Enantioselective template-directed [2+2] photocycloadditions of isoquinolones: Scope, mechanism and synthetic applications

Article abstract of DOI:10.1002/chem.201500173

A strategy for the enantioselective [2+2] photocycloaddition of isoquinolones with alkenes is presented, in which the formation of a supramolecular complex between a chiral template and the substrate ensures high enantioface differentiation by shielding one face of the substrate. Fifteen different electron-deficient alkenes and ten different substituted isoquinolones undergo efficient photocycloaddition, yielding the cyclobutane products in excellent yields and with outstanding regio-, diastereo- and enantioselectivities (up to 990 ee). The mechanism of the reaction is investigated by means of triplet sensitization/quenching and radical clock experiments, the results of which are consistent with the involvement of a triplet excited state and a 1,4-biradical intermediate. The variety of functionalized cyclobutanes obtained using this approach can be further increased by straightforward synthetic transformations of the photoadducts, allowing rapid access to libraries of compounds for various applications.

Full text of DOI:10.1002/chem.201500173

DOI: 10.1002/chem.201500173
Full Paper
&
Cycloadditions
Enantioselective Template-Directed [2+2] Photocycloadditions of
Isoquinolones: Scope, Mechanism and Synthetic Applications
Susannah C. Coote, Alexander Pçthig, and Thorsten Bach*[a]
Abstract: A strategy for the enantioselective [2+2] photocy-
cloaddition of isoquinolones with alkenes is presented, in
which the formation of a supramolecular complex between
a chiral template and the substrate ensures high enantioface
differentiation by shielding one face of the substrate. Fifteen
different electron-deficient alkenes and ten different substi-
tuted isoquinolones undergo efficient photocycloaddition,
yielding the cyclobutane products in excellent yields and
with outstanding regio-, diastereo- and enantioselectivities
(up to 99% ee). The mechanism of the reaction is investigat-
ed by means of triplet sensitization/quenching and radical
clock experiments, the results of which are consistent with
the involvement of a triplet excited state and a 1,4-biradical
intermediate. The variety of functionalized cyclobutanes ob-
tained using this approach can be further increased by
straightforward synthetic transformations of the photoad-
ducts, allowing rapid access to libraries of compounds for
various applications.
Introduction
Progress in synthetic enantioselective photochemistry remains
limited,[1] especially when compared to the great advances
made in ground-state asymmetric synthesis. Nevertheless,
light-mediated processes offer huge potential in the field of or-
ganic synthesis, both in terms of sustainability and in terms of
the wide variety of photochemical reactions available for ex-
ploitation - such processes are often complementary to
ground state methods,[2] and thus widen the toolkit available
to the synthetic chemist. Interest in the area of enantioselec-
tive photochemistry is burgeoning, and a variety of promising
catalytic approaches to photoinduced enantioselective [2+2]
cycloadditions have recently been reported.[3] However, most
of these methods have been applied only to intramolecular cy-
cloadditions, and few effective enantioselective procedures for
the corresponding intermolecular reactions have been realized
to date.[3d,g] Though more demanding, such intermolecular
photocycloadditions would provide access to more diverse
scaffolds, and the development of suitable protocols is there-
fore highly desirable.
Scheme 1. Enantioselective [2+2] photocycloadditions of quinolone and di-
hydropyridone substrates mediated by (+)-1.
lactam-containing substrates.[4] The association of 1 with a suit-
able substrate results in a supramolecular complex via the for-
mation of two hydrogen bonds, effectively shielding one face
of the substrate and allowing selective reaction on the ex-
posed face only. Intriguingly, although 1 proved very successful
in mediating the [2+2] photocycloadditions of quinolones,[4a]
attempts to carry out similar reactions using dihydropyridones
gave rather different results—although the expected photocy-
cloadducts were obtained in good yields, variable enantiose-
lectivities were obtained (40–94% ee).[5] For example, template-
directed intramolecular [2+2] photocycloaddition of quino-
lone 2 gave the expected product 3 in 89% ee, but under
comparable conditions, 5 was obtained in only 60% ee from
dihydropyridone 4 (Scheme 1). These disappointing results
were attributed to relatively poor substrate–template associa-
tion compared to the corresponding quinolone examples, and
could not be improved by increasing the amount of template
employed.
