the invention is described herein in detail using the terms defined below unless otherwise specified . when any variable ( e . g . aryl , heterocycle , r 1 , r etc .) occurs more than one time in any constituent , its definition on each occurrence is independent at every other occurrence . also , combinations of substituents / or variables are permissible only if such combinations result in stable compounds . the term “ alkyl ” refers to a monovalent alkane ( hydrocarbon ) derived radical containing from 1 to 10 carbon atoms unless otherwise defined . it may be straight , branched or cyclic . preferred alkyl groups include methyl , ethyl , propyl , isopropyl , butyl , t - butyl , cyclopentyl and cyclohexyl . when the alkyl group is said to be substituted with an alkyl group , this is used interchangeably with “ branched alkyl group ”. cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms , unless otherwise specified , without alternating or resonating double bonds between carbon atoms . it may contain from 1 to 4 rings that are fused . examples of cycloalkyl groups are cyclopropyl , cyclobutyl , cyclopentyl , cyclohexyl , and cycloheptyl . heterocycloalkyl is intended to mean cycloalkyl ring groups which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of n , o , and s , and including any bicyclic . said heterocycloalkyl can optionally be substituted with 1 to 3 groups of r a described herein . examples of heterocycloalkyls are oxane , methyloxane , dioxane , pyran , thiolane , piperidine , pyrrolidine , aziridine , azetidine , etc . alkoxy refers to c 1 - c 6 alkyl - o —, with the alkyl group optionally substituted as described herein . examples of alkoxy groups are methoxy , ethoxy , propoxy , butoxy and isomeric groups thereof . halo is short for halogen and refers to chloride , fluoride , bromide and iodide . as used herein , “ aryl ” is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring , wherein at least one ring is aromatic . examples of such aryl elements include phenyl , naphthyl , tetrahydronaphthyl , indanyl , biphenyl , phenanthryl , anthryl or acenaphthyl . the term heterocyclyl or heterocyclic , as used herein , represents a stable 5 - to 7 - membered monocyclic or stable 8 - to 11 - membered bicyclic heterocyclic ring which is either saturated or unsaturated , and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of n , o , and s , and including any bicyclic group in which any of the above - defined heterocyclic rings is fused to a benzene ring . the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure . a fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring . the term heterocycle or heterocyclic includes heteroaryl moieties . examples of such heterocyclic elements include , but are not limited to , azepinyl , benzimidazolyl , benzisoxazolyl , benzofurazanyl , benzopyranyl , benzothiopyranyl , benzofuryl , benzothiazolyl , benzothienyl , benzoxazolyl , chromanyl , cinnolinyl , dihydrobenzofuryl , dihydrobenzothienyl , dihydrobenzothiopyranyl , dihydrobenzothiopyranyl sulfone , 1 , 3 - dioxolanyl , furyl , imidazolidinyl , imidazolinyl , imidazolyl , indolinyl , indolyl , isochromanyl , isoindolinyl , isoquinolinyl , isothiazolidinyl , isothiazolyl , isothiazolidinyl , morpholinyl , naphthyridinyl , oxadiazolyl , 2 - oxoazepinyl , oxazolyl , 2 - oxopiperazinyl , 2 - oxopiperdinyl , 2 - oxopyrrolidinyl , piperidyl , piperazinyl , pyridyl , pyrazinyl , pyrazolidinyl , pyrazolyl , pyridazinyl , pyrimidinyl , pyrrolidinyl , pyrrolyl , quinazolinyl , quinolinyl , quinoxalinyl , tetrahydrofuryl , tetrahydroisoquinolinyl , tetrahydroquinolinyl , thiamorpholinyl , thiamorpholinyl sulfoxide , thiazolyl , thiazolinyl , thienofuryl , thienothienyl , thienyl and triazolyl . as used herein , “ heteroaryl ” is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring , wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of n , o , and s . examples of such heterocyclic elements include , but are not limited to , benzimidazolyl , benzisoxazolyl , benzofurazanyl , benzopyranyl , benzothiopyranyl , benzofuryl , benzothiazolyl , benzothienyl , benzoxazolyl , chromanyl , cinnolinyl , dihydrobenzofuryl , dihydrobenzofuranyl , dihydrobenzothienyl , dihydrobenzothiopyranyl , dihydrobenzothiopyranyl sulfone , furyl , imidazolyl , indolinyl , indolyl , isochromanyl , isoindolinyl , isoquinolinyl , isothiazolyl , naphthyridinyl , oxadiazolyl , pyridyl , pyrazinyl , pyrazolyl , pyridazinyl , pyrimidinyl , pyrrolyl , quinazolinyl , quinolinyl , quinoxalinyl , tetrahydroisoquinolinyl , tetrahydroquinolinyl , thiazolyl , thienofuryl , thienothienyl , thienyl and triazolyl . this invention also relates to a process for making a compound of formula iii , formula iiia or mixture thereof : in the presence of an acid such as methanesulfonic acid , ptsoh , csa , phso 3 h , phosphoric acids , tfa , acoh , h 2 so 4 and hcl ; acidic reagents such as pocl 3 and the like are also effective , ( 2 ) heating to a temperature of about 100 ° c . to about 125 ° c ., preferably about 105 ° c . to about 117 ° c . for about one to about 30 hours , preferably about 12 to about 28 hours , to produce a compound of formula vi ; ( 3 ) asymmetrically hydrogenating a compound of formula vi in the presence of a metal catalyst and ligand to produce a compound of formula iii , iiia , or mixture thereof , wherein r 3 and r 4 are as described herein , y represents or 4 or nhoh ; and r 4a represents h , c 1 - 4 alkyl , magnesium , lithium , sodium , or potassium and wherein y is nhoh only after further derivation as shown herein . the reaction of combining the compounds of formula iv and v is generally conducted using solvents such as toluene , benzene , heptane , hexane , thf and acetonitrile . when solvents such as toluene are used high - boiling co - solvents such as diethylene glycol diethylether or a solubilizing solvent such as dmac or dmf can be added . after step ( 2 ) the reaction can be cooled to a temperature of about 10 ° c . to about 1 ° c . before conducting step ( 3 ). one embodiment of this invention is realized when the ligand is a chiral monodentate or polydentate , which optionally can possess an alkylated or arylated phosphine . examples of ligands are tetrame - bitiop -( tmbtp — see benincori , t . ; cesarotti , e . ; piccolo , o . ; sannicolo , f . j . org . chem ., 2000 , 65 , 2043 - 2047 for full name ); ( s )- me - f - ketalphos -(( 3as , 3 ′ as , 4s , 4 ′ s , 6s , 6 ′ s , 6as , 6 ′ as )- 5 , 5 ′-[ 1 , 1 ′ ferrocenyl ] bis [ tetrahydro - 2 , 2 , 4 , 6 - tetramethyl - 4h - phospholo [ 3 , 4 - d ]- 1 , 3 - dioxole ] see liu , d . ; li , w . ; zhang , x . organic letters , 2002 , 4 , 4471 - 4474 ); ( s )- binap ; ( r , r )- et - ferrotane ; ( r )- xylbinap ; ( r )- phanephos ; ( s )- binaphane ; ( r )- xylphanephos ; ( r , s )- tangphos ; ( s )- me - bophoz ; ( s , s )- norphos ; ( r , r )- me - duphos ; ( r )—( s )-(( diphenylphosphino ) ferrocenyl - ethyldicyclohexylphosphine ); (( r )—( s )-(( diphenylphosphino ) ferrocenyl - ethyldi - t - butylphosphine ) see togni , a . ; breutel , c . ; schnyder , a . ; spindler , f . ; landert , h . ; tijani , a . j . am . chem . soc ., 1994 , 116 , 4062 - 4066 ); ( r , s )-(( di - t - butylphosphino ) ferrocenyl - ethyldi - 3 , 5 - dimethylphenylphosphine ); ( s )—( r )-(( diphenylphosphino ) ferrocenyl - ethyldicyclohexylphosphine ), (( s )—( r )-(( diphenylphosphino ) ferrocenyl - ethyldi - t - butylphosphine )), and ( s )—( r )-(( di - t - butylphosphino ) ferrocenyl - ethyldi - 3 , 5 - dimethylphenylphosphine ) preferably ( r )—( s )-(( diphenylphosphino ) ferrocenyl - ethyldi - t - butylphosphine or (−)- tmbtp . (−)- tmbtp and ( r )—( s )-(( diphenylphosphino ) ferrocenyl - ethyldi - t - butylphosphine phosphine ligands can be obtained from chemi s . p . a . and solivas , respectively . still another embodiment of this invention is when the metal catalyst is iridium , rhodium or ruthenium with the appropriate counterions , preferably ruthenium . examples of ruthenium catalysts are those derived from [( arene ) rux 2 ] 2 + bisphosphine or ( p — p ) rux 2 . specific examples of the catalysts are [( p - cymene ) rucl 2 ] 2 , rucl 2 ( dmf ) x , [ rh ( cod ) cl ] 2 , [ rh ( nbd ) cl ] 2 , [ rh ( cod ) 2 ] x , rh ( acac )( co ) 2 , rh ( ethylene ) 2 ( acac ), rh ( co ) 2 cl 2 , ru ( rcoo ) 2 ( diphosphine − r = alkyl or aryl ), ru ( methallyl ) 2 ( diphosphine ), ru ( cod )( methallyl ) 2 , rucl 2 ( cod ), rux 2 ( diphosphine ), [ ir ( cod ) cl ] 2 , [ ir ( cod ) 2 ] x , wherein x = halogen , bf 4 , cio 4 , sbf 6 , cf 3 so 3 , pf 6 . it is preferably that the metal catalyst and ligand are added as a complex . examples of metal catalyst / ligand complexes are (( r )—( s )-(( diphenylphosphino ) ferrocenyl - ethyldi - t - butylphosphine )( cod ) rhbf4 , (( r , r )- me - bpe ) rh ( cod ) otf , (( r )—( s )-(( diphenylphosphino ) ferrocenyl - ethyldi - t - butylphosphine ) rucl ( p - cymene )] cl , [((−)- tmbtp ) rucl ( p - cymene )] cl , (( s )—( r )-(( diphenylphosphino ) ferrocenyl - ethyldi - t - butylphosphine ) rucl ( p - cymene )] cl , [((+)- tmbtp ) rucl ( p - cymene )] cl , (( r )- binap ) ru ( p - cymene ) cl ] cl , [( s )- tol - binap ) rucl 2 * et 3 n ] 2 , (( s )- binap ) rucl 2 , , and (( r , r )- me - duphos ) rh ( cod ) bf 4 . a preferred metal catalyst - ligand complex is (( r )—( s )-(( diphenylphosphino ) ferrocenyl - ethyldi - t - butylphosphine ) rucl ( p - cymene )] cl . the catalyst can be prepared by contacting a transition metal salt or its complex and a ligand as described above . the catalyst may be prepared in situ or as an isolated compound . another embodiment of this invention is when the hydrogenation is optionally conducted in the presence of a base selected from the group consisting of primary amines such as methylamine , secondary amines such as diisopropyl amine , trialkyl amines such as triethylamine , trimethylamine , dicyclohexylmethylamine , tri - n - butylamine , and the like , alkali metal hydrides such as sodium hydride , potassium hydrogen carbonate , k 2 co 3 , potassium tert - butoxide or the equivalent lithium sodium and cesium salts and the like , using h 2 , d 2 or t 2 , preferably h 2 and solvents such as alcohols ( e . g ., ethanol , methanol , 2 - butanol , isopropanol , trifluoroethanol and the like ), thf , ethylacetate , toluene and the like , preferably the alcohols . a sub - embodiment of the process as recited above is where the hydrogenation step is carried out using a mole ratio of metal catalyst to the compound of formula ii of about 0 . 