initially discovered by high - throughput 
 screening at hoffman - la roche ( hlr ) in 2004 , the nutlins are cis - imidazoline small molecules that inhibit the mdm2-p53 
 protein  protein interaction ( ppi ) . the nutlins have been widely used to study the consequences of inducing 
 the activity of the tumor suppressor p53 when it is suppressed by 
 mdm2 in cancer cells . to date the most potent member ( and enantiomer ) in the 
 original nutlin family , ( )-nutlin-3 ( 1 , chart 1 ) , or nutlin-3a , is able to selectively disrupt 
 the binding of mdm2 and p53 by mimicking the side chains of key hydrophobic 
 p53 amino acid residues in the mdm2 binding motif . this orthosteric binding releases p53 from its heterodimer 
 complex with mdm2 , leading to cell cycle arrest and apoptosis . since 
 the initial discovery of the nutlins , a host of structurally different 
 mdm2-p53 inhibitors that function as p53 mimetics have been reported . these small molecules have received much attention 
 from academia and industry in the past decade , since the function 
 of wild - type ( wt ) p53 is inactivated by overexpression or amplification of mdm2 , even 
 though the p53 gene is either deleted or mutated in approximately 
 50% of all human cancers . additionally , since mdm2 is overexpressed 
 in many types of cancer and functions as a key negative regulator 
 of wild - type p53 , the nutlins have shown promise as anticancer therapeutics . hoffmann - la roche ( hlr ) was the first to advance a nutlin analogue 
 ( rg7112 ) into clinical trials for solid and hematological tumors . an mdm2 homologue  mdmx or mdm4is similarly overexpressed 
 in nearly one - fifth of lung cancers , breast cancers , and retinoblastomas and was most recently found to be overexpressed in 65% of 
 human melanomas . the chemistry discussed hereafter has enabled the facile synthesis 
 of a number of enantioenriched cis - imidazolines modeled 
 after ( )-nutlin that were evaluated for mdm2-p53 inhibition 
 using a previously reported fluorescence polarization competition 
 assay for p53 peptide binding to mdm2 . we recently reported the first asymmetric synthesis of 
 ( )-nutlin-3 ( 1 , scheme 1 ) . this required the development of a diastereo- 
 and enantioselective aza - henry reaction with an aryl nitromethane 
 ( 3a ) , a pronucleophile used 
 on only two prior occasions but with low levels of selectivity in 
 this context . the -amino nitroalkane 
 product ( 4aa ) was transformed in five linear steps to 
 ( )-nutlin-3 . alternatives to prepare nutlin-3 remain limited 
 to ( 1 ) the hlr synthesis of ( )-nutlin-3 followed by chromatographic separation of the enantiomers and ( 2 ) a promising enantioselective acylation of symmetric cis - stilbene diamines reported recently by seidel . further modifications to our preparation have 
 reduced chromatographic purification of intermediates to one , enabling 
 the preparation of ( )-nutlin 3 on a multigram scale ( > 17 
 g / batch ) . the use of a diaza - cope reaction 
 by hlr provided access to a large number of symmetrical cis - stilbene diamines . the diaza - cope reaction 
 is less amenable to the preparation of cis - imidazolines 
 bearing unique aromatic rings at c4 and c5 , and yet access to these 
 small molecules may eventually lead to selective and potent inhibitors 
 of protein  protein interactions . application of the aza - henry 
 approach to this problem was not without potential complication . while 
 convergence in the imidazoline synthesis would be well - served ( top 
 equation in figure 1 ) , the levels of enantioselectivity 
 can be attenuated by electronic effects . these challenges are often 
 overcome by reagent ( catalyst ) modification while maintaining a high 
 level of catalyst activity . parallel pathways to the same enantiomer of cis - imidazolines derived from nonsymmetric cis - stilbene diamines . separately , the aza - henry construction of unsymmetrical cis - stilbene diamines offered a strategic question to be 
 examined in conjunction with tactical catalyst development . as outlined 
 in figure 1 , a single enantiomer of imidazoline 6 bearing unique aromatic substituents can be prepared in 
 two ways using this strategy , on the basis of catalyst antipodes and 
 the roles of the nitroalkane and imine ( cf . the studies reported here detail 
 our work to ( 1 ) the identification of a new class of mono(amidine ) 
 organocatalyst ( mam ) that provides high levels of enantioselection 
 in the aza - henry addition involving diverse combinations of aryl nitromethane 
 donors and imine acceptors , ( 2 ) the implementation and evaluation 
 of parallel pathways to cis - imidazolines 6 , and ( 3 ) the synthesis and biological evaluation of novel cis - imidazoline mdm2 inhibitors rationally designed from 
 ( )-nutlin-3 . as a result , highly enantioenriched cis - imidazolines bearing either identical or differentiated aryl substituents 
 at c4 and c5 are now more generally accessible and can be applied 
 to therapeutically valuable small molecules . we elected to first study the use of an electron - deficient aldimine 
 ( 2b ) paired with a relatively unbiased aryl nitromethane 
 ( 3a ) using a standard set of conditions ( 24 h at 20 
 c ) . the boc - imine of 3-(trifluoromethoxy ) benzaldehyde was prepared 
 in good yield using a standard procedure . two of our most reactive and selective catalysts were evaluated , and as in previous studies , we hypothesized that the combination 
 of a brnsted basic catalyst with a brnsted acidic aryl 
 nitromethane would form a salt ( e.g. , 7hch(ar)no2 ) that can , in turn , function as a bifunctional 
 brnsted acid / brnsted base in the reaction . first - generation 
 brnsted basic catalysts ( s , s)-pbam ( 7 ) and ( r , r)-(meo)pbam ( 8) afforded the aza - henry adduct 
 ( ent-4ab and 4ab ) in 52% 
 and 61% ee , respectively . although the reactivity and diastereoselectivity 
 were generally comparable to those of past pyrrolidine bis(amidine ) 
 ( pbam ) catalysts , the enantioselectivity was diminished . in theory , 
 this may be due to the elevated temperature of the reaction ( 20 
 c in contrast with 78 c of past reactions ) and/or 
 intolerable steric interactions with the catalyst . as an alternative 
 to an extensive exploration of the impact of quinoline substituents 
 on enantioselection , an effort that afforded 
 little improvement in this case , we reasoned that the insensitivity 
 of aryl nitromethane additions to added strong acid ( e.g. , tfoh ) might 
 offer the opportunity to explore combinations of amidine and amide functionalities projected from the diamine backbone . 
 the conceptual framework for this modification was also rather different 
 by comparison to previous bis(amidine ) modifications . beginning from 
 its free base form , the catalyst would be expected to form a salt 
 with the aryl nitromethane at the amidine ( eq 1 , figure 2 ) , but the greatest level of dual activation is expected to involve electrophile binding to the polar ionic hydrogen 
 bond concomitant with nitronate counterion binding to the ( amide ) 
 polar covalent hydrogen bond . figure 2 illustrates 
 this conceptually , progressing from substrates and catalyst in a to catalyst - bound product in d. the initial 
 activation event is catalyst deprotonation of the nitroalkane , but 
 in this arrangement ( b ) , the nitronate reactivity may 
 be attenuated by a strong ion pair and imine activation by an amide 
 n  h may be relatively weak . exchange of the hydrogen bond acceptors 
 ( figure 2 , c ) , however , leads 
 to a more reactive nitronate due to charge separation and increased 
 activation of the imine . an arrangement such as this might maximize 
 the benefit of drawing the counterion away from the electrophile binding 
 site while providing discrete directional control . elements of this 
 approach overlap with developments in the field of anion binding catalysis , 
 particularly when the catalyst involves two polar covalent hydrogen 
 bond donors . other catalyst systems use 
 not only a brnsted basic catalyst but also a brnsted base 
 additive ( e.g. , et3n ) . outline for 
 activation of aryl nitromethane ( nucleophile , nu ) and 
 imine ( electrophile , e ) by a bifunctional catalyst . the mono(amidine ) ( mam ) catalysts in scheme 2 were prepared in five steps using an approach that 
 mirrored our preparation of unsymmetrical bis(amidine ) ligands in 
 prior studies . under reaction conditions identical with those used for 7 and 8 , ( s , s)-pivmam ( ent-9 ) afforded the addition adduct in an improved 87% 
 ee and 5:1 dr ( 54% yield ) , while ( s , s)-benzmam ( ent-10 ) afforded 
 the adduct in 94% ee and 6:1 dr ( 62% yield ) . the diastereomeric ratio ( dr ) and enantiomeric 
 excess ( ee ) were determined by chiral hplc . using this enantiomeric diamine backbone , a similar comparative analysis was made using aldimine 2a in combination with a range of electronically diverse aryl 
 nitromethanes 3x , yielding adducts 4xa ( table 1 ) . the aryl nitromethanes were prepared from their 
 corresponding and commercially available benzaldehyde derivatives , 
 and all were successful feedstock for the aza - henry reaction using 
 representative conditions ( 5 mol % catalyst loading , 20 c , 
 toluene ; table 1 ) . we first examined mam catalyst 10 efficacy with 4-chlorophenyl nitromethane and 4-chlorophenyl 
 boc - imine ( table 1 , entry 1 ) , to compare the 
 new catalyst directly to 8 ; the resulting aza - henry adduct 4aa can lead to ( )-nutlin-3 ( 1 ) . benzmam 
 ( 10 ) provided the adduct in 96% ee and 53:1 dr at 20 
 c , in comparison to 91% ee and 13:1 dr at 78 c 
 when using 8 ( table 1 , entries 
 1 and 2 , respectively ) . high levels of selectivity continued during 
 the evaluation of a range of electronically deficient ( table 1 , entries 37 ) and electronically neutral 
 ( table 1 , entry 8) aryl nitromethanes , providing 
 the aza - henry adducts with excellent enantioselection ( 9294% 
 ee ) . 2-fluoro-5-bromoaryl nitromethane ( table 1 , entry 6 ) provided an exception to the trend , however , as the bis(amidine ) 
 free base of ( meo)pbam ( 8) provided the aza - henry 
 adduct in the highest ee in comparison to pivmam ( 9 ) 
 and benzmam ( 10 ) . the most electron rich case , 3,4-dimethoxyaryl 
 nitromethane ( table 1 , entry 10 ) , converted 
 with lower enantioselectivity and reaction rate , perhaps due to its 
 diminished brnsted acidity . dialing back the electronic effects 
 to ( mono)methoxyaryl nitromethane 3i ( table 1 , entry 11 ) , however , reestablishes good levels 
 of stereocontrol ( 95% ee and > 20:1 dr ) . interestingly , pivmam ( 9 ) enhanced enantioselectivity for meta - substituted arenes 
 ( table 1 , entries 4 , 5 , 8 , and 9 ) . for example , 
 the adduct of 3-chloroaryl nitroalkane ( table 1 , entry 5 ) was formed in 89% ee with benzmam ( 10 ) , in 
 comparison to 93% ee when pivmam ( 9 ) ( table 1 , entry 4 ) was employed . all reactions employed 1.1 equiv of nitroalkane 
 in toluene ( 0.1 m ) at 20 c with 2436 h reaction 
 time . catalyst prepared 
 from ( r , r)-cyclohexanediamine or 
 ( s , s)-cyclohexanediamine ( denoted ent ) . diastereomeric 
 ratio ( dr ) and enantiomeric excess ( ee ) determined by chiral hplc 
 following vacuum filtration or silica column chromatogaphy ( see the supporting information ) . the substrate scope for aryl boc - imines 
 ( 2x ) was investigated next ( table 2 ) . the synthesis of aryl boc - aldimines from -amido sulfones is well established , and a wide array of aldimine 
 substrates can be prepared . a range of 
 aryl boc - imines was prepared for analysis , leading to -amino 
 nitroalkanes ( 4ax ) in very high enantio- and diastereoselectivity 
 ( up to 99% ee and > 200:1 dr ; table 2 ) . haloaryl 
 ( table 2 , entries 15 , 7 , 8 , and 10 ) , 
 electron - deficient imines ( table 2 , entries 
 710 ) , and electron - neutral ( table 2 , entry 6 ) and electron - rich imines ( table 2 , entries 11 and 12 ) were transformed to -amino nitroalkanes 
 in uniformly good to excellent dr / ee and isolated yield . all reactions 
 employed 1.1 equiv of nitroalkane in toluene ( 0.1 m ) at 20 
 c with 2436 h reaction time . catalyst prepared from ( r , r)-cyclohexanediamine or ( s , s)-cyclohexanediamine ( denoted ent ) . diastereomeric ratio ( dr ) and enantiomeric 
 excess ( ee ) were determined by chiral hplc following vacuum filtration 
 or silica column chromatography ( see the supporting 
 information ) . the behaviors outlined 
 in table 2 suggest that electronic variations 
 to the aldimine affected stereoselection to a lesser degree than that 
 observed with aryl nitromethane donors . this was more carefully investigated 
 by examining each pairing of aldimine ( 2 ) and aryl nitromethane 
 ( 3 ) substrates to explore and better gauge reactivity 
 trends ( table 3 ) . the arenes selected in table 3 contain a wide range of functionalities with the 
 purpose of maximizing diversity to a reasonable extent . using a standard 
 set of reaction conditions , aryl boc - imines 2j , k and their nitroalkane counterparts 3d , h are notable challenges , as they represent 
 highly electron poor and rich substrates , respectively , in the aza - henry 
 reaction . as was expected , the ee and dr values observed for neutral 
 and moderately electron deficient aryl nitromethanes are uniformly 
 high ( table 3 , entries 14 , 3a , b , f , c ) . the comparison of ent-4fh with 4cg , however , is 
 an exception to this trend . under identical reaction conditions with 
 benzmam ( 10 ) , 3-chloro nitroalkane ( 3c ) 
 behaves remarkably better than its imine counterpart ( 2h ) on reaction with the 3-methyl arene partner ( 99% ee , > 20:1 dr 
 by h nmr and 85% ee , 8:1 dr , respectively ) . aza - henry adducts where 
 the electron - poor 2-fluoro-5-bromo arene is employed as the nitroalkane 
 ( 3d ) consistently resulted in low dr  presumably 
 due to the increased -hydrogen acidity in the product ( up to 
 5:1 dr , 4dg ) . fortunately , the 2-fluoro-5-bromoaryl imine 
 ( 2j ) delivers adducts with improved diastereoselectivity 
 and enantioselectivity in specific cases ( 4fj , 85% ee/40:1 
 dr , in comparison to 4dg , 68% ee/5:1 dr ) . in the case 
 of the 3,4-dimethoxyaryl substrate , employing this electron - rich arene 
 as the nitroalkane ( 3h ) proved unsatisfactory ( up to 
 78% ee/20:1 dr , 4hg ) in almost every case . gratifyingly , 
 significantly higher ee and dr was observed when this arene was employed 
 as the imine ( up to 93% ee/56:1 dr , 2k ) . to further illustrate the value of this observation , entries 4hh and 4ck should be compared . in cases where 
 the adducts were generated in suboptimal ee and dr , switching catalyst 
 antipode and arene pairings proved beneficial in almost all cases , 
 using the tactic outlined in figure 1 . the 
 36 compounds outlined in table 3 represent 
 a wide range of possibilities when targeting symmetrical or unsymmetrical cis - stilbene diamines . these experiments further demonstrate 
 synthetic flexibility using a pair of mono(amidine ) ( mam ) amide catalysts 
 ( 9 and 10 ) to access highly diastereo- and 
 enantiomerically enriched aza - henry adducts . all reactions 
 employed 1.1 equiv of nitroalkane in toluene ( 0.1 m ) at 20 
 c with 2436 h reaction time . catalyst prepared from ( r , r)-cyclohexanediamine or ( s , s)-cyclohexanediamine ( denoted ent ) . diastereomeric 
 ratio ( dr ) and enantiomeric excess ( ee ) were determined by chiral 
 hplc following vacuum filtration or silica column chromatography ( see 
 the supporting information ) . table 3 gives adducts that contain either 
 an underlying symmetric cis - stilbene diamine backbone 
 ( results along the diagonal from top left to bottom right ) , or a nonsymmetric cis - stilbene diamine backbone . this 
 relationship was considered when converting these intermediates to 
 their derived cis - imidazolines ( cf . if the two constitutional isomers in figure 1 are transformed into their derived cis - imidazolines 
 using identical procedures and reagents , the final 
 imidazolines would be enantiomeric at their c4 and 
 c5 carbon centers ( although overall constitutionally isomeric cis - imidazolines ) . however , if the constitutional isomers 
 are formed using enantiomeric catalysts , and the 
 order of steps 2 ( amide formation ) and 4 ( urea formation ) is reversed , 
 then the same enantiomer of the cis - imidazoline will 
 be formed , as outlined in figure 1 . additionally , 
 the benefits of this method allow for direct and predictable functionalization 
 at a given nitrogen due to their protected nature . previous attempts 
 at monoderivatization from symmetric ( meso ) or nonsymmetrical 
 stilbene diamines are notorious for generating a mixture of mono- 
 and disubstituted products . this strategy 
 was reduced to practice using the example in scheme 3 . in the first case , p - chloro 
 aldimine 2a was converted to 4ba using ( r , r)-benzmam ( 10 ) and p - bromoaryl nitromethane 3b . this adduct was then converted to cis - imidazoline 11 using the five steps outlined in scheme 3 . in the second case , the identities of the aldimine and aryl 
 nitromethane were reversed ( to 2c and 3a , respectively ) , and ( s , s)-benzmam ( ent-10 ) was deployed 
 to promote a similarly highly diastereo- and enantioselective addition . the adduct 4ac was converted to the corresponding cis - imidazoline , but the amine produced by nitro reduction 
 was subjected to urea  as opposed to amide  formation . deprotection , amide formation , and dehydrative cyclization then furnished 
 the identical cis - imidazoline 11 . hence , 
 by using an enantiomeric catalyst and reversing the order of amide 
 and urea formation in the finishing sequence , the same enantiomer 
 of cis - imidazoline was formed by straightforward 
 permutation of aldimine and aryl nitromethane substrates . each 
 case illustrated in scheme 3 works equally 
 well such that less obvious factors might lead one to choose one route 
 over the other . however , we have identified situations where only 
 one of the two options may be optimal , or even available . for example , 
 we targeted the cis - imidazoline 15 ( scheme 4 ) bearing p - chloroaryl and m-(trifluoromethoxy)aryl substituents . attempts to prepare 
 the aryl nitromethane 3i bearing a m - trifluoromethoxy substituent were unsuccessful . although aldoximine 13 was isolated in 53% yield , a range of oxidants uniformly 
 failed to yield the nitroalkane , presumably due to the electron - withdrawing 
 nature of the substituent ( scheme 4 ) . conversely , 
 -amido sulfone formation and its conversion to the corresponding 
 aldimine 2b was successful . since p - chloroaryl 
 nitromethane 3a is readily available , this combination 
 could be transformed into the desired cis - imidazoline 15 ( scheme 4 ) . by employment of ( s , s)-benzmam ( ent-10 ) , the desired -amino nitroalkane enantiomer ent-4ab was generated in 94% ee and 
 6:1 dr ( scheme 5 ) . subsequent isocyanate formation using carbonyl 
 diimidazole and its reaction with oxopiperazine 16 led 
 to urea 17 . straightforward boc deprotection with tfa 
 afforded the free amine , which underwent an acylation with acid 18 using edc coupling conditions to generate benzamide urea 19 . triphenylphosphine oxide and triflic acid generated a 
 phosphonium anhydride in situ ( hendrickson s reagent ) , promoting regioselective dehydrative cyclization 
 to provide the imidazoline 15 as a single diastereomer 
 in 94% ee . this ability to generate nonsymmetrical cis - imidazolines from a host of halogenated arenes could 
 provide a platform for further derivatization using common metal - catalyzed 
 transformations . for example , we postulated that the bromoaryl derivative 11 ( scheme 6 ) might be functionalized 
 selectively , as oxidative addition should be accelerated in comparison 
 to the neighboring chloroarene . we decided to employ traditional suzuki cross - coupling conditions 
 with pd(0)tetrakis(triphenylphosphine ) and an aryl boronic 
 ester ( 20 ) to test this hypothesis ( scheme 6 ) . after the mixtue was stirred 
 for 24 h at 75 c , formation of the desired pyrazole adduct 21 was confirmed by its isolation in 62% yield . the aryl chloride 
 subunit was clearly intact ( confirmed by hrms ) , and oxidation to imidazole 
 was not observed . this example establishes the feasibility of late - stage , 
 site - selective functionalization from differentiated haloarenes leading 
 to novel heterocyclic derivatives within this family . the synthetic studies detailed above were driven in part 
 by a parallel program in the detailed exploration of cis - imidazolines as inhibitors of protein  protein interactions . we investigated the binding sites of mdm2 reported from its cocrystal 
 structure complexed with ( )-nutlin-3 ( pdb 4hg7 ) to improve the 
 mdm2-p53 ( wt ) binding inhibitory activity . these compounds are uniformly 
 more potent in their binding to mdm2 as the 4s,5r - configured cis - imidazolines ; therefore , 
 their preparation in high ee was considered paramount . as a part of 
 the effort not only to explore mdm2 affinity but also to access 
 structural novelty , our focus was on three hydrophobic side chains 
 that exist within the p53 binding pocket ( phe19 , trp23 , and leu26 ) 
 and structural modifications were made to both cis - arenes ( ar1 and ar2 , table 4 ) employing the optimal synthetic pathway ( cf . top and bottom 
 equations in figure 1 ) . we also addressed optimization 
 of para substituents of ring a by replacing the electron - donating 
 group ( methoxy ) with electron - withdrawing groups , including halogens 
 and a nitrile , to explore electrostatic effects . a total of 12 cis - imidazoline analogues were designed and prepared to 
 probe structure  activity relationships ( sar ; table 4 ) . according to recent 
 literature , affinity for mdm2 can be improved 
 by varying the aromatic substituents on the phenyl ring that occupy 
 the leu26 pocket and by enhancing a  stacking 
 interaction with the his96 residue on mdm2 . in an attempt to occupy 
 the leu26 pocket , several analogues were designed and synthesized 
 by introducing different halogens and other functional groups at either 
 the para or meta position on the ar2 ring . from the outset , 
 it was clear that any substituents larger than cl at the meta position 
 slightly decreased the affinity ( 15 , 23 , 
 and 27 ) . however , the only slightly larger p - br - substituted compound 11 showed potency equivalent 
 with that of 1 . an exception to this trend was the n - methylpyrazole 21 , which was surprisingly 
 well tolerated given its size . in order to explore possible secondary 
 interactions with a loop of mdm2 crossing the binding site , substituents 
 ( halogen , nitrile ) were introduced on the para position of the a ring 
 to replace the methoxy group ( r group in table 4 ) ; no dramatic improvement was observed , but these analogues still 
 exhibited submicromolar affinities ( 24 , 25 , 28 , and 30 ) . the synthetic studies detailed above were driven in part 
 by a parallel program in the detailed exploration of cis - imidazolines as inhibitors of protein  protein interactions . we investigated the binding sites of mdm2 reported from its cocrystal 
 structure complexed with ( )-nutlin-3 ( pdb 4hg7 ) to improve the 
 mdm2-p53 ( wt ) binding inhibitory activity . these compounds are uniformly 
 more potent in their binding to mdm2 as the 4s,5r - configured cis - imidazolines ; therefore , 
 their preparation in high ee was considered paramount . as a part of 
 the effort not only to explore mdm2 affinity but also to access 
 structural novelty , our focus was on three hydrophobic side chains 
 that exist within the p53 binding pocket ( phe19 , trp23 , and leu26 ) 
 and structural modifications were made to both cis - arenes ( ar1 and ar2 , table 4 ) employing the optimal synthetic pathway ( cf . top and bottom 
 equations in figure 1 ) . we also addressed optimization 
 of para substituents of ring a by replacing the electron - donating 
 group ( methoxy ) with electron - withdrawing groups , including halogens 
 and a nitrile , to explore electrostatic effects . a total of 12 cis - imidazoline analogues were designed and prepared to 
 probe structure  activity relationships ( sar ; table 4 ) . according to recent 
 literature , affinity for mdm2 can be improved 
 by varying the aromatic substituents on the phenyl ring that occupy 
 the leu26 pocket and by enhancing a  stacking 
 interaction with the his96 residue on mdm2 . in an attempt to occupy 
 the leu26 pocket , several analogues were designed and synthesized 
 by introducing different halogens and other functional groups at either 
 the para or meta position on the ar2 ring . from the outset , 
 it was clear that any substituents larger than cl at the meta position 
 slightly decreased the affinity ( 15 , 23 , 
 and 27 ) . however , the only slightly larger p - br - substituted compound 11 showed potency equivalent 
 with that of 1 . an exception to this trend was the n - methylpyrazole 21 , which was surprisingly 
 well tolerated given its size . in order to explore possible secondary 
 interactions with a loop of mdm2 crossing the binding site , substituents 
 ( halogen , nitrile ) were introduced on the para position of the a ring 
 to replace the methoxy group ( r group in table 4 ) ; no dramatic improvement was observed , but these analogues still 
 exhibited submicromolar affinities ( 24 , 25 , 28 , and 30 ) . generalization 
 of the first highly selective aza - henry addition reaction between 
 aryl nitromethanes and aryl boc - imines has been achieved , leading 
 to orthogonally protected , cis - stilbene diamine precursors 
 ( up to 99% ee as a single diastereomer ) . the unprecedented selectivity 
 reported for this transformation lies in the discovery of novel mono(amidine ) 
 ( mam ) bifunctional catalysts that not only afford aza - henry adducts 
 in high levels of stereocontrol but can achieve this at noncryogenic 
 temperature ( 20 c ) . the goal to generalize these additions 
 to include an array of aryl nitromethanes and aryl boc - imine substrates 
 was achieved . in cases where a nitroalkane / imine pair led to an addition 
 product with low stereoselection , a strategy - level solution was postulated 
 and reduced to practice , involving a straightforward exchange of nitroalkane / imine 
 identity . by utilization of this methodology , a number of biologically 
 active cis - imidazoline small molecules reminiscent 
 of the nutlin family were accessed from enantioenriched aza - henry 
 adducts in subsequent transformations . the realization that constitutionally 
 isomeric products could be transformed to the same cis - imidazoline small molecule ( see scheme 3 ) 
 further improved access , and this was demonstrated in cases where 
 exchange of electrophile and pronucleophile identity in the aza - henry 
 step led to a combination with markedly higher stereoselection . operationally , 
 synthetic points of variation for this strategy when pursuing a target 
 synthesis are ( 1 ) the sense of the chiral catalyst employed ( r , r vs s , s diamine ) and ( 2 ) the sequence of amine coupling reactions more broadly , the ability to access 
 enantioenriched , protected cis - stilbene diamines 
 now allows for direct and predictable functionalization at each nitrogen  an 
 unsolved problem associated with approaches based on meso - stilbene diamine intermediates . furthermore , unsymmetrical nutlin-3 
 analogues bearing differentiated haloarenes can be selectively functionalized 
 via late - stage cross - coupling reactions , allowing for more direct 
 access to analogues for screening aimed at ppi drug discovery efforts . among the designed nutlin analogues , four new compounds ( sj000773209 - 5 , 
 sj000773211 - 3 , sj000801055 - 1 , and sj000801057 - 1 ) showed levels of 
 mdm2-p53 inhibition activity similar to that of ( )-nutlin-3 
 ( 1 ) , measured by a fluorescence - polarization assay . these 
 findings provide a robust framework together with a streamlined , enantioselective 
 synthesis in which to develop an in vivo candidate for mdm2-p53 inhibition , 
 as well as pursue cis - imidazoline - class mdmx - p53 
 inhibitors . all reagents 
 and solvents were commercial grade and were purified prior to use 
 when necessary . toluene ( tol ) and dichloromethane ( ch2cl2 ) were dried by passage through a column of activated alumina 
 as described by grubbs . thin - layer chromatography ( tlc ) was performed using glass - backed 
 silica gel ( 250 m ) plates , and flash chromatography utilized 
 230400 mesh silica gel . uv light and/or the use of potassium 
 iodoplatinate and potassium permanganate solutions were used to visualize 
 products . ira-900-no2 resin was prepared by washing ira900-cl 
 resin with aqueous nano2 until the wash no longer tested 
 positive for chloride by an agno3 test . nuclear magnetic 
 resonance spectra ( nmr ) were acquired at 400 , 500 , or 600 mhz , and 
 chemical shifts were measured relative to residual solvent peaks as 
 an internal standard set to  7.26 and 77.0 ( cdcl3 ) . ir spectra were recorded as neat films on a nacl plate ( transmission ) 
 and are reported in wavenumbers ( cm ) . mass spectra 
 were recorded on a high - resolution spectrometer by use of the ionization 
 method noted ( apci or esi ) and used tof mass analysis . absolute and relative configuration of the aza - henry 
 adducts ( 4aa4hk ) were assigned by 
 analogy to previously synthesized adducts , for which a crystal structure 
 was obtained . scheme 7 gives the general scheme to access cis - imidazoline / nutlin 
 derivatives . gst - mdm2 ( 1 - 188 ) was cloned , expressed , and purified as described 
 previously . the fluorescence polarization ( fp ) assay was performed 
 with 1 m gst - mdm2 ( 1 - 188 ) in 10 mm tris ( ph 8.0 ) , 42.5 mm nacl , 
 and 0.0125% tween-20 assay buffer . for testing , a dilution series 
 of small molecules ( spanning 10 mm to 0.5 m in dmso , in 3-fold 
 steps ) was added by direct addition to protein using pin transfer 
 ( 100ss pins , v&p scientific ) , giving a test dilution series spanning 
 65 m to 3.2 nm with a final concentration of 0.65% dmso . the 
 increasing concentrations of small molecules dissolved in dmso were 
 preincubated with protein for 30 min in black 384-well plates and 
 then treated with texas red labeled wild - type p53 peptide ( 15 nm , 
 amino acids 1529 : gsgssqetfsdlwkllpen ) and incubated for an 
 additional 45 min . after incubation the fp signal was measured on 
 a multilabel plate reader fitted with a 555 nm excitation filter , 
 632 nm static and polarized filters , and a texas red fp dichroic mirror . unlabeled wt - p53 peptide was used as a positive control , and dmso 
 was used as a negative control . technical triplicate data were 
 normalized to the positive ( 100% inhibition ) and negative ( 0% inhibition ) 
 controls on the corresponding row of the 384-well plate ( percentage 
 inhibition = 100  ( ( sample result )  ( negative control))/((positive 
 control mean )  ( negative control ) ) ) . two to seven independent 
 experiments of normalized data were combined into a data set and then 
 fit using a nonlinear regression in graphpad prism with the formula 
 log ( inhibitor ) vs response  variable slope ( four parameters ) . additionally the residuals of the curve fit were plotted to determine 
 the fit of the theoretical curve . ic50 and 95% confidence intervals 
 ( ci ) were determined from these graphs . in a flame - dried flask equipped with a magnetic 
 stir bar were placed na2so4 ( 384 mg , 2.69 mmol ) , 
 cs2co3 ( 293 mg , 8.98 mol ) , and tert - butyl ( tosyl(3-(trifluoromethoxy)phenyl)methyl)carbamate 
 ( 200 mg , 449 mol ) . the solids were suspended in thf ( 2.2 ml ) 
 at room temperature . the solution was filtered through 
 a plug of celite with excess dichloromethane and concentrated to a 
 white oil which was 90% pure by h nmr ( 128 mg , about 98% ) . this material was used without further purification : h 
 nmr ( 400 mhz , cdcl3 )  8.82 ( s , 1h ) , 7.80 ( d , j = 6.8 hz , 2h ) , 7.51 ( t , j = 8.0 hz , 1h ) , 
 7.40 ( m , 1h ) , 1.58 ( s , 9h ) . the extent to which this compound was 
 prone to decomposition precluded acquisition of the remaining analytical 
 data . in a flame - dried round - bottom flask equipped 
 with a magnetic stir bar were placed mgso4 ( 888 mg , 7.4 
 mmol ) , cs2co3 ( 240 mg , 0.74 mmol ) , and then tert - butyl ( ( 4-iodophenyl)(tosyl)methyl)carbamate ( 175 mg , 
 0.37 mmol ) . the solids were suspended in thf ( 2.8 ml ) , and the mixture 
 was stirred for 4.5 h at room temperature and then filtered through 
 a bed of celite on an oven - dried frit and washed with dichloromethane . concentration of the filtrate revealed a white oil ( 106 mg , 87% ) that 
 solidified after sitting in a freezer at 20 c overnight 
 to give a white waxy solid : mp 46 c ; rf = 0.40 ( 20% etoac / hexanes ) ; ir ( film ) 2978 , 2931 , 1715 , 1629 , 
 1584 , 1483 cm ; h nmr ( 400 mhz , cdcl3 )  8.81 ( s , 1h ) , 7.85 ( d , j = 8.0 
 hz , 2h ) , 7.64 ( d , j = 8.4 hz , 2h ) , 1.60 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 168.6 , 162.3 , 138.2 , 
 133.4 , 131.2 , 101.2 , 82.5 , 27.8 ; hrms ( esi ) exact mass calcd for c12h14innao2 [ m + na ] 353.9961 , 
 found 353.9955 . in a 
 flame - dried flask equipped with a magnetic stir bar were placed cs2co3 ( 488 mg , 1.50 mmol ) , na2so4 ( 850 mg , 5.99 mmol ) , and then tert - butyl ( ( 3-iodophenyl)(tosyl)methyl)carbamate 
 ( 355 mg , 749 mol ) and toluene ( 7.7 ml ) . the mixture was vigorously 
 stirred for 2.5 h and monitored by h nmr . the reaction 
 mixture was filtered through a plug of celite with excess dichloromethane 
 and concentrated to a clear oil containing analytically pure aldimine : 
 ir ( film ) 2978 , 2930 , 1719 , 1631 , 1367 , 1255 cm ; h nmr ( 400 mhz , cdcl3 )  8.75 ( s , 
 1h ) , 8.31 ( s , 1h ) , 7.87 ( d , j = 7.6 hz , 1h ) , 7.82 
 ( d , j = 7.6 hz , 1h ) , 7.21 ( t , j = 
 7.6 hz , 1h ) , 1.59 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 167.8 , 162.1 , 142.1 , 138.2 , 136.0 , 130.5 , 129.7 , 94.5 , 82.7 , 
 27.9 ( 3c ) ; hrms ( esi ) exact mass calcd for c12h14innao2 [ m + na ] 353.9967 , found 353.9961 . in a flame - dried flask equipped with a 
 magnetic stir bar were placed sodium sulfate ( 7.95 g , 56 mmol ) , potassium 
 carbonate ( 6.77 g , 49 mmol ) , and tert - butyl ( ( 5-bromo-2-fluorophenyl)(tosyl)methyl)carbamate 
 ( 3.11 g , 7.0 mmol ) . the solids were suspended in thf ( 70 ml ) , and 
 the mixture was refluxed for 7 h , cooled , filtered through an oven - dried 
 frit , and concentrated in vacuo to reveal a white oil ( 1.881 g , 89% ) 
 which solidified to a white waxy solid after being stored at 20 
 c : mp 3940 c ; rf = 
 0.47 ( 30% etoac / hexanes ) ; ir ( film ) 2982 , 2930 , 1728 , 1621 , 1584 cm ; h nmr ( 400 mhz , cdcl3 )  
 9.06 ( s , 1h ) , 8.27 ( d , j = 6.0 hz , 1h ) , 7.63 ( m , 
 1h ) , 7.05 ( dd , j = 9.2 , 9.2 hz , 1h ) , 1.59 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 162.7 ( d , jcf = 256 hz ) , 161.1 ( d , jcf = 5 hz ) , 137.7 ( d , jcf = 8 hz ) , 130.8 ( d , jcf = 15 hz ) , 123.6 ( d , jcf = 10 hz ) , 117.8 ( d , jcf = 22 hz ) , 117.5 ( d , jcf = 
 3 hz ) , 82.9 , 27.8 ; hrms ( esi ) exact mass calcd for c12h14brfno2 [ m + h ] 302.0192 , found 302.0193 . aldehyde ( 1.00 mmol ) , pyridine ( 1.80 mmol ) , hydroxylamine 
 hydrochloride ( 1.20 mmol ) , and ethanol ( 333 l ) were combined 
 ( in order ) in a flask at room temperature . the mixture was stirred 
 for 120 h , and ethanol was evaporated under reduced pressure . the mixture was diluted with etoac , washed twice with 1 m aqueous 
 hcl , once with saturated aqueous nahco3 , and brine . the 
 organic layer was dried ( mgso4 ) , filtered , and concentrated 
 to a white crystalline solid . the aldoxime ( 1.00 mmol ) , mcpba ( 2.03.0 mmol ) , 
 and dichloromethane ( 1.0 ml ) were combined in a flask at room temperature . the reaction was monitored by tlc or h nmr , and after 
 13 days the mixture was quenched with saturated aqueous nahco3 and the aqueous layer was extracted with dichloromethane . the combined organic layers were dried ( mgso4 ) , filtered , 
 and concentrated . column chromatography ( sio2 , meoh / dichloromethane ) 
 of the residue provided the title compound . ( e)-5-bromo-2-fluorobenzaldehyde 
 oxime ( 1.01 g , 4.63 mmol ) , mcpba ( 1.60 g , 9.27 mmol ) , and dichloromethane 
 were combined in a flask at room temperature . after 48 h , the mixture 
 was quenched with saturated aqueous nahco3 and the aqueous 
 layer was extracted with dichloromethane . the combined organic layers 
 were dried ( mgso4 ) , filtered , and concentrated . column 
 chromatography ( sio2 , 02% methanol in dichloromethane ) 
 of the residue provided the compound as a bronze oil ( 502 mg , 46% ) : rf = 0.85 ( ch2cl2 ) ; ir 
 ( film ) 3074 , 2915 , 2369 , 1761 , 1560 , 1491 cm ; h nmr ( 400 mhz , cdcl3 )  7.56 ( m , 2h ) , 7.06 
 ( t , j = 8.8 hz , 1h ) , 5.47 ( s , 2h ) ; c 
 nmr ( 100 mhz , cdcl3 ) ppm 161.6 ( d , jcf = 251 hz ) , 135.2 , 134.8 ( d , jcf = 3 hz ) , 119.0 ( d , jcf = 16 hz ) , 117.7 ( d , jcf = 23 hz ) , 116.9 ( d , jcf = 4 hz ) , 72.2 ( d , jcf = 
 3 hz ) ; hrms ( apci ) exact mass calcd for c7h5brfno2 [ m ] 232.9482 , found 232.9476 . 3,4-dimethoxybenzaldehyde ( 3.0 g , 18.0 
 mmol ) , hydroxylamine hydrochloride ( 1.50 g , 21.7 mmol ) , pyridine ( 2.62 
 ml , 32.5 mmol ) , and ethanol ( 6.0 ml ) were combined in a flask at room 
 temperature . the mixture was stirred for 15 h , and ethanol was evaporated 
 under reduced pressure . the mixture was diluted with etoac and washed 
 twice with 1 m aqueous hcl and once with saturated aqueous nahco3 and brine . the organic layer was dried ( mgso4 ) , 
 filtered , and concentrated to a white crystalline solid . the resulting aldoxime 
 ( 3.3 g , 18.2 mmol ) , mcpba ( 6.29 g , 36.4 mmol ) , and dichloromethane 
 ( 18 ml ) were combined in a flask at room temperature . after 18 h , 
 the mixture was quenched with saturated aqueous nahco3 and 
 the aqueous layer was extracted with dichloromethane . the combined 
 organic layers were dried ( mgso4 ) , filtered , and concentrated . column chromatography ( sio2 , dichloromethane ) of the residue 
 provided the compound as a yellow solid ( 1.26 g , 36% ) : mp 6667 
 c ; rf = 0.9 ( ch2cl2 ) ; ir ( film ) 3016 , 2948 , 2838 , 1554 , 1506 , 1376 cm ; h nmr ( 400 mhz , cdcl3 )  7.01 ( dd , j = 2.0 , 1.6 hz , 1h ) , 6.94 ( d , j = 2.0 
 hz , 1h ) , 6.87 ( d , j = 8.4 hz , 1h ) , 5.36 ( s , 2h ) , 
 3.89 ( s , 6h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 150.3 , 
 149.2 , 123.0 , 122.1 , 112.6 , 111.1 , 79.9 , 55.9 ( 2c ) ; hrms ( ci ) exact 
 mass calcd for c9h11no4 [ m ] 197.0604 , found 197.0602 . in a 200 ml flask were placed silver nitrite ( 1.68 g , 
 10.94 mmol ) and 1-methoxy-3-benzyl bromide ( 2.0 g , 9.95 mmol ) . the 
 flask was purged with n2 and covered with aluminum foil . 
