Stereoselective Visible-Light Catalyzed Cyclization of Bis(enones): A Viable Approach to the Synthesis of Enantiomerically Enriched Cyclopentane Rings

Article abstract of DOI:10.1002/ejoc.202100397

Photoredox catalytic cyclization of aryl enones in the presence of visible light, promoted either by metals or organic dyes, represent a valuable strategy for the synthesis of cycloalkanes. The development of a stereoselective version of such transformation, in the presence of the metal-free catalyst Eosin Y was studied, with the aim to realize an efficient protocol for the in-flow synthesis of enantiomerically enriched functionalized cyclopentane rings, taking advantage of the flow reactors technology. The use of a chiral auxiliary on the bisenone to be cyclized offers a straightforward and convenient option to exert a stereocontrol on the light-driven cyclization. By exploiting Evans’ oxazolidinones, the stereoselective light-driven cyclization affords, after the removal of the chiral auxiliary, a functionalized 1,2-trans cyclopentane ring in up to 83/17 enantiomeric ratio. When the reaction was performed in continuo, in a homemade coil photoreactor, high yields were observed. The cyclization was also successfully realized in a 3D-printed mesoreactor, without any change in the diastereoseletctivity of the process.

Full text of DOI:10.1002/ejoc.202100397

Communications
doi.org/10.1002/ejoc.202100397
Stereoselective Visible-Light Catalyzed Cyclization of
Bis(enones): A Viable Approach to the Synthesis of
Enantiomerically Enriched Cyclopentane Rings
Fabrizio Medici,[a] Simonetta Resta,[a] Piero Presenti,[a] Lucia Caruso,[a] Alessandra Puglisi,[a]
Laura Raimondi,[a] Sergio Rossi,[a] and Maurizio Benaglia*[a]
Dedicated to Prof. Franco Cozzi on the occasion of his 70th birthday.
Photoredox catalytic cyclization of aryl enones in the presence
of visible light, promoted either by metals or organic dyes,
represent a valuable strategy for the synthesis of cycloalkanes.
The development of a stereoselective version of such trans-
formation, in the presence of the metal-free catalyst Eosin Y
was studied, with the aim to realize an efficient protocol for the
in-flow synthesis of enantiomerically enriched functionalized
cyclopentane rings, taking advantage of the flow reactors
technology. The use of a chiral auxiliary on the bisenone to be
cyclized offers a straightforward and convenient option to exert
a stereocontrol on the light-driven cyclization. By exploiting
Evans’ oxazolidinones, the stereoselective light-driven cycliza-
tion affords, after the removal of the chiral auxiliary, a
functionalized 1,2-trans cyclopentane ring in up to 83/17
enantiomeric ratio. When the reaction was performed in
continuo, in a homemade coil photoreactor, high yields were
Scheme 1. A stereoselective approach for the synthesis of enantiomerically
enriched 1,2-trans cyclopentane rings.
observed. The cyclization was also successfully realized in a 3D-
printed mesoreactor, without any change in the diastereoseletc-
tivity of the process.
reported that also a commercially available and low cost
Light represents an abundant, renewable, low cost and environ-
mentally friendly resource to build new CÀ C bonds, exploring
non-conventional synthetic pathways characterized by the
presence of radical intermediates.[1] One of the most popular
strategies to realize efficient reactions promoted by visible light
involves the use of photosensitizers and photocatalysts, which,
upon irradiation, serve as electron donors or electron
acceptors.[2]
Many kinds of photocatalysts are known and are typically
metal-based, such as iridium or ruthenium catalysts.[3] Based on
the pioneering studies of Krische,[4] Yoon published in 2008 the
Ru-based photoredox catalytic cyclization of bis-aryl enones in
the presence of visible light (Scheme 1A).[5] Soon after, Zeitler
organic dye, like Eosin Y, could be employed in the cyclization,
to afford 1,2-substituted cyclopentane rings.[6] The combination
of an organocatalytic thiourea with Eosin Y allowed to obtain in
good yields racemic trans-1,2-cycloalkanes (Scheme 1B).
We have decided to develop a stereoselective version of
such transformation, and to realize an efficient protocol for the
in-flow synthesis of enantiomerically enriched functionalized
cyclopentane rings, taking advantage of the flow reactors
technology,[7] including 3D-printed devices.[8]
The use of chiral catalysts is the most attractive option,[3d–e]
but the setup of a successful chiral photocatalytic system is a
very challenging task. We thought that the use of a chiral
auxiliary on the bisenone to be cyclized could offer
a
straightforward and convenient option to exert a stereocontrol
on the light-driven cyclization. The removal of the auxiliary, that
can ben conveniently recovered, would afford enantiomerically
enriched cyclopentanes (Scheme 1C).
