Irreversible endo-Selective Diels-Alder Reactions of Substituted Alkoxyfurans: A General Synthesis of endo-Cantharimides

Article abstract of DOI:10.1002/chem.201406286

The [4+2] cycloaddition of 3-alkoxyfurans with N-substituted maleimides provides the first general route for preparing endo-cantharimides. Unlike the corresponding reaction with 3H furans, the reaction can tolerate a broad range of 2-substitued furans including alkyl, aromatic, and heteroaromatic groups. The cycloaddition products were converted into a range of cantharimide products with promising lead-like properties for medicinal chemistry programs. Furthermore, the electron-rich furans are shown to react with a variety of alternative dienophiles to generate 7-oxabicyclo[2.2.1]heptane derivatives under mild conditions. DFT calculations have been performed to rationalize the activation effect of the 3-alkoxy group on a furan Diels-Alder reaction.

Full text of DOI:10.1002/chem.201406286

DOI: 10.1002/chem.201406286
Full Paper
&
Organic Synthesis
Irreversible endo-Selective Diels–Alder Reactions of Substituted
Alkoxyfurans: A General Synthesis of endo-Cantharimides
[a]
[a]
[a]
[a]
ˇ
ˇ
Robert W. Foster, Laure Benhamou, Michael J. Porter, Dejan-Kresimir Bucar,
Helen C. Hailes,[a] Christopher J. Tame,*[b] and Tom D. Sheppard*[a]
Abstract: The [4+2] cycloaddition of 3-alkoxyfurans with N-
substituted maleimides provides the first general route for
preparing endo-cantharimides. Unlike the corresponding re-
action with 3H furans, the reaction can tolerate a broad
range of 2-substitued furans including alkyl, aromatic, and
heteroaromatic groups. The cycloaddition products were
converted into a range of cantharimide products with prom-
ising lead-like properties for medicinal chemistry programs.
Furthermore, the electron-rich furans are shown to react
with a variety of alternative dienophiles to generate 7-oxabi-
cyclo[2.2.1]heptane derivatives under mild conditions. DFT
calculations have been performed to rationalize the activa-
tion effect of the 3-alkoxy group on a furan Diels–Alder reac-
tion.
Introduction
less, smaller natural products contain ring systems that are po-
tentially ideal scaffolds for use in medicinal chemistry, provided
that efficient synthetic routes can be developed with appropri-
ate functional groups at positions on the central core.
To access new areas of chemical space, medicinal chemistry
programs are increasingly focusing on fragments and scaffolds
with rigid 3D structures that contain a significant proportion of
sp3 carbon atoms.[1] This in turn presents a considerable syn-
thetic challenge as these molecules are generally not straight-
forward to synthesize, and late-stage derivatization is often far
from trivial. Further challenges reside in the control of relative
and absolute stereochemistry due to the presence of numer-
ous chiral centres. Current structural scaffolds of interest in-
clude strained small-ring molecules (cyclopropanes, oxetanes,
azetidines),[2] as well as fused (dihydrobenzofurans, indolines,
tetrahydroquinolines)[3] and bridged bicylic and polycyclic com-
pounds (bicyclopentanes, cubanes, etc).[4] Natural products
have also traditionally provided chemists with inspiration, as
they include bioactive molecules with complex 3D architec-
tures.[5] Many of these compounds, however, have high molec-
ular weights or are too structurally complex to be suitable for
use as scaffolds for medicinal chemistry applications. Neverthe-
The exo-cantharimide skeleton (Figure 1, derived from can-
tharidin, a natural product secreted by many species of blister
beetle with well-established cytotoxic activity)[6] has been ex-
ploited in a wide range of molecules with useful biological
Figure 1. Natural product cantharidin and cantharimide.
