Intramolecular [2+2] photocycloaddition of substituted isoquinolones: Enantioselectivity and kinetic resolution induced by a chiral template

Article abstract of DOI:10.1002/anie.201103051

From simple to complex: Starting from easily accessible isoquinolones 1 (X=Br, OH), complex cyclobutane photoproducts such as compound 2 can be obtained with high enantioselectivity (88-96% ee) through the use of a chiral template. Compound 3, which was i

Full text of DOI:10.1002/anie.201103051

Communications
DOI: 10.1002/anie.201103051
Photochemistry
Intramolecular [2+2] Photocycloaddition of Substituted
Isoquinolones: Enantioselectivity and Kinetic Resolution Induced by a
Chiral Template**
Kerrie A. B. Austin, Eberhardt Herdtweck, and Thorsten Bach*
Dedicated to Professor Dieter Hoppe on the occasion of his 70th birthday
Although intermolecular [2+2] photocycloadditions of iso-
quinolones have been studied for some time,[1] the corre-
sponding intramolecular reactions of this substrate class have
received little attention. To date, only isoquinolones that
carry the olefin for an intramolecular cycloaddition in an
N-tethered chain have been examined.[2] Given the preva-
lence of isoquinoline-derived natural products,[3] the intra-
molecular [2+2] photocycloaddition of isoquinolones could
potentially be very useful,[4] particularly if these reactions
could be performed regio- and enantioselectively. We have
now studied the photocycloaddition reactions of a selection of
3- and 4-substituted isoquinolones 1–9 (Scheme 1). The
various cyclobutane products were formed in high yields
and, in the case of 4-substituted isoquinolones, with high
enantioselectivities (88–96% ee) by employing a chiral tem-
plate. Moreover, it was shown for the first time that kinetic
resolution is possible in template-based organic photochem-
istry.
The starting materials for this study were prepared from
4-hydroxyisoquinolone[5] (substrates 1, 4–7), 4-bromoisoqui-
nolone[6] (substrates 2, 8, 9), and 3-hydroxyisoquinolone[7]
(substrate 3). Further details on the synthesis of these
substrates are found in the Supporting Information. Initial
reactions were performed with 4-(but-3-enyloxy)isoquino-
lone (1). The optimum wavelength for irradiation was found
to be around l = 366 nm (fluorescence light tubes), and
racemic photocycloaddition products were obtained after
50 min of irradiation at ambient temperature in trifluoroto-
luene or toluene as the solvent. When performed in the
presence of chiral template 10[8] (2.6 equiv in all experiments),
the [2+2] photocycloaddition of isoquinolone 1 (c = 5 mm)
was found to occur in a highly enantioselective manner
(Scheme 2).[9,10] The best results were achieved at low
temperature: the straight photoproduct 11-s was obtained
Scheme 2. Typical irradiation conditions for the enantioselective intra-
molecular [2+2] photocycloaddition of isoquinolones, exemplified in
the reaction of substrate 1.
Scheme 1. Substrates 1–9 employed to probe the selectivity in the
intramolecular [2+2] photocycloaddition of isoquinolones. PG=pro-
tecting group.
with 93% ee and the crossed photoproduct 11-c with 96% ee.
The absolute configuration of compound 11-s was proven by
conversion into the corresponding N-(ꢀ)-menthyloxycar-
bonyl derivative and subsequent X-ray crystal structure
analysis (see the Supporting Information).
Based on these results, the mode of action of template 10
is likely effected by hydrogen bonding to substrate 1 and its
ability to provide significant enantioface differentiation to the
bulky 5,6,7,8-tetrahydronaphtho[2,3-d]oxazole substituent
(“steric shield”).[11] Still, it is surprising that the enantiomeric
excess is so high given the fact that the reactive olefinic
carbon–carbon bond of the isoquinolone is located on the
periphery[12] of the shielding substituent (vide infra).
[*] Dr. K. A. B. Austin, Dr. E. Herdtweck, Prof. Dr. T. Bach
Department Chemie and Catalysis Research Center (CRC)
Technische Universitꢀt Mꢁnchen
Lichtenbergstrasse 4, 85747 Garching (Germany)
E-mail: thorsten.bach@ch.tum.de
Homepage: http://www.oc1.ch.tum.de/home/
[**] E.H. performed the X-ray structure analyses. K.A.B.A. acknowledges
support by the Alexander von Humboldt foundation. This project
was supported by the Deutsche Forschungsgemeinschaft as part of
the Schwerpunktprogramm Organokatalyse (Ba 1372-10).
