we initiated our study by investigating the reactivity of substrates derived from geraniol under our previously reported hydroamination conditions ( table 1 ) .
a variety of leaving groups , including alkoxy , silyloxy , carbonate , phosphate , and carboxylates , provided the desired product with high levels of enantioselectivity ( entries 16 ) .
the stable and readily - prepared allylic benzoate was found to provide the desired product in high yield .
incorporation of an electron - withdrawing group on the benzoate to increase the nucleofugality of the leaving group was found instead to significantly reduce the yield ( entry 7 ) .
in contrast , the use of electron - donating substituents on the benzoate , such as a 4-dimethylamino group ( entry 8) , produced near quantitative yield of the -chiral amine ( s)-3a . an evaluation of ligands revealed dtbm - segphos to give superior results compared to all others tested ( entry 8 vs. entries 912 ) . under the optimized conditions ,
the scope of allylic benzoates that could be transformed was investigated ( table 2 ) .
a variety of substrates were converted into the corresponding chiral amines with high enantioselectivity and in moderate to excellent yields .
a variety of 3,3-dialkyl substituted allylic 4-(dimethylamino)benzoates were first investigated ( table 2a ) . when the isomeric nerol - derived 4-(dimethylamino)benzoate containing a ( z)-configured allylic double bond was exposed to the optimized conditions , the opposite enantiomer ( r)-3a was obtained with slightly lower yield and enantioselectivity ( 3a vs. 3a ) .
bulky groups at the 3-position of the allylic system were tolerated and provided chiral amine products in moderate to good yields and exceptionally high enantioselectivity ( 3b  d ) .
a variety of functional groups were readily accommodated , including a ketal ( 3d ) , an aryl group ( 3e ) , a sulfonamide ( 3f ) , an alkyl chloride ( 3 g ) , ethers ( 3h , 3j ) , an ester ( 3k ) , a free alcohol ( 3i ) and an unprotected secondary amine ( 3l ) .
when an aldehyde - containing substrate was employed , not surprisingly , reduction to the alcohol was observed to produce the amino alcohol product ( 3 m ) .
protected amino acid - containing substrate 1n could be transformed to -chiral amine ( 3n , 3n ) without carbonyl reduction or epimerization , reflecting the mildness of the reaction conditions . additionally , 3-aryl - substituted allylic benzoates could also undergo reductive relay hydroamination ( table 2b ) .
substrates bearing electron - rich ( 3p , 3u ) and electron - poor ( 3qs ) aryl substituents were tolerated . a 3-thienyl substituted substrate
( 3 t ) , as well as a chromane - derived bicyclic substrate ( 3u ) , were also compatible with these conditions .
likewise , a silyl - substituted allylic benzoate ( table 3a , 1v ) was converted into the -chiral silylamine ( 3v ) .
in addition to 3,3-disubstituted allylic benzoates , this protocol was also applicable to racemic 1-aryl-3-alkyl - substituted allylic benzoate ( table 3a , 1w ) , which reacted in an enantioconvergent manner to provide the -branched chiral amine product ( 3w ) .
we reasoned that substrates containing an appropriate duo of vicinal allylic and homoallylic substituents would undergo sequential insertion / elimination sequences before undergoing hydroamination .
such a cascade process would lead to the formation of -chiral amines . to test this idea , allylic epoxide ( table 3a , 1x ) and allylic acetonide ( table 3a , 1y ) substrates
as predicted , racemic epoxide 1x reacted in an enantioconvergent manner to provide the -chiral amine 3x with high enantioselectivity .
likewise , enantioenriched acetonide 1y also underwent the cascade hydroamination process to afford either enantiomer ( 3y , 3y ) of the -chiral amine product under catalyst control .