 at room temperature , the reaction 
 mixture was stirred at room temperature in the dark for 46 h and then 
 filtered and concentrated . the crude product was purified on a column 
 ( sio2 , 020% ethyl acetate in hexanes ) to give the 
 desired product as a pale yellow solid ( 0.60 g , 36% ) : rf = 0.9 ( ch2cl2 ) ; ir ( film ) 3069 , 
 2916 , 2365 , 1760 , 1558 , 1310 cm ; h 
 nmr ( 400 mhz , cdcl3 )  7.387.31 ( m , 1h ) , 
 7.03 ( dt , j = 7.6 , 1.3 hz , 1h ) , 7.016.95 
 ( m , 2h ) , 5.41 ( s , 2h ) , 3.83 ( s , 3h ) ; c nmr ( 101 mhz , 
 cdcl3 )  160.0 , 130.9 , 130.1 , 122.1 , 115.6 , 115.3 , 
 80.0 , 55.4 ; hrms ( esi ) exact mass calcd for c8h10no3 [ m + h ] 168.0661 , found 168.0662 . the synthesis was derived from the previously 
 reported assembly of chiral bis(amidine ) catalysts . a flame - dried flask equipped with a stir 
 bar was charged with pd(dba)2 ( 208 mg , 362 mol ) , rac - binap ( 225 mg , mol ) , cesium carbonate ( 8.84 g , 
 27.1 mmol ) , the amine ( 2.21 g , 9.05 mmol ) , and 2,4-dichloroquinoline 
 ( 1.79 g , 9.05 mmol ) . an oven - dried condenser was attached , and the 
 apparatus was purged twice with argon . toluene ( 45 ml ) was added , 
 and the resulting solution was stirred under reflux for 27 h. the 
 reaction mixture was then cooled to room temperature , filtered through 
 a celite pad with ch2cl2 and etoac , and concentrated . flash column chromatography of the residue afforded the desired product 
 as a light yellow foam ( 1.53 g , 42% ) : [ ]d = + 96 ( c 0.68 , chcl3 ) ; rf = 0.31 ( 20% etoac / hexanes ) ; ir ( film ) 3381 , 
 3060 , 2935 , 2858 , 1767 , 1705 , 1606 , 1567 , 1531 cm ; h nmr ( 400 mhz , cdcl3 )  7.65 ( d , j = 7.6 hz , 1h ) , 7.49 ( m , 3h ) , 7.38 ( ddd , j = 8.0 , 6.8 , 1.2 hz , 1h ) , 7.31 ( dd , j = 5.6 , 3.2 
 hz , 2h ) , 7.06 ( ddd , j = 8.0 , 8.0 , 1.2 hz , 1h ) , 6.59 
 ( s , 1h ) , 4.84 ( dddd , j = 10.8 , 10.8 , 10.8 , 4.0 hz , 
 1h ) , 4.74 ( d , j = 10.0 hz , 1h ) , 4.08 ( ddd , j = 10.8 , 10.8 , 4.0 hz , 1h ) , 2.66 ( dddd , j = 12.8 , 12.8 , 12.8 , 3.6 hz , 1h ) , 2.23 ( br m , 1h ) , 1.85 ( m , 3h ) , 
 1.66 ( ddddd , j = 13.2 , 13.2 , 13.2 , 3.2 , 3.2 hz , 1h ) , 
 1.421.30 ( m , 2h ) ; c nmr ( 125.8 mhz , cdcl3 ) ppm 168.8 , 156.0 , 148.1 , 142.3 , 133.1 , 131.3 , 129.9 , 126.3 , 
 123.3 , 122.4 , 122.3 , 120.9 , 111.0 , 56.1 , 51.3 , 33.4 , 28.7 , 25.5 , 24.8 ; 
 hrms ( esi ) exact mass calcd for c23h21cln3o2 [ m + h ] 406.1322 , found 406.1308 . in a flask equipped with a stir bar were 
 placed the quinoline ( 596 mg , 1.47 mmol ) and ethanol ( 3 ml ) , and the 
 resulting solution was stirred at room temperature for 5 min . hydrazine 
 monohydrate ( 264 l , 5.43 mmol ) was added , and the reaction 
 mixture was stirred under reflux for 3 h , whereupon a white solid 
 precipitated out of solution . after the reaction mixture was cooled 
 to room temperature , the solid was washed with ether and filtered . the remaining solid was triturated with ether , the suspension was 
 filtered once more , and the filtrate was concentrated to an orange 
 foam ( 401 mg , 99% ) : [ ]d = 3.3 
 ( c 0.61 , chcl3 ) ; rf = 0.25 ( 10% meoh/1%acoh / ch2cl2 ) ; ir 
 ( film ) 3268 , 2930 , 2857 , 1609 , 1538 cm ; h nmr ( 400 mhz , cdcl3 )  7.91 ( d , j = 8.0 hz , 1h ) , 7.61 ( d , j = 8.4 hz , 1h ) , 7.49 ( ddd , j = 8.4 , 8.4 , 1.2 hz , 1h ) , 7.20 ( ddd , j = 8.0 , 8.0 , 0.8 hz , 1h ) , 6.75 ( s , 1h ) , 5.19 ( d , j = 8.4 hz , 1h ) , 3.64 ( m , 1h ) , 2.44 ( ddd j = 10.0 , 
 10.0 , 4.0 hz , 1h ) , 2.07 ( br m , 1h ) , 1.90 ( br m , 1h ) , 1.691.64 
 ( br m , 4h ) , 1.391.14 ( m , 3h ) , 1.07 ( ddd , j = 12.8 , 12.8 , 3.2 hz , 1h ) ; c nmr ( 125.8 mhz , cdcl3 ) ppm 156.7 , 148.5 , 142.4 , 130.2 , 126.1 , 123.7 , 122.3 , 121.3 , 
 111.0 , 57.4 , 55.8 , 35.2 , 32.5 , 24.9 , 24.8 ; hrms ( esi ) exact mass calcd 
 for c15h19cln3 [ m + h ] 276.1268 , found 276.1260 . in a flame - dried flask equipped with a 
 stir bar were placed the amine ( 200 mg , 725 mol ) , the carboxylic 
 acid ( 187 mg , 725 mol ) , and dichloromethane ( 4 ml ) . the resulting 
 solution was chilled to 0 c , and edc ( 181 mg , 943 mol ) 
 and dmap ( 9.00 mg , 72.5 mol ) were added . after 20 h , 
 the reaction mixture was diluted with water and extracted with ch2cl2 . the combined organic layers were washed once 
 with water , dried over mgso4 , and concentrated . flash column 
 chromatography of the residue ( sio2 , 540% ethyl 
 acetate in hexanes ) afforded the desired amide as a white amorphous 
 solid ( 291 mg , 78% ) : [ ]d = + 291 
 ( c 1.11 , chcl3 ) ; rf = 0.43 ( 30% etoac / hexanes ) ; ir ( film ) 3335 , 2937 , 2861 , 1654 , 
 1608 , 1536 cm , h nmr ( 600 mhz , cdcl3 )  8.60 ( br d , j = 5.4 hz , 1h ) , 7.94 
 ( s , 2h ) , 7.93 ( dd , j = 9.0 , 0.6 hz , 1h ) , 7.74 ( s , 
 1h ) , 7.61 ( d , 7.8 hz , 1h ) , 7.55 ( ddd , j = 7.8 , 7.8 , 
 0.6 hz , 1h ) , 7.29 ( ddd , j = 7.8 , 7.8 , 0.6 hz , 1h ) , 
 6.71 ( s , 1h ) , 4.70 ( d , j = 7.2 hz , 1h ) , 4.26 ( m , 
 1h ) , 3.86 ( m , 1h ) , 2.46 ( m , 1h ) , 2.12 ( m , 1h ) , 1.90 ( br dd , j = 5.4 , 1.8 hz , 1h ) , 1.83 ( br s , 1h ) , 1.47 ( m , 4h ) ; c nmr ( 150.9 mhz , cdcl3 ) ppm 164.9 , 156.8 , 147.6 , 
 143.3 , 137.0 , 131.7 ( q , jfc = 34.0 hz , 
 1c ) , 131.2 , 127.1 , 125.7 , 124.5 ( q , jfc = 3.5 hz , 1c ) , 124.1 , 123.4 , 122.7 ( q , jfc = 273.0 hz , 1c ) , 121.7 , 112.1 , 58.9 , 53.4 , 33.2 , 32.1 , 25.3 , 24.3 ; 
 hrms ( esi ) exact mass calcd for c24h21clf6n3o [ m + h ] 516.1278 , found 516.1254 . in a flame - dried flask equipped with a 
 stir bar were placed the amine ( 60.0 mg , 218 mol ) and dichloromethane 
 ( 3 ml ) , immediately followed by the addition of n , n - diisopropylethylamine ( 46.0 l , 261 mol ) , 
 the acid chloride ( 32.0 l , 261 mol ) , and dmap ( 2.70 
 mg , 22.0 mol ) . the reaction mixture was stirred at room temperature 
 for 24 h , quenched with 1 m hcl , and extracted with dichloromethane . the organic extracts were then washed with saturated aqueous nahco3 , extracted with dichloromethane , dried ( mgso4 ) , 
 filtered and concentrated . flash column chromatography of the residue 
 ( sio2 , 2050% ethyl acetate in hexanes ) afforded 
 the desired amide as a white solid ( 57.9 mg , 74% ) : mp 213 - 216 c ; 
 [ ]d = + 281 ( c 0.45 , chcl3 ) ; rf = 0.38 ( 40% 
 etoac / hexanes ) ; ir ( film ) 3313 , 2932 , 2858 , 1607 , 1576 , 1535 cm ; h nmr ( 600 mhz , cdcl3 )  
 7.96 ( dd , j = 7.8 , 0.6 hz , 1h ) , 7.64 ( d , j = 7.8 hz , 1h ) , 7.56 ( ddd , j = 8.4 , 6.6 , 
 1.2 hz , 1h ) , 7.27 ( ddd , j = 7.8 , 7.8 , 1.2 hz , 1h ) , 
 6.84 ( d , j = 6.0 hz , 1h ) , 6.71 ( s , 1h ) , 5.03 ( br 
 d , j = 7.8 hz , 1h ) , 4.18 ( m , 1h ) , 3.71 ( m , 1h ) , 2.16 
 ( m , 2h ) , 1.82 ( m , 1h ) , 1.78 ( d , j = 10.8 hz , 1h ) , 
 1.471.28 ( m , 4h ) , 0.87 ( s , 9h ) ; c nmr ( 150.9 
 mhz , cdcl3 ) ppm 179.1 , 156.7 , 148.3 , 142.6 , 130.5 , 126.2 , 
 124.0 , 122.6 , 121.6 , 112.2 , 56.1 , 53.5 , 38.4 , 33.1 , 32.5 , 27.3 , 25.1 , 
 24.7 ; hrms ( esi ) exact mass calcd for c20h26cln3nao [ m + na ] 382.1662 , found 382.1658 . a 0.52 ml microwave vial was charged 
 with n-((1r,2r)-2-((4-chloroquinolin-2-yl)amino)cyclohexyl)pivalamide 
 ( 40.0 mg , 111 mol ) , pyrrolidine ( 37.0 l , 445 mol ) , 
 and trifluorotoluene ( 800 l ) . this suspension was heated at 
 150 c and stirred in the microwave for 90 min . the reaction 
 mixture was concentrated and purified by flash column chromatography 
 ( 110% methanol in dichloromethane w/1% acoh ) to provide a 
 yellow oil . the organic layers were combined and washed 
 three times more with 3 m aqueous naoh . the combined organic layers 
 were dried ( mgso4 ) and concentrated to afford a tan amorphous 
 solid ( 23.5 mg , 54% ) : mp 251256 c ; [ ]d = + 143 ( c 0.69 , chcl3 ) ; rf = 0.35 ( 5% meoh/1% acoh / ch2cl2 ) ; ir ( film ) 3299 , 2929 , 2856 , 2361 , 1630 , 1588 , 
 1534 cm ; h nmr ( 600 mhz , cdcl3 )  7.97 ( d , j = 7.8 hz , 1h ) , 7.58 
 ( br d , j = 7.8 hz , 1h ) , 7.47 ( br s , 1h ) , 7.42 ( dd , j = 7.8 , 7.8 hz , 1h ) , 7.06 ( dd , j = 7.8 , 
 7.8 hz , 1h ) , 5.64 ( s , 1h ) , 4.34 ( br s , 1h ) , 4.21 ( m , 1h ) , 3.603.54 
 ( m , 5h ) , 2.22 ( br d , j = 11.4 hz , 1h ) , 2.06 ( br m , 
 1h ) , 1.99 ( m , 4h ) , 1.80 ( br d , j = 10.8 hz , 1h ) , 
 1.73 ( br d , j = 12.0 hz , 1h ) , 1.461.28 ( m , 
 4h ) , 0.84 ( s , 9h ) ; c nmr ( 150.9 mhz , cdcl3 ) ppm 178.9 , 158.1 , 153.9 , 149.6 , 128.7 , 126.6 , 124.9 , 119.8 , 118.8 , 
 92.0 , 57.5 , 52.3 , 52.0 , 38.3 , 33.5 , 32.4 , 27.3 , 25.8 , 25.4 , 24.6 ; 
 hrms ( esi ) exact mass calcd for c24h34n4nao [ m + na ] 417.2630 , found 417.2630 . a 25 ml microwave vial was charged 
 with n-((1r,2r)-2-((4-chloroquinolin-2-yl)amino)cyclohexyl)-3,5-bis(trifluoromethyl)benzamide 
 ( 291 mg , 564 mol ) , pyrrolidine ( 185 l , 2.26 mmol ) , and 
 trifluorotoluene ( 3.52 ml ) . this suspension was heated at 150 c 
 and stirred in the microwave for 90 min . the reaction mixture was 
 concentrated and purified by flash column chromatography ( 110% 
 methanol in dichloromethane w/1% acoh ) to provide a yellow oil . this 
 material was diluted with dichloromethane and washed with 6 m aqueous 
 naoh . the organic layers were combined and washed twice more with 
 3 m aqueous naoh . the combined organic layers were dried over mgso4 and concentrated to afford a white amorphous solid ( 215 mg , 
 69% ) : [ ]d = + 184 ( c 0.93 , chcl3 ) ; rf = 0.15 ( 5% 
 meoh/1% acoh / ch2cl2 ) ; ir ( film ) 3343 , 2935 , 
 2861 , 1655 , 1589 , 1531 cm ; h nmr ( 600 
 mhz , cdcl3 )  9.52 ( d , j = 4.2 hz , 
 1h ) , 7.98 ( s , 2h ) , 7.96 ( dd , j = 8.4 , 0.6 hz , 1h ) , 
 7.73 ( s , 1h ) , 7.51 ( d , j = 8.4 hz , 1h ) , 7.39 ( ddd , j = 8.4 , 8.4 , 1.2 hz , 1h ) , 7.07 ( ddd , j = 8.4 , 7.2 , 1.2 hz , 1h ) , 5.65 ( s , 1h ) , 4.34 ( br s , 1h ) , 4.21 ( m , 
 1h ) , 3.73 ( m , 1h ) , 3.55 ( m , 4h ) , 2.51 ( d , j = 12.0 
 hz , 1h ) , 2.07 ( m , 1h ) , 1.98 ( m , 4h ) , 1.87 ( d , j = 
 4.8 hz , 1h ) , 1.81 ( d , j = 6.0 hz , 1h ) , 1.44 ( m , 4h ) ; c nmr ( 150.9 mhz , cdcl3 ) ppm 165.2 , 158.3 , 154.0 , 
 149.0 , 137.6 , 131.5 ( q , jfc = 33.7 hz , 
 1c ) , 129.3 , 127.3 , 126.1 , 124.9 , 124.2 , 122.8 ( q , j = 273.1 hz , 1c ) , 120.3 , 118.6 , 91.2 , 59.6 , 53.1 , 51.9 , 33.3 , 31.9 , 
 25.8 , 25.5 , 24.4 ; hrms ( esi ) exact mass calcd for c28h29f6n4o [ m + h ] 551.2246 , 
 found 551.2237 . aldehyde ( 2.0 ml , 16.8 mmol ) , hydroxylamine 
 hydrochloride ( 1.40 g , 20.2 mmol ) , pyridine ( 2.45 ml , 30.3 mmol ) , 
 and ethanol ( 5.6 ml ) were combined in a flask at room temperature . the mixture was stirred for 10 h , and ethanol was evaporated under 
 reduced pressure . the mixture was diluted with etoac and washed twice 
 with 1 m aqueous hcl and once with saturated aqueous nahco3 and brine . the organic layer was dried ( mgso4 ) , filtered , 
 and concentrated to give a white crystalline solid ( 3.6 g , 98% ) : mp 
 7677 c ; rf = 0.6 ( ch2cl2 ) ; ir ( film ) 3285 ( br ) , 3079 , 3017 , 1904 , 1492 
 cm ; h nmr ( 400 mhz , cdcl3 )  8.69 ( br s , 1h ) , 8.30 ( s , 1h ) , 7.89 ( dd , j = 8.8 , 4.0 hz , 1h ) . 7.46 ( m , 1h ) , 6.97 ( t , j = 
 9.2 hz , 1h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 161.0 
 ( d , jcf = 255 hz ) , 143.1 ( d , jcf = 3 hz ) , 134.2 , 129.6 ( d , jcf = 3 hz ) , 121.8 , 117.7 ( d , jcf = 22 hz ) , 117.1 ( d , jcf = 3 hz ) ; hrms ( apci ) : exact mass 
 calcd for c7h5brfno [ m ] 216.9533 , 
 found 216.9539 . aryl 
 boc - imine ( 4a  k ; 100 mol ) 
 and benzmam ( 10 ; 2.8 mg , 5.0 mol ) or pivmam ( 9 ; 2.0 mg , 5.0 mol ) were dispensed into a flame - dried 
 vial with a stir bar . toluene ( 1.0 ml ) was added , and the reaction 
 was stirred at room temperature until homogeneous . the reaction mixture 
 was chilled to 78 c before the aryl nitroalkane 3a  i ( 110 mol ) was added . the reaction mixture 
 was warmed to 20 c and stirred for 1860 h. the 
 chilled mixture was either diluted with ch2cl2 to dissolve precipitate and quickly flushed through a pad of silica 
 gel or diluted with cold hexanes and filtered through a buchner funnel 
 with filter paper ( scale 0.2 mmol ) . if the product 
 was added to silica , the pad was flushed with ch2cl2 , the filtrate was concentrated , and the residue was purified 
 by column chromatography ( sio2 , ethyl acetate in hexanes ) , 
 if needed . imine 2b ( 163 mg , 564 mol ) 
 and ( s , s)-10 ( 15.4 mg , 28 mol ) 
 were placed in a flask in toluene ( 5.6 ml ) under argon . the mixture 
 was cooled to 20 c , and nitroalkane 3a ( 106 
 mg , 620 mol ) was added . after 48 h the reaction mixture was 
 filtered through a plug of silica gel and concentrated . column chromatography 
 ( sio2 , 015% ethyl acetate in hexanes ) afforded 
 the product as a white crystalline solid ( 160 mg , 62% ) . the major 
 diastereomer was determined to be 94% ee and the minor to be 92% ee , 
 with 6:1 dr determined by chiral hplc ( chiralcel ad : 6% proh / hexanes , 1.0 ml / min : tr(d2e2 minor / minor ) = 11.5 min , tr(d1e1 major / major ) = 13.4 min , tr(d1e2 major / minor ) = 15.4 min , tr(d2e1 minor / major ) = 20.3 min ) : mp 145 c ; rf = 0.58 ( 20% etoac / hexanes ) ; ir ( film ) 3372 , 2981 , 2927 , 
 1686 , 1558 , 1498 cm ; h nmr ( 400 mhz , 
 cdcl3 )  7.49 ( d , j = 8.4 hz , 1h ) , 
 7.39 ( m , 4h ) , 7.29 ( m , 2h ) , 7.20 ( m , 1h ) , 5.78 ( br dd , 1h ) , 5.61 ( br 
 d , 2h ) , 1.28 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 154.7 , 154.3 , 139.5 , 136.6 , 130.5 , 130.0 , 129.6 , 129.3 , 129.2 
 ( 2c ) , 125.7 , 125.4 , 124.7 , 121.2 , 120.4 ( q , jcf = 249 hz ) , 119.9 , 93.0 , 28.3 , 28.0 ; hrms ( apci ) : exact 
 mass calcd for c20h20clf3n2nao5 [ m + na ] 483.0911 , found 483.0907 . imine 2a ( 348 mg , 1.45 mmol ) and 
 ( r , r)-10 ( 40.0 mg , 73.0 mol ) 
 were placed in a flask in toluene ( 14.5 ml ) under argon . the mixture 
 was cooled to 78 c and nitroalkane 3b ( 377 
 mg , 1.61 mmol ) added . after 36 h the white precipitate was vacuum - filtered 
 and washed with hexanes to afford the title compound as a white crystalline 
 solid ( 493 mg , 75% ) . the major diastereomer was determined to be 94% 
 ee with > 200:1 dr determined by chiral hplc ( chiralcel ia : 15% proh / hexanes , 1.0 ml / min : tr(d1e2 major / minor ) = 10.2 min , tr(d2e1 minor / major ) = 11.8 min , tr(d1e1 major / major ) = 24.2 min , tr(d2e2 minor / minor ) = 33.4 min ) : [ ]d = 23 ( c 0.27 , chcl3 ) ; mp 183184 c ; rf = 0.40 ( 20% etoac / hexanes ) ; ir ( film ) 3375 , 2980 , 1683 , 1544 , 1523 
 cm ; h nmr ( 400 mhz , cdcl3 )  7.55 ( d , j = 8.4 hz , 2h ) , 7.43 ( d , j = 8.4 hz , 2h ) , 7.34 ( d , j = 8.4 hz , 2h ) , 
 7.27 ( d , j = 8.4 hz , 2h ) , 5.74 ( d , j = 8.8 hz , 1h ) , 5.57 ( dd , j = 9.2 , 8.8 hz , 1h ) , 
 4.82 ( br d , 1h ) , 1.28 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 154.2 , 134.8 , 132.1 , 130.3 , 129.3 , 129.0 , 128.6 , 128.2 , 
 124.8 , 93.2 , 30.9 , 28.0 ; hrms ( esi ) exact mass calcd for c19h20brcln2nao4 [ m + na ] 477.0193 , found 477.0211 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-9 ( 5 mol % ) with a 48 h reaction time . the 
 reaction precipitate was added to the filter paper a buchner funnel 
 and washed with cold hexanes to afford the product as a white crystalline 
 solid ( 35 mg , 81% ) that was found to be 93% ee and > 200:1 dr by 
 chiral hplc ( chiralcel ia : 9% proh / hexanes , 
 0.6 ml / min : tr(d1e1 major / major ) 
 = 12.6 min , tr(d2e1 minor / major ) 
 = 15.0 min , tr(d1e2 major / minor ) 
 = 17.1 min , tr(d2e2 minor / minor ) 
 = 18.6 min ) : [ ]d = 37 
 ( c 0.44 , chcl3 ) ; mp 182183 c ; rf = 0.55 ( 25% etoac / hexanes ) ; ir ( film ) 3389 , 
 3056 , 2980 , 1683 , 1490 cm ; h nmr ( 400 
 mhz , cdcl3 )  7.57 ( m , 1h ) , 7.44 ( m , 2h ) , 7.377.28 
 ( m , 5h ) , 5.76 ( br d , 1h ) , 5.56 ( br dd , 1h ) , 4.86 ( br d , 1h ) , 1.29 
 ( s , 9h ) ; c nmr ( 100 mhz . cdcl3 ) ppm 154.2 , 
 134.9 , 134.8 , 133.1 , 130.5 , 130.3 , 130.2 , 130.1 , 129.3 , 129.1 , 128.9 , 
 128.6 , 128.3 , 128.0 , 126.8 , 93.2 , 28.1 ; hrms ( esi ) exact mass calcd 
 for c19h20cl2n2nao4 [ m + na ] 433.0698 ; found 433.0715 . the reaction was run with catalyst ( r , r)-8 ( 2 mol % ) at 78 
 c for 8 h and the mixture was then warmed to 20 c 
 for an additional 24 h. following silica plug removal of the catalyst , 
 column chromatography ( sio2 , 010% ethyl acetate 
 in hexanes ) afforded the product as a white crystalline solid ( 422 
 mg , 65% ) . the major diastereomer was determined to be 92% ee and the 
 minor to be 90% ee , with 3:1 dr determined by chiral hplc ( chiralcel 
 ia : 10% proh / hexanes , 0.8 ml / min : tr(d1e1 minor / major ) = 17.6 min , tr(d1e2 minor / minor ) = 18.6 min , tr(d2e1 major / major ) = 20.9 min , tr(d1e2 major / minor ) = 44.6 min ) : mp 184185 
 c ; rf = 0.30 ( 25% etoac / hexanes ) ; 
 ir ( film ) 3505 , 3374 ( br ) , 2976 , 2935 , 1698 , 1561 , 1492 cm ; h nmr ( 400 mhz , cdcl3 )  7.85 ( dd , j = 2.4 , 2.4 hz , 1h ) , 7.52 ( m , 1h ) , 7.36 ( d , j = 7.6 hz , 2h ) , 7.30 ( d , j = 7.6 hz , 2h ) , 7.04 ( t , j = 8.8 hz , 1h ) , 6.10 ( d , j = 10.4 hz , 
 1h ) , 5.64 ( br d , 1h ) , 4.84 ( d , j = 9.6 hz , 1h ) , 1.29 
 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 161.0 
 ( d , jcf = 259 hz ) , 154.6 , 
 135.3 , 135.0 , 134.9 , 130.9 , 129.4 , 129.2 , 128.5 , 128.2 ( d , jcf = 4 hz ) , 127.9 ( d , jcf = 4 hz ) , 120.8 ( d , jcf = 24 hz ) , 117.3 , 85.4 , 28.0 ; hrms ( apci ) exact mass 
 calcd for c19h19brclfn2nao4 [ m + na ] 495.0098 , found 495.0107 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-10 ( 5 mol % ) with a 48 h reaction time . the reaction precipitate was added to the filter paper of a buchner 
 funnel and washed with cold hexanes to afford the adduct as a white 
 crystalline solid ( 42 mg , 54% ) , which was found to be 35:1 dr and 
 92% ee by chiral hplc analysis ( chiralpak ad - h , 8% iproh / hexanes , 1 ml / min , tr(d1e1 , major / major ) = 21.6 min , tr(d2e2 , minor / minor ) = 23.8 min , tr(d2e2 , minor / minor ) 
 = 30.9 min , tr(d1e2 , major / minor ) = 40.2 min ) : 
 mp 162164 c ; rf = 0.53 ( 33% 
 etoac / hexanes ) ; ir ( film ) 3379 , 2977 , 1680 , 1553 , 1523 , 1289 , 1252 , 
 1160 cm ; h nmr ( 400 mhz , cdcl3 )  7.35 ( m , 6 h ) , 7.18 ( m , 2 h ) , 5.80 ( s , 1 h ) , 5.59 
 ( s , 1 h ) , 4.92 ( s , 1 h ) , 1.31 ( s , 9h ) ; c nmr ( 100 mhz , 
 cdcl3 ) ppm 163.8 , 161.3 , 154.2 , 135.6 , 134.8 , 133.4 , 133.3 , 
 131.2 , 130.5 , 130.4 , 129.2 , 129.1 , 129.0 , 128.6 , 128.3 , 128.2 , 125.2 , 
 124.5 , 117.5 , 117.3 , 115.9 , 115.6 , 93.2 , 93.1 , 80.8 , 28.2 , 28.1 , 28.0 , 
 27.8 ; hrms exact mass calcd for c19h20clfn2nao4 [ m + na ] 417.0993 , found 417.1101 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-9 ( 5 mol % ) with a 60 h reaction time . column 
 chromatography ( sio2 , 05% ethyl acetate in hexanes ) 
 afforded the adduct as a white crystalline solid ( 22 mg , 65% ) , which 
 was found to be 21:1 dr and 93% ee by chiral hplc analysis ( chiralpak 
 ad - h , 10% proh / hexanes , 1.0 ml / min : tr(d2e1 , minor / major ) = 17.9 min , tr(d1e2 , , major / minor ) 
 = 22.0 min , tr(d2e2 , minor / minor ) = 26.3 , tr(d1e1 , major / major ) = 32.0 min ) . the 79% ee and 34:1 dr material 
 was used for optical rotation : [ ]d 25.8 ( c 1.13 , chcl3 ) ; mp 127130 c ; rf = 0.56 ( 33% etoac / hexanes ) ; ir ( film ) 3385 , 1681 , 1548 , 1521 , 1365 , 
 1161 cm ; h nmr ( 400 mhz , cdcl3 )  7.377.22 ( m , 8 h ) , 5.72 ( d , j = 8.8 hz , 1 h ) , 5.61 ( dd , j = 8.8 , 8.8 hz , 1 h ) , 
 4.74 ( d , j = 7.6 hz , 1 h ) , 2.39 ( s , 3 h ) , 1.28 ( s , 
 9 h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 138.8 , 134.5 , 
 131.4 , 131.1 , 130.8 , 129.1 , 128.8 , 128.6 , 125.6 , 94.0 , 68.1 , 38.7 , 
 28.9 , 28.2 , 28.0 , 23.7 , 22.9 , 21.3 ; hrms ( esi ) exact mass calcd for 
 c20h23cln2nao4 [ m + na ] 413.1244 , found 413.1252 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-9 ( 5 mol % ) with a 48 h reaction time . the 
 crude product that precipitated out was filtered and washed with cold 
 hexanes to give a off - white crystalline solid ( 740 mg , 78% ) that was 
 found to be 92% ee and 25:1 dr by chiral hplc ( chiralcel ad - h : 8% 
 etoh / hexanes , 1.0 ml / min : tr(d1e2 major / minor ) = 11.5 min , tr(d2e1 minor / major ) = 14.0 min , tr(d1e1 minor / minor ) = 18.6 min , tr(d2e2 major / major ) = 21.3 min ) : [ ]d = 26.7 
 ( c 0.26 , ch3oh ) ; mp 172173 c ; 
 ir ( film ) 3388 , 2982 , 1681 , 1549 , 1519 , 1493 cmh nmr ( 400 mhz , cdcl3 )  7.71 ( t , j = 1.8 hz , 1h ) , 7.627.55 ( m , 1h ) , 7.52 ( d , j = 7.9 hz , 1h ) , 7.387.33 ( m , 2h ) , 7.337.27 ( m , 3h ) , 
 5.75 ( s , 1h ) , 5.56 ( t , j = 9.7 hz , 1h ) , 4.83 ( s , 
 1h ) , 1.28 ( s , 9h ) ; c nmr ( 126 mhz , cd3od ) 
  156.8 , 138.2 , 135.9 , 135.5 , 134.4 , 133.0 , 131.7 , 130.3 , 130.0 , 
 128.6 , 123.5 , 94.5 , 80.9 , 57.1 , 28.4 ; hrms ( esi ) exact mass calcd 
 for c19h20brcln2nao4 [ m 
 + na ] 477.0193 , found 477.0218 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-10 ( 5 mol % ) with a 48 h reaction time . column chromatography ( sio2 , 1025% ethyl acetate 
 in hexanes ) afforded the adduct as an off - white solid ( 56.0 mg , 76% ) 
 that was found to be 76% ee and 37:1 dr by chiral hplc ( chiralcel 
 ia : 12% proh / hexanes , 1.0 ml / min : tr(d2e1 minor / major ) = 16.9 min , tr(d1e1 major / major ) = 19.2 min , tr(d1e2 major / minor ) = 20.1 min , tr(d2e2 minor / minor ) = 25.5 min ) : [ ]d = 4.5 ( c 0.40 , chcl3 ) ; mp 148149 c ; rf = 0.25 ( ch2cl2 ) ; ir ( film ) 3367 , 2975 , 2837 , 
