Total synthesis of the aromatase inhibitor dihydroisocoumarin via protective opening of lactones

Article abstract of DOI:10.1016/j.tetlet.2012.05.012

Asymmetric total synthesis of a dihydroisocoumarin, (3R,4R)-(-)-6-methoxy- 1-oxo-3-pentyl-3,4-dihydro-1H-isochromen-4-yl acetate (1) starting from commercially available m-anisic acid is described. Herein, we depict the use of protective opening of lactones and construction of δ lactone. The synthesis involves Wittig, Grubbs cross metathesis, and Sharpless dihydroxylation reactions.

Full text of DOI:10.1016/j.tetlet.2012.05.012

Tetrahedron Letters 53 (2012) 3633–3636
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of the aromatase inhibitor dihydroisocoumarin via
protective opening of lactones
⇑
D. Chanti Babu, Ch. Bhujanga Rao, D. Ramesh, S. Raghavendra Swamy, Y. Venkateswarlu
Division of Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric total synthesis of a dihydroisocoumarin, (3R,4R)-(ꢀ)-6-methoxy-1-oxo-3-pentyl-3,4-dihy-
dro-1H-isochromen-4-yl acetate (1) starting from commercially available m-anisic acid is described.
Herein, we depict the use of protective opening of lactones and construction of d lactone. The synthesis
involves Wittig, Grubbs cross metathesis, and Sharpless dihydroxylation reactions.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 31 March 2012
Revised 30 April 2012
Accepted 3 May 2012
Available online 11 May 2012
Keywords:
Xyris pterygoblephara
Dihydroisocoumarin
Wittig
Grubbs cross metathesis
Sharpless dihydroxylation and lactonization
Cancer chemotherapy relies on therapeutic agents with cyto-
toxic properties that inhibit tumor cell proliferation and cause cell
death. Aromatase inhibitors have shown improved efficacy and re-
duced side effects against advanced and early stage breast cancer
in comparison with the estrogen antagonist tamoxifen.1–4 The pro-
cess of drug discovery through the use of small-molecule natural
products is well established.5 In some illustrations, the natural
products themselves are developed and recorded as medicines6
and help as a guide for medicinal chemistry investigations and to
find final drugs.7–10
In the anticancer drug discovery, the coumarin functionality is
an important feature for anticancer agents.11–13 The tenacity
needed to preserve the configuration and functionality of drugs
from natural products call for estimable efforts and skills toward
their synthesis in enantiomerically pure form.14
tive synthesis that would provide a basis for suitable derivatiza-
tions and allow further biological evaluations. Total synthesis of
compound 1 was already at an advanced stage,17 but different from
ours.
O
O
O
O
O
1
The retro synthetic analysis of the dihydroisocoumarin (1) is de-
picted in Scheme 1. We envisaged that protective opening of five
membered lactone 18 exposed to acetyl chloride would give target
molecule 1, which in turn could be obtained from E-olefin 10 by
employing Sharpless asymmetric dihydroxylation followed by lact-
onization as key steps.
E-Olefin 10 can be derived from acid 4 using Wittig homologation
and Grubbs cross metathesis sequentially, which could be furnished
from 2 via protective opening of phthalide. The synthesis was com-
menced from the commercially available m-methoxybenzoic acid 2
(Scheme 2), which was converted into phthalide 3 following the lit-
erature procedure.19 The lactone ring in compound 3 was opened
with methanol20 in the presence of K2CO3 to obtain potassium salt
of the acid, which was protected with benzyl bromide in the pres-
ence of NaH to form the compound 4. The acid group in 4 was con-
verted into alcohol 5 by the reduction with LAH, followed by the
The dihydroisocoumarin, (3R,4R)-(ꢀ)-6-methoxy-1-oxo-3-pen-
tyl-3,4-dihydro-1H-isochromen-4-yl acetate (1) was isolated from
aerial parts of Xyris pterygoblephara,15 showed aromatase inhibi-
tory activity at concentration16 of IC50 = 1.6 0.1
lM and was ac-
tive against dermatophytic fungi.15 For the past several years we
have been engaged in the total synthesis of biologically active nat-
ural products by using natural and commercial available sources.18
We now report our latest efforts at expanding the scope of the syn-
thetic utility for the conversion of c-lactone into d lactone. In this
context, the potent biological activities and the structural features
of dihydroisocoumarin (1) have inspired us to pursue stereoselec-
⇑
Corresponding author. Tel.: +91 40 27193167; fax: +91 40 27160512.
E-mail address: luchem@iict.res.in (Y. Venkateswarlu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.012