properties. The motif is present in several cytotoxic com-
pounds,[7] antiplasmodial agents,[8] androgen receptor antago-
nists[9] and in a positive allosteric modulator of the metabo-
tropic glutamate receptor 4 (mGlu4).[10] More generally, the 7-
oxabicyclo[2.2.1]heptyl skeleton is found in a number of other
important natural products[11–13] and it has proved to be a val-
uable intermediate for synthetic chemists.[14–17] The properties
of the exo-cantharimide skeleton have been extensively ex-
plored with a range of N-substituted derivatives showing
useful biological properties. However, there are few methods
for the introduction of substituents around the 7-oxabicy-
clo[2.2.1]heptyl ring system.[18] Furthermore, the corresponding
endo-cantharimide scaffold has rarely been reported at all.[19]
The exo-cantharimide skeleton is typically prepared by the
[4+2] cycloaddition of furans and maleic anhydride, followed
by alkene reduction and condensation with an amine
(Scheme 1).[20] A curious feature of the cycloaddition reaction is
ˇ
[a] R. W. Foster, Dr. L. Benhamou, Dr. M. J. Porter, Dr. D.-K. Bucar,
Prof. H. C. Hailes, Dr. T. D. Sheppard
Department of Chemistry, University College London
Christopher Ingold Laboratories, 20 Gordon Street
London, WC1H 0AJ (UK)
E-mail: tom.sheppard@ucl.ac.uk
[b] Dr. C. J. Tame
GlaxoSmithKline, Medicines Research Centre
Gunnels Wood Road, Stevenage, Herts, SG1 2NY (UK)
E-mail: christopher.j.tame@gsk.com
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406286.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons At-
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medium, provided the original work is properly cited.
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Scheme 2. Gold-catalysed synthesis of 3-alkoxyfurans 2 from propargylic al-
cohols 1.[27]
proach should enable control of substituents at a variety of po-
sitions on the tricyclic ring system.
Results and Discussion
The reaction of 3-ethoxyfuran 2a with 1.2 equivalents of N-
methylmaleimide proceed in a variety of solvents at room tem-
perature to give cantharimide 3a in near quantitative yield
(Table 1, entries 1 to 4). Crucially the cantharimide was formed
with a clear preference for the endo diastereomer and the two
isomers could be readily separated by flash column chroma-
Scheme 1. Synthetic approaches to cantharimides.
the high stereoselectivity for the exo diastereomer ob-
served, believed to be the result of a highly reversible cy-
cloaddition process which is operating under thermody-
namic control.[21,22] It is possible to access the corre-
sponding endo-cantharimide by a Diels–Alder reaction of
furan with maleimide;[23] however, experimental and com-
putational studies have shown that this reaction is under
thermodynamic control with the exo-cantharimide being
the thermodynamic product.[24] As a consequence, the
endo-adduct of maleimide and furan is known to rapidly
isomerize either in hot solvent or when exposed to visi-
ble light, which impedes both the isolation and applica-
tion of these compounds.[25] Another serious limitation of
furan Diels–Alder reactions is that any deactivating sub-
stituents on the furan have a profound effect on the
equilibrium position of the cyclization. For example, there
are no reported examples of the [4+2] cycloaddition of
2-aryl or 2-heteroaryl furans with dienophiles of any type.
There is a long tradition of activating dienes for Diels–
Alder reactions through the use of electron-donating
substituents, which are known to reduce the activation
energy for the cycloaddition reaction.[26] However, this is gener-
ally a kinetic effect and reducing the kinetic barriers to a ther-
modynamically controlled reaction would only increase the
rate at which isomerization occurs. To access stable endo-can-
tharimides it is therefore necessary to develop reactions with
a significantly improved thermodynamic driving force.[24]
We have recently developed a straightforward approach to
2-substituted-3-alkoxyfurans by gold-catalysed solvolytic cycli-
sation of suitably functionalised propargylic alcohols
(Scheme 2).[27] Preliminary studies indicated that 3-alkoxyfurans
underwent rapid and endo-selective reactions with N-methyl-
maleimide to generate kinetically stable cantharimide prod-
ucts. The distinct 3D structure of the endo-cantharimide motif,
coupled with its physical properties, should make it a valuable
new scaffold for medicinal chemistry applications. Such an ap-
Table 1. [4+2] cycloaddition of 3-alkoxyfurans 2 with N-methylmaleimide.