1 % to about 5 %, preferably about 0 . 25 to about 1 mole %, at a temperature of about 0 ° c . to about 60 ° c ., preferably about about 25 ° c . to about 35 ° c . still another sub - embodiment of this invention is realized when the metal catalyst - ligand complex is [(( r )—( s )-(( diphenylphosphino ) ferrocenyl - ethyldi - t - butylphosphine ) rucl ( p - cymene )] cl , [(( s )—( r )-(( diphenylphosphino ) ferrocenyl - ethyldi - t - butylphosphine ) rucl ( p - cymene )] cl , [((−)- tmbtp ) rucl ( p - cymene )] cl , or (+)- tmbtp ) rucl ( p - cymene )] cl . this invention further relates to a process for making a compound of formula iv : ( 1 ) contacting a solution containing a compound of formula vii or salt thereof : ( 2 ) adding a dialkyloxalate ; and ( 3 ) adding an acid while maintaining the temperature at about or below 10 ° c . to produce a compound of formula iv as an ester ( r 4 is c 1 - 4 alkyl ), or adding a base to produce the compound of formula iv as an acid ( r 4 is hydrogen ), wherein r 4 represents h , c 1 - 4 alkyl , and r 4a represents h , c 1 - 4 alkyl , magnesium , lithium or sodium . generally , the strong base is added to the solution at a temperature of about − 20 ° c . to about 5 ° c ., preferably 10 ° c . to about 0 ° c . solutions of formula vii can comprise solvents such as thf , ether and the like . the dialkyloxalate is generally added at a temperature of about − 30 ° c . to about − 0 ° c ., preferably about − 20 ° c . to about − 5 ° c . examples of salts of formula vii are magnesium , lithium , potassium and sodium , wherein r 4a is mg , li or na for this particular reaction . examples of strong bases are alkyl magnesium halides such as iprmgcl , prmgcl , etmgcl , memgcl , lda , mg diisopropylamide , and sodium , potassium or lithium hydride and the like . examples of the dialkyloxalate are dimethyloxalate , diethyloxoate and the like . examples of acids are tfa , hcl , h 2 so 4 and the like . examples of bases that are added to provide r 4 = acid are naoh , lioh , koh and the like . this invention also relates to a process for making a compound of formula iii , iiia or mixture thereof as recited above or a pharmaceutically acceptable salt thereof , comprising in the presence of a rhodium or ruthenium catalyst / ligand complex to produce a compound of formula ixa , ixb or a mixture thereof ; ( 2 ) hydrogenolysis of a compound of formula ixa , ixb or a mixture thereof in the presence of a palladium catalyst to produce a compound of formula viii , viiia , a pharmaceutically acceptable salt or mixture thereof , wherein p * is an acid selected from the group consisting of hcl , hi , hbr , acetic acid , tfa , ptsa , and hbf4 ; ( 3 ) coupling the compound of formula viii or viiia or mixture thereof with compound of formula ix ( 4 ) hydrolyzing and purifying the coupled compound to produce a compound of formula iii , iiia or mixture thereof , wherein the base is triethylamine , diisopropylethylamine , tri - n - butylamine , naoh , lioh , koh , nahco 3 , na 2 co 3 and the like , r 3 is as described herein and r 4a represents h , c 1 - 4 alkyl , magnesium , lithium or sodium . examples of rhodium or ruthenium catalyst / ligand complex are (+)- 1 , 2 - bis ( 2r , 5r )- 2 , 5 - dimethylphospholano ) ethane ( cyclooctadiene ) rhodium ( i ) trifluoromethanesulfonate = rh ( cod )( 2r , 5r - bpe ) otf ; (( r , r )- me - duphos ) rh ( cod ) bf 4 ; ( cod ) 2 rhotf /(( r )—( s )-(( diphenylphosphino ) ferrocenyl - ethyldi - t - butylphosphine ), and (( r , r )- me - bpe ) rh ( cod ) otf , [(( r )—( s )-(( diphenylphosphino ) ferrocenyl - ethyldi - t - butylphosphine ) rucl ( p - cymene )] cl , [(( s )—( r )-(( diphenylphosphino ) ferrocenyl - ethyldi - t - butylphosphine ) rucl ( p - cymene )] cl , [((+)- tmbtp ) rucl ( p - cymene )] cl and [((−)- tmbtp ) rucl ( p - cymene )] cl . an example of a palladium catalysts is pd / c . the hydrogenolysis can be conducted using hydrogen gas or a compound which forms hydrogen . the preferred reaction involves h 2 gas with a palladium ( pd / c ) catalyst . if necessary , a base can be added . a preferred base is sodium hydroxide or sodium bicarbonate . suitable pharmaceutically acceptable salts of the compounds used in this invention include acid addition salts such as hydrochloride , hydrobromide , citrate , maleate and salts formed with phosphoric and sulphuric acid . in another aspect suitable salts are base salts such as an alkali metal salt for example sodium or potassium , an alkaline earth metal salt for example calcium or magnesium , an organic amine salt for example triethylamine , morpholine , n - methylpiperidine , n - ethylpiperidine , procaine , dibenzylamine , n , n - dibenzylethylamine or amino acids for example lysine . preferred pharmaceutically acceptable salts are sodium and potassium salts . in vivo hydrolysable esters are those pharmaceutically acceptable esters that hydrolyze in the human body to produce the parent compound . such esters can be identified by administering , e . g . intravenously to a test animal , the compound under test and subsequently examining the test animal &# 39 ; s body fluids . suitable in vivo hydrolysable esters for carboxy include c1 - 6alkoxymethyl esters for example methoxymethyl , c1 - 6 alkanolyloxymethyl esters for example pivaloyloxymethyl , phthalidyl esters and the additional esters disclosed in u . s . pat . no . 5 , 478 , 820 , which is herein incorporated by reference in its entirety . the following non - limiting examples , given by way of illustration , is demonstrative of the present invention . hobt — hydroxybenzotriazole ; dmf — dimethylformamide ; dmac — dimethylacetamide ; diea — diisopropylethylamine ; tmsonh2 — o - trimethylsilylhydroxylamine ; tfa — trifluoroacetic acid ; ptsa — toluenesulfonic acid ; dcm — dichloromethane ; edc — 1 -( 3 - dimethylaminopropyl )- 3 - ethylcarbodiimide ; thf — tetrahydrofuran ; dic — n , n ′ diisopropylcarbodiimide ; dmf — dimethylformamide ; dmap — 4 - dimethylaminopyridine ; nmp — 1 - methyl - 2 - pyrrolidinone ; edta — ethylenediaminetetraacetic acid , sat &# 39 ; d = saturated ; h = hour ; ppm = parts per million ; min = minute ; hplc = high performance liquid chromatography ; rt or rt = room temperature ; temp = temperature ; kf = karl fisher ; nmr = nuclear magnetic resonance ; g = gram ; mtbe = tert - butyl methyl ether ; tea = triethylamine ; l = liter ; ptfe = polytetrafluoroethylene ; ipa = isopropyl alcohol ; ipac = isopropylacetate mixture of chlorosulfonic acid ( 40 ml , 600 mmol ) and 1 , 2 - dichloroethane ( 90 ml ) was cooled to & lt ; 2 ° c . o - fluorotoluene 9 ( 22 . 02 g , 200 mmol ) was added slowly over 3 h at & lt ; 5 ° c . the resulting solution was warmed to rt and was stirred at rt for 4 h . the solution was cooled to & lt ; 0 ° c . heptane ( 200 ml ) was added , followed by 100 ml of water at & lt ; 10 ° c . ( hcl gas generated ). aqueous layer was cut . organic layer was washed with 100 ml of 10 % brine . the organic solution was concentrated at 40 ° c . under 20 mmhg . crude sulfonyl chloride 2 ( 39 . 7 g ) was obtained as oil . by hplc , it was 96 . 9 a %. ( derivatized with piperidine ). the oily 2 was dissolved in 40 ml of heptane . the solution was cooled to 18 ° c . and was seeded . slurry formed and it was cooled to 4 ° c . slowly . filtration afforded some white solid 2 . after vacuum drying , 31 . 55 g solid sulfonyl chloride 2 was obtained . it was 99 . 0 a % and 96 . 2 wt % pure and yield was 73 %. crystalline sulfonyl chloride 2 ( 31 . 52 g , 96 . 2 wt % pure , 145 mmol , 0 . 8 %) from above procedure was dissolved in 190 ml of mtbe . ammonium hydroxide solution ( 28 %, 30 ml ) and water ( 30 ml ) were added . the mixture was stirred for 1 . 5 h . 75 ml of 1 m h 2 so 4 was added . aqueous layer was cut . organic layer was washed with 100 ml of 10 % brine . the organic solution was concentrated to 100 ml and 40 ml of heptane was added . the mixture was heated to 48 ° c . to dissolve all solids . resulting solution was cooled to 40 ° c . and was seeded . slurry formed . 160 ml of heptane was added over 1 h at 40 ° c . the slurry was cooled to rt over 1 h , then was cooled & lt ; 5 ° c . and was aged at & lt ; 5 ° c . for 20 min . filtration afforded some crystalline solid . cake was rinsed with 50 ml of 1 : 2 mtbe / heptane . after vacuum oven drying , 27 . 20 g of sulfonamide 7 was obtained as white crystalline solid . by hplc it was 99 . 9 a % and ˜ 100 wt % ( vs . reference ) pure and yield was 99 %. mp : 98 ° c . 1 h - nmr ( 400 mhz , cd 3 cn ): δ 2 . 32 ( d , 2 . 0 hz , 3h ), 5 . 68 ( broad , 2h ), 7 . 20 ( t , 9 . 1 hz , 1h ), 7 . 70 ˜ 7 . 74 ( m , 1h ), 7 . 78 ˜ 7 . 80 ( m , 1h ). 13 c - nmr ( 100 mhz , cd 3 cn ): δ 13 . 6 ( d , 3 . 9 hz ), 115 . 4 ( d , 24 . 0 hz ), 125 . 9 ( d , 9 . 5 hz ), 126 . 2 ( d , 18 . 4 hz ), 129 . 6 ( d , 6 . 4 hz ), 139 . 0 ( d , 3 . 2 hz ), 163 . 1 ( d , 250 hz ). anal . calcd for c 7 h 8 fno 2 s : ( 189 . 21 ): c , 44 . 44 ; h , 4 . 26 ; s , 16 . 95 . found : c , 44 . 51 ; h , 4 . 05 ; s , 16 . 