 1703 , 1557 , 1521 cm ; h nmr ( 400 mhz , 
 cdcl3 )  7.33 ( d , j = 8.8 hz , 2h ) , 
 7.29 , ( d , j = 8.8 hz , 2h ) , 7.07 ( d , j = 4.0 hz , 1h ) , 7.05 ( d , j = 2.0 hz , 1h ) , 6.86 ( d , j = 8.4 hz , 1h ) , 5.70 ( d , j = 10.0 hz , 
 1h ) , 5.64 ( d , j = 8.4 hz , 1h ) , 4.82 ( d , j = 8.4 hz , 1h ) , 3.90 ( s , 3h ) , 3.89 ( s , 3h ) , 1.28 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 154.3 , 150.7 , 149.2 , 136.2 , 
 134.6 , 129.2 , 128.6 , 123.5 , 122.1 , 110.9 , 93.9 , 80.6 , 56.0 ( 2c ) , 28.1 ; 
 hrms ( esi ) exact mass calcd for c21h25cln2nao6 [ m + na ] 459.1299 , found 459.1309 . the reaction employed catalyst ( r , r)-9 ( 5 mol % ) with a 48 h reaction 
 time . the crude precipitated product was filtered and washed with 
 cold hexanes to give a white solid ( 1.05 g , 87% ) that was found to 
 be 95% ee and 23:1 dr by chiral hplc ( chiralcel ad : 10% etoh / hexanes , 
 1.0 ml / min : tr(d2e1 minor / major ) 
 = 9.1 min , tr(d1e1 major / major ) 
 = 11.3 min , tr(d2e2 minor / minor ) 
 = 13.0 min , tr(d1e2 major / minor ) 
 = 32.1 min ) : h nmr ( 400 mhz , cdcl3 )  
 7.377.27 ( m , 5h ) , 7.09 ( dd , j = 5.1 , 2.8 
 hz , 2h ) , 7.006.94 ( m , 1h ) , 5.73 ( d , j = 9.8 
 hz , 1h ) , 5.62 ( d , j = 9.8 hz , 1h ) , 4.89 ( s , 1h ) , 
 3.82 ( s , 3h ) , 1.27 ( s , 9h ) ; lrms ( esi ) c20h24cln2o5 [ m + h ] 406.86 , found 407.58 . this compound was prepared according to the 
 general procedure employing catalyst ( s , s)-10 ( 5 mol % ) with a 36 h reaction time . the reaction 
 precipitate was added to the filter paper in a buchner funnel and 
 washed with cold hexanes to afford the adduct as a white crystalline 
 solid ( 310 mg , 88% ) that was found to be 93% ee with > 200:1 dr 
 determined by chiral hplc ( chiralcel ad - h : 15% proh / hexanes , 1.0 ml / min : tr(d1e1 major / major ) = 10.5 min , tr(d2e1 minor / minor ) = 12.4 min , tr(d1e2 major / minor ) = 22.0 min , tr(d2e1 minor / minor ) = 36.7 min ) : [ ]d = + 28 
 ( c 0.24 , chcl3 ) ; mp 185186 c ; rf = 0.42 ( 20% etoac / hexanes ) ; ir ( film ) 3389 , 
 2976 , 1681 , 1552 , 1519 , 1498 cm ; h 
 nmr ( 400 mhz , cdcl3 )  7.49 ( m , 4h ) , 7.38 ( d , j = 8.4 hz , 2h ) , 7.21 ( d , j = 8.4 hz , 2h ) , 
 5.75 ( br d , 1h ) , 5.56 ( br dd , 1h ) , 4.84 ( br d , 1h ) , 1.28 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 154.2 , 136.6 , 132.2 , 
 130.1 , 129.7 , 129.1 , 128.9 , 123.0 , 93.1 , 20.0 ; hrms ( esi ) exact mass 
 calcd for c19h20brcln2nao4 [ m + na ] 477.0193 , found 477.0216 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-10 ( 5 mol % ) with a 48 h reaction time . column chromatography ( sio2 , 110% ethyl acetate 
 in hexanes ) afforded the adduct as an off - white crystalline solid 
 ( 21 mg , 82% ) that was found to be 94% ee and 9:1 dr by chiral hplc 
 ( chiralcel ad - h : 8% proh / hexanes , 1.0 
 ml / min : tr(d1e2 major / minor ) = 11.7 min , tr(d2e1 major / minor ) = 19.6 min , tr(d1e1 major / major ) = 25.7 min , tr(d2e2 minor / minor ) = 40.2 min ) : mp 179181 
 c ; rf = 0.49 ( 20% etoac / hexanes ) ; 
 ir ( film ) 3378 , 2977 , 2922 , 1678 , 1560 , 1519 cm ; h nmr ( 400 mhz , cdcl3 )  7.51 ( d , j = 8.4 hz , 2h ) , 7.40 ( d , j = 8.4 hz , 2h ) , 
 7.32 ( dd , j = 8.4 , 8.4 hz , 2h ) , 7.05 ( dd , j = 8.4 , 8.4 hz , 2h ) , 5.75 ( br d , 1h ) , 5.59 ( br dd , 1h ) , 
 4.80 ( br d , 1h ) , 1.28 ( s , 9h ) ; c nmr ( 150 mhz , cdcl3 ) ppm 162.4 ( d , jcf = 249 hz ) , 154.2 , 136.5 , 133.0 , 130.1 , 129.8 , 129.1 , 129.0 ( d , jcf = 7.5 hz ) , 116.1 ( d , jcf = 23 hz ) , 93.4 , 80.8 , 28.0 ; 
 hrms ( esi ) exact mass calcd for c19h20clfn2nao4 [ m + na ] 417.0993 , found 417.1010 . this compound 
 was prepared according to the general procedure employing catalyst 
 ( s , s)-10 ( 5 mol % ) 
 with a 24 h reaction time . column chromatography ( sio2 , 
 05% ethyl acetate in hexanes ) afforded the adduct as a white 
 crystalline solid ( 27 mg , 84% ) that was found to be a 99% ee and > 100:1 
 dr by chiral hplc ; ( chiralpak ad - h , 15% proh / hexanes , 1.0 ml / min : tr(d1e1 , major / major ) 
 = 11.8 min , tr ( d2e1 , minor / major ) = 14.1 min , tr ( d1e1 , major / major ) = 22.8 min , tr ( d2e2 , minor / minor 
 = 42.4 min ) : [ ]d + 22 
 ( c 0.16 , chcl3 ) ; mp 189190 c ; rf = 0.50 ( 20% etoac in hexanes ) ; ir ( film ) 3380 , 
 2979 , 1679 , 1548 , 1520 cm ; h nmr ( 400 
 mhz , cdcl3 )  7.71 ( d , j = 8.4 hz , 
 2h ) , 7.49 ( d , j = 8.4 hz , 2h ) , 7.40 ( d , j = 8.4 hz , 2h ) , 7.09 ( d , j = 8.4 hz , 2h ) , 5.75 ( d , j = 8.8 hz , 1h ) , 5.55 ( dd , j = 9.4 , 8.8 
 hz , 1h ) , 4.76 ( d , j = 9.2 hz , 1h ) , 1.27 ( s , 9h ) ; c nmr ( 100.6 mhz , ( cd3)2so ) ppm 154.7 , 
 138.4 , 137.9 , 135.4 , 131.1 , 130.9 , 130.3 , 129.2 , 95.3 , 92.9 , 79.2 , 
 55.9 , 28.2 ; hrms ( esi ) exact mass calcd for c19h20clin2nao4 [ m + na ] 525.0054 , found 
 525.0082 . this 
 compound was prepared according to the general procedure employing 
 catalyst ( s , s)-9 ( 5 
 mol % ) with a 72 h reaction time . the reaction precipitate was added 
 to the filter paper of a buchner funnel and washed with cold hexanes 
 to afford the adduct as a white crystalline solid ( 360 mg , 80% ) . the 
 major diastereomer was determined to be 99% ee with > 200:1 dr determined 
 by chiral hplc ( chiralcel ad - h : 15% proh / hexanes , 
 0.6 ml / min : tr(d1e1 major / major ) 
 = 14.3 min , tr(d2e2 minor / minor ) 
 = 15.2 min , tr(d1e2 major / minor ) 
 = 29.5 min , tr(d2e1 minor / minor ) 
 = 32.4 min ) : [ ]d = + 220 ( c 0.20 , chcl3 ) ; mp 170172 c ; rf = 0.45 ( 20% etoac / hexanes ) ; ir ( film ) 3393 , 
 2981 , 2360 , 1679 , 1545 , 1518 cm ; h 
 nmr ( 400 mhz , cdcl3 )  7.68 ( m , 2h ) , 7.49 ( d , j = 7.6 hz , 2h ) , 7.39 ( d , j = 7.6 hz , 2h ) , 
 7.30 ( d , j = 7.6 hz , 1h ) , 7.09 ( dd , j = 7.6 , 7.6 hz , 1h ) , 5.72 ( br d , j = 9.2 hz , 1h ) , 
 5.55 ( br dd , 1h ) , 4.82 ( br d , 1h ) , 1.28 ( s , 9h ) ; c nmr 
 ( 100 mhz , cdcl3 ) ppm 154.1 , 139.4 , 138.0 , 136.6 , 136.1 , 
 130.7 , 130.1 , 129.7 , 129.4 , 129.1 , 126.6 , 94.8 , 93.1 , 28.0 ; hrms ( esi ) 
 exact mass calcd for c19h20clin2nao4 [ m + na ] 525.0054 , found 525.0071 . this 
 compound was prepared according to the general procedure employing 
 catalyst ( r , r)-10 ( 5 
 mol % ) with a 48 h reaction time , and following silica filtration 
 the product was isolated as a white crystalline solid ( 48 mg , 98% 
 overall ) that was found to be 88% ee and 50:1 dr by chiral hplc ( chiralpak 
 ia , 10% proh / hexanes , 1 ml / min , tr(d1e1 major / major ) = 9.6 min , tr(d2e2 minor / minor ) 
 = 12.4 min , tr(d1e2 minor / major ) = 14.9 , tr(d1e2 major / minor ) = 32.7 min ) : [ ]d = 38 ( c 0.11 , chcl3 , recrystallized material , 96% ee , 200:1 dr ) ; mp 186188 c ; rf = 0.56 ( 33% etoac / hexanes ) ; ir ( film ) 3399 , 
 2984 , 2921 , 2359 , 1688 cm ; h nmr ( 400 
 mhz , cdcl3 )  7.55 ( d , j = 8.4 hz , 
 2 h ) , 7.41 ( d , j = 8.4 hz , 1 h ) , 7.28 ( m , 2 h ) , 7.15 
 ( m , 3 h ) , 5.76 ( d , j = 10.0 hz , 1 h ) , 5.64 ( m , 1 
 h ) , 4.71 ( d , j = 9.6 hz , 1 h ) , 2.48 ( s , 3 h ) , 1.3 
 ( s , 9 h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 154.2 , 
 138.9 , 137.0 , 136.3 , 130.2 , 130.0 , 129.7 , 129.0 , 128.9 , 127.9 , 124.0 , 
 94.6 , 80.4 , 56.5 , 28.0 , 21.4 ; hrms ( esi ) exact mass calcd for c20h23cln2nao4 [ m + na ] 413.1243 , found 413.1262 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-10 ( 5 mol % ) with a 24 h reaction time . column chromatography ( sio2 , 05% ethyl acetate 
 in hexanes ) afforded the adduct as a white crystalline solid ( 23 mg , 
 71% ) that was found to be 97% ee and 9:1 dr determined by chiral hplc 
 ( chiralcel ia : 5% proh / hexanes , 1.0 ml / min : tr(d2e2 minor / minor ) = 18.4 min , tr(d2e1 minor / major ) = 21.3 min , tr(d1e1 major / major ) = 31.3 min , tr(d1e1 major / minor ) = 47.8 min ) : mp 174175 
 c ; rf = 0.58 ( 20% etoac / hexanes ) ; 
 ir ( film ) 3385 , 2977 , 1685 , 1553 , 1526 cm ; h nmr ( 400 mhz , cdcl3 )  7.50 ( d , j = 8.0 hz , 2h ) , 7.39 ( d , j = 8.0 hz , 2h ) , 
 7.347.22 ( m , 4h ) , 5.73 ( br d , 1h ) , 5.60 ( br m , 1h ) , 4.71 ( br 
 d , 1h ) , 1.28 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 154.2 , 139.2 , 136.6 , 135.0 , 130.4 , 130.1 , 129.7 , 129.1 , 127.4 , 
 125.5 , 93.1 , 28.0 ; hrms ( esi ) exact mass calcd for c19h20cl2n2nao4 [ m + na ] 433.0698 , found 433.0713 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-10 ( 5 mol % ) with an 18 h reaction time , 
 and following silica gel filtration , the product was isolated as a 
 white crystalline solid ( 37 mg , 98% ) , which was found to be 60:1 dr 
 and 88% ee by chiral hplc analysis ( chiralpak ad - h , 5% iproh / hexanes , 1.0 ml / min : tr(d2e1 , minor / major ) 
 = 28.7 min , tr(d1e2 , major / minor ) = 34.8 min , tr(d1e1 , major / major ) = 48.5 , tr(d2e2 , minor / minor ) 
 = 70 min ) : [ ]d = 11 ( c 0.11 , chcl3 , 40% ee ) ; mp 169171 c ; rf = 0.58 ( 33% etoac / hexanes ) ; ir ( film ) 3383 , 
 2983 , 1681 , 1551 , 1524 , 1366 , 1162 cm ; h nmr ( 400 mhz , cdcl3 )  7.53 ( d , j = 8.4 hz , 2 h ) , 7.42 ( d , j = 8.4 hz , 2 h ) , 7.37 
 ( m , 1 h ) , 7.15 ( d , j = 8.0 hz , 1 h ) , 7.08 ( m , 2 h ) , 
 5.77 ( br d , 1 h ) , 5.64 ( br dd , 1 h ) , 4.86 ( br d , 1 h ) , 1.30 ( s , 9 
 h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 164.1 , 161.6 , 
 136.6 , 130.74 , 130.66 , 130.0 , 129.6 , 129.1 , 122.8 , 116.0 , 115.8 , 114.4 , 
 114.2 , 93.1 , 27.9 ; hrms ( esi ) exact mass calcd for c19h20clfn2nao4 [ m + na ] 417.0993 , 
 found 417.1080 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-10 ( 5 mol % ) with a 48 h reaction time . column chromatography ( sio2 , 05% ethyl acetate 
 in hexanes ) afforded an off - white crystalline solid ( 29.0 mg , 53% ) 
 that was found to be 84% ee and 25:1 dr by chiral hplc ( chiralcel 
 ad : 6% proh / hexanes , 1.0 ml / min : tr(d1e2 minor / major ) = 12.9 min , tr(d2e1 minor / major ) = 14.6 min , tr(d2e2 minor / minor ) = 29.6 min , tr(d1e1 major / major ) = 32.8 min ) : [ ]d = 11 ( c 0.40 , chcl3 ) ; mp 165 c ( dec . ) ; rf = 
 0.60 ( 20% etoac / hexanes ) ; ir ( film ) 3327 , 2980 , 2924 , 1704 , 1565 , 
 1489 cm ; h nmr ( 400 mhz , cdcl3 )  7.54 ( d , j = 8.0 hz , 2h ) , 7.44 
 ( m , 1h ) , 7.41 ( d , j = 8.0 hz , 2h ) , 7.28 ( m , 1h ) , 
 7.00 ( dd , j = 8.8 , 8.8 hz , 1h ) , 5.80 ( br d , 1h ) , 
 5.64 ( br d , 1h ) , 5.07 ( br d , 1h ) , 1.24 ( s , 9h ) ; c nmr 
 ( 100 mhz , cdcl3 ) ppm 159.0 ( d , jcf = 246 hz ) , 154.1 , 136.6 , 133.7 ( d , jcf = 8.0 hz ) , 132.5 , 130.1 , 129.5 , 129.3 , 129.1 , 
 126.0 ( d , jcf = 13 hz ) , 117.9 
 ( d , jcf = 23 hz ) , 117.3 , 92.1 , 
 28.1 , 27.9 ; hrms ( esi ) exact mass calcd for c19h19brclfn2nao4 [ m + na ] 495.0109 , 
 found 495.0098 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-10 ( 5 mol % ) with a 48 h reaction time . column chromatography ( sio2 , 010% ethyl acetate 
 in hexanes ) afforded the adduct as a white crystalline solid ( 19 mg , 
 75% ) that was found to be 84% ee and 9:1 dr by chiral hplc ( chiralcel 
 ia : 6% proh / hexanes , 1.0 ml / min : tr(d1e1 major / major ) = 15.9 min , tr(d1e2 major / minor ) = 17.4 min , tr(d2e1 minor / major ) = 20.1 min , tr(d2e2 minor / minor ) = 50.5 min ) : mp 178179 
 c dec ; rf = 0.54 ( 20% etoac / hexanes ) ; 
 ir ( film ) 3370 , 2980 , 2918 , 1679 , 1549 , 1529 cm ; h nmr ( 400 mhz , cdcl3 )  7.55 ( d , j = 8.8 hz , 2h ) , 7.49 ( d , j = 8.8 hz , 2h ) , 
 7.42 ( d , j = 8.8 hz , 2h ) , 7.21 ( d , j = 8.8 hz , 2h ) , 5.73 ( d , j = 6.8 hz , 1h ) , 5.56 ( dd , j = 9.6 , 8.8 hz , 1h ) , 4.85 ( br d , 1h ) , 1.26 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 154.2 , 136.1 , 132.3 , 
 132.1 , 130.3 , 128.9 , 128.6 , 124.8 , 123.0 , 93.2 , 28.2 , 28.0 ; hrms ( esi ) 
 exact mass calcd for c19h20br2n2nao4 [ m + na ] 520.9687 , found 520.9703 . this compound was prepared according to the 
 general procedure employing catalyst ( r , r)-10 ( 5 mol % ) with a 48 h reaction time . column chromatography 
 ( sio2 , 010% ethyl acetate in hexanes ) afforded 
 the adduct as an off - white crystalline solid ( 23 mg , 80% ) that was 
 found to be 95% ee and 5:1 dr by chiral hplc ( chiralcel ia : 10% proh / hexanes , 0.6 ml / min : tr(d1e1 major / major ) = 21.0 min , tr(d1e2 major / minor ) = 25.1 min , tr(d2e1 minor / major ) = 29.6 min , tr(d2e2 major / major ) = 30.8 min ) : mp 184 c ; rf = 0.49 ( 25% etoac / hexanes ) ; ir ( film ) 3368 , 
 2976 , 2914 , 1677 , 1554 , 1519 cm ; h 
 nmr ( 400 mhz , cdcl3 )  7.57 ( s , 1h ) , 7.50 ( d , j = 8.4 hz , 2h ) , 7.42 ( m , 2h ) , 7.35 ( m , 1h ) , 7.23 ( d , j = 8.4 hz , 2h ) , 5.76 ( br d , 1h ) , 5.56 ( br dd , j = 8.0 hz , 1h ) , 4.85 ( br d , 1h ) 1.28 ( s , 9h ) ; c nmr 
 ( 100 mhz , cdcl3 ) ppm 154.2 , 136.1 , 134.8 , 133.1 , 132.2 , 
 130.5 , 130.2 , 128.9 , 128.6 , 126.8 , 123.0 , 93.1 , 28.0 ; hrms ( esi ) exact 
 mass calcd for c19h20brcln2nao4 [ m + na ] 477.0193 , found 477.0208 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-10 ( 5 mol % ) with a 36 h reaction time . column chromatography ( sio2 , 030% ethyl acetate 
 in hexanes ) afforded the adduct as an off - white crystalline solid 
 ( 15.0 mg , 80% ) that was found to be 93% ee and 3:1 dr by chiral hplc 
 ( chiralcel ad - h : 3% etoh / hexanes , 0.8 ml / min : tr(d2e2 minor / minor ) = 22.8 min , tr(d2e1 minor / major ) = 25.6 min , tr(d1e1 major / major ) = 31.0 min , tr(d1e2 major / minor ) = 43.5 min ) : mp 170171 c ; rf = 0.6 ( 20% etoac / hexanes ) ; ir ( film ) 3335 , 
 2975 , 2926 , 1708 , 1563 , 1486 cm ; h 
 nmr ( 400 mhz , cdcl3 )  7.72 ( dd , j = 6.0 , 2.0 hz , 1h ) , 7.48 ( m , 1h ) , 7.44 ( d , j = 
 8.8 hz , 2h ) , 7.13 ( d , j = 8.4 hz , 2h ) , 6.94 ( dd , j = 9.2 , 8.4 hz , 1h ) , 6.22 ( d , j = 6.0 
 hz , 1h ) , 5.58 ( d , j = 6.0 hz , 1h ) , 5.52 ( d , j = 7.6 hz , 1h ) , 1.35 ( s , 9h ) ; c nmr ( 100 mhz , 
 cdcl3 ) ppm 159.6 ( d , jcf = 249 hz ) , 154.6 , 147.9 , 135.3 , 134.8 ( d , jcf = 7.5 hz ) , 132.2 ( 2c ) , 131.0 , 128.4 ( 2c ) , 
 122.7 , 120.9 ( d , jcf = 13.5 
 hz ) , 117.7 , 117.6 , 85.5 ( d , jcf = 3 hz ) , 28.1 ; hrms ( esi ) exact mass calcd for c19h19br2fn2nao4 [ m + na ] 538.9593 , found 538.9606 . this 
 compound was prepared according to the general procedure employing 
 catalyst ( r , r)-9 ( 5 
 mol % ) with a 48 h reaction time . column chromatography ( sio2 , 010% ethyl acetate in hexanes ) afforded the adduct as an 
 off - white crystalline solid ( 29 mg , 92% ) that was found to be 87% 
 ee and 7:1 dr by chiral hplc ( chiralcel ad - h : 8% proh / hexanes , 1.0 ml / min : tr(d2e1 minor / major ) = 25.9 min , tr(d2e2 minor / minor ) = 30.8 min , tr(d1e2 major / minor ) = 38.3 min , tr(d1e1 major / major ) = 43.8 min ) : mp 165166 c ; rf = 0.53 ( 25% etoac / hexanes ) ; ir ( film ) 3379 , 2965 , 2924 , 
 2848 , 1689 , 1551 , 1517 cm ; h nmr ( 400 
 mhz , cdcl3 )  7.48 ( d , j = 8.4 hz , 
 2h ) , 7.40 ( m , 1h ) , 7.35 ( s , 1h ) , 7.31 ( m , 2h ) , 7.23 ( d , j = 8.4 hz , 2h ) , 5.71 ( br d , 1h ) , 5.58 ( br dd , 1h ) , 5.44 ( br d , 1h ) , 
 2.37 ( s , 3h ) , 1.27 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 154.3 , 138.8 , 136.8 , 131.1 , 129.2 , 129.0 , 128.8 , 128.7 , 
 127.5 , 125.6 , 122.7 , 93.9 , 29.7 , 28.2 , 28.0 ; hrms ( esi ) exact mass 
 calcd for c20h23brn2nao4 [ m + na ] 457.0689 , found 457.0696 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-10 ( 5 mol % ) with a 72 h reaction time . column chromatography ( sio2 , 05% ethyl acetate 
 in hexanes ) afforded the adduct as a white solid ( 27 mg , 51% ) that 
 was found to be 73% ee and 31:1 dr by chiral hplc ( chiralpak ia , 7% 
 etoh / hexanes , 1.0 ml / min : tr(d1e2 major / minor ) = 16.1 min , tr(d1e1 major / major ) = 18.4 min , tr(d2e2 minor / minor ) = 21.0 min , tr(d2e1 minor / major ) = 28.8 min ) : [ ]d = 5.4 
 ( c 0.37 , chcl3 ) ; mp 183184 c ; rf = 0.24 ( 20% etoac in hexanes ) ; ir ( film ) 3376 , 
 2975 , 2926 , 1687 , 1556 , 1521 cm ; h 
 nmr ( 400 mhz , cdcl3 )  7.48 ( d , j = 8.4 hz , 2h ) , 7.23 ( d , j = 8.4 hz , 2h ) , 7.097.05 
 ( m , 2h ) , 6.85 ( d , j = 8.0 hz , 1h ) , 5.70 ( d , j = 10.0 hz , 1h ) , 5.62 ( br dd , 1h ) , 4.86 ( d , j = 8.8 hz , 1h ) , 3.90 ( s , 3h ) , 3.89 ( s , 3h ) , 1.28 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 143.3 , 150.7 , 149.2 , 136.7 , 
 132.1 , 129.0 ( 2c ) , 128.2 , 125.3 , 123.5 , 122.8 , 122.1 , 110.9 , 93.8 , 
 56.0 , 28.1 ; hrms ( esi ) exact mass calcd for c21h25brn2nao6 [ m + na ] 503.0794 ; found 
 503.0777 . this compound 
 was prepared according to the general procedure employing catalyst 
 ( r , r)-10 ( 5 mol % ) 
 with a 48 h reaction time . following silica plug filtration , the adduct 
 was isolated as an off - white solid ( 35 mg , 88% ) that was found to 
 be 85% ee and 68:1 dr by chiral hplc ( chiralcel ia : 7% proh / hexanes , 1.0 ml / min : tr(d2e1 minor / major ) = 15.6 min , tr(d1e2 major / minor ) = 17.5 min , tr(d1e1 major / major ) = 21.1 min , tr(d2e2 minor / minor ) = 49.1 min ) : [ ]d = 33 ( c 0.54 , chcl3 ) ; mp 184185 c ; rf = 0.57 
 ( 25% etoac / hexanes ) ; ir ( film ) 3379 , 2972 , 2917 , 1696 , 1551 , 1517 
 cm ; h nmr ( 400 mhz , cdcl3 )  7.54 ( d , j = 8.0 hz , 2h ) , 7.46 ( j = 8.0 hz , 2h ) , 7.25 ( m , 1h ) , 7.13 ( m , 3h ) , 5.73 ( d , j = 9.6 hz , 1h ) , 5.6 ( br dd , 1h ) , 4.82 ( br d , 1h ) , 2.35 
 ( s , 3h ) , 1.27 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 154.2 , 138.9 , 137.0 , 132.3 , 131.9 , 131.6 , 130.5 , 129.7 , 129.0 , 
 127.9 , 124.6 , 124.0 , 93.6 , 28.0 , 21.4 ; hrms ( esi ) exact mass calcd 
 for c20h23brn2nao4 [ m 
 + na ] , 457.0739 , found 457.0720 . this 
 compound was prepared according to the general procedure employing 
 catalyst ( r , r)-10 ( 5 
 mol % ) with a 48 h reaction time . following silica plug filtration , the adduct was isolated as an off - white crystalline solid ( 22 mg , 
 97% ) that was found to be 99% ee and 20:1 dr by chiral hplc ( chiralcel 
 ia : 8% proh / hexanes , 1.0 ml / min : tr(d2e2 minor / minor ) = 10.5 min , tr(d1e1 major / major ) = 14.1 min , tr(d1e2 major / minor ) = 15.5 min , tr(d2e1 minor / major ) = 23.7 min ) : mp 151152 
 c ; rf = 0.45 ( 25% etoac / hexanes ) ; 
 ir ( film ) 3391 , 2977 , 2922 , 1692 , 1553 , 1519 cm ; h nmr ( 400 mhz , cdcl3 )  7.69 ( m , 
 1h ) , 7.50 ( d , j = 7.2 hz , 1h ) , 7.41 ( d , j = 8.0 hz , 1h ) , 7.287.24 ( m , 1h ) , 7.14 ( m , 3h ) , 5.73 ( d , j = 9.2 hz , 1h ) , 5.60 ( br d , 1h ) , 4.77 ( d , j = 9.2 hz , 1h ) , 2.36 ( s , 3h ) , 1.27 ( s , 9h ) ; c nmr ( 125 
 mhz , cdcl3 ) ppm 154.1 , 139.0 , 136.9 , 133.4 , 130.3 , 130.0 , 
 129.7 , 129.0 , 127.9 , 126.9 , 124.0 , 93.6 , 28.0 , 21.4 ; hrms ( esi ) exact 
 mass calcd for c20h23cln2nao4 [ m + na ] , 413.1244 , found 413.1247 . this 
 compound was prepared according to the general procedure employing 
 catalyst ( r , r)-9 ( 5 
 mol % ) with a 42 h reaction time . column chromatography ( sio2 , 010% ethyl acetate in hexanes ) afforded the adduct as an 
 off - white crystalline solid ( 34 mg , 80% ) that was found to be 68% 
 ee and 5:1 dr by chiral hplc ( chiralcel ad : 7% etoh / hexanes , 1.0 ml / min : tr(d2e1 minor / major ) = 9.5 min , tr(d1e1 major / major ) = 10.5 min , tr(d2e2 minor / minor ) = 12.2 min , tr(d1e2 major / minor ) = 34.6 min ) : mp 150151 
 c ; rf = 0.60 ( 25% etoac / hexanes ) ; 
 ir ( film ) 3297 , 2974 , 2919 , 1707 , 1563 , 1487 cm ; h nmr ( 400 mhz , cdcl3 )  7.92 ( d , j = 4.0 hz , 1h ) , 7.51 ( m , 1h ) , 7.25 ( m , 1h ) , 7.16 ( m , 2h ) , 
 7.00 ( m , 2h ) , 6.12 ( d , j = 10.4 hz , 1h ) , 5.61 ( d , j = 10.0 hz , 1h ) , 4.88 ( br d , 1h ) , 2.36 ( s , 3h ) , 1.26 ( s , 
 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 159.9 ( d , jcf = 248 hz ) , 154.1 , 139.0 , 136.7 , 
 134.7 ( d , jcf = 8 hz ) , 129.8 , 
 129.1 , 127.8 , 127.3 , 124.0 , 121.2 ( d , jcf = 13 hz ) , 117.4 ( d , jcf = 23 hz ) , 117.1 ( d , jcf = 3 hz ) , 85.9 ( d , jcf = 
 13 hz ) , 28.1 , 21.4 ; hrms ( esi ) exact mass calcd for c20h22brfn2nao4 [ m + na ] , 475.0645 , found 475.0663 . this 
 compound was prepared according to the general procedure employing 
 catalyst ( r , r)-10 ( 5 
 mol % ) with a 48 h reaction time . the filtrate was analytically pure , 
 and the adduct was isolated as a white crystalline solid ( 40.0 mg , 
 95% ) that was found to be 86% ee and 50:1 dr by chiral hplc ( chiralcel 
 ad - h : 10% proh / hexanes , 1.0 ml / min : tr(d2e1 minor / major ) = 9.8 min , tr(d2e2 minor / minor ) = 15.2 min , tr(d1e1 major / major ) = 16.4 min , tr(d1e2 major / minor ) = 18.1 min ) : [ ]d = 35 ( c 0.29 , chcl3 ) ; mp 179180 c ; rf = 0.38 ( 25% etoac / hexanes ) ; ir ( film ) 3384 , 2911 , 2857 , 1686 , 1549 , 
 1529 cm ; h nmr ( 400 mhz , cdcl3 )  7.387.36 ( m , 2h ) , 7.29 ( dd , j = 7.2 , 7.2 hz , 1h ) , 7.167.23 ( m , 2h ) , 7.157.13 ( m , 
 3h ) , 5.72 ( d , j = 9.6 hz , 1h ) , 5.64 ( br dd , 1h ) , 
 4.82 ( d , j = 8.0 hz , 1h ) , 2.38 ( s , 3h ) , 2.35 ( s , 
 3h ) , 1.26 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) 
 ppm 154.2 , 138.7 , 138.6 , 137.6 , 131.5 , 130.9 , 129.4 , 129.3 , 128.9 , 
 128.7 , 127.9 , 125.8 , 124.0 , 94.4 , 80.2 , 28.0 , 21.4 , 21.3 ; hrms ( esi ) 
 exact mass calcd for c21h26n2nao4 [ m + na ] 393.1790 , found 393.1794 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-10 ( 5 mol % ) with a 20 h reaction time . 