the successful extension of the reductive relay hydroamination protocol to this complex cascade serves to illustrate the flexibility and generality of this strategy . in some cases ,
the free allylic alcohols could be used directly in the current catalytic system ( table 3b ) . by adding an extra equivalent of silane
the use of the free alcohol did not affect the enantioselectivity of the process , although the yields obtained in this extended cascade were somewhat diminished relative to the use of the corresponding ( 4-dimethylamino)benzoate esters ( table 2a , 3a , 3e , 3 g ) . to demonstrate the scalability of this process
under slightly modified reaction conditions , a catalyst loading of 0.5 mol% proved sufficient for a reaction on this scale ( table 3c ) . as first observed by lipshutz ,
the inclusion of triphenylphosphine as an additive led to improved stability of the active catalyst , allowing higher catalyst turnover numbers to be attained without any significant effect on the enantioselectivity .
the utility of this catalytic system was further demonstrated through the use of a number of hydroxylamine esters as aminating reagents ( table 4 ) . despite the presence of a stereocenters adjacent to the nitrogen atom of the electrophilic aminating reagent , the hydroamination reaction proceeded in a completely catalyst - controlled manner ( 4a , 4a ) to form a minimally differentiated stereocenter ( methyl vs ethyl ) with excellent selectivity . in addition ,
acyclic ( 4b ) , cyclic ( 4d ) , and sterically hindered ( 4c ) hydroxylamine esters could be utilized , as could one containing a carbamate protecting group ( 4d ) .
furthermore , substrates containing heterocycles , such as pyridine ( 4e ) , pyrimidine ( 4f ) , benzothiadiazole ( 4 g ) , and piperazine ( 4f , 4 g ) were handled without event .
finally , duloxetine , a drug used to treat depression and generalized anxiety disorder , could be functionalized with complete control of diastereoselectivity ( 4h , 4h ) , demonstrating the potential utility of this protocol in the late - stage functionalization of complex molecules .
we investigated the reactivity of substrates containing multiple c  c double bonds and found that the hydroamination protocols described here and previously exhibited excellent chemoselectivity when different types of double bonds were present . in general , styrenyl and terminal double bonds both react in preference to trisubstituted allylic esters , and this difference in reactivity was exploited for sequential chemoselective hydroamination .
for example , sequential hydroamination of diolefin 5 containing a trisubstituted allylic ester and terminal olefin with two different aminating reagents resulted in the formation of diamine 7 with excellent chemo- and enantioselectivity ( fig .
furthermore , by simultaneously taking advantage of the difference in reactivity between mono- and dialkyl aminating reagents , as well as between styrenyl double bonds and trisubstituted allylic esters , a three component coupling of two aminating reagents with diolefin 8 could be achieved with good chemo- , diastereo- , and enantioselectivity ( fig .
importantly , this strategy can also be employed to form all four stereoisomers of a diamine product in uniformly high stereoselectivity depending on the enantiomer of chiral ligand used in each step ( 17:1 to 28:1 dr , > 99% ee ) ( fig . 2c , 11a - d ) . in summary , we have developed a cuh - catalysed reductive relay process to access - and -chiral amines .
this method allows for the installation of a stereocenter and a distal amino group in a single operation under mild conditions .
excellent enantio- , regio- , and chemoselectivity were observed for a broad range of substrates with high functional group tolerance .
furthermore , this system was found to be applicable to the late - stage modification of a pharmaceutical agent and was suitable for large - scale synthesis .
lastly , we also demonstrated that the cuh - catalysed protocol could be applied to the chemoselective sequential amination of substrates containing more than one olefin .
the expansion of this relay strategy to other areas including drug and natural product synthesis is currently underway and will be reported in due course .
we initiated our study by investigating the reactivity of substrates derived from geraniol under our previously reported hydroamination conditions ( table 1 ) .
a variety of leaving groups , including alkoxy , silyloxy , carbonate , phosphate , and carboxylates , provided the desired product with high levels of enantioselectivity ( entries 16 ) .
the stable and readily - prepared allylic benzoate was found to provide the desired product in high yield .