3634
D. Chanti Babu et al. / Tetrahedron Letters 53 (2012) 3633–3636
O
O
TBSO
O
O
O
O
O
O
3
3
O
O
OBn
10
18
1
O
O
O
OH
OH
OBn
2
4
Scheme 1. Retrosynthetic analysis of dihydroisocoumarin (1).
O
O
O
O
O
O
OH
c
O
OH
d
a
b
OH
O
O
3
5
OBn
OBn
2
4
OH
O
O
O
O
e
H
g
3
3
O
6
7
OBn
OBn
8
undisered compound
x
f
OBn
h
O
O
O
O
i
3
+
OBn
OBn
OBn
(80%)
9
10 b
(7%)
j
10
O
O
O
OH
O
O
O
O
l
k
3
3
OH
OBn
11
3
12
14
13 undisered compound
OBn
m
O
O
O
O
O
O
3
o
O
3
OH
OH
15
16
n
Scheme 2. Reagents and conditions: (a) CH2O, Glacial acetic acid, 11 N HCl, reflux, 1 h, 75%; (b) (i) methanol, K2CO3, reflux 3 h; (ii) NaH, benzyl bromide, 4 h, over two steps
84%; (c) LAH, THF 1 h, 90%; (d) (COCl)2, DMSO, triethylamine, ꢀ78 °C, 1 h, 95%; (e) 1-bromo hexane, Mg, THF, 0 °C, 3 h, 89%; (f) PTSA, THF reflux; (g) 11 N HCl, ethanol, reflux,
75%; (h) t-BuOK, PPh3PCHþBr, THF, ꢀ10 °C, 4 h, 80%; (i) Grubbs 2nd generation catalyst (10 mol %), DCM, reflux, 12 h, 80%; (j) AD-mix-b, CH3SO3NH2, t-butanol/H2O (1:1), 0 °C,
3
24 h, 95%; (k) 2,2 DMP, PTSA, DCM, rt, 5 h, 95%; (l) Pd/C, H2, ethylacetate, reflux, 5 h, 95%; (m) Raney-Nickel, H2, ethanol, rt, 48 h, 95%; (n) (COCl)2, DMSO, triethylamine ꢀ78 °C
1 h, 95%; (o) NaClO2, NaH2PO4, t-Butanol/H2O (7:3), rt, 8 h, 94%.
Swern oxidation to afford aldehyde 6. The aldehyde 6 was subjected
to Grignard reaction with hexylmagnesium bromide to afford the
secondary benzyl alcohol 7 in 89% yield. Dehydration of secondary
alcohol 7 to compound 10 was unsuccessful with various reagents

D. Chanti Babu et al. / Tetrahedron Letters 53 (2012) 3633–3636
3635
AcO
O
3
a
O
16
1
(10%)
+
O
b
19 (55%)
O
O
HO
TBSO
18
O
O
O
O
O
3
3
d
O
O
c
O
O
17
1
Scheme 3. Reagents and conditions: (a) FeCl3, acetyl acetone, toluene, reflux, 24 h, 65%; (b) HCl, methanol, rt, 93%; (c) TBSCl, imidizole, rt, 3 h, 93%; (d) (i) K2CO3, methanol,
reflux 3 h; (ii) THF/acetyl chloride 8 h; (iii) HCl, methanol, rt, overall yield 70%.
such as p-TSA in dry THF at reflux condition,18e dehydromesyla-
Acknowledgments
tion21, and dehydrohalozenation.22 Interestingly, when compound
7 reacted with 11 N HCl in ethanol,23 it afforded undesired com-
The authors D.C., C.B.R., D.R., and K.R. are thankful to the UGC
pound 8. The attempts were therefore abandoned. Then, to over-
come the first impediment toward the synthesis of 1, the aldehyde
6 was converted into the terminal alkene 9 using Wittig reaction
with methyltriphenylphosphonium bromide salt in the presence
of tert-BuOK, which was subjected to cross metathesis reaction24
with 1-heptene by using Grubbs 2nd generation catalyst in CH2Cl2
to afford the E-olefin 10 along with by product 10b (trans dimer of
9). E-Olefin 10 was subjected to Sharpless dihydroxylation25 with
b-AD-mix to afford 11 in 95% yield, which was modified as an aceto-
nide compound 12 with 2, 2 DMP in dry DCM and p-TSA as catalyst.
The removal of benzyl protecting group in compound 12 was
unsuccessful to give alcohol 14, with Li/naphthalene reaction.
When compound 12 was subjected to hydrogenation in the pres-
ence of palladium catalysts like palladium(II) acetate, palladium
hydroxide, and palladium–carbon in various solvents (ethyl ace-
tate, ethanol and methanol) at either reflux or room temperature
conditions at hydrogen atmosphere afforded compound 13. Com-
pound 12 was subjected to hydrogenation in the presence of Raney
nickel in ethanol at reflux condition also yielded compound 13 but,
fortunately at room temperature afforded alcohol 14. Thus, alcohol
14 was oxidized to aldehyde 15 using IBX in DMSO, which was
immediately further oxidized to acid 16 by treating with NaClO2/
NaH2PO4.
and CSIR, New Delhi for the financial support and thankful to the
Director J. S. Yadav, IICT for his constant encouragement.
Supplementary data
Supplementary data (experimental procedures and data for rep-
resentative new compounds) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.05.012.
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ꢁ
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