While the regioselectivity of the intermolecular [2+2]
photocycloaddition is significantly influenced by the fact that
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103051.
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the intermediate (di)radical is stabilized in the benzylic
position, that is, at the C4 carbon atom of isoquinolones,[1d]
in the intramolecular case the regioselectivity is usually
controlled by the operation of the “rule of five”.[13] This led us
to anticipate that cycloaddition of substrate 1 would result in
exclusive formation of 11-s. However, it appears that the
stability of the benzylic (di)radical is further enhanced by the
4-alkoxy substituent,[14] resulting in the formation of relatively
high amounts of crossed product 11-c. Indeed, for substrates
lacking an alkoxy substituent at the C4 carbon atom, only
straight photocycloaddition products were observed
(Scheme 3). Substrate 2 delivered exclusively tetracyclic
product 12-s, and substrate 3 gave product 13-s as a single
position C12 of the tetracyclic skeleton. The relative config-
uration of the product was found to be independent of the
relative configuration of the starting material (stereoconver-
gent reaction course). Both E isomer 6 or Z isomer 7 gave the
product rac-16-c, in which the methyl group (R = Me) is cis-
oriented relative to the oxepane ring. This stereoconvergency
is in agreement with a stepwise photocycloaddition, in which
the intermediate triplet 1,4-diradical has sufficient time to
undergo rotation about the carbon–carbon single bonds.[16]
Still, it was not evident to us when we looked at molecular
models, why the methyl group would point into a seemingly
more congested position. In order to confirm our assignment
we obtained a single-crystal X-ray crystal structure of the
major photoproduct. The X-ray data[17] support the structure
that we had proposed based on analysis of the NMR spectra
(Figure 1). When the reaction was performed in the presence
of template 10, product 16-c was obtained as a single isomer in
high yield and with close to perfect enantioselectivity
(96% ee).
Scheme 3. Enantiomerically enriched, diastereomerically pure products
12–14 obtained as pure straight (s) or crossed (c) regioisomers from
the [2+2] photocycloaddition of substrates 2–4 in the presence of
template 10.
regioisomer. The somewhat lower enantioselectivity in the
latter case can be explained by the interference of the
substituent at C3 in the binding to template 10. In all cases,
template recovery was high and close to quantitative.
Isoquinolone 4 gave the expected crossed product[13] 14-c
with high enantiomeric excess.
Given that the enantioselective [2+2] photocycloaddition
of 4-(pent-4-enyloxy)quinolone affords exclusively the
straight product,[8a,11a] we were quite surprised that 4-(pent-
4-enyloxy)isoquinolone (5) delivered predominantly—exclu-
sively in the presence of template 10 (Scheme 4)—the crossed
Figure 1. Proof of structure and relative configuration of the crossed
product rac-16-c by a single-crystal structure analysis; ellipsoids drawn
at the 50% probability level.
Experiments conducted with the racemic starting material
rac-8 (TBS = tert-butyldimethylsilyl) demonstrated convinc-
ingly that a high degree of facial diastereoselectivity can be
achieved in the intramolecular [2+2] photocycloaddition of
substituted isoquinolones. Even upon irradiation at ambient
temperature, the photocycloaddition product rac-17-s was
isolated as a single diastereomer. The relative configuration
can be explained by assuming conformation rac-8’ to be
primarily responsible for the first carbon–carbon bond-
forming step in the reaction (Scheme 5). 1,3-Allylic strain[18]
Scheme 4. Highly enantioselective [2+2] photocycloaddition of isoqui-
nolones 5 and 6 to afford the crossed products 15 and 16.
product 15-c. Again, we believe that this is related to the
increased stabilization of the alkoxy-substituted (di)radical,
which can be formed only upon ring closure of a seven-
membered oxepane in the initial reaction step. The enantio-
selectivity of the process is very high, which suggests that the
photoproduct 15-c has a lower association affinity to template
10 than the starting material.[15]
Scheme 5. Perfect facial diastereoselectivity in the intramolecular [2+2]
photocycloaddition of isoquinolone rac-8 via conformation rac-8’ lead-
ing to product rac-17-s.
