Total synthesis of coriandrin and 7-demethylcoriandrin via a new synthesis of isocoumarins

Article abstract of DOI:10.1016/S0040-4039(00)00441-X

Indenone epoxides 8, prepared from the corresponding indenones, have been shown to undergo clean thermal rearrangement to give isocoumarins 10 in high yields. This synthesis of isocoumarins, when applied to oxaindace-none 7, resulted in the total synthesis of coriandrin (1). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00441-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3677–3680
Total synthesis of coriandrin and 7-demethylcoriandrin via a new
synthesis of isocoumarins
∗
Dipakranjan Mal, Mousumi Bandyopadhyay, Sujit K. Ghorai and Kalyani Datta
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Received 9 February 2000; accepted 13 March 2000
Abstract
Indenone epoxides 8, prepared from the corresponding indenones, have been shown to undergo clean thermal
rearrangement to give isocoumarins 10 in high yields. This synthesis of isocoumarins, when applied to oxaindace-
none 7, resulted in the total synthesis of coriandrin (1). © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: coriandrin; isocoumarins; thermal rearrangement; epoxide.
Coriandrin (1), one of the two naturally occurring furoisocoumarins known to date, was isolated in
1
1
988 from dry coriander leaves. Its structure was elucidated by extensive analysis of NMR spectra, and
confirmed by an X-ray crystallographic study. Structurally quite similar to psoralens (furocoumarins),
coriandrin (1) exhibits an interesting combination of biological activities. In addition to the expected
2
psoralen activity, it shows in vitro anti-HIV activity. Unlike psoralens, coriandrin (1) binds with
components of the cell membranes for its biological action. These unique structural and biological
characteristics have promoted interest in the synthesis of coriandrin (Scheme 1). Recently, Kraus and
Ridgeway reported a nine-step total synthesis of coriandrin (1), starting from 5-methylcyclohexane-1,3-
3
dione. A Stille coupling and a Pd(II)-catalyzed pyrone formation were used as the key steps.
Scheme 1.
In a recent study directed towards generation of psoralen analogs, we have demonstrated that oxa-
indacenone 5 can be readily prepared in three steps from furoate (2) in high overall yield (Scheme 2).4
In view of the close structural resemblance between oxaindacenone 5 and coriandrin (1), and rapid
∗
Corresponding author.
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040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00441-X
tetl 16721

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5
accessibility of indenones by a variety of synthetic routes, we were intrigued by the possibility of
the rearrangement of epoxide 6 to 1 (Scheme 1). Although such a rearrangement is not known in the
literature, the rearrangement of cyclopentadienone monoepoxides to 2-pyrones, proceeding through an
6
initial thermally allowed [π4a+π2a] cycloreversion has been briefly discussed. However, it has not been
7
examined for the synthesis of isocoumarins or fused isocoumarins, which are of considerable utility as
8
intermediates in the synthesis of natural products. We now report that indenone epoxides 8 can be
thermally rearranged to the corresponding isocoumarins 10 in excellent yields, and an application of the
rearrangement in the total synthesis of coriandrin (1).
Scheme 2.
In order to lay the foundation for the crucial rearrangement, indenone epoxide 8a, prepared in 76%
yield from indenone by epoxidation with H O /Na CO in acetone was submitted to flash vacuum
2
2
2
3
4
pyrolysis (FVP) (450°C/0.1 mm). The crude pyrolysate after chromatographic purification provided
the parent isocoumarin 10a in 95% yield (Scheme 3). Although the rearrangement required disruption
of aromaticity of the benzene ring in 8a for the initial formation of the ketene aldehyde intermediate
9
a, the outcome of the reaction was as expected. Similarly, the linearly condensed indenone epoxide 8b
9
was prepared from the corresponding benz[f]indenone in 55% yield by treatment with H O /Et N in
2
2
3
acetone. When it was pyrolyzed under the above FVP conditions, benzisocoumarin 10b was obtained
in 92% yield. No significant side product was detected. Considering that coriandrin (1) has a methyl
group at C-7, we then intended to examine the reactivity of the epoxide of 2-methylindenone towards
the thermal rearrangement. 2-Methylindenone was prepared by alkylation (LDA, CH I) of the cyclo-
3
adduct of indenone and cyclopentadiene, followed by a retro Diels–Alder reaction. The corresponding
epoxide 8c was prepared by treatment with H O /Et N in acetone. Flash vacuum pyrolysis of 8c
2
2
3
furnished 3-methylisocoumarin (10c) in 95% yield. Similarly, oxaindacenone 5 was carried forward to
-demethylcoriandrin (10d). Epoxide 8d, prepared in 75% yield by treatment of 5 with H O /NaOH,
7
2
2
10
underwent the rearrangement on flash vacuum pyrolysis to give demethylcoriandrin (10d) (90%).
Scheme 3.
Having successfully worked out model rearrangements of indenone epoxides 8, we focused our
attempts on the preparation of oxaindacenone 7. Initially, we attempted to utilize 5, of which Zn–AcOH
reduction gave the corresponding 6,7-dihydro product 11 (60%). However, its selective monoalkylation
at C-6 was not successful. An alternative route to 7 via monoalkylation of the N,N-dimethylhydrazone