incorporation of an electron - withdrawing group on the benzoate to increase the nucleofugality of the leaving group was found instead to significantly reduce the yield ( entry 7 ) .
in contrast , the use of electron - donating substituents on the benzoate , such as a 4-dimethylamino group ( entry 8) , produced near quantitative yield of the -chiral amine ( s)-3a . an evaluation of ligands revealed dtbm - segphos to give superior results compared to all others tested ( entry 8 vs. entries 912 ) .
under the optimized conditions , the scope of allylic benzoates that could be transformed was investigated ( table 2 ) .
a variety of substrates were converted into the corresponding chiral amines with high enantioselectivity and in moderate to excellent yields .
a variety of 3,3-dialkyl substituted allylic 4-(dimethylamino)benzoates were first investigated ( table 2a ) . when the isomeric nerol - derived 4-(dimethylamino)benzoate containing a ( z)-configured allylic double bond was exposed to the optimized conditions , the opposite enantiomer ( r)-3a was obtained with slightly lower yield and enantioselectivity ( 3a vs. 3a ) .
bulky groups at the 3-position of the allylic system were tolerated and provided chiral amine products in moderate to good yields and exceptionally high enantioselectivity ( 3b  d ) .
a variety of functional groups were readily accommodated , including a ketal ( 3d ) , an aryl group ( 3e ) , a sulfonamide ( 3f ) , an alkyl chloride ( 3 g ) , ethers ( 3h , 3j ) , an ester ( 3k ) , a free alcohol ( 3i ) and an unprotected secondary amine ( 3l ) .
when an aldehyde - containing substrate was employed , not surprisingly , reduction to the alcohol was observed to produce the amino alcohol product ( 3 m ) .
protected amino acid - containing substrate 1n could be transformed to -chiral amine ( 3n , 3n ) without carbonyl reduction or epimerization , reflecting the mildness of the reaction conditions . additionally , 3-aryl - substituted allylic benzoates could also undergo reductive relay hydroamination ( table 2b ) .
substrates bearing electron - rich ( 3p , 3u ) and electron - poor ( 3qs ) aryl substituents were tolerated . a 3-thienyl substituted substrate
( 3 t ) , as well as a chromane - derived bicyclic substrate ( 3u ) , were also compatible with these conditions .
likewise , a silyl - substituted allylic benzoate ( table 3a , 1v ) was converted into the -chiral silylamine ( 3v ) .
in addition to 3,3-disubstituted allylic benzoates , this protocol was also applicable to racemic 1-aryl-3-alkyl - substituted allylic benzoate ( table 3a , 1w ) , which reacted in an enantioconvergent manner to provide the -branched chiral amine product ( 3w ) .
we reasoned that substrates containing an appropriate duo of vicinal allylic and homoallylic substituents would undergo sequential insertion / elimination sequences before undergoing hydroamination .
such a cascade process would lead to the formation of -chiral amines . to test this idea , allylic epoxide ( table 3a , 1x ) and allylic acetonide ( table 3a , 1y ) substrates
as predicted , racemic epoxide 1x reacted in an enantioconvergent manner to provide the -chiral amine 3x with high enantioselectivity .
likewise , enantioenriched acetonide 1y also underwent the cascade hydroamination process to afford either enantiomer ( 3y , 3y ) of the -chiral amine product under catalyst control .
the successful extension of the reductive relay hydroamination protocol to this complex cascade serves to illustrate the flexibility and generality of this strategy . in some cases ,
the free allylic alcohols could be used directly in the current catalytic system ( table 3b ) . by adding an extra equivalent of silane
the use of the free alcohol did not affect the enantioselectivity of the process , although the yields obtained in this extended cascade were somewhat diminished relative to the use of the corresponding ( 4-dimethylamino)benzoate esters ( table 2a , 3a , 3e , 3 g ) . to demonstrate the scalability of this process
under slightly modified reaction conditions , a catalyst loading of 0.5 mol% proved sufficient for a reaction on this scale ( table 3c ) . as first observed by lipshutz ,
the inclusion of triphenylphosphine as an additive led to improved stability of the active catalyst , allowing higher catalyst turnover numbers to be attained without any significant effect on the enantioselectivity .