If the double bond of the tethered olefin is a-substituted
(R ¼ H), an additional stereogenic center is formed at
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Communications
between the hydrogen atom at the stereogenic center and the
starting material had been consumed, it never reached the
expected value of 0% ee.[24] On the contrary, the enantiomeric
excess was still significant (53% ee) at the end of the reaction.
This observation can be explained by the fact that the
resolution is accompanied by side reactions (e.g. hydrogen
abstraction, dimerization) of enantiomer ent-9, which in turn
are a result of the previously mentioned inaccessibility of
conformation ent-9’. In other words, the disfavored enantio-
mer ent-9 is not recovered but rather undergoes unspecific
photochemical reactions, which lead to its disappearance.
Unfortunately, these side reactions complicate the analysis of
the product mixture, but it can safely be said that there is also
a significant enrichment of the substrate ent-9 (23% ee at
about 40% conversion). Similar experiments performed with
racemic compound rac-8 have not been successful. With the
bulkier OTBS group, initial results indicate that there is no
preference for the respective conformations 8’ and ent-8’ in
the presence of template 10.
In summary, it was shown that intramolecular [2+2]-
photocycloaddition reactions of substituted isoquinolones
proceed enantioselectively in the presence of chiral template
10. If the binding of the substrate to the template is favored—
as is the case for 4-substituted isoquinolones—high enantio-
selectivities result. In fact, the association of some isoquino-
lones to template 10 appears to be so high that the template is
able to bias enantiomorphic conformations in a 1:1 assembly
of isoquinolone and template. An application of this phe-
nomenon to the kinetic resolution of racemic isoquinolone
rac-9 was successfully performed.
C5 carbon atom of the isoquinolone defines the orientation of
the tethered alkene and controls the mode of attack. It also
limits the conformational flexibility and, as opposed to alkoxy
substrates 5–7, six-membered-ring formation is the exclusive
reaction pathway.
The high enantioselectivity of the intramolecular [2+2]-
photocycloaddition reactions described at the beginning of
this report and the high facial diastereoselectivity observed in
the reaction discussed above led us to consider combining
both stereochemical aspects to attempt a kinetic resolu-
tion[19–21] of a chiral isoquinolone by reaction in the presence
of template 10. Given that the facial diastereoselectivity in the
reaction of rac-8 was governed by 1,3-allylic strain, we
envisioned that one of the two enantiomorphic transition
states of a racemic compound would be severely disfavored if
the substrate were bound to template 10. Indeed, it can be
expected, based on previous association data for aromatic six-
membered lactams,[22] that the isoquinolone would be bound
quantitatively to the template at ꢀ608C in a nonpolar solvent,
if ꢁ 2.5 equiv of the template were used. In a situation such as
that depicted in Scheme 6, when isoquinolone rac-9 is
associated to template 10, one enantiomer, 9, is able to
adopt the conformation 9’ required for intramolecular ring
closure (complex 9’·10). The relatively small OH group[23]
points into the limited space between substrate and template,
but should not interfere significantly with the binding event.
In the complex of the other enantiomer ent-9, however, the
required conformation ent-9’ cannot be adopted and complex
ent-9·10 will not undergo cycloaddition. Indeed, at low
conversion we observed formation of only a single enantio-
meric [2+2]-photocycloaddition product from substrate rac-9
(> 95% ee at roughly 2% conversion), to which structure 18
was assigned based on NMR data and on the known face
differentiation exerted by template 10.
Received: May 3, 2011
Published online: July 19, 2011
Keywords: cycloaddition · enantioselectivity · hydrogen bonds ·
.
kinetic resolution · photochemistry
As the reaction progressed the enantiomeric excess of the
photoproduct decreased but, even when almost all of the
[1] a) G. R. Evanega, D. L. Fabiny, Tetrahedron Lett. 1971, 12,
1749 – 1752; b) T. Naito, C. Kaneko, Tetrahedron Lett. 1981, 22,
2671 – 2674; c) T. Naito, C. Kaneko, Chem. Pharm. Bull. 1985,
33, 5328 – 5331; d) T. Chiba, Y. Takada, C. Kaneko, F. Kiuchi, Y.
