Electrocyclization of oxatrienes in the construction of structurally complex pyranopyridones

Article abstract of DOI:10.1021/ol3026457

Application of a tandem Knoevenagel/6π-electrocyclization sequence is able to produce highly substituted pyranopyridones from moderate to high yields in a one-step reaction. High diasteroselectivity is observed in some cases and was rationalized on the basis of the thermodynamic control of the evidenced reversibility of a 6π-electrocyclization reaction. Numerous examples are provided establishing a novel entry in natural product-like structures of pyranopyridone alkaloids.

Full text of DOI:10.1021/ol3026457

ORGANIC
LETTERS
2012
Vol. 14, No. 22
5664–5667
Electrocyclization of Oxatrienes in the
Construction of Structurally Complex
Pyranopyridones
Anna D. Fotiadou and Alexandros L. Zografos*
Department of Chemistry, Laboratory of Organic Chemistry,
Aristotle University of Thessaloniki, University Campus, 54124, Thessaloniki, Greece
alzograf@chem.auth.gr
Received September 25, 2012
ABSTRACT
Application of a tandem Knoevenagel/6π-electrocyclization sequence is able to produce highly substituted pyranopyridones from moderate to
high yields in a one-step reaction. High diasteroselectivity is observed in some cases and was rationalized on the basis of the thermodynamic
control of the evidenced reversibility of a 6π-electrocyclization reaction. Numerous examples are provided establishing a novel entry in natural
product-like structures of pyranopyridone alkaloids.
Improvements on the understanding of biosynthetic
pathways during the last two decades provided the oppor-
tunity to scientists to recognize and utilize common syn-
thetic intermediates in order to access structurally unrelated
natural compounds.1 In this endeavor, recently, the authors
reported a unique synthetic access to the structural diversity
presented by pyridone alkaloids.2 In the course of their
study toward the total synthesis of citridone A,3 the authors
have witnessed the formation of a small amount of pyr-
anopyridone 5, representing the core structure of calcium
channel inhibitor YCM1008A4 (2) (Figure 1). Aimed at
developing a unified synthetic strategy to construct pyr-
idone natural products enclosing compounds such as
YCM1008A or leporins (1a,b), a research project toward
pyranopyridone heterocycles was initiated. Our previous
experiments showed that when hydroxypyridone 3 was
allowed to react under microwave irradiation with aldehyde
4 at 150 °C a 10% yield of pyranopyridone 5 was isolated
along with compound 6 (Figure 1). On the other hand,
when the same reactants reacted at lower microwave tem-
perature (60 °C) and were directly treated with bismuth
triflate a 3:1 mixture of citridone derivative 8 and pyrano-
pyridone 5 was observed, evidencing for a cycloisomeriza-
tion versus electrocyclization dual mechanistic pathway. On
the basis of these observations, the use of unsaturated
aldehydes was considered as the potential optimal way to
access pyranopyridones constructs. Wishing to explore the
synthetic feasibility of the described idea, citral was used
as the model unsaturated aldehyde. To our delight, when
(1) Anagnostaki, E. E.; Zografos, A. L. Chem. Soc. Rev. 2012, 41,
5613–5625.
(2) Fotiadou, A. D.; Zografos, A. L. Org. Lett. 2011, 13, 4592–4595.
(3) Fukuda, T.; Tomoda, H.; Omura, S. J. Antibiot. 2005, 58
315–321.
(4) Koizumi, F; Fukumitsu, N.; Zhao, J.; Chanklan, R.; Miyakawa,
T.; Kawahara, S.; Iwamoto, S.; Suzuki, M.; Kakita, S.; Rahayu, E. S.;
Hosokawa, S.; Tatsuta, K.; Ichimura, M. J. Antibiot. 2007, 60, 455–458.
(5) (a) Thompson, S.; Coyne, A. G.; Knipe, P. C.; Smith, M. D.
Chem. Soc.Rev. 2011, 40, 4217–4231. For excellent reviews on oxa-[3 þ 3]
annulations, see: (b) Buchanan, G. S.; Feltenberger, J. B.; Hsung, R. P.
Curr. Org. Synth. 2010, 7, 363–401. (c) Hsung, R. P.; Kurdyumov, A. V.;
Sydorenko, N. Eur. J. Org. Chem. 2005, 23–44.
r
10.1021/ol3026457
Published on Web 11/01/2012
2012 American Chemical Society