Entry
R
Solvent[a] T [8C] Reaction t [h] Product Yield [%] endo/exo[b]
1
2
3
4
5[e]
6
Et
Et
Et
Et
Et
Et
Et2O
25
25
25
25
25
4
4
4
4
4
3a
3a
3a
3a
3a
3a
3b
98[c]
100[c]
100[c]
93[d]
65:35
65:35
70:30
70:30
75:25
55:45
80:20
PhMe
EtOH
DMC
DMC
DMC
95[d]
80 16
25
93[d]
89[d]
7
Me DMC
4
[a] DMC refers to dimethyl carbonate. [b] Determined by analysis of the crude
1H NMR spectrum. [c] Yield determined by 1H NMR spectroscopy using penta-
chlorobenzene as an internal standard. [d] Isolated yield. [e] Reaction conducted
with 1.0 g of furan 2a.
tography. The identity of the solvent had little impact on yield
or diastereoselectivity, so dimethyl carbonate (DMC) was se-
lected on the grounds of its excellent environmental profile.[28]
The reaction could also be scaled up to use 1 g of furan 2a,
giving cantharimide 3a in 95% yield (entry 5, endo/exo ratio of
75:25). A purified sample of endo-3a was treated under the
same reaction conditions and no isomerization was observed,
suggesting the reaction proceeds under kinetic control. How-
ever, it was possible to increase the proportion of exo-3a by
heating the reaction at 808C for 16 h (entry 6). The cyclization
was equally effective when 3-methoxyfuran 2b was used as
a diene, giving the corresponding adduct in excellent yield as
an 80:20 mixture of endo and exo diastereomers (entry 7).
These reaction conditions were applied to a wide range of
3-ethoxyfurans with different substituents at the 2-position,
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with the results summarized in Table 2. The reaction
tolerated furans with primary and secondary aliphat-
ic substituents (Table 2, entries 2 and 3). It was also
possible to incorporate a tert-butoxycarbonyl (N-Boc)
piperidine, as shown in entry 4. The reaction was
very effective with an aromatic group at the 2-posi-
tion, giving the first reported examples of 4-arylcan-
tharimides (entries 5 to 10). The reaction of 2-phenyl-
furan 2 f gave an 80:20 mixture of endo and exo dia-
stereomers in good yield. This reaction could also be
conducted on a 1.0 g scale, giving the two diastereo-
mers 3 f in a combined yield of 86%, and with com-
plete isomeric separation following chromatography
on silica gel. The relative stereochemistry of the two
Figure 2. Crystal structures of cantharimides 3 f. Ellipsoids are shown at the 50% proba-
bility level. Only hydrogen atoms belonging to the cyclic core are shown for clarity.[29]
diastereomers was confirmed by X-ray crystallography
Table 2. [4+2] cycloaddition of 3-alkoxyfurans 2 with N-methylmalei-
mide.
(Figure 2).
The reaction was tolerant of electron-poor aromatic substitu-
ents (Table 2, entries 6 and 9), an electron-rich aromatic sub-
stituent (entry 8) and an aryl bromide substituent (entry 7). It
was also possible to use a sterically encumbered 2-tolyl sub-
stituent to give cantharimide 3k in 86% yield. Furthermore,
the reaction was effective when the 3-alkoxyfuran possessed
a heteroaromatic substituent, as can be seen in entries 11 to
13 (85–96% yields). The chemoselective reaction of bis-furan
2l with N-methylmaleimide to give exclusively the enol ether
adduct is an interesting demonstration of the high reactivity of
the 3-alkoxyfuran unit in a [4+2] cycloaddition reaction. It was
also possible to functionalize a 3-alkoxyfuran at the 5-position
prior to the cycloaddition reaction, in order to introduce a sub-
stituent at the 7-position of the endo-cantharimide scaffold
(Scheme 3).
Entry
1
R
Isolated yield [%][a]
93
endo/exo[b]
70:30
2
3
4
95
90
85
85:15
80:20
75:25
5
6
7
8
86 (86)[c]
80:20
80:20
80:20
80:20
75
78
95
Scheme 3. Synthesis of a 7-substituted endo-cantharimide: i) (H2C=NMe2)I
(2 equiv), MeCN, 16 h, RT; ii) N-methylmaleimide (1.2 equiv), DMC, 24 h, RT.
9
84
75:25
The cycloaddition of 3-alkoxyfuran 2a was effective with
a number of alternative N-substituted maleimides, as illustrat-
ed in Table 3.[30] Sterically more challenging N-substituents
could be incorporated in high yield and without an extended
reaction time.