To help address the challenges associated with intermolecu-
lar photocycloadditions, we chose to employ chiral template
1 (Scheme 1), which was developed in our group as a chiral
template to direct enantioselective photoreactions of prochiral
[a] Dr. S. C. Coote,+ Dr. A. Pçthig, Prof. Dr. T. Bach
Department Chemie, Technische Universitꢀt Mꢁnchen
Lichtenbergstrasse 4, 85747 Garching (Germany)
E-mail: thorsten.bach@ch.tum.de
[+] Current address:
Department of Chemistry, Lancaster University
Bailrigg, Lancaster, LA1 4YB (U.K.)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500173.
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Inspired by the large number of isoquinoline-derived natural
products,[6] we were particularly interested in developing enan-
tioselective [2+2] photocycloadditions of isoquinolones using
1. However, at the outset of our studies, it was unclear wheth-
er 1 would be capable of providing the desired levels of enan-
tiocontrol—upon inspection of molecular models, it was clear
that in the expected supramolecular complex between isoqui-
nolone and 1, the reactive isoquinolone double bond is situat-
ed at the outside edge of the template’s shielding motif (see
below), suggesting that enantioface differentiation might be
compromised. However, the corresponding intramolecular [2+
2] photocycloadditions of substituted isoquinolones proceeded
in a highly enantioselective manner,[7] encouraging us to
pursue the more challenging intermolecular variants of these
reactions. Our preliminary work focused on the [2+2] photo-
cycloaddition of isoquinolone with electron-deficient alkenes
in the presence of chiral template (+)-1, generating the corre-
sponding functionalized cyclobutanes with outstanding regio-,
diastereo-, and enantioselectivities (up to 99% ee).[8] Coupled
with impressive recent advances in the synthesis of isoquino-
lones,[9] this methodology offers a particularly appealing ap-
proach to the synthesis of isoquinoline-derived natural prod-
ucts, as well as numerous other target molecules. We wished
to further probe the scope of our methodology, with particular
focus on generating a variety of functionalized cyclobutanes
bearing diverse substituents, which would also ideally undergo
further synthetic transformations. Herein, we report the suc-
cessful realization of these goals, as well as related mechanistic
studies.
lective intermolecular [2+2] photocycloadditions of isoquino-
lones.
Building on our success using monosubstituted alkenes, we
next turned our attention to polysubstituted alkenes. We
chose a varied set of alkenes, with the aim of generating func-
tionalized cyclobutane products suitable for further synthetic
transformations. Gratifyingly, the use of both 1,1-disubstituted
and cyclic 1,2-disubstituted alkenes delivered single isomers of
cyclobutane products (7i–7l) upon [2+2] photocycloaddition
with isoquinolone 6 (Scheme 3; r.r.=regioisomeric ratio; i.r.=
Results and Discussion
Initially, we studied the [2+2] photocycloaddition of the
parent isoquinolone 6 with eight different monosubstituted al-
kenes (Scheme 2). The optimized conditions involved the use
Scheme 3. Enantioselective [2+2] photocycloadditions of isoquinolone with
polysubstituted alkenes. [a] Photoreaction performed at lower substrate con-
centration (5 mm); [b] using trans-dichloroethylene.