the topic to the best of our knowledge, there are no reports
on the synthesis of pyranopyridones based on a formal
[3 þ 3] reaction.7
Following our early success utilizing citral as the
unsaturated aldehyde component, the quest for optimal
reaction conditions revealed that even in the absence of
piperidine the reaction proceeds in lower yields (23ꢀ27%)
but without the formation of 1,4-adduct (entries 2 and 3,
Table 1). This result, which comes in contrast to the reported
studies by Hsung,6 can be rationalized by an internal
pyridoneꢀiminium aldehyde activation.
Table 1. Optimization of Formal [3 þ 3] Reactiona
base
tempb
time
yieldd
(%)
Figure 1. (A) Selected natural pyranopyridones and (B) lead
experiments to pyranopyridones.
entry
(x equiv)
(°C)
solvent
EtOH
(min)
1
2
piperidine (1)
none
150
150
150
60
10
10
20
10
10
10
15
15
15
15
15
10
15
53
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
H2O
23
4-hydroxypyrid-2-one (3) was heated with citral (9) in the
presence of an equivalent amount of piperidine in ethanol
the [3 þ 3] adduct 10 was isolated in 53% yield (entry 1,
Table 1).
3
none
27
4
piperidine (1)
piperidine (0.3)
piperidine (1)
piperidine (0.3)
piperidine (0.3)
piperidine (0.3)
piperidine (0.3)
piperidine (0.3)
DMAP (1)
13
5
100
100
100
100
100
100
100
150
100
68
6
67
Regardless of the several examples that have been
amassed in the literature demonstrating the capacity of
pericyclic reactions in biosynthetic routes of natural pro-
ducts, only lately have pericyclic reactions been considered
as convenient, selective, and powerful bond-forming pro-
cesses with application in the construction of complex
molecules.5 In an elegant array of publications, Hsung’s
and Hua’s groups demonstrated the ability of unsaturated
aldehydes to react with dicarbonyl compounds to prepare
pyranoheterocycles.6 Despite their extensive research on
7
87
8
5
9
THF
72
10
11
12
13
CH3CN
EtOH/H2Oc
EtOH
EtOH
60
45
37
proline (0.3)
70 (0% ee)
a Conditions: substrate 3 (0.16 mmol), citral (9, 0.16 mmol, 1.0 equiv),
base (x equiv), solvent (0.4 mL, 0.4 M). b Heating under MW irradiation.
c Ratio 1:1. d Isolated yields.
(6) (a) Hsung, R. P.; Shen, H. C.; Douglas, C. J.; Morgan, C. D.;
Degen, S. J.; Yao, L. J. J. Org. Chem. 1999, 64, 690–691. (b) Shen, H. C.;
Wang, J.; Cole, K. P.; McLaughlin, M. J.; Morgan, C. D.; Douglas,
C. J.; Hsung, R. P.; Coverdale, H. A.; Gerasyuto, A. I.; Hahn, J. M.; Liu,
J.; Sklenicka, H. M.; Wei, L.; Zehnder, L. R.; Zificsak, C. A. J. Org.
Chem. 2003, 68, 1729–1735. (c) Hua, D. H.; Chen, Y.; Sin, H.-S.;
Maroto, M. J.; Robinson, P. D.; Newell, S. W.; Perchellet, E. M.;
Ladesich, J. B.; Freeman, J. A.; Perchellet, J.-P.; Chiang, P. K. J. Org.
Chem. 1997, 62, 6888–6896. (d) McLaughlin, M. J.; Shen, H. C.; Hsung,
R. P. Tetrahedron Lett. 2001, 42, 609–613. (e) Buchanan, G. S.; Dai, H.;
Hsung, R. P.; Gerasyuto, A. I.; Scheinebeck, C. M. Org. Lett. 2011, 13,
4402–4405.
(7) The closest literature precedent concerning the preparation of
hydroxy quinolones: (a) McLaughlin, M. J.; Hsung, R. P. J. Org. Chem.
2001, 66, 1049–1053. For selected publications on the preparation of
pyranopyridones, see: (b) Fan, X.; Feng, D.; Qu, Y.; Zhang, X.; Wang,
J.; Loiseau, P. M.; Andrei, G.; Snoeck, R.; De Clercq, E. Biorg. Med.
Chem. Lett. 2010, 20, 809–813. (c) Magedov, I. V.; Manpadi, M.;
Ogasawara, M. A.; Dhawan, A. S.; Rogelj, S.; Van slambrouck, S.;
Steelant, W. F. A.; Evdokimov, N. M.; Uglinskii, P. Y.; Elias, E. M.;
Knee, E. J.; Tongwa, P.; Antipin, M. Y.; Kornienko, A. J. Med. Chem.
2008, 51, 2561–2570. (d) Magedov, I. V.; Manpadi, M.; Evdokimov,
N. M.; Elias, E. M.; Rozhkova, E.; Ogasawara, M. A.; Bettale, J. D.;
Przheval’skii, N. M.; Rojelj, S.; Kornienko, A Biorg. Med. Chem. Lett.
2007, 17, 3872–3876.
Lowering the microwave temperature to 100 °C led to
cleaner reactions even when longer reaction times were
applied avoiding the formation of dipyridone byproduct
(entries 6 and 7, Table 1). Substoichiometric quantities of
piperidine at 0.3 equiv did not affect the yield (entry 5),
while ethanol was established as the optimal solvent
(entries 8ꢀ11). Other bases, including chiral proline, had
inferior results. In the case of proline, no enantioselectivity
was observed, indicating a mechanism through the forma-
tion of an achiral oxatriene intermediate.
To further support our mechanistic assumption, an
internal trap of the hypothetical oxatriene intermediate
was envisioned. Thus, when electron-rich aromatic alde-
hyde 11 was applied on our optimal reaction conditions no
electrocyclization reaction was observed, but instead com-
pound 14 was isolated in 22% yield through an intramo-
lecular FriedelꢀCrafts-type reaction on the oxatriene
intermediate (Scheme 1).
Org. Lett., Vol. 14, No. 22, 2012
5665

