three key components of the chemistry phase of distributed drug discovery ( d)(1 ) are reagent rehearsal,(2 ) virtual library enumeration , and targeted library synthesis . in the rehearsal laboratories , diversity reagents are evaluated in duplicate for potential use at each step of a distributed drug discovery combinatorial synthesis . virtual d catalogs are then generated using only those diversity reagents that perform satisfactorily or whose potential is well - precedented from the literature . our first virtual d catalog was reported in the previous paper.(2 ) it is now freely available to the global community for analysis by computational models appropriate for neglected diseases . while waiting for molecular targets to emerge from this process , a disease and class of target molecules was identified that would allow testing the capability of d methodologies to make new , high - quality , potentially biologically active molecules . in 2005 researchers at the university of illinois reported the discovery , from a combinatorial library , of molecules that induced apoptosis in a melanoma cell line . the most potent molecule ( ic50 = 0.5 m ) in their collection was 1 ( from the r - isomer of phenylalanine ) . we had already demonstrated a distributed drug discovery synthesis procedure that can provide , from alkylating agents r1x and acylating agents r2cocl , acylated unnatural amino acids of general structure 7 ( original route , scheme 1 ) . the four - step sequence involves the alkylation of resin - bound glycinate ( 3  4 ) , followed by imine hydrolysis ( 4  5 ) , n - acylation ( 5  6 ) , and final cleavage from the resin ( 6  7 ) . it was apparent that modification of this procedure ( modified route , scheme 1 ) could produce numerous phenylalanine methyl ester analogs , 8 , of 1 and 2 . in part i , we report using this adaptation to perform the first successful demonstration of targeted d synthesis . in part ii , we enumerate , for open - access analysis , an accompanying virtual d catalog of acylated unnatural amino acid methyl esters . the synthesis of 6 was carried out as previously reported.(2 ) cleavage of 6 to 8 by transesterification with methanol in triethylamine at 55 c for 48 h proceeded smoothly and with good conversion . in the student laboratory , this modified route to compounds 8 proceeded uneventfully . in addition to the two known compounds 8a and 8b , 38 new compounds were prepared in duplicate . the results for the alkylating agents used and the products formed are shown in table 1 . superscript one indicates isolated , overall purified yields for four step synthesis to a and b , respectively , and superscript two indicates a result that is greater than the theoretical result based on presumed resin loading ( see ref ( 7 ) ) . as predicted from the database of alkylating agents reported in the previous paper in this journal,(2 ) the desired molecules were obtained in all cases , even with the problematic methoxy - substituted benzene derivatives 8{23}a , b , 8{24}a , b , and 8{25}a , b . each product from this laboratory was subsequently purified by manual silica gel chromatography , six compounds at a time , using a bill - board setup modified for purification rather than synthesis . the final products were , on average , > 95% pure by lc / ms . sufficient material was obtained to provide product for testing , with an average isolated chemical yield of 48% for the four - step , 50 mol reaction sequence ( see experimental section ) . figure 2 shows crude and purified product for a representative case where the crude purity was close to the average for all the samples . an essential component of distributed drug discovery is the open - access availability of databases of molecules accessible through distributed chemistry.(1 ) computational chemists can analyze these large databases to identify and make globally available smaller databases of potential drug leads targeted for developing world diseases . subsequently , the synthesis of the selected molecules will be carried out , in a distributed fashion , at sites across the world . as new d compatible synthetic procedures are developed , accompanying virtual d catalogs will be enumerated for open - access retrieval and searching . since the present work demonstrates the d route to acylated unnatural amino acid methyl esters , a new virtual d catalog based on this chemistry was created . the compounds ( including stereoisomers when appropriate ) in this virtual d catalog were enumerated with commercial software.(9 ) the complete virtual d catalog is freely available online through the collaborative drug discovery interface.(10 ) utilizing the same electrophiles and carboxylic acids ( and rationale for selection ) as in our previous synthesis of acylated unnatural amino acids,(2 ) 24  192 acylated unnatural amino acid methyl esters were enumerated . as in the previous enumeration , this 24  192-member virtual catalog contains more than the 10  000 members that would arise from a simple 100  100 combinatorial process . this is because the alkylation step provides racemic products , and the acylation step can lead to additional stereoisomers , each of which is listed separately . this allows appropriate computational discrimination and selection when three - dimensional molecular modeling software is employed and chirality is important . see the earlier article for a more complete discussion of these stereochemical issues.(2 ) the compound structures in the virtual catalog were further adjusted to take into consideration possible transformations in the final methanolysis step ( e.g. , transesterification of ethyl esters to methyl esters ) . this laboratory exercise demonstrates the ability to carry out a critical component of distributed drug discovery : the targeted , replicated synthesis , by students in their normal undergraduate laboratory , of new molecules selected from a large virtual catalog of molecules accessible from student - rehearsed diversity reagents . because these reagents had been previously rehearsed globally in indianapolis , barcelona , lublin and moscow , d correctly predicted every combinatorial synthesis would work . a 24  192-member virtual d catalog based on this chemistry was enumerated and is available through open - access . all resins were purchased from polymer laboratories , and all reactions and washes were conducted at ambient temperature unless otherwise noted . anhydrous n - methylpyrrolidinone ( nmp ) , chloroform - d1 , 2-fluorobenzyl bromide , 4-fluorobenzyl bromide , 2-(trifluoromethyl)benzyl bromide , 4-(trifluoromethyl)benzyl bromide , 2-bromobenzyl bromide , 2-methoxybenzyl chloride , and 4-methylbenzyl bromide were purchased from acros organics . btpp ( tert - butyl - imino - tri(pyrrolidino)phosphorane)(17 ) and fmoc chloride were purchased from fluka . n , n - diisopropylethylamine ( diea ) , benzyl bromide , 3-fluorobenzyl chloride , 3-(trifluoromethyl)benzyl chloride , 3-bromobenzyl bromide , 4-bromobenzyl bromide , 3-(bromomethyl)benzonitrile , 4-(bromomethyl)benzonitrile , 2-iodobenzyl bromide , 4-iodobenzyl bromide , 3-methoxybenzyl chloride , 4-methoxybenzyl chloride , 1-(chloromethyl)naphthalene , 2-(bromomethyl)naphthalene , and methanol - d4 were obtained from aldrich chemical co. manual solid - phase organic syntheses at ambient temperature were carried out in 3.5 ml fritted glass reaction vessels equipped with polypropylene screw caps with teflon faced silicon septa on the bill - board set , which was designed by one of us ( wls ) as inexpensive equipment(8 ) to simplify and expedite multiple , manual solid - phase syntheses . the bill - board reaction vessel components are available from chemglass : iup-0305 - 270h for 3.5 ml reaction vessel ; iup-0305 - 280h ( polypropylene screw cap ) ; iup-0305 - 281h ( teflon faced silicone septa ) . analytical thin layer chromatography ( tlc ) was performed with merck silica gel 60 f254 , 0.25 mm precoated glass plates . flash column chromatography was performed on silica gel 60 ( 230400 mesh ) from silicycle chemical division . the yields of the final compounds , after chromatographic purification , were calculated on the basis of the initial loading of the starting resins and are the overall yields of all reaction steps starting from these resins . h nmr spectra were recorded at 200 mhz ( varian spectrometer ) in chloroform - d1 and methanol - d4 ( 310% ) , with tms as standard . electrospray ionization mass spectrometry was conducted using a pesciex api iii triple - stage quadrupole mass spectrometer operated in either positive - ion or negative - ion detection mode . the composition of crude reaction mixtures was determined based on the integration of nmr spectra , as well as lc - ms results . lc - ms analyses were conducted using an agilent system , consisting of a 1100 series hplc connected to a diode array detector and a 1946d mass spectrometer configured for positive - ion / negative - ion electrospray ionization . the lc - ms samples were analyzed as solutions in ch3cn , prepared at 0.080.12 mg / ml concentration . the composition of mixtures was determined by lc - ms based on uv integration at 210 nm . the bill - boards ( 19 , one for each student in the laboratory , a total of 114 reactions ) were placed in their drain trays and , from a neutral buoyancy suspension in dichloromethane ( dcm)/nmp , 50 mols of the benzophenone imine of glycine wang resin ( 3 , resin loading = 0.7 mmol / g ) was distributed , via repeated 1 ml aliquots , to each of the 6 reaction vessels in a given bill - board 6-pack . during the distribution of the resin , when distribution was complete , residual solvent was removed with an  air - push  from a disposable plastic pipet fitted with a pierced septum that could be placed over the open mouth of the reaction vessel . the bottom of each reaction vessel was capped and a new calibrated disposable plastic pipet was used for each alkylating agent . the first r1-x ( benzyl bromide ) [ 0.5 ml of a 0.20 m solution in nmp , 100 mols , 2 equiv ] was added to the resin in the two reaction vessels in the first column positions ( i.e. , a1 and b1 ) . then the second r1-x [ 0.5 ml of a 0.20 m solution in nmp , 100 mols , 2 equiv ] was added to the resin in the two vessels in the second column positions ( i.e. , a2 and b2 ) . finally , the third r1-x [ 0.5 ml of a 0.20 m solution in nmp , 100 mols , 2 equiv ] was added to the resin in the two vessels in the third column positions ( i.e. , a3 and b3 ) . base was then added [ 0.5 ml of a 0.20 m solution of btpp in nmp , 100 mols , 2 equiv ] to each of the six reaction vessels . the tops of all reaction vessels were capped and the bill - board was placed in a rotation apparatus . the alkylation reaction was allowed to proceed for two days with rotation.(18 ) the bill - board was removed from the rotation apparatus and , after inverting the board , the bottom caps were removed . the board was then placed , top side up , in the drain tray ; the top caps were removed , and the reagents from the alkylation step were allowed to drain , followed by an air - push . the resin - bound alkylated products 4 were washed with thf ( 1  3 ml ) . using 6 clean caps , the bottom of each reaction vessel was capped , and a 1 n aqueous hcl - thf solution ( 1:2 , 2.5 ml ) was added to each of the six reaction vessels . the caps were then put on the top of each vessel , and the bill - board was returned to the rotator for 20 min . the reagents and byproduct from the hydrolysis were then removed from hydrolyzed resin - bound product ( 5 ) by filtration and washing with thf ( 1  3 ml ) and then nmp ( 1  3 ml ) . using clean caps , the bottom of each reaction vessel was capped , and the first acylating agent , triphenylacetyl chloride [ 0.5 ml of a 0.30 m solution of r2cocl in nmp , 150 mols , 3 equiv ] was added to the resin 5 in each of the three vessels in row a ( a1 , a2 , and a3 ) . then the second acylating agent , triphenylpropionyl chloride [ 0.5 ml of a 0.30 m solution of r2cocl in nmp , 150 mols , 3 equiv ] was added to the resin 5 in each of the three vessels in row b ( b1 , b2 , and b3 ) . this was followed by addition of diea [ 0.5 ml of a 0.60 m solution in nmp , 300 mols , 6 equiv ] to each of the six reaction vessels . the tops of the reaction vessels were capped and the reaction was allowed to proceed with rotation for 30 min . the bill - board was removed from the rotation apparatus , followed by the usual filtration / washing procedure . acylated resin - bound product 6 was washed with nmp ( 2  3 ml ) , ch2cl2 ( 2  3 ml ) , thf ( 2  3 ml ) , and meoh ( 2  3 ml ) . the bottom of each reaction vessel was capped with a clean cap and et3n / meoh ( 3:7 , 2.5 ml ) was added to each vessel . after securely capping the top of each reaction vessel with a clean cap , the reaction vessels were placed in an oven for two days at 55 c . the resin was rinsed with thf ( 1  2 ml ) , and this rinse was also collected . after each collection vial was swirled to thoroughly mix the cleavage and rinse solutions , a sample of each solution ( 100 l ) containing product 8 was transferred to an autosampler vial for lc / ms analysis . the cleavage solvent and rinses were evaporated with a simple , inexpensive apparatus designed to speed up the evaporation with a stream of nitrogen . to enable an efficient selection of gradient conditions , the products were gathered in groups of 6 according to retention times from the lc / ms data . the purifications were done six at a time , using a modified bill - board in which the reaction vessel plate was suspended above the collection vial rack and silica gel cartridges ( 6  3 ml/500 mg , fisher cat . 