Scheme 2. Enantioselective [2+2] photocycloadditions of isoquinolone with
monosubstituted alkenes. pin=pinacolato; EWG=electron-withdrawing
group.
isomeric ratio), as observed with the monosubstituted alkenes,
and again with very high enantioselectivity (95-98% ee). In the
remaining cases (acyclic 1,2-disubstituted and trisubstituted al-
kenes), mixtures of cyclobutane isomers resulted, although
synthetically useful selectivity was still achieved in all cases. In
common with previous examples, the regio- and diastereose-
lectivities of these reactions was greatly improved compared
to the corresponding racemic reactions, which were carried
out at room temperature in the absence of the chiral template
(see the Supporting Information for full details). Notably, cyclo-
butanes 7h, 7j, 7k, and 7l represent particularly versatile syn-
of 2.5 equivalents of chiral template (+)-1 and ten equivalents
of the alkene partner, irradiating with a 300 nm light source.
Carrying out the reaction in toluene at low temperature
(À758C) guaranteed high yields of functionalized cyclobutane-
s 7a–7h (up to 99% ee). Although these types of reactions
had been reported sporadically in the racemic series,[10] our
preliminary work represented the first examples of enantiose-
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thetic intermediates that are primed for further functionaliza-
tion (see below).
We also investigated the use of longer wavelengths of light
to promote these reactions. In general, irradiation using lamps
with emission centered at 366 nm also effected the desired
[2+2] photocycloadditions, although the reaction rate was sig-
nificantly slower (up to 12 h irradiation was required). This was
in line with our expectations, since the absorption of 6 in tolu-
ene is much greater at 300 nm (e=3152mÀ1 cmÀ1) than at
longer wavelengths, such as 350 nm (e=286mÀ1 cmÀ1) and
366 nm (no discernable absorption; see the Supporting Infor-
mation for the absorption spectrum of 6 and emission spectra
of the light sources employed). For example, when irradiating
with 300 nm lamps, cyclobutyl ester 7h was obtained in 93%
yield and 98% ee after two hours, whereas when irradiating
with 366 nm lamps, 7h was obtained in 98% yield and 99% ee
(12 h irradiation) under otherwise identical reaction conditions.
As expected, irradiation using 419 nm lamps led only to traces
of the desired products even after extended reaction times.[11]
Interestingly, and in good agreement with literature prece-
dent,[10] we found that photocycloaddition reactions of isoqui-
nolone using more electron-rich alkenes proceeded extremely
slowly, and are thus of limited synthetic value.
Having studied the alkene scope in detail, we next investi-
gated the propensity of substituted isoquinolones to undergo
similar [2+2] photocycloadditions. At the outset of our stud-
ies, there were very few examples of intermolecular [2+2]
photocycloadditions on substituted isoquinolones,[12] and it
was feared that small changes in the photophysical properties
of substituted isoquinolones (relative to 6) might have a delete-
rious effect on their reactivity in [2+2] photocycloadditions. In
general, these reservations proved to be unfounded, and ten
diversely substituted isoquinolones underwent efficient [2+2]
photocycloaddition with tert-butyl acrylate, furnishing the cor-
responding cyclobutanes in excellent yields and with outstand-
ing enantioselectivities (Scheme 4). In all cases, single isomers
were obtained (>20:1 isomer ratio, determined by 1H NMR
spectroscopy on the crude product). A wide range of substitu-
ents was tolerated, including ester, nitrile, bromo, alkyl, alkynyl,
acetoxy, methoxy and methylthio groups, and substitution was
tolerated at all six aromatic positions around the isoquinolone
moiety.
Scheme 4. Enantioselective [2+2] photocycloadditions of substituted isoqui-
nolones with tert-butyl acrylate. [a] Photoreaction performed at lower sub-
strate concentration (5 mm); [b] photoreaction performed at longer wave-
length (366 nm lamps).