 following silica plug filtration , the product was isolated as an an 
 off - white crystalline solid ( 27 mg , 78% ) that was found to be 90% 
 ee and 70:1 dr by chiral hplc ( chiralcel ad - h : 10% proh / hexanes , 1.0 ml / min : tr(d2e1 minor / major ) = 13.4 min , tr(d1e2 major / minor ) = 14.9 min , tr(d1e1 major / major ) = 20.9 min , tr(d2e2 minor / minor ) = 35.9 min ) : [ ]d = 30 
 ( c 0.25 , chcl3 ) ; mp 175176 c ; rf = 0.54 ( 25% etoac / hexanes ) ; ir ( film ) 3391 
 ( s ) , 2991 , 2928 , 1692 , 1560 , 1526 cm ; h nmr ( 400 mhz , cdcl3 )  7.54 ( d , j = 8.0 hz , 2h ) , 7.43 ( j = 8.0 hz , 2h ) , 7.33 ( d , j = 8.4 hz , 2h ) , 7.297.22 ( m , 2h ) , 5.73 ( br d , j = 10.0 hz , 1h ) , 5.95 ( br d , 1h ) , 4.85 ( br d , 1h ) , 1.28 
 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 154.2 , 
 139.1 , 135.0 , 132.1 , 130.4 , 130.3 , 130.2 , 129.1 , 127.4 , 125.5 , 124.8 , 
 93.2 , 28.1 ; hrms ( esi ) exact mass calcd for c19h20brcln2nao4 [ m + na ] , 477.0193 , 
 found 477.0190 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-9 ( 5 mol % ) with a 48 h reaction time . column 
 chromatography ( sio2 , 510% ethyl acetate in hexanes ) 
 afforded the adduct as a white crystalline solid ( 27.0 mg , 90% ) that 
 was found to be 93% ee and 30:1 dr by chiral hplc ; ( chiralcel ia : 
 8% proh / hexanes , 1.0 ml / min : tr(d2e1 minor / major ) = 10.6 min , tr(d1e2 major / minor ) = 12.9 min , tr(d1e1 major / major ) = 14.3 min , tr(d2e2 minor / minor ) = 17.5 min ) : [ ]d = 44 ( c 0.29 , chcl3 ) ; mp 170171 c ; rf = 0.63 ( 20% etoac / hexanes ) ; ir ( film ) 3372 , 2986 , 2924 , 1682 , 1558 , 
 1524 cm ; h nmr ( 400 mhz , cdcl3 )  7.58 ( s , 1h ) , 7.477.43 ( m , 2h ) , 7.387.31 
 ( m , 3h ) , 7.307.24 ( m , 2h ) , 5.75 ( br d , 1h ) , 5.59 ( br dd , 1h ) , 
 4.98 ( br d , 1h ) , 1.30 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 154.2 , 139.1 , 135.0 , 134.8 , 133.0 , 130.5 , 130.4 , 130.2 , 
 129.2 , 128.9 , 127.4 , 126.8 , 125.5 , 93.1 , 28.2 ; hrms ( esi ) exact mass 
 calcd for c19h20cl2n2nao4 [ m + na ] 433.0698 , found 433.0715 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-10 ( 5 mol % ) with a 24 h reaction time . 
 following silica plug filtration , h column chromatography ( sio2 , 010% ethyl acetate 
 in hexanes ) afforded the adduct as an off - white crystalline solid 
 ( 24 mg , 66% ) that was found to be 76% ee and 1:1 dr by chiral hplc 
 ( chiralcel oj - h : 3% etoh / hexanes , 1.0 ml / min : tr(d1e2 major / minor ) = 20.2 min , tr(d1e1 major / major ) = 22.8 min , tr(d2e2 minor / minor ) = 25.3 min , tr(d2e2 minor / minor ) = 27.5 min ) : mp 158159 c ; rf = 0.55 ( 20% etoac / hexanes ) ; ir ( film ) 3372 , 
 2986 , 2924 , 1682 , 1558 , 1524 cm ; h 
 nmr ( 400 mhz , cdcl3 )  7.89 ( dd , j = 6.0 , 2.4 , 1h ) , 7.54 ( m , 1h ) , 7.34 ( m , 2h ) , 7.25 ( m , 2h ) , 7.04 
 ( dd , j = 9.2 , 9.2 hz , 1h ) , 6.10 ( d , j = 9.6 hz , 1h ) , 5.66 ( br d , j = 9.4 hz , 1h ) , 4.90 
 ( br d , 1h ) , 1.29 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 158.9 ( d , jcf = 249 
 hz ) , 154.0 , 138.3 , 134.9 ( d , jcf = 23 hz ) , 134.8 ( d , jcf = 
 8 hz ) , 130.5 , 129.3 , 127.4 , 124.9 , 120.8 ( d , jcf = 12 hz ) , 117.6 ( d , jcf = 24 hz ) , 117.3 ( d , jcf = 3 hz ) , 85.6 ( d , jcf = 
 4 hz ) , 28.0 ; hrms ( esi ) exact mass calcd for c19h19brclfn2nao4 [ m + na ] , 495.0098 , 
 found 495.0115 . this compound 
 was prepared according to the general procedure employing catalyst 
 ( r , r)-10 ( 5 mol % ) 
 with a 48 h reaction time . column chromatography ( sio2 , 
 05% ethyl acetate in hexanes ) afforded the adduct as a white 
 crystalline solid ( 25 mg , 74% ) that was found to be 85% ee and 8:1 
 dr by chiral hplc ( chiralcel ad : 10% proh / hexanes , 1.0 ml / min : tr(d2e1 minor / major ) = 9.1 min , tr(d1e2 major / minor ) = 12.8 min , tr(d2e2 minor / minor ) = 14.8 min , tr(d1e1 major / major ) = 15.9 min ) : mp 153154 c ; rf = 0.50 ( 20% etoac / hexanes ) ; ir ( film ) 3390 , 2980 , 1687 , 
 1548 , 1515 , 1365 cm ; h nmr ( 400 mhz , 
 cdcl3 )  7.347.23 ( m , 8h ) , 5.71 ( d , j = 9.6 hz , 1h ) , 5.62 ( dd , j = 9.6 , 8.0 
 hz , 1h ) , 4.79 ( d , j = 8.8 hz , 1h ) , 2.38 ( s , 3h ) , 
 1.27 ( s , 9h ) ; c nmr ( 150 mhz . cdcl3 ) ppm 154.2 , 
 139.7 , 138.8 , 134.8 , 131.2 , 131.1 , 130.2 , 129.2 , 128.9 ( 2c ) , 127.4 , 
 125.7 , 125.5 , 94.0 , 28.0 , 21.3 ; hrms ( esi ) exact mass calcd for c20h23cln2nao4 [ m + na ] 413.1241 ; found 413.1245 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-10 ( 5 mol % ) with a 72 h reaction time . the reaction precipitate was added to the filter paper of a buchner 
 funnel and washed with cold hexanes to afford the product as a light 
 brown crystalline solid ( 38 mg , 68% ) that was found to be 70% ee and 
 23:1 dr determined by chiral hplc ( chiralcel ia : 7% etoh / hexanes , 
 1.0 ml / min : tr(d1e2 major / minor ) 
 = 8.5 min , tr(d1e1 major / major ) 
 = 9.3 min , tr(d2e1 minor / major ) 
 = 10.6 min , tr(d2e2 minor / minor ) 
 = 12.8 min ) : mp 161162 c ; rf = 0.4 ( 20% etoac / hexanes ) ; ir ( film ) 3342 , 2975 , 2940 , 1701 , 1563 , 
 1521 , 1376 cm ; h nmr ( 400 mhz , cdcl3 )  7.35 ( m , 1h ) , 7.307.28 ( m , 2h ) , 7.257.22 
 ( m , 1h ) , 7.097.05 ( m , 2h ) , 6.85 ( d , j = 8.0 
 hz , 1h ) , 5.70 ( m , 2h ) , 4.88 ( br d , 1h ) , 3.90 ( s , 3h ) , 3.89 ( s , 3h ) , 
 1.28 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 154.3 , 
 150.7 , 149.2 , 139.7 , 134.8 , 130.2 , 128.9 , 127.4 , 125.5 , 123.5 , 122.1 , 
 93.8 , 56.0 , 28.6 ; hrms ( esi ) exact mass calcd for c21h25cln2nao6 [ m + na ] 459.1299 , 
 found 459.1301 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-10 ( 5 mol % ) with a 48 h reaction time . column chromatography ( sio2 , 010% ethyl acetate 
 in hexanes ) afforded the product as an off - white crystalline solid 
 ( 95 mg , 87% ) that was found to be 86% ee and 60:1 dr by chiral hplc 
 ( chiralcel ad - h : 10% proh / hexanes , 1.0 
 ml / min : tr(d1e2 major / minor ) = 9.8 min , tr(d2e1 minor / major ) = 11.0 min , tr(d1e1 major / major ) = 21.9 min , tr(d2e2 minor / minor ) = 25.9 min ) : [ ]d = 14 ( c 0.43 , chcl3 ) ; mp 160161 c ; rf = 0.53 ( 20% etoac / hexanes ) ; ir ( film ) 3397 , 2982 , 2926 , 1708 , 1563 , 
 1500 , 1376 cm ; h nmr ( 400 mhz , cdcl3 )  7.56 ( d , j = 8.4 hz , 2h ) , 7.51 
 ( m , 1h ) , 7.497.43 ( m , 3h ) , 7.00 ( dd , j = 
 8.8 , 8.8 hz , 1h ) , 5.79 ( m , 2h ) , 5.04 ( br d , 1h ) , 1.25 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 160.1 ( , jcf = 241 hz ) , 154.1 , 133.7 ( d , jcf = 9 hz ) , 132.3 , 132.1 , 130.3 , 
 130.0 , 126.0 ( d , jcf = 15 
 hz ) , 124.9 , 117.9 ( d , jcf = 
 23 hz ) , 117.4 , 92.3 , 28.0 ; hrms ( esi ) exact mass calcd for c19h19br2fn2nao4 [ m + na ] , 538.9593 , found 538.9596 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-9 ( 5 mol % ) with a 48 h reaction time . column 
 chromatography ( sio2 , 05% ethyl acetate in hexanes ) 
 afforded the adduct as a white solid ( 28 mg , 90% ) that was found to 
 be 88% ee and 8:1 dr determined by chiral hplc ( chiralcel ad - h : 8% proh / hexanes , 1.0 ml / min : tr(d1e2 major / minor ) = 10.6 min , tr(d2e1 minor / major ) = 13.8 min , tr(d2e2 minor / minor ) = 19.1 min , tr(d1e1 major / major ) = 22.2 min ) : mp 185186 
 c ; rf = 0.45 ( 20% etoac / hexanes ) ; 
 ir ( film ) 3361 , 2973 , 2924 , 1710 , 1565 , 1482 cm ; h nmr ( 400 mhz , cdcl3 )  7.60 ( s , 
 1h ) , 7.547.51 ( m , 2h ) , 7.487.42 ( m , 2h ) , 7.407.33 
 ( m , 1h ) , 7.01 ( dd , j = 8.8 , 8.8 hz , 1h ) , 5.80 ( m , 
 2h ) , 5.03 ( d , j = 9.6 hz , 1h ) , 1.25 ( s , 9h ) ; c nmr ( 150 mhz , cdcl3 ) ppm 160.2 ( d , jcf = 244 hz ) , 133.8 , 133.7 , 132.8 , 130.9 
 ( 2c ) , 130.6 , 130.2 , 129.1 , 128.8 ( 2c ) , 126.7 , 125.9 , 118.0 ( d , jcf = 23 hz ) , 117.4 , 92.2 , 28.1 ; 
 hrms ( esi ) exact mass calcd for c19h19brclfn2nao4 [ m + na ] 495.0095 , found 495.0100 . this compound was prepared according to the general procedure 
 employing catalyst ( r , r)-10 ( 5 mol % ) with a 48 h reaction time . column chromatography ( sio2 , 05% ethyl acetate in hexanes ) afforded the product 
 as a white crystalline solid ( 22 mg , 56% ) that was found to be 78% 
 ee and 2:1 dr by chiral hplc ; ( chiralpak ia , 10% proh / hexanes , 1.0 ml / min : tr(d1e1 major / major ) = 5.9 min , tr(d2e1 minor / major ) = 6.5 min , tr(d2e2 minor / minor ) = 7.1 min , tr(d1e2 major / minor ) = 8.9 min ) : mp 156157 c ; rf = 0.78 ( 20% etoac in hexanes ) ; ir ( film ) 3324 , 2965 , 
 2924 , 1710 , 1565 , 1489 cm ; h nmr for 
 both diastereomers reported ( 600 mhz , cdcl3 )  7.91 
 ( s , 1h ) , 7.72 ( dd , j = 4.8 hz , 1h ) , 7.537.37 
 ( m , 4h ) , 7.03 ( m , 2h ) , 6.94 ( m , 2h ) , 6.28 ( br d , 1h ) , 6.21 ( d , j = 10.8 hz , 1h ) , 5.795.71 ( m , 2h ) , 5.10 ( d , j = 9.6 hz , 1h ) , 1.39 ( s , 9h ) , 1.26 ( s , 9h ) ; c nmr ( 150 mhz , cdcl3 ) ppm 159.8 ( d , jcf = 249 hz ) , 159.4 ( d , jcf = 249 hz ) , 154.5 , 154.1 , 135.0 ( 2c ) , 133.9 
 ( 2c ) , 133.7 , 133.5 , 133.4 , 132.1 , 131.9 , 130.1 , 125.6 , 120.7 , 118.2 , 
 118.0 , 117.8 , 117.6 , 117.4 ( 2c ) , 117.2 , 84.7 , 84.4 , 81.2 , 81.0 , 29.7 , 
 28.3 , 28.1 ; hrms ( esi ) exact mass calcd for c19h18br2f2n2nao4 [ m + na ] 556.9499 ; found 556.9482 . this 
 compound was prepared according to the general procedure employing 
 catalyst ( r , r)-9 ( 5 
 mol % ) with a 48 h reaction time . column chromatography ( sio2 , 510% ethyl acetate in hexanes ) afforded the adduct as a 
 white crystalline solid ( 23 mg , 42% ) that was found to be 82% ee and 
 40:1 dr by chiral hplc ( chiralcel ia : 10% proh / hexanes , 1.0 ml / min : tr(d2e1 minor / major ) = 7.4 min , tr(d1e1 major / major ) = 14.9 min , tr(d1e2 major / minor ) = 6.6 min , tr(d2e2 minor / minor ) = 9.2 min ) : [ ]d = 13 
 ( c 0.31 , chcl3 , 76% ee , 20:1 dr ) ; mp 159165 
 c ; rf = 0.48 ( 20% etoac in hexanes ) ; 
 ir ( film ) 3450 , 3000 , 2950 , 2410 , 1710 , 1590 , 1490 , 1260 cm ; h nmr ( 400 mhz , cdcl3 )  7.53 ( br 
 s , 1h ) , 7.44 ( ddd , j = 8.8 , 4.8 , 2.8 hz , 1h ) , 7.38 
 ( s , 1h ) , 7.36 ( s , 1h ) , 7.31 ( t , j = 7.6 hz , 1h ) , 
 7.25 ( s , 1h ) , 7.00 ( dd , j = 10.8 , 9.2 hz , 1h ) , 5.80 
 ( m , 2h ) , 4.98 ( br d , 1h ) , 2.38 ( s , 3h ) , 1.25 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 159.4 ( d , jcf = 249 hz ) , 154.5 , 138.7 , 133.4 , 131.1 ( d , jcf = 8 hz ) , 130.9 , 129.1 , 128.8 , 
 125.6 , 118.0 , 117.5 ( d , jcf = 23 hz ) , 92.8 , 27.9 , 21.3 ; hrms ( esi ) exact mass calcd for c20h22brfn2nao4 [ m + na ] 477.0646 , found 477.0660 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-10 ( 5 mol % ) with a 72 h reaction time . 
 following silica plug filtration , h nmr showed > 20:1 
 dr . column chromatography ( sio2 , 1040% ethyl acetate 
 in hexanes ) afforded the adduct as an off - white solid ( 31.0 mg , 70% ) 
 that was found to be 56% ee and 4:1 dr ( racemized on silica ) by chiral 
 hplc ( chiralcel ia : 12% proh / hexanes , 
 1.0 ml / min : tr(d1e2 major / minor ) 
 = 9.5 min , tr(d2e1 minor / major ) 
 = 10.3 min , tr(d2e2 minor / minor ) 
 = 16.8 min , tr(d1e1 major / major ) 
 = 23.4 min ) : mp 131132 c ; rf = 0.66 ( 50% etoac / hexanes ) ; ir ( film ) 3368 , 2974 , 2928 , 1703 , 1556 , 
 1518 , 1279 cm ; h nmr ( 400 mhz , cdcl3 )  7.52 ( d , j = 4.8 hz , 1h ) , 7.44 
 ( m , 1h ) , 7.15 ( br s , 1h ) , 7.09 ( dd , j = 8.4 , 2.0 
 hz , 1h ) , 7.00 ( dd , j = 8.8 , 1.6 hz , 1h ) , 6.88 ( dd , j = 8.0 , 8.0 hz , 1h ) , 5.77 ( m , 2h ) , 5.00 ( d , j = 8.8 hz , 1h ) , 3.94 ( s , 3h ) , 3.87 ( s , 3h ) , 1.26 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 154.2 , 150.1 ( d , jcf = 253 hz ) , 133.5 ( d , jcf = 9 hz ) , 126.5 ( d , jcf = 9 hz ) , 123.2 ( d , jcf = 27 hz ) , 122.3 , 122.1 , 117.9 ( d , jcf = 23 hz ) , 117.3 , 112.6 , 111.1 , 110.8 , 110.7 , 
 92.8 ( d , jcf = 5 hz ) , 80.5 , 
 56.0 ( 2c ) , 28.1 ; hrms ( esi ) exact mass calcd for c21h24brfn2nao6 [ m + na ] 521.0699 , 
 found 521.0701 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-10 ( 5 mol % ) with a 44 h reaction time . the reaction precipitate was added to the filter paper of a buchner 
 funnel and washed with cold hexanes to afford the product as an off - white 
 crystalline solid ( 33 mg , 60% ) that was found to be 85% ee and 9:1 
 dr by chiral hplc ( chiralcel ad - h : 9% etoh / hexanes , 1.0 ml / min : tr(d1e2 major / minor ) = 16.3 min , tr(d2e1 minor / major ) = 19.5 min , tr(d1e1 major / major ) = 22.4 min , tr(d2e2 major / major ) = 53.5 min ) : mp 153154 
 c ; rf = 0.19 ( 25% etoac / hexanes ) ; 
 ir ( film ) 3368 , 2973 , 2938 , 1697 , 1551 , 1516 cm ; h nmr ( 400 mhz , cdcl3 )  7.54 ( d , j = 8.8 hz , 2h ) , 7.44 ( d , j = 8.4 hz , 2h ) , 
 6.86 ( m , 3h ) , 5.76 ( d , j = 9.2 hz , 1h ) , 5.54 ( dd , j = 9.6 , 9.2 hz , 1h ) , 4.83 ( br d , 1h ) , 3.87 ( s , 3h ) , 1.28 
 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 154.3 , 
 149.4 , 149.2 , 131.9 , 130.6 , 130.5 , 129.5 , 124.6 , 119.2 , 111.3 , 110.6 , 
 93.5 , 56.0 , 55.9 , 28.0 ; hrms ( esi ) exact mass calcd for c21h25brn2nao6 [ m + na ] , 503.0790 , found 503.0794 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-10 ( 5 mol % ) with a 60 h reaction time . 
