Stereocontrol in the Synthesis of β-Lactams Arising from the Interlocked Structure of Benzylfumaramide-Based Hydrogen-Bonded [2]Rotaxanes

Dedicated to the memory of our friend and colleague Professor Angel Vidal

Abstract

β-Lactams are highly valuable compounds due to their antibiotic activity. Among the number of well-established methodologies for building this privileged scaffold, our research group has settled on a novel synthetic approach for their preparation. This Account focuses on our latest progress in the synthesis of these compounds through a novel base-promoted intramolecular cyclization of benzylfumaramide-based rotaxanes. The mechanical bond plays a significant role in the process by activating the cyclization inside the macrocycle void, avoiding the formation of byproducts and fully controlling the diastereoselectivity. Further investigations on this transformation led to the formation of ­enantioenriched 2-azetidinones. The cyclization of enantiopure interlocked α-methylbenzylfumaramides allows the formation of two new stereogenic centers in the lactamic four-membered ring, one of them a quaternary carbon, keeping the initial configuration of the chiral group of the starting material.

1 Introduction

1.1 Mechanically Interlocked Molecules and Applications

1.2 Chemical Stabilization of the Mechanical Bond

2 Literature Methods for 4-exo-trig Ring Closures of Fumaramides for the Synthesis of β-Lactams

3 Our First Encounter with Interlocked β-Lactams

3.1 An Unexpected Result in Our Laboratory

3.2 Finding the Optimal Reaction Conditions

3.3 Elucidating the Effects of the Mechanical Bond

4 Diastereoselective Synthesis of Interlocked and Non-Interlocked β-Lactams

5 Asymmetric Cyclization of Enantiopure Interlocked Fumaramides

6 Conclusions

Key words

mechanical bonding - cyclization - stereoselectivity - β-lactams - macrocycles

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