Asymmetric Diels–Alder reaction between furans and propiolates

Article abstract of DOI:10.1016/j.tetlet.2021.153075

We report the first asymmetric Diels–Alder reaction between furan and propiolates. Propiolate, a dienophile, was equipped with an Evans’ auxiliary and a sulfonyl group to control and facilitate diastereoselective cycloaddition. Treatment with furan as a diene and aluminium Lewis acid afforded a 7-oxabicyclo[2.2.1]heptadiene skeleton diastereoselectively. The origin of diastereoselectivity can be explained by chelation of aluminium center to carbonyl groups and oxygen of furan. Friedel–Crafts-type products were obtained when pyrrole was used as diene.

Full text of DOI:10.1016/j.tetlet.2021.153075

Tetrahedron Letters 72 (2021) 153075
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Tetrahedron Letters
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Asymmetric Diels–Alder reaction between furans and propiolates
⇑
⇑
Akihiro Ogura , Taisuke Ito, Koujiro Moriya, Hiroki Horigome, Ken-ichi Takao
Department of Applied Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the first asymmetric Diels–Alder reaction between furan and propiolates. Propiolate, a dieno-
phile, was equipped with an Evans’ auxiliary and a sulfonyl group to control and facilitate diastereoselec-
tive cycloaddition. Treatment with furan as a diene and aluminium Lewis acid afforded a 7-oxabicyclo
[2.2.1]heptadiene skeleton diastereoselectively. The origin of diastereoselectivity can be explained by
chelation of aluminium center to carbonyl groups and oxygen of furan. Friedel–Crafts-type products were
obtained when pyrrole was used as diene.
Received 26 February 2021
Revised 31 March 2021
Accepted 7 April 2021
Available online 20 April 2021
Keywords:
Diels–Alder reaction
Furan
Ó 2021 Elsevier Ltd. All rights reserved.
Propiolate
Introduction
Yet, despite extensive reports of the asymmetric synthesis of the
corresponding bicycloheptene core [4–6,31–35], enantioselective
Enantioselective Diels–Alder reactions have been developed
using either chiral auxiliaries [1] or asymmetric catalysts [2,3]. In
particular, when an enone and a cyclic diene are used, bicyclic
Diels–Alder adducts can be obtained with good stereoselectivity
[4–6]. Secondary orbital interaction [7] limits the direction from
which the diene approaches, thus single adduct can obtained if
face-selectivity is achieved. Four stereogenic centers are con-
structed in a single reaction as shown in Scheme 1A.
In contrast to the alkene-diene Diels–Alder reaction, the Diels–
Alder reaction between an alkyne and diene remains underdevel-
oped. The most important reason for this is the difficulty of stere-
ochemical control. Unlike the case of enones described above, an
synthesis of the bicycloheptadiene core by Diels–Alder reaction
has been a difficult task.
In particular, 7-oxabicyclo[2.2.1]heptadiene, which can be pre-
pared by Diels–Alder reaction between an alkyne and furan, has
recently garnered much attention. The oxabicycloheptadiene
skeleton has been extensively studied as a chemical probe for thi-
ols [36–43]. Although bicycloheptadiene skeletons are stable under
normal conditions, thiol adducts can induce a controllable retro-
Diels–Alder reaction (Scheme 1C). However, racemic mixtures
have been used for this research, and the reactivity of the individ-
ual enantiomers has not been discussed. Considering the three-
dimensional structures of bioactive proteins and peptides, an
enantioselective supply of this skeleton would be beneficial for fur-
ther fine-tuning the characteristics of the retro-Diels–Alder
reaction.
This bicycloheptadiene skeleton is also an attractive starting
point for constructing complex polycyclic structure. After the
appropriate introduction of substituents, the endo-cis-disubsti-
tuted bicycloheptadiene would be obtained by chemoselective
functionalization of the resultant Diels–Alder adduct. This partial
structure can be found in a number of acetogenin natural product
such as maneonenes (Scheme 1D) [44,45]. Although a trans-disub-
stituted [46] or exo-cis bicyclic core [47–50] can be obtained with
good selectivity in a few steps, the enantioselective synthesis of the
endo-cis bicyclic skeleton has so far been limited to enzymatic
desymmetrization after saturation of a double bond, reduction,
and acylation [51–53]. Herein, we report the first example of an
intermolecular asymmetric Diels–Alder reaction between propio-
lates and furans.
alkyne has two degenerated
p-orbitals distributed uniformly
around its sp-hybridized carbons, meaning that there is no face
or planarity (Scheme 1B). This leaves no means for stereochemical
control based on the approach of the diene. To our knowledge,
there are limited examples of diastereo- or enantio-controlled
Diels–Alder reactions between an alkyne and diene [8–23].
Although asymmetric metal-catalyzed formal [4 + 2] cycloaddition
reactions using alkynes and linear dienes have been also developed
[24–30], there have been no example of constructing a bridged
bicyclic skeleton by this method so far.
The bicyclo[2.2.1]heptadiene skeleton is one of the adducts of a
Diels–Alder reaction between an alkyne and cyclic diene. Here, if
the two olefins are non-uniformly substituted, the bridgehead car-
bons become chiral centers, giving a possible pair of enantiomers.
⇑
Corresponding authors.
E-mail addresses: ogura@applc.keio.ac.jp (A. Ogura), takao@applc.keio.ac.jp
(K. Takao).
https://doi.org/10.1016/j.tetlet.2021.153075
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