Table 2. Scope of the Carbonyl Partnera
Scheme 1. Trapping Experiment of Oxatriene Intermediate
In order to explore the scope and limitations of the
formal [3 þ 3] reaction on the synthesis of complex
pyranopyridones, a numberofunsaturatedaldehydes were
allowed to react with 4-hydroxypyridone-2 under our
optimal conditions. In this study, no concern is given in
preparing pure Z or E isomers of the unsaturated alde-
hydes due to their known thermal equilibration of unsa-
turated imines under these conditions.8 Following our
results as summarized in Table 2, unsaturated aldehydes
(9, 16aꢀc) bearing substituents in both R and β-positions
are well tolerated providing moderate to high yields of
pyranopyridone compounds along with unreacted starting
material (entries 1ꢀ4) regarding the bulkiness of the
aldehyde (16d, entry 5). Unsaturatedaldehydesconjugated
with aromatics can also be applied to produce low yields of
R-phenyl pyranopyridone compounds (16e, entry 6). On
the other hand, nonaromatic conjugated aldehydes failed
to couple with hydroxypyridone (16f, entry 7) but instead
provided the self-cyclized product by thermal ene-type
reaction. Finally, an attempt to couple pyridone with
unsaturated ketones provided only the unreacted starting
components.
While this annulation appears to be an attractive strategy
for the construction of YCM1008A (2) and leporin natural
products (1a,b), it was considered that it would probably lack
the essential stereoselectivity on the newly formed CꢀO bond
because of the pericyclic nature of the reaction. Surprisingly,
when commercially available enantiopure unsaturated alde-
hydes 16g and 16h were used, high diastereoselectivities were
observed (entries 1 and 2, Table 3). To this end, enantiopure
aldehydes (16iꢀk) have been prepared and used in order to
verify their ability to produce enantiopure pyranopyridones.
Unfortunately, utilization of 16iꢀk revealed only moderate
diastereoselectivities (64ꢀ75% dr) as this was determined by
1H NMR but comparable yields of products with those of
a Conditions: substrate 3 (0.16 mmol), substrate 16 (0.16 mmol,
1.0 equiv), piperidine (0.3 equiv), solvent (4 mL, 0.4 M), 100 °C,
15 min MW irradiation. b Isolated yields. c Solvent: EtOH/H2O.
aldehydes 16aꢀe. Chiral saturated aldehydes bearing a
β-silyloxy or acetoxy group can also be used as precursors
to the requisite unsaturated aldehydes. Thus, when aldehyde
16k was used, comparable yield and diastereoselectivity with
aldehyde 16i were provided.
(8) Cossio, F. P.; Arrieta, A.; Sierra, M. A Accounts Chem. Res. 2008,
41, 925–936.
5666
Org. Lett., Vol. 14, No. 22, 2012