In two cases (8e, 8i), slightly disappointing results were ob-
tained, in that incomplete reaction was observed (approxi-
mately 70% conversion in both cases), despite extended reac-
tion times. In the case of the alkynyl-substituted isoquinolone,
this problem was easily overcome by changing the irradiation
wavelength to 366 nm, resulting in complete conversion into
cyclobutane 8i in excellent yield and with excellent enantiose-
lectivity (93% yield, 95% ee). However, in the case of 6,7-dime-
thoxyisoquinolone, similar results were obtained using both
300 nm lamps (64% yield, 92% ee, plus 12% recovered starting
material; Scheme 4) and 366 nm lamps (62% yield, 92% ee,
plus 20% recovered starting material). Since excess alkene was
always present at the end of the irradiation (as confirmed by
1H NMR spectroscopy of the crude products), it seemed unlike-
ly that these curious results could be caused by low alkene
concentrations. However, the incomplete conversion could be
rationalized by retro-photocycloaddition of the cyclobutane
product under the reaction conditions, which would lead to
a photostationary state comprising both isoquinolone and
product. It is known that isoquinolone [2+2] photocycload-
ducts undergo such retro-cycloadditions,[10b,d,13] although these
reactions are usually promoted by shorter wavelengths of
light. For example, 7 f (EWG=CN) is reported to undergo
retro-cycloaddition upon irradiation at 254 nm, generating
a mixture of its isoquinolone precursor and an N-vinylisoindoli-
none product.[10b,d] To investigate whether a similar cyclorever-
sion might be responsible for the atypical results observed for
8e and 8i, we subjected a pure sample of photocycloadduct
8e to irradiation at 300 nm in toluene (10 mm) for two hours.
As suspected, 8e does indeed undergo extensive retro-photo-
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cycloaddition under these conditions, generating a mixture of
8e and 6,7-dimethoxyisoquinolone (1:4.5). Although longer-
wavelength absorptions by 8e and 8i were not apparent from
their UV/Vis spectra, it seems likely that low-intensity absorp-
tions account for our findings; we postulate that 8e absorbs
light from both the 300 nm and 366 nm light sources, hence
similar results are obtained upon photocycloaddition using
either wavelength. In contrast, we believe that 8i absorbs light
from 300 nm lamps, but not from 366 nm lamps, thus com-
plete conversion can be achieved at 366 nm but not at
300 nm. In any case, even for 8e, synthetically useful yields of
photoadduct can still be obtained, with high enantioselectivity
and perfect regio- and diastereoselectivities.
state, we examined the influence of both triplet quenchers
and triplet sensitizers on the reaction rate. Thus, the [2+2]
photocycloaddition of isoquinolone with ten equivalents of di-
methylvinylphosphonate was carried out in toluene in the
presence of different amounts of 1,3-cyclohexadiene as a triplet
quencher (Figure 1a).
Kaneko and co-workers suggested that the intermolecular
[2+2] photocycloaddition of isoquinolone with chlorinated al-
kenes proceeds through a triplet biradical intermediate 9,
which reacts with an alkene to generate a 1,4-biradical inter-
mediate 10 that ultimately undergoes ring closure to the cy-
clobutane product 7 (Scheme 5).[10g] However, no mechanistic
Figure 1. [2+2] photocycloaddition of isoquinolone 6 with dimethyl vinyl-
phosphonate in the presence of (a) 1,3-cyclohexadiene as a triplet quencher
and (b) acetophenone as a triplet sensitizer.
Scheme 5. Proposed mechanism for the [2+2] photocycloaddition reaction
of isoquinolone 6.
studies dealing with isoquinolone [2+2] photocycloadditions
have been reported,[14] although some theoretical and experi-
mental studies focusing on excited states of isoquinolones
have appeared.[15] Aiming to gain deeper insights into our pho-
tocycloaddition methodology, we sought to obtain experimen-
tal evidence for the proposed intermediates as well as a greater
understanding of the striking regioselectivity observed in these
reactions.
