Enantioselective preparation of mechanically planar chiral rotaxanes by kinetic resolution strategy

Abstract

Asymmetric synthesis of mechanically planar chiral rotaxanes and topologically chiral catenanes has been a long-standing challenge in organic synthesis. Recently, an excellent strategy was developed based on diastereomeric synthesis of rotaxanes and catenanes with mechanical chirality followed by removal of the chiral auxiliary. On the other hand, its enantioselective approach has been quite limited. Here, we report enantioselective preparation of mechanically planar chiral rotaxanes by kinetic resolution of the racemates via remote asymmetric acylation of a hydroxy group in the axis component, which provides an unreacted enantiomer in up to >99.9% ee in 29% yield (the theoretical maximum yield of kinetic resolution of racemate is 50%). While the rotaxane molecules are expected to have conformational complexity, our original catalysts enabled to discriminate the mechanical chirality of the rotaxanes efficiently with the selectivity factors in up to 16.

Fig. 1. Chirality in mechanically interlocked molecules and its construction.

a A schematic presentation of a mechanically planar chiral rotaxane and a topologically chiral catenane. b Takata’s pioneering approach toward catalytic enantioselective synthesis of a mechanically planar chiral rotaxane. c This work: Highly efficient acylative kinetic resolution of racemic mechanically planar chiral rotaxane 1a. The absolute configurations of the acylated product and the recovered rotaxane alcohol were not determined. The ring component and the axis component of rotaxanes are shown in red and blue, respectively, throughout the text.

Fig. 2. Strategy for kinetic resolution of racemic rotaxanes.

a Uncommon acylative kinetic resolution based on the recognition of remote chirality: Chirality of the substrate is hardly discriminated by the catalyst and/or the reagent upon asymmetric acylation when the chiral element is distal from the reacting center (OH). b Common acylative kinetic resolution based on the recognition of proximal chirality: The substrate chirality is effectively discriminated by the catalyst and/or the reagent upon asymmetric acylation when the chiral center is located close to the reacting center (OH). c Structure of target mechanically planar chiral rotaxane and its schematic presentation. d A hint for remote asymmetric acylation from our previous work: Contrasting chemoselectivity in the acylation of (5S)-4 and (5R)-4 with catalyst 3.

Fig. 3. Structure of catalysts.

Catalysts 7 and 8 are the analogues of catalysts 2 and 3 with different side chains for substrate recognition. Birman’s catalyst 9 is a representative catalyst for acylative kinetic resolution of racemic alcohols.

Fig. 4. Mechanistic implication for remote asymmetric acylation.

a Relationship between substrate structure and the selectivity factor (s) of the kinetic resolution. The absolute configuration of recovered rotaxanes was not determined. b left: A calculated transition state model A for remote asymmetric acylation of rotaxane alcohol 1a with a catalyst model of 2 (the corresponding methyl ester of 2). Right: a schematic drawing of model A in which catalyst, ring component, axis component, and carboxylate anion are shown in grey, red, blue, and black, respectively. Key hydrogen bonds are indicated by yellow circles. Structure A was generated by an ONIOM method (see S12) with constraint of hydrogen bonds indicated by yellow circles. Note that transition state model A is generated based on the assumption above, and it does not mean the most stable transition state structure.