the catalytic functionalization 
 of aldehyde c  h bonds represents 
 a mild and atom - economical approach to prepare esters . while there has been much progress in developing hydroacylation 
 of aldehydes , the hydroacylation of ketones is relatively unexplored and warrants 
 attention due to its potential for constructing chiral esters .
our laboratory has demonstrated intramolecular 
 ketone hydroacylations , including the first examples of enantioselective 
 lactonizations . due to the propensity 
 of nonchelating aldehydes to engage in decarbonylation , tishchenko dimerizations , and aldol 
 condensations , intermolecular hydroacylations 

are considerably more challenging . herein , we report the 
 design and development of the first enantioselective intermolecular 
 ketone hydroacylation .
we imagined a novel cross - coupling between 
 a broad range of aldehydes 1 and ketones bearing a directing 
 group ( dg ) 2 ( scheme 1 ) . on the 
 basis of previous studies
, 
 we proposed that this functional group would promote preferential 
 ketone binding to the rh(i ) center and favor chemoselective 
 cross - coupling over aldehyde dimerization or decarbonylation . in the presence of a suitable 
 bidentate phosphine ligand , coordination of ketone 2 to 
 rh , followed by oxidative addition of aldehyde 1 ,
would 
 generate coordinatively saturated rh(iii)-hydride i. 
 octahedral complex i has a lower propensity to undergo 
 carbonyl deinsertion , a process that deactivates the rhodium catalyst .
ketone insertion into acyl - rh(iii)-hydride i would lead to rh(iii)-alkoxide ii , followed 
 by reductive elimination to give ester 3 with concomitant 
 regeneration of the rh(i ) catalyst . in comparison to conventional 
 approaches to ester synthesis , this catalytic method obviates the 
 need for prefunctionalization of the acyl component and is amenable 
 to enantioselective synthesis of esters .
to test our hypothesis , 
 we chose 
 hydrocinnamaldehyde ( 1a ) and -ketoamide 2a as model substrates ( chart 1 ) . a 
 number of rh - bis(phosphine )
catalysts were examined because previous 
 studies in our lab had demonstrated that these complexes promote intramolecular 
 ketone hydroacylation . after studying various ligands , 
 we found rh(i)-josiphos catalysts most promising .
commercially available 
 ligand l1 provides modest yield and 13% ee . changing 
 to ligand l2 , which contains a diphenylphosphine 
 and a dialkylphosphine , results in a small improvement in enantioselectivity 
 ( 21% ee ) .
josiphos l3 containing a more -accepting 
 difurylphosphine and a -donating di - tert - butylphosphine affords the desired -acyloxyamide 3a in 46% yield and 73% ee .
we reason that this c1-symmetric ligand may facilitate the product - determining 
 hydride delivery via the trans effect ; the hydride trans to the electron - rich dialkylphosphine becomes 
 more hydridic , while the ketone trans to the -acceptor 
 becomes more prone to insertion ( scheme 2 ) .
aconditions : 1a ( 1.2 
 equiv ) , 2a ( 1 equiv ) , [ rh(cod)2]bf4 ( 0.1 equiv ) , ligand ( 0.1 equiv ) , dce , rt ( 23 c ) , 24 h. conditions : 1a ( 1.2 
 equiv ) , 2a ( 1 equiv ) , [ rh(cod)2]bf4 ( 0.1 equiv ) , ligand ( 0.1 equiv ) , dce , rt ( 23 c ) , 24 h. inspired by l3 , we created new 
 josiphos ligands to 
 study the steric influence of the phosphine substituents . in comparison 
 to commercial l3
in contrast , l5 with bulkier -accepting dibenzofurylphosphines 
 affords better results than l3 ( 65% yield , 87% ee ) .
the 
 rh - l5 catalyst shows excellent chemoselectivity with 
 no observable aldehyde dimerization .
this 
 mild rh(i)-catalyzed method offers an attractive approach to enantioenriched 
 esters that are structurally related to those obtained via the multicomponent 
 passerini reaction
. a conventional route to these motifs would involve 
 enantioselective ketone reduction followed by an additional 
 acylation step ( which generally requires stoichiometric activating 
 agents ) to obtain the -acyloxyamides .
moreover , 
 the asymmetric reduction of -ketoamides has not been 
 well - studied and remains limited in scope and/or selectivity . a method 
 featuring rh catalysis with bidentate amidophosphine
 phosphinite 
 ligands appears most promising and has been applied to reduce -ketoamides 
 with good enantioselectivity for a few aryl - substituted ketones .
there is one example of ruthenium - catalyzed 
 -ketoamide hydrogenation where excellent ee was achieved following 
 recrystallization for a bulky tert - butyl - substituted 
 ketone .
biocatalytic methods have also 
 been reported for reducing -ketoamides , although with low efficiency .
thus , with rh - l5 in hand , 
 we studied the coupling of -ketoamides 2 with 
 nonchelating aliphatic aldehydes 1 ( table 1 ) .
aryl ketones containing various substituents and substitution 
 patterns undergo hydroacylation with hydrocinnamaldehyde ( 1a ) ( entries 17 ) and hexanal ( 1b ) ( entries 
 814 ) in good to high yields ( 5398% ) and high enantioselectivities 
 ( 8496% ) .
sterically demanding 2-methylphenyl ( entries 
 2 and 9 ) , mesityl ( entries 4 and 11 ) , and 1-naphthyl ketones ( entries 
 5 and 12 ) tend to give higher conversions and selectivities even with 
 lower ( 5 mol % ) catalyst loadings , resulting in 7398% yields 
 of the -acyloxyamides with 9496% ee .
