,
41.71, 38.72, 38.09, 36.83, 36.02, 34.16, 33.41, 25.08, 24.64, 22.47, 21.20, 20.84,
20.53. HRMS [M þH]þ m=z 435.1468 (C23H32BrO3, calcd. 435.1529).
ACKNOWLEDGMENT
We thank the Department of Analytical Chemistry for their effort in providing
1H NMR, 13C NMR, mass, HRMS, and HPLC data.
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