Enantioselectivity in visible light-induced, singlet oxygen [2+4] cycloaddition reactions (type II photooxygenations) of 2-pyridones

Article abstract of DOI:10.1039/c2cc35621j

3-Substituted 2-pyridones were enantioselectively (68-90% ee) converted into the respective 3-hydroxypyridine-2,6-diones by a sequence consisting of a template-mediated type II photooxygenation and an acid-catalysed rearrangement.

Full text of DOI:10.1039/c2cc35621j

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Enantioselectivity in visible light-induced, singlet oxygen [2+4]
cycloaddition reactions (type II photooxygenations) of 2-pyridonesw
Christian Wiegand, Eberhardt Herdtweck and Thorsten Bach*
Received 2nd August 2012, Accepted 22nd August 2012
DOI: 10.1039/c2cc35621j
3-Substituted 2-pyridones were enantioselectively (68–90% ee)
converted into the respective 3-hydroxypyridine-2,6-diones by a
sequence consisting of a template-mediated type II photooxy-
genation and an acid-catalysed rearrangement.
reactions can be achieved.8 In addition, there are a number of
biologically relevant pyridine-2,6-diones, such as hermidin9 and
the speranskatines,10 with a structural motif, which seemed
synthetically accessible via the respective endoperoxide. The type
II photooxygenation of 3- and 6-substituted 2-pyridones has
been previously studied by Kanaoka et al.11 They performed the
reaction in the presence of para-toluenesulfonic acid (TsOH)
and obtained directly the corresponding ring-opened products
(vide infra). Initially, we planned to access and isolate the
endoperoxides because we noted that both the parent pyridone
substrate 2 and its 3-methyl derivative 3 underwent a clean
[2+4] photocycloaddition with singlet oxygen, which in turn
was generated by TPP-sensitised visible light irradiation
(Scheme 2).
Singlet oxygen belongs to the most versatile and most readily
available reagents to be generated by visible light irradiation.
The low energy gap between triplet and singlet oxygen allows
for a sensitised excitation, which can be achieved at long
wavelengths using low catalytic loadings of appropriate dyes
such as rose bengal, methylene blue or tetraphenylporphyrin
(TPP). Subsequent reaction pathways accessible to singlet
oxygen include the formation of hydroperoxides by an ene-type
reaction, the formation of 1,2-dioxetanes by a [2+2] cycloaddition
and the [2+4] cycloaddition to 1,3-dienes.1 In particular, the
latter reaction2,3 appealed as a way to prepare endoperoxides
enantioselectively in the presence of chiral complexing agent 14,5
(Scheme 1). Provided that the 1,3-diene structure of the
substrate was attached to an amide or embedded in a lactam
ring, one could hope for an enantioselective reaction course6 in
a 1 : 1 complex between the substrate and template 1. We now
show that this approach has indeed been successful and report
the first highly enantioselective (up to 90% ee) singlet oxygen
[2+4] cycloaddition reactions.7
All attempts, however, to characterise endoperoxides rac-4
and rac-5 upon isolation were hampered by the fact that the
retro-[2+4] cycloaddition is relatively fast.12 It was therefore
decided to perform a consecutive reaction, which preserved at
least one of the newly generated stereogenic centers. Indeed, it
was confirmed that the acid-catalysed ring opening of product
rac-5 proceeded by the well known Kornblum–DeLaMare
rearrangement.3a–d,13 Pyridine-2,6-dione rac-6 was obtained
in 32% yield if the type II photooxygenation and the ring
opening reaction were conducted in successive order. Compound
rac-6 has been obtained previously by Kanaoka et al. employing
an in situ opening of the endoperoxide in 14% yield starting from
3-methyl-2-pyridone (3).11
2-Pyridones (pyridine-2(1H)-ones) were considered to be
particularly promising 1,3-diene substrates for this study. It has
previously been shown that they bind to bicyclic lactams such as
1 by two-point hydrogen bonding and that enantioselective
Scheme 1 Binding of chiral template 1 to a prochiral lactam or amide
via two hydrogen bonds.
Department Chemie and Catalysis Research Center (CRC),
Technische Universitat Munchen, 85747 Garching, Germany.
¨
¨
E-mail: thorsten.bach@ch.tum.de; Fax: +49 89 28913315;
Tel: +49 89 28913330
w Electronic supplementary information (ESI) available. CCDC
894230. For ESI and crystallographic data in CIF of other electronic
format see DOI: 10.1039/c2cc35621j
Scheme 2 Formation of endoperoxides rac-4 and rac-5 by singlet
oxygen addition and Kornblum–DeLaMare rearrangement of product
rac-5.
c
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Chem. Commun., 2012, 48, 10195–10197 10195

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Since neither of the yields was acceptable, optimisation
reactions were performed, which would also allow us to perform
the reaction in the presence of template 1. By following the
reaction of substrate 3 UV-spectroscopically in the presence of
0.1 mol% TPP at ꢀ25 1C (c = 0.11 M) it was observed that
endoperoxide formation was complete within 15 minutes.