92 . the mixture of chlorosulfonic acid ( 22 ml , 330 mmol ) and 40 ml of 1 , 2 - dichloroethane was cooled to & lt ; 2 ° c . o - fluorotoluene 9 ( 11 . 0 g , 100 mmol ) was added slowly over 2 h at & lt ; 5 ° c . the resulting mixture was warmed to rt and was stirred at rt for 3 h . the mixture was cooled to & lt ; 0 ° c . heptane ( 100 ml ) was added , followed by 50 ml of water at & lt ; 10 ° c . aqueous layer was cut . organic layer was washed with 50 ml of 20 % brine then , 50 ml of 10 % khco 3 . the organic solution was concentrated at 40 ° c . under 20 mmhg . crude sulfonyl chloride 2 was obtained as greenish color oil . it was 19 . 68 g . by hplc , it was 95 . 7 a % pure . hplc sample was treated 1 drop of piperidine . the oily 2 was dissolved in 150 ml of mtbe . 17 ml of 28 % ammonium hydroxide solution was added . the mixture was stirred for 1 h . internal temperature increased slowly up to 44 ° c ., then decreased . hplc showed & lt ; 0 . 1 % of sulfonyl chloride 2 . 25 ml of 1 m hcl was added . aqueous layer was cut . organic layer was washed with 50 ml of 10 % brine . the organic solution was concentrated to 50 ml . the solution was heated to 45 ° c . and 20 ml of heptane was charged . the mixture was cooled to 43 ° c . and was seeded . slurry formed . 80 ml more of heptane was added over 2 h at 43 ° c . the slurry was cooled to rt slowly and was aged at rt overnight . the slurry was cooled to 0 ˜ 5 ° c . filtration afforded some solid cake . cake was rinsed with 30 ml of 1 : 2 mtbe / heptane . after drying , 16 . 58 g sulfonamide 7 was obtained . the material was dissolved in 30 ml of mtbe and 6 ml of heptane at 49 ° c . the solution was cooled to 45 ° c . and was seeded . a slurry formed and 54ml more heptane was added over 2 h at 45 ° c . the mixture was cooled to rt slowly and was aged at rt overnight . the mixture was cooled to & lt ; 5 ° c . filtration and cake rinse with 2 : 1 heptane / mtbe ( 20 ml ) afforded some solid 7 . after vacuum oven drying at 45 ° c ., 15 . 70 g of sulfonamide 7 was obtained as white solid . by hplc it was 98 . 9 wt % pure . yield was 79 % from 9 . concentrated sulfuric acid ( 1 . 6 l , 1 . 45 vol ) was added to a flask with 1 . 10 l ( 1 . 10 kg , 1 . 0 vol , 10 mol ) of o - fluorotoluene 9 at rt . the mixture was heated to 80 ° c . with agitation ( temperature control is important due to exothermal reaction ). the resulting oil was agitated at 80 ° c . for 3 . 5 h until hplc showed & lt ; 0 . 5 a % of 9 . the resulting oil was cooled to ˜ 75 ° c . and 10 l of cold water ( 9 . 1 vol ) was added quickly . internal temperature rose up to 96 ° c . for a moment , then dropped to 48 ° c . 1 . 1 l of acetonitrile ( 1 . 0 vol ) was added , followed by 2 . 7 kg of solid nacl . the mixture was heated to 73 ° c . to dissolve all solids . the clear solution was cooled to 70 ° c . and was seeded . a slurry formed gradually . the slurry was cooled to rt over ˜ 6 h and was aged at rt for 10 h . it was then cooled to & lt ; 4 ° c . over 1 . 5 h . filtration afforded some crude salt 10 as pink solids . the solid was washed with 3 . 3 l of 20 % brine ( 3 . 0 vol ) to give 4 . 80 kg of wet cake . a portion of the wet solid ( 3 . 60 kg , ¾ of total , ¼ of wet cake was saved for other use ) was mixed with 7 . 5 l of 20 % brine and 825 ml of acetonitrile . the mixture was heated to 71 ° c . to dissolve all solids . the solution was cooled to 70 ° c . and was seeded . a slurry formed gradually . the slurry was cooled to rt over 6 h and was aged at rt for about 10 h . the slurry was cooled to & lt ; 4 ° c . over 30 min and was aged at & lt ; 4 ° c . for 30 min . filtration afforded some pinkish color solid . the cake was washed with 2 . 5 l of 20 % brine . the salt 10 was dried in a vacuum oven at 50 ° c . to give 1 . 56 kg of solid 10 . by hplc it was 99 . 8 a % ( included regio - isomer ) and 83 . 8 wt % pure . yield was 82 % after recrystallization . some product 10 was recrystallized from hot water for analytical purpose . mp : 370 ° c . ( dec .). 1 h - nmr ( 400 mhz , d 2 o ): δ 2 . 23 ( s , 3h ), 7 . 10 ( t , 9 . 2 hz , 1h ), 7 . 54 ˜ 7 . 63 ( m , 2h ). 13 c - nmr ( 100 mhz , d 2 o ): δ 13 . 6 ( d , 1 . 9 hz ), 115 . 2 ( d , 23 . 4 hz ), 125 . 0 ( d , 9 . 4 hz ), 126 . 0 ( d , 18 . 5 hz ), 128 . 8 ( d , 6 . 1 hz ), 138 . 0 ( d , 3 . 2 hz ), 162 . 5 ( d , 248 hz ). anal . calcd for c 7 h 6 fnao 3 s : ( 212 . 17 ): c , 39 . 63 ; h , 2 . 85 ; s , 15 . 11 . found : c , 39 . 33 ; h , 2 . 58 ; s , 15 . 20 . sulfonate 10 ( 87 . 9 wt % pure , 205 . 17 g , 850 mmol , 1 . 0 equiv ) was mixed with 1 . 23 l of mtbe and 20 . 5 ml of dmf at rt . to the slurry was added 93 ml of socl 2 ( 1 . 5 equiv .). the mixture was heated to 40 ° c . and was agitated at 40 ° c . for 3 h until hplc showed 0 . 58 a % of 10 . cold water ( 615 ml ) was added to quench the reaction and dissolve all solids . aq layer was cut . organic layer was washed with 2 × 615 ml of 10 % brine . concentration of organic solution afforded 182 g of oily residue . by hplc , the residue was chloride 2 ( 99 . 8 a % pure ) sample treated with piperidine . the oil was dissolved in heptane ( about 182 ml ) and total volume was diluted to 260 ml . the solution was cooled to 20 ° c . and was seeded . a slurry formed and it was cooled slowly to 3 ° c . over 1 h . the solid was isolated by filtration . after drying under vacuum , 159 . 12 g of sulfonyl chloride 2 was obtained as off - white solid . it was 99 . 9 a % and 97 . 9 wt % pure . yield was 88 % ( 75 % from o - fluorotoluene 9 ) and loss in mother liquor was 9 . 1 %. mp : 37 ° c . 1 h - nmr ( 400 mhz , cdcl 3 ): δ 2 . 40 ( d , 2 . 0 hz , 3h ), 7 . 23 ( t , 8 . 7 hz , 1h ), 7 . 87 ˜ 7 . 94 ( m , 2h ). 13 c - nmr ( 100 mhz , cdcl 3 ): δ 14 . 5 ( d , 3 . 2 hz ), 116 . 4 ( d , 24 . 6 hz ), 127 . 2 ( d , 9 . 8 hz ), 127 . 5 ( d , 19 . 2 hz ), 130 . 7 ( d , 6 . 8 hz ), 139 . 7 ( d , 3 . 2 hz ), 165 . 0 ( d , 258 hz ). anal . calcd for c 7 h 6 clfo 2 s : ( 208 . 64 ): c , 40 . 30 ; h , 2 . 90 ; s , 15 . 37 . found : c , 40 . 41 ; h , 2 . 71 ; s , 15 . 48 . sulfonate 10 ( 83 . 8 wt % pure , 1519 g , 6 . 00 mol , 1 . 0 equiv ) was mixed with 9 . 1 l of mtbe and 151 ml of dmf at rt . to the slurry was added 656 ml of socl 2 ( 1 . 5 equiv ). the mixture was heated to 40 ° c . and was agitated at 40 ° c . for 3 h until hplc showed 0 . 30 a % of 10 . the mixture was cooled to 35 ° c . and 4 . 5 l of cold water were added to quench the reaction . internal temperature increased to 40 ° c ., and then dropped . the mixture was agitated for 5 min and was settled . the aqueous layer was cut and the organic layer was washed with 2 × 4 . 5 l of 10 % brine . the organic solution was vacuum distilled at & lt ; rt adding 9 . 0 l of fresh mtbe to maintain constant volume . after this distillation , there was no so 2 in the solution and 1 . 22 l of 28 % ammonium hydroxide solution and 1 . 22 l of water were added . the mixture was agitated for 1 h . internal temperature increased slowly up to 38 ° c ., then decreased . hplc showed & lt ; 0 . 1 % of sulfonyl chloride 2 . h 2 so 4 ( 1 m , 4 l ) was added . ph of aqueous layer was 1 . the aqueous layer was cut and the organic layer was washed with 4 . 5 l of 10 % khco 3 , then with 4 . 5 l of 10 % brine . the organic solution was concentrated to 3 l . the solution was heated to 45 - 50 ° c . and 0 . 9 l of heptane was charged . the mixture was seeded at 45 ° c . slurry formed . 3 . 6 l more of heptane was added over 1 h at 45 ° c . the slurry was cooled to 2 ° c . over 30 min and was aged at 2 ° c . for 30 min . the product was isolated by filtration . the cake was rinsed with 1 l of 1 : 1 mtbe / heptane . after vacuum oven drying at 45 ° c ., 1063 g of sulfonamide 7 was obtained as white crystalline solid . by hplc it was 99 . 4 a % and about 100 wt % pure and yield was 94 % from sulfonate 10 . 4 - fluoro - 3 - methylaniline 11 ( 12 . 52 g , 100 mmol , 1 . 0 equiv ) was dissolved in 20 ml of acetic acid . water ( 14 ml ) was added . the solution was cooled to 10 ° c . and 26 ml of conc . hcl was added , which generated a slurry . the slurry was cooled to 4 ° c . nano 2 aq ( 7 . 04 g in 12 ml of water , 1 . 02 equiv ) was added slowly at & lt ; 8 ° c . over 30 min . brownish color clear solution formed . the solution was kept at & lt ; 5 ° c . and was slowly added through a ptfe tube to another flask with mixture of 47 g of so 2 , 100 ml of acetic acid , and cucl 2 / conc . hcl solution ( 3 . 40 g / 20 ml ) over 2 . 7 h at rt . after addition , 6 ml of water was used for rinse . the green - yellow color mixture was agitated at rt for another 2 h until hplc showed no diazonium 12 . the mixture was extracted with 3 × 100 ml of heptane and the combined organic solution was washed with 100 ml of 10 % brine . concentration afforded 19 . 72 g of 2 as oil . by hplc , it was 96 . 8 a % and 94 . 2 wt % pure . yield of 2 was 89 %. oily sulfonyl chloride 2 ( 19 . 70 g , 94 . 2 wt % pure , 88 . 9 mmol ) from the above procedure was dissolved in 125 ml of mtbe . ammonium hydroxide solution ( 28 %, 16 ml ) and water ( 16 ml ) were added . the mixture was stirred for 1 . 5 h until hplc showed no 2 . h 2 so 4 ( 1 m , 40 ml ) was added and aqueous layer was cut . organic was washed with 50 ml of 10 % khco 3 , then with 50 ml of 10 % brine . the organic solution was concentrated to 50 ml and the concentrate was heated to 45 ° c . heptane ( 20 ml ) was added at 45 ° c . the solution was seeded and a slurry formed . more heptane ( 80 ml ) was added over 2 h at 45 ° c . the resulting slurry was cooled to rt over 1 h , then was cooled & lt ; 5 ° c . and was aged at & lt ; 5 ° c . for 20 min . filtration afforded some crystalline solid and the cake was rinsed with 30 ml of 1 : 2 mtbe / heptane . there was 2 . 8 % loss of product 7 . after vacuum oven drying , 16 . 06 g of sulfonamide 7 was obtained as white crystalline solid . by hplc , the solid was 99 . 