16.7 mg ( 74% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 100% , tr = 6.01 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.92 ( dd , j = 14.0 hz , j = 7.6 hz , 1h ) , 3.13 ( dd , j = 14.2 hz , j = 5.2 hz , 1h ) , 3.71 ( s , 3h ) , 4.90  5.00 ( m , 1h ) , 6.17 ( d , j = 7.2 hz , 1h ) , 7.11  7.25 ( m , 20h ) ; lc / ms calcd for c30h27no3 [ m + h ] 450.2 ; found 450.2 . 10.6 mg ( 45% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) ; initial lc / ms purity 77% , tr = 5.99 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  3.01 ( dd , j = 14.1 hz , j = 8.1 hz , 1h ) , 3.15 ( dd , j = 13.9 hz , j = 5.5 hz , 1h ) , 3.72 ( s , 3h ) , 4.874.97 ( m , 1h ) , 6.28 ( d , j = 7.4 hz , 1h ) , 6.907.02 ( m , 4h ) , 7.037.25 ( m , 15h ) ; lc / ms calcd for c30h26fno3 [ m + h ] 468.2 ; found 468.2 . 9.2 mg ( 39% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) ; initial lc / ms purity 52% , tr = 6.00 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.93 ( dd , j = 14.1 hz , j = 7.5 hz , 1h ) , 3.12 ( dd , j = 14.2 hz , j = 5.2 hz , 1h ) , 3.72 ( s , 3h ) , 4.905.02 ( m , 1h ) , 6.16 ( d , j = 7.1 hz , 1h ) , 6.586.95 ( m , 4h ) , 7.097.30 ( m , 15h ) ; lc / ms calcd for c30h26fno3 [ m + h ] 468.2 ; found 468.2 . 25.6 mg ( 110% isolated yield(7 ) ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) ; initial lc / ms purity 85% , tr = 6.01 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.91 ( dd , j = 14.1 hz , j = 7.5 hz , 1h ) , 3.09 ( dd , j = 14.1 hz , j = 5.3 hz , 1h ) , 3.71 ( s , 3h ) , 4.894.99 ( m , 1h ) , 6.17 ( d , j = 7.6 hz , 1h ) , 6.786.97 ( m , 4h ) , 7.087.30 ( m , 15h ) ; lc / ms calcd for c30h26fno3 [ m + h ] 468.2 ; found 468.2 . 9.3 mg ( 36% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 94% , tr = 6.21 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  3.01 ( m , 1h ) , 3.30 ( dd , j = 15.0 hz , j = 5.4 hz , 1h ) , 3.72 ( s , 3h ) , 4.965.08 ( m , 1h ) , 6.21 ( d , j = 7.8 hz , 1h ) , 7.047.06 ( m , 18h ) , 7.61 ( d , j = 7.8 hz , 1h ) ; lc / ms calcd for c31h26f3no3 [ m + h ] 518.2 ; found 518.2 . 8.9 mg ( 34% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 49% , tr = 6.24 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  3.02 ( dd , j = 14.1 hz , j = 7.3 hz , 1h ) , 3.21 ( dd , j = 14.1 hz , j = 5.3 hz , 1h ) , 3.70 ( s , 3h ) , 4.99 ( dd , j = 12.7 hz , j = 7.3 hz , 1h ) , 6.21 ( d , j = 7.0 hz , 1h ) , 7.09  7.35 ( m , 18h ) , 7.49 ( d , j = 7.6 hz , 1h ) ; lc / ms calcd for c31h26f3no3 [ m + h ] 518.2 ; found 518.2 . 12.7 mg ( 49% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 81% , tr = 6.28 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  3.00 ( dd , j = 14.2 hz , j = 7.2 hz , 1h ) , 3.20 ( dd , j = 14.1 hz , j = 5.3 hz , 1h ) , 3.72 ( s , 3h ) , 4.945.05 ( m , 1h ) , 6.16 ( d , j = 7.4 hz , 1h ) , 7.02 ( d , j = 8.0 hz , 2h ) , 7.127.26 ( m , 15h ) , 7.44 ( d , j = 8.0 hz , 2h ) ; lc / ms calcd for c31h26f3no3 [ m + h ] 518.2 ; found 518.2 . 3.6 mg ( 14% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 98% , tr = 6.20 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  3.05 ( dd , j = 13.9 hz , j = 9.9 hz , 1h ) , 3.28 ( dd , j = 14.2 hz , j = 5.4 hz , 1h ) , 3.73 ( s , 3h ) , 4.915.03 ( m , 1h ) , 6.34 ( d , j = 7.8 hz , 1h ) , 7.047.26 ( m,18h ) , 7.49 ( d , j = 4.5 hz , 1h ) ; lc / ms calcd for c31h26brno3 [ m + h ] 528.1 ; found 528.1 . 16.2 mg ( 62% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 81% , tr = 6.26 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.89 ( dd , j = 13.9 hz , j = 7.7 hz , 1h ) , 3.13 ( dd , j = 14.1 hz , j = 5.3 hz , 1h ) , 3.72 ( s , 3h ) , 4.884.99 ( m , 1h ) , 6.17 ( d , j = 7.4 hz , 1h ) , 6.85 ( d , j = 7.6 hz , 1h ) , 7.027.38 ( m,18h ) ; lc / ms calcd for c31h26brno3 [ m + h ] 528.1 ; found 528.1 . 18.5 mg ( 70% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 84% , tr = 6.30 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.89 ( dd , j = 14 hz , j = 7.8 hz , 1h ) , 3.08 ( dd , j = 14.2 hz , j = 5.4 hz , 1h ) , 3.71 ( s , 3h ) , 4.94 ( dd , j = 12.9 hz , j = 7.6 hz , 1h ) , 6.14 ( d , j = 7.2 hz , 1h ) , 6.76 ( d , j = 8.2 hz , 2h ) , 7.127.32 ( m , 17h ) ; lc / ms calcd for c30h26brno3 [ m + h ] 528.1 ; found 528.1 . 14.0 mg ( 59% isolated yield ) following chromatographic purification ( etoac / ch2cl2 , 20:80 ) ; initial lc / ms purity 77% , tr = 5.66 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.99 ( dd , j = 14.2 hz , j = 7.4 hz , 1h ) , 3.16 ( dd , j = 14 hz , j = 5.2 hz , 1h ) , 3.72 ( s , 3h ) , 4.99 ( dd , j = 12.0 hz , j = 7.2 hz , 1h ) , 6.19 ( d , j = 7.6 hz , 1h ) , 7.147.35 ( m , 18h ) , 7.52 ( d , j = 7.6 hz , 1h ) ; lc / ms calcd for c31h26n2o3 [ m + h ] 475.2 ; found 475.2 . 17.9 mg ( 76% isolated yield ) following chromatographic purification ( etoac / ch2cl2 , 20:80 ) ; initial lc / ms purity 75% , tr = 5.66 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  3.02 ( dd , j = 14.1 hz , j = 7.3 hz , 1h ) , 3.19 ( dd , j = 13.9 hz , j = 5.3 hz , 1h ) , 3.72 ( s , 3h ) , 5.01 ( dd , j = 14.0 hz , j = 7.2 hz , 1h ) , 6.20 ( d , j = 7.6 hz , 1h ) , 7.02 ( d , j = 8.2 hz , 2h ) , 7.157.28 ( m , 15h ) , 7.47 ( d , j = 8.4 hz , 2h ) ; lc / ms calcd for c31h26n2o3 [ m + h ] 475.2 ; found 475.2 . 17.3 mg ( 60% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 84% , tr = 6.27 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.953.10 ( m , 1h ) , 3.29 ( dd , j = 14.2 hz , j = 7.4 hz , 1h ) , 3.74 ( s , 3h ) , 4.93 ( m , 1h ) , 6.32 ( d , j = 7.6 hz , 1h ) , 6.917.25 ( m , 18h ) , 7.79 ( d , j = 7.0 hz , 1h ) ; lc / ms calcd for c30h26ino3 [ m + h ] 576.1 ; found 576.1 . 