Asymmetric [2+2] photocycloadditionviacharge transfer complex for the synthesis of tricyclic chiral ethers

Article abstract of DOI:10.1039/d1cc00035g

The asymmetric synthesis of chiral polycyclic ethers by an intramolecular [2+2] photocycloaddition is described. This process proceeded through a photocatalytically active iminium ion-based charge transfer (CT) complex under visible light irradiation. In this way a stereocontrolled [2+2] photocycloaddition is enabled leading to tricyclic products with good enantiomeric ratios.

Full text of DOI:10.1039/d1cc00035g

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Asymmetric [2+2] photocycloaddition via charge
transfer complex for the synthesis of tricyclic
chiral ethers†
Cite this: Chem. Commun., 2021,
57, 3046
Received 4th January 2021,
Accepted 9th February 2021
a
a
Ana M. Martınez-Gualda,
Pablo Domingo-Legarda,a Thomas Rigotti,
´
bc
ac
ac
Sergio Dıaz-Tendero,
Alberto Fraile
and Jose Aleman
*
´
´
´
DOI: 10.1039/d1cc00035g
rsc.li/chemcomm
The asymmetric synthesis of chiral polycyclic ethers by an intramolecular intramolecular [2+2] photocycloaddition represents a straightfor-
[2+2] photocycloaddition is described. This process proceeded through ward strategy for the synthesis of chiral polycyclic molecules in a
a photocatalytically active iminium ion-based charge transfer (CT) single step. The group of Bach described different asymmetric
complex under visible light irradiation. In this way a stereocontrolled intramolecular [2+2] photocycloadditions employing hydrogen
[2+2] photocycloaddition is enabled leading to tricyclic products with bonding or Lewis acid catalysis to induce stereocontrol.11,12 In the
good enantiomeric ratios.
first pioneering example, the use of a bifunctional xanthone-
containing catalyst allowed the obtainment of the targeted cyclobu-
Chiral polycyclic compounds have a huge importance in medical tane via a triplet energy transfer mechanism (Scheme 1a).11a
chemistry since many bioactive molecules and drugs contain A second strategy reported by the same group unlocked the
polycyclic scaffolds in their structures.1 Among them, polycyclic construction of interesting tricyclic compounds through the pre-
ethers are found in many natural products (Fig. 1),2 and some of ferential photoexcitation of a chiral Lewis acid-substrate complex
the most useful and employed drugs in pain treatment, such as chromophore (Scheme 1b).12a In addition, other innovative photo-
Morphine and Codeine, contain a 5-membered ring ether motif.3 catalytic strategies have been described by Yoon’s and Meggers’
On the other hand, the corresponding 6-membered ring is found research groups through different activation modes.13 In this
in the main core of rotenoids such as Rotenone, which is a context, our research group has recently demonstrated that
naturally occurring insecticide and pesticide with anticancer iminium ion catalysis and charge transfer (CT) complex photo-
properties, or in Anthopogochromane, a complex cyclobutane- activity could be exploited for the synthesis of enantioenriched
containing natural product.4,5 In addition, a polycyclic 7-mem- cyclobutanes via [2+2] photocycloaddition.14 This strategy consti-
bered ether scaffold is found in Enokipodin A, a compound tuted an unprecedented aminocatalytic activation mode in [2+2]
isolated from nature which shows antimicrobial activity.6
photocycloaddition, showcasing that the photoactivity of CT
On the other hand, the 4-membered ring motif of cyclobu- complexes is not limited to photoredox reactions but it can be
tanes is found in many natural products,7 whereas cyclobutane exploited to unlock novel light-driven reactions.15 With these
derivatives have been employed as suitable building blocks and precedents in mind, we investigated the intramolecular [2+2]
intermediates in organic synthesis and in the construction of
biologically active molecules.8,9 Considering the importance of
this type of scaffold, new catalytic asymmetric synthetic routes
should be explored to allow the obtainment of cyclobutanes in
an enantioenriched form.
Photocatalysis has appeared as a new synthetic tool for the
construction of organic molecules.10 In this context, enantioselective
a
´
Organic Chemistry Department, Universidad Autonoma de Madrid, Madrid 28049,
Spain. E-mail: jose.aleman@uam.es
b
´
Chemistry Department, Universidad Autonoma de Madrid, Madrid 28049, Spain
c Institute for Advanced Research in Chemical Sciences (IAdChem),
´
Universidad Autonoma de Madrid, Madrid 28049, Spain
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Fig. 1 Examples of biologically relevant polycyclic ethers.
d1cc00035g
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Table
1
Optimization of the [2+2] photocycloaddition (selected
examples)a
Scheme 1 Enantioselective [2+2] photocycloaddition approaches for the
construction of enantioenriched polycyclic ethers.