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679
derivative of 11 was foiled by the fact that the hydrazone could not be prepared. At this point it was
decided to make use of the pentacyclic precursor 4. Treatment of the lithiosalt of 4, prepared by the
action of LDA (1 equiv.), with CH I (1 equiv.) furnished 12 in a 50% yield together with 30% of the
3
starting material (Scheme 4). The retro Diels–Alder reaction of 12 at 450°C/0.1 mm furnished 7 (93%)
which could be purified by quick silica gel filtration. Epoxidation of 7 by treatment with H O /Et N
2
2
3
1
0
in acetone gave the epoxide 6 (40%). This was then subjected to FVP to conclude the synthesis of
coriandrin (1) in 88% yield. The spectral data of the synthetic material were in excellent agreement with
those reported for the natural product.
Scheme 4. Reagents and conditions: (i) LDA, THF, MeI; (ii) FVP (450–475°C, 0.1 mm); (iii) Et
450–475°C, 0.1 mm)
3 2 2
N, H O , acetone; (iv) FVP
(
In summary, we have introduced a new synthesis of isocoumarins from indenones and achieved a total
synthesis of coriandrin. Currently, we are in the process of preparing 2-substituted analogs of coriandrin
via lithiation of 12.
Acknowledgements
The authors gratefully acknowledge financial support from the Department of Science and Technology,
New Delhi.
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9
. Mal, D.; Ghorai, S. K.; Hazra, N. K. Terahedron Lett. 1998, 39, 689.
−1
1
1
0. Physical data for 10d: mp 126°C; IR (cm ) 1721; H NMR (CDCl
3
) δ 7.64 (d, 1H, J=2), 7.20 (s, 1H), 7.19 (d, 1H, J=5.5),
13
7
1
.08 (m, 1H), 6.46 (d, 1H, J=5.5), 4.23 (s, 3H); C NMR (CDCl ) δ 159.5, 159.1, 157.5, 145.4, 143.4, 135.3, 119.8, 108.4,
3
+
−1
1
07.2, 105.7, 102.5, 61.5. MS (m/e) 216 (M ), 173 (100%). Compound 7: mp 86°C; IR (cm ) 1686; H NMR (CDCl
3
3
)
)
1
3
δ 7.43 (d, 1H, J=2), 6.95 (m, 1H), 6.84–6.83 (m, 1H), 6.67 (s, 1H), 4.26 (s, 3H), 1.83 (d, 3H, J=1.6); C NMR (CDCl
+
δ 194.7, 159.7, 152.5, 144.0, 143.9, 140.9, 137.6, 119.5, 112.2, 106.7, 101.8, 61.2, 10.2; MS (m/e) 214 (M , 100%), 199,
−
1
1
1
6
85, 171,128. Compound 6: mp 115–116°C; IR (cm ) 1711; H NMR (CDCl
3
) δ 7.58 (d, 1H, J=2), 7.28 (d, 1H, J=1),
+
.98 (m, 1H), 4.29 (s, 1H), 4.25 (s, 3H), 1.71 (s, 3H); MS (m/e) 230 (M ), 201 (100%), 187, 159, 144, 129, 116.