6 a % and 100 wt % ( vs . reference ) pure . the yield of 7 was 95 % from 2 . thp methyl ester 15 ( 3 . 03 kg , 21 mol ) was charged to a mechanically - stirred 22 l round bottom flask , followed by water ( 3 . 0 l ) and this mixture was cooled to 10 ° c . naoh ( 50 wt %, 1 . 15 l , 1 . 04 equiv ) was then added at a rate such that the internal temperature did not exceed 50 ° c . upon completion of the addition , a batch concentrator was used to remove ˜ 1 . 3 l of solvent . the resulting solution was cooled to 10 ° c ., then concentrated hcl ( 300 ml ) was added , followed by mtbe ( 3 . 6 l ), and the remainder of the concentrated hcl ( 1590 ml ), keeping the temperature below 20 ° c . the organic layer was then separated and the aqueous treated with nacl ( 525 g ). the aqueous layer was then extracted with mtbe ( 3 . 6 l ), and the combined organics were filtered to remove residual nacl then stripped to ˜ ½ the original volume . n - heptane ( 1 . 8 l ) was added , followed by batch concentration to remove residual mtbe . more n - heptane ( 1 . 8 l ) was added with vigorous stirring . the resulting thick white solid precipitate was then filtered and dried under n 2 for 1 h , then at 40 ° c . under vacuum for 64 h to give 2 . 47 kg ( 91 % yield ) of thp acid 16 . solvents : 0 to 3 min : 35 % acn , 65 % kh 2 po 4 / k 2 hpo 4 buffer ; 3 to 5 min : 60 % acn , 40 % kh 2 po 4 / k 2 hpo 4 buffer ; 5 to 7 min : 35 % acn , 65 % kh 2 po 4 / k 2 hpo 4 buffer ; flow : 1 . 0 ml / min ; sample volume : 5 μl ; wavelength : 210 nm ; retention times : thp ester 15 : 4 . 6 min ; thp acid 16 : 2 . 1 min . thp acid 16 ( 1 . 0 kg , 7 . 7 mol ) was added to a 22 l round bottom flask with mechanical stirrer and thermocouple , attached to a batch - concentrator . thf ( 3 . 0 l ) was added to dissolve 16 then the solvent was stripped to 1 l . thf ( 2 . 0 l ) was added , and the solvent was again stripped to 1 l . a karl fisher ( kf ) of the mixture was & lt ; 500 ppm . an addition - funnel was then added , and the mixture was cooled to ˜− 30 ° c . iprmgcl ( 2m in thf , 8 . 1 l , 16 . 2 mol ) was then added over 1 h , maintaining the temperature between − 10 ° c . and 0 ° c . diisopropylamine ( 1 . 19 l , 8 . 5 mol ) was then added all at once . this dark solution was then warmed to 35 ° c . and stirred at this temperature for 30 min . vigorous evolution of propane gas was observed . the initial 35 ° c . temperature plateau is designed to complete formation of the magnesium diisopropylamide , without grignard addition to the carboxylate . the reaction mixture was then was warmed to 55 ° c . and stirred for 2 h . an off - white slurry formed after ˜ 30 min at 55 ° c . this mixture was then cooled to − 20 ° c ., and diethyl oxalate ( 1 . 15 l , 8 . 5 mol ) was added over 25 min keeping the temperature below − 5 ° c . after warming to rt over 90 min , the mixture was stirred for 1 h and stored overnight at 3 ° c . aging this solution at rt for 20 h does not result in any significant loss in yield . the resulting solution was cooled to 0 ° c ., then etoh ( 500 ml ) was added over 15 min , forming a light yellow precipitate and giving a slight exotherm . this mixture was cooled to − 10 ° c ., then hcl ( concentrated , 2 . 03 l ) was added carefully over 1 h , so that the internal temperature did not exceed 10 ° c ., with evolution of co 2 . the mixture grew thick upon acid addition , but was easy to stir . off - gassing of co 2 should be carefully controlled by the rate of hcl addition so that the batch does not bump . this mixture was warmed to 50 ° c . for 45 min , then cooled to rt and diluted with water ( 2 . 0 l ) and mtbe ( 1 . 0 l ). all of the solids immediately dissolved . the aqueous layer was then cut , and the organics were diluted with mtbe ( 3 . 0 l ), and the resultant was washed successively with 1 . 0 n hcl ( 2 . 0 l ) and brine ( 20 % sat &# 39 ; d ., 2 . 0 l ). hplc assay yield analysis of 3 using the protocol described below showed : hplc assay yield of α - ketoester 17b . g product % product final organics 1066 74 . 5 aqueous cut 1 77 5 . 4 aqueous cut 2 66 4 . 6 aqueous cut 3 11 0 . 8 total : 1220 85 . 3 due to poor hplc peak shape of the α - ketoester 17b , an analysis was developed using the 2 , 4 - dinitrophenylhydrazine derivative 22 , which showed improved peak shape and uv response . a reference standard of the hydrazone was prepared by mixing 2 , 4 - dinitrophenylhydrazine ( 2 . 50 g , ˜ 70 % pure , 8 . 8 mmol ) and chromatography - purified ester 17b ( 1 . 87 g , 10 mmol ) in meoh at rt for 2 h , followed by filtration of the precipitate product and recrystallization from hot meoh to afford 1 . 94 g of high purity material . the reaction assay was run as follows : 2 , 4 - dinitrophenylhydrazine ( 11 . 32 g ) was dissolved in acetonitrile ( 800 ml ). a sample containing approximately 20 mg of α - ketoester 17b was dissolved in 3 ml of the hydrazine solution , and then 50 μl of conc . h 2 so 4 was added . this was aged for 1 h at rt , then diluted to 50 ml in a volumetric flask with acetonitrile for hplc analysis . this assay agreed well with a 1 h - nmr assay for the α - ketoester 17b that was developed using mesitylene as an internal standard . column : zorbax rx - c8 , 4 . 6 mm × 250 mm ; solvents : 50 % ch 3 cn , 50 % 0 . 25 % hclo 4 ; flow : 1 . 0 ml / min ; temperature : 25 ° c . ; sample volume : 5 1 μl ; wavelength : 210 nm ( ref 300 , 100 ); retention times : dinitrophenylhydrazine : 3 . 3 min ; hydrazone adduct 22 : 6 . 6 min . the organic solution containing thp α - ketoester 17b ( 1 . 07 kg , 5 . 79 mol ) was added to a solution containing water ( 3 . 5 l ), koh ( 89 %, 486 g , 7 . 70 mol ) and k 2 hpo 4 ( 435 g , 2 . 50 mol ). use of a buffered hydrolysis system minimizes side - products . this was stirred at rt for 2 h , then the organic layer was cut . the aqueous layer was then concentrated to remove etoh . to the resulting solution was added a 3 : 1 mtbe / thf mixture ( 5 . 0 l ) and this solution was cooled to 10 ° c . concentrated hcl ( 1 . 0 l ) was added , followed by nacl ( 500 g ). the organic layer was collected , then the aqueous layer was washed with 3 : 1 mtbe / thf ( 2 × 5 . 0 l ). the resulting combined organics was stripped to a thick residue , then was flushed with mtbe ( 4 . 0 l ). the resulting solution was filtered through an in - line filter , then concentrated to 1 . 7 l and heated to 49 ° c . to dissolve all solids . the solution was cooled to 45 ° c ., then seed was added . upon cooling to 40 ° c ., a slurry formed . n - heptane ( 5 . 1 l ) was then added over 2 h at 40 ° c . the mixture was then cooled to 5 ° c . over 50 min and filtered rinsing the solids with n - heptane ( 1 . 0 l ). after drying at 50 ° c . in a vacuum oven , 891 . 4 g ( 95 . 3 % yield from 17b ) of off - white solid was obtained ( 99 . 3 a %, 97 . 9 wt %). the overall yield of 18 from 16 was 71 . 7 %. column : zorbax rx - c8 , 4 . 6 mm × 250 mm ; solvents : 50 % ch 3 cn , 50 % 0 . 25 % hclo 4 ; flow : 1 . 0 ml / min ; temperature : 25 ° c . ; sample volume : 5 μl ; wavelength : 210 nm ( ref 360 , 100 ); retention times : α - ketoacid 18 : 2 . 7 min ; α - ketoester 17b : ( broad ) 4 . 7 min . α - ketoacid 18 ( 185 . 0 g , 1 . 17 mol ) was mixed with sulfonamide 11 ( 201 . 3 g , 1 . 06 mol ) in a 5 l round bottom flask with a mechanical stirrer , a thermocouple and a dean - stark trap . diethylene glycol diethyl ether ( 185 ml ) and toluene ( 1 . 3 l ) were added , followed by methanesulfonic acid ( 5 . 5 ml , 85 mmol ). diethylene glycol diethyl ether is a high - boiling solvent added to keep the product , which is very insoluble in toluene , in solution throughout the reaction . this mixture was heated to reflux ( 116 - 117 ° c .) for 28 h , monitored by lc analysis . some toluene was lost during the reaction . to the dark solution was then added toluene ( 2 . 6 l ) keeping the temperature above 110 ° c . near the end of toluene addition , a seed bed formed . this mixture was cooled slowly to 5 ° c . over 3 h , was aged at this temperature for 1 h . the solids were isolated by filtration rinsing with toluene ( 2 × 1 . 3 l ). if conversion is lower than expected , additional toluene washes can be used to remove unreacted starting materials from the solids with minimal loss of product . the resulting solid was dried under air for 64 h , giving 281 g of 19 . mother liquor and rinse losses were 12 . 3 g ( 3 . 5 %) of product 19 and 19 . 8 g of unreacted sulfonamide ( 9 . 8 %). the solids ( 275 g ) were then dissolved in meoh ( 825 ml ) at 50 ° c ., then water ( 1 . 0 l ) was added over 30 min until a seed - bed formed . after aging 30 min , more water ( 925 ml ) was added , and the mixture was cooled to rt . the solids were filtered and washed with water ( 1 . 0 l ), then dried overnight under air giving 280 g of material as the hydrate ( 93 . 4 wt %, kf = 52200 ppm ). mother liquor and rinse losses were 6 . 1 g ( 2 . 2 %). this material ( 278 g ) was dried by dissolving in etoh ( 3 . 0 l , kf ˜ 300 μg / ml ), and flushing the solution with dry etoh ( 4 . 0 l , kf ˜ 50 μg / ml ) until the kf of the solution was ˜ 600 μg / ml . the final solution was in ˜ 1840 ml etoh (˜ 16 . 5 wt %). lc assay showed 256 g ( 73 % yield ) of 19 in the solution . including the solid samples removed gives a yield of 75 %. column : zorbax rx - c8 , 4 . 6 mm × 250 mm ; solvents : 0 to 3 min : 35 % acn , 65 % kh 2 po 4 / k 2 hpo 4 buffer ; 3 to 5 min : 60 % acn , 40 % kh 2 po 4 / k 2 hpo 4 buffer ; 5 to 7 min : 35 % acn , 65 % kh 2 po 4 / k 2 hpo 4 buffer ; flow : 1 . 0 ml / min ; sample volume : 5 μl ; wavelength : 210 nm retention times : α - ketoacid 18 : 1 . 9 min ; sulfonenamide acid 19 : 2 . 2 min ; sulfonamide 11 : 5 . 8 min . in a nitrogen - filled glovebox (& lt ; 10 ppm o 2 )[( p - cymene ) rucl 2 ] 2 ( 1 . 