15.9 mg ( 55% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 81% , tr = 6.38 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.87 ( dd , j = 14 hz , j = 7.6 hz , 1h ) , 3.07 ( dd , j = 14.1 hz , j = 5.3 hz , 1h ) , 3.71 ( s , 3h ) , 4.94 ( dd , j = 14 hz , j = 7.6 hz , 1h ) , 6.13 ( d , j = 7.4 hz , 1h ) , 6.63 ( d , j = 8.2 hz , 2h ) , 7.12  7.27 ( m , 15h ) , 7.50 ( d , j = 8.2 hz , 2h ) ; lc / ms calcd for c30h26ino3 [ m + h ] 576.1 ; found 576.1 . 3.9 mg ( 8% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) of pooled duplicate samples ; initial lc / ms purity 24%25% , tr = 6.07 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.913.12 ( m , 2h ) , 3.43 ( s , 3h ) , 3.72 ( s , 3h ) , 4.754.85 ( m , 1h ) , 6.59 ( d , j = 6.6 hz , 1h ) , 6.727.10 ( m , 4h ) , 7.117.29 ( m,15h ) ; lc / ms calcd for c31h29no4 [ m + h ] 480.2 ; found 480.2 . 12.0 mg ( 25% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) of pooled duplicate samples ; initial lc / ms purity 37%38% , tr = 5.97 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.88 ( dd , j = 13.9 hz , j = 8.1 hz , 1h ) , 3.12 ( dd , j = 14.1 hz , j = 5.3 hz , 1h ) , 3.69 ( s , 3h ) , 3.72 ( s,3h ) , 4.874.97 ( m , 1h ) , 6.17 ( d , j = 7.2 hz , 1h ) , 6.456.78 ( m , 4h ) , 7.067.29 ( m,15h ) . lc / ms calcd for c31h29no4 [ m + h ] 480.2 ; found 480.2 . 12.0 mg ( 25% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) of pooled duplicate samples ; initial lc / ms purity 38%46% , tr = 5.94 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.86 ( dd , j = 14.2 hz , j = 7.6 hz , 1h ) , 3.05 ( dd , j = 14.1 hz , j = 5.1 hz , 1h ) , 3.71 ( s , 3h ) , 3.78 ( s , 3h ) , 4.854.96 ( m , 1h ) , 6.15 ( d , j = 7.6 hz , 1h ) , 6.686.82 ( m , 4h ) , 7.127.26 ( m,15h ) ; lc / ms calcd for c31h29no4 [ m + h ] 480.2 ; found 480.2 . 14.7 mg ( 64% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 97% , tr = 6.21 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.31 ( s , 3h ) , 2.87 ( dd , j = 14.0 hz , j = 7.6 hz , 1h ) , 3.07 ( dd , j = 14.0 hz , j = 5.0 hz , 1h ) , 3.71 ( s , 3h ) , 4.864.96 ( m , 1h ) , 6.15 ( d , j = 7.2 hz , 1h ) , 6.76 ( d , j = 7.8 hz , 2h ) , 6.99 ( d , j = 7.8 hz , 2h ) , 7.127.25 ( m , 15h ) ; lc / ms calcd for c34h29no3 [ m + h ] 464.2 ; found 464.2 . 8.8 mg ( 35% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 64% , tr = 6.31 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  3.263.74 ( m , 2h ) , 3.67 ( s , 3h ) , 5.02 ( dd , j = 15.0 hz , j = 7.0 hz , 1h ) , 6.23 ( d , j = 6.8 hz , 1h ) , 6.957.51 ( m , 19h ) , 7.80 ( m , 2h ) , 8.00 ( d , j = 7.6 hz , 1h ) ; lc / ms calcd for c30h26brno3 [ m + h ] 500.2 ; found 500.2 . 17.7 mg ( 71% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 88% , tr = 6.32 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  3.05 ( dd , j = 14.1 hz , j = 8.1 hz , 1h ) , 3.33 ( dd , j = 13.9 hz , j = 5.1 hz , 1h ) , 3.74 ( s , 3h ) , 4.975.07 ( m , 1h ) , 6.17 ( d , j = 7.0 hz , 1h ) , 7.077.33 ( m , 15h ) , 7.447.83 ( m , 7h ) ; lc / ms calcd for c34h29no3 [ m + h ] 500.2 ; found 500.2 . 18.3 mg ( 79% isolated yield ) following chromatographic purification ( ch2cl2/etoac / hexanes , 10:15:75 to 20:20:60 ) of pooled duplicate samples ; initial lc / ms purity 86 , 87% , tr = 5.92 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.742.78 ( m , 2h ) , 3.52 ( d , j = 15.0 hz , 1h ) , 3.56 ( s , 3h ) , 3.66 ( d , j = 15.0 hz , 1h ) , 4.59 ( dd , j = 14 hz , j = 6.2 hz , 1h ) , 5.40 ( d , j = 7.4 hz , 1h ) , 6.826.87 ( m , 2h ) , 7.187.29 ( m , 18h ) ; lc / ms calcd for c31h29no3 [ m + h ] 464.2 ; found 464.2 . 12.6 mg ( 52% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) ; initial lc / ms purity 83% , tr = 5.91 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.792.84 ( m , 2h ) , 3.57 ( d , j = 14.8 hz , 1h ) , 3.58 ( s , 3h ) , 3.63 ( d , j = 14.8 hz , 1h ) , 4.56 ( dd , j = 13.5 hz , j = 6.4 hz , 1h ) , 5.44 ( d , j = 7.0 hz , 1h ) , 6.857.26 ( m , 19h ) ; lc / ms calcd for c31h28fno3 [ m + h ] 482.2 ; found 482.2 . 7.7 mg ( 32% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) ; initial lc / ms purity 70% , tr = 5.95 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.732.79 ( m , 2h ) , 3.54 ( d , j = 15.2 hz , 1h ) , 3.58 ( s , 3h ) , 3.67 ( d , j = 15.2 hz , 1h ) , 4.60 ( dd , j = 13.4 hz , j = 6.2 hz , 1h ) , 5.40 ( d , j = 7.0 hz , 1h ) , 6.546.93 ( m , 3h ) , 7.097.30 ( m , 16h ) ; lc / ms : calcd for c31h28fno3 [ m + h ] 482.2 ; found 482.2 . 18.1 mg ( 75% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) ; initial lc / ms purity 83% , tr = 5.93 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.712.76 ( m , 2h ) , 3.53 ( d , j = 14.6 hz , 1h ) , 3.57 ( s , 3h ) , 3.67 ( d , j = 14.6 hz , 1h ) , 4.58 ( dd , j = 13.4 hz , j = 6.0 hz , 1h ) , 5.39 ( d , j = 7.2 hz , 1h ) , 6.756.92 ( m , 4h ) , 7.167.30 ( m , 15h ) ; lc / ms : calcd for c31h28fno3 [ m + h ] 482.2 ; found 482.2 . 16.6 mg ( 63% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 ) ; initial lc / ms purity 89% , tr = 6.13 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.662.93 ( m , 2h ) , 3.51 ( d , j = 15.0 hz , 1h ) , 3.52 ( s , 3h ) , 3.66 ( d , j = 15.2 hz , 1h ) , 4.60 ( dd , j = 15.0 hz , j = 7.6 hz , 1h ) , 5.41 ( d , j = 7.6 hz , 1h ) , 7.127.43 ( m , 18h ) , 7.59 ( d , j = 7.2 hz , 1h ) ; lc / ms calcd for c32h29f3no3 [ m + h ] 532.2 ; found 532.2 . 5.7 mg ( 22% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 ) ; initial lc / ms purity 72% , tr = 6.21 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.702.91 ( m , 2h ) , 3.54 ( d , j = 14.8 hz , 1h ) , 3.56 ( s , 3h ) , 3.66 ( d , j = 15.0 hz , 1h ) , 4.61 ( dd , j = 13.3 hz , j = 6.3 hz , 1h ) , 5.39 ( d , j = 7.2 hz , 1h ) , 7.05 ( d , j = 7.6 hz , 1h ) , 7.147.35 ( m , 17h ) , 7.47 ( d , j = 7.6 hz , 1h ) ; lc / ms calcd for c32h29f3no3 [ m + h ] 532.2 ; found 532.2 . 18.5 mg ( 70% isolated yield ) following chromatographic purification ( etoac / hexanes in ch2cl2 , 4:46:50 ) ; initial lc / ms purity 80% , tr = 6.22 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.702.97 ( m , 2h ) , 3.54 ( d , j = 15.0 hz , 1h ) , 3.58 ( s , 3h ) , 3.68 ( d , j = 15.0 hz , 1h ) , 4.64 ( dd , j = 13.4 hz , j = 6.0 hz , 1h ) , 5.39 ( d , j = 7.4 hz , 1h ) , 6.95 ( d , j = 8.0 hz , 2h ) , 7.107.35 ( m , 15h ) , 7.43 ( d , j = 8.0 hz , 2h ) ; lc / ms calcd for c32h29f3no3 [ m + h ] 532.2 ; found 532.2 . 8.8 mg ( 33% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 ) ; initial lc / ms purity 94% , tr = 6.11 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.77 ( dd , j = 14.1 hz , j = 7.5 hz , 1h ) , 2.92 ( dd , j = 14.1 hz , j = 6.7 hz , 1h ) , 3.54 ( d , j = 14.8 hz , 1h ) , 3.57 ( s , 3h ) , 3.63 ( d , j = 14.8 hz , 1h ) , 4.60 ( dd , j = 14.5 hz , j = 7.3 hz , 1h ) , 5.39 ( d , j = 7.2 hz , 1h ) , 6.93 ( d , j = 7.0 hz , 1h ) , 7.007.30 ( m , 17h ) , 7.50 ( d , j = 7.8 hz , 1h ) ; lc / ms : calcd for c31h29brno3 [ m + h ] 542.1 ; found 542.2 . 