A. Ogura, T. Ito, K. Moriya et al.
Tetrahedron Letters 72 (2021) 153075
Fig. 1. Characteristics of propiolates.
Scheme 2. Preparation of substrate.
Table 1
Optimization of reaction conditions.
Scheme 1. Synthesis and applications of the oxabicycloheptadiene core.
Result and discussion
Sulfonylated propiolamide was selected as a substrate and sub-
jected to the Diels–Alder reaction with furan. Conjugation with a
carbonyl group and a sulfonyl group was considered beneficial
for promoting the Diels–Alder reaction while also distinguishing
the two resultant sp2 carbons [54]. Introduction of the carbonyl
group was also advantageous because the LUMO of the dienophile
is fixed orthogonal to the carbonyl-alkyne plane (Fig. 1A) [15]. Sev-
eral attempts have been made to use asymmetric catalysts, but
they did not achieve asymmetric induction. We attributed this to
the spatial distance between the carbonyl group and the alkyne.
Unlike acrylates, the alkyne is directed away from the carbonyl
group, which is the coordination center for the catalyst [13]. There-
fore, we decided to utilize a chiral oxazolidinone-based approach
by Evans [23,55], anticipating that the auxiliary would cover the
chemical space far from the carbonyl group (Fig. 1B).
The synthesis of the substrate is shown in Scheme 2. Protected
propiolic acid 1 was condensed with valine-derived oxazolidinone
2 [55] to afford protected propiolamide 3. Removal of the terminal
silyl group followed by terminal phenylthiolation provided sulfide
4. Subsequent oxidation afforded substrate 5. Other substrates
with various pendant groups were prepared similarly from known
chiral auxiliaries [56–62].
Lewis acid, and the expected Diels–Alder reaction products 7A and
7B were obtained (entries 1–4). Although diastereoselectivity was
not observed, use of aluminum chloride as the Lewis acid gave the
highest yield (entry 4). Solvent screening revealed that moderate
stereoselectivity could be achieved in ethereal solvent (entries 5–
7). Although usage of substoichiometric amount of the Lewis acid
deteriorated the selectivity (entry 8), a dilution improved the
selectivity (entries 9 and 10).
With substrates in hand, we next turned to optimizing the reac-
tion conditions (Table 1). Substrate 5 was treated with furan and a
Having optimized the reaction conditions, effects of the pen-
dant group were investigated (Table 2). Bulkier substituents gave
2

A. Ogura, T. Ito, K. Moriya et al.
Tetrahedron Letters 72 (2021) 153075
Table 2
Optimization of the pendant group.
Scheme 4. Reaction reversibility test.
that no retro-Diels–Alder reaction or selective decomposition of
one diastereomer occurred under these conditions, and the reac-
tion therefore gives kinetic product.
We explain the origin of the stereoselectivity as shown in Fig. 2.
As proposed by Evans [23], the carbonyl groups are expected to be
parallel and are activated by coordination to aluminum. Diethyl
ether may also coordinate to the aluminum centers, forming clus-
ters. At the same time, the pendant group of the oxazolidinone
moiety covers one of the alkyne ‘faces’ by stacking, restricting
the reactive face of the LUMO (see also Fig. 1). Then, furan
approaches the propiolate by way of coordination to aluminum.
Although an unparallel coordination model has been proposed to
explain the selectivity of an oxazolidinone-based auxiliary [63],
the large difference in reactivity between 9 and 13 is likely to be
better explained by the steric bulk around the alkyne moiety (see
also Table 2).
higher diastereoselectivity, accompanied by a slight decrease in
yield. Phenylglycine or substituted phenylalanine derivatives gen-
erally gave good results (entries 1–5), and an electron-donating
group further improved the selectivity. The best diastereoselectiv-
ity was achieved with isopropylated tyrosine derivative 11, which
gave a satisfactory dr of 10:1 (entry 4). Use of silver tetrafluorobo-
rate as an additive prevented Michael addition of chloride ion to
alkyne moiety and improved yield, but slightly lowered dr (entry
5). Notably, the bulkier substituents benzyloxybenzyl and
diphenylmethyl substitution completely inhibited the reaction
(entries 6 and 7).
The auxiliary can be removed in a single step. For example, 14B,
a minor adduct from 9 and furan, was treated with titanium ethox-
ide to afford 15 without giving any byproduct (Scheme 3). This was
further converted to a known desulfonylated compound 18 [31] via
4-step sequence. The absolute configuration of the Diels–Alder
adducts was thus confirmed.
Fig. 2. Proposed origin of stereoselectivity.
Table 3
Substrate scope.
Because the Diels–Alder adduct of furan is susceptible to the
retro-Diels–Alder reaction, a control experiment was performed
to determine whether the stereoselectivity was the result of kinetic
or thermodynamic control. Thus, a 1:1 diastereomeric mixture of
the bicyclic moiety was again subjected to the Diels–Alder reaction
conditions (Scheme 4). The substrate remained intact, indicating
Scheme 3. Confirmation of the absolute configuration.
3

