Synthesis of a 2(1 h)-pyridone library via rhodium-catalyzed formation of isomunchones

Article abstract of DOI:10.1021/co400067q

Through the use of the dipolar cycloaddition of isomunchones with olefins the 2(1H)-pyridone ring system has been synthesized.(1) The use of different cyclization partners followed by diversification of the initial scaffold has provded libraries of 4-hydroxy-2(1H)-pyridones. There are no examples of this ring system in either PubChem or the MLSMR

Full text of DOI:10.1021/co400067q

Letter
pubs.acs.org/acscombsci
Synthesis of a 2(1H)‑Pyridone Library via Rhodium-Catalyzed
Formation of Isomunchones
Subhasis De,† Lu Chen,‡ Shuxing Zhang,‡ and Scott R. Gilbertson*,†
†Department of Chemistry, University of Houston, Houston Texas 77204-5003, United States
‡Integrative Molecular Discovery Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson
Cancer Center, Houston Texas 77054, United States
S
* Supporting Information
ABSTRACT: Through the use of the dipolar cycloaddition of
isomunchones with olefins the 2(1H)-pyridone ring system
has been synthesized.1 The use of different cyclization partners
followed by diversification of the initial scaffold has provded
libraries of 4-hydroxy-2(1H)-pyridones. There are no examples
of this ring system in either PubChem or the MLSMR
KEYWORDS: pyridone, rhodium, carbene, isomunchone
he 2(1H)-pyridone structure is found in a large number of
conversion of the hydroxyl functionality to a triflate group,
2
Tnatural products such as camptothecin (1), as well as followed by a palladium-catalyzed cross-coupling and amination
reactions.1,6c7
synthetic elastase and thrombin inhibitors. Both antibacterial
The reported library was synthesized from one diazoimide
(5) and three different electron defficient olefins (7{1−3}).
The rhodium catalyzed reactions followed by triflate formation
proceeded in 40%, 55%, and 45%, respectively. Following the
formation of the 4-hydroxy-2(1H)-pyridones, the compounds
(9 {1−3}) with the free hydroxyl, were found to be somewhat
labile so they were immediately converted to their respective
triflates (10{1−3}). Additional diversity was then intro-
duced by Suzuki reaction on the triflate formed from the
initially formed 4-hydroxy-2(1H)-pyridones (Table 1). All
compounds in Table 1 were produced in greater than 20 mg
quantity. The Suzuki reaction used to produce these libraries
proceeded in yields from 95% to 35% with 78% being the
average yield.
and antifungal activities have been ascribed to molecules with
this functionality. The 4-hydroxy-2(1H)-pyridones such as
pyridoxatin (2)3 and huperzine A4 have been investigated as
potential therapeutics and pyridone acids (3) obtained from
fermentation have been found to be angiotensin-converting-
enzyme (ACE) inhibitors by Eli Lilly.5 Tricyclic pyridones
have been identified as subtype-selective GABAA receptor
agonists, and therefore have potential as nonsedating
anxiolytics.6 Despite its documented activity, this ring
system is nearly completely unrepresented in PubChem
and the Molecular Library Small Molecule Repository
(MLSMR) of the NIH, with only twelve compounds being
identified as 90% similar to 4.
While there are numerous methods for the preparation of
substituted 2-pyridones the chemistry developed by Padwa was
selected for access to the desired molecules.1 This approach
provides highly functionalized 4-hydroxy-2(1H)-pyridones (9)
from readily available starting materials. The method involves
the rhodium-catalyzed formation of an isomunchone (6) that
then undergoes a dipolar cycloaddition with an olefin to
form intermediate 8 which then decomposes to form 2(1H)-
pyridone 9. A strength of this approach is that a variety of
alkenes can be used in the cycloaddition to the isomunchones,
allowing for the introduction of different groups in the 5
position. While both electron-rich and electron-deficient
alkenes have been reported to proceed in high yield and with
good selectivity, the most useful examples are with electron
deficient versions (Scheme 1). Another important feature is the
availability of the starting diazoimides. By appropriate selection
of the diazo precursor (5) and dipolarophile (7), various groups
can be introduced into the C6−C8 positions from the diazo
compound and C-4 and C-5 positions from the dipolarophile