The conversion of isoquinolone into the cyclobutane prod-
1
uct 7a was monitored by H NMR spectroscopy[18] and all three
experiments were carried out simultaneously alongside a con-
trol reaction that contained no triplet quencher. The presence
of just two equivalents of 1,3-cyclohexadiene slowed the reac-
tion considerably and only traces of the products were ob-
served when five equivalents were employed. Ten equivalents
of the triplet quencher completely suppressed the photocy-
cloaddition and, under these conditions, no product formation
was observed after 2.5 h of irradiation. Conversely, the addition
of a triplet sensitizer (acetophenone, 0.5 equivalents) resulted
in an increase in the reaction rate; after one hour of irradiation
the sensitized reaction was complete (Figure 1b), whereas the
control reaction (without sensitizer) was somewhat slower
(83% conversion). It is reported that isoquinolone undergoes
efficient intersystem crossing from the singlet to the triplet ex-
cited state,[15b] so it is perhaps not surprising that the increase
in rate in the presence of the triplet sensitizer is subtle. It
should be noted that the triplet quencher and triplet sensitizer
experiments were not carried out under identical conditions,
thus the plots for the control experiments (in the absence of
quencher or sensitizer) are not identical (Figure 1a and 1b; the
Analysis of the proton/carbon NMR shifts of isoquinolone 6
confirmed that in the ground state, the isoquinolone double
bond has considerable enamine-type character.[16] Thus, the
C4-position of isoquinolone is nucleophilic, whereas the C3-po-
sition is electrophilic. In the excited state, the polarity is re-
versed so that C3 is now nucleophilic, which is consistent with
the preferential head-to-tail regioselectivity observed when
employing electron-deficient alkenes in [2+2] photocycloaddi-
tions with 6 (Scheme 5). The presumed triplet excited state (T1)
is depicted as a biradical intermediate (9) comprising a benzylic
radical at C4 and a reactive, nucleophilic a-amino radical[17] at
C3 that is expected to add to the electrophilic end of the
alkene to generate the postulated 1,4-biradical intermediate
10. To gain evidence for the intermediacy of a triplet excited
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sensitized experiments were deliberately slowed down by re-
ducing the photon flux).
Finally, we wished to gain evidence for the proposed 1,4-bi-
radical intermediate that would arise from reaction of an elec-
tron-deficient alkene with the triplet excited state of isoquino-
lone (Scheme 5). We postulated that alkene 11, which bears
a cyclopropyl group, would act as a radical clock,[19] such that
if the expected 1,4-biradical intermediate was formed, frag-
mentation of the cyclopropyl ring would likely occur,[20] result-
ing in the formation of product 13 (Scheme 6). In the event, ir-
Figure 2. Enantioface differentiation in the complex of template (+)-1 with
isoquinolone 6.
C3 of the isoquinolone, so that photocycloaddition takes place
preferentially on the exposed si face (Figure 2).[21]
This assignment was confirmed by obtaining a single-crystal
X-ray structure of photoadduct 8g, which fully supported our
original assumption (see the Supporting Information for full
details). Remarkably, carbon atom C3 is at the edge of the pre-
viously drawn shielding range of the tetrahydronaphthalene
backbone of template (+)-1 (dark gray),[5] and this range there-
fore needs to be expanded based on the present findings
(light gray). Moreover, the binding between the photoexcited
isoquinolone to the template might be facilitated by p–p inter-
actions (p stacking),[22] which supports our assumption (see
above) that template association is most critical for the success
of enantioselective reactions with (+)-1.[5]
In an extension to our photocycloaddition methodology, we
wanted to expand the range of available products through fur-
ther synthetic transformations of the photoadducts. To this
end, we found that cyclobutyl ester 7h (EWG=CO2tBu) is a par-
ticularly useful photoproduct, which can be selectively trans-
formed in excellent yield into the corresponding free acid 14[23]
or alcohol 15 (Scheme 7).
