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. 2012 Apr 9;14(4):280-4.
doi: 10.1021/co200200u. Epub 2012 Mar 16.

Isoxazolodihydropyridinones: 1,3-dipolar cycloaddition of nitrile oxides onto 2,4-dioxopiperidines

Keith C Coffman  1 , Timothy P Hartley, Jerry L Dallas, Mark J Kurth
Affiliations

Isoxazolodihydropyridinones: 1,3-dipolar cycloaddition of nitrile oxides onto 2,4-dioxopiperidines

Keith C Coffman et al. ACS Comb Sci. .

Abstract

Practical and efficient methods have been developed for the diversity-oriented synthesis of isoxazolodihydropyridinones via the 1,3-dipolar cycloaddition of nitrile oxides onto 2,4-dioxopiperidines. A select few of these isoxazolodihydropyridinones were further elaborated with triazoles by copper-catalyzed azide-alkyne cycloaddition reactions. A total of 70 compounds and intermediates were synthesized and analyzed for drug likeness. Sixty-four of these novel compounds were submitted to the NIH Molecular Libraries Small Molecule Repository for high-throughput biological screening.

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Figures

Figure 1
Figure 1
INADEQUATE-based assignments of C3, C4, C5 and C6 in 5{3}.
Figure 2
Figure 2
Assignments for 6{1} based on the INADEQUATE data from 5{3}.
Figure 3
Figure 3
Lipinski rules analysis for 70 compounds and intermediates; calculated using Molinspirations Online Molecular Properties Calculator [http://www.molinspiration.com/cgi-bin/properties?textMode=1].
Scheme 1
Scheme 1
Synthesis of 2,4-dioxopiperidines 3 (R1 = H and Me).
Scheme 2
Scheme 2
CuAAC of the isoxazolodihydropyridinones.
Scheme 3
Scheme 3
Azide synthesis for CuAAC.
See this image and copyright information in PMC

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