(olefin). Moreover, substituents can be introduced at C-3 by
To visualize the diversity of the library, it was subjected to
principal component analysis (PCA).8 The chemical com-
pounds were characterized with 186 2D descriptors derived
from Molecular Operating Environment (MOE version
2010.10).9 PCA was performed on the descriptor matrix to
reduce the dimensionality of chemical space as described
previously.10 The three-dimensional plots of the top three
principal components illustrate that within each set of com-
pounds there are members of the library that differ con-
siderably from the aggregate. The labeled circles represent
the examples that fall the farthest from the cluster center
of each chemical series (Figure 2). The LogP for the
library ranged from 0.33 to 4.82 with a mean value of 2.64.
The molecular weight of the compounds on average is
about 313.10 varying from 242.30 to 424.46, while the total
Received: May 14, 2013
Revised: June 5, 2013
© XXXX American Chemical Society
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Letter
Figure 1.
Scheme 1
Figure 2. Principal component analysis.
polar surface area (TPSA) ranged from 37.38 Å2 to 120.50
Å2 with a mean value of 56.08 Å2. Detailed methods and
histograms are presented in the Supporting Information.
Thus far, 68 members of this library have gone out to the
NIH screening centers. Of those, 5 have been designated as a
hit in a luminescence cell-based primary high throughput
screening assay to identify activators of the DAF-12 from the
parasite H. contortus (hcDAF-12). This screen was carried out
at The Scripps Research Institute Molecular Screening Center
on a screen submitted by David Mangelsdorf from University of
Texas Southwestern Medical Center.
In conclusion, a 128-member library was synthesized by
combining three different olefins in isomunchone dipolar
cycloadditions followed by Suzuki reaction of the resulting
triflate with 81 78 boronic acids. PCA indicates that while the
molecules are clustered, specific members are significantly
different from the group. The molecules have been
submitted to the NIH MLSMR to be distributed to the
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Letter
a
Table 1. Library Members
11{1,1}
11{1,2}
11{1,3}
11{1,4}
11{1,6}
11{1,7}
11{1,8}
11{1,9}
11{1,10}
11{1,11}
11{1,12}
11{1,13}
11{1,14}
11{1,15}
11{1,16}
11{1,17}
11{1,18}
11{1,19}
11{1,20}
11{1,21}
11{1,22}
11{1,23}
11{1,24}
11{1,25}
11{1,27}
11{1,28}
11{1,29}
11{1,30}
11{1,32}
11{1,33}
11{1,34}
11{1,35}
11{1,36}
11{1,37}
11{1,38}
11{1,39}
11{1,40}
11{1,42}
11{1,45}
11{1,46}
11{1,47}
11{1,51}
11{1,56}
11{1,65}
11{1,73}
11{2,1}
11{2,2}
11{2,3}
11{2,4}
11{2,5}
11{2,6}
11{2,7}
11{2,8}
11{2,9}
11{2,10}
11{2,11}
11{2,12}
11{2,13}
11{2,14}
11{2,15}
11{2,16}
11{2,17}
11{2,18}
11{2,19}
11{2,20}
11{2,24}
11{2,31}
11{2,35}
11{2,36}
11{2,39}
11{2,10}
11{2,44}
11{2,45}
11{2,46}
11{2,47}
11{2,48}
11{2,49}
11{2,50}
11{2,51}
11{2,52}
11{2,53}
11{2,54}
11{2,57}
11{2,58}
11{2,59}
11{2,60}
11{2,61}
11{2,62}
11{2,63}
11{2,64}
11{2,65}
11{2,66}
11{2,67}
11{2,68}
11{2,69}
11{2,70}
11{2,71}
11{2,72}
11{2,74}
11{2,75}
11{2,76}
11{2,79}
11{2,80}
11{3,1}
11{3,2}
11{3,3}
11{3,4}
11{3,5}
11{3,6}
11{3,7}
11{3,8}
11{3,9}
11{3,10}
11{3,11}
11{3,13}
11{3,22}
11{3,23}
11{3,29}
11{3,39}
11{3,40}
11{3,44}
11{3,45}
11{3,46}
11{3,47}
11{3,48}
11{3,50}
11{3,51}
11{3,77}
11{3,81}
a
1
All members of the library were analyzed by H and 13C NMR and mass spectrometry. All compounds were found to be 95% purity of greater.
Notes
NIH screening centers. With 68 of them having been
subjected to 9 assays thus far.
The authors declare no competing financial interest.
This work was supported by NIGMS GM079558 and
GM089173, the Robert A. Welch Foundation, and the M. D.
Anderson Foundation.
ASSOCIATED CONTENT
■
S
* Supporting Information
General procedures for library synthesis and H NMR data for
the compounds. This information is available free of charge via
the Internet at http://pubs.acs.org.
1
ACKNOWLEDGMENTS
■
We would like to thank University of Kansas Chemical
Methodologies and Library Development Center of Excellence
in particular Frank Schoenen and Benjamin Neuenswander for
providing analytical and purification support and David Hill for
chemoinformatics support.
AUTHOR INFORMATION
■
Corresponding Author
*Email: srgilbe2@central.uh.edu.
C
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