 following the silica plug filtration , the resulting white solid was 
 added to the filter paper of a buchner funnel and washed with cold 
 hexanes to afford the pure compound as an off - white solid ( 15.3 mg , 
 64% ) that was found to be 93% ee and 56:1 dr by chiral hplc ( chiralcel 
 ad - h : 6% etoh / hexanes , 1.0 ml / min : tr(d1e2 major / minor ) = 19.9 min , tr(d2e1 minor / major ) = 23.3 min , tr(d1e1 major / major ) = 25.5 min , tr(d2e2 minor / minor ) = 35.2 min ) : [ ]d = 8.8 ( c 0.25 , chcl3 ) ; mp 185 c ( dec . ) ; rf = 0.17 ( 25% 
 etoac / hexanes ) ; ir ( film ) 3351 , 2979 , 2937 , 1703 , 1565 , 1517 cm ; h nmr ( 400 mhz , cdcl3 )  
 7.56 ( s , 1h ) , 7.49 ( d , j = 7.2 hz , 1h ) , 7.41 ( d , j = 8.0 hz , 1h ) , 7.35 ( m , 1h ) , 6.89 ( d , j = 8.0 hz , 1h ) , 6.84 ( d , j = 7.6 hz , 2h ) , 5.77 ( d , j = 9.2 hz , 1h ) , 5.54 ( dd , j = 9.6 , 9.2 
 hz , 1h ) , 4.80 ( d , j = 9.2 hz , 1h ) , 3.88 ( s , 3h ) , 
 3.87 ( s , 3h ) , 1.28 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 154.2 , 149.4 , 149.3 , 134.6 , 133.4 , 130.3 , 130.0 , 129.5 , 
 129.1 , 126.9 , 119.2 , 111.4 , 110.6 , 93.5 , 56.0 , 55.9 , 28.0 ; hrms ( esi ) 
 exact mass calcd for c21h25cln2nao6 [ m + na ] 459.1299 , found 459.1322 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-9 ( 5 mol % ) with a 46 h reaction time . the 
 reaction precipitate was added to the filter paper of a buchner funnel 
 and washed with cold hexanes to afford the adduct as a white crystalline 
 solid ( 22 mg , 45% ) that was found to be 86% ee and 1.5:1 dr by chiral 
 hplc ( chiralcel ic : 8% proh / hexanes , 
 1.0 ml / min : tr(d2e1 minor / major ) 
 = 15.1 min , tr(d1e1 major / major ) 
 = 16.8 min , tr(d2e2 minor / minor ) 
 = 20.0 min , tr(d1e2 major / minor ) 
 = 38.3 min ) : mp 135136 c ; rf = 0.27 ( 25% etoac / hexanes ) ; ir ( film ) 3391 , 2991 , 2928 , 1692 , 1560 , 
 1526 cm ; h nmr ( 400 mhz , cdcl3 )  7.92 ( dd , j = 6.0 , 2.0 hz , 1h ) , 
 7.51 ( m , 1h ) , 7.02 ( d , j = 8.8 hz , 1h ) , 6.90 ( dd , j = 8.4 , 1.6 hz , 1h ) , 6.85 ( m , 2h ) , 6.12 ( d , j = 10.0 hz , 1h ) , 5.60 ( br d , 1h ) , 4.82 ( d , j = 9.6 
 hz , 1h ) , 3.90 ( s , 3h ) , 3.88 ( s , 3h ) , 1.29 ( s , 9h ) ; c 
 nmr ( 100 mhz , cdcl3 ) ppm 159.9 ( d , jcf = 240 hz ) , 149.5 , 149.4 , 134.7 ( d , jcf = 11 hz ) , 132.4 ( d , jcf = 9 hz ) , 129.2 , 126.9 , 121.2 , 121.1 , 119.0 , 
 117.2 ( d , jcf = 3 hz ) , 111.5 , 
 85.5 ( d , jcf = 2 hz ) , 56.0 , 
 55.9 , 28.2 , 28.0 ; hrms ( esi ) exact mass calcd for c21h24brfn2nao6 [ m + na ] , 521.0699 , 
 found 521.0684 . this 
 compound was prepared according to the general procedure employing 
 catalyst ( r , r)-9 ( 5 
 mol % ) with a 36 h reaction time . column chromatography ( sio2 , 020% ethyl acetate in hexanes ) afforded the adduct as an 
 off - white crystalline solid ( 18 mg , 65% ) that was found to be 72% 
 ee and 60:1 dr by chiral hplc ( chiralcel ia : 12% proh / hexanes , 1.0 ml / min : tr(d2e1 minor / major ) = 13.4 min , tr(d1e2 major / minor ) = 18.3 min , tr(d1e1 major / major ) = 22.2 min , tr(d2e2 minor / minor ) = 28.8 min ) : [ ]d = 16 
 ( c 0.25 , chcl3 ) ; mp 146148 c ; rf = 0.31 ( 25% etoac / hexanes ) ; ir ( film ) 3377 , 
 2987 , 2925 , 1686 , 1549 , 1522 cm ; h 
 nmr ( 400 mhz , cdcl3 )  7.36 ( m , 2h ) , 7.317.22 
 ( m , 2h ) , 6.90 ( d , j = 8.0 hz , 1h ) , 6.83 ( m , 2h ) , 
 5.74 ( d , j = 9.2 hz , 1h ) , 5.58 ( dd , j = 9.2 , 8.8 hz , 1h ) , 4.78 ( d , j = 8.8 hz , 1h ) , 3.87 
 ( s , 6h ) , 2.37 ( s , 3h ) , 1.27 ( s , 9h ) ; c nmr ( 100 mhz , 
 cdcl3 ) ppm 154.3 , 149.2 , 149.1 , 138.6 , 131.5 , 130.9 , 130.2 , 
 129.3 , 128.7 , 125.8 , 119.2 , 111.3 , 110.6 , 94.3 , 55.9 ( 2c ) , 29.7 , 28.0 , 
 21.3 ; hrms ( esi ) exact mass calcd for c22h28n2nao6 [ m + na ] , 439.1845 , found 
 439.1862 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-10 ( 5 mol % ) with a 48 h reaction time . column chromatography ( sio2 , 05% ethyl acetate 
 in hexanes ) afforded the product as a tan crystalline solid ( 28.3 
 mg , 54% ) that was found to be 92% ee and 25:1 dr by chiral hplc ( chiralpak 
 ad - h , 10% etoh / hexanes , 1.0 ml / min : tr ( anti , minor ) = 13.2 min , tr ( syn , major ) = 15.8 min , tr ( anti , major ) = 17.2 min , tr ( syn , minor ) = 36.8 min ) : [ ]d = 21 ( c 0.36 , 
 chcl3 ) ; mp 150151 c ; rf = 0.11 ( 20% etoac in hexanes ) ; ir ( film ) 3383 , 2989 , 1676 , 
 1595 , 1519 , 1463 , 1423 , 1367 cm ; h 
 nmr ( 400 mhz , cdcl3 )  7.52 ( d , j = 8.4 hz , 2h ) , 7.38 ( d , j = 8.4 hz , 2h ) , 6.826.89 
 ( m , 3h ) , 5.77 ( d , j = 9.2 hz , 1h ) , 5.54 ( dd , j = 9.4 , 9.2 hz , 1h ) , 3.87 ( br d , 1h ) , 3.87 ( s , 3h ) , 3.87 
 ( s , 3h ) , 1.28 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 154.2 , 149.3 , 149.2 , 136.3 , 130.2 , 130.0 , 129.5 , 128.9 , 119.1 , 
 111.3 , 110.5 , 93.4 , 80.5 , 55.9 , 55.8 , 29.6 , 28.0 ; hrms ( esi ) exact 
 mass calcd for c21h25cln2nao6 [ m + na ] 459.1299 ; found 459.1305 . this compound was prepared according to 
 the general procedure employing catalyst ( r , r)-10 ( 5 mol % ) with a 48 h reaction time . 
 following silica plug filtration , h nmr showed > 20:1 
 dr . column chromatography ( sio2 , 1040% ethyl acetate 
 in hexanes ) afforded the adduct as an off - white crystalline solid 
 ( 23.0 mg , 72% ) that was found to be 50% ee and 5:1 dr ( epimerized 
 on silica ) by chiral hplc ( chiralcel ia : 12% proh / hexanes , 1.0 ml / min : tr(d2e2 minor / minor ) = 15.4 min , tr(d1e2 major / minor ) = 17.8 min , tr(d1e1 major / major ) = 24.8 min , tr(d2e2 minor / minor ) = 34.5 min ) : mp 171 c dec ; rf = 0.75 ( 50% etoac / hexanes ) ; ir ( film ) 3369 , 2969 , 2930 , 
 2838 , 1699 , 1553 , 1523 , 1253 cm ; h 
 nmr ( 400 mhz , cdcl3 )  7.15 ( s , 1h ) , 7.08 ( dd , j = 8.4 , 2.0 hz , 1h ) , 6.916.83 ( m , 4h ) , 5.73 ( d , j = 10.0 hz , 1h ) , 5.63 ( dd , j = 10.0 , 8.4 
 hz , 1h ) , 4.78 ( d , j = 9.2 hz , 1h ) , 3.91 ( s , 3h ) , 
 3.89 ( s , 3h ) , 3.88 ( s , 3h ) , 3.86 ( s , 3h ) , 1.28 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 154.4 , 150.5 , 149.2 , 149.1 
 ( 2c ) , 130.1 , 123.9 , 122.2 , 119.1 , 111.3 , 122.2 , 119.1 , 111.1 , 111.0 , 
 110.7 , 110.6 , 94.2 , 80.3 , 55.9 ( 4c ) , 28.1 ; hrms ( esi ) exact mass calcd 
 for c23h30n2nao8 [ m + 
 na ] 485.1933 , found 485.1958 . this 
 compound was prepared according to the general procedure employing 
 catalyst ( r , r)-10 ( 5 
 mol % ) with a 72 h reaction time . the reaction precipitate was added 
 to the filter paper of a buchner funnel and washed with cold hexanes 
 to afford the product as a light brown crystalline solid ( 30 mg , 70% ) 
 that was found to be 78% ee and 1:1 dr ( epimerized from 20:1 dr ( h nmr ) shortly after buchner filtration ) determined by chiral 
 hplc ( chiralcel ad : 10% proh / hexanes , 
 1.0 ml / min : tr(d1e1 major / major ) 
 = 15.2 min , tr(d1e2 major / minor ) 
 = 22.4 min , tr(d2e1 minor / major ) 
 = 24.8 min , tr(d2e2 minor / minor ) 
 = 39.0 min ) : mp 175177 c ; rf = 0.31 ( 20% etoac / hexanes ) ; ir ( film ) 3344 , 2972 , 2931 , 1703 , 1558 , 
 1524 , 1468 cm ; h nmr ( 400 mhz , cdcl3 )  7.23 ( d , j = 7.2 hz , 1h ) , 7.157.08 
 ( m , 5h ) , 6.85 ( d , j = 8.4 hz , 1h ) , 5.70 ( m , 2h ) , 
 4.81 ( d , j = 8.4 hz , 1h ) , 3.91 ( s , 3h ) , 3.89 ( s , 
 3h ) , 2.34 ( s , 3h ) , 1.28 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 154.4 , 150.5 , 149.0 , 138.7 , 137.0 , 129.5 , 128.9 , 127.7 , 
 124.0 , 122.2 , 121.4 , 111.1 , 111.0 , 94.3 , 56.0 , 28.2 , 21.2 ; hrms ( esi ) 
 exact mass calcd for c22h28n2nao6 [ m + na ] , 439.1845 , found 439.1862 . -nitro boc - amine 4ba ( 470 mg , 1.03 mmol ) and cocl2 ( 134 mg , 1.03 mmol ) were 
 added to methanol ( 4.1 ml ) in a flask and chilled to 0 c before 
 nabh4 ( 194 mg , 5.15 mmol ) was added in three portions over 
 2 h. the reaction mixture was stirred at 0 c for an additional 
 15 min before the mixture was quenched with saturated aqueous nh4cl . the reaction mixture was adjusted to ph 10 with concentrated 
 aqueous nh4oh , and the aqueous layer was extracted with 
 ethyl acetate . the combined organic layers were dried ( mgso4 ) , filtered , and concentrated to a white foam ( 416 mg , 95% ) : [ ]d = + 44 ( c 0.80 , chcl3 ) ; rf = 0.40 ( 50% etoac / hexanes ) ; 
 ir ( film ) 3378 , 3274 , 2977 , 1698 , 1526 , 1491 cm ; h nmr ( 400 mhz , cdcl3 )  7.39 ( d , j = 8.0 hz , 2h ) , 7.21 ( d , j = 8.0 hz , 2h ) , 
 6.95 ( d , j = 7.2 hz , 2h ) , 6.94 ( d , j = 7.2 hz , 2h ) , 5.46 ( d , j = 6.8 hz , 1h ) , 4.79 ( br 
 t , 1h ) , 4.22 ( br d , 1h ) , 1.56 ( br s , 2h ) , 1.36 ( s , 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 155.1 , 140.8 , 133.4 , 132.6 , 
 128.7 ( 2c ) , 128.3 , 121.41 , 120.3 , 79.8 , 59.3 , 28.3 ( 3c ) ; hrms ( esi ) 
 exact mass calcd for c19h23brcln2o2 [ m + h ] 425.0631 , found 425.0643 . amine s6 ( 383 mg , 900 mol ) 
 and carboxylic acid ( 189 mg , 900 mol ) were dissolved in ch2cl2 ( 4.5 ml ) , chilled to 0 c , and treated 
 with edchcl ( 224 mg , 1.17 mmol ) and dmap ( 10 mg , 90 mol ) . the reaction mixture was stirred and gradually warmed to room temperature 
 over 2 h. after 16 h , the mixture was diluted with water and extracted 
 with dichloromethane . the combined organic layers were washed with 
 water , saturated aqueous nahco3 , and once more with water . 
 the organic layer was dried ( mgso4 ) , filtered , and concentrated . the residue was washed with a 3/7 dichloromethane / hexanes mixture 
 and decanted to afford a white solid ( 438 mg , 79% ) that was > 95% 
 pure by h nmr : [ ]d = 17 
 ( c 0.39 , chcl3 ) ; mp = 223225 c ; rf = 0.9 ( 10% meoh / ch2cl2 ) ; ir ( film ) 3350 , 2978 , 1685 , 1631 , 1611 , 1530 , 1496 cm ; h nmr ( 400 mhz , cdcl3 )  8.38 ( d , j = 6.8 hz , 1h ) , 8.18 ( d , j = 8.8 hz , 1h ) , 
 7.41 ( d , j = 8.4 hz , 2h ) , 7.21 ( d , j = 8.0 hz , 2h ) , 6.94 ( m , 4h ) , 6.59 ( dd , j = 8.8 , 
 2.4 hz , 1h ) , 6.46 ( d , j = 1.2 hz , 1h ) , 5.87 ( d , j = 4.8 hz , 1h ) , 5.75 ( d , j = 5.6 hz , 1h ) , 
 5.08 ( d , j = 3.6 hz , 1h ) , 4.68 ( qq , j = 6.0 , 6.0 hz , 1h ) , 3.84 ( s , 3h ) , 1.38 ( s , 9h ) , 1.26 ( m , 6h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 165.6 , 163.7 , 157.2 , 
 155.1 , 137.3 , 134.4 , 133.4 , 131.5 , 128.9 , 128.7 , 128.4 , 121.7 , 114.2 , 
 105.3 , 100.3 , 80.0 , 71.5 , 59.5 , 56.7 , 55.5 , 31.6 , 28.3 , 22.6 , 22.0 , 
 21.6 , 14.1 ; hrms ( esi ) exact mass calcd for c30h34brcln2nao5 [ m + na ] 639.1237 , found 
 639.1248 . amide s7 ( 374 mg , 605 mol ) 
 was dissolved in dichloromethane ( 6.0 ml ) , and the solution was treated 
 with tfa ( 1.8 ml , 24 mmol ) and stirred at room temperature for 2 h. 
 the reaction mixture was diluted with dichloromethane , poured into 
 saturated aqueous nahco3 , and extracted with dichloromethane . 
 the combined organic layers were dried ( mgso4 ) , filtered , 
 and concentrated to a white foam ( 300 mg , 96% ) : [ ]d = 103 ( c 1.07 , chcl3 ) ; rf = 0.6 ( 10% meoh / ch2cl2 ) ; ir ( film ) 3371 , 2991 , 2929 , 1643 , 1609 , 1519 , 1498 
 cm ; h nmr ( 600 mhz , cdcl3 )  8.89 ( d , j = 8.0 hz , 1h ) , 8.12 ( d , j = 8.8 hz , 1h ) , 7.34 ( d , j = 8.4 hz , 2h ) , 
 7.23 ( d , j = 8.4 hz , 2h ) , 7.02 ( d , j = 8.4 hz , 2h ) , 6.93 ( d , j = 8.4 hz , 2h ) , 6.55 ( dd , j = 8.8 , 2.0 hz , 1h ) , 6.48 ( d , j = 2.0 
 hz , 1h ) , 5.40 ( dd , j = 8.0 , 8.0 hz , 1h ) , 4.75 ( qq , j = 6.0 , 6.0 hz , 1h ) , 4.40 ( d , j = 8.8 
 hz , 1h ) , 3.83 ( s , 3h ) , 1.70 ( br , 2h ) , 1.44 ( d , j = 
 6.0 hz , 3h ) , 1.43 ( d , j = 6.0 hz , 3h ) ; c nmr ( 150 mhz , cdcl3 ) ppm 164.6 , 163.3 , 157.2 , 140.7 , 
 137.3 , 134.1 , 133.1 , 131.1 , 129.5 , 128.4 , 128.3 , 121.4 , 114.9 , 105.1 , 
 100.3 , 71.5 , 58.9 , 58.6 , 55.5 , 22.2 , 22.0 ; hrms ( esi ) exact mass calcd 
 for c25h26brcln2nao3 [ m 
 + na ] 539.0713 , found 539.0696 . amine s8 ( 267 mg , 516 mol ) 
 was added to carbonyl diimidazole ( 109 mg , 671 mol ) in dichloromethane 
 ( 1.8 ml ) . the mixture was stirred at room temperature for 90 min ( or 
 until no starting material remained by tlc ) , at which point the oxopiperazine 
 ( 103 mg , 1.03 mol ) was added . the mixture was stirred for 16 
 h and then diluted with dichloromethane and water . the aqueous layer 
 was extracted with dichloromethane , and the organic layers were combined , 
 dried ( mgso4 ) , filtered , and concentrated to an off - white 
 oil . column chromatography ( sio2 , 03% methanol 
 in dichloromethane ) afforded the urea as a white solid ( 301 mg , 91% ) : 
 [ ]d = + 90 ( c 0.54 , chcl3 ) ; mp = 170 c ( dec . ) ; rf = 0.36 ( 10% meoh / ch2cl2 ) ; ir ( film ) 
 3375 , 3236 , 2980 , 1669 , 1634 , 1606 , 1537 , 1495 cm ; h nmr ( 600 mhz , cdcl3 )  8.36 ( d , j = 7.6 hz , 1h ) , 8.25 ( d , j = 8.8 hz , 1h ) , 
 7.76 ( d , j = 8.8 hz , 1h ) , 7.43 ( d , j = 8.4 hz , 2h ) , 7.16 ( d , j = 8.4 hz , 2h ) , 6.89 ( m , 
 4h ) , 6.70 ( br s , 1h ) , 6.60 ( dd , j = 8.8 , 2.0 hz , 
 1h ) , 6.45 ( d , j = 2.0 hz , 1h ) , 5.75 ( dd , j = 8.0 , 2.4 hz , 1h ) , 5.10 ( dd , j = 2.8 , 
 2.4 hz , 1h ) , 4.65 ( qq , j = 6.0 , 6.0 hz , 1h ) , 4.13 
 ( d , j = 2.4 hz , 2h ) , 3.85 ( s , 3h ) , 3.71 ( m , 1h ) , 
 3.59 ( m , 1h ) , 3.38 ( m , 2h ) , 1.19 ( d , j = 6.0 hz , 
 3h ) , 1.14 ( d , j = 6.0 hz , 3h ) ; c nmr 
 ( 150 mhz , cdcl3 ) ppm 167.8 , 167.2 , 164.0 , 157.3 , 155.0 , 
 137.0 , 136.4 , 134.4 , 133.3 , 131.6 , 129.4 , 128.7 , 128.1 , 122.0 , 113.4 , 
 105.4 , 100.3 , 71.5 , 61.8 , 57.7 , 55.6 , 47.5 , 41.1 , 40.0 , 22.0 , 21.5 ; 
 hrms ( esi ) exact mass calcd for c30h32brcln4nao5 [ m + na ] 665.1142 , found 665.1149 . -nitro boc - amine 4ac ( 265 
 mg , 581 mol ) and cocl2 ( 75.4 mg , 581 mol ) 
 were added to methanol ( 3 ml ) in a flask and chilled to 0 c 
 before nabh4 ( 110 mg , 2.91 mmol ) was added in three portions 
 over 45 min . the reaction mixture was stirred at 0 c for an 
 additional 15 min before the mixture was quenched with saturated aqueous 
 nh4cl . the reaction mixture was adjusted to ph 10 with 
 concentrated aqueous nh4oh , and the aqueous layer was extracted 
 with ethyl acetate . the combined organic layers were dried ( mgso4 ) , filtered , and concentrated to a white foam ( 260 mg , 99% ) : 
 [ ]d = + 40 ( c 0.27 , chcl3 ) ; rf = 0.31 ( 50% 
 etoac / hexanes ) ; ir ( film ) 3371 , 2976 , 2982 , 2859 , 1697 , 1489 , 1366 
 cm ; h nmr ( 400 mhz , cdcl3 )  7.36 ( d , j = 8.4 hz , 2h ) , 7.25 ( d , j = 8.8 hz , 2h ) , 7.00 ( d , j = 8.0 hz , 2h ) , 
 6.87 ( d , j = 8.0 hz , 2h ) , 5.45 ( br s , 1h ) , 4.77 ( br 
 s , 1h ) , 4.23 ( s , 1h ) , 1.36 ( s , 9h ) , 1.25 ( d , j = 
 6.4 hz , 2h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 155.0 , 
 140.3 , 133.3 , 131.5 , 131.2 , 129.1 , 128.4 , 128.3 , 121.5 , 59.1 , 28.3 
 ( 3c ) ; hrms ( esi ) exact mass calcd for c19h23brcln2o2 [ m + h ] 425.0631 , found 
 425.0641 . amine s10 ( 241 mg , 566 mol ) 
 was added to carbonyl diimidazole ( 119 mg , 736 mol ) in dichloromethane 
 ( 2.0 ml ) . the mixture was stirred at room temperature for 3 h ( or 
 until no starting material remained by tlc ) , at which point the oxopiperazine 
 ( 113 mg , 1.13 mmol ) was added . the mixture was stirred for 16 h and 
 then diluted with dichloromethane and water . the aqueous layer was 
 extracted with dichloromethane , and the organic layers were combined , 
 dried ( mgso4 ) , filtered , and concentrated to an off - white 
 solid . the solid was washed with 1/1 dichloromethane / hexanes ( 6 ml ) , 
 and the wash layer was decanted to afford the desired product as a 
 1/1 mixture with imidazole . the urea ( 230 mg , 417 mol ) was dissolved in dichloromethane 
 ( 5.0 ml ) , and the solution was treated with tfa ( 1.26 ml , 16.0 mmol ) 
 and stirred at room temperature for 3 h. the reaction mixture was 
 diluted with dichloromethane , poured into saturated aqueous nahco3 , and extracted with dichloromethane . the combined organic 
 layers were dried ( mgso4 ) , filtered , and concentrated to 
 a brown oil ( 170 mg , 67% over two steps ) : [ ]d = + 32 ( c 0.24 , chcl3 ) ; rf = 0.23 ( 10% meoh / ch2cl2 ) ; ir ( film ) 3344 , 3262 , 3069 , 2924 , 2848 , 1675 , 1537 , 1496 cm ; h nmr ( 600 mhz , cdcl3 )  
 7.40 ( d , j = 8.0 hz , 2h ) , 7.19 ( d , j = 8.0 hz , 2h ) , 6.92 ( d , j = 8.4 hz , 2h ) , 6.92 ( d , j = 8.4 hz , 2h ) , 6.84 ( br s , 1h ) , 5.89 ( d , j = 7.2 hz , 1h ) , 5.00 ( t , j = 6.4 hz , 1h ) , 4.26 ( d , j = 4.8 hz , 1h ) , 4.05 ( s , 2h ) , 3.60 ( d , j = 2.8 hz , 2h ) , 3.33 ( br d , 2h ) , 1.85 ( br s , 2h ) ; c 
 nmr ( 150 mhz , cdcl3 ) ppm 167.3 , 155.7 , 140.8 , 136.7 , 133.4 , 
 131.4 , 128.8 , 128.5 ( 2c ) , 128.3 , 121.5 ( 2c ) , 59.3 , 59.1 , 47.6 , 40.9 , 
 39.7 , 29.7 ; hrms ( esi ) exact mass calcd for c19h21brcln4o2 [ m + h ] 451.0536 , found 
 451.0536 . amine s11 ( 116 mg , 257 mol ) 
 and carboxylic acid ( 54.0 mg , 257 mol ) were dissolved in dichloromethane 
 ( 1.3 ml ) , chilled to 0 c , and treated with edchcl ( 64.0 
 mg , 334 mol ) and dmap ( 3.1 mg , 26 mol ) . the reaction 
 mixture was stirred and gradually warmed to room temperature over 
 2 h. after 5 h , the mixture was diluted with water and extracted with 
 dichloromethane . the combined organic layers were washed with water , 
 saturated aqueous nahco3 , and once more with water . the 
 organic layer was dried ( mgso4 ) , filtered , and concentrated . column chromatography ( sio2 , 06% methanol in dichloromethane ) 
 afforded the amide as a white solid ( 112 mg , 68% ) : [ ]d = + 32 ( c 0.65 , chcl3 ) ; mp = 169 c ; rf = 0.60 ( 10% meoh / ch2cl2 ) ; ir ( film ) 3367 , 2978 , 2934 , 1638 , 1604 , 1532 , 
 1492 , 1259 cm ; h nmr ( 400 mhz , cdcl3 )  8.35 ( d , j = 8.0 hz , 1h ) , 8.24 
 ( d , j = 8.8 hz , 1h ) , 7.71 ( d , j = 
 4.8 hz , 1h ) , 7.43 ( d , j = 8.4 hz , 2h ) , 7.16 ( d , j = 8.0 hz , 2h ) , 6.90 ( d , j = 8.4 hz , 2h ) , 
 6.89 ( d , j = 8.4 hz , 2h ) , 6.85 ( br s , 1h ) , 6.60 ( dd , j = 8.8 , 2.0 hz , 1h ) , 6.44 ( d , j = 2.0 
 hz , 1h ) , 5.76 ( dd , j = 8.0 , 2.8 hz , 1h ) , 5.10 ( dd , j = 2.8 , 2.0 hz , 1h ) , 4.65 ( qq , j = 6.0 , 
 6.0 hz , 1h ) , 4.10 ( d , j = 3.2 hz , 2h ) , 3.84 ( s , 3h ) , 
 3.70 ( m , 1h ) , 3.58 ( m , 1h ) , 3.37 ( m , 2h ) , 1.20 ( d , j = 6.0 hz , 3h ) , 1.14 ( d , j = 6.0 hz , 3h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 167.9 , 167.2 , 164.0 , 157.2 , 
 156.0 , 137.1 , 136.5 , 134.4 , 133.3 , 131.6 , 129.4 , 128.7 , 128.1 , 121.9 , 
 113.5 , 105.4 , 100.3 , 71.5 , 61.7 , 60.4 , 57.7 , 55.6 , 47.5 , 41.1 , 40.0 , 
 22.0 , 21.5 , 21.0 , 14.2 ; hrms ( esi ) exact mass calcd for c30h32brcln4nao5 [ m + na ] 665.1142 , found 665.1165 . tf2o ( 143 l , 845 mol ) was added 
 to a stirred solution of ph3po ( 470 mg , 1.69 mmol ) in 
 dichloromethane ( 1.0 ml ) at 0 c , and this mixture was stirred 
 for 10 min and then treated with the cis - amide urea s11 or s8 ( 272 mg , 422 mol ) as a solution 
 in dichloromethane ( 2.0 ml ) . the mixture was stirred at 0 c 
 for 1 h prior to stirring at room temperature for 4 h. the reaction 
 mixture was quenched with nahco3 , the aqueous layer was 
 extracted with dichloromethane , and the combined organic layers were 
 dried ( mgso4 ) , filtered , and concentrated . column chromatography 
 ( sio2 , 02% methanol in dichloromethane ) of the 
 residue provided the product as a white solid ( 173 mg , 66% ) : [ ]d = 69 ( c 0.70 , 
 chcl3 ) ; mp 118120 c ; rf = 0.39 ( 10% meoh / ch2cl2 ) ; ir ( film ) 
 3223 , 3077 , 2980 , 2931 , 1676 , 1613 , 1495 , 1419 cm ; h nmr ( 400 mhz , cdcl3 )  7.61 ( d , j = 8.8 hz , 1h ) , 7.24 ( d , j = 8.4 hz , 2h ) , 
 7.03 ( d , j = 8.4 hz , 2h ) , 6.88 ( d , j = 8.4 hz , 2h ) , 6.87 ( d , j = 8.4 hz , 2h ) , 6.55 ( dd , j = 8.4 , 2.0 hz , 1h ) , 6.48 ( d , j = 2.4 
 hz , 1h ) , 6.00 ( br s , 1h ) , 5.56 ( d , j = 9.6 hz , 1h ) , 
 5.46 ( d , j = 9.6 hz , 1h ) , 4.61 ( qq , j = 6.0 , 6.0 hz , 1h ) , 3.85 ( s , 3h ) , 3.77 ( d , j = 
 18.0 hz , 1h ) , 3.65 ( d , j = 18.0 hz , 1h ) , 3.88 ( m , 
 1h ) , 3.22 ( m , 1h ) , 3.01 ( m , 2h ) , 1.39 ( d , j = 6.0 
 hz , 3h ) , 1.34 ( d , j = 6.0 hz , 3h ) ; c 
 nmr ( 100 mhz , cdcl3 ) ppm 166.9 , 163.0 , 160.2 , 157.0 , 154.7 , 
 136.5 , 135.0 , 133.1 , 132.1 , 130.9 , 129.6 , 128.4,128.1 , 121.0 , 113.4 , 
 104.6 , 100.1 , 71.8 , 70.9 , 69.1 , 55.5 , 49.4 , 41.8 , 40.3 , 22.0 ( 2c ) ; 
 hrms ( esi ) exact mass calcd for c30h31brcln4o4 [ mh ] 625.1217 , found 625.1207 . -nitro boc - amine ent-4ab ( 140 mg , 304 mol ) and cocl2 ( 46.0 
 mg , 304 mol ) were added to methanol ( 1.2 ml ) in a flask and 
 chilled to 0 c before nabh4 ( 57 mg , 1.5 mmol ) was 
 added in three portions over 5 h. the reaction mixture was stirred 
 at 0 c for an additional 15 min before the mixture was quenched 
 with saturated aqueous nh4cl . the reaction mixture was 
 adjusted to ph 10 with concentrated aqueous nh4oh , and 
 the aqueous layer was extracted with ethyl acetate . the combined organic 
 layers were dried ( mgso4 ) , filtered , and concentrated . column chromatography ( sio2 , 4060% ethyl acetate 
 in hexanes ) afforded the product as a white foam ( 60 mg , 46% ) in about 
 15:1 dr ( by h nmr ) : rf = 0.40 
 ( 50% etoac / hexanes ) ; ir ( film ) 3378 , 3302 , 2977 , 2929 , 1699 cm ; h nmr ( 400 mhz , cdcl3 )  
 7.28 ( m , 1h ) , 7.23 ( d , j = 8.0 hz , 2h ) , 7.08 ( d , j = 7.6 hz , 1h ) , 6.98 ( d , j = 8.0 hz , 2h ) , 
 6.94 ( m , 1h ) , 6.86 ( s , 1h ) , 5.56 ( d , j = 8.0 hz , 
 1h ) , 4.84 ( br dd , 1h ) , 4.26 ( br d , 1h ) , 1.50 ( br m , 2h ) , 1.36 ( s , 
 9h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 155.1 , 149.0 , 
 140.1 , 133.4 , 130.6 , 129.4 , 128.4 , 128.2 , 125.9 , 121.6 , 120.3 ( q , jcf = 251 hz ) , 120.0 , 119.9 , 119.1 
 79.9 , 59.1 , 28.2 ; hrms ( esi ) exact mass calcd for c20h23clf3n2o3 [ m + h ] 431.1349 , found 431.1366 . amine s17 ( 60 mg , 139 mol ) 
 was added to carbonyl diimidazole ( 29.4 mg , 181 mol ) in dichloromethane 
 ( 0.5 ml ) . the mixture was stirred at room temperature for 90 min ( or 
 until no starting material remained by tlc ) , at which point the oxopiperazine 
 ( 27.8 mg , 278 mol ) was added . the mixture was stirred for 16 
 h and then diluted with dichloromethane and water . the aqueous layer 
 was extracted with dichloromethane , and the organic layers were combined , 
 dried ( mgso4 ) , filtered , and concentrated to an off - white 
 oil . the residue was washed with hexanes ( 4 ml ) and the wash layer 
 was decanted to afford the desired product as a 1:1 mixture with imidazole . the urea ( 47 mg , 84 mol ) 
 was dissolved in dichloromethane ( 2.0 ml ) , and the solution was treated 
 with tfa ( 180 l , 3.3 mmol ) and stirred at room temperature 
 overnight . the reaction mixture was diluted with dichloromethane , 
 poured into saturated aqueous nahco3 , and extracted with 
 dichloromethane . the combined organic layers were dried ( mgso4 ) , filtered , and concentrated to an oil . the residue was washed 
 with hexanes , and the wash layer was decanted to afford the desired 
 product as a yellow foam ( 40 mg , 63% over two steps ) in about 20:1 
 dr ( by h nmr ) : rf = 0.1 ( 5% 
 meoh / ch2cl2 ) ; ir ( film ) 3344 , 3262 , 2924 , 1668 
 cm ; h nmr ( 600 mhz , cdcl3 )  7.31 ( t , j = 7.8 hz , 1h ) , 7.18 ( d , j = 8.4 hz , 2h ) , 7.09 ( d , j = 7.8 hz , 1h ) , 
 7.04 ( m , 2h ) , 6.90 ( d , j = 8.4 hz , 2h ) , 6.88 ( s , 
 1h ) , 6.00 ( d , j = 7.2 hz , 1h ) , 5.03 ( dd , j = 12.6 , 1.8 hz , 1h ) , 4.33 ( d , j = 4.8 
 hz , 1h ) , 4.07 ( dd , j = 17.4 , 12.6 hz , 2h ) , 3.60 ( m , 
 2h ) , 3.31 ( m , 2h ) , 1.24 ( br m , 2h ) ; c nmr ( 150 mhz , cdcl3 ) ppm 167.5 , 155.7 , 149.1 , 144.5 , 136.6 , 133.4 , 129.8 , 128.8 
 ( 2c ) , 128.3 ( 2c ) , 125.2 , 120.1 , 119.5 , 59.4 , 59.0 , 47.5 , 40.9 , 39.6 , 
 14.1 ; hrms ( esi ) exact mass calcd for c20h21clf3n4o3 [ m + h ] 457.1254 , 
 found 457.1268 . tf2o ( 16 l , 96 mol ) was added 
 to a stirred solution of ph3po ( 53 mg , 191 mol ) 
 in dichloromethane ( 300 l ) at 0 c , and this mixture was 
 stirred for 10 min and then treated with cis - amide 
 urea 19 ( 30.2 mg , 48.8 mol ) as a solution in dichloromethane 
 ( 800 l ) . the mixture was stirred at 0 c for 1 h prior 
 to stirring at room temperature for 4 h. the reaction mixture was 
 quenched with nahco3 , the aqueous layer was extracted with 
 dichloromethane , and the combined organic layers were dried ( mgso4 ) , filtered , and concentrated . column chromatography ( sio2 , 04% methanol in dichloromethane ) of the residue 
 provided the product as a white solid ( 21.0 mg , 73% ) : [ ]d = 1.7 ( c 0.21 , 
 chcl3 ) ; mp 125126 c ; rf = 0.26 ( 5% meoh / ch2cl2 ) ; ir ( film ) 
 3216 , 2980 , 2932 , 1683 , 1614 , 1440 cm ; h nmr ( 400 mhz , cdcl3 )  7.60 ( d , j = 8.8 hz , 1h ) , 7.13 ( t , j = 8.0 hz , 1h ) , 7.00 ( d , j = 8.4 hz , 2h ) , 6.94 ( t , j = 8.0 hz , 2h ) , 
 6.87 ( s , 1h ) , 6.84 ( d , j = 8.4 hz , 2h ) , 6.56 ( dd , j = 8.4 , 2.0 hz , 1h ) , 6.49 ( d , j = 2.0 
 hz , 1h ) , 6.40 ( s , 1h ) , 5.59 ( d. j = 10.0 hz , 1h ) , 
 5.52 ( d , j = 10.0 hz , 1h ) , 4.61 ( qq , j = 6.0 , 6.0 hz , 1h ) , 3.83 ( s , 3h ) , 3.83 ( d , j = 
 18.0 hz , 1h ) , 3.62 ( d , j = 18.0 hz , 1h ) , 3.42 ( m , 
 1h ) , 3.18 ( m , 1h ) , 3.00 ( m , 2h ) , 1.38 ( d , j = 6.0 
 hz , 3h ) , 1.33 ( d , j = 6.0 hz , 3h ) ; c 
 nmr ( 100 mhz , cdcl3 ) ppm 166.8 , 163.0 , 160.6 , 157.1 , 154.7 , 
 148.9 , 134.8 , 133.3 , 132.1 , 129.2 , 128.2 , 128.1 , 126.4 , 121.6 , 120.6 , 
 120.4 ( q , jcf = 256 hz ) , 119.9 , 
 133.4 , 104.6 , 104.1 , 100.2 , 71.8 , 71.1 , 69.1 , 63.9 , 55.5 , 49.3 , 42.0 , 
 40.5 , 22.0 ( 2c ) , 18.0 , 15.3 ; hrms ( esi ) exact mass calcd for c31h31clf3n4o5 [ m 
 + h ] 631.1935 , found 631.1917 . n-((1r,2s)-2-amino-1-(4-chlorophenyl)-2-(3-(trifluoromethoxy)phenyl)ethyl)-3-oxopiperazine-1-carboxamide 
 ( 35 mg , 76 mol ) and carboxylic acid 18 ( 16 mg , 
 77 mol ) were dissolved in dichloromethane ( 385 l ) , and 
 the solution was chilled to 0 c and treated with edchcl 
 ( 19 mg , 99 mol ) and dmap ( 1 mg , 7.7 mol ) . the reaction 
 mixture was stirred and gradually warmed to room temperature over 
 2 h. after 17 h , the mixture was diluted with water and extracted 
 with dichloromethane . the combined organic layers were washed with 
 water , saturated aqueous nahco3 , and once more with water . 