In the consecutive acid-catalysed reaction the competing
retro-[2+4] cycloaddition compromised the yield. A relatively
large amount of TsOH (40 mol%) was found to be required to
enable a rapid rearrangement. Still, the retro-cycloaddition
was observed. In order to increase the yield, it was mandatory
to repeat the irradiation – now in the presence of acid – at low
temperature and the hydrolysis at room temperature. A third
cycle (irradiation, hydrolysis) helped to increase the yield even
further. This optimised procedure was subsequently applied to
the enantioselective irradiation in the presence of template 1
(Table 1). To our delight, significant enantioselectivities were
achieved, which reached up to 90% ee. Toluene (entries 1 and 2)
delivered moderate yields but had the benefit that the irradiation
could be performed at temperatures as low as ꢀ70 1C. The
enantioselectivity increased only slightly, however, when decreasing
the irradiation temperature from ꢀ25 1C (81% ee) to ꢀ70 1C
(85% ee). Carbon tetrachloride (entry 3) was inferior to
toluene as the solvent and product formation occurred with
only 73% ee, albeit at a higher yield. As in several other
lactam-mediated reactions14 trifluorotoluene (entry 4) turned
out to be the solvent of choice. The yield was almost quanti-
tative and product 6 was isolated in 90% ee. The result is
particularly remarkable as the second and third irradiation
runs were performed in the presence of a Brønsted acid, which
potentially disturbs the hydrogen bonding. In order to ensure
that the enantioselectivity in the studied reaction was due to
two-point hydrogen bonding, we performed an experiment with
the N-methyl derivative 7 of 3-methyl-2-pyridone (entry 5).
Expectedly, the reaction proceeded in high yield but without
any detectable enantioselectivity delivering product 8 as a
racemate. Based on the assumption of a 1 : 1 complex formed
Fig. 1 Single crystal structure analysis of the enantiomerically pure
tertiary alcohol 6.
between pyridone 3 and template 1 it was assumed that the
photooxygenation occurs from the Si face relative to carbon
atom C3 leading predominantly to the (S)-enantiomer. This
assumption was confirmed by anomalous X-ray diffraction
(Fig. 1)15 performed with a homochiral crystal of the major
product obtained in the reaction of pyridone 3 (Table 1,
entry 4).
When applying the reaction conditions to other 2-pyri-
dones, we noted varying yields and enantioselectivities
(Table 2). With 3-ethyl-2-pyridone (9)16 the reaction sequence
worked – as expected given its similarity to 3 – in the same
yield (entry 1) and with similar enantioselectivity for the final
product 10 (86% ee). In the case of the benzyl-substituted
substrate 1117 (entry 2) a significant decrease in chemo- and
enantioselectivity was noted. Indeed, the acidic conditions
Table 2 Sequence of template-mediated enantioselective type II
photooxygenation/Kornblum–DeLaMare rearrangement performed
with different 2-pyridones under optimised conditions (see Table 1)
Entry Substratea
Product
c [mM] Yieldb [%] eec [%]
1
110
37
99
73
30
86
69
79
2
3
4
Table 1 Enantioselective type II photooxygenation/Kornblum–
DeLaMare rearrangement with 3-methyl-2-pyridones 3 and 7 under
optimised conditions in various solvents
33
23
34
38
46
85
71
Entrya
R1
Solvent
Temp. [1C]
Yieldb [%]
eec [%]
1
2
3
4
5
H
H
H
H
Me
PhCH3
PhCH3
CCl4
PhCF3
PhCF3
ꢀ25
ꢀ70
ꢀ25
ꢀ25
ꢀ25
62
53
80
99
96
81
85
73
90
o5
5
a
Reactions were performed at the indicated substrate concentration in
trifluorotoluene as the solvent employing 2.5 equivalents of template 1
and 0.1 mol% of TPP. The irradiation was performed for 20 min at
ꢀ25 1C. Upon warming to room temperature the mixture was treated
with TsOH (40 mol%) for 12 h before repeating the sequence (cooling,
a
Reactions were performed at a substrate concentration of 0.11 M in
the given solvent. Irradiation was performed for 20 min at the
indicated temperature. Upon warming to room temperature the
mixture was treated with acid for 12 h before repeating the sequence
(cooling, irradiation, warming to rt) twice (for further details, see ESI).
b
irradiation, warming to rt) twice (for further details, see ESI). Yield
c
of the isolated product. The enantiomeric excess (ee) was determined
b
c
Yield of the isolated product. The enantiomeric excess (ee) was
determined by chiral HPLC analysis.
