Protecting group free syntheses of (±)-columbianetin and (±)-angelmarin

Article abstract of DOI:10.1016/j.tetlet.2011.10.036

A five-step and protecting group free synthesis of (±)-columbianetin from cyclohexane-1,3-dione is reported. The former compound was converted into its p-hydroxycinnamate derivative, (±)-angelmarin, using Coster's esterification procedure. Efforts to modi

Full text of DOI:10.1016/j.tetlet.2011.10.036

Tetrahedron Letters 52 (2011) 6887–6889
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Protecting group free syntheses of ( )-columbianetin and ( )-angelmarin
⇑
Eric B.J. Harris, Martin G. Banwell , Anthony C. Willis
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra ACT 0200, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
A five-step and protecting group free synthesis of ( )-columbianetin from cyclohexane-1,3-dione is
reported. The former compound was converted into its p-hydroxycinnamate derivative, ( )-angelmarin,
using Coster’s esterification procedure. Efforts to modify the synthesis so as to prepare angelmarin and
columbianetin in an enantioselective manner are described.
Received 23 August 2011
Revised 27 September 2011
Accepted 7 October 2011
Available online 17 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Angelmarin
Aromatization
Columbianetin
Coumarin
Intramolecular hydroarylation
The coumarin-containing natural product (+)-angelmarin (1)
was isolated in 2006 by Kadota and co-workers1 from a CH2Cl2-sol-
uble extract of Angelica pubescens, a plant used in Japanese Kampo
medicine.2 The compound was characterized by NMR techniques
and shown to display completely selective cytotoxicity against
PANC-1 cells at concentrations as low as 0.01 l
g/mL.1 Since
PANC-1 cells are a pancreatic cancer cell line able to tolerate ex-
treme conditions created by low nutrient and oxygen supplies,
angelmarin represents a novel anti-cancer agent capable of elimi-
nating the tolerance of cancer cells to nutrient starvation. Couma-
rin 1 can, therefore, be regarded as a lead compound for the
development of a so-called anti-austerity cancer chemotherapeutic
regime for the treatment of certain highly refractory forms of the
disease.3 Indeed, the compound shows particular potential for
treating pancreatic cancer, victims of which have especially low
five-year survival rates.4
Two total syntheses of angelmarin (1) have been reported so far,
one by Coster5 and the other by Hamada.6 Each of these involves
esterification of the related natural product columbianetin (2)7
with p-hydroxycinnamic acid or an equivalent thereof. Compound
2 was, in turn, prepared from the commercially available coumarin
umbelliferone (3) using a regioselective Claisen rearrangement/Shi
epoxidation/5-exo-tet cyclization sequence.5,6 This represents an
adaptation of a protocol reported by Bohlmann and Franke in
19718 for the synthesis of the racemic modification of
columbianetin.
Herein we report a quite distinct synthesis of ( )-columbianetin
[( )-2] that employs cyclohexane-1,3-dione (4) as starting material
and a late-stage Au(I)-catalyzed intramolecular hydroarylation
(IMHA)9 reaction to form the six-membered heterocyclic ring of
the target. Furthermore, no protecting groups are required during
the course of the five-step synthesis, details of which are presented
in Scheme 1. Thus, diketone 4 was efficiently C-alkylated with pre-
nyl bromide (5) under conditions defined by Marazano et al.10 and
so affording the previously reported10 b-hydroxycyclohexenone 6
(75%). Subjection of compound 6 to reaction with m-chloroperben-
zoic acid (m-CPBA) in the presence of potassium carbonate gave,
presumably via the intermediate epoxide, dihydrofuran ( )-7
(95%), the structure of which was confirmed by single-crystal X-
ray analysis.11 In an initial attempt to aromatize the carbocyclic
ring within the latter compound it was treated with manganese
⇑
Corresponding author. Tel.: +61 2 6125 8202; fax: +61 2 6125 8114.
E-mail address: mgb@rsc.anu.edu.au (M.G. Banwell).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.036