 the organic layer was dried ( mgso4 ) , filtered , and concentrated . column chromatography ( sio2 , 04% methanol in dichloromethane ) 
 afforded a single diastereomer of the amide as a yellow oil ( 42 mg , 
 87% ) : [ ]d = + 84 ( c 1.01 , chcl3 ) ; rf = 0.2 ( 5% 
 meoh / ch2cl2 ) ; ir ( film ) 3368 , 3257 , 2980 , 2931 , 
 1676 , 1641 , 1537 , 1503 cm ; h nmr ( 400 
 mhz , cdcl3 )  8.38 ( d , j = 8.0 hz , 
 1h ) , 8.24 ( d , j = 8.8 hz , 1h ) , 7.66 ( d , j = 5.2 hz , 1h ) , 7.37 ( t , j = 8.0 hz , 1h ) , 7.17 ( m , 
 1h ) , 7.16 ( d , j = 8.0 hz , 2h ) , 7.09 ( d , j = 7.6 hz , 1h ) , 6.88 ( d , j = 8.0 hz , 2h ) , 6.87 ( m , 
 1h ) , 6.83 ( br d , 1h ) , 6.60 ( dd , j = 8.8 , 2.0 hz , 
 1h ) , 6.45 ( d , j = 2.0 hz , 1h ) , 5.85 ( dd , j = 8.0 , 2.4 hz , 1h ) , 5.14 ( dd , j = 2.4 , 
 2.4 hz , 1h ) , ( qq , j = 6.0 , 6.0 hz , 1h ) , 4.12 ( br 
 m , 2h ) , 3.85 ( s , 3h ) , 3.70 ( m , 1h ) , 3.58 ( m , 1h ) , 3.38 ( br m , 2h ) , 
 1.19 ( d , j = 6.0 hz , 3h ) , 1.16 ( d , j = 6.0 hz , 3h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 
 167.9 , 167.2 , 157.3 , 155.9 , 149.2 , 140.5 , 136.3 , 134.5 , 133.4 , 130.0 , 
 129.2 , 128.1 , 125.8 , 121.0 ( q , jcf = 254 hz ) , 120.5 , 119.8 , 113.4 , 105.4 , 100.3 , 71.6 , 61.8 , 
 57.7 , 55.6 , 47.5 , 41.1 , 40.0 , 21.8 , 21.4 ; hrms ( esi ) exact mass calcd 
 for c31h33clf3n4o6 [ m + h ] 649.2041 , found 649.2023 . in a microwave vial under an inert atmosphere was placed pd(pph3)4 ( 4.7 mg , 4.1 mol ) . the vial was charged 
 with k2co3 ( 13.3 mg , 96.0 mol ) , boronic 
 ester 20 ( 10.0 mg , 48.0 mol ) , and cis - imidazoline 11 ( 20.0 mg , 32.0 mol ) . a 5/1 mixture of dioxanes in water ( 865 l ) 
 was then added via syringe under argon . the mixture was stirred for 
 20 h at 80 c ( conventional heating ) , and the solvent was then 
 evaporated after cooling . column chromatography ( sio2 , 05% 
 methanol in dichloromethane ) of the residue afforded the adduct as 
 an off - white foam ( 13 mg , 62% ) : [ ]d = 37 ( c 0.27 , chcl3 ) ; rf = 0.68 ( 10% meoh / ch2cl2 ) ; ir ( film ) 3259 , 2923 , 2852 , 1674 , 1607 , 1423 cm ; h nmr ( 400 mhz , cdcl3 )  7.65 ( d , j = 8.8 hz , 1h ) , 7.48 ( d , j = 1.6 hz , 1h ) , 
 7.14 ( d , j = 8.0 hz , 2h ) , 7.06 ( d , j = 8.0 hz , 2h ) , 7.00 ( d , j = 8.4 hz , 2h ) , 6.89 ( d , j = 8.4 hz , 2h ) , 6.57 ( dd , j = 8.4 , 2.0 
 hz , 1h ) , 6.49 ( d , j = 2.0 hz , 1h ) , 6.24 ( d , j = 2.0 hz , 1h ) , 5.86 ( br s , 1h ) , 5.62 ( d , j = 9.6 hz , 1h ) , 5.58 ( d , j = 9.6 hz , 1h ) , 4.61 ( qq , j = 6.0 , 6.0 hz , 1h ) , 3.85 ( s , 3h ) , 3.76 ( s , 3h ) , 3.73 ( m , 
 2h ) , 3.38 ( m , 1h ) , 3.28 ( m , 1h ) , 3.04 ( m , 2h ) , 1.40 ( d , j = 6.0 hz , 3h ) , 1.62 ( d , j = 6.0 hz , 3h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 166.5 , 163.0 , 160.3 , 157.1 , 
 154.9 , 143.2 , 138.4 , 138.0 , 135.3 , 133.1 , 132.2 , 129.5 , 128.4 , 128.2 
 ( 2c ) , 127.9 , 105.8 , 104.6 , 100.2 , 72.2 , 71.1 , 69.3 , 68.4 , 63.7 , 55.6 , 
 49.8 , 41.7 , 40.5 , 37.3 , 29.7 , 22.1 ; hrms ( esi ) exact mass calcd for 
 c34h36cln6o4 [ m + h ] 627.2487 , found 627.2466 . -nitro boc - amine 4ad ( 301 mg , 760 mol ) , methanol ( 2.9 ml ) , and cobalt(ii ) chloride 
 ( 49.3 mg , 379 mol ) were combined and stirred . the solution 
 was cooled to 0 c , and sodium borohydride ( 431 mg , 11.2 mmol ) 
 was added in five portions over 1 h. the reaction mixture was stirred 
 at 0 c for an additional 30 min before the mixture was quenched 
 with saturated aqueous nh4cl . the 
 mixture was placed on a glass frit and washed with water , and the 
 aqueous layer was collected . the remaining solid was thoroughly washed 
 with ch2cl2 and collected in a separate flask . the organic layers were dried ( mgso4 ) , filtered , and concentrated 
 to afford a white solid ( 221 mg , 75% ) : [ ]d = 45 ( c 0.84 , chcl3 ) ; 
 mp 144146 c ; rf = 0.36 ( 50% 
 etoac in hexanes ) ; ir ( film ) 3371 , 2970 , 2922 , 2355 , 1692 , 1602 , 1512 
 cm ; h nmr ( 400 mhz , cd3od ) 7.58 ( d , j = 8.4 hz , 2h ) , 7.026.92 
 ( m , 6h ) , 4.81 ( br m , 1h ) , 4.24 ( br d , 1h ) , 1.481.38 ( m , 12h ) ; c nmr ( 100 mhz , cd3od ) ppm 163.7 ( d , jcf = 244 hz ) , 157.2 , 142.2 , 137.6 , 134.2 , 
 130.7 ( d , jcf = 8.0 hz ) , 130.4 , 
 129.3 , 116.2 ( d , jcf = 22.0 
 hz ) , 80.2 , 61.5 , 60.9 , 28.6 ; lrms ( esi ) exact mass calcd for c19h22clfn2o2 [ m + h ] 365.135 , found 365.57 , amine s19 ( 210 mg , 575 mol ) , 
 dichloromethane ( 2.9 ml ) , and carbonyl diimidazole ( 112 mg , 689 mol ) 
 were combined , and the mixture was stirred at room temperature for 
 1 h before adding oxopiperazine ( 115 mg , 1.15 mmol ) . the resulting 
 mixture was stirred for 5 h before quenching with water and extracting 
 with dichloromethane . the organic layers were combined , dried ( mgso4 ) , filtered , and concentrated to afford a white solid ( 166 
 mg , 54% ) : [ ]d = + 16 ( c 0.09 , ch3coch3 ) ; mp : 216218 
 c ; rf = 0.54 ( 10% meoh in ch2cl2 ) ; ir ( film ) 3379 ( br ) , 2981 , 1505 , 1682 , 1608 
 cm ; h nmr ( 400 mhz , cd3od )  7.68 ( s , 1h ) , 7.457.40 ( m , 4h ) , 7.32 ( d , j = 8.4 hz , 2h ) , 7.05 ( dd , j = 8.8 hz , 
 8.0 hz , 4h ) , 5.06 ( d , j = 10.8 hz , 1h ) , 4.97 ( d , j = 10.8 hz , 1h ) , 3.90 ( d , j = 17.6 hz , 
 1h ) , 3.72 ( d , j = 17.6 hz , 1h ) , 3.623.42 
 ( m , 1h ) , 3.373.36 ( m , 1h ) , 3.10 ( m , 2h ) , 1.25 ( s , 9h ) ; c nmr ( 100 mhz , cd3od ) ppm 169.9 , 163.5 ( d , jcf = 243 hz ) , 157.9 , 157.3 , 140.9 , 
 138.2 , 136.2 , 134.2 , 130.7 , 130.6 ( d , jcf = 8.0 hz ) , 129.2 , 116.0 ( d , jcf = 21 hz ) , 80.3 , 59.5 , 58.5 , 48.2 , 41.33 , 41.26 , 28.6 ; 
 hrms ( esi ) exact mass cald for c24h28clfn4nao4 [ m + na ] 513.1681 , found 513.1704 . boc - protected urea s20 ( 150 
 mg , 306 mol ) was dissolved in dichloromethane ( 3.0 ml ) , and 
 the solution was treated with tfa ( 702 l , 9.80 mmol ) and stirred 
 at room temperature overnight . the aqueous layer was extracted with dichloromethane , and the organic 
 layers were combined , dried ( mgso4 ) , filtered , and concentrated 
 to an off - white oil ( 100 mg , 84% ) : [ ]d = 1.8 ( c 0.61 , meoh ) ; rf = 0.36 ( 10% meoh in ch2cl2 ) ; ir 
 ( film ) 3352 br , 3067 , 2936 , 2890 , 1664 , 1518 cm ; h nmr ( 400 mhz , cdcl3 )  7.17 ( d , j = 8.4 hz , 2h ) , 7.03 ( m , 6h ) , 5.97 ( d , j = 7.2 hz , 1h ) , 4.99 ( dd , j = 7.2 , 6.0 hz , 1h ) , 
 4.28 ( d , j = 5.6 hz , 1h ) , 4.01 ( d , j = 5.6 hz , 2h ) , 3.603.56 ( m , 2h ) , 3.29 ( br m , 2h ) , 1.26 ( m , 
 2h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 167.5 , 162.1 
 ( d , jcf = 243 hz ) , 155.7 , 
 137.5 ( d , jcf = 3 hz ) , 137.0 , 
 133.3 , 128.9 , 128.4 , 128.3 ( d , jcf = 9 hz ) , 115.1 ( d , jcf = 21 hz ) , 59.4 , 58.9 , 47.5 , 40.8 , 39.6 ; hrms ( esi ) exact mass cald 
 for c19h20clfn4nao2 [ m 
 + na ] 413.1157 , found 413.1145 . amine s21 ( 80.0 mg , 205 mol ) 
 and 2-isopropoxy-4-methoxybenzoic acid ( 43.1 mg , 205 mol ) were 
 combined in dichloromethane ( 1.0 ml ) . the solution was chilled to 
 0 c , and dmap ( 2.5 mg , 21 mol ) and edchcl ( 51.0 
 mg , 266 mol ) were added . the mixture was gradually warmed to 
 room temperature and stirred for 24 h before it was diluted with dichloromethane 
 and water . the combined organic layers were dried ( mgso4 ) , 
 filtered , and concentrated . the resulting residue was purified via 
 column chromatography ( 06% methanol in dichloromethane ) to 
 afford an off - white oil ( 74 mg , 62% ) . [ ]d = + 61 ( c 0.36 , chcl3 ) ; rf = 0.56 ( 10% meoh in ch2cl2 ) ; ir ( film ) 3369 , 3259 , 2975 , 2926 , 1666 , 1646 , 1542 , 1493 cm ; h nmr ( 400 mhz , cdcl3 )  
 8.35 ( d , j = 7.6 hz , 1h ) , 8.22 ( d , j = 8.8 hz , 1h ) , 7.74 ( d , j = 5.2 hz , 1h ) , 7.27 ( br 
 m , 1h ) , 7.15 ( d , j = 8.4 hz , 2h ) , 7.00 ( m , 4h ) , 6.91 
 ( d , j = 8.4 hz , 2h ) , 6.58 ( dd , j = 9.2 , 8.8 hz , 1h ) , 6.44 ( d , j = 2.0 hz , 1h ) , 5.77 
 ( dd , j = 8.0 , 7.6 hz , 1h ) , 5.08 ( dd , j = 3.2 , 3.2 hz , 1h ) , 4.64 ( qq , j = 6.0 , 6.0 hz , 
 1h ) , 4.10 ( s , 2h ) , 3.83 ( s , 3h ) , 3.66 ( m , 1h ) , 3.56 ( m , 1h ) , 3.35 
 ( br m , 2h ) , 1.19 ( d , j = 6.0 hz , 3h ) , 1.13 ( d , j = 6.0 hz , 3h ) c nmr ( 100 mhz , cdcl3 ) ppm 168.1 , 167.0 , 163.9 , 162.3 ( d , jcf = 244 hz ) , 157.2 , 155.9 , 136.7 , 134.2 ( d , jcf = 27 hz ) , 134.0 , 133.2 , 129.4 , 128.8 , 
 128.0 , 115.3 ( d , jcf = 21 
 hz ) , 113.5 , 105.4 , 100.3 , 71.4 , 61.7 , 57.5 , 55.0 , 47.4 , 40.9 , 40.0 , 
 21.9 , 21.5 ; hrms ( esi ) exact mass calcd for c30h33clfn4o5[m + h ] 583.2124 , found 
 583.2134 . triphenylphosphine oxide ( 136 mg , 488 mol ) and dichloromethane 
 ( 200 l ) were placed in a flame - dried flask . the solution was 
 chilled to 0 c , treated with triflic anhydride ( 41 l , 
 244 mol ) , and stirred for 10 min . cis - amide 
 urea s22 ( 71 mg , 122 mol ) as a solution in dichloromethane 
 ( 800 l ) was placed in the reaction flask and stirred for 1 
 h at 0 c . the mixture was extracted 
 with dichloromethane , and the combined organic layers were dried ( mgso4 ) , filtered , and concentrated . purification via column chromatography 
 ( 05% methanol in dichloromethane ) yielded an off - white foam 
 ( 60 mg , 88% ) : [ ]d = + 137 ( c 0.28 , chcl3 ) ; rf = 0.33 ( 5% meoh in ch2cl2 ) ; ir ( film ) 3217 , 
 1982 , 1926 , 1680 , 1611 , 1514 , 1424 cm ; h nmr ( 400 mhz , cdcl3 )  7.60 ( d , j = 8.4 hz , 1h ) , 7.00 ( d , j = 8.4 hz , 2h ) , 6.956.92 
 ( m , 2h ) , 6.886.84 ( m , 3h ) , 6.78 ( dd , j = 
 8.8 , 8.4 hz , 2h ) , 6.53 ( dd , j = 8.4 , 8.4 hz , 1h ) , 
 6.46 ( dd , j = 2.0 hz , 1h ) , 5.53 ( d , j = 10.0 hz , 1h ) , 5.48 ( d , j = 10.0 hz , 1h ) , 4.59 
 ( qq , j = 6.0 , 6.0 hz , 1h ) , 3.82 ( s , 3h ) , 3.73 ( d , j = 18.4 hz , 1h ) , 3.62 ( d , j = 18.4 hz , 
 1h ) , 3.35 ( m , 1h ) , 3.18 ( m , 1h ) , 2.95 ( br m , 2h ) , 1.37 ( d , j = 6.0 hz , 3h ) , 1.32 ( d , j = 6.0 hz , 3h ) ; c nmr ( 100 mhz , cdcl3 ) 167.0 , 163.9 , 161.9 ( d , jcf = 244 hz ppm ) , 160.0 , 156.9 , 
 154.8 , 135.1 , 133.1 ( d , jcf = 3 hz ) , 133.0 , 132.2 , 129.3 ( d , jcf = 8 hz ) , 128.3 , 128.0 , 114.6 ( d , jcf = 21 hz ) , 113.5 , 104.5 , 100.1 , 71.7 , 70.9 , 69.2 , 55.5 , 
 49.4 , 41.8 , 40.3 , 22.0 ( 2c ) ; hrms ( esi ) exact mass calcd for c30h31clfn4o4 [ m + h ] 565.2018 , found 565.1992 . -nitro boc - amine 4da ( 430 mg , 0.908 mol ) and cocl2 ( 118 mg , 0.908 mol ) 
 were added to methanol ( 3.7 ml ) in a flask and chilled to 0 c 
 before nabh4 ( 343 mg , 9.08 mmol ) was added in two portions 
 over 1 h. the reaction mixture was stirred at 0 c for an additional 
 15 min before the mixture was quenched with saturated aqueous nh4cl . the reaction mixture was adjusted to ph 10 with concentrated 
 aqueous nh4oh , and the aqueous layer was extracted with 
 etoac . the combined organic layers were dried ( mgso4 ) , 
 filtered , and concentrated . column chromatography ( sio2 , 2040% ethyl acetate in hexanes ) afforded the product as 
 a white oil ( 172 mg , 43% ) in 6:1 dr ( by h nmr ) : rf = 0.71 ( 50% etoac / hexanes ) ; ir ( film ) 3378 , 
 2975 , 2920 , 1691 , 1527 , 1486 cm ; h 
 nmr ( 400 mhz , cdcl3 )  7.34 ( dd , j = 4.0 , 4.0 hz , 1h ) , 7.25 ( d , j = 7.6 hz , 2h ) , 7.20 
 ( d , j = 4.8 hz , 1h ) , 7.03 , ( d , j = 7.6 hz , 2h ) , 6.92 ( t , j = 8.8 hz , 1h ) , 5.50 ( d , j = 6.4 hz , 1h ) , 4.79 ( br d , 1h ) , 4.46 ( d , j = 6.4 hz , 1h ) , 1.40 ( br m , 2h ) , 1.33 ( s , 9h ) ; c nmr 
 ( 100 mhz , cdcl3 ) ppm 160.6 ( d , jcf = 255 hz ) , 133.6 , 131.9 , 131.8 , 131.1 ( d , jcf = 4 hz ) , 128.6 , 128.5 , 128.2 , 117.2 
 ( d , jcf = 24 hz ) , 116.8 ( d , jcf = 4 hz ) , 79.0 , 58.6 , 53.4 , 
 28.2 ; hrms ( esi ) exact mass calcd for c19h22brclfn2o2 [ m + h ] 443.0537 , found 
 443.0547 . amine s13 ( 172 mg , 388 mol ) 
 and carboxylic acid ( 81.6 mg , 388 mol ) were dissolved in dichloromethane 
 ( 1.75 ml ) at room temperature . the solution was chilled to 0 c , 
 and edchcl ( 96.6 mg , 504 mol ) and dmap ( 4.8 mg , 39 mol ) 
 were added . the reaction mixture was stirred and gradually warmed 
 to room temperature over 2 h. after 17 h , the reaction mixture was 
 diluted with water and extracted with dichloromethane . the combined 
 organic layers were washed with water , saturated aqueous nahco3 , and once more with water . the organic layer was dried ( mgso4 ) , filtered , and concentrated . column chromatography ( sio2 , 2030% ethyl acetate in hexanes ) afforded the amide 
 as a clear foam ( 213 mg , 87% ) : rf = 0.77 
 ( 50% etoac / hexanes ) ; ir ( film ) 3373 , 3318 , 2980 , 2925 , 2247 , 1714 , 
 1645 , 1604 , 1536 cm ; h nmr ( 400 mhz , 
 cdcl3 )  8.48 ( d , j = 9.2 hz , 1h ) , 
 8.13 ( d , j = 9.2 hz , 1h ) , 7.37 ( m , 1h ) , 7.23 ( d , j = 8.4 hz , 2h ) , 7.17 ( d , j = 7.7 hz , 1h ) , 
 7.06 ( d , j = 7.6 hz , 1h ) , 6.97 ( t , j = 8.8 hz , 1h ) , 6.54 ( dd , j = 9.2 , 1.6 hz , 1h ) , 
 6.44 ( s , 1h ) , 5.97 ( dd , j = 9.2 , 9.2 hz , 1h ) , 5.74 
 ( m , 1h ) , 5.08 ( m , 1h ) , 4.69 ( qq , j = 6.0 , 6.0 hz , 
 1h ) , 3.82 ( s , 3h ) , 1.32 ( br s , 16h ) ; c nmr ( 100 mhz , 
 cdcl3 ) ppm 165.3 , 163.7 , 157.2 ( d , jcf = 244 hz ) , 134.4 , 133.6 , 132.3 ( 2c ) , 132.2 , 
 128.7 , 128.6 , 128.5 ( d , jcf = 4 hz ) , 117.6 ( d , jcf = 
 22 hz ) , 116.5 ( d , jcf = 4 
 hz ) , 114.0 , 105.5 , 100.1 , 77.2 , 71.5 , 55.5 , 28.1 , 21.8 , 21.7 ; hrms 
 ( esi ) exact mass calcd for c30h33brclfn2nao5 [ m + na ] 657.1143 , found 657.1113 . amide s14 ( 210 mg , 330 mol ) 
 was dissolved in dichloromethane ( 3.0 ml ) and treated with tfa ( 758 
 l , 9.91 mmol ) . the mixture was stirred at room temperature 
 for 3 h and then diluted with dichloromethane , poured into saturated 
 aqueous nahco3 , and extracted with dichloromethane . the 
 combined organic layers were dried ( mgso4 ) , filtered , and 
 concentrated to a yellow oil . column chromatography ( sio2 , 3050% ethyl acetate in hexanes ) afforded the product as 
 a foam ( 153 mg , 87% ) and > 20:1 dr by h nmr : rf = 0.15 ( 50% etoac / hexanes ) ; ir ( film ) 3382 , 
 2980 , 2945 , 1648 , 1606 , 1495 cm ; h 
 nmr ( 400 mhz , cdcl3 )  8.69 ( d , j = 8.8 hz , 1h ) , 8.09 ( d , j = 8.8 hz , 1h ) , 7.41 , 
 ( dd , j = 6.4 , 2.0 hz , 1h ) , 7.34 ( m , 1h ) , 7.23 ( d , j = 8.4 hz , 2h ) , 7.10 ( d , j = 8.4 hz , 2h ) , 
 6.88 ( t , j = 8.8 hz , 1h ) , 6.53 ( dd , j = 8.8 , 2.0 hz , 1h ) , 6.45 ( d , j = 2.0 hz , 1h ) , 5.71 
 ( dd , j = 9.2 , 1.6 hz , 1h ) , 4.73 ( qq , j = 6.0 , 6.0 hz , 1h ) , 4.43 ( d , j = 6.4 hz , 1h ) , 3.82 
 ( s , 3h ) , 1.42 ( d , j = 6.0 hz , 3h ) , 1.41 ( d , j = 6.0 hz , 3h ) , 1.36 ( d , j = 5.6 hz , 2h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 164.8 , 163.4 , 160.8 
 ( d , jcf = 245 hz ) , 157.2 , 
 139.9 , 134.2 , 133.4 , 132.5 ( d , jcf = 4 hz ) , 132.0 ( 2c ) , 128.9 , 128.8 , 128.5 , 128.4 , 117.5 ( d , jcf = 24 hz ) , 116.6 ( d , jcf = 4 hz ) , 114.6 , 105.8 , 104.1 , 100.2 , 
 77.2 , 71.4 , 63.8 , 58.4 , 55.5 , 54.0 , 21.9 ( 2c ) ; hrms ( esi ) exact mass 
 calcd for c25h26brclfn2o3 [ m + h ] 535.0799 , found 535.0790 . amine s15 ( 150 mg , 277 mol ) 
 was added to carbonyl diimidazole ( 53.0 mg , 332 mol ) in dichloromethane 
 ( 6.5 ml ) . the mixture was stirred at room temperature for 3 h , or 
 until no starting material remained by tlc , at which point oxopiperazine 
 ( 55.0 mg , 554 mol ) was added . the mixture was stirred for 16 
 h. the reaction mixture was concentrated and purified by column chromatography 
 ( sio2 , 40100% ethyl acetate in hexanes ) to afford 
 the product as a white solid ( 68 mg , 40% ) : [ ]d = + 90 ( c 0.20 , chcl3 ) ; 
 mp 150152 c ( dec . ) ; rf = 
 0.61 ( 10% meoh / ch2cl2 ) ; ir ( film ) 3371 , 3260 , 
 3074 , 2977 , 2928 , 1650 , 1602 , 1533 cm ; h nmr ( 400 mhz , cdcl3 )  8.49 ( d , j = 8.8 hz , 1h ) , 8.15 ( d , j = 8.8 hz , 1h ) , 7.39 ( m , 
 1h ) , 7.31 ( d , j = 9.6 hz , 1h ) , 7.19 ( d , j = 8.0 hz , 2h ) , 7.03 ( d , j = 8.0 hz , 2h ) , 6.97 ( m 
 3h ) , 6.55 ( dd , j = 9.2 , 1.6 hz , 1h ) , 6.44 ( d , j = 1.6 hz , 1h ) , 6.07 ( dd , j = 9.2 , 9.2 
 hz , 1h ) , 5.13 ( m , 1h ) , 4.67 ( qq , j = 6.0 , 6.0 hz , 
 1h ) , 4.10 ( d , j = 1.6 hz , 2h ) , 3.83 ( s , 3h ) , 3.68 
 ( m , 1h ) , 3.56 ( m , 1h ) , 3.38 ( br m , 2h ) , 1.26 ( dd , j = 6.0 , 6.0 hz , 6h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 167.9 , 166.6 , 163.9 , 159.1 ( d , jcf = 246 hz ) , 157.3 , 155.8 , 137.0 , 134.4 , 133.5 , 132.4 
 ( 2c ) , 131.1 ( d , jcf = 4 hz ) , 
 129.2 , 128.3 , 128.1 , 117.7 ( d , jcf = 24 hz ) , 116.4 ( d , jcf = 4 hz ) , 113.4 , 105.2 , 100.2 , 71.6 , 60.1 , 55.5 , 52.2 , 47.4 , 41.1 , 
 39.9 , 21.9 , 21.6 ; hrms ( esi ) exact mass calcd for c30h31brclfn4nao5 [ m + na ] 683.1048 , 
 found 683.1021 . tf2o ( 35.8 l , 212 mol ) was added 
 to a stirred solution of ph3po ( 118 mg , 424 mol ) 
 in dichloromethane ( 300 l ) at 0 c . the mixture was stirred 
 for 10 min before cis - amide urea s16 ( 70 mg , 106 mol ) was added as a solution in dichloromethane 
 ( 800 l ) , and the mixture was stirred at 0 c and warmed 
 to room temperature over 3 h. the reaction mixture was quenched with 
 nahco3 at room temperature , and the aqueous layer was extracted 
 with dichloromethane . column chromatography ( sio2 , 04% methanol in dichloromethane ) of the residue 
 provided the product as a white solid ( 52.0 mg , 78% ) : [ ]d = 57 ( c 0.71 , 
 chcl3 ) ; mp 123124 c ; rf = 0.57 ( 10% meoh / ch2cl2 ) ; ir ( film ) 
 3229 , 2981 , 2933 , 2361 , 1680 , 1604 cm ; h nmr ( 400 mhz , cdcl3 )  7.66 ( d , j = 8.0 hz , 2h ) , 7.52 ( d , j = 6.8 hz , 1h ) , 7.16 ( m , 
 1h ) , 7.02 ( s , 4h ) , 6.64 ( s , 1h ) , 6.56 ( d , j = 8.4 
 hz , 1h ) , 6.47 ( s , 1h ) , 5.76 ( d , j = 10.0 hz , 1h ) , 
 5.55 ( d , j = 10.0 hz , 1h ) , 4.59 ( qq , j = 6.0 , 6.0 hz , 1h ) , 3.84 ( s , 3h ) , 3.80 ( d , j = 
 18.0 hz , 1h ) , 3.58 ( d , j = 18.0 hz , 1h ) , 3.42 ( m , 
 1h ) , 3.12 ( m 1h ) , 3.02 ( br m , 2h ) , 1.36 ( d , j = 6.0 
 hz , 3h ) , 1.27 ( d , j = 6.0 hz , 3h ) ; c 
 nmr ( 100 mhz , cdcl3 ) ppm 166.9 , 163.1 , 160.6 , 158.7 ( d , jcf = 244 hz ) , 156.9 , 154.9 , 153.3 , 
 133.4 , 132.4 , 132.1 ( 2c ) , 131.9 , 131.7 ( 2c ) , 128.5 , 128.4 , 128.3 , 
 128.1 , 127.9 , 116.5 ( d , jcf = 4 hz ) , 116.1 ( d , jcf = 
 24 hz ) , 113.4 , 104.6 , 100.0 , 70.8 , 68.1 , 66.6 , 55.5 , 49.7 , 42.1 , 40.3 , 
 22.1 , 22.0 ; hrms ( esi ) exact mass calcd for c30h30brclfn4o4 [ m + h ] 643.1123 , found 
 643.1127 . to amine s27 ( 298 mg , 782 
 mol ) and 4-bromo-2-isopropoxybenzoic acid ( 202 mg , 782 mol ) 
 in dichloromethane ( 4.0 ml ) were added edchcl ( 195 mg , 1.02 
 mmol ) and dmap ( 9.55 mg , 78 mol ) at 0 c , and the reaction 
 mixture was gradually warmed to room temperature over 16 h. the reaction 
 mixture was diluted with water and extracted with dichloromethane . the combined organic layers were washed with brine , dried ( na2so4 ) , filtered , and concentrated to give a white 
 solid . the crude product was triturated with dichloromethane and hexanes , 
 filtered , and dried under vacuum to give a white solid ( 438 mg , 90% ) 
 which was used for the next step directly . to tert - butyl ( ( 1r,2s)-2-(4-bromo-2-isopropoxybenzamido)-2-(3-chlorophenyl)-1-(4-chlorophenyl)ethyl)carbamate 
 ( 240 mg , 386 mol ) in dichloromethane ( 3.8 ml ) was added tfa 
 ( 1.191 ml , 15.46 mmol ) , and the reaction mixture was stirred at room 
 temperature for 16 h. the reaction mixture was then poured into saturated 
 aqueous nahco3 and extracted with dichloromethane . the 
 organic layers were combined , washed with brine , dried ( na2so4 ) , filtered , and concentrated . the residue was purified 
 by column chromatography ( sio2 , 07% methanol in 
 dichloromethane ) to give a white foam ( 151 mg , 75% ) : h 
 nmr ( 400 mhz , cdcl3 )  8.88 ( d , j = 8.1 hz , 1h ) , 8.02 ( d , j = 8.4 hz , 1h ) , 7.267.21 
 ( m , 3h ) , 7.217.15 ( m , 2h ) , 7.14 ( d , j = 2.0 
 hz , 3h ) , 7.01 ( d , j = 8.4 hz , 2h ) , 6.84 ( d , j = 7.6 hz , 1h ) , 5.42 ( dd , j = 8.2 , 4.9 
 hz , 1h ) , 4.874.73 ( m , 1h ) , 4.40 ( d , j = 4.9 
 hz , 1h ) , 1.521.41 ( m , 7h ) ; hrms ( esi ) exact mass calcd for 
 c24h24brcl2n2o2 [ m + h ] 521.0400 , found 521.0392 . to amine s30 ( 221 mg , 423 mol ) in dichloromethane ( 2.1 ml ) was 
 added cdi ( 103 mg , 635 mol ) at room temperature under nitrogen , 
 the reaction mixture was stirred for 1 h , piperazin-2-one ( 85 mg , 
 846 mol ) was then added , and this mixture was stirred for 15 
 h at room temperature . the solvent was removed , and the crude product 