A. Ogura, T. Ito, K. Moriya et al.
Tetrahedron Letters 72 (2021) 153075
Table 4
Heteroaromatics other than furan were also subjected to reac-
tion conditions (Table 4). Reaction with N-substituted pyrroles
proceeded smoothly, but Friedel–Crafts-type products were gener-
ated. Interestingly, E/Z selectivity of products was dependent on
reaction conditions: reaction with AlCl3 in ether at low tempera-
ture afforded the E-acrylate preferentially (entries 1 and 2). On
the other hand, only the Z-acrylate was obtained without AlCl3 in
dichloromethane at room temperature (entries 1 and 2). In the case
of Boc-protected pyrrole, Z isomer was selectively obtained in good
yield (entry 3). Thiophene, the isostere of furan, resulted in no
reaction or a complex mixture in both conditions (entry 4).
The selectivity in E/Z-geometry can be rationalized as described
in Scheme 5: the pyrrole attacks the b-position of activated propi-
olamide from bottom side to afford allenoate (Scheme 5A, right
top). Then, upon aqueous workup, water molecule approaches
the allenoate by way of coordination to aluminium center and
Reaction with other heteroaromatics.
hydrogen bonding to sulfone moiety (right bottom). Thus
a-posi-
tion is protonated from the same side as sulfone to afford E-acry-
late. In the case of N-Boc-protected 34, the carbamate moiety
might act better as hydrogen bond acceptor than sulfone to yield
Z-acrylate. On the other hand, in the absence of aluminium, the
conjugate addition occurs to inactivated propiolamide, hence
higher temperature required for 32 and 33, to afford zwitterion
intermediate (Scheme 5B, center). Subsequent deprotonation-pro-
tonation takes place in intramolecular fashion to provide Z-
acrylate.
Following optimization of the reaction conditions, we examined
various substituted furans as the reaction partner (Table 3). Asym-
metrically substituted furans 20–22 led to an inseparable complex
mixture of diastereomers, suggesting regioselectivity was difficult
to achieve (entries 1–3). Removal of the chiral auxiliary from these
adducts failed, possibly due to a competing retro-Diels–Alder reac-
tion because substitution at the bridgehead position and coordina-
tion of a Lewis acid to the carbonyl group resulted in increased
steric repulsion. Therefore, we decided to focus on 3,4-disubsti-
tuted furan derivatives. Moderate to good stereoselectivity was
observed for alkyl- or halogen-substituted furans 23–28 (entries
4–9), and especially high selectivity and yield was achieved when
3,4-bis(methoxymethyl)furan 27 or 3,4-bis(benzyloxymethyl)fu-
ran 28 was used (entries 8 and 9). On the other hand, electron-
withdrawing groups in 29 and 30 completely inhibited the reaction
(entries 10 and 11). Isobenzofuran 31 was reactive but had little
selectivity (entry 12).
Conclusion
In conclusion, we have achieved the first intermolecular asym-
metric Diels–Alder reaction between propiolates and furans. A chi-
ral auxiliary worked effectively to control the reaction ‘face’ of the
alkyne carbons, and a three-dimensional structure was constructed
from the combination of one- and two-dimensional substrates.
Further studies to improve the yield and selectivity of the reaction
and apply it in the total synthesis of natural product are under way
in our laboratory.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgement
This research was supported by JSPS KAKENHI Grant Number
19 K15571, the Tobe Maki Scholarship Foundation, Keio Gijuku
Academic Development Funds, and Keio Leading-edge Laboratory
of Science and Technology for financial support.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153075.
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