-ketoamides 
 bearing smaller aryl groups , such as 3-methylphenyl ( entries 
 3 and 10 ) , 4-chlorophenyl ( entries 6 and 13 ) , and 3,5-difluorophenyl 
 groups ( entries 7 and 14 ) , require a higher catalyst loading to provide 
 the corresponding -acyloxyamides in 5381% yields 
 and 8490% ee . conditions : 
 0.12 mmol of 1 , 0.1 mmol of 2 .
enantiomeric excess determined by 
 chiral sfc analysis . with 1.2 mmol of 1 , 
 1.0 mmol of 2 .
sterically encumbered 
 primary aldehydes ( r = i - bu and neopentyl , entries 
 1517 ) are effective coupling partners , 
 providing the desired products in high yields and ee .
using aldehyde 1d and ketone 2e , we show that the reaction can 
 also be performed on a larger scale ( 1.0 mmol , 353 mg product isolated , 
 91% yield , 93% ee ) at 5 mol % catalyst loading ( entry 16 ) .
the rhodium 
 loading can be further reduced to 3.5 mol % at elevated temperature 
 conditions ( 60 c ) , providing hydroacylation product 3p in 92% yield and 87% ee ( entry 17 ) . transforming -branched 
 cyclohexanecarboxaldehyde ( entry 18 )
requires elevated 
 temperatures ( 50 c ) to proceed and furnishes the desired -acyloxyamide 3q in 57% yield and 90% ee .
aryl aldehydes do not participate 
 in hydroacylation to any appreciable extent under the current reaction 
 conditions ( < 5% conversion ) , perhaps due to a higher barrier to 
 c  h activation .
compared to the n , n-alkylarylamide , ketones 
 containing n , n-diaryl- or dialkylamides are also less effective ( entries 19 and 
 20 ) and provide -acyloxyamides 3r and 3s with modest yields and enantioselectivities .
a cyclic 
 ketoamide is converted to 3-acyloxyindolinone 3 t ( entry 
 21 ) in 54% yield and 58% ee .
the efficacy of this reaction is improved 
 by employing l3 , which provides heterocycle 3 t in 88% yield and 69% ee .
the amide motif impacts both reactivity 
 and enantioselectivity , presumably due to a directing group role .
the absolute configuration of the products was assigned based on 
 x - ray analysis of -acyloxyamide 3c ( see supporting information ) .
the observed s - enantiomer is consistent with a 
 proposed model that invokes the trans - effect in promoting 
 the product - determining ketone insertion step ( scheme 2 ) . in this model ,
the c1-symmetric 
 ligand cooperatively renders the hydride more nucleophilic and the 
 ketone more electrophilic ( complex a ) , and thus substantially 
 favors formation of the s - stereoisomer in the case 
 of ( sp , r)-l5 . conversely , the alternative complex b is stabilized 
 by the trans - effect which would result in an increased 
 barrier to migratory insertion .
we propose the acyl 
 group to be situated on the  bottom  apical position , 
 with the less hindering n , n-disubstituted 
 amide carbonyl bound to the  top  apical position .
this 
 ligand arrangement minimizes unfavorable steric interactions between 
 the acyl group and the substituents on the phosphines and is supported 
 by dft calculations .
we find that 
 morpholine amides direct hydroacylation effectively 
 to yield cross - coupled products in good yields and enantioselectivities 
 ( table 2 )
. a similar trend is observed in which 
 ketones bearing larger aryl groups perform better , both in terms of 
 isolated yields and enantioselectivities .
phenyl ketone 4a is hydroacylated with 3,3-dimethylbutanal ( 1d ) to furnish ester 5a in 67% yield and 80% 
 ee , whereas larger mesityl and 1-naphthyl ketones give 5b and 5d in 94 and 75% yields , respectively ( 95 and 92% 
 ee ) .
other aldehydes including cyclohexanecarboxaldehyde , 
 hexanal , and hydrocinnamaldehyde are also good coupling 
 partners . the use of the morpholine amide as a directing group provides 
 a handle for further chemical manipulations .
the catalyst was hydrogenated at 
 rt for 45 min prior to adding substrates ( see supporting information ) . the rh - l5 catalyst described in this study ,
however , 
 is not effective with -keto - weinreb amide 2k ( scheme 3 ) . to this end
, we have identified an alternative 
 rhodium catalyst derived from methoxy - biphep l6 , which 
 provides good reactivity and modest enantioselectivity for this transformation 
 to yield ester 6 ( 93% , 51% ee ) .
the catalyst 
 was hydrogenated 
 at rt for 45 min prior to adding substrates ( see supporting information ) .