 was purified by column chromatography ( sio2 , 010% 
 methanol in dichloromethane ) to give a white solid ( 160 mg , 58% ) : h nmr ( 400 mhz , cdcl3 )  8.38 ( d , j = 7.9 hz , 1h ) , 8.18 ( dd , j = 8.5 , 1.1 
 hz , 1h ) , 7.54 ( d , j = 5.2 hz , 1h ) , 7.337.28 
 ( m , 2h ) , 7.257.22 ( m , 1h ) , 7.217.17 ( m , 2h ) , 7.11 
 ( dt , j = 1.9 , 0.9 hz , 1h ) , 7.067.00 ( m , 1h ) , 
 6.92 ( d , j = 2.0 hz , 1h ) , 6.906.84 ( m , 2h ) , 
 6.13 ( s , 1h ) , 5.825.72 ( m , 1h ) , 5.17 ( dd , j = 5.4 , 2.4 hz , 1h ) , 4.794.62 ( m , j = 6.2 , 
 5.8 hz , 1h ) , 4.14 ( t , j = 1.4 hz , 2h ) , 3.74 ( dt , j = 13.6 , 4.8 hz , 1h ) , 3.60 ( ddd , j = 13.5 , 
 6.1 , 4.7 hz , 1h ) , 3.483.35 ( m , 2h ) , 1.251.16 ( m , 6h ) ; 
 hrms ( esi ) exact mass calcd for c29h30brcl2n4o4 [ m + h ] 647.0829 , found 
 647.0826 . to triphenylphosphine oxide ( 251 mg , 0.901 mmol ) in dichloromethane 
 ( 2.5 ml ) was added trifluoromethanesulfonic anhydride ( 0.076 ml , 0.450 
 mmol ) ) at 0 c , the reaction mixture was stirred for 10 min , 
 amide - urea s31 ( 146 mg , 0.225 mmol ) in dichloromethane 
 ( 2 ml ) was then added , and the reaction mixture was stirred at 0 c 
 for 1 h and warmed to room temperature before the addition of saturated 
 aqueous nahco3 . the dichloromethane layer was separated , 
 and the aqueous layer was extracted with dichloromethane . the combined 
 organic layers were washed with brine , dried ( na2so4 ) , filtered , and concentrated . the crude product was purified 
 by column chromatography ( sio2 , 07% methanol in 
 dichloromethane ) to give a white solid ( 98 mg , 69% ) : [ ]d = 81.9 ( c 0.5 , 
 ch3oh ) ; ir ( film ) 3263 , 2979 , 1680 , 1589 , 1488,1406 cm ; h nmr ( 400 mhz , cdcl3 )  
 7.56 ( d , j = 8.1 hz , 1h ) , 7.19 ( dd , j = 8.1 , 1.6 hz , 1h ) , 7.11 ( d , j = 1.5 hz , 1h ) , 7.097.01 
 ( m , 4h ) , 6.98 ( s , 1h ) , 6.87 ( dd , j = 7.7 , 6.1 hz , 
 3h ) , 6.03 ( s , 1h ) , 5.685.50 ( m , 2h ) , 4.744.56 ( m , 
 1h ) , 3.923.65 ( m , 3h ) , 3.35 ( s , 1h ) , 3.25 ( ddd , j = 13.5 , 7.2 , 4.2 hz , 1h ) , 3.142.95 ( m , 2h ) , 1.41 ( d , j = 6.1 hz , 3h ) , 1.37 ( d , j = 6.0 hz , 3h ) ; c nmr ( 101 mhz , cdcl3 )  166.7 , 160.1 , 156.2 , 
 154.7 , 139.4 , 134.7 , 133.9 , 133.5 , 132.0 , 129.1 , 128.4 , 128.2 , 127.9 , 
 127.4 , 126.0 , 125.9 , 123.7 , 120.1 , 116.3 , 72.4 , 71.6 , 69.0 , 49.5 , 
 41.7 , 40.3 , 36.7 , 24.7 , 22.0 ( 2c ) ; hrms ( esi ) exact mass calcd for 
 c29h28brcl2n4o3 [ m + h ] 629.0722 , found 629.0716 . to amine s27 ( 186 mg , 905 
 mol ) in dichloromethane ( 4.0 ml ) were added edchcl ( 225 
 mg , 1.18 mmol ) and dmap ( 11.05 mg , 90 mol ) at 0 c , and 
 the reaction mixture was gradually warmed to room temperature over 
 16 h. the reaction mixture was diluted with water and extracted with 
 dichloromethane . the organic layers were combined , washed with brine , 
 dried ( na2so4 ) , filtered , and concentrated to 
 give a white solid . the crude product was triturated with dichloromethane 
 and hexanes , filtered , and dried under vacuum to give a white solid 
 ( 428 mg , 83% ) , which was used for the next step directly . to tert - butyl ( ( 1r,2s)-2-(3-chlorophenyl)-1-(4-chlorophenyl)-2-(4-cyano-2-isopropoxybenzamido)ethyl)carbamate 
 ( 390 mg , 686 mol ) in dichloromethane ( 6.5 ml ) was added tfa 
 ( 2.12 ml , 27.5 mmol ) , and the reaction mixture was stirred at room 
 temperature for 16 h. the reaction mixture was then poured into saturated 
 aqueous nahco3 and extracted with dichloromethane . the 
 combined organic layers were washed with brine , dried ( na2so4 ) , filtered , and concentrated . the residue was purified 
 by column chromatography ( sio2 , 07% methanol in 
 dichloromethane ) to give a white solid ( 290 mg , 90% ) : [ ]d = 21.0 ( c 0.275 , 
 ch3oh ) ; mp = 165166 c ; ir ( film ) 3378 , 2980 , 
 2935 , 2231 , 1655 , 1603 , 1573 , 1557 , 1515 , 1489 , 1411 cm ; h nmr ( 400 mhz , cdcl3 )  8.97 ( d , j = 8.0 hz , 1h ) , 8.24 ( dd , j = 8.1 , 1.4 
 hz , 1h ) , 7.32 ( dd , j = 8.1 , 1.4 hz , 1h ) , 7.287.19 
 ( m , 4h ) , 7.187.11 ( m , 2h ) , 7.046.97 ( m , 2h ) , 6.81 
 ( d , j = 7.6 hz , 1h ) , 5.39 ( dd , j = 8.0 , 4.9 hz , 1h ) , 4.83 ( p , j = 6.1 hz , 1h ) , 4.39 
 ( d , j = 4.7 hz , 1h ) , 1.551.50 ( m , 6h ) , 1.45 
 ( d , j = 11.3 hz , 2h ) ; c nmr ( 101 mhz , 
 cdcl3 )  163.0 , 155.8 , 140.3 , 139.6 , 134.2 , 133.6 , 
 133.4 , 129.3 , 128.5 , 128.2 , 127.9 , 127.5 , 126.4 , 126.2 , 124.5 , 118.1 , 
 116.7 , 115.8 , 72.6 , 58.9 , 58.9 , 22.03 , 21.96 ; hrms ( esi ) exact mass 
 calcd for c25h24cl2n3o2 [ m + h ] 468.1247 , found 468.1239 . to amine s32 ( 252 mg , 538 
 mol ) in dichloromethane ( 3.0 ml ) was added cdi ( 131 mg , 807 
 mol ) at room temperature under n2 . the reaction 
 mixture was stirred for 1 h , piperazin-2-one ( 108 mg , 1.08 mmol ) was 
 then added , and this mixture was stirred for 15 h at room temperature . the solvent was removed , and the crude product was purified by column 
 chromatography ( sio2 , 010% methanol in dichloromethane ) 
 to give a white solid ( 292 mg , 91% ) . [ ]d = 16.4 ( c 0.30 , ch3oh ) ; mp 196197 
 c ; ir ( film ) 3314 , 2981 , 2231 , 1637 , 1538 , 1492 , 1413 cm ; h nmr ( 400 mhz , cdcl3 )  
 8.41 ( dd , j = 12.2 , 8.0 hz , 2h ) , 7.38 ( dd , j = 8.1 , 1.1 hz , 1h ) , 7.30 ( dt , j = 9.1 , 
 5.3 hz , 3h ) , 7.21 ( d , j = 8.1 hz , 3h ) , 7.05 ( d , j = 6.3 hz , 1h ) , 6.95 ( s , 1h ) , 6.89 ( d , j = 8.4 hz , 2h ) , 6.28 ( s,1h ) , 5.76 ( dd , j = 8.0 , 
 2.5 hz , 1h ) , 5.21 ( dd , j = 5.3 , 2.6 hz , 1h ) , 4.74 
 ( p , j = 6.0 hz , 1h ) , 4.12 ( s , 2h ) , 3.73(dt , j = 13.0 , 4.9 hz , 1h ) , 3.683.51 ( m , 1h ) , 3.41 ( s , 
 2h ) , 1.351.13 ( m , 6h ) ; c nmr ( 126 mhz , cdcl3 )  167.3 , 165.5 , 155.8 , 139.5 , 136.0 , 134.7 , 133.9 , 
 133.7 , 130.1 , 129.2 , 128.5 , 128.3 , 126.9 , 125.4 , 124.6 , 124.5 , 117.8 , 
 116.7 , 116.7 , 72.8 , 61.5 , 58.4 , 47.6 , 41.2 , 39.9 , 21.8 , 21.4 ; hrms 
 ( esi ) exact mass calcd for c30h30cl2n5o4 [ m + h ] 594.1677 , found 594.1674 . to triphenylphosphine 
 oxide ( 324 mg , 1.164 mmol ) in dichloromethane ( 2.5 ml ) was added trifluoromethanesulfonic 
 anhydride ( 0.099 ml , 0.586 mmol ) at 0 c , the reaction mixture 
 was stirred for 10 min , amide - urea s33 ( 170 mg , 0.286 
 mmol ) in dichloromethane ( 1.5 ml ) was then added , and the reaction 
 mixture was stirred at 0 c for 1 h and then warmed to room temperature 
 before the addition of saturated aqueous nahco3 . the dichloromethane 
 layer was separated , and the aqueous layer was extracted with dichloromethane . 
 the combined organic layers were washed with brine , dried ( na2so4 ) , filtered , and concentrated . the crude product 
 was purified by column chromatography ( sio2 , 07% meoh in dichloromethane ) 
 to give a white solid ( 135 mg , 82% ) : [ ]d = 85.1 ( c 0.5 , ch3oh ) ; 
 ir ( film ) 3231 , 2981 , 2230 , 1676 , 1599 , 1573 , 1541 , 1493 , 1414 cmh nmr ( 400 mhz , cdcl3 )  
 7.81 ( dd , j = 7.8 , 1.2 hz , 1h ) , 7.35 ( dt , j = 7.9 , 1.4 hz , 1h ) , 7.20 ( s , 1h ) , 7.116.96 ( m , 
 5h ) , 6.946.81 ( m , 3h ) , 6.75 ( d , j = 3.4 hz , 
 1h ) , 5.755.53 ( m , 2h ) , 4.69 ( hept , j = 6.2 
 hz , 1h ) , 3.81 ( q , j = 17.7 hz , 2h ) , 3.29 ( q , j = 5.8 hz , 2h ) , 3.10 ( dq , j = 12.3 , 4.7 , 
 4.0 hz , 1h ) , 3.062.95 ( m , 1h ) , 1.451.35 ( m , 6h ) ; c nmr ( 101 mhz , cdcl3 )  166.4 , 159.9 , 155.6 , 
 154.7 , 139.2 , 134.4 , 134.0 , 133.8 , 131.7 , 129.2 , 128.4 , 128.3 , 127.9 , 
 127.5 , 126.3 , 125.9 , 124.2 , 118.2 , 115.8 , 115.1 , 73.0 , 71.9 , 69.0 , 
 49.6 , 41.4 , 40.4 , 21.9 ( 2c ) ; hrms ( esi ) exact mass calcd for c30h28cl2n5o3 [ m 
 + h ] 576.1569 , found 576.1572 . -nitro boc - amine ent-4ea ( 500 mg , 1.27 mmol ) and cocl2 ( 165 mg , 
 1.27 mmol ) were dissolved in methanol ( 16.7 ml ) at room temperature 
 and then cooled to 0 c with stirring . nabh4 ( 716 
 mg , 19.0 mmol ) was added in three portions over 1 h. the reaction 
 mixture was then stirred for 1 h and acidified to ph 2 with 1 m hcl . the solution was readjusted to ph 10 with 1 m aqueous nh4oh and filtered through a glass frit , washing with deionized water . the solid on the filter was washed heavily with dichloromethane , and 
 the filtrate was collected , dried ( mgso4 ) , filtered , and 
 concentrated to yield the product as a white solid ( 355 mg , 77% ) : 
 mp 141143 c ; rf = 0.51 ( 10% 
 meoh / ch2cl2 ) ; ir ( film ) 3380 , 2981 , 2935 , 1682 , 
 1523 , 1490 , 1249 , 1167 cm ; h nmr ( 400 
 mhz , cdcl3 )  7.27 ( d , j = 6.5 hz , 
 1 h ) , 7.23 ( d , j = 8.3 hz , 3 h ) , 6.95 ( m , 3 h ) , 6.99 
 ( d , j = 7.7 hz , 1 h ) , 6.83 ( d , j = 9.5 hz ) , 5.55 ( br d , j = 6.5 hz , 1 h ) , 4.84 ( br 
 dd , 1 h ) , 4.27 ( br d , 1 h ) , 1.39 ( br s , 9 h ) ; c nmr ( 100 
 mhz , cdcl3 ) ppm 162.6 ( d , jcf = 244 hz ) , 155.0 , 144.7 , 144.6 , 133.3 , 129.8 , 129.7 , 
 128.6 , 128.2 , 127.7 , 122.5 , 114.5 , 114.3 , 113.9 , 113.7 , 79.7 , 59.3 , 
 28.2 ; hrms ( esi ) exact mass calcd for c19h23clfn2o2 [ m + h ] 365.1432 , found 
 365.1448 . amine s23 ( 300 mg , 0.82 mmol ) 
 was dissolved in dichloromethane ( 9.7 ml ) at room temperature . to 
 the solution was added cdi ( 174 mg , 1.07 mmol ) with stirring under 
 argon . oxopiperazine ( 164 mg , 1.64 mmol ) was delivered after 1 h , 
 and the reaction mixture was stirred for 18 h. the reaction mixture 
 was then concentrated by rotary evaporation , triturated with dichloromethane , 
 and filtered through qualitative filter paper , washing with a small 
 amount of dichloromethane . the product was removed from the filter 
 paper and dried under high vacuum to yield the title compound as a 
 light yellow solid ( 217 mg , 54% ) : mp 181184 c ; rf = 0.36 ( 10% meoh / ch2cl2 ) ; ir ( film ) 3366 , 2980 , 2930 , 1678 , 1632 , 1526 , 1250 , 1168 ; h nmr ( 400 mhz , dmso - d6 )  
 7.88 ( br d , 1 h ) , 7.49 ( d , j = 8.0 hz , 2 h ) , 7.447.27 
 ( m , 6 h ) , 7.03 ( br m , 1 h ) , 6.87 ( d , j = 8.0 hz , 
 1 h ) , 4.93 ( m , 2 h ) , 3.76 ( d , j = 16.8 hz , 1 h ) , 
 3.53 ( d , j = 18 hz , 1 h ) , 3.27 ( m , 2 h ) , 2.92 ( br 
 m , 2 h ) , 1.15 ( s , 9 h ) ; c nmr ( 100 mhz , dmso - d6 ) ppm 166.9 , 155.8 , 154.9 , 145.5 , 141.4 , 131.9 , 
 129.9 , 129.8 , 128.2 , 124.7 , 118.4 , 115.0 , 114.8 , 113.7 , 78.2 , 58.0 , 
 56.6 , 55.3 , 47.6 , 28.4 ; hrms ( esi ) exact mass calcd for c24h28clfn4nao4 [ m + na ] 513.1681 , found 513.1704 . the urea s24 ( 178 mg , 0.36 
 mmol ) was dissolved in methanol ( 16 ml ) at room temperature and the 
 solution then cooled to 0 c . acetyl chloride ( 206 l , 
 2.90 mmol ) was added via syringe to the cold solution , and the reaction 
 mixture was stirred under an ar atmosphere for 15 h , at which point 
 the solvent was removed by rotary evaporation and high vacuum . the aqueous layer was back - extracted 10 times with 
 dichloromethane to afford the deprotected amine as a light yellow 
 solid ( 84 mg , 60% ) : mp 139142 c ; rf = 0.21 ( 10% meoh / ch2cl2 ) ; ir ( film ) 
 3329 , 3054 , 2926 , 1669 , 1636 , 1542 , 1343 , 1245 cm ; h nmr ( 400 mhz , dmso - d6 )  7.93 ( br s , 1 h ) , 7.42 ( d , j = 8.4 hz , 
 2 h ) , 7.34 ( m , 3 h ) , 7.25 ( d , j = 10.8 hz , 1 h ) , 
 7.17 ( d , j = 7.6 hz , 1 h ) , 7.05 ( m , 3 h ) , 6.75 ( d , j = 8.8 hz , 1 h ) , 4.73 ( dd , j = 9.2 , 9.2 
 hz , 1 h ) , 4.10 ( d , j = 9.6 hz , 1 h ) , 3.85 ( m , 1 h ) , 
 3.61 ( m , 1 h ) , 2.99 ( br m , 2 h ) , 1.93 ( br m , 2 h ) ; c 
 nmr ( 100 mhz , dmso - d6 ) ppm 166.7 , 161.2 , 
 156.0 , 145.6 , 144.1 , 131.4 , 129.9 , 129.6 , 128.0 , 124.7 , 115.0 , 114.8 , 
 114.0 , 113.8 , 60.8 , 58.9 , 47.7 ; hrms ( esi ) exact mass calcd for c19h21clfn4o2 [ m + h ] 391.1337 , found 391.1342 . in a glass vial equipped with a magnetic 
 stir bar and argon balloon were placed amine s25 ( 49 
 mg , 0125 mmol ) , carboxylic acid ( 26.3 mg , 0.125 mmol ) , and dichloromethane 
 ( 1.0 ml ) . the mixture was cooled to 0 c with stirring before 
 addition of edchcl ( 31 mg , 0.163 mmol ) and dmap ( 1.6 mg , 13 
 mol ) . the reaction mixture was stirred for 18 h before dilution 
 with dichloromethane and aqueous extraction . the combined organic 
 layers were dried with mgso4 and concentrated to a light 
 yellow solid ( 62 mg , 85% ) . the solid was redissolved in ch2cl2 and purified by column chromatography ( 210% 
 meoh / ch2cl2 , 55% ) : mp 123136 c ; rf = 0.27 ( 10% meoh / ch2cl2 ) , ir ( film ) 3369 , 2933 , 1639 , 1605 , 1533 , 1493 , 1257 cm ; h nmr ( 400 mhz , cdcl3 )  8.43 ( d , j = 8.4 hz , 1 h ) , 8.27 ( d , j = 9.2 hz , 
 1 h ) , 7.71 ( d , j = 4.8 hz ) , 7.28 ( s , 1 h ) , 7.15 ( m , 
 1 h ) , 6.55 ( d , j = 8.4 hz , 2 h ) , 6.77 ( d , j = 10.0 hz , 1 h ) , 6.66 ( d , j = 7.2 hz , 
 1 h ) , 6.62 ( dd , j = 9.2 , 2.4 hz , 1 h ) , 6.46 ( d , j = 2.0 hz , 1 h ) , 6.43 ( s , 1 h ) , 5.80 ( dd , j = 8.0 , 2.4 hz , 1 h ) , 5.13 ( dd , j = 4.8 , 2.8 hz , 
 1 h ) , 4.67 ( qq , j = 6.0 , 6.0 hz , 1 h ) , 4.14 ( s , 2 
 h ) , 3.85 ( s , 3 h ) , 3.70 ( m , 1 h ) , 3.60 ( m , 1 h ) , 3.41 ( br m , 2 h ) , 
 1.22 ( d , j = 6.0 hz , 3 h ) , 1.15 ( d , j = 6.0 hz , 3 h ) ; c nmr ( 100 mhz , cdcl3 ) ppm 
 168.0 , 167.1 , 163.9 , 162.1 ( d , jcf = 243 hz ) , 157.2 , 156.0 , 140.8 , 140.7 , 136.6 , 134.4 , 133.8 , 
 129.3 , 129.2 , 128.6 , 128.4 , 124.1 , 114.9 , 114.6 , 114.5 , 114.3 , 113.5 , 
 105.3 , 100.3 , 71.4 , 61.8 , 57.5 , 55.5 , 47.4 , 41.0 , 40.0 , 22.0 , 21.3 ; 
 hrms ( esi ) exact mass calcd for c30h33clfn4o5 [ m + h ] 583.2124 , found 583.2126 . triphenylphosphine 
 oxide ( 92 mg , 0.330 mmol ) was dissolved in dichloromethane ( 0.65 ml ) 
 at room temperature . triflic anhydride ( 27.8 l , 0.165 mmol ) 
 was delivered via syringe , and the solution was stirred for 30 min . 
 the cis - amide urea ( 48 mg , 0.082 mmol ) was delivered 
 as a solution in dichloromethane ( 0.65 ml , 1.30 ml total ) , and the 
 reaction mixture was stirred for 18 h. the reaction mixture was diluted 
 with dichloromethane , quenched with saturated aqueous nahco3 , and extracted once . the aqueous layer was back - extracted with dichloromethane , 
 and the organic layers were combined , dried ( mgso4 ) , filtered , 
 and concentrated to a yellow - orange foam . this material was redissolved 
 in dichloromethane and purified by column chromatography ( sio2 , 04% methanol in dichloromethane ) to afford the desired 
 product as a light yellow solid ( 30 mg , 65% ) in 9:1 dr : mp 112114 
 c ; rf = 0.40 ( 10% meoh / ch2cl2 ) ; ir ( film ) 3223 , 2979 , 2929 , 1676 , 1607 , 1424 , 1340 , 
 1280 ; h nmr ( 400 mhz , cdcl3 )  7.62 ( d , j = 8.4 hz , 1 h ) , 7.06 ( d , j = 8.4 hz , 
 2 h ) , 6.99 ( m , 1 h ) , 6.94 ( d , j = 8.0 hz ) , 6.76 ( m , 
 2 h ) , 6.62 ( d , j = 8.0 hz ) , 6.58 ( s , 1 h ) , 6.55 ( dd , j = 8.4 , 2.0 hz , 1 h ) , 6.48 ( d , j = 2.0 
 hz , 1 h ) , 5.55 ( d , j = 9.6 hz , 1 h ) , 5.49 ( d , j = 9.6 hz , 1 h ) , 4.61 ( qq , j = 6.0 , 6.0 
 hz , 1 h ) , 3.84 ( s , 3 h ) , 3.80 ( d , j = 18.4 hz , 1 
 h ) , 3.60 ( d , j = 18.0 hz , 1 h ) , 3.44 ( m , 1 h ) , 3.15 
 ( m , 1 h ) , 2.99 ( m , 2 h ) , 1.39 ( d , j = 6.0 hz , 3 h ) , 
 1.33 ( d , j = 6.0 hz , 3 h ) ; c nmr ( 100 
 mhz , cdcl3 ) ppm 166.9 , 163.0 , 162.5 ( d , jcf = 244 hz ) , 160.2 , 157.0 , 154.8 , 139.2 , 139.1 , 
 135.9 , 132.8 , 132.3 , 129.5 , 129.4 , 129.1 , 128.4 , 127.8 , 122.7 , 114.4 , 
 114.2 , 114.1 , 113.8 , 113.3 , 104.5 , 100.0 , 71.9 , 70.9 , 69.3 , 55.5 , 
 53.4 , 49.5 , 42.0 , 40.4 , 29.6 , 22.0 , 21.7 ; hrms ( esi ) exact mass calcd 
 for c30h31clfn4o4 [ m + 
 h ] 565.2018 , found 565.2023 . in a 100 ml flask was placed -nitro 
 boc - amine 4ga ( 700 mg , 1.54 mmol ) in meoh ( 15 ml ) , the 
 reaction mixture was stirred at room temperature , and then cobalt(ii ) 
 chloride ( 199 mg , 1.54 mmol ) was added . the purple solution was cooled 
 to 0 c , and then sodium borohydride ( 872 mg , 23.0 mmol ) was 
 added in three portions over 45 min . the reaction mixture was stirred 
 at 0 c for 75 min and then quenched with saturated aqueous nh4cl . the aqueous layer was extracted with ethyl acetate , and 
 the combined organic layers were washed with brine , dried ( na2so4 ) , filtered , and concentrated to give a white 
 solid ( 615 mg , 94% ) : [ ]d = 5.4 
 ( c 0.36 , ch3oh ) ; mp 158159 c ; 
 ir ( film ) 3373 , 2981 , 1683 , 1594 , 1570 , 1524 , 1493 cm ; h nmr ( 400 mhz , cdcl3 )  7.38 ( dt , j = 8.1 , 1.3 hz , 1h ) , 7.27 ( s , 1h ) , 7.257.20 ( m , 
 2h ) , 7.14 ( t , j = 7.8 hz , 1h ) , 6.99 ( dt , j = 7.8 , 1.3 hz , 1h ) , 6.94 ( d , j = 8.1 
 hz , 2h ) , 5.47 ( s , 1h ) , 4.80 ( s , 1h ) , 4.21 ( d , j = 
 5.6 hz , 1h ) , 1.37 ( s , 11h ) ; c nmr ( 126 mhz , cdcl3 )  155.0 , 144.4 , 136.7 , 133.4 , 130.7 , 130.1 , 129.9 , 
 128.8 , 128.3 , 125.5 , 122.5 , 79.9 , 59.4 , 28.3 ; hrms ( esi ) exact mass 
 calcd for c19h23brcln2o2 [ m + h ] 425.0633 , found 425.0634 . to amine s37 ( 350 mg , 0.822 
 mmol ) and 2-isopropoxy-4-methoxybenzoic acid ( 173 mg , 822 mol ) 
 in dichloromethane ( 4.1 ml ) were added edchcl ( 205 mg , 1.07 
 mmol ) and dmap ( 10.0 mg , 820 mol ) at 0 c , and the reaction 
 mixture was gradually warmed to room temperature over 16 h. the reaction 
 mixture was diluted with water and extracted with dichloromethane . the organic layers were combined , washed with brine , dried ( na2so4 ) , filtered , and concentrated to give a white 
 solid . the crude product was triturated with dichloromethane and hexanes , 
 filtered , and dried under vacuum to give a white solid ( 500 mg , 98% ) , 
 which was used for the next step directly . to tert - butyl ( ( 1r,2s)-2-(3-bromophenyl)-1-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxybenzamido)ethyl)carbamate 
 ( 330 mg , 534 mol ) in dichloromethane ( 5.0 ml ) was added tfa 
 ( 1.65 ml , 21.4 mmol ) at room temperature , and the reaction mixture 
 was stirred under n2 for 16 h. the reaction mixture was 
 poured into saturated aqueous nahco3 and extracted with 
 dichloromethane . the organic layer was washed with brine , dried ( na2so4 ) , filtered , and concentrated to afford a yellow 
 oil . this oil was purified by column chromatography ( sio2 , 010% methanol in dichloromethane ) to give a white solid 
 ( 202 mg , 73% ) : h nmr ( 400 mhz , cdcl3 )  
 8.83 ( d , j = 8.2 hz , 1h ) , 8.13 ( d , j = 8.8 hz , 1h ) , 7.36 ( ddd , j = 7.9 , 2.0 , 1.0 hz , 
 1h ) , 7.31 ( t , j = 1.8 hz , 1h ) , 7.267.22 ( m , 
 2h ) , 7.08 ( t , j = 7.8 hz , 1h ) , 7.067.00 ( m , 
 2h ) , 6.966.89 ( m , 1h ) , 6.56 ( dd , j = 8.8 , 
 2.3 hz , 1h ) , 6.49 ( d , j = 2.3 hz , 1h ) , 5.45 ( dd , j = 8.3 , 5.0 hz , 1h ) , 4.76 ( p , j = 6.1 
 hz , 1h ) , 4.40 ( d , j = 5.0 hz , 1h ) , 3.84 ( s , 3h ) , 
 1.571.38 ( m , 8h ) ; hrms ( esi ) exact mass calcd for c25h27brcln2o3 [ m + h ] 517.0895 , 
 found 517.0882 . to amine s38 ( 190 mg , 367 
 mol ) in dichloromethane ( 2 ml ) was added cdi ( 95 mg , 59 mol ) 
 at room temperature under n2 . the reaction mixture was 
 stirred for 1 h , piperazin-2-one ( 77 mg , 0.771 mmol ) was then added , 
 and this mixture was warmed to room temperature over 4 h. the solvent 
 was removed , and the crude product was purified by column chromatography 
 ( sio2 , 010% methanol in dichloromethane ) to give 
 a white solid ( 137 mg , 58% ) : h nmr ( 400 mhz , cdcl3 )  8.39 ( d , j = 8.0 hz , 1h ) , 8.27 
 ( d , j = 8.9 hz , 1h ) , 7.75 ( d , j = 
 5.0 hz , 1h ) , 7.45 ( dt , j = 8.2 , 1.4 hz , 1h ) , 7.23 
 ( d , j = 8.3 hz , 1h ) , 7.217.16 ( m , 2h ) , 7.08 
 ( dd , j = 6.9 , 1.3 hz , 2h ) , 6.906.85 ( m , 2h ) , 
 6.62 ( dd , j = 8.9 , 2.3 hz , 1h ) , 6.506.40 
 ( m , 2h ) , 5.79 ( dd , j = 8.1 , 2.5 hz , 1h ) , 5.13 ( dd , j = 5.0 , 2.5 hz , 1h ) , 4.66 ( hept , j = 6.0 
 hz , 1h ) , 4.15 ( d , j = 1.7 hz , 2h ) , 3.86 ( s , 3h ) , 
 3.73 ( ddd , j = 13.3 , 5.9 , 4.1 hz , 1h ) , 3.60 ( ddd , j = 13.3 , 6.4 , 4.6 hz , 1h ) , 3.443.38 ( m , 2h ) , 1.221.18 
 ( m , 6h ) ; hrms ( esi ) exact mass calcd for c30h33brcln4o5 [ m + h ] 643.1325 , found 
 643.1309 . to triphenylphosphine oxide ( 185 mg , 0.665 mmol ) in dichloromethane 
 ( 1.3 ml ) was added trifluoromethanesulfonic anhydride ( 0.056 ml , 0.332 
 mmol ) at 0 c , the reaction mixture was stirred at 0 c 
 for 10 min , amide - urea s39 ( 107 mg , 0.166 mmol ) in dichloromethane 
 ( 1 ml ) was then added , and the reaction mixture was stirred at 0 c 
 for 1 h and then allowed to warmed to room temperature before the 
 addition of aqueous nahco3 . the dichloromethane layer was 
 separated , and the aqueous layer was extracted with dichloromethane . 