the utility of this catalytic system was further demonstrated through the use of a number of hydroxylamine esters as aminating reagents ( table 4 ) . despite the presence of a stereocenters adjacent to the nitrogen atom of the electrophilic aminating reagent , the hydroamination reaction proceeded in a completely catalyst - controlled manner ( 4a , 4a ) to form a minimally differentiated stereocenter ( methyl vs ethyl ) with excellent selectivity .
in addition , acyclic ( 4b ) , cyclic ( 4d ) , and sterically hindered ( 4c ) hydroxylamine esters could be utilized , as could one containing a carbamate protecting group ( 4d ) .
furthermore , substrates containing heterocycles , such as pyridine ( 4e ) , pyrimidine ( 4f ) , benzothiadiazole ( 4 g ) , and piperazine ( 4f , 4 g ) were handled without event .
finally , duloxetine , a drug used to treat depression and generalized anxiety disorder , could be functionalized with complete control of diastereoselectivity ( 4h , 4h ) , demonstrating the potential utility of this protocol in the late - stage functionalization of complex molecules .
we investigated the reactivity of substrates containing multiple c  c double bonds and found that the hydroamination protocols described here and previously exhibited excellent chemoselectivity when different types of double bonds were present . in general , styrenyl and terminal double bonds both react in preference to trisubstituted allylic esters , and this difference in reactivity was exploited for sequential chemoselective hydroamination . for example , sequential hydroamination of diolefin 5 containing a trisubstituted allylic ester and terminal olefin with two different aminating reagents resulted in the formation of diamine 7 with excellent chemo- and enantioselectivity ( fig .
furthermore , by simultaneously taking advantage of the difference in reactivity between mono- and dialkyl aminating reagents , as well as between styrenyl double bonds and trisubstituted allylic esters , a three component coupling of two aminating reagents with diolefin 8 could be achieved with good chemo- , diastereo- , and enantioselectivity ( fig .
importantly , this strategy can also be employed to form all four stereoisomers of a diamine product in uniformly high stereoselectivity depending on the enantiomer of chiral ligand used in each step ( 17:1 to 28:1 dr , > 99% ee ) ( fig . 2c , 11a - d ) .
in summary , we have developed a cuh - catalysed reductive relay process to access - and -chiral amines .
this method allows for the installation of a stereocenter and a distal amino group in a single operation under mild conditions .
excellent enantio- , regio- , and chemoselectivity were observed for a broad range of substrates with high functional group tolerance .
furthermore , this system was found to be applicable to the late - stage modification of a pharmaceutical agent and was suitable for large - scale synthesis .
lastly , we also demonstrated that the cuh - catalysed protocol could be applied to the chemoselective sequential amination of substrates containing more than one olefin .
the expansion of this relay strategy to other areas including drug and natural product synthesis is currently underway and will be reported in due course .
to an oven - dried 4 ml screw - cap vial equipped with a magnetic stir bar was added cu(oac)2 ( 2.05.0 mol% ) and ( r)-dtbm - segphos ( 2.25.5 mol% ) .
the tube was sealed with a teflon - lined screw cap , evacuated , and backfilled with argon ( this process was repeated a total of three times ) by piercing with a needle attached to a schlenk line .
anhydrous thf ( 1.0 ml ) was added by syringe , and the mixture was stirred for 10 min at room temperature . at this time diethoxymethylsilane
( 560720 l , 3.54.5 mmol , 3.54.5 equiv ) was added by syringe and stirring was continued for another 5 min . into a separate oven - dried medium - sized screw - cap test tube
was added -disubstituted allylic benzoate ( 1.0 mmol , 1.0 equiv ) and o - benzoyl - n , n - dibenzylhydroxylamine ( 381 mg , 1.2 mmol , 1.2 equiv ) .
the tube was sealed with a teflon - lined screw cap , evacuated , and backfilled with argon ( this process was repeated a total of three times ) .
the catalyst solution was then transferred via syringe to the reaction tube containing the substrates , and the reaction mixture was stirred at 4050 c for up to 36 h. after the reaction was complete , the reaction mixture was allowed to cool to room temperature and was directly filtered through a short pad of silica gel ( using ethyl acetate in hexanes ) to give the crude product .
