we prepared a collection of racemic lactam substrates ( i.e. , 1a - h ) for palladium - catalyzed decarboxylative allylic alkylation and performed a reactivity and enantioselectivity screen across an array of solvents employing two chiral ligands , ( s)-t - buphox and ( s)-(cf3)3-t - buphox . preliminary data suggested that electron rich n - alkyl lactam derivatives were poor substrates for decarboxylative alkylation due to low reactivity . we screened these substrates across a series of four solvents ( thf , mtbe , toluene , and 2:1 hexane  toluene ) while employing two electronically distinct ligands on pd . the results of this broad screen were highly encouraging ( figure 2 , see also supplementary information ) . reactivity across all substrates with either ligand was uniformly good , as all of the compounds were completely converted to the desired product . strikingly , as the n - substituent group was changed from sulfonyl to carbamoyl to acyl functionalities , the enantioselectivity rose from nearly zero to nearly perfect . there was also a substantial difference between the two ligands , and electron poor ( s)-(cf3)3-t - buphox was clearly the superior choice . as the solvent system became less polar , a distinct increase in enantiomeric excess was observed , however , this effect was substantially less pronounced for reactions employing the electron poor ligand and for reactions varying the n - substituent . ultimately , with the n - benzoyl group ( bz ) on the substrate ( i.e. , 1h ) and ( s)-(cf3)3-t - buphox as ligand , the reaction produced lactam 2h in > 96% ee in each of the four solvents . with these stunning results in hand , we initiated efforts to investigate the reaction scope by exploring a range of substituted n - acyl lactam derivatives ( figure 3 ) . importantly , reproducing the screening reaction on preparative scale furnishes n - bz piperidinone 2h in 85% isolated yield and 99% ee ( figure 3b ) . alteration of the c()-group to other alkyl and functionalized alkyl units ( e.g. , ch2ch3 and ch2ph ) , as well as to moieties possessing additional acidic protons ( e.g. , ch2ch2co2me and ch2ch2cn ) leads to high yields of lactams 36 in uniformly excellent enantioenrichment ( 99% ee ) . common silyl protecting groups are tolerated in the transformation and lactam 7 is furnished in 85% yield and 96% ee . substituted allyl groups can be incorporated , however only at c(2 ) , leading to products such as methallyl lactam 8 and chloroallyl lactam 9 in good yield and outstanding enantioselectivity ( 95% ee ) . beyond piperidinones , we have demonstrated that pyrrolidinones and caprolactams are also exceptional substrate classes , furnishing heterocycles 1013 in excellent yield and ee ( figure 3c ) . additionally , morpholine - derived product 14 , containing a c()-tetrasubstituted tertiary center , is produced in 91% yield and 99% ee . c()-fluoro substitution is readily introduced into the 1,3-dicarbonyl starting material and is viable in the enantioselective reaction leading to fluoropyrrolidinone 12 ( 86% yield , 98% ee ) and fluoropiperidinone 15 ( 89% yield , 99% ee ) . moreover , n - bz glutarimides serve as outstanding substrates smoothly reacting to provide cyclic imides 16 and 17 in high yield and enantioselectivity . finally , alteration of the n - bz group is possible ( figure 3d ) , giving lactams with an n - acetyl group ( 18 ) , n - carbamates ( 19 and 20 ) , and a variety of n - aroyl derivatives ( 2123 ) . the enantioenriched lactam products formed by our catalytic asymmetric alkylation chemistry are envisioned to be of broad utility in synthetic chemistry . to illustrate this point , lactam 3 can be transformed into the aspidosperma alkaloid ( + ) -quebrachamine by modification of a previous route that employed a chiral auxiliary . additionally , cleavage of the n - bz group of lactam 3 produces chiral lactam 24 , a compound previously used as a racemate in the synthesis of rhazinilam , a microtubule - disrupting agent that displays similar cellular characteristics to paclitaxel ( figure 4 ) . finally , reduction of lactam 24 produces the c(3)-quaternary piperidine ( 25 ) and demonstrates access to the corresponding amine building blocks . in summary , we have reported the first method for catalytic enantioselective alkylation of monocyclic 5- , 6- , and 7-membered lactam enolate derivatives to form -quaternary and -tetrasubstituted tertiary lactams . the reaction discovery process was enabled by parallel screening of reaction parameters and led to the identification of a sterically and electronically tuned system for highly enantioselective alkylation . we have applied this method to the catalytic asymmetric synthesis of key intermediates previously employed for the construction of aspidosperma alkaloids . finally , the asymmetric products formed in this investigation are envisioned to be widely useful as building blocks for the preparation of range of nitrogen containing heterocycles in materials science , medicinal chemistry and natural products synthesis .
the enantioselective synthesis of nitrogen - containing heterocycles ( n - heterocycles ) represents a substantial chemical research effort and resonates across numerous disciplines including the total synthesis of natural products and medicinal chemistry . in this manuscript 
 , we describe the highly enantioselective palladium - catalyzed decarboxylative allylic alkylation of readily available lactams to form 3,3,-disubstituted pyrrolidinones , piperidinones , caprolactams , and structurally related lactams . given the prevalence of quaternary n - heterocycles in biologically active alkaloids and pharmaceutical agents , we envision that our method will provide a synthetic entry into the de novo asymmetric synthesis of such structures . as an entry for these investigations 
 we demonstrate how the described catalysis affords enantiopure quaternary lactams that intercept synthetic intermediates previously employed in the synthesis of the aspidosperma alkaloids quebrachamine and rhazinilam , but that were previously only available by chiral auxiliary approaches or as racemic mixtures .