Accessing columbianetin-containing natural products via a domino on-water, in-water process

Article abstract of DOI:10.1016/j.tetlet.2012.11.150

A domino on-water, in-water process has been developed for the rapid and efficient synthesis of (±)-columbianetin. This highlights the operational simplicity of on-water chemistry. The domino process forms the key step in the synthesis of the columbianetin-containing natural products (±)- columbianetin acetate, (±)-zosimin, (±)-libanorin and (±)-angelmarin.

Full text of DOI:10.1016/j.tetlet.2012.11.150

Tetrahedron Letters 54 (2013± 1056–1058
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Accessing columbianetin-containing natural products via a domino
on-water, in-water process
⇑
Kaitlin D. Beare, Christopher S. P. McErlean
School of Chemistry, The University of Sydney, NSW 2006, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
A domino on-water, in-water process has been developed for the rapid and efficient synthesis of
Received 21 October 2012
Revised 22 November 2012
Accepted 28 November 2012
Available online 20 December 2012
(
± ±-columbianetin. This highlights the operational simplicity of on-water chemistry. The domino process
forms the key step in the synthesis of the columbianetin-containing natural products (± ±-columbianetin
acetate, (± ±-ꢀosimin, (± ±-libanorin and (± ±-angelmarin.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
On-water chemistry
Rearrangement
Catalysis
Oxygen heterocycles
Natural products
An increased awareness of environmental sustainability, step-
economy and atom-economy has led to the development of many
innovative synthetic processes. Of these, perhaps none offers more
promise than on-water chemistry. Popularised by Sharpless and
co-workers, ‘on-water’ catalysis is an operationally simple meth-
contain a columbianetin (1± substructure (Scheme 1±,10 including
molecules in which the columbianetin skeleton has been modified
1
4,15
by oxidation, glycosylation and esterification.
Although the
1
6
chemistry of columbianetin has a long history, there has been a
recent revival in synthetic approaches to this molecule due to
1
–7
odology that has been enthusiastically adopted in many areas,
the discovery of angelmarin (6±, a columbianetin cinnamate that
8,9
10,11,13,17–19
but has only rarely been employed in total synthesis. The term
on-water catalysis’ describes the rate enhancements observed
displays promising anti-cancer properties.
More than
‘
40 years ago it was hypothesised that columbianetin was biosyn-
when certain reactions are performed as aqueous emulsions. The
advantages are often touted: water is cheap, readily available,
non-flammable, has a high heat capacity and allows for simplified
product isolation. We recently extended the utility of the process
by engineering a domino in-water, on-water sequence in which
the reaction of an aqueous soluble starting material gave an insol-
uble product that migrated into the oil droplets of the emulsion
and subsequently participated in an on-water catalysed reaction
thesised by prenylation of umbelliferone (2± followed by epoxida-
2
0
tion and cyclisation (Scheme 1±. That sequence of reactions
constitutes a straight-forward synthetic route to columbianetin.
The enꢀymes responsible for the direct prenylation of 2 to give 3
2
1
have been characterised, and whilst there is no evidence for its
involvement in columbianetin biosynthesis, the aromatic Claisen
(
Fig. 1±.5 There is no inherent reason why this shuttling of mole-
cules between the phases of the emulsion should be restricted to
one direction, that is, in-water followed by on-water. We elected
to explore the corresponding on-water, in-water domino process
in the context of the synthesis of coumarin-containing natural
products. Herein we describe a concise synthesis of osthenol, (± ±-
1
0
11
12
columbianetin, (± ±-ꢀosimin, (± ±-libanorin and (± ±-angelma-
1
3
rin using an on-water, in-water domino process.
Coumarin-containing natural products are widespread in
nature. To date, more than 150 members have been isolated that
⇑
Corresponding author. Fax: +61 2 9351 3329.
E-mail address: christopher.mcerlean@sydney.edu.au (C.S.P. McErlean±.
Figure 1. Domino processes with in-water and on-water components.
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.150