6888
E. B. J. Harris et al. / Tetrahedron Letters 52 (2011) 6887–6889
Figure 1. ORTEP derived from the single-crystal X-ray analysis of compound ( )-2
with labeling of non-hydrogen atoms. Anisotropic displacement ellipsoids display
30% probability levels. Hydrogen atoms are drawn as circles with small radii.
Scheme 1. Syntheses of ( )-columbianetin and ( )-angelmarin.
dioxide but this gave furan 812 (44%) as the only isolable product.
In contrast, reaction of compound ( )-7 with 2,3-dichloro-5,6-dicy-
ano-1,4-benzoquinone (DDQ) in hot 1,4-dioxane effected the de-
sired oxidation and thus afforded phenol ( )-913 in 80% yield. In
anticipation of effecting an IMHA reaction9 to generate the six-
membered heterocyclic ring of target ( )-2, compound ( )-9 was
coupled with propiolic acid in the presence of dicyclohexylcarbodi-
imide (DCC) to afford ester ( )-10 in 70% yield. Finally, exposure of
compound ( )-10 to Echavarren’s Au(I) catalyst14 in dichlorometh-
ane at room temperature resulted in the anticipated IMHA reac-
tion9,15 and formation of ( )-columbianetin [( )-2] which was
obtained as a crystalline solid in 75% yield.
All of the spectral data derived from coumarin ( )-2 were in
complete accord with the assigned structure and matched those
reported previously5,6,13 but final confirmation of this followed
from a single-crystal X-ray analysis.11 The ORTEP arising from this
analysis is shown in Figure 1 and further details are presented in
the Supplementary data.
Scheme 2. Attempted enantioselective synthesis of (+)-angelmarin.
Various attempts have been made to adapt the chemistry
shown in Scheme 1 to the enantioselective preparation of (+)-
angelmarin. For example, reaction of compound 6 using the Shi re-
agent16 was examined on the basis that epoxide 11 might be
formed preferentially and that this would engage in a stereoselec-
tive 5-exo-tet cyclization process to form the dihydrofuran (+)-7. In
the event, when substrate 6 was treated under the relevant condi-
tions compound (+)-7 was formed in just 13% ee as determined by
chiral HPLC analysis.17
While the acquisition of ( )-columbianetin constitutes a formal
total synthesis of ( )-angelmarin,5,6 in order to secure a sample of
the latter for biological evaluation the procedure described by Cos-
ter5 was employed to effect the desired conversion. Thus, treatment
of compound ( )-2 with Meldrum’s acid followed by Knoevenagel
condensation of the resulting malonate half-ester with p-hydroxy-
benzaldehyde gave a crystalline sample of ( )-angelmarin [( )-1]
in 76% yield. All the NMR, IR, and mass spectral data obtained on this
material matched those reported1,5,6 for both the naturally- and syn-
thetically-derived samples of (+)-angelmarin.
In another attempt to prepare (+)-angelmarin, the alkylation of
cyclohexane-1,3-dione (4) with the epoxy bromide ( )-12 was ex-
plored (Scheme 2). This study was carried out on the basis that the