Our study started with the preparation of phenyl bis-enones
featuring different chiral oxazolidinones, to verify the chemical
compatibility of the chiral auxiliary with the photoredox
conditions, and to investigate the ability of the different chiral
[a] Dr. F. Medici, Dr. S. Resta, Dr. P. Presenti, Dr. L. Caruso, Prof. Dr. A. Puglisi,
Prof. Dr. L. Raimondi, Dr. S. Rossi, Prof. Dr. M. Benaglia
Dipartimento di Chimica,
Università degli Studi di Milano
Via Golgi, 19, 20133 Milano, Italy
E-mail: maurizio.benaglia@unimi.it
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100397
Part of the “Franco Cozzi’s 70th Birthday” Special Collection.
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units to control the stereochemical outcome of the cyclization
(Scheme 2).
Starting from α-bromoacetophenone, ylide 2 was prepared
and reacted with glutaric aldehyde to afford in 75% yield
compound 3, the common intermediate for the synthesis of
different bisenones featuring a chiral moiety. Oxazolidinones
4a–e were converted in 50–75% yields to the corresponding
ylides 6a–e, which were reacted with 3 to yield the enantiopure
bisenones 7a–e in 45–72% isolated yields, as E,E isomer as
largely major diastereoisomer.[9]
Based on the experimental conditions reported in the
previous works,[6] the in batch cyclization of derivatives 7a–e
was then studied in the presence of light (green LED at 530 nm)
and Eosin Y (Scheme 3). In a 10 ml Schlenk tube equimolar
amounts of the bisenone, iPr2NEt and Hantzsch ester, in the
presence of 1,3-bis(3,5-bis(trifluoromethyl)phenyl)thiourea (0.2
eq) and 2.5% of Eosin Y in CH2Cl2 were irradiated for 4 h using
green LEDs (see the Supporting Information for details on the
LEDs characterization).
Under the present conditions, the cyclization of compound
7a, featuring the (S)-4-phenyloaxazolidinone ring, produced
cyclopentane 8a in 70% yield, >98/2 trans/cis selectivity and
75:25 diastereoisomeric ratio. The use of other chiral oxazolidi-
nones in compounds 7b–d did not lead to any improved
diastereoselectivity, while the reaction of bisenone 7e, featuring
the (S)-4-t-butyloxazolidinone, led to the formation of cyclo-
pentane 8e in 80% yield, as single trans isomer and a 83/17
diastereoselectivity.[10] At the present, only a highly speculative
mechanism and stereoselectivity model may be proposed, as
working hypothesis; although the steric hindrance of the
substituent on the oxazolidinone ring is responsible for the
observed selectivity, since many different orientations in the
space are possible for the chiral auxiliary moiety, further studies
will be necessary to “lock” the auxiliary in a well-defined
conformation (see the supporting information for a proposed
mechanism and a tentative stereoselection model).
The removal of the chiral auxiliary was realized by reaction
with sodium methoxide in methanol,[11] to give in quantitative
yield the enantiomerically enriched cyclopentane 9. The
enantiomeric excess was evaluated by HPLC analysis on chiral
stationary phase and confirmed the diastereoisomeric ratio
evaluated by NMR on purified products 8a–e.
The absolute configuration of the major enantiomer of
cyclopentane
(Scheme 4).
9 was established by chemical correlation
Bayer-Villiger oxidation[12] of 9 led to the diester derivative
10, that was hydrolyzed to 2,2’-(-cyclopentane-1,2-diyl)diacetic
acid 11, whose absolute configuration was established to be
(1R,2R) by comparison of the optical rotatory power of the
sample with the data reported in literature.[13]
We then moved to study the diatereoselective cylicaztion
under continuous flow condtions (Scheme 5).
The advantages and the beneficial effects of performing a
light-driven transformation in flow, and the possibility to
overcome the well known limitations of the in batch reactions
are well documented.l[14] Therefore, we decided to perform the
cyclization of bisenone 7e in a homemade coil photoredox
reactor (Scheme 5, see the Supporting Information for details
on the device).
Scheme 2. Synthesis of phenyl enones 7a–e featuring different chiral
oxazolidinones.
In a typical experiment, syringe A was filled with a 0.4 M
solution of bisenone 7e in DCM (total volume 500 μl). Syringe B
was filled with
a mixture obtained dissolving 2,6 mg
(0,004 mmol) of Eosin Y, 50 mg (0.2 mmol) of Hantzsch ester,
20 mg (0.04 mmol) of Schreiner thiourea and 34 μl (0.2 mmol)
of iPrNEt2 in DCM (total volume 500 μl). Syringes A and B were
connected to a syringe pump and the reagents were fed into
PFA reactor through a T-junction at the desired flow rate
Scheme 3. Synthesis of enantiomerically enriched cyclopentane 9 by cycliza-
tion of phenyl enones 7a–e to afford cyclopentanes 8a–e, followed by
removal of the oxazolidinones ring.
