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. 2012 Mar 12;14(3):218-23.
doi: 10.1021/co2001873. Epub 2012 Feb 10.

Synthesis of a γ-lactam library via formal cycloaddition of imines and substituted succinic anhydrides

Darlene Q Tan  1 , Amy L Atherton, Austin J Smith, Cristian Soldi, Katherine A Hurley, James C Fettinger, Jared T Shaw
Affiliations

Synthesis of a γ-lactam library via formal cycloaddition of imines and substituted succinic anhydrides

Darlene Q Tan et al. ACS Comb Sci. .

Abstract

Formal cycloaddition reactions between imines and cyclic anhydrides serve as starting point for the synthesis of diverse libraries of small molecules. The synthesis of succinic anhydrides substituted with electron-withdrawing groups is facilitated by new mild conditions for alkylation of aryl-substituted acetyl esters with ethyl bromoacetate. These anhydrides are then used in formal cycloaddition reactions with imines to produce γ-lactams. 2-Fluoro-5-nitrophenylsuccinic anhydride reacts efficiently with imines to provide lactams that are further diversified by conversion of the nitro group to either an aniline and an azide for subsequent reactions with acylating agents and alkynes, respectively. The synthesis of cyanosuccinic anhydride is reported for the first time, and the use of this compound in reactions with imines and subsequent functionalization of the resultant lactams is demonstrated.

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Figures

Figure 1
Figure 1
Summary of Library Strategy Based on the Formal Cycloaddition of Imines with Substituted Succinic Anhydrides.
Figure 2
Figure 2
Diversity Reagents Employed in Scheme 4.
Figure 3
Figure 3
Summary of the molecular properties computed for library members. Calculated partition coefficients (cLogP) are based on the XLOGP method of Wang.
Scheme 1
Scheme 1
Alkylation of Cyano- and 2-Benzothiazole Acetic Esters.
Scheme 2
Scheme 2
Conversion of Diesters to Substituted Succinic Anhydrides.
Scheme 3
Scheme 3
Imine-Anhydride Reactions of 2a Followed by Ester and Amide Formation.
Scheme 4
Scheme 4
Spirocyclization Reactions of 19, 20 and 22.
Scheme 5
Scheme 5
Reduction and Acylation of 40.
Scheme 6
Scheme 6
Library Synthesis Using 25, 26, 27, 34.
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