Asymmetric Allylic Alkylation in Combination with Ring-Closing Metathesis for the Preparation of Chiral N-Heterocycles

Abstract

Asymmetric copper-catalyzed allylic substitution with methylmagnesium bromide is employed in combination with ring-closing olefin metathesis or ene-yne metathesis to achieve the synthesis of chiral, unsaturated nitrogen heterocycles. The resulting six-to eight-membered chiral heterocycles are accessible in high yields and with excellent enantioselectivities.Nitrogen-containing heterocycles are ubiquitous in naturally occurring compounds, such as alkaloids, but are also key structural features in many biologically active products. 1-4 Among these, nitrogen heterocycles with various ring sizes bearing stereogenic centers are frequently observed. 5-10 For example, poisonous frogs produce a variety of biologically active chiral piperidines featuring methyl substituents at the stereocenters. 11,12 These structures represent interesting targets for synthesis, [13][14][15][16] imposing particular challenges with regard to the construction of the stereogenic centers with high selectivity. One approach that has been frequently exploited is the use of ring-closing metathesis for the construction of N-heterocycles, 14,[17][18][19] which has among

Recent Advances in the Application of Ring-Closing Metathesis for the Synthesis of Unsaturated Nitrogen Heterocycles

“…Another advance in the metathesis-mediated formation of nitrogen heterocycles is the strategic implementation of this synthetic tool to access highly desired chiral nitrogen heterocycles. 37 One such example came from Feringa and co-workers, 38 who developed a copper-catalyzed method for the asymmetric substitution of allylic bromides with Grignard reagents through the use of chiral ferrocene-based bisphosphine ligands L1. Recognizing that this method produced terminal olefins, they utilized it to convert the allyl bromides 26 and 29 into the chiral olefin metathesis substrate 27 and chiral ene-yne metathesis substrate 30, which were then subjected to metathesis conditions to obtain access to enantioenriched products 28 and 31, respectively (Scheme 6).…”

Evolution of Strategies in Paraconic Acids Synthesis

“…al. [68] achieved the total synthesis of (À )nephrosteranic acid and (À )-roccellaric acid by hetero-allylic asymmetric allylation (h-AAA) and ring-closing metathesis protocol [69] (Scheme 40). The allylic ester 202 was obtained from 200 and 201 following reported procedure.…”

Rapid synthesis of bicyclic lactones via palladium-catalyzed aminocarbonylative lactonizations

“…Starting materials S1 [1] , S2 [2] , S3 [3] are prepared according to the previously reported procedures.…”