A flexible route to bioactive 6-alkyl-α-pyrones

Article abstract of DOI:10.1016/j.tetlet.2017.01.063

Both 6-chloro-α-pyrones and 3-chlorobenzopyran-1-ones react with malonates followed by a double decarboalkoxylation to give the corresponding alkyl and alkenyl products.

Full text of DOI:10.1016/j.tetlet.2017.01.063

Tetrahedron Letters 58 (2017) 892–893
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A flexible route to bioactive 6-alkyl-a-pyrones
⇑
Yang Qu, George A. Kraus
Department of Chemistry, Iowa State University, Ames, IA 50010, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Both 6-chloro-
decarboalkoxylation to give the corresponding alkyl and alkenyl products.
Ó 2017 Elsevier Ltd. All rights reserved.
a-pyrones and 3-chlorobenzopyran-1-ones react with malonates followed by a double
Received 7 November 2016
Revised 19 January 2017
Accepted 20 January 2017
Available online 22 January 2017
Keywords:
6-Chloro-
Bioactive
Malonate
a-pyrone
Common intermediate
Double decarboalkoxylation
Bioactive 6-alkyl-
6-(1-pentenyl)-
-pyrone (2)2 and viridepyronone (3)3 are repre-
sentative of a growing class of -pyrones (Fig. 1). They exhibit a
diverse portfolio of useful activities including the regulation of root
architecture, plant growth promotion, and antipathogenic fungal
activity. Several researchers have developed routes to 1, including
Dickschat, Schreiber and Pale.4 The route described herein is
strategically distinct from previous approaches in that pyrones
1–3 can all be constructed from a common intermediate.
a
-pyrones such as 6-pentyl-
a
-pyrone (1),1
the second decarboalkoxylation through the pyrone carbonyl led to
1. Reaction of 5 with 1-iodohexane followed by double decar-
boalkoxylation generated 10 in 58% yield over two steps. Reaction
of 5 with allyl bromide and crotyl bromide produced pyrones 11
and 12 in 45% and 51% yields, respectively. Pyrone 12 was treated
with chlorobis(cyclooctene)iridium(I) catalyst9 to isomerize the
alkene to generate 2 in 86% yield based on recovered starting
material.
Alkyl malonates react with 4 as shown below in Scheme 2.
Double decarboalkoxylation then affords pyrone 13 in 43% overall
yield. In practice, the crude adduct was taken directly on to the
decarboalkoxylation reaction.
To demonstrate the scope of this reaction, 3-chlorobenzopyran-
1-one (14) was synthesized by treating homophthalic acid with
POCl3.10 This compound has been employed in palladium mediated
couplings such as the Sonogashira and Suzuki reactions.10 Using
the reaction conditions described in Scheme 1, benzopyran-1-ones
15 and 1611 were synthesized in 52% and 57% yields, respectively
(Scheme 3).
Pyrone 17 was readily prepared from the reaction of 5 with
cesium carbonate and 4-bromo-1-butene. Wacker oxidation using
palladium acetate and oxygen12 followed by double decar-
boalkoxylation afforded viridepyronone (3) in 48% overall yield.
Alternatively, reaction of 5 with methyl vinyl ketone and cesium
carbonate followed by double decarboalkoxylation produced 3 in
38% yield over two steps. Viridepyronone showed excellent anti-
fungal activity against several different soil-borne pathogenic
fungi. The antifungal activity of this compound was comparable
to commercial fungicide Hexaconazole.3b Evidente and coworkers
have shown in vitro antifungal activity of this compound against
a
a
The route begins with 6-chloro-a-pyrone (4), easily available
from commercially available trans-glutaconic acid in one step.5
Although 4 has been reported to undergo Sonogashira reactions
with a number of acetylenes, there are no reports of successful
additions with organometallic reagents such as cuprates or Grig-
nard reagents.5,6 Although reports of nucleophilic substitutions of
6-halo pyrones with enolates of carbonyl compounds are rare,
Stoltz has recently shown that nucleophilic substitution of the
chlorine in 4 with dimethyl malonate affords malonate 5 in good
yield.7 Based on this precedent, we reacted 5 with 1-iodobutane.
While the use of NaH in THF led to recovered starting material,
the use of cesium carbonate in boiling acetonitrile afforded 6 in
69% isolated yield. The reaction of 6 with standard Krapcho decar-
boalkoxylation protocols (NaCl, DMSO) led to the recovery of 6.
However, the reaction of 6 with magnesium chloride hexahydrate
in dimethylacetamide (DMA) at 140 °C produced pyrone 1 in 82%
yield.8 Normally, SN2 type decarboalkoxylations of malonates
afford the monoacid; however, the stabilization of the anion from
⇑
Corresponding author.
E-mail address: gakraus@iastate.edu (G.A. Kraus).
http://dx.doi.org/10.1016/j.tetlet.2017.01.063
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.

Y. Qu, G.A. Kraus / Tetrahedron Letters 58 (2017) 892–893
893
Fig. 1. Representative of bioactive 6-alkyl-a-pyrones.
Scheme 4. Synthesis of viridepyronone 3.
operationally convenient and proceed in good overall yields. The
routes are scalable and will provide quantities of 1, 2 and 3 for
additional biological evaluation.
Acknowledgments
We thank the NSF Engineering Center for Biorenewable
Chemicals (CBiRC) which was awarded NSF grant EEC-0813570
for support of this research.
A. Supplementary material
Scheme 1. Preparation of 6-alkyl-a-pyrones.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2017.01.
063.
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S. rolfsii at a minimum inhibitory concentration of 196 l
g/mL.3a To
the best of our knowledge, this is the first total synthesis of
viridepyronone to be reported (see Scheme 4).
Both 6-Chloropyrone (4) and 3-chlorobenzopyran-1-one (14)
provide direct access to bioactive pyrones. The routes are