Compounds 14 and 15 represent valuable synthetic inter-
mediates that promise straightforward access to numerous
other substituted cyclobutane motifs through standard func-
tional group interconversions. Alcohol 15 is not available
Scheme 6. Radical clock experiment employing isoquinolone and alkene 11.
radiation of a solution of isoquinolone 6 containing ten equiv-
alents of alkene 11 resulted in a complex mixture of products
comprising both the expected fragmentation product 13 and
several isomeric products resulting from [2+2] photocycloaddi-
tion. Pleasingly, the two major products could be isolated in
appreciable yields and fully characterized: 12 (22%; 6:1 mix-
ture of isomers) and 13 (18%). In addition, the formation of
fragmented product 13 confirms the mode of attack in these
photocycloadditions—if the photoproducts 12 and 13 had
arisen from initial attack of the isoquinolone C4 carbon atom
onto the more substituted alkene carbon atom, a different 1,4-
biradical intermediate would form, thus precluding the ob-
served fragmentation of the cyclopropyl ring.
Taken together, our mechanistic data support the mecha-
nism outlined in Scheme 5, as proposed by Kaneko and co-
workers.[10g] The high regioselectivity observed in these pro-
cesses is dictated by the polarity of the excited state of the iso-
quinolone, and the relative configuration of the photoadducts
7 and 8 can be readily explained based on steric considera-
tions. Thus, the two most sterically demanding groups are ori-
ented trans to each other, resulting in the substituent EWG
being located exo relative to the dihydroisoquinolone moiety.
The resulting “exo-head-to-tail” selectivity has significant prece-
dent within the literature.[10]
The assignment of absolute configuration was based on the
known enantioface differentiation in similar reactions employ-
ing (+)-1.[4] Hence, the formation of a hydrogen-bonded supra-
molecular complex between isoquinolone and (+)-1 results in
the selective shielding of the re face relative to carbon atom
Scheme 7. Synthetic transformations of 7h, 7k, and 7l.
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through direct photocycloaddition, since no photocycloaddi-
tion takes place with more electron-rich alkenes. Interestingly,
although the direct [2+2] photocycloaddition of isoquinolone
with acrylic acid takes place readily, attempted enantioselective
reaction in the presence of chiral template 1 led to a mixture
of isomers and proceeded with very low enantioselectivity. It
seems likely that, in this case, the free acid disrupts the hydro-
gen bonding between the template and substrate, thus pre-
venting formation of the required supramolecular complex
and removing the control element that operates so effectively
with the other alkenes examined. Furanone 7k and sultone 7l
also represent highly flexible synthetic intermediates that can
be readily opened with nucleophiles to yield a variety of
densely functionalized cyclobutane motifs (Scheme 7). For ex-
ample, heating 7k with benzylamine generated amido alcohol
16 in 90% yield, whereas reaction of 7k with acetyl bromide
in ethanol gave bromoester 17 in 81% yield. In a similar fash-
ion, ring opening of sultone 7l with aqueous ammonia fur-
nished the corresponding sulfonic acid salt 18 in essentially
quantitative yield (Scheme 7).
cations of our methodology, as well as investigating mechanis-
tic details. The use of a wide range of alkenes (many of which
have never been used before in [2+2] photocycloadditions of
any type) is particularly noteworthy; the use of these alkenes is
not limited to isoquinolone photochemistry, and we envisage
that our work will inspire their wider application in organic
synthesis. We have shown that a wide range of substituted iso-
quinolones can also be employed, significantly expanding the
substrate scope of these photocycloadditions and highlighting
the synthetic potential of these substrates, for example in li-
brary synthesis and in total synthesis programs. Starting from
the range of photoadducts available through direct photocy-
cloaddition of isoquinolones, we have demonstrated that
a range of other isoquinolone-containing scaffolds are accessi-
ble through simple functional group conversions, and that the
isoquinolone ring can be cleaved in a straightforward manner,
leading to densely functionalized cyclobutane motifs. The use
of chiral template 1 allows the photocycloadditions to be car-
ried out with exquisite diastereo-, regio-, and enantioselectivi-
ties, and along with our preliminary communication, these are
the first reported examples of enantioselective, intermolecular
[2+2] photocycloadditions of isoquinolones. As a complement
to our synthetic efforts, we have also carried out mechanistic
studies, the results of which are fully consistent with the in-
volvement of a triplet excited state as well as a 1,4-biradical in-
termediate. Our studies have allowed us to rationalize the ex-
cellent diastereo-, regio-, and enantioselectivities obtained in
these cycloadditions, leading to a deeper understanding of the
photochemistry of isoquinolones.