16 g , 1 . 90 mmol ) and ( r )—( s )-(( diphenylphosphino ) ferrocenyl - ethyldi - t - butylphosphine ( 2 . 11 g , 3 . 90 mmol , 2 . 05 equiv ) were combined in a 1 l round bottom flask . to the solids were added nitrogen degassed ethanol ( 234 ml ) and dce ( 130 ml ). if dce is added first then the resulting solution will be immediately homogeneous , although the order of addition does not affect the outcome of the reaction . solution will be dark red / brown at this time . the flask was septum sealed and brought outside the glovebox where it was placed in a heating mantle . a gentle nitrogen sweep was applied and a thermocouple was inserted into the solution . gentle heating was applied until t = 50 ° c . and then was kept at 50 ° c . for 1 h . once the reaction temperature has been reached the solution will darken until it is opaque in appearance . after 1 h , beating was discontinued and the solution was allowed to cool to rt . the flask was then taken again into a nitrogen - filled glovebox . in a nitrogen filled glovebox (& lt ; 10 ppm o 2 ), the solution of [(( r )—( s )-(( diphenylphosphino ) ferrocenyl - ethyldi - t - butylphosphine ) rucl ( p - cymene )] cl ( 340 ml , 3 . 56 mmol , 0 . 54 mol %, substrate / catalyst = 187 ) was transferred to a 0 . 5 l stainless steel vessel ( see figure below ). ethanol ( 100 ml ) was charged to a 0 . 15 l stainless steel vessel . these two vessels were connected with a ball - valve separating the two vessels . to the ethanol solution of 19 was added tea ( 34 . 4 g , 340 mmol , 0 . 51 equiv ). prior to addition of tea , water content of the ethanol solution of 19 was determined to be approximately 1000 ppm . higher water content has been observed to negatively impact the selectivity of the hydrogenation . this solution was drawn into a 1 gallon stirred autoclave via vacuum followed by an ethanol ( 300 ml ) rinse . the solution was then degassed with nitrogen ( 3 ×). the stainless steel vessels containing the catalyst solution were connected to the autoclave via flexible tubing . the autoclave was placed under partial vacuum and the catalyst solution was drawn into the autoclave followed by the etoh rinse . the solution was degassed with h 2 ( 500 psig ) 3 × with stirring . the reaction temperature was increased to 30 ° c . the reaction progress was monitored by hydrogen uptake from a reservoir . uptake was very rapid for the first 1 . 5 h with no uptake being observed after 3 h . end of reaction was determined by hplc analysis . upon completion , the hydrogen was vented and the reaction was drained into a polyjug . the vessel was rinsed with etoh ( 1 l ). the hplc assay yield was determined to be 97 . 2 % and the ee was 96 . 9 %. column : chiralpak ad - h , 25 cm × 4 . 6 mm ; solvents : 90 / 10 heptane / ipa ( 0 . 4 % triethylamine , 0 . 4 % trifluoroacetic acid ); flow : 1 . 0 ml / min , 40 ° c . ; sample volume : 5 μl ; wavelength : 224 nm ; retention times : ( s )- sulfonamide acid 8 : 16 . 95 min ; ( r )- sulfonamide acid 8 : 21 . 54 min sulfonenamide acid 19 : 23 . 09 min . cymene catalyst preparation is known in the art . illustrations for the process are disclosed in mashina , k . et al ., journal of the chemical society , chemical comm . 1989 , vol . 17 page 1208 - 1210 and takaya , h . et al ., pure and applied chemistry 1990 , vol 62 , issue 6 , page 1135 - 1138 . sulfonamide acid 8 ( 436 g , 1 . 32 mol , in etoh ) was concentrated to ˜ 1 l vol by rotary evaporation ( 50 ° c . bath , 29 in hg ) and evaporated at constant volume adding 2 . 3 l of ipac . the dark solution was diluted to 2 . 6 l vol with more ipac and transferred to an extractor with a 1 l ipac rinse . 1n hcl ( 680 ml } was added ( to ph 1 . 3 ) to neutralize the hemi - triethylamine salt . the aqueous layer was cut ( 0 . 4 % prod loss ) and the organic layer was washed with 960 ml of water ( ph 3 , 0 . 7 % prod loss ). the ipac solution was agitated with 925 ml of 1 . 5 n koh to adjust the ph to 10 . 4 . the clear aqueous layer was collected and the rag layer was filtered through solka floc pad , rinsing with 200 ml of water . the combined aqueous layer was stirred 30 min with 220 g of ecosorb c - 941 and was filtered through a medium frit sintered glass funnel . the resin was slurry rinsed with 3 × water ( 1 . 2 l total ). the basic solution ˜ 2 . 5 l ) was mixed with 2 . 2 l of methanol ( exothermed from 18 ° c . to 26 ° c .) and 1 : 1 conc hcl / h 2 o ( 210 ml ) was added , followed by 40 ml of conc hcl to adjust the ph to 1 . the mixture was heated to 40 ° c . after seeding , no slurry formed , so more water ( 400 ml ) was added at 40 ° c . over 5 min . the solution was seeded again and a slurry gradually formed . more water ( 2 . 4 l ) was added at 40 ° c . over 2 h . the mixture was allowed to cool slowly to rt and age overnight . the resulting slurry was cooled to 4 ° c ., aged for 30 min and filtered , rinsing with 3 : 1 h 2 o / meoh ( 400 ml ). the white solids were dried 2 d in a 50 ° c . vacuum oven to afford 398 g ( 98 wt %, & gt ; 99 a %, 1 . 3 wt % water ) with 89 % recovery of 8 . heavy metals were & lt ; 3 ppm ru and & lt ; 3 ppm fe and optical purity was 99 . 5 % ee . in an nitrogen filled glovebox (& lt ; 10 ppm o 2 ), tosyl - valine substrate 23 was combined with anhydrous ethanol ( 0 . 32 ml ) and tea ( 9 . 4 mg , 0 . 093 mmol ) in an 8 ml septum - capped vial fitted with a vent needle . the solution was agitated until homogeneous . once homogeneous , the catalyst solution was added ( 0 . 18 ml , 1 . 86 × 10 − 3 mmol ). the vial was placed in a glass fisher porter hydrogenation bottle . the bottle was pressurized with h 2 gas ( 90 psig ) and vented 3 times to degas and finally pressurized again to 90 psig h 2 . the reaction was agitated for 17 hours at ambient temperature . the fisher porter was depressurized and the reaction was sampled for hplc analysis . assay yield was determined to be & gt ; 99 % and enantiomeric excess ( ee ) was determined to be 97 . 3 % ee giving preferentially the ( r )- enantiomer of 24 . the following table of substrates were hydrogenated in a manner similar to that described for 23 . entry id scale ( mg ) r 1 r 2 r 3 ligand mol % ru t ( c ) time ( h ) ee assay yield 1 , 2 config 1 25 150 . 9 me me 4 - me - c6h4 (-)- tmbtp 1 . 0 % 25 24 97 . 0 % & gt ; 99 % d 2 26 150 . 4 me me 4 - ome - c6h4 (-)- tmbtp 1 . 0 % 25 24 97 . 6 % 93 % d 3 27 150 . 7 me me 4 - f - c6h4 (-)- tmbtp 1 . 0 % 25 24 97 . 2 % 95 % d 4 28 150 . 0 me me c6h5 - ch2 (-)- tmbtp 1 . 0 % 25 24 97 . 3 % & gt ; 99 % d 5 29 150 . 6 me me c6h5 -( ch2 ) 3 (-)- tmbtp 1 . 0 % 25 24 98 . 1 % 98 % d 6 30 150 . 9 —( ch2 ) 5 — 4 - me - c6h4 ( r , s )- tbu - josiphos 3 2 . 0 % 25 24 95 . 9 % & gt ; 99 d 7 31 150 . 0 —( ch2 ) 5 — 4 - f - c6h4 ( r , s )- tbu - josiphos 3 1 . 1 % 25 24 95 . 9 % 98 % d 8 32 150 . 1 me h 4 - me - c6h4 ( s , s , s , s )- me - f - katalphos 1 . 0 % 25 24 91 . 4 % 95 % l 9 33 100 . 0 ipr h 4 - me - c6h4 ( s , s , s , s )- me - f - ketalphos 5 . 0 % 40 24 89 . 6 % & gt ; 99 % l 1 all reactions were determined to be & gt ; 99 % conversion . 2 assay yields were determined using hplc and comparison to authentic standards . 3 ( r , s )- tbu - josiphos = ( r -( s )-(( diphenylphosphino ) ferrocenyl - ethyldi - t - butylphosphine hplc assays : ( all hplc analyses were preformed using a chiralpak ad - h guard column ( 10 mm × 4 . 0 mm , 5 μm ) coupled in line with stated column ) a : chiralpak ad - h , 25 cm × 4 . 6 mm , 5 μm , at 40 ° c ., 90 / 10 heptane / ipa ( 0 . 4 % triethylamine , 0 . 4 % trifluoroacetic acid ), flow rate - 1 . 0 ml / min , detection = 224 nm b : chiralpak ad - h , 25 cm × 4 . 6 mm , 5 μm + astec chirobiotic v 10 cm × 4 . 6 mm , at 40 ° c ., 90 / 10 heptane / ipa ( 0 . 4 % triethylamine , 0 . 4 % trifluoroacetic acid ), flow rate - 1 . 0 ml / min , detection = 224 nm c : chiralpak ad - h , 25 cm × 4 . 6 mm , 5 μm , at 40 ° c ., 95 / 4 / 1 heptane / ipa ( 0 . 4 % triethylamine , 0 . 4 % trifluoroacetic acid )/ etoh , flow rate - 1 . 0 ml / min , detection = 224 nm to ethyl 3 - methyl - 2 - oxobutanoate , ( 15 . 0 g , 104 . 0 mmol ) in thf ( 150 ml ) was added lioh . h 2 o ( 5 . 30 g , 125 . 0 mmol ). this stirred at rt overnight , then the solvent was stripped . the resulting white solid was slurried in mtbe ( 150 ml ) and cooled to 0 c ., then hcl ( 12 . 1 n , 11 . 0 ml ) was added . the resulting biphasic was warmed to rt , then saturated with na 2 so 4 . the inorganic solids were filtered and washed with mtbe ( 50 ml ). the combined organics were stripped to give a light yellow oil . this oil was dissolved in toluene ( 84 ml ) and diethyleneglycol diethyl ether ( 12 ml ) and p - toluenesulfonamide ( 14 . 2 g , 83 . 2 mmol ) then methanesulfonic acid ( 0 . 54 ml , 8 . 3 mmol ) were added . the resulting mixture was heated at reflux with dean - stark removal of water for 24 h , then cooled to rt . the resulting mixture was mixed with etoac ( 45 ml ) and nahco 3 ( 14 . 1 g ) in water ( 150 ml ). upon complete co 2 evolution and dissolution , the aqueous layer was separated , then the organics were washed with nahco 3 ( 1 . 6 g ) in water ( 45 ml ). the combined aqueous layers were washed with etoac ( 2 × 45 ml ), then cooled to 0 c , and treated with hcl ( 12 . 1n , 15 . 4 ml ), to give a white solid precipitate , which upon filtration and drying gave 15 . 0 g of crude material . this material was dissolved in meoh ( 45 ml ), then toluene ( 100 ml ) was added . this was heated to 90 c , and the meoh was removed . then n - heptane ( 100 ml ) was added slowly over 2 h at 80 c , then cooled slowly to 0 c . filtration gave 12 . 0 g of pure white material ( 54 % yield ). mp 188 . 5 - 189 . 5 ° c . 1 h - nmr ( 400 mhz , cd 3 od ), d 7 . 67 ( d , 2h , 20 . 1 hz ), 7 . 32 ( d , 2h , 20 . 1 hz ), 2 . 42 ( s , 3h ), 2 . 09 ( s , 3h ), 1 . 