K. D. Beare, C. S. P. McErlean / Tetrahedron Letters 54 (2013) 1056–1058
1057
Table 1
Conditions for the aromatic Claisen rearrangement
Entry
Solvent
Temp (°C±
Time (h±
Yielda (%±
88c
87
30
—
Ratio 3:8b
1
2
3
4
5
6
7
8
9
Neat
Neat
130
130
45
45
45
75
75
75
75
75
1.5
1.5
72
72
72
1
2
2
2
2.5
5.28:1
4.64:1
n.d.
—
—
6.50:1
5.07:1
—
—
5.07:1
d
H
2
O + CH
2
Cl
2
Neat
Toluene
—
H
H
2
O
O
60
91
—
—
85
2
Neat
Toluene
Sat. aq NaHCO
10
3
a
b
c
Isolated yield after chromatography.
Determined after isolation.
Data from Ref. 23.
Scheme 1. Proposed biosynthesis of columbianetin.
d
Data from Ref. 11. n.d. = not determined.
rearrangement of 2 is known to give osthenol (3±.22 Sharpless re-
ported a single example of an aromatic Claisen rearrangement that
was subject to on-water catalysis.1 We therefore anticipated that
the transformation of 2 into 3 could be conducted on-water. Franke
provided support for the biosynthetic proposal by showing that
epoxy osthenol (4± could be cyclised to give the required
five-membered heterocycle using a biphasic solvent system of
dichloromethane and aqueous sodium bicarbonate.23 We antici-
pated that the organic solvent in that reaction was superfluous,
and that the phenolate 5 ought to have some water solubility, that
is, the transformation of 4 into 1 could be conducted in-water.
With a synthetic strategy that incorporated both on-water and
in-water reactions, we pursued the development of a domino on-
water, in-water process for the synthesis of (± ±-columbianetin (1±.
As shown in Scheme 2, umbelliferone (2± was converted into
the prenyl ether 7 directly using a palladium-catalysed coupling
in the manner described by Hamada.11 This compound has previ-
ously been employed in thermal aromatic Claisen rearrangements
at temperatures in excess of 130 °C (Table 1, entries 1 and 2±. Our
first priority was to ascertain that this substrate did indeed under-
go an on-water accelerated Claisen rearrangement. Initial attempts
to carry out the desired on-water rearrangement at ambient tem-
perature were frustrated by an inability to generate an emulsion
using the solid compound 7. The formation of an emulsion is an
absolute requirement for on-water catalysis and there is only a sin-
gle report of solid compounds participating in an on-water cata-
gratified to find that when compound 7 melted, an oil-in-water
emulsion was readily generated and the on-water aromatic Claisen
rearrangement progressed to 60% completion in just 1 h (entry 6±.
Extending the reaction time to 2 h gave the rearranged product in
91% yield and with the same regiochemical outcome as the thermal
reaction (entry 7±. To confirm that the rearrangement was not
being thermally effected, but was indeed accelerated by the
on-water effect, the reaction was attempted neat at 75 °C and in
toluene at 75 °C for the same period of time (entries 8 and 9±. In
neither instance was any rearranged product detected.
Franke demonstrated that epoxide 4 could be opened under ba-
sic conditions to generate the desired dihydrobenꢀofuran ring
rather than the dihydrobenꢀopyran ring (see Scheme 1±.23 In order
for the proposed on-water, in-water domino process to be viable,
the on-water step of the sequence would have to be effected ‘on’
saturated aqueous sodium bicarbonate. We have previously dem-
onstrated acid catalysis ‘on’ sodium hydroxide solutions,4 so we
were confident that the transformation was feasible. Pleasingly,
the aromatic Claisen rearrangement ‘on’ saturated aqueous sodium
bicarbonate gave the rearranged product in high yield and with the
same regioselectivity as the on-water reaction (Table 1, entry 10±.
This confirmed that the on-water step of the proposed domino pro-
cess was viable.
The ‘on-water’ emulsion containing the desired compound 3
was milky-white, whereas the ‘on’ saturated aqueous sodium
bicarbonate reaction mixture containing compound 3 changed
from milky-white to purple. We took this as evidence for the for-
mation of the phenolate 9 (see Scheme 3±. Given that m-CPBA is
appreciably water soluble and assuming that the phenolate 9 is
also water soluble, we felt confident that the in-water step of the
domino process was also viable, and that the biphasic reaction
system utilised by Franke was not required. Safety considerations
2
4
lysed reaction. We therefore added a few drops of an organic
solvent to generate a liquid oil phase. When the reaction was con-
ducted at 45 °C the Claisen rearrangement proceeded to a small ex-
tent (entry 3±. Whilst an extended reaction time rendered the
process synthetically impractical, we were encouraged by the
observation that no rearrangement occurred either neat, or in an
organic solvent at the same temperature (entries 4 and 5±. The pre-
nyl ether 7 has a melting point of ca. 72 °C, so we next performed
the reaction slightly in excess of that temperature. We were
Scheme 2. On-water synthesis of osthenol (3±.
Scheme 3. Domino on-water, in-water synthesis of (± ±-columbianetin (1±.

