Brønsted Acid Catalyzed Asymmetric Hydroamination of Alkenes: Synthesis of Pyrrolidines Bearing a Tetrasubstituted Carbon Stereocenter

Abstract

The first highly enantioselective Brønsted acid catalyzedi ntramolecular hydroamination of alkenes enables the efficient construction of as eries of chiral (spirocyclic) pyrrolidines with an a-tetrasubstituted carbon stereocenter with excellent functional group tolerance.Aunique feature of this strategy is the use of at hiourea group acting as both the activating and the directing group through cooperative multiple hydrogen bonding with aB r ø nsted acid and the double bond. The utility of this method is highlighted by the facile construction of chiral synthetic intermediates and important structural motifs that are widely found in organic synthesis.Chiral amines bearing an a-tetrasubstituted carbon stereocenter are important structural motifs in numerous biologically active compounds and potent pharmaceutical agents. [1] Consequently,m ethods that enable their asymmetric construction are in great demand, [1,2] as this process still remains af ormidable synthetic challenge because of the difficulties associated with overcoming the steric hindrance and controlling the correct orientation of the four attached substituents. Recent years have witnessed as ignificant increase in the utilization of asymmetric intramolecular hydroamination reactions of alkenes as ah ighly valuable synthetic approach for the construction of chiral azaheterocycles with applications as biologically active compounds and powerful organocatalysts or ligands.[3] Numerous elegant metal-catalyzed asymmetric intramolecular olefin hydroaminations have been developed that either proceed by olefin activation through coordination to increase the electrophilicity of the olefin or by N À Hb ond activation to increase the nucleophilicity of the amine. [3,4] Despite these studies,amethod with which the more challenging hydroamination products that bear ac hiral quaternary center can be obtained with high enantioselectivity has not been reported to date. [5] On the other hand, unlike the well-established metalcatalyzed counterparts,t he organocatalytic hydroamination of alkenes still represents aformidable challenge.[3d,6] Thefirst enantioselective variant of this transformation, which involved the use of ac hiral phosphoric acid as the catalyst, resulted in poor stereocontrol with up to 17 % ee.[6a] However, only recently Toste et al. achieved asignificant breakthrough by using ad ithiophosphoric acid to enable the hydroamination of dienes and allenes.T heir approach involved the transient covalent attachment of achiral leaving group to the allylic system to obtain high enantioselectivities, [3d,6b] which was supported by the findingt hat the presence of the sulfur atom in the catalyst was necessary because the oxygenated analogues of the dithiophosphoric acid were less efficient. Alternatively,J acobsen and co-workers have developed asymmetric thiourea-catalyzed Cope-type alkene hydroamination reactions that proceed through dipolar transition states with multiple hydrogen bonding interactions.[6c] Although these pioneering reports provide str...

Catalytic asymmetric radical aminoperfluoroalkylation and aminodifluoromethylation of alkenes to versatile enantioenriched-fluoroalkyl amines

“…1). Several challenges are associated with the development of this reaction, such as (1) stoichiometric amount of strong achiral Brønsted acid HCl would be generated, which might not only result in strong background reactions against the chiral acid-catalysed process but also lead to competitive hydroamination of alkene as previous report40; (2) it is not easy to search for a uniform catalytic system broadly applicable to a variety of electronically distinct fluoroalkylsulfonyl chlorides, such as perfluoroalkyl, trifluoromethyl, difluoroacetyl and even difluoromethyl radical precursors. Most notable is that difluoromethylsulfonyl chloride is only used as the suitable radical source for the intramolecular aminofluoroalkylation reaction in racemic form under photoredox catalysis37.…”

Copper‐Catalyzed Intramolecular Radical Amination of Tertiary C(sp3)−H Bonds to Access α‐Quaternary Pyrrolidines

“…Regarding the mechanism of this reaction, we initially conducted a control experiment using terminal alkene by‐product BP2 (from Table 1) as the substrate under otherwise standard reaction conditions and failed to afford product 1 (Scheme 5a). This experiment excluded the formation of the amination products directly from intramolecular hydroamination of alkenes [8a,b] . In addition, a completely inhibition effect was observed when TEMPO was added into the model reaction and the formation of TEMPO‐trapped product 23 was detected by high‐resolution mass spectrometry (HRMS) analysis (Scheme 5b).…”

Electrophilic Aminating Agents in Total Synthesis

“…Hydroamination of alkenes and alkynes is ap owerful strategy for the formation of CÀNb onds.Such processes are complementary to aza-Heck reactions because the product is generated at alower unsaturation level. Avariety of strategies have emerged for effecting alkene and alkyne hydroaminations,i ncluding metal- [198][199][200][201][202][203][204][205][206][207][208][209][210][211] and Bronsted acid catalyzed [212][213][214] methods,r adical-mediated processes [215][216][217][218][219] and pericyclic-based methods. [220,221] Conventional hydroamination protocols are designed to enable the addition of an amine NÀHbond across an alkene or alkyne p-bond.…”