Entry
Catalyst
Solvent
Conversion (%)
er
1
2
3
4
5
6
7
8
C1
C2
C3
C4
C5
C6
C7
C8
C8
C8
—
No light
Diethyl ether
Diethyl ether
Diethyl ether
Diethyl ether
Diethyl ether
Diethyl ether
Diethyl ether
Diethyl ether
MeCN
7
0
5
100
90
93
—
—
—
72 : 27
75 : 25
71 : 29
79 : 21
83 : 17
83 : 17
—
photocycloaddition of enones bearing an O-tethered alkene
moiety for the synthesis of enantioenriched tricyclic ethers
through an aminocatalytic strategy enabled by the enhanced
absorption observed upon formation of an electron donor–accep-
tor (EDA) or CT complex (Scheme 1c).
The targeted model substrate 1a was easily synthesized by
allylation of salicylaldehyde and subsequent aldol reaction with
acetone. We started to investigate the intramolecular [2+2]
photocycloaddition of 1a employing a 20 mol% catalyst load-
ing, 1 equivalent of trifluoroacetic acid and diethyl ether as the
solvent under blue LED irradiation (Table 1). As expected, the
use of catalysts C1-2 (entries 1 and 2) predictably led to a
negligible conversion due to the lack of a suitable donor in
92
100 (52)b
9
50
0
0
10
11
12
DMSO
Diethyl ether
Diethyl ether
—
—
0
a
The conversion was determined by 1H NMR analysis of the crude
mixture after 15 h. The er was determined by chiral SFC analysis of the
isolated product. Isolated yield.
b
their structure that could unlock the formation of an intra- quaternary stereocenter) and only one diastereoisomer (dr 498 : 2)
molecular CT complex (vide infra). Catalyst C3 was not effective is achieved.
either, leading to a low conversion (entry 3). On the other hand,
Firstly, we decided to study the effect of the substitution of
employing the enantiopure diamine C4 we were able to obtain the aryl group of the salicylaldehyde core. The reaction of
the desired tricyclic compound in 38% yield and moderate substrates with moderate electron-donating substituents, in
enantioselectivity (73 : 27 er, entry 4). Thus, we studied the para- and meta-positions to the enone double bond (R1 = 4-Me,
effect of various substitutions on the aryl scaffold (catalysts 5-Me), afforded the corresponding cyclobutanes 2b and 2c in
C5-8, entries 5–8) to increase the steric hindrance provided by 63% and 46% yields and with 85: 15 and 82: 18 er, respectively
the organocatalyst with the aim of achieving a higher stereo- (Table 2). The presence of a strong electron-donating substituent
induction. The best result was accomplished by catalyst C8, in the para-position (R1 = 4-MeO) had a beneficial impact on the
bearing 1-naphthyl substituents as the aryl moieties, obtaining enantioselectivity, obtaining compound 2d in 62% yield and
the targeted cyclobutane in 52% yield and 83 : 17 er. As high- 91: 9 er. On the other hand, the employment of enones 1e or 1f,
lighted by the corresponding control experiments both the bearing a methoxy group in the 3-position (3-MeO) or a bulky
organocatalyst and light were crucial to obtain the desired tert-butyl group in the 6-position (4,6-di-t-Bu), afforded products
product (entries 11 and 12), confirming the required mediation 2e and 2f in 38% and 58% yields but with strongly diminished
of an iminium ion and the photocatalytic nature of the [2+2] stereoinduction (66: 34 and 65: 35 er, respectively). This suggests
cycloaddition. Although only a moderate yield is obtained, due that the ortho-substitution is not well tolerated. The use of
to the evidenced degradation of both starting material and enones with electron-withdrawing groups (R1 = m-Cl, p-CF3) led
product under the reaction conditions (see the ESI,† for to the obtainment of products 2g and 2h in 38% and 51% yields
details), it should be highlighted that during this process a and with 87 : 13 and 81: 19 er, respectively. Enone 2i, bearing
tricyclic product with three chiral centers (one of which is a a branched alkyl chain at the a-carbonyl position of the ketone
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Table 2 Scope of the intramolecular [2+2] photocycloaddition
Scheme 2 Intramolecular [2+2] photocycloaddition to obtain an enan-
tioenriched seven-membered ring polycyclic ether scaffold.