Scheme 4. Determination of absolute configuration of cyclopentane 9
obtained by stereoselective photocyclization.
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Scheme 5. In flow cyclization of aryl bisenones in a homemade coil photoredox reactor.
were pleased to find that under continuous flow conditions the
product 8e was obtained with the same diastereoselectivity as
the batch reaction, as demonstrated by conversion of 8e to
ester 9 and determination of e.e. by HPLC analysis. With 30
minutes residence time, 65% conversion was observed and 8e
was produced in 45% isolated yield; however, operating with a
residence time of 40 minutes, a 90% conversion and 87%
isolated yields were observed.
In Figure 1 the setup configuration is reported.
We performed a preliminary investigation into the use of
3D-printed reactors (for the details on 3D-printed reactor
fabrication see the Supporting Information).[15] The 500 μL
reactor was realized using a Formlabs Form 2 3D printer (SLA
Technology) with Clear v4 resin. The channels present a 1×
1 mm2 squared section.
The set-up is reported in Figure 2.
The flow reactor was fed by a continuous flow of reagents
and reactants: Syringes A and B, filled as described for the
reaction in Figure 1, were connected to a syringe pump and the
reagents were fed into the 3D printed device at the desired
flow rate at room temperature. Light irradiation was performed
using Green LEDs. By operating with 30 minutes residence time,
the product was isolated in 50% yield and 78:22 level of
stereoselectivity.
Figure 1. Reaction setup using homemade coil photoreactor. A) Device with
green LEDs off, B) Device with green LEDs on.
In conclusion, the use of the chiral auxiliary strategy to
control the stereochemical outcome of the photoredox catalytic
cyclization of bisenones has been studied. By employing Evans’
oxazolidinones, the light driven cyclization afforded, after the
auxiliary removal, a functionalized, enantiomerically enriched
cyclopentane ring, in up to 83/17 enantioselectivity. Note-
worthy, the reaction has been successfully performed under
continuous flow conditions, both in a homemade photoredox
coil reactor and in a 3D-printed mesoreactor, with good to
excellent yields and no appreciable loss of stereoselectivity.
Although the level of stereocontrol cannot be considered
satisfactory, and further studies are needed to improve the
stereoselectivity of the process, the present study demonstrates
the chiral auxiliary approach may indeed represent a valuable,
and easy to explore, alternative option to realize diastereose-
lective, photoredox catalytic in-flow transformations.
Figure 2. Reaction setup using 3D printed photoreactor. A) green LEDs off,
B) green LEDs on.
(6.66 μL/min for 30 min residence time and 5 μL/min for 40 min
residence time) at room temperature. Light irradiation was
performed using Green LEDs. A dark shield was used as eye
protection system. One reactor volume was discarded before
starting sample collection in order to achieve steady-state
conditions. Reaction outcome was collected in the dark into a
vial and the crude was purified by column chromatography. We
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Acknowledgements
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MB thanks MUR for the project PRIN 2017 “NATURECHEM“. MB
thanks Università degli Studi di Milano for PSR 2019 -financed
project “Catalytic strategies for the synthesis of high added-value
molecules from bio-based starting material”. AP thanks MUR for
the project PRIN 2017 “SURSUMCAT“. LC thanks. Università degli
Studi di Milano for a PhD fellowship. FM thanks MUR project PRIN
2017 “SURSUMCAT for a postdoctoral fellowship.
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[10] The reaction was typically performed on the pure E,E isomer of the
compounds 7a-e; however, with products 7d and 7e, the cyclization
was performed also on a mixture of isomers (E,E and E,Z) and gave the
expected cyclopentane with no appreaciable difference in yield and
diastereoselectivity.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: Chiral auxiliary · Flow reactors · Photoredox ·
Stereoselectivity · Visible Light-driven reactions
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Manuscript received: March 31, 2021
Revised manuscript received: May 14, 2021
Accepted manuscript online: May 22, 2021
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COMMUNICATIONS
Dr. F. Medici, Dr. S. Resta, Dr. P.
Presenti, Dr. L. Caruso, Prof. Dr. A.
Puglisi, Prof. Dr. L. Raimondi, Dr. S.
Rossi, Prof. Dr. M. Benaglia*
1 – 5
Stereoselective Visible-Light
Catalyzed Cyclization of Bis
(enones): A Viable Approach to
the Synthesis of Enantiomerically
Enriched Cyclopentane Rings
An efficient protocol for the in-flow
synthesis of enantiomerically enriched
functionalized cyclopentane rings has
been developed. By exploiting Evans’
oxazolidinones, the stereoselective
light-driven cyclization of bisenones
in a coil photoreactor affords, after
the removal of the chiral auxiliary, an
enantiomerically enriched cyclopen-
tane. The cyclization was also success-
fully realized in a 3D-printed meso-
reactor.