8.5 mg ( 31% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 ) ; initial lc / ms purity 84% , tr = 6.21 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.602.85 ( m , 2h ) , 3.54 ( d , j = 15.2 hz , 1h ) , 3.58 ( s , 3h ) , 3.67 ( d , j = 15.2 hz , 1h ) , 4.59 ( dd , j = 13.3 hz , j = 6.3 hz , 1h ) , 5.38 ( d , j = 7.2 hz , 1h ) , 6.79 ( d , j = 7.8 hz , 1h ) , 6.957.40 ( m , 18h ) ; lc / ms calcd for c31h29brno3 [ m + h ] 542.1 ; found 542.2 . 12.9 mg ( 48% isolated yield ) following chromatographic purification ( etoac / hexanes in ch2cl2 , 4:46:50 ) ; initial lc / ms purity 87% , tr = 6.23 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.602.90 ( m , 2h ) , 3.53 ( d , j = 15.0 hz , 1h ) , 3.57 ( s , 3h ) , 3.67 ( d , j = 15.0 hz , 1h ) , 4.59 ( dd , j = 13.3 hz , j = 6.3 hz , 1h ) , 5.38 ( d , j = 7.4 hz , 1h ) , 6.70 ( d , j = 8.4 hz , 2h ) , 7.107.38 ( m , 17h ) ; lc / ms calcd for c31h29brno3 [ m + h ] 542.1 ; found 542.2 . 7.5 mg ( 31% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) ; initial lc / ms purity 78% , tr = 5.67 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.622.91 ( m , 2h ) , 3.55 ( d , j = 15.2 hz , 1h ) , 3.58 ( s , 3h ) , 3.67 ( d , j = 15.2 hz , 1h ) , 4.62 ( dd , j = 12.9 hz , j = 6.1 hz , 1h ) , 5.42 ( d , j = 7.2 hz , 1h ) , 7.057.39 ( m , 18h ) , 7.50 ( d , j = 7.8 hz , 1h ) ; lc / ms calcd for c32h29n2o3 [ m + h ] 489.2 ; found 489.2 . 19.1 mg ( 78% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) ; initial lc / ms purity 76% , tr = 5.65 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.77 ( dd , j = 13.9 hz , j = 6.1 hz , 1h ) , 2.87 ( dd , j = 13.9 hz , j = 6.1 hz , 1h ) , 3.54 ( d , j = 15.0 hz , 1h ) , 3.57 ( s , 3h ) , 3.68 ( d , j = 15.0 hz , 1h ) , 4.63 ( dd , j = 13.3 hz , j = 6.3 hz , 1h ) , 5.41 ( d , j = 7.4 hz , 1h ) , 6.96 ( d , j = 8.4 hz , 2h ) , 7.107.38 ( m , 15h ) , 7.46 ( d , j = 8.4 hz , 2h ) ; lc / ms calcd for c32h29n2o3 [ m + h ] : 489.2 ; found 489.3 . 18.9 mg ( 64% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 ) ; initial lc / ms purity 86% , tr = 6.18 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.74 ( dd , j = 14.2 hz , j = 7.6 hz , 1h ) , 2.89 ( dd , j = 14.1 hz , j = 6.9 hz , 1h ) , 3.54 ( d , j = 15.2 hz , 1h ) , 3.57 ( s , 3h ) , 3.64 ( d , j = 15.2 hz , 1h ) , 4.60 ( dd , j = 14.7 , hz , j = 7.3 hz , 1h ) , 5.37 ( d , j = 7.2 hz , 1h ) , 6.92 ( d , j = 7.6 hz , 2h ) , 7.087.40 ( m , 16h ) , 7.78 ( d , j = 7.8 hz , 1h ) ; lc / ms calcd for c31h29ino3 [ m + h ] 590.1 ; found 590.1 . 19.6 mg ( 67% isolated yield ) following chromatographic purification ( etoac / hexanes in ch2cl2 , 4:46:50 ) ; initial lc / ms purity 81% , tr = 6.31 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.592.82 ( m , 2h ) , 3.53 ( d , j = 15.2 hz , 1h ) , 3.57 ( s , 3h ) , 3.67 ( d , j = 15.2 hz , 1h ) , 4.59 ( dd , j = 13.4 hz , j = 6.0 hz , 1h ) , 5.38 ( d , j = 7.4 hz , 1h ) , 6.58 ( d , j = 8.2 hz , 2h ) , 7.107.32 ( m , 15h ) , 7.49 ( d , j = 8.2 hz , 2h ) ; lc / ms calcd for c31h29ino3 [ m + h ] 590.1 ; found 590.1 . 4.3 mg ( 9% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) of pooled duplicate samples ; initial lc / ms purity 40%42% , tr = 5.96 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.732.76 ( m , 2h ) , 3.43 ( d , j = 15.0 hz , 1h ) , 3.56 ( s , 3h ) , 3.63 ( d , j = 15.0 hz , 1h ) , 3.73 ( s , 3h ) , 4.47 ( dd , j = 13.6 hz , j = 6.8 hz , 1h ) , 5.58 ( d , j = 6.6 hz , 1h ) , 6.796.81 ( m , 3h ) , 7.147.26 ( m , 16h ) ; lc / ms calcd for c32h31no4 [ m + h ] 494.2 ; found 494.3 . 4.3 mg ( 17% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) ; initial lc / ms purity 61% , tr = 5.90 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.702.75 ( m , 2h ) , 3.53 ( d , j = 15.2 hz , 1h ) , 3.57 ( s , 3h ) , 3.65 ( d , j = 15.2 hz , 1h ) , 3.74 ( s , 3h ) , 4.58 ( dd , j = 14.0 hz , j = 6.2 hz , 1h ) , 5.39 ( d , j = 7.4 hz , 1h ) , 6.416.45 ( m , 2h ) , 6.736.76 ( m , 1h ) , 7.067.63 ( m , 16h ) ; lc / ms calcd for c31h29no3 [ m + h ] 494.2 ; found 494.3 . 4.0 mg ( 16% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) ; initial lc / ms purity 57% , tr = 5.86 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.692.71 ( m , 2h ) , 3.52 ( d , j = 15.2 hz , 1h ) , 3.57 ( s , 3h ) , 3.66 ( d , j = 15.2 hz , 1h ) , 3.77 ( s , 3h ) , 4.55 ( dd , j = 13.4 hz , j = 6.2 hz , 1h ) , 5.38 ( d , j = 7.4 hz , 1h ) , 6.74 ( m , 4h ) , 7.187.26 ( m , 15h ) ; lc / ms : calcd for c31h29no3 [ m + h ] 494.2 ; found 494.3 . 9.5 mg ( 40% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 ) ; initial lc / ms purity 100% , tr = 6.12 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.30 ( s , 3h ) , 2.602.81 ( m , 2h ) , 3.52 ( d , j = 15.2 hz , 1h ) , 3.57 ( s , 3h ) , 3.65 ( d , j = 15.2 hz , 1h ) , 4.56 ( dd , j = 13.2 hz , j = 6.2 hz , 1h ) , 5.39 ( d , j = 7.6 hz , 1h ) , 6.73 ( d , j = 7.8 hz , 2h ) , 6.99 ( d , j = 7.8 hz , 2h ) , 7.107.32 ( m , 15h ) ; lc / ms calcd for c32h32no3 [ m + h ] 478.2 ; found 478.3 . 5.0 mg ( 20% isolated yield ) following chromatographic purification ( etoac / hexanes in ch2cl2 , 4:46:50 ) ; initial lc / ms purity 80% , tr = 6.23 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  3.033.31 ( m , 2h ) , 3.45 ( s , 3h ) , 3.57 ( s , 2h ) , 4.68 ( dd , j = 14.0 hz , j = 7.0 hz , 1h ) , 5.43 ( d , j = 7.0 hz , 1h ) , 6.94 ( d , j = 6.8 hz , 1h ) , 7.078.00 ( m , 21h ) ; lc / ms calcd for c35h32no3 [ m + h ] 514.2 ; found 514.3 . 14.7 mg ( 57% isolated yield ) following chromatographic purification ( etoac / hexanes in ch2cl2 , 4:46:50 ) ; initial lc / ms purity 87% , tr = 6.26 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.803.21 ( m , 2h ) , 3.52 ( d , j = 15.2 hz , 1h ) , 3.56 ( s , 3h ) , 3.66 ( d , j = 15.2 hz , 1h ) , 4.71 ( dd , j = 13.4 hz , j = 6.2 hz , 1h ) , 5.39 ( d , j = 7.4 hz , 1h ) , 7.00 ( d , j = 6.8 hz , 1h ) , 7.02  7.82 ( m , 21h ) ; lc / ms calcd for c35h32no3 [ m + h ] 514.2 ; found 514.3 . to enable an efficient selection of gradient conditions , the products were gathered in groups of 6 according to retention times from the lc / ms data . the purifications were done six at a time , using a modified bill - board in which the reaction vessel plate was suspended above the collection vial rack and silica gel cartridges ( 6  3 ml/500 mg , fisher cat 16.7 mg ( 74% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 100% , tr = 6.01 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.92 ( dd , j = 14.0 hz , j = 7.6 hz , 1h ) , 3.13 ( dd , j = 14.2 hz , j = 5.2 hz , 1h ) , 3.71 ( s , 3h ) , 4.90  5.00 ( m , 1h ) , 6.17 ( d , j = 7.2 hz , 1h ) , 7.11  7.25 ( m , 20h ) ; lc / ms calcd for c30h27no3 [ m + h ] 450.2 ; found 450.2 . 