Short Flow-Photochemistry Enabled Synthesis of the Cytotoxic Lactone (+)-Goniofufurone

Article abstract of DOI:10.1021/acs.orglett.6b00067

A photochemical approach to the cytotoxic lactone (+)-goniofufurone (1) is reported. Paternò-Büchi [2 + 2] photocycloaddition from known enol ether 4, derived from the readily available sugar d-isosorbide, yielded oxetane 7. This slow, dilute reaction was

Full text of DOI:10.1021/acs.orglett.6b00067

Letter
pubs.acs.org/OrgLett
Short Flow-Photochemistry Enabled Synthesis of the Cytotoxic
Lactone (+)-Goniofufurone
Michael Ralph,*,† Sean Ng,‡ and Kevin I. Booker-Milburn*,†
†School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, U.K.
‡Syngenta U.K., Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6EY, U.K.
S
* Supporting Information
ABSTRACT: A photochemical approach to the cytotoxic lactone
(+)-goniofufurone (1) is reported. Paterno−Buchi [2 + 2] photo-
̀
̈
cycloaddition from known enol ether 4, derived from the readily
available sugar D-isosorbide, yielded oxetane 7. This slow, dilute
reaction was scaled up by using flow photochemistry to yield >40 g of
7. Installation of the key lactone ring was achieved via a unique Wacker-
style oxidation of an enol−ether bond. Acid-catalyzed aqueous ring
opening provided 1 in five steps from 4 (11.5% overall).
Scheme 1. Proposed Oxetane Ring-Opening Strategy to
(+)-Goniofufurone and Analogues and a Concise Route
from D-Isosorbide via a Paterno−Buchi Photocycloaddition
(+)-Goniofufurone (1) is an example of a number of styryl-
lactone containing natural products isolated from Goniothala-
mus trees of the plant family Annonaceae in South East Asia.1
Extracts from these plants have been used as traditional
medicines in the treatment of edema and rheumatism as well as
mosquito repellents. A number of total synthesis of 1 and its
congeners have been reported,2 as well as progress in the
synthesis and evaluation of biological activity of analogues. Of
particular significance is the extensive work of Popsavin et al.3
who have demonstrated that analogues of 1 have potent
antiproliferative effects against a number of human cell lines. In
particular, the oxetane 2, which was formed from 7-epi-
(+)-goniofufurone, had a cytotoxic potency greater than that of
the natural product and, with some cell lines, even greater
activity than the anticancer drug standard doxorubicin (Figure
1).
̀
̈
Synthetic Strategy
As part of a program exploring the use of synthetic
photochemistry in drug discovery, we were intrigued with the
possibility of synthesizing 1 by hydrolysis of the oxetane 3,
which as an epimer of 2 should undergo hydrolytic inversion of
the benzylic C-7 center during ring opening (Scheme 1). An
efficient synthesis of 3 would also prove useful for the
preparation of a range of ring-opened analogues for use in drug
discovery (1, Nu = OR, NHR, SR, CN, etc.). If successful ring-
opening protocols could be developed, then a diverse range of
nucleophiles could be investigated under protic or Lewis acid
conditions. In order to achieve this, we proposed a route
toward 3 that involved a Paterno−Buchi [2 + 2] photo-
̀
̈
cycloaddition between the bicyclic enol ether 4 and
benzaldehyde (Scheme 1).
There have been many reports on the scope of the Paterno−
̀
Buchi reaction in the synthesis of oxetanes and their subsequent
̈
ring-opening reactions.4 Although this photocycloaddition has
some significant limitations, it often provides the most direct
and economic route to this class of four-membered hetero-
cycle.5 Although at this stage the stereoselectivity of 4 to 3 was
Figure 1. IC50 values of (+)-goniofufurone (1) and oxetane analogue 2
and their comparison to anticancer drug standard doxorubicin (DOX).
Received: January 8, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00067
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Letter
untested, the regiochemistry of a model photocycloaddition of
benzaldehyde with dihydrofuran6 was clearly in our favor.
Furthermore, we have shown that the model cycloaddition of
benzaldehyde with dihydrofuran could be scaled up very
effectively (e.g., 150 g/24 h) using our FEP flow photochemical
Scheme 2. Total Synthesis of (+)-Goniofufurone and X-ray
Crystallography of 1 and 11
reactors.7 Thus, if the Paterno−
̀
Buchi photochemistry to 3
̈
could be realized, then a short and scalable route to 1 and
analogues could be developed.
The requisite enantiomer of the enol ether 4 is conveniently
available from D-isosorbide in a two-step sequence according to
the protocol of Berini and Deniau.8 In our hands, this was
found to be highly scalable, and 50 g batches of 4 could be
produced routinely. Irradiation of 4 with benzaldehyde in
acetonitrile in a batch immersion well (400 mL) with a 400 W
medium-pressure lamp gave a 2:1 inseparable mixture of the
desired oxetane 7 and a structural regioisomer 6. Although the
batch irradiation proceeded in good overall yield (93%), the
reaction was slow and required running at fairly high dilution.