1
058
K. D. Beare, C. S. P. McErlean / Tetrahedron Letters 54 (2013) 1056–1058
augments our previous work on the on-water, in-water domino
process and shows that the concept of shuttling molecules be-
tween the phases of an emulsion is general. Additionally, this work
provides an illustration of the advantages of using water in hetero-
cyclic synthesis. Interfacial water functioned as a catalyst that al-
lowed a significant reduction in the thermal requirements of the
aromatic Claisen rearrangement, whilst having no effect on the
regiochemical outcome. Although claims regarding the ‘greenness’
of on-water chemistry at temperatures above ambient may be
dubious, the operational simplicity of these domino processes
should see them adopted in other synthetic settings.
Acknowledgment
We gratefully acknowledge the Australian Research Council
(
DP120102466± for financial support.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2
012.11.150.
Scheme 4. Synthesis of columbianetin-containing natural products.
References and notes
prevented us from having m-CPBA present in the on-water reaction
mixture at temperatures above 50 °C. However, the domino on-
water, in-water domino process was realised by conducting the
1
.
Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2005, 44, 3275.
2. Chanda, A.; Fokin, V. V. Chem. Rev. 2009, 109, 725.
3
4
5
.
.
.
Butler, R. N.; Coyne, A. G. Chem. Rev. 2010, 110, 6302.
Beattie, J. K.; McErlean, C. S. P.; Phippen, C. B. W. Chem. Eur. J. 2010, 16, 8972.
Norcott, P.; Spielman, C.; McErlean, C. S. P. Green Chem. 2012, 14, 605.
‘
on’ saturated sodium bicarbonate catalysed aromatic Claisen rear-
rangement followed by the addition of m-CPBA (Scheme 3± when
the mixture had cooled to 50 °C. This operationally simply proce-
dure delivered (± ±-columbianetin (1± in 71% yield from 7, and in
6. Phippen, C. B. W.; McErlean, C. S. P. Tetrahedron Lett. 2011, 52, 1490.
7
.
Phippen, C. B. W.; Beattie, J. K.; McErlean, C. S. P. Chem. Commun. 2010, 46,
234.
Jeon, J. H.; Kim, M. R.; Jun, J. G. Synthesis 2011, 370.
8
6
5% overall yield from umbelliferone (2± in just two synthetic
operations.
With a straightforward domino on-water, in-water route to
± ±-columbianetin secured, we then generated several coumarin-
8
.
9. Nicolaou, K. C.; Xu, H.; Wartmann, M. Angew. Chem., Int. Ed. 2005, 44, 756.
10. Willette, R. E.; Soine, T. O. J. Pharm. Sci. 1964, 53, 275.
1
1
1
1. Jiang, H.; Hamada, Y. Org. Biomol. Chem. 2009, 7, 4173.
(
2. Ermatov, N.; Ban’kovskii, A.; Perel’son, M. Chem. Nat. Prod. 1969, 5, 189.
3. Awale, S.; Nakashima, E. M. N.; Kalauni, S. K.; Teꢀuka, Y.; Kurashima, Y.; Lu, J.;
Esumi, H.; Kadota, S. Bioorg. Med. Chem. Lett. 2006, 16, 581.
containing natural products. As shown in Scheme 4, acylation with
acetyl chloride gave (± ±-columbianetin acetate (10± in high
1
0,25
14. EsteveꢀBraun, A.; Gonꢀaleꢀ, A. G. Nat. Prod. Rep. 1997, 14, 465.
yield.
structure of (± ±-ꢀosimin (11± in excellent yield.
reaction with senecioyl chloride gave (± ±-libanorin (12± in high
Acylation with tigloyl chloride gave the reported
15. Murray, R. D. H. Nat. Prod. Rep. 1995, 12, 477.
10,11
Similarly,
16. Nielsen, B. E.; Lemmich, J. Acta Chem. Scand. 1964, 18, 2111.
17. Harris, E. B. J.; Banwell, M. G.; Willis, A. C. Tetrahedron Lett. 2011, 52, 6887.
18. Magolan, J.; Coster, M. J. J. Org. Chem. 2009, 74, 5083.
1
2
yield. To the best of our knowledge, this is the first synthesis of
this natural product. Finally, reaction with tert-butyldimethylsilyl-
p-coumaroyl chloride followed by desilylation gave (± ±-angelmarin
19. Jiang, H.; Sugiyama, T.; Hamajima, A.; Hamada, Y. Adv. Synth. Catal. 2011, 353,
155.
20. Steck, W.; Eldakhak, M.; Brown, S. A. Tetrahedron Lett. 1969, 4805.
21. Yaꢀaki, K.; Sasaki, K.; Tsurumaru, Y. Phytochemistry 2009, 70, 1739.
1
3
(
6± in high yield.
2
2
2. Murray, R. D. H.; Ballantyne, M. M.; Mathai, K. P. Tetrahedron 1971, 27, 1247.
3. Bohlmann, F.; Franke, H. Chem. Ber. 1971, 104, 3229.
In summary, we have used a domino on-water, in-water process
as the key step in the synthesis of (± ±-columbianetin (1± and
several columbianetin-containing natural products. This work
24. Zhang, H. B.; Liu, L.; Chen, Y. J.; Wang, D.; Li, C. J. Eur. J. Org. Chem. 2006, 869.
5. Hata, K.; Koꢀawa, M.; Baba, K.; Yen, K.-Y. Chem. Pharm. Bull. 1971, 19, 640.
2