The use of parallel synthesis protocols for asymmetric reaction discovery has increased the need for new methods to rapidly determine enantiomeric excess (ee) values. Most chirality sensing is performed on stereocenters that are a (i.e., proximal) to the target functional group. Herein, we demonstrate a design principle to ''reach out'' to more distant stereocenters. Therefore, we see the design principles established in this work as a step forward in sensing distant point chirality and, eventually, multi-stereocenter relationships.
The atroposelective synthesis of N-aryl 1,2,4-triazoles was developed. A cyclodehydration reaction was rendered asymmetric with the use of a chiral phosphoric acid catalyst to afford atropisomeric N-aryl 1,2,4-triazoles in up to 91:9 er. Recrystallization of the isolated heterocycle further enriched the atropisomeric ratio of several analogs to 99:1 er or greater. A divergent and substrate-dependent reaction pathway yielding a different heterocyclic product is also disclosed. Note pubs.acs.org/joc
Atropisomeric scaffolds are a common design element found in pharmaceuticals, many deriving from an N-C axis of chirality. The handedness associated with atropisomeric drugs is oftentimes crucial for their efficacy...
We describe the synthesis of a family of chiral, nonracemic 3,4-disubstituted 2-N-oxazolidinoyl-1,3-dienes (10 and 15a−15i) via Stille− Furstner coupling. These chiral dienes were converted to the corresponding iron(0) tricarbonyl complexes (11 and 16a−16i) with good to high diastereoselectivity (3:1 to >15:1). The combined chemical yields of these steps, as well as the complexation diastereoselectivities, were generally superior to the analogous chiral 2-sulfinyl-1,3-dienes we reported earlier. Stereochemical assignments of the diene iron(0) tricarbonyl complexes were facilitated by X-ray crystallography and circular dichroism, and a computational search for the lowest energy confirmation of 10 was undertaken to understand the origin of the complexation diastereoselectivity. Complexes 16b and 16e were each carried through synthetic pathways that included RCM to make an initial comparison of the reactivity of this family of diene iron tricarbonyl complexes with the previously reported sulfinyl-1,3-diene iron(0) tricarbonyl complexes. Sidechains of complexes 43 and 44 were each modified for introduction of an α-diazoester unit, and diastereoselective Rh 2 (OAc) 4 -catalyzed intramolecular C−H insertions were carried with to afford pentacyclic complexes 48 and 49. Demetallation of 48, subsequent elaboration of the oxazolidinoyl diene, and intramolecular aza-Michael gave fused N-Ts pyrrolidine 54 as a single diastereomer.
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