Tsuda, Chem. Pharm. Bull. 1990, 38, 3317 – 3325; e) N. Al-Jalal,
M. G. B. Drew, A. Gilbert, J. Chem. Soc. Perkin Trans. 1 1996,
965 – 966; f) N. Al-Jalal, C. Covell, A. Gilbert, J. Chem. Res.
Synop. 1998, 678; g) D. E. Minter, C. D. Winslow, W. H. Watson,
S. Bodgie, Magn. Reson. Chem. 2002, 40, 412 – 414; h) D. E.
Minter, C. D. Winslow, J. Org. Chem. 2004, 69, 1603 – 1606.
[2] a) C. Kaneko, N. Katagiri, K. Uchiyama, T. Yamada, Chem.
Pharm. Bull. 1985, 33, 4160 – 4166; b) C. Kaneko, K. Uchiyama,
M. Sato, N. Katagiri, Chem. Pharm. Bull. 1986, 34, 3658 – 3671.
[3] For most recent reviews, see: a) K. W. Bentley, Nat. Prod. Rep.
2006, 23, 444 – 463; b) Z. Jin, Nat. Prod. Rep. 2011, 28, 1126 –
1142, and references therein.
[4] a) T. Bach, J. P. Hehn, Angew. Chem. 2011, 123, 1032 – 1077;
Angew. Chem. Int. Ed. 2011, 50, 1000 – 1045; b) N. Hoffmann,
Chem. Rev. 2008, 108, 1052 – 1103.
[5] E. Kapatsina, M. Lordon, A. Baro, S. Laschat, Synthesis 2008,
2551 – 2560.
[6] A. D. Sercel, J. P. Sanchez, H. D. H. Showalter, Synth. Commun.
2007, 37, 4199 – 4208.
Scheme 6. Kinetic resolution in the intramolecular [2+2] photocycload-
dition of isoquinolone rac-9.
[7] G. C. Crockett, B. J. Swanson, D. R. Anderson, T. H. Koch,
Synth. Commun. 1981, 11, 447 – 454.
8418
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Angew. Chem. Int. Ed. 2011, 50, 8416 –8419

[8] a) T. Bach, H. Bergmann, K. Harms, Angew. Chem. 2000, 112,
2391 – 2393; Angew. Chem. Int. Ed. 2000, 39, 2302 – 2304; b) T.
Bach, H. Bergmann, B. Grosch, K. Harms, E. Herdtweck,
Synthesis 2001, 1395 – 1405.
[17] Colorless fragment, C15H17NO2, Mr = 243.30; monoclinic, space
group P21/n (no. 14), a = 9.4221(7), b = 11.5322(9), c =
11.0577(8) ꢂ, b = 95.851(3)8, V= 1195.24(16) ꢂ3, Z = 4, l-
(CuKa) = 1.54180 ꢂ, m = 0.716 mmꢀ1 1calcd = 1.352 gcmꢀ3
, , T=
[9] Reviews: a) C. Mꢀller, T. Bach, Aust. J. Chem. 2008, 61, 557 –
564; b) Y. Inoue in Molecular and Supramolecular Photochem-
istry, Vol. 11 (Eds.: Y. Inoue, V. Ramamurthy), Marcel Dekker,
New York, 2004, pp. 129 – 177.
123(1) K, F(000) = 520, qmax: 66.148, R1 = 0.0301 (1967 observed
data), wR2 = 0.0716 (all 2017 data), GOF = 1.063, 232 parame-
ters, D1max/min = 0.25/ꢀ0.15 eꢂꢀ3; CCDC 823670 (rac-16-c) con-
tains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif. For more details, see the Supporting Information.
[18] R. W. Hoffmann, Chem. Rev. 1989, 89, 1841 – 1860.
[19] Examples for a kinetic resolution in photochemical reactions by
circularly polarized light, see: a) M. Zandomeneghi, M. Cavazza,
J. Am. Chem. Soc. 1984, 106, 7261 – 7262; b) Y. Zhang, G. B.
Schuster, J. Org. Chem. 1995, 60, 7192 – 7197; c) Y. Shimizu, S.
Kawanishi, Chem. Commun. 1996, 819 – 820; d) H. Nishino, A.