10.6 mg ( 45% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) ; initial lc / ms purity 77% , tr = 5.99 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  3.01 ( dd , j = 14.1 hz , j = 8.1 hz , 1h ) , 3.15 ( dd , j = 13.9 hz , j = 5.5 hz , 1h ) , 3.72 ( s , 3h ) , 4.874.97 ( m , 1h ) , 6.28 ( d , j = 7.4 hz , 1h ) , 6.907.02 ( m , 4h ) , 7.037.25 ( m , 15h ) ; lc / ms calcd for c30h26fno3 [ m + h ] 468.2 ; found 468.2 . 9.2 mg ( 39% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) ; initial lc / ms purity 52% , tr = 6.00 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.93 ( dd , j = 14.1 hz , j = 7.5 hz , 1h ) , 3.12 ( dd , j = 14.2 hz , j = 5.2 hz , 1h ) , 3.72 ( s , 3h ) , 4.905.02 ( m , 1h ) , 6.16 ( d , j = 7.1 hz , 1h ) , 6.586.95 ( m , 4h ) , 7.097.30 ( m , 15h ) ; lc / ms calcd for c30h26fno3 [ m + h ] 468.2 ; found 468.2 . 25.6 mg ( 110% isolated yield(7 ) ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) ; initial lc / ms purity 85% , tr = 6.01 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.91 ( dd , j = 14.1 hz , j = 7.5 hz , 1h ) , 3.09 ( dd , j = 14.1 hz , j = 5.3 hz , 1h ) , 3.71 ( s , 3h ) , 4.894.99 ( m , 1h ) , 6.17 ( d , j = 7.6 hz , 1h ) , 6.786.97 ( m , 4h ) , 7.087.30 ( m , 15h ) ; lc / ms calcd for c30h26fno3 [ m + h ] 468.2 ; found 468.2 . 9.3 mg ( 36% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 94% , tr = 6.21 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  3.01 ( m , 1h ) , 3.30 ( dd , j = 15.0 hz , j = 5.4 hz , 1h ) , 3.72 ( s , 3h ) , 4.965.08 ( m , 1h ) , 6.21 ( d , j = 7.8 hz , 1h ) , 7.047.06 ( m , 18h ) , 7.61 ( d , j = 7.8 hz , 1h ) ; lc / ms calcd for c31h26f3no3 [ m + h ] 518.2 ; found 518.2 . 8.9 mg ( 34% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 49% , tr = 6.24 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  3.02 ( dd , j = 14.1 hz , j = 7.3 hz , 1h ) , 3.21 ( dd , j = 14.1 hz , j = 5.3 hz , 1h ) , 3.70 ( s , 3h ) , 4.99 ( dd , j = 12.7 hz , j = 7.3 hz , 1h ) , 6.21 ( d , j = 7.0 hz , 1h ) , 7.09  7.35 ( m , 18h ) , 7.49 ( d , j = 7.6 hz , 1h ) ; lc / ms calcd for c31h26f3no3 [ m + h ] 518.2 ; found 518.2 . 12.7 mg ( 49% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 81% , tr = 6.28 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  3.00 ( dd , j = 14.2 hz , j = 7.2 hz , 1h ) , 3.20 ( dd , j = 14.1 hz , j = 5.3 hz , 1h ) , 3.72 ( s , 3h ) , 4.945.05 ( m , 1h ) , 6.16 ( d , j = 7.4 hz , 1h ) , 7.02 ( d , j = 8.0 hz , 2h ) , 7.127.26 ( m , 15h ) , 7.44 ( d , j = 8.0 hz , 2h ) ; lc / ms calcd for c31h26f3no3 [ m + h ] 518.2 ; found 518.2 . 3.6 mg ( 14% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 98% , tr = 6.20 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  3.05 ( dd , j = 13.9 hz , j = 9.9 hz , 1h ) , 3.28 ( dd , j = 14.2 hz , j = 5.4 hz , 1h ) , 3.73 ( s , 3h ) , 4.915.03 ( m , 1h ) , 6.34 ( d , j = 7.8 hz , 1h ) , 7.047.26 ( m,18h ) , 7.49 ( d , j = 4.5 hz , 1h ) ; lc / ms calcd for c31h26brno3 [ m + h ] 528.1 ; found 528.1 . 16.2 mg ( 62% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 81% , tr = 6.26 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.89 ( dd , j = 13.9 hz , j = 7.7 hz , 1h ) , 3.13 ( dd , j = 14.1 hz , j = 5.3 hz , 1h ) , 3.72 ( s , 3h ) , 4.884.99 ( m , 1h ) , 6.17 ( d , j = 7.4 hz , 1h ) , 6.85 ( d , j = 7.6 hz , 1h ) , 7.027.38 ( m,18h ) ; lc / ms calcd for c31h26brno3 [ m + h ] 528.1 ; found 528.1 . 18.5 mg ( 70% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 84% , tr = 6.30 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.89 ( dd , j = 14 hz , j = 7.8 hz , 1h ) , 3.08 ( dd , j = 14.2 hz , j = 5.4 hz , 1h ) , 3.71 ( s , 3h ) , 4.94 ( dd , j = 12.9 hz , j = 7.6 hz , 1h ) , 6.14 ( d , j = 7.2 hz , 1h ) , 6.76 ( d , j = 8.2 hz , 2h ) , 7.127.32 ( m , 17h ) ; lc / ms calcd for c30h26brno3 [ m + h ] 528.1 ; found 528.1 . 14.0 mg ( 59% isolated yield ) following chromatographic purification ( etoac / ch2cl2 , 20:80 ) ; initial lc / ms purity 77% , tr = 5.66 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.99 ( dd , j = 14.2 hz , j = 7.4 hz , 1h ) , 3.16 ( dd , j = 14 hz , j = 5.2 hz , 1h ) , 3.72 ( s , 3h ) , 4.99 ( dd , j = 12.0 hz , j = 7.2 hz , 1h ) , 6.19 ( d , j = 7.6 hz , 1h ) , 7.147.35 ( m , 18h ) , 7.52 ( d , j = 7.6 hz , 1h ) ; lc / ms calcd for c31h26n2o3 [ m + h ] 475.2 ; found 475.2 . 17.9 mg ( 76% isolated yield ) following chromatographic purification ( etoac / ch2cl2 , 20:80 ) ; initial lc / ms purity 75% , tr = 5.66 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  3.02 ( dd , j = 14.1 hz , j = 7.3 hz , 1h ) , 3.19 ( dd , j = 13.9 hz , j = 5.3 hz , 1h ) , 3.72 ( s , 3h ) , 5.01 ( dd , j = 14.0 hz , j = 7.2 hz , 1h ) , 6.20 ( d , j = 7.6 hz , 1h ) , 7.02 ( d , j = 8.2 hz , 2h ) , 7.157.28 ( m , 15h ) , 7.47 ( d , j = 8.4 hz , 2h ) ; lc / ms calcd for c31h26n2o3 [ m + h ] 475.2 ; found 475.2 . 17.3 mg ( 60% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 84% , tr = 6.27 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.953.10 ( m , 1h ) , 3.29 ( dd , j = 14.2 hz , j = 7.4 hz , 1h ) , 3.74 ( s , 3h ) , 4.93 ( m , 1h ) , 6.32 ( d , j = 7.6 hz , 1h ) , 6.917.25 ( m , 18h ) , 7.79 ( d , j = 7.0 hz , 1h ) ; lc / ms calcd for c30h26ino3 [ m + h ] 576.1 ; found 576.1 . 15.9 mg ( 55% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 81% , tr = 6.38 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.87 ( dd , j = 14 hz , j = 7.6 hz , 1h ) , 3.07 ( dd , j = 14.1 hz , j = 5.3 hz , 1h ) , 3.71 ( s , 3h ) , 4.94 ( dd , j = 14 hz , j = 7.6 hz , 1h ) , 6.13 ( d , j = 7.4 hz , 1h ) , 6.63 ( d , j = 8.2 hz , 2h ) , 7.12  7.27 ( m , 15h ) , 7.50 ( d , j = 8.2 hz , 2h ) ; lc / ms calcd for c30h26ino3 [ m + h ] 576.1 ; found 576.1 . 3.9 mg ( 8% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) of pooled duplicate samples ; initial lc / ms purity 24%25% , tr = 6.07 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.913.12 ( m , 2h ) , 3.43 ( s , 3h ) , 3.72 ( s , 3h ) , 4.754.85 ( m , 1h ) , 6.59 ( d , j = 6.6 hz , 1h ) , 6.727.10 ( m , 4h ) , 7.117.29 ( m,15h ) ; lc / ms calcd for c31h29no4 [ m + h ] 480.2 ; found 480.2 . 