by chiral HPLC analysis.
c
10196 Chem. Commun., 2012, 48, 10195–10197
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required for endoperoxide opening may in this case lead to
elimination of the tertiary alcohol 12. The sensitivity towards
acidic conditions was even more pronounced for ether substrates
13 (entry 4) and 15 (entry 5).18 Again, elimination reactions are
likely to account for a loss of the respective products 14 and 16. It
must be said, however, that an increased yield could have possibly
been achieved in these cases, if the standard reaction protocol had
been modified. The emphasis of the present study was on the
enantioselectivity, however, which remained in a relatively high
range for all substrates (69–86% ee). A bicyclic substrate (17,
entry 5)19 also exhibited a significant face differentiation
delivering product 18 in 46% yield and with 71% ee. The
assignment of the absolute configuration for the respective
major enantiomers as depicted in Table 2 is based on analogy
to the transformation 3 - 6. Indeed, all products (6, 10, 12,
14, 16, 18) have been shown to be consistently levorotatory
indicating that the major enantiomers possess identical absolute
configurations. The chiral template remained unaffected by singlet
oxygen and was recovered chromatographically in yields between
80–90%. The varying enantioselectivities are very likely due to the
different association constants, with which the substrates bind to
template 1. Pyridones with sterically bulkier substituents suffer
from a repulsive van der Waals interaction with the tricyclic
10-oxa-30-azacyclopenta[b]naphthalene group of template 1.
For these cases, substrate dimerisation by hydrogen bonding
becomes significant,14c which in turn leads to an ee decrease
because reactions occurring in the dimer do not proceed
enantioselectively.
Sci., 1935, 201, 280; (d) G. O. Schenck, Naturwissenschaften, 1954,
32, 452–453.
3 Recent examples of singlet oxygen [2+4] cycloaddition reactions:
(a) M. J. Palframan, G. Kociok-Kohn and S. E. Lewis, Chem.–Eur.
J., 2012, 18, 4766–4774; (b) K. C. Nicolaou, S. Totokotsopoulos,
D. Giguere, Y.-P. Sun and D. Sarlah, J. Am. Chem. Soc., 2011,
133, 8150–8153; (c) G. S. Buchanan, K. P. Cole, Y. Tang and
R. P. Hsung, J. Org. Chem., 2011, 76, 7027–7039; (d) V. L.
Paddock, R. J. Phipps, A. Conde-Angulo, A. Blanco-Martin,
C. Giro-Manas, L. J. Martin, A. J. P. White and A. C. Spivey,
J. Org. Chem., 2011, 76, 1483–1486; (e) N. Charbonnet, E. Riguet
and C. G. Bochet, Synlett, 2011, 2231–2233; (f) G. Mehta and
P. Maity, Tetrahedron Lett., 2011, 52, 5161–5165; (g) J. A. Celaje,
D. Zhang, A. M. Guerrero and M. Selke, Org. Lett., 2011, 13,
4846–4849.
4 T. Bach, H. Bergmann, B. Grosch, K. Harms and E. Herdtweck,
Synthesis, 2001, 1395–1405.
5 Examples: (a) T. Bach, H. Bergmann and K. Harms, Angew.
Chem., Int. Ed., 2000, 39, 2302–2304; (b) T. Bach, T. Aechtner
and B. Neumuller, Chem. Commun., 2001, 607–608; (c) T. Bach,
H. Bergmann, B. Grosch and K. Harms, J. Am. Chem. Soc., 2002,
124, 7982–7990; (d) T. Aechtner, M. Dressel and T. Bach, Angew.
Chem., Int. Ed., 2004, 43, 5849–5851; (e) P. Selig and T. Bach,
Angew. Chem., Int. Ed., 2008, 47, 5082–5084; (f) K. A. B. Austin,
E. Herdtweck and T. Bach, Angew. Chem., Int. Ed., 2011, 50,
8416–8419.
6 Review: C. Muller and T. Bach, Aust. J. Chem., 2008, 62, 557–564.
7 For an enantioselective access to endoperoxides by an auxiliary-
based method, see: W. Adam, M. Guthlein, E.-M. Peters, K. Peters
and T. Wirth, J. Am. Chem. Soc., 1998, 120, 4091–4093.