Kosaka, G. A. Hembury, F. Aoki, K. Miyauchi, H. Shitomi, H.
Onuki, Y. Inoue, J. Am. Chem. Soc. 2002, 124, 11618 – 11627.
[20] Examples for a kinetic resolution in photochemical reactions
induced by a chiral auxiliary, see: a) P. J. Wagner, K. McMahon,
J. Am. Chem. Soc. 1994, 116, 10827 – 10828; b) T. Poon, J.
Sivaguru, R. Franz, S. Jockusch, C. Martinez, I. Washington, W.
Adam, Y. Inoue, N. J. Turro, J. Am. Chem. Soc. 2004, 126, 10498 –
10499.
[10] For the use of other chiral hydrogen-bonding templates in
enantioselective photochemistry, see: a) D. F. Cauble, V. Lynch,
M. J. Krische, J. Org. Chem. 2003, 68, 15 – 21; b) K. Tanaka, T.
Fujiwara, Org. Lett. 2005, 7, 1501 – 1503; c) B. Gerard, S. Sangji,
D. J. OꢁLeary, J. A. Porco, Jr., J. Am. Chem. Soc. 2006, 128,
7754 – 7755; d) J. Mizoguchi, Y. Kawanami, T. Wada, K.
Kodama, K. Anzai, T. Yanagi, Y. Inoue, Org. Lett. 2006, 8,
6051 – 6054; e) Y. Kawanami, T. C. S. Pace, J. Mizoguchi, T.
Yanagi, M. Nishijima, T. Mori, T. Wada, C. Bohne, Y. Inoue, J.
Org. Chem. 2009, 74, 7908 – 7921.
[11] a) T. Bach, H. Bergmann, B. Grosch, K. Harms, J. Am. Chem.
Soc. 2002, 124, 7982 – 7990; b) P. Wessig, Angew. Chem. 2006,
118, 2224 – 2227; Angew. Chem. Int. Ed. 2006, 45, 2168 – 2171.
[12] D. Albrecht, F. Vogt, T. Bach, Chem. Eur. J. 2010, 16, 4284 – 4296.
[13] a) R. Srinivasan, K. H. Carlough, J. Am. Chem. Soc. 1967, 89,
4932 – 4936; b) R. S. H. Liu, G. S. Hammond, J. Am. Chem. Soc.
1967, 89, 4936 – 4944; c) D. J. Maradyn, A. C. Weedon, J. Am.
Chem. Soc. 1995, 117, 5359 – 5360.
[21] For the kinetic resolution of (E)-cyclooctene by enantioselective
sensitization, see: R. Lu, C. Yang, Y. Cao, L. Tong, W. Jiao, T.
Wada, Z. Wang, T. Mori, Y. Inoue, J. Org. Chem. 2008, 73, 7695 –
7701, and references therein.
[22] A. Bakowski, M. Dressel, A. Bauer, T. Bach, Org. Biomol.
Chem. 2011, 9, 3516 – 3529.
[14] A similar outcome was also observed for the [2+2] photo-
cycloaddition of 2-(alkenyloxy)cyclohex-2-enones. See: a) M.
Ikeda, J. Org. Chem. 1983, 48, 4241 – 4247; b) M. Ikeda, M.
Takahashi, T. Uchino, Y. Tamura, Chem. Pharm. Bull. 1984, 32,
538 – 542.
[15] It was previously shown that photoproducts that exhibit a
significantly lower association to template 10 than the respective
substrates are formed with high enantiomeric excess: B. Grosch,
C. N. Orlebar, E. Herdtweck, M. Kaneda, T. Wada, Y. Inoue, T.
Bach, Chem. Eur. J. 2004, 10, 2179 – 2189.
[23] The A value for a hydroxy group, reported as A(OH) = 0.60, is
much lower than the A value of
a primary alkyl chain
(corresponding to the side chain in ent-9’·10), A(CH2CH3) =
1.79. Data from: E. L. Eliel, S. H. Wilen, Stereochemistry of
Organic Compounds, Wiley, New York, 1994, pp. 696 – 697.
[24] H. B. Kagan, J. C. Fiaud, Top. Stereochem. 1988, 18, 249 – 330.
[16] D. I. Schuster, G. N. Lem, A. Kaprinidis, Chem. Rev. 1993, 93, 3 –
22.
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