12.0 mg ( 25% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) of pooled duplicate samples ; initial lc / ms purity 37%38% , tr = 5.97 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.88 ( dd , j = 13.9 hz , j = 8.1 hz , 1h ) , 3.12 ( dd , j = 14.1 hz , j = 5.3 hz , 1h ) , 3.69 ( s , 3h ) , 3.72 ( s,3h ) , 4.874.97 ( m , 1h ) , 6.17 ( d , j = 7.2 hz , 1h ) , 6.456.78 ( m , 4h ) , 7.067.29 ( m,15h ) . lc / ms calcd for c31h29no4 [ m + h ] 480.2 ; found 480.2 . 12.0 mg ( 25% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) of pooled duplicate samples ; initial lc / ms purity 38%46% , tr = 5.94 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.86 ( dd , j = 14.2 hz , j = 7.6 hz , 1h ) , 3.05 ( dd , j = 14.1 hz , j = 5.1 hz , 1h ) , 3.71 ( s , 3h ) , 3.78 ( s , 3h ) , 4.854.96 ( m , 1h ) , 6.15 ( d , j = 7.6 hz , 1h ) , 6.686.82 ( m , 4h ) , 7.127.26 ( m,15h ) ; lc / ms calcd for c31h29no4 [ m + h ] 480.2 ; found 480.2 . 14.7 mg ( 64% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 97% , tr = 6.21 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.31 ( s , 3h ) , 2.87 ( dd , j = 14.0 hz , j = 7.6 hz , 1h ) , 3.07 ( dd , j = 14.0 hz , j = 5.0 hz , 1h ) , 3.71 ( s , 3h ) , 4.864.96 ( m , 1h ) , 6.15 ( d , j = 7.2 hz , 1h ) , 6.76 ( d , j = 7.8 hz , 2h ) , 6.99 ( d , j = 7.8 hz , 2h ) , 7.127.25 ( m , 15h ) ; lc / ms calcd for c34h29no3 [ m + h ] 464.2 ; found 464.2 . 8.8 mg ( 35% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 64% , tr = 6.31 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  3.263.74 ( m , 2h ) , 3.67 ( s , 3h ) , 5.02 ( dd , j = 15.0 hz , j = 7.0 hz , 1h ) , 6.23 ( d , j = 6.8 hz , 1h ) , 6.957.51 ( m , 19h ) , 7.80 ( m , 2h ) , 8.00 ( d , j = 7.6 hz , 1h ) ; lc / ms calcd for c30h26brno3 [ m + h ] 500.2 ; found 500.2 . 17.7 mg ( 71% isolated yield ) following chromatographic purification ( etoac / hexanes , 15:85 ) ; initial lc / ms purity 88% , tr = 6.32 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  3.05 ( dd , j = 14.1 hz , j = 8.1 hz , 1h ) , 3.33 ( dd , j = 13.9 hz , j = 5.1 hz , 1h ) , 3.74 ( s , 3h ) , 4.975.07 ( m , 1h ) , 6.17 ( d , j = 7.0 hz , 1h ) , 7.077.33 ( m , 15h ) , 7.447.83 ( m , 7h ) ; lc / ms calcd for c34h29no3 [ m + h ] 500.2 ; found 500.2 . 18.3 mg ( 79% isolated yield ) following chromatographic purification ( ch2cl2/etoac / hexanes , 10:15:75 to 20:20:60 ) of pooled duplicate samples ; initial lc / ms purity 86 , 87% , tr = 5.92 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.742.78 ( m , 2h ) , 3.52 ( d , j = 15.0 hz , 1h ) , 3.56 ( s , 3h ) , 3.66 ( d , j = 15.0 hz , 1h ) , 4.59 ( dd , j = 14 hz , j = 6.2 hz , 1h ) , 5.40 ( d , j = 7.4 hz , 1h ) , 6.826.87 ( m , 2h ) , 7.187.29 ( m , 18h ) ; lc / ms calcd for c31h29no3 [ m + h ] 464.2 ; found 464.2 . 12.6 mg ( 52% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) ; initial lc / ms purity 83% , tr = 5.91 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.792.84 ( m , 2h ) , 3.57 ( d , j = 14.8 hz , 1h ) , 3.58 ( s , 3h ) , 3.63 ( d , j = 14.8 hz , 1h ) , 4.56 ( dd , j = 13.5 hz , j = 6.4 hz , 1h ) , 5.44 ( d , j = 7.0 hz , 1h ) , 6.857.26 ( m , 19h ) ; lc / ms calcd for c31h28fno3 [ m + h ] 482.2 ; found 482.2 . 7.7 mg ( 32% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) ; initial lc / ms purity 70% , tr = 5.95 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.732.79 ( m , 2h ) , 3.54 ( d , j = 15.2 hz , 1h ) , 3.58 ( s , 3h ) , 3.67 ( d , j = 15.2 hz , 1h ) , 4.60 ( dd , j = 13.4 hz , j = 6.2 hz , 1h ) , 5.40 ( d , j = 7.0 hz , 1h ) , 6.546.93 ( m , 3h ) , 7.097.30 ( m , 16h ) ; lc / ms : calcd for c31h28fno3 [ m + h ] 482.2 ; found 482.2 . 18.1 mg ( 75% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) ; initial lc / ms purity 83% , tr = 5.93 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.712.76 ( m , 2h ) , 3.53 ( d , j = 14.6 hz , 1h ) , 3.57 ( s , 3h ) , 3.67 ( d , j = 14.6 hz , 1h ) , 4.58 ( dd , j = 13.4 hz , j = 6.0 hz , 1h ) , 5.39 ( d , j = 7.2 hz , 1h ) , 6.756.92 ( m , 4h ) , 7.167.30 ( m , 15h ) ; lc / ms : calcd for c31h28fno3 [ m + h ] 482.2 ; found 482.2 . 16.6 mg ( 63% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 ) ; initial lc / ms purity 89% , tr = 6.13 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.662.93 ( m , 2h ) , 3.51 ( d , j = 15.0 hz , 1h ) , 3.52 ( s , 3h ) , 3.66 ( d , j = 15.2 hz , 1h ) , 4.60 ( dd , j = 15.0 hz , j = 7.6 hz , 1h ) , 5.41 ( d , j = 7.6 hz , 1h ) , 7.127.43 ( m , 18h ) , 7.59 ( d , j = 7.2 hz , 1h ) ; lc / ms calcd for c32h29f3no3 [ m + h ] 532.2 ; found 532.2 . 5.7 mg ( 22% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 ) ; initial lc / ms purity 72% , tr = 6.21 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.702.91 ( m , 2h ) , 3.54 ( d , j = 14.8 hz , 1h ) , 3.56 ( s , 3h ) , 3.66 ( d , j = 15.0 hz , 1h ) , 4.61 ( dd , j = 13.3 hz , j = 6.3 hz , 1h ) , 5.39 ( d , j = 7.2 hz , 1h ) , 7.05 ( d , j = 7.6 hz , 1h ) , 7.147.35 ( m , 17h ) , 7.47 ( d , j = 7.6 hz , 1h ) ; lc / ms calcd for c32h29f3no3 [ m + h ] 532.2 ; found 532.2 . 18.5 mg ( 70% isolated yield ) following chromatographic purification ( etoac / hexanes in ch2cl2 , 4:46:50 ) ; initial lc / ms purity 80% , tr = 6.22 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.702.97 ( m , 2h ) , 3.54 ( d , j = 15.0 hz , 1h ) , 3.58 ( s , 3h ) , 3.68 ( d , j = 15.0 hz , 1h ) , 4.64 ( dd , j = 13.4 hz , j = 6.0 hz , 1h ) , 5.39 ( d , j = 7.4 hz , 1h ) , 6.95 ( d , j = 8.0 hz , 2h ) , 7.107.35 ( m , 15h ) , 7.43 ( d , j = 8.0 hz , 2h ) ; lc / ms calcd for c32h29f3no3 [ m + h ] 532.2 ; found 532.2 . 8.8 mg ( 33% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 ) ; initial lc / ms purity 94% , tr = 6.11 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.77 ( dd , j = 14.1 hz , j = 7.5 hz , 1h ) , 2.92 ( dd , j = 14.1 hz , j = 6.7 hz , 1h ) , 3.54 ( d , j = 14.8 hz , 1h ) , 3.57 ( s , 3h ) , 3.63 ( d , j = 14.8 hz , 1h ) , 4.60 ( dd , j = 14.5 hz , j = 7.3 hz , 1h ) , 5.39 ( d , j = 7.2 hz , 1h ) , 6.93 ( d , j = 7.0 hz , 1h ) , 7.007.30 ( m , 17h ) , 7.50 ( d , j = 7.8 hz , 1h ) ; lc / ms : calcd for c31h29brno3 [ m + h ] 542.1 ; found 542.2 . 8.5 mg ( 31% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 ) ; initial lc / ms purity 84% , tr = 6.21 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.602.85 ( m , 2h ) , 3.54 ( d , j = 15.2 hz , 1h ) , 3.58 ( s , 3h ) , 3.67 ( d , j = 15.2 hz , 1h ) , 4.59 ( dd , j = 13.3 hz , j = 6.3 hz , 1h ) , 5.38 ( d , j = 7.2 hz , 1h ) , 6.79 ( d , j = 7.8 hz , 1h ) , 6.957.40 ( m , 18h ) ; lc / ms calcd for c31h29brno3 [ m + h ] 542.1 ; found 542.2 . 