The proposed mechanism of the intramolecular [2+2] photo-
cycloaddition is based on our previous studies,14 and is supported
by UV-Vis absorption measurements, which highlighted the for-
mation of an iminium ion-based CT complex intermediate upon
addition of catalyst C8 (Fig. 2a). On the other hand, the use of
catalyst C1 did not lead to the formation of a photoactive inter-
mediate due to the lack of a suitable donor moiety in its structure.
The proposed mechanism (Fig. 2b) starts with the acid-promoted
condensation of catalyst C8 with enone 1a to form the iminium ion
intermediate I, which due to the contiguous presence of a suitable
donor (naphthyl) and a suitable acceptor (iminium ion) gives a
coloured ground state CT complex. Under blue LED irradiation the
intermediate I can reach the CT excited state II by an intramolecular
single electron transfer (SET) from the donor moiety to the transient
generated acceptor fragment. The excited state II is an unproductive
species for the photocycloaddition since its reaction would lead to a
regioisomer that has not been experimentally observed.16 Thus, the
formation of this species is only triggering the excitation process due
to the appearance of a new CT band that allows the excitation of an
otherwise not photoactive chiral iminium ion under visible light
irradiation. Therefore, II can restore the ground state CT complex by
(R2 = i-Pr), provided the desired product in 39% yield and 78: 22 back electron transfer (BET) or lead to an excited species III by
er. Finally, different aryl substitutions in the O-tethered styrene means of a thermal equilibrium in the excited state.17 Once
moiety were tolerated. The employment of enones 1j and 1k populated, the iminium-localized excited species III can react
(R3 = p-Me–C6H4, p-F–C6H4) led to the obtainment of the intramolecularly with the O-tethered alkene chain via a [2+2] photo-
corresponding cyclobutanes in moderate yields (54% and 42%) cycloaddition to give the cyclobutyl iminium ion IV, and furnishing
and enantioselectivity (80 : 20 and 84: 16 er).
the desired cyclobutane 2a.18
Furthermore, we wondered if a different substitution pattern
In conclusion, we have developed an intramolecular [2+2]
at the alkene double bond could be tolerated (Scheme 2), using photocycloaddition enabled by the photoactivity of an iminium
1l as a starting material. In this case, we were delighted to ion-based intramolecular CT complex. The excitation of a chiral
obtain the corresponding and interesting crossed seven- intermediate was achieved without provoking a racemic back-
membered ring product 2l with high stereocontrol (93 : 7 er) ground reaction of the enone, unlocking a stereoselective
and as a single diastereoisomer (dr 498 : 2). Indeed, as transformation which furnished the corresponding enantioen-
expected, the inverse regioselectivity for the cyclobutane ring riched cyclobutanes. Upon visible light irradiation a CT excited
formation (confirmed by 2D-NMR experiments, see the ESI†) is state is obtained, which allows the population of an iminium-
due to the generation of the more stable diradical intermediate localized excited state by means of a thermal equilibrium in the
upon formation of the first C–C bond of the [2+2] photocy- excited state.
cloaddition, which, in this case, is favouring a dibenzylic
Financial support was provided by the European Research
diradical (vide infra). The absolute configuration of the tricyclic Council (ERC-CoG, Contract No. 647550), the Spanish Government
products was obtained by circular dichroism of 2d (see the (RTI2018-095038-B-I00, PID2019-110091GB-I00), ‘‘Comunidad de
ESI†) and also in comparison with the one observed in the Madrid’’, and European Structural Funds (S2018/NMT-4367). The
corresponding intermolecular reaction, which was supported authors acknowledge the generous allocation of computer time at
by X-ray analysis.14
the CCC-UAM.
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Fig. 2 UV-Visible absorption spectra (a) and the corresponding mechanistic proposal for the intramolecular [2+2] photocycloaddition (b).
´
J. Aleman, Chem. Commun., 2020, 56, 11169; (i) M. Silvi and
All authors have given approval to the final version of the
manuscript.
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P. Melchiorre, Nature, 2018, 554, 41; ( j) Y.-Q. Zou, F. M. Hormann
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J. Morrisson, A. D. Smith and E. Zysman-Colman, Beilstein J. Org.
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11 (a) C. Mu¨ller, A. Bauer and T. Bach, Angew. Chem., Int. Ed., 2009,
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There are no conflicts to declare.
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