Lewis acid mediated condensation reactions of α,β-unsaturated acids with 4-hydroxy-2-pyrones. A concise structural assignment of Fleischmann's α,α-bispyrone and Praill's α,γ-bispyrone

Article abstract of DOI:10.1016/S0040-4039(00)00057-5

Unambiguous assignments of Fleischmann's α,α-bispyrone 3 and Praill's α,γ-bispyrone 6 have been carried out by exploring Lewis acid mediated condensation reactions of α,β-unsaturated carboxylic acids with 4-hydroxy- 2-pyrones. This protocol is shown to be useful for synthesis of a BCDE-ring tetracyclic analog of arisugacin. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00057-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1901–1905
Lewis acid mediated condensation reactions of α,β-unsaturated
acids with 4-hydroxy-2-pyrones. A concise structural assignment
of Fleischmann’s α,α-bispyrone and Praill’s α,γ-bispyrone
†
∗
Luke R. Zehnder, Jason W. Dahl and Richard P. Hsung
Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA
Received 29 November 1999; accepted 18 December 1999
Abstract
Unambiguous assignments of Fleischmann’s α,α-bispyrone 3 and Praill’s α,γ-bispyrone 6 have been carried
out by exploring Lewis acid mediated condensation reactions of α,β-unsaturated carboxylic acids with 4-hydroxy-
2-pyrones. This protocol is shown to be useful for synthesis of a BCDE-ring tetracyclic analog of arisugacin.
©
2000 Elsevier Science Ltd. All rights reserved.
Fleischmann reported the first condensation reaction of triacetic acid or 4-hydroxy-6-methyl-2-pyrone
1
1
with ethyl acetoacetate and assigned the condensation product as the ‘pyrone-lactone’ 2 (Scheme
). Fifty-four years later, Praill observed a different product upon treatment of the β-diketone 4 with
1
HClO , which he assigned as the α,γ-bispyrone 6, presumably via an acid-promoted rearrangement of
the γ,γ-bispyrone 5. This finding led Praill to suggest that Fleischmann had in fact synthesized the α,α-
bispyrone 3. Subsequently, Tan and Talapatra reported reactions of dehydroacetic acid 7 with ethyl
acetoacetate but gave conflicting assignments of their products. Tan reported his product to be 3, while
Talapatra assigned his as 6 and provided the first H NMR data. However, Talapatra’s H NMR data are
different from those provided recently by Crombie, who reported to obtain 6 upon treating dehydroacetic
4
2
3
4
1
4
1
5
acid 7 with Ac O and HClO .
2
4
These condensation reactions became attractive to us because the α,γ-bispyrone 6 could be useful
in our studies related to [4+2] cycloadditions using γ-pyrones as dienophiles.6 It was not clear what
product was actually obtained in Fleischmann’s or Praill’s work since mechanistically both 3 and 6 may
–8
9
be attainable from either reaction. Given the difficulty in distinguishing 3 and 6 and the lack of consistent
literature data, we pursued alternative methods for preparing 3 and 6. We report here the unambiguous
assignment of Fleischmann’s α,α-bispyrone 3 and Praill’s α,γ-bispyrone 6, and a Lewis acid mediated
∗
†
Corresponding author.
UMN Undergraduate Research Participant. Recipient of a UMN UROP Fellowship 1999–2000.
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00057-5
tetl 16337

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902
Scheme 1.
one-pot condensation reaction between α,β-unsaturated acids and 4-hydroxypyrones for preparation of
the α,γ-bispyrone 6.
Our attempts to reproduce Fleischmann’s condensation under acidic, basic, or neutral conditions all
1
4
5
yielded a single product with H NMR data identical to Talapatra’s but dissimilar to those of Crombie.
1
Given these differences in H NMR data, we prepared pyrones 3 and 6 using step-wise sequences shown
in Scheme 2. From our previous work, we recognize that reaction pathways producing 3 and 6 would
originate from an initial preference of either O- or C-acylation of 1.
1
0
Scheme 2.
With this in mind, we O-acylated triacetic acid 1 using crotyl chloride to provide the ester 8 in 45%
1
1
12
yield. Subsequently, instead of a 1,3-acyl migration, cyclization occurred readily when 8 was refluxed
in toluene in the presence of catalytic DMAP, leading to the lactone 9 in 48% yield. A quantitative
dehydrogenation of compound 9 using DDQ led to the isolation of the same product (3) as we obtained
1
from Fleischmann’s condensation. Although the H chemical shift of the tertiary H in 9 suggests the
correct sequence of O-acylation/cyclization had occurred, the structure of 9 was not unambiguously
assigned until the dihydro-γ-pyrone 10 was prepared. Toward this goal, we explored a useful Lewis acid
mediated one-pot condensation reaction of α,β-unsaturated acids with 4-hydroxy-pyrones (Scheme 2).
Because C-acylation of triacetic acid 1 may be achieved using Lewis acids and acid chlorides in a
1
3
Friedel–Crafts manner, we examined the possibility of using α,β-unsaturated acid chlorides in a similar
manner and attempted to generate them in situ from the corresponding α,β-unsaturated carboxylic acids.
As shown in Scheme 2, when triacetic acid 1 was treated with 1.0 equiv. crotonic acid and 4.0 equiv.
ZnCl in POCl (optimally 4.0–10.0 equiv.) at 80–90°C for 4 h, the desired product 10 was obtained in
2
3
57% yield. This reaction essentially accomplishes three separate operations: acid chloride formation, C-
acylation, and cyclization, thereby constituting a sequential protocol that constructs two bonds in addition
to a potential stereocenter adjacent to the oxygen atom. Although we examined other conditions for the