closely from mechanistic perspective. A [3 þ 3] annulation
under these conditions is not expected to provide any
diastereomeric induction due to the high degree of con-
formational freedom on the chirality of the alkyl chain.
Under this logic, a reversible nature in the formation of
pyrane ring was considered. To support the reversibily of
6π-pericyclic process, the major isomer of 17i was isolated
and subjected to microwave irradiation at 100 °C with or
without the aid of piperidine. In either case, the formation
of a 64:36 mixture of isomers was obtained witnessing for
the heating equilibration of the pyrane skeleton.
Table 3. Diastereoselective Electrocyclizationa
Scheme 2. Pyranopyridones as Tools for Accessing Natural
Diversity
Adding in the synthetic utility of pyranopyridones com-
pounds, 17i and 17j were further transformed to access two
diverse core structures presented in pyridone alkaloids
(Scheme 2). When compound 17i was subjected in reaction
with bismuth triflate a highly stereoselective cationic cycli-
zation was realized to produce compounds 21 and 22 in
62% and 10% yields, respectively. A high-yielding alumi-
num chloride rearrangement of compound 21 to compound
22 allowed the palladium on carbon mediated ether opening
of the latter compound to produce 23 in 46% yield, repre-
senting the core structure for epi-cordypyridone A and B
natural products.9 On the other hand, compound 17j was
chlorohydroxylated with NCS and radically reduced with
(TMS)3SiH to afford compound 18, a potential precursor to
YCM1008A natural product.
a Conditions: substrate 3 (0.16 mmol), aldehyde (16hꢀk, 0.16 mmol,
1.0 equiv), piperidine (0.3 equiv), solvent (4 mL, 0.4 M) 100 °C, 15 min,
MW irradiation. b The major product is represented. c Ratio determined
by NMR. d Isolated yields.
In conclusion, the utilization of a tandem Knoevenagel/
electrocyclization sequence is described for the first time as
an efficient method to access structurally complex pyra-
nopyridones. Selected pyranopyridones can serve as excel-
lent precursors for the synthesis of structurally diverse
natural product-like pyridones.
Interestingly, the reactions, as was evidenced by 2D
NMR experiments in isomeric mixtures, had always a
preference in producing the thermodynamically more
stable isomer in accordance with SpartanTM AM1 calcula-
tions. While these ratios are modest, this result provides an
opportunity to examine oxatriene pericyclic reaction more
Supporting Information Available. Experimental details
and NMR spectral characterization for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(9) Isaka, M.; Tanticharoen, M.; Kongsaeree, P.; Thebtaranonth, Y.
J. Org. Chem. 2001, 66, 4803–4808.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 22, 2012
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