79 ( s , 3h ); 13 c nmr ( 100 mhz , dmso - d6 ), 166 . 8 , 146 . 9 , 142 . 8 , 138 . 6 , 129 . 6 , 126 . 9 , 122 . 1 , 22 . 1 , 21 . 4 , 21 . 3 ppm . hrms calcd for c12h14no4s : ( m - h ): 268 . 0644 , found : 268 . 0638 . 3 - methyl - 2 - oxobutyic acid , sodium salt ( 2 . 0 g , 14 . 2 mmol ) was slurried in mtbe ( 10 ml ) and cooled to 0 c , then hcl ( 12 . 1 n , 1 . 3 ml ) was added . the resulting biphasic was warmed to rt , then saturated with na 2 so 4 . the inorganic solids were filtered and washed with mtbe ( 10 ml ). the combined organics were stripped to give a light - yellow oil . this oil was dissolved in toluene ( 14 ml ) and diethyleneglycol diethyl ether ( 2 ml ) and p - methoxybenzenesulfonamide ( 2 . 2 g , 11 . 6 mmol ) then methanesulfonic acid ( 0 . 08 ml , 1 . 2 mmol ) were added . the resulting mixture was heated at reflux ( 65 c ) at reduced pressure with dean - stark removal of water for 16 h . the resulting mixture was mixed with etoac ( 25 ml ) and nahco 3 ( 2 . 0 g ) in water ( 40 ml ). upon complete co 2 evolution and dissolution , the aqueous layer was separated , then the organics were washed with nahco 3 ( 0 . 2 g ) in water ( 11 ml ). the combined aqueous layers were washed with etoac ( 11 ml ), then cooled to 0 c , and treated with hcl ( 12 . 1n , 2 . 1 ml ), to give a white solid precipitate , which upon filtration and drying gave 0 . 45 g of crude material . this material was passed though silica - gel , eluting with etoac to give 0 . 44 g of pure white product ( 13 % yield ). mp 162 . 5 - 163 . 5 ° c . 1 h - nmr ( 400 mhz , cd 3 od ), d 7 . 72 ( d , 2h , 22 . 2 hz ), 7 . 02 ( d , 2h , 22 . 7 hz ), 3 . 86 ( s , 3h ), 2 . 09 ( s , 3h ), 1 . 81 ( s , 3h ); 13 c nmr ( 100 mhz , cd 3 od ), 167 . 0 , 163 . 2 , 150 . 7 , 132 . 0 , 129 . 2 , 121 . 2 , 113 . 7 , 54 . 9 , 21 . 9 , 20 . 5 ppm . hrms calcd for c12h14no5s : ( m - h ): 284 . 0593 , found : 284 . 0591 . 3 - methyl - 2 - oxobutyic acid , sodium salt ( 5 . 0 g , 36 . 2 mmol ) was slurried in mtbe ( 25 ml ) and cooled to 0 c , then hcl ( 12 . 1 n , 3 . 1 ml ) was added . the resulting biphasic was warmed to rt , then saturated with na 2 so 4 . the inorganic solids were filtered and washed with mtbe ( 25 ml ). the combined organics were stripped to give a light - yellow oil . this oil was dissolved in toluene ( 35 ml ) and diethyleneglycol diethyl ether ( 5 ml ) and p - toluenesulfonamide ( 5 . 1 g , 29 . 0 mmol ) then methanesulfonic acid ( 0 . 19 ml , 2 . 9 mmol ) were added . the resulting mixture was heated at reflux with dean - stark removal of water for 24 h , then cooled to 5 c . the resulting solid was filtered , and dried to give 5 . 4 g of crude material , which was recrystallized from meoh / water ( 16 ml / 38 ml ) to give 4 . 90 g of pure white solid ( 62 % isolated yield ). mp 172 - 173 ° c . 1 h - nmr ( 400 mhz , cd 3 od ), d 7 . 83 - 7 . 86 ( m , 2h ), 7 . 22 - 7 . 27 ( m , 2h ), 2 . 12 ( s , 3h ), 1 . 87 ( s , 3h ); 13 c nmr ( 100 mhz , cd 3 od ), 166 . 6 , 166 . 3 , 163 . 7 , 151 . 6 , 136 . 7 ( 2 peaks ), 129 . 9 , 129 . 8 , 120 . 8 , 115 . 5 , 115 . 3 , 22 . 0 , 20 . 4 ppm . hrms calcd for c11h11fno4s : ( m - h ): 272 . 0393 , found : 272 . 0398 . 3 - methyl - 2 - oxobutyic acid , sodium salt ( 5 . 0 g , 36 . 2 mmol ) was slurried in mtbe ( 25 ml ) and cooled to 0 c , then hcl ( 12 . 1 n , 3 . 1 ml ) was added . the resulting biphasic was warmed to rt , then saturated with na 2 so 4 . the inorganic solids were filtered and washed with mtbe ( 25 ml ). the combined organics were stripped to give a light - yellow oil . this oil was dissolved in toluene ( 35 ml ) and diethyleneglycol diethyl ether ( 5 ml ) and alpha - toluenesulfonamide ( 4 . 90 g , 29 . 0 mmol ) then methanesulfonic acid ( 0 . 19 ml , 2 . 9 mmol ) were added . the resulting mixture was heated at reflux with dean - stark removal of water for 24 h , then cooled to 5 c . the resulting solid was dissolved in etoac ( 25 ml ) and nahco 3 ( 4 . 8 g ) in water ( 50 ml ), then the aqueous was cut and the organics were washed with nahco 3 ( 0 . 50 g ) in water ( 20 ml ). the aqueous layer was then treated with concentrated hcl ( 5 . 2 ml , conc .) at 0 c , to give a solid which was recrystallized from toluene / heptane to give 4 . 0 g ( 51 % yield ) of white solid . mp 194 - 195 ° c . 1 h - nmr ( 400 mhz , cd 3 od ), d 7 . 45 - 7 . 47 ( m , 2h ), 7 . 33 - 7 . 37 ( m , 3h ), 4 . 43 ( s , 2h ), 2 . 21 ( s , 3h ), 2 . 02 ( s , 3h ); 13 c nmr ( 100 mhz , cd 3 od ), 167 . 2 , 151 . 4 , 130 . 7 , 129 . 7 , 128 . 0 , 127 . 8 , 121 . 3 , 59 . 0 , 22 . 5 , 20 . 6 ppm . hrms calcd for c12h14no4s : ( m - h ): 268 . 0644 , found : 268 . 0644 . 3 - methyl - 2 - oxobutyic acid , sodium salt ( 2 . 6 g , 18 . 8 mmol ) was slurried in mtbe ( 20 ml ) and cooled to 0 c , then hcl ( 12 . 1 n , 1 . 6 ml ) was added . the resulting biphasic was warmed to rt , then saturated with na 2 so 4 . the inorganic solids were filtered and washed with mtbe ( 20 ml ). the combined organics were stripped to give a light - yellow oil . this oil was dissolved in toluene ( 20 ml ) and diethyleneglycol diethyl ether ( 3 ml ) and 3 - phenylpropane - 1 - sulfonamide ( 3 . 0 g , 15 . 1 mmol ) then methanesulfonic acid ( 0 . 10 ml , 1 . 5 mmol ) were added . the resulting mixture was heated at reflux with dean - stark removal of water for 18 h , then cooled to rt . etoac ( 25 ml ) and nahco 3 ( 2 . 5 g ) in water ( 50 ml ) were added , and this was stirred until all materials dissolved . the aqueous was separated , then the organics were washed with nahco 3 ( 0 . 40 g ) in water ( 10 ml ). the combined aqueous layers were then washed with etoac ( 20 ml ). the aqueous layer was cooled to 0 c , then hcl ( 12 . 1 n , 2 . 8 ml ) was added . the resulting oil was extracted into etoac ( 2 × 50 ml ), while still cold . the organics were passed through a plug of silica - gel , then stripped and the resulting solids recrystallized from toluene ( 30 ml ) to give pure material 2 . 87 g ( 67 %). mp 104 . 5 - 106 ° c . 1 h - nmr ( 400 mhz , cdcl 3 ), d 7 . 27 - 7 . 31 ( m , 2h ), 7 . 16 - 7 . 23 ( m , 3h ), 5 . 84 ( s , 1h ), 3 . 07 - 3 . 11 ( m , 2h ), 3 . 74 ( t , 2h , 18 . 8 hz ), 2 . 30 ( s , 3h ), 2 . 17 - 2 . 24 ( m , 2h ), 2 . 16 ( s , 3h ); 13 c nmr ( 100 mhz , cdcl 3 ), 170 . 2 , 159 . 6 , 140 . 2 , 128 . 5 , 128 . 3 , 126 . 3 , 119 . 5 , 52 . 8 , 34 . 2 , 25 . 1 , 25 . 0 , 22 . 6 ppm . hrms calcd for c14h18no4s : ( m - h ): 296 . 0957 , found : 296 . 0951 . 2 - cyclohexyl - 2 - oxoethanoic acid ( 3 . 0 g , 19 . 2 mmol ) was combined with p - toluenesulfonamide ( 2 . 63 g , 15 . 4 mmol ) in toluene ( 21 ml ) and diethyleneglycol diethyl ether ( 3 ml ). msa ( 0 . 10 ml , 1 . 5 mmol ) was added , and this mixture was heated at reflux for 24 h , then cooled to rt . the resulting solids were mixed with etoac ( 35 ml ) and nahco 3 ( 2 . 6 g ) in water ( 60 ml ), until all materials dissolved . the aqueous was separated , and the organics were washed with nahco 3 ( 0 . 40 g ) in water ( 10 ml ). the combined aqueous layer was then washed with etoac ( 20 ml ). the aqueous layer was cooled to 0 ° c ., then treated with hcl ( 12 . 1 n , 3 . 1 ml ). the resulting solids were filtered and washed with water and dried to give 4 . 45 g of crude material . the solids were then recrystallized from etoac / meoh / n - heptane ( 40 ml / 15 ml / 70 ml ) to give 4 . 1 g of pure white solid ( 86 % yield ). mp 221 - 222 ° c . 1 h - nmr ( 400 mhz , cdcl 3 ), d 7 . 69 ( d , 2h , 20 . 8 hz ), 7 . 33 ( d , 2h , 20 . 0 hz ), 2 . 58 - 2 . 61 ( m , 2h ), 2 . 41 ( s , 3h ), 2 . 13 - 2 . 16 ( m , 2h ), 1 . 48 - 1 . 60 ( m , 4h ), 1 . 32 - 1 . 38 ( m , 2h ); 13 c nmr ( 100 mhz , cd 3 od ), 167 . 4 , 154 . 2 , 143 . 2 , 137 . 3 , 128 . 9 , 127 . 0 , 118 . 6 , 30 . 8 , 30 . 5 , 27 . 5 , 27 . 1 , 25 . 7 , 20 . 0 ppm . hrms calcd for c15h19no4s : ( m - h ): 308 . 0957 , found : 308 . 0953 . 2 - cyclohexyl - 2 - oxoethanoic acid ( 3 . 0 g , 19 . 2 mmol ) was combined with p - toluenesulfonamide ( 2 . 70 g , 15 . 4 mmol ) in toluene ( 21 ml ) and diethyleneglycol diethyl ether ( 3 ml ). msa ( 0 . 10 ml , 1 . 5 mmol ) was added , and this mixture was heated at reflux for 28 h , then cooled to rt . the resulting solids were mixed with etoac ( 35 ml ) and nahco 3 ( 2 . 6 g ) in water ( 60 ml ), until all materials dissolved . the aqueous was separated , and the organics were washed with nah co 3 ( 0 . 40 g ) in water ( 10 ml ). the combined aqueous layer was then washed with etoac ( 20 ml ). the aqueous layer was cooled to 0 c , then treated with hcl ( 12 . 1 n , 3 . 1 ml ). the resulting solids were filtered and washed with water and dried to give 3 . 0 g of crude material . the solids were then recrystallized from toluene / methanol to give 2 . 8 g of white solid ( 58 % yield ). mp 214 - 215 ° c . 1 h - nmr ( 400 mhz , cd 3 od ), d 7 . 83 - 7 . 88 ( m , 2h ), 7 . 23 - 7 . 29 ( m , 2h ), 2 . 61 - 2 . 65 ( m , 2h ), 2 . 21 - 2 . 24 ( m , 2h ), 1 . 55 - 1 . 59 ( m , 4h ), 1 . 41 - 1 . 46 ( m , 2h ); 13 c nmr ( 100 mhz , cd 3 od ), 167 . 2 , 166 . 3 , 163 . 7 , 155 . 3 , 136 . 5 ( 2 peaks ), 129 . 9 ( 2 peaks ), 118 . 3 , 115 . 5 , 115 . 3 , 31 . 0 , 30 . 5 , 27 . 6 , 27 . 2 , 25 . 7 ppm . hrms calcd for c14h15fno4s : ( m - h ): 312 . 0706 , found : 312 . 0707 . 2 - oxobutyric acid ( 10 . 0 g , 97 . 9 mmol ) was combined with p - toluenesulfonamide ( 13 . 4 g , 78 . 4 mmol ) and msa ( 0 . 51 ml , 7 . 8 mmol ) in toluene ( 70 ml ) and diethyleneglycol diethyl ether ( 10 ml ). this mixture was heated at reflux for 28 h , then cooled to rt . to the resulting mixture was added etoac ( 50 ml ) and nahco 3 ( 13 . 1 g ) in water ( 150 ml ). upon complete dissolution , the aqueous was separated , and the organics washed with nahco 3 ( 2 . 0 g ) in water ( 50 ml ). the combined aqueous layer was then washed with etoac ( 50 ml ), then cooled to 0 c and treated with 12 . 