12.9 mg ( 48% isolated yield ) following chromatographic purification ( etoac / hexanes in ch2cl2 , 4:46:50 ) ; initial lc / ms purity 87% , tr = 6.23 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.602.90 ( m , 2h ) , 3.53 ( d , j = 15.0 hz , 1h ) , 3.57 ( s , 3h ) , 3.67 ( d , j = 15.0 hz , 1h ) , 4.59 ( dd , j = 13.3 hz , j = 6.3 hz , 1h ) , 5.38 ( d , j = 7.4 hz , 1h ) , 6.70 ( d , j = 8.4 hz , 2h ) , 7.107.38 ( m , 17h ) ; lc / ms calcd for c31h29brno3 [ m + h ] 542.1 ; found 542.2 . 7.5 mg ( 31% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) ; initial lc / ms purity 78% , tr = 5.67 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.622.91 ( m , 2h ) , 3.55 ( d , j = 15.2 hz , 1h ) , 3.58 ( s , 3h ) , 3.67 ( d , j = 15.2 hz , 1h ) , 4.62 ( dd , j = 12.9 hz , j = 6.1 hz , 1h ) , 5.42 ( d , j = 7.2 hz , 1h ) , 7.057.39 ( m , 18h ) , 7.50 ( d , j = 7.8 hz , 1h ) ; lc / ms calcd for c32h29n2o3 [ m + h ] 489.2 ; found 489.2 . 19.1 mg ( 78% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) ; initial lc / ms purity 76% , tr = 5.65 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.77 ( dd , j = 13.9 hz , j = 6.1 hz , 1h ) , 2.87 ( dd , j = 13.9 hz , j = 6.1 hz , 1h ) , 3.54 ( d , j = 15.0 hz , 1h ) , 3.57 ( s , 3h ) , 3.68 ( d , j = 15.0 hz , 1h ) , 4.63 ( dd , j = 13.3 hz , j = 6.3 hz , 1h ) , 5.41 ( d , j = 7.4 hz , 1h ) , 6.96 ( d , j = 8.4 hz , 2h ) , 7.107.38 ( m , 15h ) , 7.46 ( d , j = 8.4 hz , 2h ) ; lc / ms calcd for c32h29n2o3 [ m + h ] : 489.2 ; found 489.3 . 18.9 mg ( 64% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 ) ; initial lc / ms purity 86% , tr = 6.18 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.74 ( dd , j = 14.2 hz , j = 7.6 hz , 1h ) , 2.89 ( dd , j = 14.1 hz , j = 6.9 hz , 1h ) , 3.54 ( d , j = 15.2 hz , 1h ) , 3.57 ( s , 3h ) , 3.64 ( d , j = 15.2 hz , 1h ) , 4.60 ( dd , j = 14.7 , hz , j = 7.3 hz , 1h ) , 5.37 ( d , j = 7.2 hz , 1h ) , 6.92 ( d , j = 7.6 hz , 2h ) , 7.087.40 ( m , 16h ) , 7.78 ( d , j = 7.8 hz , 1h ) ; lc / ms calcd for c31h29ino3 [ m + h ] 590.1 ; found 590.1 . 19.6 mg ( 67% isolated yield ) following chromatographic purification ( etoac / hexanes in ch2cl2 , 4:46:50 ) ; initial lc / ms purity 81% , tr = 6.31 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.592.82 ( m , 2h ) , 3.53 ( d , j = 15.2 hz , 1h ) , 3.57 ( s , 3h ) , 3.67 ( d , j = 15.2 hz , 1h ) , 4.59 ( dd , j = 13.4 hz , j = 6.0 hz , 1h ) , 5.38 ( d , j = 7.4 hz , 1h ) , 6.58 ( d , j = 8.2 hz , 2h ) , 7.107.32 ( m , 15h ) , 7.49 ( d , j = 8.2 hz , 2h ) ; lc / ms calcd for c31h29ino3 [ m + h ] 590.1 ; found 590.1 . 4.3 mg ( 9% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) of pooled duplicate samples ; initial lc / ms purity 40%42% , tr = 5.96 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.732.76 ( m , 2h ) , 3.43 ( d , j = 15.0 hz , 1h ) , 3.56 ( s , 3h ) , 3.63 ( d , j = 15.0 hz , 1h ) , 3.73 ( s , 3h ) , 4.47 ( dd , j = 13.6 hz , j = 6.8 hz , 1h ) , 5.58 ( d , j = 6.6 hz , 1h ) , 6.796.81 ( m , 3h ) , 7.147.26 ( m , 16h ) ; lc / ms calcd for c32h31no4 [ m + h ] 494.2 ; found 494.3 . 4.3 mg ( 17% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) ; initial lc / ms purity 61% , tr = 5.90 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.702.75 ( m , 2h ) , 3.53 ( d , j = 15.2 hz , 1h ) , 3.57 ( s , 3h ) , 3.65 ( d , j = 15.2 hz , 1h ) , 3.74 ( s , 3h ) , 4.58 ( dd , j = 14.0 hz , j = 6.2 hz , 1h ) , 5.39 ( d , j = 7.4 hz , 1h ) , 6.416.45 ( m , 2h ) , 6.736.76 ( m , 1h ) , 7.067.63 ( m , 16h ) ; lc / ms calcd for c31h29no3 [ m + h ] 494.2 ; found 494.3 . 4.0 mg ( 16% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 to 15:85 ) ; initial lc / ms purity 57% , tr = 5.86 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.692.71 ( m , 2h ) , 3.52 ( d , j = 15.2 hz , 1h ) , 3.57 ( s , 3h ) , 3.66 ( d , j = 15.2 hz , 1h ) , 3.77 ( s , 3h ) , 4.55 ( dd , j = 13.4 hz , j = 6.2 hz , 1h ) , 5.38 ( d , j = 7.4 hz , 1h ) , 6.74 ( m , 4h ) , 7.187.26 ( m , 15h ) ; lc / ms : calcd for c31h29no3 [ m + h ] 494.2 ; found 494.3 . 9.5 mg ( 40% isolated yield ) following chromatographic purification ( etoac / hexanes , 8:92 ) ; initial lc / ms purity 100% , tr = 6.12 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.30 ( s , 3h ) , 2.602.81 ( m , 2h ) , 3.52 ( d , j = 15.2 hz , 1h ) , 3.57 ( s , 3h ) , 3.65 ( d , j = 15.2 hz , 1h ) , 4.56 ( dd , j = 13.2 hz , j = 6.2 hz , 1h ) , 5.39 ( d , j = 7.6 hz , 1h ) , 6.73 ( d , j = 7.8 hz , 2h ) , 6.99 ( d , j = 7.8 hz , 2h ) , 7.107.32 ( m , 15h ) ; lc / ms calcd for c32h32no3 [ m + h ] 478.2 ; found 478.3 . 5.0 mg ( 20% isolated yield ) following chromatographic purification ( etoac / hexanes in ch2cl2 , 4:46:50 ) ; initial lc / ms purity 80% , tr = 6.23 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  3.033.31 ( m , 2h ) , 3.45 ( s , 3h ) , 3.57 ( s , 2h ) , 4.68 ( dd , j = 14.0 hz , j = 7.0 hz , 1h ) , 5.43 ( d , j = 7.0 hz , 1h ) , 6.94 ( d , j = 6.8 hz , 1h ) , 7.078.00 ( m , 21h ) ; lc / ms calcd for c35h32no3 [ m + h ] 514.2 ; found 514.3 . 14.7 mg ( 57% isolated yield ) following chromatographic purification ( etoac / hexanes in ch2cl2 , 4:46:50 ) ; initial lc / ms purity 87% , tr = 6.26 min ; h nmr ( 200 mhz , 10% cd3od / cdcl3 )  2.803.21 ( m , 2h ) , 3.52 ( d , j = 15.2 hz , 1h ) , 3.56 ( s , 3h ) , 3.66 ( d , j = 15.2 hz , 1h ) , 4.71 ( dd , j = 13.4 hz , j = 6.2 hz , 1h ) , 5.39 ( d , j = 7.4 hz , 1h ) , 7.00 ( d , j = 6.8 hz , 1h ) , 7.02  7.82 ( m , 21h ) ; lc / ms calcd for c35h32no3 [ m + h ] 514.2 ; found 514.3 .
for the successful implementation of distributed drug discovery ( d3 ) ( outlined in the accompanying perspective ) , students , in the course of their educational laboratories , must be able to reproducibly make new , high quality , molecules with potential for biological activity . 
 this article reports the successful achievement of this goal . 
 using previously rehearsed alkylating agents , students in a second semester organic chemistry laboratory performed a solid - phase combinatorial chemistry experiment in which they made 38 new analogs of the most potent member of a class of antimelanoma compounds . 
 all compounds were made in duplicate , purified by silica gel chromatography , and characterized by nmr and lc / ms . as a continuing part of the distributed drug discovery program , a virtual d3 catalog based on this work 
 was then enumerated and is made freely available to the global scientific community .