1,1,2,2-tetrachloroethane ( 84 mg , 0.50 mmol ) was added as internal standard for h nmr analysis of the crude material .
the product was purified by chromatography on silica gel or by acid - base extraction as indicated for each substrate .
the enantiomeric excesses ( % ee ) were determined by hplc analysis using chiral stationary phases as described in the supplementary information .
the x - ray crystallographic coordinate for 3 g is deposited at the cambridge crystallographic data centre ( ccdc ) under deposition number ccdc 1413400 .
to an oven - dried 4 ml screw - cap vial equipped with a magnetic stir bar was added cu(oac)2 ( 2.05.0 mol% ) and ( r)-dtbm - segphos ( 2.25.5 mol% ) .
the tube was sealed with a teflon - lined screw cap , evacuated , and backfilled with argon ( this process was repeated a total of three times ) by piercing with a needle attached to a schlenk line .
anhydrous thf ( 1.0 ml ) was added by syringe , and the mixture was stirred for 10 min at room temperature . at this time diethoxymethylsilane
( 560720 l , 3.54.5 mmol , 3.54.5 equiv ) was added by syringe and stirring was continued for another 5 min . into a separate oven - dried medium - sized screw - cap test tube
was added -disubstituted allylic benzoate ( 1.0 mmol , 1.0 equiv ) and o - benzoyl - n , n - dibenzylhydroxylamine ( 381 mg , 1.2 mmol , 1.2 equiv ) .
the tube was sealed with a teflon - lined screw cap , evacuated , and backfilled with argon ( this process was repeated a total of three times ) .
the catalyst solution was then transferred via syringe to the reaction tube containing the substrates , and the reaction mixture was stirred at 4050 c for up to 36 h. after the reaction was complete , the reaction mixture was allowed to cool to room temperature and was directly filtered through a short pad of silica gel ( using ethyl acetate in hexanes ) to give the crude product .
1,1,2,2-tetrachloroethane ( 84 mg , 0.50 mmol ) was added as internal standard for h nmr analysis of the crude material .
the product was purified by chromatography on silica gel or by acid - base extraction as indicated for each substrate .
the enantiomeric excesses ( % ee ) were determined by hplc analysis using chiral stationary phases as described in the supplementary information .
the x - ray crystallographic coordinate for 3 g is deposited at the cambridge crystallographic data centre ( ccdc ) under deposition number ccdc 1413400 .
 amines with remote stereocenters ( stereocenters that are three or more bonds away from the c  
 n bond ) are important structural elements in many pharmaceutical agents and natural products . however , previously reported methods to prepare these compounds in an enantioselective manner are indirect and require multistep synthesis . here 
 we report a copper hydride - catalysed , enantioselective synthesis of - or -chiral amines from readily available allylic alcohols , esters , and ethers using a reductive relay hydroamination strategy ( a net reductive process in which an amino group is installed at a site remote from the original c  c double bond ) . 
 the protocol was suitable for substrates containing a wide range of functional groups and provided remote chiral amine products with high levels of regio- and enantioselectivity . 
 sequential amination of substrates containing several carbon - carbon double bonds could be achieved , demonstrating the high chemoselectivity of this process . 
Results and discussion
Reaction development and optimization
Substrate scope
Applications of chemoselectivity
Conclusions
Methods
General procedure for reductive relay hydroamination
Supplementary Material