we initiated 
 mechanistic studies by examining the kinetics for 
 the cross - coupling of aldehyde 1d and -ketoamide 2e by h nmr .
these particular substrates were 
 chosen because their h nmr signals are distinct and no 
 products of decomposition were observed over the course of reaction 
 progress , thus simplifying data analysis .
initial rates for the hydroacylation 
 of 2e were then measured by varying the concentrations 
 of 1d , 2e , and rhodium catalyst .
these experiments 
 revealed a first - order dependence of the rate on both aldehyde 1d ( figure 1 ) and ketone 2e concentrations ( figure 2 ) .
more intriguing 
 is the observed second - order rate dependence on catalyst concentration 
 ( figure 3 ) , which suggests the involvement 
 of two rhodium species in the turnover - limiting step . a study on the 
 correlation between the enantiomeric excess of the catalyst and that 
 of the product yielded a small , positive nonlinear relationship ( figure 4 ) .
such a phenomenon 
 is consistent with the added degree of complexity in the reaction 
 mechanism as indicated by the kinetic profile .
plot of initial rates 
 ( kobs ) with respect 
 to [ aldehyde 1d ] showing first - order dependence ; [ 2e ] = 0.17 m , [ catalyst ] = 0.0083 m. plot of initial rates ( kobs ) with respect 
 to [ -ketoamide 2e ] showing first - order dependence ; 
 [ 1d ] = 0.20 m , [ catalyst ] = 0.0083 m. plot of initial rates ( kobs ) with respect 
 to [ catalyst ] showing second - order dependence ; 
 [ 1d ] = 0.20 m , [ 2e ] = 0.17 m. relationship between the enantioselectivity of the reaction 
 and 
 the ee of the chiral catalyst .
the rate data obtained from the 
 kinetics experiments allowed us 
 to calculate initial turnover frequencies . under standard catalytic 
 conditions using 5 mol % catalyst ,
1.0 equiv of ketone , and 1.2 equiv 
 of aldehyde at 25 c , the initial turnover frequency is determined 
 to be 4.8  10 s. to gain further insight into 
 the mechanism , we measured the kinetic isotope effect ( kie ) by running 
 two independent , side - by - side experiments using protio-1a and deuterated 1a - d ( scheme 4 ) .
aldehyde 1a - d was chosen 
 ( over 1d and others ) for this study due to ease of isolation . 

examination of the initial rates resulted in a kie of 2.6 and supports 
 c  h bond activation to be turnover - limiting .
this value is 
 larger than that previously observed for an intramolecular ketone hydroacylation where insertion was implicated as the turnover - limiting 
 step ( kie = 1.79  0.06 ) .
the absence of a directing 
 group on the aldehyde in the present system likely increases the barrier 
 to oxidative addition significantly . on the basis of the kinetic 
 analysis and kie ,
we propose a mechanism 
 invoking homobimetallic activation of the aldehyde where one rhodium catalyst acts as a lewis acid 
 by coordinating the oxygen atom of the aldehyde and a second rhodium 
 catalyst participates in the oxidative addition of the formyl c  h 
 bond to produce acyl - rh(iii)-hydride iv ( scheme 5 ) .
a report of cationic 
 rhodium complexes behaving as lewis acid catalysts supports this proposal .
in addition , lewis acid additives ( i.e. , zncl2 , znbr2 , zni2 , etc . ) have been found 
 to be beneficial in a study on intermolecular alkene hydroacylation , 
 although their role is unclear .
the mechanism 
 proceeds with insertion to generate acyl - rh(iii)-alkoxide v , followed by reductive elimination to furnish the product and turnover 
 the rh(i ) catalyst .
it is possible for the reaction to occur through 
 bimetallic intermediates following oxidative addition ; however , reactive 
 intermediates were not observed spectroscopically .
we believe that rapid coordination and dissociation of 
 solvent and substrate leads to broadening of the p nmr 
 resonance signals and is thus consistent with [ rh(diphosphine)(solvent)2]iii being a resting state .
by developing a new rh - josiphos catalyst , 
 we achieved the first 
 enantioselective intermolecular ketone hydroacylation , which features 
 the rare use of nonchelating aldehydes .
kinetic analysis reveals a 
 second - order rate dependence on the rhodium catalyst and , together 
 with a study on nonlinear relationship and the kie , points to a unique 
 mechanism involving homobimetallic oxidative addition as the turnover - limiting 
 step . this work provides a foundation for understanding c  h 
 activation and hydroacylation using nonactivated aldehydes which will 
 guide future studies and applications .
 under rh(i ) catalysis , 
 -ketoamides undergo intermolecular 
 hydroacylation with aliphatic aldehydes . a newly designed josiphos 
 ligand enables access to -acyloxyamides with high atom - economy 
 and enantioselectivity . on the basis of mechanistic and kinetic 
 studies , 
 we propose a pathway in which rhodium plays a dual role in 
 activating the aldehyde for cross - coupling . a stereochemical 
 model is provided to rationalize the sense of enantioinduction observed . 
Introduction
Results and Discussion
Conclusions