Recent Progress in the Chemistry of Mucohalic Acids: Versatile Building Blocks in Organic Synthesis

Dedicated to the Ann Arbor Laboratories of Parke-Davis/Pfizer where Lipitor and Lyrica were invented and developed.

Abstract

This account documents our recent progress in exposing some of the potential of mucohalic acids in synthetic applications. Understanding their stability and reactivity in different reaction media allows the development of mild and regioselective methods to access various substituted butenolides, butenolactams, and 4,5-di­halopyridazin-3(2H)-ones and to create other novel, multifunctionalized building blocks.

1 Introduction

2 The Rationale for the Reinvestigation of Mucohalic Acid Chemistry

3 Understanding the Stability of Mucohalic Acids

4 One-Pot Synthesis of a 4,5-Dihalopyridazin-3(2H)-one and the Process Chemistry of ABT-963

5 Reductive Amination of Mucochloric Acid and Synthesis of Antiseizure Drug Levetiracetam (Keppra)

6 Reduction of Mucohalic Acids and Synthesis of Anti-­inflammatory Agent Rofecoxib (Vioxx)

7 Lewis Acid Catalyzed Knoevenagel Aldol Reaction

8 Lewis and Brønsted Acid Promoted Friedel–Crafts ­Hydroxyalkylation

9 Lewis Acid Facilitated Mukaiyama Aldol Reaction

10 Indium-Mediated Allylation in Water

11 Palladium-Free Regioselective Etherification and Amination

12 Novel Building Blocks Derived from Mucohalic Acids

13 Direct Vinylogous Aldol Addition Using α,β-Dihalo-­Substituted Butenolides and Butenolactams

14 Other Applications

15 Summary and Conclusion

Key words

mucohalic acids - butenolides - γ-lactones - γ-lactams - building blocks

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