Regio‐ and Diastereoselective and Enantiospecific Metal‐Free C(sp³)H Arylation: Facile Access to Optically Active 5‐Aryl 2,5‐Disubstituted Pyrrolidines

Abstract

Optically active 5-aryl 2,5-disubstituted pyrrolidines are the principal structural moiety of many bioactive compounds including natural products and catalysts for asymmetric synthesis. A highly regio- and diastereoselective and enantiospecific method for direct C-H arylation of aliphatic amine has been developed. Structurally diverse enantiopure arylated pyrrolidines were synthesized from commercially available starting materials, through a single-step three-component reaction under metal- and oxidant-free conditions. Furthermore, the complex analogous structure of CCK antagonist RP 66803 and angiotensin-converting enzyme inhibitors was easily constructed using the synthesized arylated pyrrolidine derivative. Detailed theoretical calculations (M06-2X/TZVPP/SMD//M06-2X/6-31+G(d,p) level) were also carried to investigate the mechanism and high level of stereocontrol involved in this direct sp(3) C-H arylation reaction. Preference for a given regio- and stereoselectivity in the arylated product can be explained through elucidation of the mechanism for dehydration, generating azomethine ylide, and for the final re-aromatization step. The calculated energies reveals that the re-aromatization step is essentially rate determining, accompanying an activation barrier of Δ(≠) G=25.6 kcal mol(-1) .

Understanding the Reactivity and Selectivity of Fluxional Chiral DMAP‐Catalyzed Kinetic Resolutions of Axially Chiral Biaryls

“…[28] Overall, the data reveal ar ich interplay of non-covalent interactions that underlie nearly all aspects of this reaction. [91,[114][115][116][117][118] First, even though the catalysti tself is highly fluxional, exhibiting two interconverting conformations at room temperature, the active, acylated form of the catalyst is conformationally rigid due to p···p + interactions. This rigidity,c om- bined with an etwork of other non-covalenti nteractions, underlies the high degree of stereoselectivity.O ur data also support an ucleophilic mode of catalysis,w hich is rendered more favorable than alternative, base-catalyzed mechanisms due to the impacts of non-covalenti nteractions.F inally,w es howed near quantitative reproduction of experimental selectivities for six substrates and developed as tereochemical model of this reactioni nw hich p···p + interactions, ah ydrogen-bonding network involving the counteranion, and ak ey CH···O interaction between the a-hydrogens of substituents independently control the stereoselectivity.T hese latteri nteractions can be used to explain the selectivity of other substrates, including those that have not yet been tested experimentally.W hile similar non-covalent interactions have been shown to play important roles in KRs, [32,33,81,119] the reaction in Scheme 1i su nique in that these interactions control essentially all aspects of the reaction:t he rigidity of the active catalyst, the preferred mechanism, and the stereoselectivity.T his rich interplay of competing non-covalent interactions underscoret he resemblanceo fs ome organocatalytic systemst oe nzymes, in which selectivity,r eactivity,a nd mechanism are all modulated through the subtle effects of myriad stabilizing non-covalent interactions.…”

Classical-Reaction-Driven Stereo- and Regioselective C(sp3)-H Functionalization of Aliphatic Amines

“…Various naphthol and phenol derivatives including hydroxycoumarin and chrysin were reacted with prolinol to obtain the corresponding 5-aryl 2,5-disubstituted pyrrolidine derivatives with very good yields (up to 90%) and excellent enantiopurity (up to >99%). [24] In all cases, retention of the chiral center occurred to produce only the syn diastereomer. Similar reactivity was observed for 2-methylpyrrolidine and prolinol methyl ether.…”

“…The proposed stereoselective arylation was tested on the methyl and ethyl esters of proline. [24] Unfortunately, like proline, its ester derivatives also underwent decarboxylation to provide the corresponding arylated pyrrolidine. However, prolinol provided the desired arylated product 34 as a single syn regioisomer with excellent enantiopurity.…”

“…Therefore, facial approach of the aryl group can be directed by tuning the bulkiness of R, CHAr□Ar□ and Ar. The proposed stereoselective arylation was tested on the methyl and ethyl esters of proline 24. Unfortunately, like proline, its ester derivatives also underwent decarboxylation to provide the corresponding arylated pyrrolidine.…”

“…Fluorenone imine 33 was found to be the best activator for this regio‐ and diastereoselective and enantiospecific direct arylation reaction, whereas other related carbonyl compounds like anthrone and anthraquinone were ineffective. Various naphthol and phenol derivatives including hydroxycoumarin and chrysin were reacted with prolinol to obtain the corresponding 5‐aryl 2,5‐disubstituted pyrrolidine derivatives with very good yields (up to 90%) and excellent enantiopurity (up to >99%) 24. In all cases, retention of the chiral center occurred to produce only the syn diastereomer.…”