Ring‐to‐Thread Chirality Transfer in [2]Rotaxanes for the Synthesis of Enantioenriched Lactams

Abstract

The synthesis of chiral mechanically interlocked molecules has attracted a lot of attention in the last few years, with applications in different fields, such as asymmetric catalysis or sensing. Herein we describe the synthesis of orientational mechanostereoisomers, which include a benzylic amide macrocycle with a stereogenic center, and nonsymmetric N-(arylmethyl)fumaramides as the axis. The base-promoted cyclization of the initial fumaramide thread allows enantioenriched value-added compounds, such as lactams of different ring sizes and amino acids, to be obtained. The chiral information is effectively transmitted across the mechanical bond from the encircling ring to the interlocked lactam. High levels of enantioselectivity and full control of the regioselectivity of the final cyclic compounds are attained.

The Role of Dethreading Process in Pseudorotaxanes and Rotaxanes towards Advanced Applications: Recent Examples

“…An illustrative example of this molecular nanoreactor is the ring‐to‐thread chirality transfer of the fumaramide‐based rotaxanes 6 bearing a single stereogenic center in the tetralactam macrocycle towards the preparation of the enantioenriched lactams 7 (Figure 3). [62] Rotaxanes 6 are orientational mechanostereoisomers which are constituted by nonsymmetric N ‐(arylmethyl)fumaramides as threads and a tetralactam polyamide macrocycle having an α‐methyl group with R configuration. The cesium hydroxide‐induced cyclization followed by a thermally promoted dethreading yielded majorly the same trans ‐β‐lactam enantiomer from each intertwined mechanical epimer.…”

Stereoselective synthesis of β-lactams: recent examples

“…But in addition to the regio- and diastereoselections, this research group carried out a rational design incorporating stereocenters, either positioned in the linear counterpart 72 or in the cyclic one, 73 to induce enantioselection in the process.…”

“…In a more recent example, one methyl group having R configuration was incorporated in the tetralactam macrocycle, thus affording N -(arylmethyl)fumaramide-based rotaxanes 103 , which are orientational mechanostereoisomers. 73 Through a one pot protocol involving cesium hydroxide-promoted cyclization and the subsequent dethreading process, the enantioenriched β-lactams 104 were obtained in high yield (up to 94%). Interestingly, the lactams ( 3S , 4R )- 104 were obtained as the main products (up to 86 : 14 er) independently of the interlocked mechanical epimer [( R , R mp )- 103 or ( R , S mp )- 103 ] employed as starting material (Scheme 19).…”

“…In order to obtain the noninterlocked β-lactams, a dethreading process is carried out, 71 thus allowing the obtention of the target bioactive heterocycles. But in addition to the regio-and diastereoselections, this research group carried out a rational design incorporating stereocenters, either positioned in the linear counterpart 72 or in the cyclic one, 73 to induce enantioselection in the process.…”

Post‐Mechanical Bond Formation Desymmetrization Approach to Obtain Mechanically Planar Chiral Rotaxanes

“…In parallel, the preparation of chiral mechanically interlocked molecules (MIMs), [1] mainly rotaxanes and catenanes, has experienced a great progress with the appearance of new chiral elements as a consequence of the mechanical bond, such as topological chirality, [2,3] mechanically planar chirality [4,5] and mechanical axially chirality. [6] Mechanically chiral molecules exhibit potential applications in different areas, including chiroptical switching [7] and stereoselective synthesis of target molecules, [8] among others.…”