E. B. J. Harris et al. / Tetrahedron Letters 52 (2011) 6887–6889
2. Okamoto, H. Mini-Rev. Med. Chem. 2006, 6, 543.
6889
enantiomerically pure iodo-analog of compound 12 would be
available18 as the replacement electrophile if needed. In the event,
when the relevant experiment was carried out using equimolar
quantities of substrates 4 and ( )-12 a ca. 1:7 mixture of the chro-
matographically separable C- and O-alkylation products ( )-7 (9%)
and ( )-13 (71%), respectively, was obtained. The structure of the
latter product was confirmed by single-crystal X-ray analysis.11
Presumably, the former product arises from intermediate ( )-11,
the same species involved in the conversion 6 ? ( )-7 shown in
Scheme 1. Various efforts to improve the C- to O-alkylation ratio
associated with the reaction 4 + ( )-12 ? ( )-7 + ( )-13 proved
fruitless.
3. Esumi, H.; Lu, J.; Kurashima, Y.; Hanaoka, T. Cancer Sci. 2004, 95, 685.
4. Li, D.; Xie, K.; Wolff, R.; Abbruzzese, J. L. Lancet 2004, 363, 1049.
5. Magolan, J.; Coster, M. J. J. Org. Chem. 2009, 74, 5083.
6. Jiang, H.; Hamada, Y. Org. Biomol. Chem. 2009, 7, 4173.
7. Columbianetin has been isolated from various plant sources and shown to
display a range of interesting biological activities including anti-inflammatory
effects: Jeong, H.-J.; Na, H.-J.; Kim, S.-J.; Rim, H.-K.; Myung, N.-Y.; Moon, P.-D.;
Han, N.-R.; Seo, J.-U.; Kang, T.-H.; Kim, J.-J.; Choi, Y.; Kang, I.-C.; Hong, S.-H.;
Kim, Y.-A.; Seo, Y.-W.; Kim, H.-M.; Um, J.-Y. Biol. Pharm. Bull. 2009, 32, 1027.
and references therein.
8. Bohlmann, F.; Franke, H. Chem. Ber. 1971, 104, 3229.
9. For reviews of the IMHA process, see: (a) Nevado, C.; Echavarren, A. M.
Synthesis 2005, 167; (b) Shen, H. C. Tetrahedron 2008, 64, 3885; (c) Skouta, R.;
Li, C.-J. Tetrahedron 2008, 64, 4917; (d) Kitamura, T. Eur. J. Org. Chem. 2009,
1111.
Other methods for exploiting the synthetic sequence detailed in
Scheme 1 so as to obtain (+)-angelmarin [(+)-1] in enantiomerically
enriched form are now under investigation. Results will be re-
ported in due course.
10. Nuhant, P.; David, M.; Pouplin, T.; Delpech, B.; Marazano, C. Org. Lett. 2007, 9,
287.
11. X-ray crystal data for compounds ( )-2, ( )-7, and ( )-13 can be found in the
Supplementary data. These data (excluding structure factors) have been
deposited with the Cambridge Crystallographic Data Centre (CCDC nos.
829569, 829570, and 832013, respectively). Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
Acknowledgments
12. Compound
8 is an established precursor to the angular furanocoumarin
oroselol. See: Lee, Y. R. Tetrahedron 1995, 51, 3087.
We thank the Institute of Advanced Studies and the Australian
Research Council for financial support.
13. Compound ( )-9 has been prepared previously, in nine steps from 2,6-
dihydroxybenzoic acid, and used in a synthesis of ( )-columbianetin. See:
Shipchandler, M.; Soine, T. O.; Gupta, P. K. J. Pharm. Sci. 1970, 59, 67.
14. Herrero-Gómez, E.; Nieto-Oberhuber, C.; López, S.; Benet-Buchholz, J.;
Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 5455.
Supplementary data
15. Menon, R. S.; Findlay, A. D.; Bissember, A. C.; Banwell, M. G. J. Org. Chem. 2009,
74, 8901.
16. For applications of the Shi and related reagents in similar contexts see: Jiang,
H.; Sugiyama, T.; Hamajima, A.; Hamada, Y. Adv. Synth. Catal. 2011, 353, 155.
17. The constituent enantiomers associated with compound ( )-7 could be
Supplementary data ([experimental procedures and product
characterization for compounds ( )-7, 8, ( )-9, ( )-10, ( )-2, ( )-1,
and ( )-13 as well as the X-ray crystallographic data for com-
pounds ( )-2, ( )-7, and ( )-13]) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2011.10.036.
separated from one another on
a
Daicel Chiracel OJ-H 5 mm
250 m analytical HPLC column using a 19:1 v/v mixture of hexane
l
m  4.6 l
and iso-propanol at a flow rate of 0.5 mL/min.
18. The R-enantiomeric form of the iodo-analog of compound ( )-12 has been
prepared using Sharpless asymmetric epoxidation techniques: Xiao, X.-y.; Park,
S.-K.; Prestwich, G. D. J. Org. Chem. 1988, 53, 4869.
References and notes
1. Awale, S.; Nakashima, E. M. N.; Kalauni, S. K.; Tezuka, Y.; Kurashima, Y.; Lu, J.;
Esumi, H.; Kadota, S. Bioorg. Med. Chem. Lett. 2006, 16, 581.