10
11
12
86
85
96
80:20
90:10
70:30
Additionally, it was possible to combine the gold-mediated
furan synthesis with the cycloaddition reaction in a single step
(Scheme 4, conditions i). Treating propargylic alcohol 1a with
gold catalyst and N-methylmaleimide gave diethyl acetal 6 in
good yield. It appeared that the gold catalyst was responsible
for the in situ conversion of enol ether 3a into the correspond-
ing diethyl acetal, as the interconversion can be avoided by
poisoning the catalyst with 2.5 mol% PPh3 prior to addition of
13
92
70:30
[a] Combined isolated yield of endo-3 and exo-3. [b] Determined by analy-
sis of the H NMR spectrum of the crude product. [c] Reaction conducted
with 1.0 g of furan 2 f.
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The enol ether also underwent hydroboration and oxidation to
give alcohol 8, with complete regio- and stereocontrol. Enol
ether endo-3 f could be hydrolysed to give ketone 9 in good
yield by passing it through a strong cation exchange (SCX-2)
cartridge.[32] Treating ketone 9 with NaBH4 afforded alcohol 10,
again with high stereocontrol.
Table 3. [4+2] cycloaddition of 3-alkoxyfuran 2a with maleimides 4.
The acid-mediated aromatization of 7-oxabicyclo[2.2.1]hep-
tane derivatives has been previously applied to the synthesis
of aromatic rings, and this approach could be used to prepare
substituted phthalimide 11.[33] The one-pot cantharimide syn-
thesis described in Scheme 4 was used to convert alcohol 1 f
into the crude cantharimide, which could be converted into
phthalimide 11 by acid-mediated ring-opening and aromatiza-
tion (Scheme 6).
Entry
R
Yield 5 [%]
endo/exo[a]
1
2
3
Ph 4a
4-MeC6H4 4b
c-Pr 4c
94
83
87
65:35
55:35
60:40
1
[a] Determined by analysis of the H NMR spectrum of the crude product.
Scheme 6. Synthesis of substituted phthalimide 11 by acid-catalysed aroma-
tisation of cantharimide intermediates.
Scheme 4. One-pot cantharimide synthesis from propargylic alcohol 1a. i) N-
methylmaleimide, 2 mol% PPh3AuNTf2, EtOH; ii) 2 mol% PPh3AuNTf2, EtOH
then 2.5 mol% PPh3 then N-methylmaleimide.
Physicochemical properties
An important challenge for drug development is the genera-
tion of novel heterocyclic building blocks with suitable proper-
ties for use in screening and medicinal chemistry programs.[34]
The cantharimides accessed using this methodology have ap-
propriate physicochemical properties for lead-like compounds,
including lipophilicity,[35] molecular weight and polar surface
area[36] (Figure 3). Another attractive feature of these scaffolds
the N-methylmaleimide, to give enol ether 3a (endo/exo ratio
of 70:30). Treatment of a sample of enol ether 3a with catalyt-
ic PPh3AuNTf2 in ethanol was also observed to result in forma-
tion of acetal 6.
Transformation of cycloaddition products
The endo-cantharimides contain an enol ether moiety, which
can be readily transformed into a variety of functional groups
(Scheme 5). For example, enol ether endo-3 f can by hydrogen-
ated to generate ether 7 with complete diastereocontrol.[31]
Figure 3. Physicochemical properties of endo-cantharimides.[39]
is the high proportion of sp3-hybridized carbon atoms, which
is typically associated with improved protein binding selectivity
and frequency, better solubility and a reduced chance of off-
target effects.[37] Indeed, cantharimides 7, 10, endo-3 f and exo-
3 f were screened against the hERG receptor (IC50 >50 mm) and
the aryl hydrocarbon receptor (EC50 >100 mm), which are re-
sponsible for common off target effects, and no affinity was
observed. In addition the in vitro clearance of alcohol 10 in the
presence of human microsomes was determined and only
a low level of turnover was observed (<0.53 mLminÀ1 gÀ1).[38]
Scheme 5. Functional-group interconversion of enol ether endo-3 f: i) H2,
10% Pd/C; ii) 9-BBN then H2O2/NaOH; iii) SCX-2 cartridge; iv) NaBH4, MeOH.
9-BBN=9-borabicyclo[3.3.1]nonane.
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times stoichiometric) loading re-
ported for the Lewis acid-cata-
lyzed reactions of 3H furans and
acrylates.[41,43]
Table 4. [4+2] cycloaddition of 3-alkoxyfuran 2a with different dienophiles.