Having established that a wide range of isoquinolone-fused
cyclobutanes can be obtained either through direct [2+2] pho-
tocycloaddition or by further transformations on the photoad-
ducts thus obtained, we also wanted to investigate the poten-
tial of our methodology to access other ring systems. Pleasing-
ly, we were able to convert cyclobutane 7j into functionalized
diketone 19 in high yield through a retro-benzilic acid rear-
rangement (Scheme 8).[24] In addition, the dihydroisoquinolone
Experimental Section
Photochemical experiments were performed in Duran phototubes
(diameter: 1 cm, volume: 10 or 20 mL each) in an RPR-100 photo-
chemical reactor (Southern New England Ultra Violet Company,
Branford, CT, USA) equipped with fluorescent lamps (l=300 nm or
366 nm). Non-commercial isoquinolones were generally recrystal-
lized before use in photochemical experiments.
General procedure for enantioselective intermolecular
[2+2] photocycloadditions
A solution of isoquinolone (0.10 mmol) and chiral template (+)-1
(88.0 mg, 0.25 mmol) in toluene (10 mL) was purged with argon in
an ultrasonic bath for 15 min. The appropriate alkene (1.00 mmol,
10 equiv) was added via syringe (non-volatile alkenes were added
before argon purging) and the resulting mixture was cooled to
À758C, then irradiated (l=300 nm) until no starting material was
detected by TLC analysis (generally 1–2 h). The solvent was re-
moved under reduced pressure and the crude material was sub-
jected to flash column chromatography.
Scheme 8. Synthetic transformations to access other ring systems.
ring of photoadduct 7h can be cleaved by Boc protection fol-
lowed by reaction with sodium hydroxide, to yield cyclobutyla-
mine 20 (Scheme 8). Thus, in addition to accessing isoquino-
lone-containing moieties, our methodology also allows us to
exploit the isoquinolone ring as a stereocontrol element en
route to stereodefined arylated cyclobutylamines.
Acknowledgements
Conclusion
We have completed an in-depth study of the intermolecular
[2+2] photocycloadditions of isoquinolones, emphasizing the
alkene scope, the isoquinolone scope and the synthetic appli-
S.C.C. acknowledges support by the Alexander von Humboldt
Foundation. We thank Florian Mayr, Olaf Ackermann, and
Marcus Wegmann for their help in conducting the HPLC analy-
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for X-ray analysis.
Keywords: asymmetric synthesis
·
enantioselectivity
·
hydrogen bonding · photochemistry · synthetic methods
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Figure 2, reaction takes place on the si face (relative to C3) of the iso-
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[2] For selected books on synthetic photochemistry: a) Handbook of Syn-
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Received: January 15, 2015
Published online on && &&, 0000
Chem. Eur. J. 2015, 21, 1 – 8
www.chemeurj.org
7
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
FULL PAPER
&
Cycloadditions
S. C. Coote, A. Pçthig, T. Bach*
&& – &&
Enantioselective Template-Directed
[2+2] Photocycloadditions of
Isoquinolones: Scope, Mechanism and
Synthetic Applications
The higher the better: Isoquinolones
were identified as ideal substrates for
highly enantioselective intermolecular
[2+2] photocycloaddition reactions
mediated by chiral template 1 (see
scheme). A wide variety of products was
generated, which promise extensive
synthetic applications.
&
&
Chem. Eur. J. 2015, 21, 1 – 8
www.chemeurj.org
8
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!