This meant that meaningful scale up in batch was rather
restricted. Previously, we demonstrated7 that FEP continuous
flow reactors can be useful in the scale up of organic
photochemistry, especially in the case of high dilution reactions
where the large volumes of solvent are not compatible with
fixed volume batch reactors. Using a three-layer FEP flow
reactor in conjunction with a 400 W medium-pressure lamp, we
were able to considerably upscale the productivity of this key
reaction, enabling the formation of over 40 g of the 6/7 mixture
(97% isolated yield) in a single 83 h run (1 mL/min, 70 min
residence time). We were pleased to observe the formation of 7
not only as the major regioisomer but also with the correct C-7
stereochemistry. Basic methanolysis gave a 2:1 mixture of the
alcohols 8 and 9, which were easily separable at this stage
(Scheme 2).
With multigram quantities of 9 in hand, we then explored the
installation of the lactone ring. Triflation of 9 immediately
followed by DBU elimination of the resulting triflate gave the
enol ether 10 in 41% yield. The intermediate triflate of 9
proved to be rather unstable and on one occasion decomposed
exothermically on standing at room temperature. Unfortu-
nately, the corresponding less labile mesylate and tosylate of 9
were unreactive toward basic elimination. Despite this, we were
able to carry out the triflation/elimination of 9 on up to an 8.0
g scale to prepare 2.6 g (35%) batches of 10.
this reaction could be carried out on gram scale; e.g., 2.6 g of 10
gave 1.62 g of 3 (58%).
At this stage, we attempted to investigate the installation of
the lactone ring by direct oxidation of 10. There are a number
of reports in the literature regarding the direct oxidation of 5-
and 6-membered enol ethers to the corresponding lactones.
The most common of these is a chromate-based oxidation
system.9 Unfortunately, a number of the chromate systems
explored (e.g., PCC, PDC, Jones oxidation) gave rise to rapid
decomposition of 10, and none of the lactone−oxetane 3 could
be isolated. We then screened 10 under a variety of different
oxidation conditions, but despite a study of over 20 oxidants10
we were unable to isolate any of the desired lactone 3. It
became frustratingly clear that many of the conditions required
to oxidize the enol−ether bond in 10 would always be
incompatible with the acid-sensitive oxetane ring. In a change
of strategy, we postulated that a Wacker-type oxidation may be
more successful as the initial step would involve a metal−π
interaction under mild conditions. On treatment of 10 under
standard Wacker conditions, we were delighted to see rapid and
clean oxidation to the elusive lactone 3 in 60% yield. Pleasingly,
Initial attempts to complete the synthesis of 1 by oxetane
ring opening proved to be very interesting. Treatment of 3 with
dilute aqueous HCl in dioxane yielded the chloride 11 (91%),
which after confirmation by X-ray crystallography appeared to
have undergone substitution with overall retention of C-7
stereochemistry. However, as traces (≤5%) of 1 were also
isolated from the reaction mixture it is likely that 1 is formed
initially and then undergoes subsequent acid-catalyzed chloride
substitution in an overall double-inversion sequence. Repeating
the sequence with the less nucleophilic TsOH yielded
(+)-goniofufurone (1) in 88% yield (Scheme 2).
In light of the extreme difficulty faced in the oxidation of enol
ether 10 to lactone 3, the surprisingly effective Pd(II)-mediated
oxidation deserves further comment. Although Pd(II) Wacker
style oxidations of enol ethers to enones are well
documented,11 we believe that the present result represents
the first example of a Wacker style oxidation of a cyclic enol
ether to a lactone. It has been reported that the oxidation of
dihydrofuran with PdCl2 leads to a mixture where the major
B
DOI: 10.1021/acs.orglett.6b00067
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Letter
product is 2-hydroxy-3-chlorotetrahydrofuran.12 This suggests
that the mode of oxidation to lactone 3 is specific to the
particular structural features present in 10. It is reasonable to
propose that coordination of the alkene to Pd(II) is facilitated
by the furan oxygen such that it proceeds from the concave face
of 10 to give the complex 12 (Scheme 3). Metalation proceeds
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00067.
■
S
Experimental procedures and NMR data (PDF)
Scheme 3. Proposed Mechanism for Selective Enol−Ether
Oxidation to Lactone 3 under Wacker Conditions
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail:k.booker-milburn@bristol.ac.uk; http://www.chm.bris.
ac.uk/org/bmilburn/index2.htm.
*E-mail: michael.ralph@bristol.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EPSRC Bristol Chemical Synthesis Doctoral
Training Centre (EP/G036764/1) and Syngenta for Ph.D.
studentship funding (M.J.R.).
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̀
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̈
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