Computational study
Entry Dienophile 12
Reaction Product 13
t [h]
Isolated yield Product
[%]
ratio[a]
The reactions of five 3-alkoxy-
furans and N-methylmaleimide
were explored with the M06-2X
exchange–correlation function
1
72
70
12:1
of Truhlar et al.,[44]
a density
functional that has been suc-
cessfully used to model the re-
action and activation energies
of different cycloaddition pro-
2
3
4
4
77
89
15:85
15:85
cesses.[45]
2-Substituted-3-me-
thoxyfurans were chosen as
suitable models for our 3-al-
koxyfurans and these were
compared to the corresponding
3H furans.
4[b,c]
16
60
89
95:5
The 3-alkoxy group has a dra-
matic effect on the thermody-
namics of the cycloaddition re-
action, as is evident in Table 5.
All five reactions of 3-alkoxyfur-
ans have a clear thermodynamic
driving force for the formation
of both endo- and exo-addition
products (Figure 5) and the
data is consistent with a reaction
that is likely to be kinetically
5[c,d]
6
95: 5
[a] Determined by analysis of the 1H NMR spectrum of the crude product. [b] Reaction conducted at 808C.
[c] Crude product flushed through a SCX-2 cartridge. [d] Reaction conducted with 2 mol% HfCl4.[41]
[4+2] cycloadditions with other dienophiles
controlled. In contrast, the values of DG for the corresponding
reactions of 3H furans are all greater by 24–34 kJmolÀ1
The [4+2] cycloaddition of furans with maleate esters is known
but was reported to require either forcing pressure[40] or high
catalyst loadings of a Lewis acid.[41] In contrast, the catalyst-
free reaction of dimethyl maleate 12a and furan 2a proceeded
at room temperature to give adduct 13a in a good yield and
with excellent endo selectivity (Table 4, entry 1). The reactions
of dimethyl and diethyl fumarate (12b and 12c) with furan 2a
proceeded more rapidly, giving the corresponding adducts in
77–89% yield after 4 h (entries 2 and 3). There is a clear selec-
tivity in both examples for the product which possessed exo
stereochemistry with respect to the 3-position (3-exo-13).[42]
Heating furan 2a with ethyl vinyl ketone at 808C for 16 h, fol-
lowed by hydrolysis of the enol ether on an SCX-2 cartridge,
gave diketone 13d with high regiocontrol (95:5), although as
a 60:40 mixture of endo/exo isomers.
Table 5. Calculated DG and DG° for the reactions of furans 14 and N-
methylmaleimide 15.[a]
14
R
X
endo
DG
exo
DG
DG°
DG°
14a
14b
14c
14d
14e
Me
cPr
OMe
OMe
OMe
OMe
OMe
À41.5
À44.1
À32.5
À34.0
À25.3
81.1
75.0
76.8
83.6
85.9
À47.7
À53.2
À30.1
À28.2
À23.8
82.1
78.6
85.3
91.4
96.8
4-MeOC6H4
Ph
4-F3CC6H4
The catalyst-free reaction of furan 2a with ethyl acrylate
12e was relatively slow at room temperature, with <100%
conversion after 24 h. However, it was possible to accelerate
the reaction through the use of 2 mol% HfCl4, giving the
ketone 13e in 89% yield and with good regiocontrol (95:5)
after 6 h at room temperature (Table 4, entry 5). The catalyst
loading for this reaction is much lower than the high (some-
14 f
14g
14h
14i
Me
cPr
H
H
H
H
H
À11.8
À12.5
À6.1
97.9
92.2
95.4
101.1
101.6
À16.8
À10.3
À3.6
0.7
96.2
92.8
98.8
105.5
108.3
4-MeOC6H4
Ph
4-F3CC6H4
À1.7
14j
À0.9
0.9
[a] All values in kJmolÀ1. All data is calculated for species in the gas
phase.
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Figure 4. Calculated DG and DG° values for the reactions of 2-phenylfurans
14d and 14i and N-methylmaleimide 15 in kJmolÀ1
.
Scheme 7. Thermodynamic cycle involving the hydrogenation of dienes 17
and 20.