1n hcl ( 16 . 0 ml ). the product did not crystallize , so it was quickly extracted with etoac ( 150 ml ). the organics were dried ( mgso4 ), and passed through silica - gel ( 150 ml ) to remove dark color . the resulting organics were stripped to give 13 . 1 g of off - white solid . this was recrystallized from toluene / n - heptane , then again from toluene to give 9 . 1 g of white solid . materials in the mother liquors were recrystallized from toluene to give an additional 2 . 6 g of material . total yield was 11 . 7 g ( 59 % yield ). mp 150 . 5 - 151 . 5 ° c . 1 h - nmr ( 400 mhz , cd 3 od ), d 7 . 69 ( d , 2h , 20 . 8 hz ), 7 . 32 ( d , 2h , 20 . 7 hz ), 6 . 92 ( q , 1h , 17 . 8 hz ), 2 . 41 ( s , 3h ), 1 . 81 ( d , 3h , 17 . 8 hz ); 13 c nmr ( 100 mhz , cd 3 od ), 165 . 8 , 143 . 4 , 138 . 9 , 137 . 4 , 128 . 9 , 127 . 0 , 126 . 8 , 20 . 0 , 13 . 3 ppm . hrms calcd for c11h12no4s : ( m - h ): 254 . 0487 , found : 254 . 0482 . 4 - methyl - 2 - oxopentanoic acid , sodium salt ( 5 . 0 g , 32 . 9 mmol ) was slurried in mtbe ( 25 ml ) and cooled to 0 c , then hcl ( 12 . 1 n , 3 . 0 ml ) was added . the resulting biphasic was warmed to rt , then saturated with na 2 so 4 . the inorganic solids were filtered and washed with mtbe ( 25 ml ). the combined organics were stripped to give a light - yellow oil . this oil was dissolved in toluene ( 35 ml ) and diethyleneglycol diethyl ether ( 5 ml ) and p - toluenesulfonamide ( 4 . 5 g , 26 . 3 mmol ) then methanesulfonic acid ( 0 . 17 ml , 2 . 6 mmol ) were added . the resulting mixture was heated at reflux with dean - stark removal of water for 24 h , then cooled to 5 c . the resulting solids were mixed with etoac ( 75 ml ) and nahco 3 ( 4 . 2 g ) in water ( 100 ml ), until all materials dissolved . the aqueous was separated , and the organics were washed with nahco 3 ( 0 . 50 g ) in water ( 20 ml ). the combined aqueous layer was then washed with etoac ( 25 ml ). the aqueous layer was cooled to 0 c , then treated with hcl ( 12 . 1 n , 5 . 0 ml ). the resulting oil was extracted into etoac ( 2 × 50 ml ), then stripped to give a solid , a 10 : 1 mixture of olefin isomers by 1h - nmr analysis the solids were then recrystallized from toluene / hexanes to give 4 . 2 g of white solid ( 57 % yield ), as a single isomer . mp 166 . 5 - 167 . 5 ° c . 1 h - nmr ( 400 mhz , cd 3 od ), d 7 . 69 ( d , 2h , 20 . 8 hz ), 7 . 32 ( d , 2h , 20 . 0 hz ), 6 . 56 ( d , 1h , 26 . 9 hz ), 2 . 86 - 2 . 93 ( m , 1h ), 2 . 40 ( s , 3h ), 0 . 95 ( d , 6h , 16 . 6 hz ); 13 c nmr ( 100 mhz , cd 3 od ), 166 . 3 , 149 . 7 , 143 . 4 , 137 . 3 , 128 . 9 , 127 . 1 , 123 . 5 , 27 . 3 , 20 . 6 , 20 . 1 ppm . hrms calcd for c13h16no4s : ( m - h ): 282 . 0800 , found : 282 . 0805 . racemic amino acids used for chiral hplc analysis were prepared by one of two methods . the yields were not determined . method a . racemic compounds 34 , 35 , 36 , 37 , 38 , 41 , were prepared by dissolving the corresponding dl - amino acid in water using naoh ( 2 equiv . ), then adding the sulfonyl chloride ( 1 equiv .). upon completion of reaction , the mixture was acidified with hcl , and the products crystallized in high purity from water and recrystallized if necessary . method b . racemic compounds 39 , 40 , 42 were prepared by hydrogenation of the corresponding dehydroamino esters in methanol at room temperature , using 10 % pd / c ( 25 wt %), 40 psi h2 . the reactions proceeded cleanly , in quantitative yield . the products were isolated by filtration through celite , then passing through silica - gel to remove polar impurities . non - racemic amino acids were prepared using the following method . the yields were not determined . non - racemic , commercially available amino acid was slurried in acetone / water ( 1 : 1 ) at 0 c , then naoh ( 2 . 0 n , 1 equiv .) was added to dissolve . then diisopropyl ethyl amine ( 1 . 1 equiv .) was added , followed by the corresponding sulfonyl chloride ( 1 . 1 equiv .). the reaction was allowed to warm to rt , then the acetone was removed by rotary evaporation . the resulting water was diluted with water , then hcl ( 2n , 1 equiv .) was added . the pure derivatized amino acid was isolated from water , then crystallized or chromatographed to high - purity . mp 149 - 150 . 5 ° c . 1 h - nmr ( 400 mhz , cd 3 od ), d 7 . 72 ( d , 2h , 20 . 9 hz ), 7 . 33 ( d , 2h , 21 . 7 hz ), 3 . 61 ( d , 1h , 14 . 0 hz ), 2 . 41 ( s , 3h ), 1 . 99 - 2 . 04 ( m , 1h ), 0 . 94 ( d , 3h , 17 . 0 hz ), 0 . 89 ( d , 3h , 17 . 1 hz ); 13 c nmr ( 100 mhz , cd 3 od ), 172 . 8 , 143 . 1 , 137 . 7 , 129 . 0 , 126 . 8 , 61 . 3 , 30 . 9 , 20 . 0 , 18 . 1 , 16 . 6 ppm . hrms calcd for c12h16no4s : ( m - h ): 270 . 0800 , found : 270 . 0803 . mp 116 . 5 - 117 . 5 ° c . 1 h - nmr ( 400 mhz , cd 3 do ), d 7 . 77 ( d , 2h , 22 . 6 hz ), 7 . 02 ( d , 2h , 22 . 5 hz ), 3 . 86 ( s , 3h ), 3 . 52 ( d , 1h , 12 . 9 hz ), 3 . 32 ( m , 1h ), 0 . 94 ( d , 3h , 17 . 0 hz ), 0 . 87 ( d , 3h , 17 . 0 hz ); 13 c nmr ( 100 mhz , cd 3 od ), 174 . 7 , 162 . 8 , 132 . 1 , 128 . 9 , 113 . 6 , 61 . 9 , 54 . 7 , 31 . 0 , 18 . 4 , 16 . 6 ppm . hrms calcd for c12h16no5s : ( m - h ): 286 . 0749 , found : 286 . 0746 . mp 132 - 133 ° c . 1 h - nmr ( 400 mhz , cd 3 od ), δ 7 . 90 ( m , 2h ), 7 . 25 ( m , 2h ), 3 . 65 ( d , 1h , 14 . 0 hz ), 1 . 99 - 2 . 10 ( m , 1h ), 0 . 96 ( d , 3h , 17 . 0 hz ), 0 . 90 ( d , 3h , 17 . 1 hz ); 13 c nmr ( 100 mhz , cd 3 od ), 172 . 7 , 166 . 1 , 163 . 6 , 137 . 0 , 136 . 9 , 129 . 7 , 129 . 6 , 115 . 6 , 115 . 3 , 61 . 3 , 30 . 9 , 18 . 2 , 16 . 6 ppm . hrms calcd for c11h13fno4s : ( m - h ): 274 . 0549 , found : 274 . 0552 . mp 120 - 121 . 5 ° c . 1 h - nmr ( 400 mhz , cd 3 od ), 7 . 42 ( m , 2h ), 7 . 34 ( m , 3h ), 4 . 31 ( m , 2h ), 3 . 75 ( d , 2h , 13 . 0 hz ), 2 . 09 ( m , 1h ), 0 . 98 ( d , 3h , 17 . 1 hz ), 0 . 91 ( d , 3h , 17 . 1 hz ); 13 c nmr ( 100 mhz , cd 3 od ), 173 . 6 , 130 . 8 , 129 . 7 , 128 . 2 , 128 . 1 , 61 . 8 , 59 . 1 , 31 . 1 , 18 . 2 , 16 . 8 ppm . h s calcd for c12h16no4s : ( m - h ): 270 . 0800 , found : 270 . 0804 . mp 151 - 152 ° c . 1 h - nmr ( 400 mhz , cd 3 od ), d 7 . 26 - 7 . 30 ( m , 2h ), 7 . 16 - 7 . 22 ( m , 3h ), 3 . 77 ( d , 1h , 13 . 4 hz ), 2 . 98 - 3 . 02 ( m , 2h ), 2 . 71 - 2 . 75 ( m , 2h ), 2 . 03 - 2 . 20 ( m , 3h ), 1 . 0 ( d , 3h , 17 . 0 hz ), 0 . 93 ( d , 3h , 17 . 1 hz ); 13 c nmr ( 100 mhz , cd 3 od ), 173 . 6 , 140 . 6 , 128 . 0 ( 2 peaks ), 125 . 7 , 61 . 3 , 52 . 1 , 33 . 7 , 30 . 7 , 25 . 0 , 18 . 3 , 16 . 5 ppm . hrms calcd for c14h20no4s : ( m - h ): 298 . 1113 , found : 298 . 1112 . mp 182 - 184 ° c . 1 h - nmr ( 400 mhz , cd 3 od ), d 7 . 72 ( d , 2h , 20 . 8 hz ), 7 . 33 ( d , 2h , 20 . 1 hz ), 3 . 61 ( d , 1h , 14 . 8 hz ), 2 . 41 ( s , 3h ), 1 . 56 - 1 . 75 ( m , 6h ), 0 . 97 - 1 . 28 ( m , 5h ); 13 c nmr ( 100 mhz , cd 3 od ), 172 . 7 , 143 . 0 , 137 . 7 , 129 . 0 , 126 . 8 , 60 . 7 , 40 . 4 , 29 . 2 , 27 . 9 , 25 . 6 , 25 . 5 ( 2 peaks ), 19 . 9 ppm . hrms calcd for c15h20no4s : ( m - h ): 310 . 1113 , found : 310 . 1111 . mp 143 - 145 ° c . 1 h - nmr ( 400 mhz , cd 3 od ), δ 7 . 87 - 7 . 91 ( m , 2h ), 7 . 23 - 7 . 27 ( m , 2h ), 3 . 64 ( d , 1h , 14 . 8 hz ), 1 . 57 - 1 . 76 ( m , 6h ), 1 . 00 - 1 . 32 ( m , 5h ); 13 c nmr ( 100 mhz , cd 3 od ), 172 . 6 , 166 . 1 , 163 . 6 , 137 . 0 ( 2 peaks ), 129 . 7 , 129 . 6 , 115 . 3 ( 2 peaks ), 60 . 8 , 40 . 3 , 29 . 3 , 27 . 8 , 25 . 6 , 25 . 5 ppm . hrms calcd for c14h17no4s : ( m - h ): 314 . 0862 , found : 314 . 0861 . mp 133 . 5 - 135 . 5 ° c . 1 h - nmr ( 400 mhz , cd 3 od ), δ 7 . 73 ( d , 2h , 16 . 6 hz ), 7 . 34 ( d , 2h , 20 . 1 hz ), 3 . 72 ( m , 1h ), 2 . 41 ( s , 3h ), 1 . 72 - 1 . 77 ( m , 1h ), 1 . 59 - 1 . 66 ( m , 1h ), 0 . 90 ( t , 3h , 18 . 3 hz ); 13 c nmr ( 100 mhz , cd 3 od ), 173 . 2 , 143 . 1 , 137 . 8 , 129 . 0 , 126 . 7 , 57 . 0 , 25 . 9 , 20 . 0 , 8 . 7 ppm . hrms calcd for c11h14no4s : ( m - h ): 256 . 0644 , found : 256 . 0648 . mp 122 - 123 ° c . 1 h - nmr ( 400 mhz , cd 3 od ), δ 7 . 72 ( d , 2h , 20 . 8 hz ), 7 . 34 ( d , 2h , 20 . 0 hz ), 3 . 80 ( m , 1h ), 2 . 41 ( s , 3h ), 1 . 66 - 1 . 78 ( m , 1h ), 1 . 48 ( m , 2h ), 0 . 89 ( d , 3h , 16 . 8 hz ), 0 . 81 ( d , 16 . 4 hz ); 13 c nmr ( 100 mhz , cd 3 od ), 174 . 3 , 143 . 3 , 137 . 9 , 129 . 2 , 126 . 9 , 54 . 4 , 41 . 8 , 24 . 2 , 21 . 9 , 20 . 4 , 20 . 2 ppm . hrms calcd for c13h18no4s : ( m - h ): 284 . 0957 , found : 284 . 0957 . sulfonamide acid 8 was dissolved in 3 . 2 l of thf ( 4 vol ). this water level was high ( kf = 2400 μg / ml ) due to water in the solid 8 . more thf ( 4 l ) was added and the solution was batch concentrated to the initial vol ( kf = 1200 μg / ml ). a caustic scrubber was connected to the reaction flask . dmf ( 18 . 5 ml ) was added , the solution was cooled over a − 15 ° c . dry ice / acetone bath to 5 ° c . and 248 ml of oxalyl chloride was added from an addition funnel over 20 min at ˜ 5 ° c . the mixture was allowed to age 2 h , after which the batch was cooled to − 42 ° c . and 790 ml of aqueous 50 wt % nh 2 oh was poured in from an open neck . the resulting reaction was exothermic and the batch temperature rose to 35 ° c . quickly before drifting down . the mixture was diluted with 630 ml of water and 410 ml of conc hcl was added to adjust the ph to 4 . 5 . etoac ( 9 . 5 l ) was added along with 100 ml water and the mixture was warmed to 45 ° c . to dissolve the solids that were present . the mixture was transferred to an extractor , the aqueous layer was cut , and the organic layer was washed with 960 ml of water . the organic layer was passed through a pad of solka floc and then batch concentrated to 4 l in a 22 l round bottom flask . evaporation was continued with addition of 13 l of etoac to remove thf . a thick mixture of solids formed during this distillation and required ˜ 9 l vol to maintain good mixing . the slurry was heated to 70 ° c . and aged for 3 h . n - heptane ( 8 . 