8 (a) T. Bach, H. Bergmann and K. Harms, Org. Lett., 2001, 3,
601–603; (b) D. Albrecht, F. Vogt and T. Bach, Chem.–Eur. J.,
2010, 16, 4284–4296; (c) P. Fackler, S. M. Huber and T. Bach,
J. Am. Chem. Soc., 2012, 134, 12869–12878.
9 (a) G. A. Swan, Experientia, 1984, 40, 687–688; (b) G. A. Swan,
J. Chem. Soc., Perkin Trans. 1, 1985, 1757–1766.
In summary, it was shown that visible light irradiation can
be successfully employed for the enantioselective synthesis of
3-hydroxypyridine-2,6-diones from the respective pyridones
via type II photooxygenation intermediates. In an optimised
reaction protocol high yields and enantioselectivities could be
obtained for the selected substrates 3 and 9. In order to guarantee
high yields for other substrates the reaction conditions need to be
modified.20 In particular the acidic conditions employed for
endoperoxide opening are not compatible with every substitution
pattern and induce side reactions, which in turn compromise the
yield. Enantioselectivities have been consistently above 65% ee,
however, indicating that a high enantioface differentiation is
mediated upon binding of the substrate to template 1.
10 (a) J.-G. Shi, H.-Q. Wang, M. Wang and Y. Zhu, Phytochemistry,
1995, 40, 1299–1302; (b) J.-G. Shi, H.-Q. Wang, M. Wang,
Y.-C. Yang, W.-Y. Hu and G.-X. Zhou, J. Nat. Prod., 2000, 63,
782–786.
11 E. Sato, Y. Ikeda and Y. Kanaoka, Chem. Pharm. Bull., 1987, 35,
507–513.
12 M. Matsumoto, M. Yamada and N. Watanabe, Chem. Commun.,
2005, 483–485.
13 (a) N. Kornblum and H. E. DeLaMare, J. Am. Chem. Soc., 1951,
73, 880–881; (b) S. T. Staben, X. Linghu and F. D. Toste, J. Am.
Chem. Soc., 2006, 128, 12658–12659.
14 (a) M. Dressel and T. Bach, Org. Lett., 2006, 8, 3145–3148;
(b) C. Muller, A. Bauer and T. Bach, Angew. Chem., Int. Ed.,
2009, 48, 6640–6642; (c) A. Bakowski, M. Dressel, A. Bauer and
T. Bach, Org. Biomol. Chem., 2011, 9, 3516–3529; (d) C. Muller,
M. M. Maturi, A. Bauer, M. C. Cuquerella, M. A. Miranda and
T. Bach, J. Am. Chem. Soc., 2011, 133, 16689–16697.
15 The asymmetric unit contains two crystallographically independent
but chemically identical molecules. CCDC 894230 (6); for more
details see ESIw.
16 S. Yamaguchi, E. Hamade, H. Yokoyama, Y. Hirai and
S. Shiotani, J. Heterocycl. Chem., 2002, 39, 335–339.
17 L. I. Kruse, C. Kaiser, W. E. DeWolf, J. A. Finkelstein,
J. S. Frazee, E. L. Hilbert, S. T. Ross, K. E. Flaim and
J. L. Sawyer, J. Med. Chem., 1990, 33, 781–789.
This project was supported by the Deutsche Forschungsge-
meinschaft (Ba 1372-10; Graduiertenkolleg GRK 1626 Chemical
Photocatalyis). C. Cornaggia and M. Cakmak are acknowledged
for preliminary studies on 4 and 5.
Notes and references
1 Reviews: (a) M. R. Iesce and F. Cermola, in CRC Handbook of
Organic Photochemistry and Photobiology, ed. A. Griesbeck,
M. Oelgemoller and F. Ghetti, CRC Press, Boca Raton, 3rd ed.,
2012, pp. 727–764; (b) M. Zamadar and A. Greer, in Handbook
of Synthetic Photochemistry, ed. A. Albini and M. Fagnoni,
Wiley-VCH, Weinheim, 2010, pp. 353–386; (c) E. L. Clennan
and A. Pace, Tetrahedron, 2005, 61, 6665–6691.
2 Pioneering studies: (a) M. Fritzsche, C. R. Acad. Sci., 1867, 64,
1035–1037; (b) A. Windaus and J. Brunken, Liebigs Ann. Chem.,
1928, 460, 225–235; (c) C. Dufraisse and A. Etienne, C. R. Acad.
18 Compounds 13 and 15 were prepared in analogy to a known
procedure (see ESIw for further information): D. B. Moran,
G. O. Morton and J. D. Albright, J. Heterocycl. Chem., 1986,
23, 1071–1077.
19 E. Ochiai and Y. Kawazoe, Pharm. Soc. Jpn, 1957, 5, 606–610.
20 For singlet oxygen reactions, performed in a continuous flow
system, see: (a) F. Levesque and P. H. Seeberger, Org. Lett.,
2011, 13, 5008–5011; (b) F. Levesque and P. H. Seeberger, Angew.
Chem., Int. Ed., 2012, 51, 1706–1709; (c) K. Booker-Milburn, Nat.
Chem., 2012, 4, 433–435.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 10195–10197 10197