Conclusions
We have demonstrated that 3-alkoxyfurans are excellent
dienes for [4+2] cycloadditions with a wide variety of male-
imides and other dienophiles. This methodology significantly
expands the nature of cantharimides that can be readily pre-
pared with high endo selectivity. The reaction tolerates alkyl,
aryl and heteroaryl substituents and the enol ether cycloaddi-
tion product can be transformed into a diverse collection of
drug-like compounds. Finally, DFT calculations have confirmed
that a 3-alkoxy group has a significant effect on both the ther-
modynamic driving-force and the activation energy of the
Diels–Alder reaction of 2-substituted furans with N-methylma-
leimides. The former effect can potentially be attributed to the
3-alkoxygroup leading to a reduced energetic penalty associat-
ed with the loss of furan aromaticity that occurs during the cy-
cloaddition reaction.
Figure 5. M06-2X/6-31G(d)-optimized endo and exo transition states for the
reaction of furan 14d and N-methylmaleimide 15.[46] Distances in ꢁ.
(Figure 4). This effect is most significant when the 2-substitu-
ent is aromatic, as this results in a value of DG close to zero
for the furans 14h–j. As expected, the 3-alkoxy group also has
a significant effect on the free energy of activation for the cy-
cloaddition reaction, with the kinetic barrier reduced by 11–
23 kJmolÀ1. The effect of solvation on these reactions was also
considered but was found to have little effect (see Supporting
Information).
Experimental Section
The reversibility of most furan Diels–Alder reactions has
been attributed to the loss of aromatic stabilization upon for-
mation of an adduct, which results in a facile retro-cycloaddi-
tion.[22] In order to examine the effect of a 3-methoxy group
on this phenomenon, thermodynamic cycles involving the par-
tial hydrogenation of 3-methoxyfuran 17a and furan 20a to
the corresponding 2,5-dihydrofurans 18a and 21a were con-
sidered (Scheme 7). It is notable that the free energy of hydro-
genation for furan 20a was 25.9 kJmolÀ1 greater than for 3-
methoxyfuran 17a. The corresponding reaction free energies
for cyclopentadienes 17b and 20b were also calculated but
no significant difference was observed. The implications of
these calculations are that 1) the difference in behaviour be-
tween 3H and 3-methoxy furans in cycloaddition reactions can
be attributed to differences associated with loss of aromaticity
rather than with CÀC bond formation and 2) a 3-methoxy
General cycloaddition procedure
A solution of the maleimide (1.2 equiv) in dimethyl carbonate
(3.6m) was added to a stirring solution of 3-alkoxyfuran (1.0 equiv)
in dimethyl carbonate (1.5m) at room temperature and the reac-
tion stirred at room temperature for 4–24 h. The reaction was then
diluted with ethyl acetate and loaded onto an aminopropyl car-
tridge. After 5 min the cartridge was then flushed with ethyl ace-
tate and the solvent removed in vacuo to give the crude cycload-
dition product.
1
Experimental procedures, H and 13C NMR spectra, characterization
data of all compounds, compound screening data, details of com-
putational studies including energy minimized geometries and
XRD crystallography files are available in the Supporting Informa-
tion.
group can reduce the energetic penalty associated with the Acknowledgements
loss of aromaticity upon the Diels–Alder reaction of a furan, in-
creasing the thermodynamic stability of the cycloaddition
product.
This work was supported by GlaxoSmithKline and the Engi-
neering and Physical Sciences Research Council (EPSRC Indus-
trial CASE Award) and the UCL Ph.D. program in Drug Discov-
ery.
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Keywords: cantharimides · cycloadditions · dienes · furans ·
phthalimide
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Received: November 29, 2014
Published online on && &&, 0000
&
&
Chem. Eur. J. 2015, 21, 1 – 9
www.chemeurj.org
8
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
&
Organic Synthesis
R. W. Foster, L. Benhamou, M. J. Porter,
ˇ
D.-K. Bucar, H. C. Hailes, C. J. Tame,*
T. D. Sheppard*
&& – &&
No going back! 3-Alkoxyfurans have
been shown to readily undergo irrever-
sible [4+2] cycloaddition reactions with
maleimides to form kinetically stable
endo-cantharimides, which have promis-
ing medicinal properties. This reactivity
has been explored using DFT calcula-
tions and the reaction scope expanded
to include a wide variety of dienophiles
(see scheme).
Irreversible endo-Selective Diels–Alder
Reactions of Substituted
Alkoxyfurans: A General Synthesis of
endo-Cantharimides
Chem. Eur. J. 2015, 21, 1 – 9
www.chemeurj.org
9
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