2 l ) was added over 2 h , the mixture was aged for 1 h at 70 ° c . and allowed to cool and age overnight . the slurry ( 25 ° c .) was filtered ( filter pot ) rinsing with 4 l of 1 : 1 etoac / n - heptane . the solids were dried for 5 h under nitrogen and then were transferred to three trays and dried 2 days at 40 ° c . to afford 783 g ( 99 . 6 wt %, 99 . 9 a %, 94 . 4 % yield ) of product . tetramethylguanidine ( 1 . 91 g , 16 . 6 mmol ) was added to a solution of n -( benzyloxycarbonyl )- α - phosphonoglycine trimethyl ester 1 ( 5 . 00 g , 15 . 09 mmol ) in anhydrous thf ( 7 . 5 ml ) at − 20 ° c . after stirring for 1 h at − 20 ° c ., a solution of tetrahydro - 4h - pyran - 4 - one 2 ( 1 . 89 g , 16 . 6 mmol ) in thf ( 2 ml ) was added . the cooling bath was removed and the mixture was stirred at rt for 1 day . the assay yield was 82 %. the reaction mixture was diluted with 25 ml of etoac and washed with 2 × 25 ml of 0 . 1n hcl and 50 ml of brine . the loss to washes was 1 %. the organic layer was concentrated and the residue was dissolved in 20 ml of toluene at 60 ° c . slow cooling to rt afforded a slurry , which was further cooled over an ice bath and aged 3 h . the solids were filtered and washed with 4 ml of cold toluene to afford after drying 3 . 27 g of cbz - enamide ester 3 ( 71 % yield ) the mother liquor loss was 9 %. the solids were recrystallized from toluene with 90 % recovery of 3 . mp = 112 ° c . 1 h - nmr ( cdcl 3 , 400 mhz ): δ 7 . 36 - 7 . 27 ( m , br , 5h ), 6 . 13 ( s , 1h ), 5 . 14 ( s , 2h ), 3 . 75 ( m , br , 7h ), 2 . 92 ( m , 2h ), 2 . 43 - 2 . 40 ( t , 2h , j = 11 hz ); 13 c - nmr ( cdcl 3 , 100 mhz ): δ 165 . 1 , 154 . 9 , 146 . 9 , 136 . 0 , 128 . 5 , 128 . 3 , 128 . 1 , 119 . 5 , 68 . 2 , 67 . 9 , 67 . 3 , 51 . 9 , 32 . 0 . 31 . 2 . anal . calcd for c 16 h 19 no5 : c , 62 . 94 ; h , 6 . 27 ; n , 4 . 59 . found : c , 62 . 77 ; h , 6 . 20 ; n , 4 . 47 . the cbz - enamide 3 ( 5 . 00 g , 16 . 4 mmol ) was dissolved in meoh ( 180 ml , n 2 sparged to exclude oxygen ) and degassed ( vacuum / n 2 fill cycles ). the catalyst , (+)- 1 , 2 - bis (( 2r , 5r )- 2 , 5 - dimethylphospholano ) ethane ( cyclooctadiene ) rhodium ( i ) trifluoromethanesulfonate ( 100 mg , 0 . 16 mmol , strem cat # 45 - 0171 ) was added under a n 2 blanket . the mixture was shaken in a parr apparatus for 15 h under 45 psi h 2 . the catalyst was filtered and the solvent was evaporated to afford 5 . 0 g (& gt ; 95 % uncorrected yield ) of cbz - aminoester 4 as a colorless oil . a 100 g scale - up run was done at 90 psi h 2 and afforded & gt ; 99 % ee . note : the use of pure cbz - enamide ester 3 is required for successful hydrogenation . 1 h - nmr ( cdcl 3 , 500 mhz ): δ 1 . 47 ( m , 3h ), 1 . 55 ( m , 1h ), 2 . 03 ( m , 1h ), 3 . 36 ( m , 2h ), 3 . 76 ( s , 3h ), 3 . 98 ( m , 2h ), 4 . 35 ( m , 1h ), 5 . 11 ( s , 2h ), 5 . 32 ( d , j = 9 hz , 1h ), 7 . 4 ( m , 5h ). the aminoester 4 was hydrogenated in meoh over pd / c and the aminoester was isolated as its crystalline hcl salt 5 . mp = 143 ° c . 1 h - nmr ( d 6 dmso , 400 mhz ): δ 8 . 81 ( s , 3h ), 3 . 83 ( m , 3h ), 3 . 73 ( s , 3h ), 3 . 22 ( t , j = 11 hz , 2h ), 2 . 10 ( m , 1h ), 1 . 57 ( t , j = 14 hz , 2h ), 1 . 45 ( dq , j = 4 , 12 hz , 1h ), 1 . 26 ( dq , j = 4 , 12 hz , 1h ). 13 c - nmr ( d 6 dmso , 100 mhz ): δ 28 . 2 , 28 . 7 , 36 . 4 , 52 . 9 , 56 . 5 , 66 . 8 , 66 . 9 , 169 . 2 . anal . calcd for c 8 h 16 clno 3 : c , 45 . 83 ; h , 7 . 69 ; n , 6 . 68 . found : c , 45 . 38 ; h , 7 . 84 ; n , 6 . 47 . concentrated sulfuric acid ( 80 ml , 1 . 47 mol ) was added to a flask containing o - fluorotoluene 6 ( 55 . 07 g , 0 . 500 mol ) at rt . the mixture was heated slowly to ˜ 80 ° c . over 30 min with agitation ( the reaction is exothermic and gradual heatup is recommended to prevent heatup & gt ; 80 ° c ., which results in a colored product ). the resulting oil was agitated at 80 ° c . for 3 h until & lt ; 0 . 7 a % of sm 6 remained . the reaction mixture was quenched with cold water ( 500 ml , the internal temperature rose to 110 ° c . briefly at the beginning of addition then quickly dropped to 50 ° c . after all water was added ). acetonitrile ( 55 ml ) was added , followed by solid nacl ( 135 g , 2 . 31 mol ). the mixture was heated to 75 ° c . to dissolve all solids and was then cooled to 72 ° c . at which temperature seeds were added ( 100 mg of 7 ). solids formed gradually at 70 ° c . the slurry was cooled to rt over 2 h and was cooled to & lt ; 4 ° c . for 0 . 5 h . the solids were filtered , rinsed with 20 % aqueous nacl ( 165 ml ), and dried in a 50 ° c . vacuum oven to afford 111 . 3 g ( 85 % yield , 99 . 8 a %, 80 . 6 wt % purity ) sodium sulfonate 7 note : the regioisomer 7a was present at 1 . 5 % and co - elutes with 7 in the hplc assay . mp = decomp 370 ° c . 1 h - nmr ( 400 mhz , d 2 o ): δ 2 . 23 ( s , 3h ), 7 . 10 ( t , j = 9 . 2 hz , 1h ), 7 . 54 ˜ 7 . 63 ( m , 2h ). 13 c - nmr ( 100 mhz , d 2 o ): δ 13 . 6 ( d , j = 1 . 9 hz ), 115 . 2 ( d , j = 23 . 4 hz ), 125 . 0 ( d , j = 9 . 4 hz ), 126 . 0 ( d , j = 18 . 5 hz ), 128 . 8 ( d , j = 6 . 1 hz ), 138 . 0 ( d , j = 3 . 2 hz ), 162 . 5 ( d , j = 248 hz ). the sodium sulfonate 7 ( 79 . 0 g , 80 . 6 wt % pure , 300 mmol ) was added to mtbe ( 474 ml ) and dmf ( 7 . 9 ml ) at rt . to the slurry was added socl 2 ( 53 . 8 g , 450 mmol ). the mixture was warmed to 40 ° c . and agitated 3 h until & lt ; 1 . 7 a % of sm 7 remained . the reaction was quenched with cold water ( 237 ml ), agitated for 5 min , and was allowed to settle . the aqueous layer was cut and the organic layer was washed with 10 % nacl ( 2 × 237 ml ) and was concentrated to afford the sulfonyl chloride 8 as a pale yellow oil ( 63 . 6 g , 1 . 5 % region - isomer 8a ). this was diluted in heptane ( 90 ml ) and seeded at rt with 8 to afford a slurry . ( note : alternatively , the solution of 8 in mtbe can be solvent - switched to heptane with & lt ; 2 % residual mtbe and concentrated to 90 ml volume ). the slurry was cooled to & lt ; 3 ° c . over 2 h ( note : fast cooling results in solids precipitating on the walls of the flask ). the solids were filtered and dried under vacuum at rt to afford 55 . 4 g ( 88 % yield , & gt ; 99 . 9 a %, 98 . 9 wt % purity ) sulfonyl chloride 8 . ml loss was 9 %. mp = 36 ° c . 1 h - nmr ( 400 mhz , cdcl 3 ): δ 2 . 40 ( d , j = 2 . 0 hz , 3h ), 7 . 22 ( t , j = 8 . 7 hz , 1h ), 7 . 87 ˜ 7 . 94 ( m , 2h ). 13 c - nmr ( 100 mhz , cdcl 3 ): δ 14 . 5 ( d , j = 3 . 2 hz ), 116 . 4 ( d , j = 24 . 6 hz ), 127 . 2 ( d , j = 9 . 8 hz ), 127 . 5 ( d , j = 19 . 2 hz ), 130 . 7 ( d , j = 6 . 8 hz ), 139 . 7 ( d , j = 3 . 2 hz ), 165 . 0 ( d , j = 258 hz ). anal . calcd for c 7 h 6 clfo 2 s : c , 40 . 30 ; h , 2 . 90 ; s , 15 . 37 . found : c , 40 . 41 ; h , 2 . 71 ; s , 15 . 48 . oily sulfonyl chloride 2 ( 19 . 70 g , 94 . 2 wt % pure , 88 . 9 mmol ) from above slow reverse addition procedure was dissolved in 125 ml of mtbe . ammonium hydroxide solution ( 28 %, 16 ml ) and water ( 16 ml ) was added . the mixture was stirred for 1 . 5 h until hplc showed no 2 . h 2 so 4 ( 1 m , 40 ml ) was added and aqueous layer was cut . organic was washed with 50 ml of 10 % khco 3 , then with 50 ml of 10 % brine . the organic solution was concentrated to 50 ml and the concentrate was heated to 45 ° c . heptane ( 20 ml ) was added at 45 ° c . the solution was seeded and a slurry formed . more heptane ( 80 ml ) was added over 2 h at 45 ° c . the resulting slurry was cooled to rt over 1 h , then was cooled & lt ; 5 ° c . and was aged at & lt ; 5 ° c . for 20 min . filtration afforded some crystalline solid and the cake was rinsed with 30 ml of 1 : 2 mtbe / heptane . after vacuum oven drying , 16 . 06 g of sulfonamide 7 was obtained as white crystalline solid . by hplc , the solid was 99 . 6 a % and 100 wt % ( vs . reference ) pure . there was no regioisomer 7a in the product . the yield of 7 was 95 % from 2 . the aminoester salt 5 ( 50 g , 238 mmol ) was suspended in thf ( 300 ml ), diea ( 87 . 2 ml , 501 mmol ) was added , then a solution of sulfonyl chloride 8 ( 49 . 8 g , 238 mmol ) in thf ( 170 ml ) was added over 10 min ( exothermed from rt to 37 ° c .). the mixture was stirred 13 h at 40 ° c . and then was allowed to cool and age overnight . the reaction mixture was diluted with ipac ( 300 ml ) and water ( 200 ml ) and adjusted to ph 3 - 4 with 1n hcl ( 30 ml ). the aqueous layer was cut and the organic layer was washed with water ( 200 ml ). the organic layer was concentrated to 400 ml and was evaporated with ipac ( 3 × 300 ml ). the resulting slurry ( 420 ml ) was heated to 82 ° c . to dissolve the solids and was cooled to 75 ° c . where crystallization was observed . the slurry was cooled at 13 ° c ./ h to rt , then heptane ( 840 ml ) was added over ˜ 2 h , and the slurry was stirred overnight . the solids were filtered and rinsed with 2 : 1 heptane / ipac ( 60 ml ) to afford after drying in a 40 ° c . oven 75 . 9 g ( 92 % yield , 99 . 7 a % purity , & gt ; 99 % ee ) of the sulfonamide ester 9 . mp = 145 ° c . 1 h - nmr ( d 6 dmso , 400 mhz ): δ 8 . 31 ( d , j = 9 hz , 1h ), 7 . 68 ( d , j = 7 hz , 1h ), 7 . 60 ( m , 1h ), 7 . 33 ( t , j = 9 hz , 1h ), 3 . 79 ( m , 2h ), 3 . 63 ( t , j = 9 hz , 1h ), 3 . 37 ( s , 3h ), 3 . 17 ( m , 2h ), 2 . 28 ( s , 3h ), 1 . 80 ( m , 1h ), 1 . 48 ( d , j = 13 hz , 1h ), 1 . 26 ( m , 2h ), 1 . 16 ( dq , j = 4 , 12 hz , 1h ). 13 c - nmr ( d 6 dmso , 100 mhz ): δ 14 . 4 ( d , j = 3 . 2 hz ), 28 . 8 , 29 . 1 , 37 . 3 , 51 . 9 , 60 . 6 , 66 . 7 , 67 . 0 , 116 . 0 ( d , j = 23 . 8 hz ), 125 . 8 ( d , j = 18 . 6 hz ), 127 . 1 ( d , j = 9 . 5 hz ), 130 . 5 ( d , j = 6 . 3 hz ), 137 . 1 ( d , j = 3 . 2 hz ), 162 . 9 ( d , j = 250 hz ), 171 . 1 . anal . calcd for c 15 h 20 fno 5 s : c , 52 . 16 ; h , 5 . 84 ; n , 4 . 06 . found : c , 52 . 21 ; h , 5 . 78 ; n , 4 . 00 .