1
903
14
acid chloride formation, POCl appears to be the best. Oxidation of the compound 10 using I and
NaOAc provided 6 in 68% yield.
3
2
1
5
The assignment of 9 and 10 became readily apparent when chemical shifts of the tertiary H and β-
methyl group of lactone rings were revealed (Fig. 1, in the boxes). For compound 10, the chemical
shifts of these two resonances are distinctly more downfield than those of 9 due to a closer proximity
to the oxygen atom. Chemical shifts of the methyl group and vinyl H of the adjacent 2-pyrone are
essentially the same for both 9 and 10. The pyrones 3 and 6 were then unambiguously distinguished,
based on the assignment of 9 and 10 (Fig. 1). A comprehensive comparison of their characterization data
is summarized in Table 1.
1
Fig. 1. H NMR (CDCl
3
, δ) comparisons for compounds 9 and 10
Table 1
Concise characterizations of 3 and 6
1
From these H NMR data, the most distinct difference is the chemical shift of the two methyl groups
in 3 and 6. While ∆δ is 0.21 ppm for Fleischmann’s α,α-pyrone 3, ∆δ is only 0.03 ppm for Praill’s
α,γ-pyrone 6, indicating the two methyl groups are more similar in 6. In addition, we observed an
interesting solvent dependence of chemical shifts of vinyl protons in 6. In the presence of polar solvents
such as CD OD, chemical shifts of vinyl protons tend to collapse into one resonance — a singlet at
3
6
.16 ppm for 6. This dependency is less pronounced for 3. Based on these assignments, our attempts
1
at Fleischmann’s condensation have led to the α,α-pyrone 3 that has the same H NMR data as those
reported by Talapatra. Talapatra’s product should be assigned as 3, whereas both Praill and Crombie have
prepared the α,γ-pyrone 6.
Having established the assignment of 3 and 6, we further explored the synthetic scope of this Lewis
acid mediated condensation reaction between α,β-unsaturated acids and 4-hydroxypyrones because of
its convergency in leading to complex heterocycles. As shown in Scheme 3, when 4-hydroxy-2-pyrone
1
1 was treated with crotonic acid and 4.0 equiv. ZnCl in POCl (4.0 equiv.) at 85°C for 3 h, the desired
2 3
product 12 was obtained in 62% yield. The ketone functionality of 11 appears to be stable to the reaction
conditions. Reaction of 1-cyclohexene-1-carboxylic acid with triacetic acid 1 under the same reaction
conditions was also feasible, leading to the tricyclic heterocycle 13 in 47% yield. Although both cis- and
1
trans-isomers of 13 were observed initially in crude H NMR as a 1:1 mixture, the trans-isomer was

1
904
isolated as the major isomer upon work-up and column chromatography, presumably owing to a rapid
epimerization. These reactions demonstrate that various α,β-unsaturated acids and 4-hydroxypyrones
may be employed in this protocol.
Scheme 3.
1
6,17
Given our interest in arisugacin
and the hypothesis regarding the role of a DE-ring in its
inhibitory activity against acetylcholinesterase,18 6-aryl-4-hydroxy-2-pyrone 14 was reacted with 1-
18
cyclohexene-1-carboxylic acid (1.0 equiv.) in the presence of 2.5 equiv. ZnCl and 5.0 equiv. POCl3
2
at 80°C for 4 h to provide the heterocycle 15 in 52% yield (Scheme 4). Again, the trans-isomer was
isolated predominantly upon purification. The compound 15 serves as a BCDE-ring tetracyclic analog of
arisugacin. We are currently using this methodology to prepare relevant BCDE-ring analogs for studying
the structure–activity relationship of substituents on the E-ring.
Scheme 4.
We have described here a useful synthetic method leading to fused pyranone heterocycles using Lewis
acid mediated condensation reactions of α,β-unsaturated carboxylic acids with 4-hydroxy-2-pyrones.
This study has also provided unambiguous assignments of Fleischmann’s and Praill’s condensation
products as well as those obtained using similar condensation protocols.
Acknowledgements
The authors thank the University of Minnesota for financial support in the form of a Start-up Fund and
Grant-in-Aid (CUFS#: 1003-519-5984). R.P.H. thanks the American Cancer Society for an institutional
grant (IRG-58-001-40-IRG-26), and R. W. Johnson, of the Pharmaceutical Institute, for a generous grant
from the Focused Giving Program. J.W.D. thanks UMN for a UROP Fellowship.
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