 the combined dichloromethane layers were washed with brine , dried 
 ( na2so4 ) , filtered , and concentrated . the crude 
 product was purified by column chromatography ( sio2 , 07% 
 methanol in dichloromethane ) to give a white solid ( 95 mg , 91% ) : [ ]d = 110.2 ( c 0.575 , 
 ch3oh ) ; ir ( film ) 3224 , 2979 , 2936,1675 , 1608 , 1493,1424 
 cmh nmr ( 400 mhz , cdcl3 )  
 7.64 ( d , j = 8.5 hz , 1h ) , 7.21 ( dt , j = 7.7 , 1.7 hz , 1h ) , 7.11 ( t , j = 1.8 hz , 1h ) , 7.077.00 
 ( m , 2h ) , 7.016.86 ( m , 4h ) , 6.56 ( dd , j = 
 8.5 , 2.3 hz , 1h ) , 6.48 ( d , j = 2.3 hz , 1h ) , 6.43 
 ( d , j = 2.7 hz , 1h ) , 5.615.43 ( m , 2h ) , 4.61 
 ( hept , j = 6.1 hz , 1h ) , 3.85 ( s , 3h ) , 3.78 ( d , j = 18.0 hz , 1h ) , 3.63 ( d , j = 18.1 hz , 
 1h ) , 3.40 ( dt , j = 13.6 , 4.8 hz , 1h ) , 3.273.13 
 ( m , 1h ) , 3.082.94 ( m , 2h ) , 1.39 ( d , j = 6.0 
 hz , 3h ) , 1.33 ( d , j = 6.0 hz , 3h).c 
 nmr ( 101 mhz , cdcl3 )  166.9 , 163.1 , 160.4 , 157.0 , 
 154.9 , 139.9 , 135.1 , 133.3 , 132.4 , 131.0 , 130.2 , 129.3 , 128.4 , 128.0 , 
 126.5 , 122.0 , 113.5 , 104.6 , 100.2 , 72.0 , 71.0 , 69.3 , 55.6 , 50.0 , 42.0 , 
 40.5 , 22.1 ( 2c ) . hrms ( esi ) exact mass calcd for c30h31brcln4o4 [ m + h ] 625.1217 , 
 found 625.1218 . in a 100 ml flask was placed -nitro 
 boc - amine 4ca ( 1.10 g , 2.67 mmol ) in meoh ( 25 ml ) , the 
 reaction mixture was stirred at room temperature , and then cobalt(ii ) 
 chloride ( 347 mg , 2.67 mmol ) was added . the purple solution was cooled 
 to 0 c , and sodium borohydride ( 1.51 g , 40.1 mmol ) was added 
 in three portions over 45 min . stirring was continued at 0 c 
 for 2 h , and the reaction mixture was quenched with saturated aqueous 
 nh4cl and adjusted to ph 10 with concentrated nh4oh . the ethyl 
 acetate layer was washed with brine , dried ( na2so4 ) , filtered , and concentrated to give a white solid . the crude product 
 was purified on a silica gel column using a hexane / ethyl acetate ( 045% ) 
 gradient ( 670 mg , 66% ) : [ ]d = 11.9 
 ( c 0.29 , ch3oh ) ; mp 162163 c ; 
 ir ( film ) 3361 , 2983 , 1682 , 1525 , 1492 cm ; h nmr ( 400 mhz , cdcl3 )  7.257.19 
 ( m , 4h ) , 7.11 ( s , 1h ) , 6.996.91 ( m , 3h ) , 5.47 ( s , 1h ) , 4.80 
 ( s , 1h ) , 4.23 ( s , 1h ) , 1.36 ( s , 11h ) ; c nmr ( 126 mhz , 
 cdcl3 )  155.0 , 144.1 , 136.8 , 134.3 , 133.4 , 129.5 , 
 128.7 , 128.3 , 127.7 , 127.2 , 125.1 , 79.8 , 59.4 , 28.3 ; hrms ( esi ) exact 
 mass calcd for c19h23cl2n2o2 [ m + h ] 381.1138 , found 381.1131 . to amine s27 ( 300 mg , 787 
 mol ) and 4-chloro-2-isopropoxybenzoic acid ( 169 mg , 787 mol ) 
 in dichloromethane ( 4.0 ml ) were added edchcl ( 196 mg , 1.02 
 mmol ) and dmap ( 9.61 mg , 79 mol ) at 0 c , and the reaction 
 mixture was gradually warmed to room temperature . after 16 h the reaction 
 mixture was diluted with water and extracted with dichloromethane . the organic layers were combined , washed with brine , dried ( na2so4 ) , filtered , and concentrated to give a white 
 solid . the crude product was triturated with dichloromethane and then 
 hexanes and dried under vacuum to give a white solid ( 420 mg , 92% ) , 
 which was used in the next step directly . to tert - butyl ( ( 1r,2s)-2-(4-chloro-2-isopropoxybenzamido)-2-(3-chlorophenyl)-1-(4-chlorophenyl)ethyl)carbamate 
 ( 370 mg , 640 mol ) in dichloromethane ( 6 ml ) was added tfa ( 1.98 
 ml , 25.7 mmol ) , and the reaction mixture was stirred at room temperature 
 for 16 h. the reaction mixture was poured into aqueous nahco3 and extracted with dichloromethane . the combined organic layers 
 were washed with brine , dried ( na2so4 ) , filtered , 
 and concentrated . the residue was purified by column chromatography 
 ( sio2 , methanol in dichloromethane 07% ) to give 
 a white foam ( 290 mg , 95% ) : h nmr ( 400 mhz , cdcl3 )  8.89 ( d , j = 8.2 hz , 1h ) , 8.10 ( d , j = 8.4 hz , 1h ) , 7.287.18 ( m , 4h ) , 7.177.11 
 ( m , 2h ) , 7.056.96 ( m , 4h ) , 6.84 ( d , j = 7.7 
 hz , 1h ) , 5.42 ( dd , j = 8.2 , 4.9 hz , 1h ) , 4.79 ( p , j = 6.0 hz , 1h ) , 4.40 ( d , j = 4.8 hz , 1h ) , 
 1.531.40 ( m , 8h ) ; hrms ( esi ) exact mass calcd for c24h24cl3n2o2 [ m + h ] 477.0905 , found 477.0897 . to amine s28 ( 260 mg , 544 
 mol ) in dichloromethane ( 3.0 ml ) was added cdi ( 105 mg , 652 
 mol ) at 23 c under a nitrogen atmosphere ; the reaction 
 mixture was stirred for 1 h before piperazin-2-one ( 109 mg , 1.088 
 mmol ) was added , and the resulting mixture was stirred for 15 h at 
 room temperature . the solvent was removed , and the crude product was 
 purified by column chromatography ( sio2 , 010% methanol 
 in dichloromethane ) to give a white solid ( 250 mg , 76% ) : h nmr ( 400 mhz , cdcl3 )  8.39 ( d , j = 7.9 hz , 1h ) , 8.24 ( d , j = 8.5 hz , 1h ) , 7.57 ( d , j = 5.3 hz , 1h ) , 7.337.28 ( m , 2h ) , 7.227.17 
 ( m , 2h ) , 7.127.09 ( m , 2h ) , 6.976.92 ( m , 2h ) , 6.88 
 ( d , j = 8.4 hz , 2h ) , 6.45 ( s , 1h ) , 5.77 ( dd , j = 7.9 , 2.5 hz , 1h ) , 5.17 ( dd , j = 5.2 , 
 2.6 hz , 1h ) , 4.754.64 ( m , 1h ) , 4.14 ( d , j = 1.2 hz , 2h ) , 3.773.68 ( m , 1h ) , 3.60 ( dt , j = 13.3 , 5.3 hz , 1h ) , 3.423.37 ( m , 2h ) , 1.261.17 
 ( m , 6h ) ; hrms ( esi ) exact mass calcd for c29h30cl3n4o4 [ m + h ] 603.1334 , 
 found 603.1329 . to triphenylphosphine oxide ( 276 mg , 0.994 mmol ) in dichloromethane 
 ( 2 ml ) was added trifluoromethanesulfonic anhydride ( 0.084 ml , 0.497 
 mmol ) at 0 c , the reaction mixture was stirred for 10 min , amide - urea s29 ( 150 mg , 0.248 mmol ) in dichloromethane ( 1.6 ml ) was then 
 added , and the reaction mixture was stirred at 0 c for 1 h and 
 then warmed to room temperature before the addition of saturated aqueous 
 nahco3 . the dichloromethane layer was separated , and the 
 aqueous layer was extracted with dichloromethane . the combined organic 
 layers were washed with brine , dried ( na2so4 ) , filtered , and concentrated . the crude product was purified by 
 column chromatography ( sio2 , 07% methanol in dichloromethane ) 
 to give a white solid ( 125 mg , 86% ) : [ ]d = 95.2 ( c 0.5 , ch3oh ) ; 
 ir ( film ) 3226 , 2980 , 1678 , 1595 , 1490 , 1409 cm;h nmr ( 400 mhz , cdcl3 )  7.62 ( d , j = 8.2 hz , 1h ) , 7.03 ( ddt , j = 8.3 , 5.6 , 
 3.4 hz , 5h ) , 7.006.93 ( m , 2h ) , 6.87 ( t , j = 7.9 hz , 3h ) , 6.82 ( s , 1h ) , 5.655.49 ( m , 2h ) , 4.64 ( p , j = 6.1 hz , 1h ) , 3.81 ( d , j = 17.9 hz , 
 1h ) , 3.68 ( d , j = 17.9 hz , 1h ) , 3.35 ( dt , j = 12.9 , 4.6 hz , 1h ) , 3.283.14 ( m , 1h ) , 3.102.93 
 ( m , 2h ) , 1.40 ( d , j = 6.0 hz , 3h ) , 1.36 ( d , j = 6.0 hz , 3h ) ; c nmr ( 101 mhz , cdcl3 )  166.7 , 160.0 , 156.2 , 154.7 , 139.4 , 137.8 , 134.7 , 133.9 , 
 133.5 , 131.8 , 129.1 , 128.4 , 128.2 , 127.9 , 127.4 , 126.0 , 120.7 , 119.6 , 
 113.4 , 72.4 , 71.6 , 69.1 , 49.5 , 41.7 , 40.3 , 22.0 ( 2c ) ; hrms ( esi ) exact 
 mass calcd for c29h28cl3n4o3 [ m + h ] 585.1227 , found 585.1226 . to triphenylphosphine 
 oxide ( 673 mg , 2.420 mmol ) in dichloromethane ( 5 ml ) was added trifluoromethanesulfonic 
 anhydride ( 0.204 ml , 1.210 mmol ) at 0 c , the reaction mixture 
 was stirred at 0 c for 10 min , n-((1r,2s)-1-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxybenzamido)-2-(3-methoxyphenyl)ethyl)-3-oxopiperazine-1-carboxamide 
 ( 360 mg , 0.605 mmol ) in dichloromethane ( 3 ml ) was then added , and 
 the reaction mixture was stirred at 0 c for 1 h and then warmed 
 to room temperature before the addition of saturated aqueous nahco3 . the dichloromethane layer was separated , and the aqueous 
 layer was extracted with dichloromethane . the combined dichloromethane 
 layers were washed with brine , dried ( na2so4 ) , filtered , and concentrated . the crude product was purified by 
 column chromatography ( sio2 , 07% methanol in dichloromethane ) 
 to give a white solid ( 264 mg , 76% ) : [ ]d = 134.1 ( c 0.4 , ch3oh ) ; 
 ir ( film ) 3215 , 2979 , 2937 , 2837 , 1674,1607,1492,1431 cm ; h nmr ( 400 mhz , cdcl3 )  7.67 ( d , j = 8.5 hz , 1h ) , 7.02 ( dd , j = 15.7 , 8.1 
 hz , 3h ) , 6.89 ( d , j = 8.5 hz , 3h ) , 6.63 ( dd , j = 8.1 , 2.1 hz , 2h ) , 6.55 ( dd , j = 8.5 , 
 2.2 hz , 1h ) , 6.47 ( d , j = 2.1 hz , 1h ) , 6.456.40 
 ( m , 1h ) , 5.54 ( d , j = 9.7 hz , 1h ) , 5.46 ( d , j = 9.6 hz , 1h ) , 4.59 ( p , j = 6.0 hz , 1h ) , 
 3.83 ( s , 3h ) , 3.793.57 ( m , 5h ) , 3.35 ( dd , j = 8.5 , 5.0 hz , 1h ) , 3.18 ( dt , j = 12.8 , 5.3 hz , 
 1h ) , 2.96 ( t , j = 7.0 hz , 2h ) , 1.37 ( d , j = 6.0 hz , 3h ) , 1.32 ( d , j = 6.0 hz , 3h ) ; c nmr ( 101 mhz , cdcl3 )  167.2 , 163.0 , 160.1 , 159.2 , 
 157.0 , 154.9 , 138.9 , 135.4 , 132.9 , 132.4 , 128.8 , 128.5 , 127.8 , 120.3 , 
 113.8 , 113.6 , 112.9 , 104.6 , 100.1 , 72.4 , 71.0 , 69.4 , 55.5 , 55.1 , 49.4 , 
 42.0 , 40.34 , 22.1 , 22.0 ; hrms ( esi ) exact mass calcd for c31h34cln4o5 [ m + h ] 577.2218 , 
 found 577.2221 . to amine s37 ( 221 mg , 519 
 mol ) and 4-cyano-2-isopropoxybenzoic acid ( 107 mg , 519 mol ) 
 in dichloromethane ( 2.6 ml ) were added edchcl ( 129 mg , 675 mol ) 
 and dmap ( 6.3 mg , 52 mol ) at 0 c , and the reaction mixture 
 was gradually warmed to room temperature over 16 h. the reaction mixture 
 was diluted with water and extracted with dichloromethane . the combined 
 organic layers were washed with brine , dried ( na2so4 ) , filtered , and concentrated to give a white solid . the crude 
 product was triturated with dichloromethane and hexanes , filtered , 
 and dried under vacuum to give a white solid ( 500 mg , 98% ) , which 
 was used for the next step directly . to tert - butyl 
 ( ( 1r,2s)-2-(3-bromophenyl)-1-(4- 
 chlorophenyl)-2-(4-cyano-2-isopropoxybenzamido)ethyl)carbamate ( 225 
 mg , 367 mol ) in dichloromethane ( 4 ml ) was added tfa ( 1.13 
 ml , 14.7 mmol ) at room temperature , and the reaction mixture was stirred 
 under n2 for 16 h. the reaction mixture was poured into 
 saturated aqueous nahco3 and extracted with dichloromethane . the organic layer was washed with brine , dried ( na2so4 ) , filtered , and concentrated to afford an oil . this crude 
 oil was purified by column chromatography ( sio2 , 010% 
 methanol in dichloromethane ) to give a white solid ( 183 mg , 97% ) : h nmr ( 400 mhz , cdcl3 )  8.96 ( d , j = 8.0 hz , 1h ) , 8.318.20 ( m , 1h ) , 7.417.35 
 ( m , 1h ) , 7.32 ( dd , j = 8.1 , 1.5 hz , 1h ) , 7.297.20 
 ( m , 4h ) , 7.08 ( td , j = 7.8 , 1.2 hz , 1h ) , 7.036.97 
 ( m , 2h ) , 6.86 ( d , j = 7.1 hz , 1h ) , 5.565.28 
 ( m , 1h ) , 4.84 ( hept , j = 6.1 hz , 1h ) , 4.39 ( d , j = 4.9 hz , 1h ) , 1.631.44 ( m , 8h ) ; hrms ( esi ) exact 
 mass calcd for c25h24brcln3o2 [ m + h ] 512.0742 , found 512.0735 . s40 ( 105 mg , 205 
 mol ) in dichloromethane ( 1.2 ml ) was added cdi ( 49.8 mg , 307 
 mol ) at room temperature , and the reaction mixture was stirred 
 for 1 h. piperazin-2-one ( 41.0 mg , 409 mol ) was added , and 
 stirring was continued for 4 h at room temperature . the reaction mixture 
 was concentrated and purified by column chromatography ( sio2 , 010% methanol in dichloromethane ) to give a white solid 
 ( 97 mg , 74% ) : h nmr ( 400 mhz , cdcl3 )  
 8.538.34 ( m , 2h ) , 7.537.42 ( m , 1h ) , 7.37 ( dd , j = 8.1 , 1.4 hz , 1h ) , 7.307.15 ( m , 5h ) , 7.157.06 
 ( m , 2h ) , 6.946.87 ( m , 2h ) , 6.44 ( d , j = 3.2 
 hz , 1h ) , 5.75 ( dd , j = 8.1 , 3.1 hz , 1h ) , 5.20 ( dd , j = 5.7 , 3.0 hz , 1h ) , 4.74 ( hept , j = 6.0 
 hz , 1h ) , 4.174.08 ( m , 2h ) , 3.783.67 ( m , 1h ) , 3.663.55 
 ( m , 1h ) , 3.40 ( td , j = 5.5 , 4.8 , 2.0 hz , 2h ) , 1.291.23 
 ( m , 6h ) ; hrms ( esi ) exact mass calcd for c30h30brcln5o4 [ m + h ] 638.1171 , found 
 638.1158 . to triphenylphosphine oxide ( 139 mg , 0.501 mmol ) in dichloromethane 
 ( 1 ml ) was added trifluoromethanesulfonic anhydride ( 0.042 ml , 0.250 
 mmol ) at 0 c , the reaction mixture was stirred at 0 c 
 for 10 min , amide - urea s41 ( 80 mg , 0.125 mmol ) in dichloromethane 
 ( 1 ml ) was then added , and the reaction mixture was stirred at 0 c 
 for 1 h and then warmed to room temperature before the addition of 
 aqueous nahco3 . the dichloromethane layer was separated , 
 and the aqueous layer was extracted with dichloromethane . the combined 
 dichloromethane layers were washed with brine , dried ( na2so4 ) , filtered , and concentrated . the crude product was 
 purified by column chromatography ( sio2 , 07% methanol 
 in dichloromethane ) to give a white solid ( 64 mg , 82% ) : [ ]d = 75.0 ( c 0.22 , 
 ch3oh ) ; ir ( film ) 3214 , 2980 , 2923 , 2230 , 1678 , 1598 , 1566 , 
 1493 , 1413 cm ; h nmr ( 400 mhz , cdcl3 )  7.82 ( d , j = 7.8 hz , 1h ) , 7.35 
 ( dd , j = 7.9 , 1.4 hz , 1h ) , 7.257.17 ( m , 2h ) , 
 7.12 ( d , j = 1.9 hz , 1h ) , 7.107.04 ( m , 2h ) , 
 6.98 ( t , j = 7.7 hz , 1h ) , 6.956.84 ( m , 3h ) , 
 6.46 ( d , j = 3.0 hz , 1h ) , 5.695.55 ( m , 2h ) , 
 4.69 ( hept , j = 6.1 hz , 1h ) , 3.933.73 ( m , 
 2h ) , 3.30 ( t , j = 5.4 hz , 2h ) , 3.203.08 ( m , 
 1h ) , 3.02 ( dtd , j = 12.0 , 7.9 , 6.7 , 4.0 hz , 1h ) , 
 1.42 ( d , j = 6.0 hz , 3h ) , 1.39 ( d , j = 6.0 hz , 3h ) ; c nmr ( 101 mhz , cdcl3 )  
 166.2 , 160.0 , 155.5 , 154.7 , 139.4 , 134.3 , 133.9 , 131.7 , 130.8 , 130.4 , 
 129.4 , 128.4 , 128.3 , 126.3 , 124.2 , 122.2 , 118.2 , 115.8 , 115.2 , 73.0 , 
 71.9 , 69.0 , 49.7 , 41.4 , 40.4 , 29.7 , 21.9 ; hrms ( esi ) exact mass calcd 
 for c30h28brcln5o3 [ m 
 + h ] 620.1064 , found 620.1071 . in a 100 ml flask was placed -nitro 
 boc - amine 4ia ( 1.00 g , 2.46 mmol ) in meoh ( 24 ml ) , the 
 reaction mixture was stirred at room temperature , and then cobalt(ii ) 
 chloride ( 319 mg , 2.46 mmol ) was added . the purple solution was cooled 
 to 0 c , and then sodium borohydride ( 1.40 g , 36.9 mmol ) was 
 added in three portions over 45 min . stirring was continued at 0 c 
 for 75 min , and then the reaction mixture was treated with saturated 
 aqueous nh4cl and its ph adjusted to 10 with concentrated 
 nh4oh . the aqueous layer was extracted with ethyl acetate , 
 and the combined organic layers were washed with brine , dried ( na2so4 ) , filtered , and concentrated . the crude product 
 was purified by column chromatography ( sio2 , 045% 
 ethyl acetate in hexanes ) to afford an oil ( 440 mg , 48% ) : [ ]d = 6.7 ( c 0.45 , 
 ch3oh ) ; ir ( film ) 3383 , 2977 , 2836 , 1699 , 1600 , 1491 , 1436 , 
 1412 cm ; h nmr ( 400 mhz , cdcl3 )  7.237.15 ( m , 3h ) , 6.94 ( d , j = 8.0 hz , 2h ) , 6.79 ( ddd , j = 8.2 , 2.7 , 1.0 hz , 
 1h ) , 6.65 ( d , j = 7.6 hz , 1h ) , 6.59 ( t , j = 2.0 hz , 1h ) , 5.54 ( s , 1h ) , 4.82 ( s , 1h ) , 4.284.12 ( m , 
 1h ) , 3.73 ( s , 3h ) , 1.531.23 ( m , 11h ) ; c nmr ( 101 
 mhz , cdcl3 )  159.6 , 155.1 , 143.5 , 137.4 , 133.1 , 
 129.3 , 128.8 , 128.1 , 119.2 , 113.2 , 112.3 , 79.7 , 59.7 , 55.2 , 28.3 ; 
 hrms ( esi ) exact mass calcd for c20h26cln2o3 [ m + h ] 377.1634 , found 377.1635 . to amine s34 ( 403 mg , 1.07 
 mmol ) and 2-isopropoxy-4-methoxybenzoic acid ( 225 mg , 1.07 mmol ) in 
 dichloromethane ( 5.4 ml ) were added edchcl ( 266 mg , 1.39 mmol ) 
 and dmap ( 13.1 mg , 107 mol ) at 0 c , and the reaction 
 mixture was gradually warmed to room temperature over 16 h. the reaction 
 mixture was diluted with water and extracted with dichloromethane . the organic layers were combined , washed with brine , dried ( na2so4 ) , filtered , and concentrated to give a white 
 solid . the crude product was triturated with dichloromethane and hexanes , 
 filtered , and dried under vacuum to give a white solid ( 580 mg , 95% ) , 
 which was used for the next step directly . to tert - butyl ( ( 1r,2s)-1-(4-chlorophenyl)-2-(2-isopropoxy-4-methoxybenzamido)-2-(3-methoxyphenyl)ethyl)carbamate 
 ( 560 mg , 0.984 mmol ) in dichloromethane ( 9 ml ) was added tfa ( 3.04 
 ml , 39.5 mmol ) , and the reaction mixture was stirred at room temperature 
 for 16 h. the reaction mixture was then poured into saturated aqueous 
 nahco3 and extracted with dichloromethane . the organic 
 layers were combined and washed with brine , dried ( na2so4 ) , filtered , and concentrated . the residue was purified by 
 column chromatography ( sio2 , 07% methanol in dichloromethane ) 
 to give a white foam ( 459 mg , 99% ) : h nmr ( 400 mhz , cdcl3 )  8.84 ( d , j = 8.3 hz , 1h ) , 8.14 
 ( d , j = 8.8 hz , 1h ) , 7.23 ( d , j = 
 8.3 hz , 2h ) , 7.16 ( t , j = 7.9 hz , 1h ) , 7.07 ( d , j = 8.4 hz , 2h ) , 6.76 ( dd , j = 8.2 , 2.5 
 hz , 1h ) , 6.70 ( d , j = 7.7 hz , 1h ) , 6.60 ( s , 1h ) , 
 6.55 ( dd , j = 8.8 , 2.2 hz , 1h ) , 6.48 ( d , j = 2.2 hz , 1h ) , 5.45 ( dd , j = 8.3 , 5.2 
 hz , 1h ) , 4.74 ( p , j = 6.1 hz , 1h ) , 4.40 ( d , j = 5.2 hz , 1h ) , 3.82 ( s , 3h ) , 3.68 ( s , 3h ) , 1.641.36 
 ( m , 8h ) ; hrms ( esi ) exact mass calcd for c26h30cln2o4 [ m + h ] 469.1896 , found 
 469.1902 . to amine s35 ( 290 mg , 618 
 mol ) in dichloromethane ( 3.0 ml ) was added cdi ( 150 mg , 928 
 mol ) at room temperature under n2 . the reaction 
 mixture was stirred for 1 h , piperazin-2-one ( 124 mg , 1.24 mmol ) was 
 then added , and the reaction mixture was stirred for 15 h at room 
 temperature . the solvent was removed , and the crude product was purified 
 by column chromatography ( sio2 , 010% methanol in 
 dichloromethane ) to give a white solid ( 360 mg , 98% ) : h nmr ( 400 mhz , cdcl3 )  8.41 ( d , j = 7.7 hz , 1h ) , 8.28 ( d , j = 8.8 hz , 1h ) , 7.94 ( d , j = 5.0 hz , 1h ) , 7.187.13 ( m , 2h ) , 7.10 ( d , j = 1.1 hz , 1h ) , 6.956.86 ( m , 2h ) , 6.876.80 
 ( m , 1h ) , 6.666.58 ( m , 2h ) , 6.55 ( dd , j = 
 8.0 , 1.5 hz , 1h ) , 6.46 ( d , j = 2.2 hz , 1h ) , 6.27 
 ( d , j = 3.2 hz , 1h ) , 5.74 ( dd , j = 7.7 , 2.2 hz , 1h ) , 5.14 ( dd , j = 5.0 , 2.3 hz , 
 1h ) , 4.65 ( hept , j = 6.1 hz , 1h ) , 4.16 ( d , j = 1.3 hz , 2h ) , 3.86 ( s , 3h ) , 3.813.70 ( m , 4h ) , 
 3.60 ( ddd , j = 13.4 , 6.5 , 4.4 hz , 1h ) , 3.41 ( tdd , j = 9.3 , 5.9 , 3.6 hz , 2h ) , 1.19 ( d , j = 
 6.0 hz , 3h ) , 1.15 ( d , j = 6.1 hz , 3h ) ; hrms ( esi ) 
 exact mass calcd for c31h36cln4o6 [ m + h ] 595.2325 , found 595.2313 .
the 
 finding by scientists at hoffmann - la roche that cis - imidazolines could disrupt the protein  protein interaction 
 between p53 and mdm2 , thereby inducing apoptosis in cancer cells , 
 raised considerable interest in this scaffold over the past decade . 
 initial routes to these small molecules ( i.e. , nutlin-3 ) provided 
 only the racemic form , with enantiomers being enriched by chromatographic 
 separation using high - pressure liquid chromatography ( hplc ) and a 
 chiral stationary phase . reported here is the first application of 
 an enantioselective aza - henry approach to nonsymmetric cis - stilbene diamines and cis - imidazolines . 
 two novel 
 mono(amidine ) organocatalysts ( mam ) were discovered to provide high 
 levels of enantioselection ( > 95% ee ) across a broad range of substrate 
 combinations . 
 furthermore , the versatility of the aza - henry strategy 
 for preparing nonsymmetric cis - imidazolines is illustrated 
 by a comparison of the roles of aryl nitromethane and aryl aldimine 
 in the key step , which revealed unique substrate electronic effects 
 providing direction for aza - henry substrate 
 catalyst matching . 
 this method was used to prepare highly substituted cis-4,5-diaryl imidazolines that project unique aromatic rings , and 
 these were evaluated for mdm2-p53 inhibition in a fluorescence polarization 
 assay . 
 the diversification of access to cis - stilbene 
 diamine - derived imidazolines provided by this platform should streamline 
 their further development as chemical tools for disrupting protein  protein 
 interactions .