Patent Application: US-87612097-A

Abstract:
the present invention relates to rigid chiral ligands usefull in making catalysts for asymmetric synthesis . more particularly , the present invention relates to new monodentate and bidentate cyclic chiral phosphine ligands which are formed into catalysts to provide high selectivity of the enantiomeric structure of the end - product .

Description:
in the description of the cyclic chiral phosphine ligands above the term aryl includes phenyl , furan , thiophene , pyridine , pyrole , naphthyl and similar aromatic rings . substituted aryl and substituted vinyl refer to an aryl or vinyl , respectively , substituted with one or more alkyl groups having 1 - 8 carbon atoms , alkoxy having 1 - 8 carbon atoms , alkylcarbonyl having 1 - 8 carbon atoms , carboxy , alkoxycarbonyl having 2 - 8 carbon atoms , halo ( cl , br , f or i ) amino , alkylamino or dialkylamino . a suitable aryl , divalent aryl or divalent fused aryl for use in the present invention includes but is not limited to those derived from the parent compound benzene , anthracene or fluorene . a suitable 5 - membered ring heterocyclic group for use herein includes but is not limited to one derived from the parent heterocyclic compound furan , thiophene , pyrrole , tetrahydrofuran , tetrahydrothiopene , pyrrolidine , arsole or phosphole . a suitable fused heterocyclic group for use herein includes but is not limited to one derived from the parent compound bipyridine , carbazole , benzofuran , indole , benzpyrazole , benzopyran , benzopyronone or benzodiazine . a suitable aryloxy group for use in the present invention includes but is not limited to an aryl having an oxygen atom as a substituent . ## str3 ## alkyls having 1 - 8 carbon atoms includes straight or branched chain alkyls and cycloalkyls having 3 to 8 carbon atoms . representative examples are methyl , ethyl , propyl , isopropyl , butyl , tertiary butyl , pentyl , cyclopentyl , hexyl cyclohexyl and the like . the alkyl group may be substituted with phenyl , substituted phenyl or alkoxy , carboxy , alkyoxycarbonyl , halo , amino , or alkyl amino or dialkylamino as defined above . certain compounds of the present invention provide a phosphine ligand attached to an organic substrate or backbone . in such cases , the chemical bridging group or the allyl or akyl groups adjacent to phosphine may include a linker to a polymer ; the polymer supported - catalyst is a heterogenous or homogenous catalyst dependent upon the solubility of the polymer in the reaction medium . those skilled in the chemical art will recognize a wide variety of equivalent substituents . the cyclic chiral phosphine ligands of the present invention are reacted with transistion metals to form catalyst . preferably group viii transition metals are used and most preferably the catalyst is formed with rhodium , iridium , ruthenium , or palladium . the invention encompasses a variety of asymmetric reactions utilizing catalyst of the invention , such as hydrogenation , hydride transfer , hydrosilylation , grignard cross - coupling , hydrocyanation , isomerisation , cycloadditions , sigmatropic rearrangement , hydroboration , hydroformylation , hydrocarboxylation , allylic alkylation , hydrovinylation , cyclopropanation , aldol reaction , heck reaction , michael addition , and stereo - selective polymerization can be carried out with these ligand systems . the catalyst of this invention provides efficient and practical methods for producing chiral drugs for antihypertensive , antihistamine , cardiovascular and central nervous system therapies . the transition metal complexes of cyclic chiral phosphine ligands of the present invention are also important in the production of chiral agrochemicals . the invention is illustrated by the synthesis and application of a chiral 1 , 4 - bisphosphine , ( 2r , 2 &# 39 ; r )- bis ( diphenylphosphino )-( 1r , 1 &# 39 ; r )- dicyclopentane ( 1 ) ( abbreviated ( r , r )- bicp ) ( scheme 2 ) in the rhodium catalyzed asymmetric hydrogenation of α -( acylamino ) acrylic acids . an important feature of this ligand is that it contains two cyclopentane rings in its backbone which are present to restrict its confornational flexibility leading to high enantioselectivity in asymmetric reactions . ## str4 ## the bisphosphine ligand ( 1 , r , r - bicp ) was synthesized from readily available 1 , 1 &# 39 ;- dicyclopentene ( 2 ) 11 as shown in scheme 2 . asymmetric hydroboration of 2 using (+)- monoisopinocamphenylborane [(+) ipcbh 2 ] followed by oxidation with h 2 o 2 12 gave the desired chiral diol ( 3 ) ( 100 % ee after recrystallization from ether / hexanes ), which was then converted to the dimesylate in high yield . subsequent reaction of the dimesylate with lithium diphenylphospine afforded the bisphosphine 1 . ## str5 ## hydrogenation of α - acetoamidocinnamnic acid was carried out at rt and 1 atm of hydrogen in the presence of the catalyst formed in situ from [ rh ( cod ) 2 ] bf 4 and bisphosphine 1 ( 1 : 1 . 1 ). table 1 shows the results of hydrogenation of α - acetoamidocinnamic acid under a variety of conditions . the addition of a catalytic amount of triethylamine ( rh : 1 : et 3 n = 1 : 1 . 1 : 50 ) gave a better optical yield than without triethylamine ( entry 1 vs 2 ). this effect may be due to a conformational change in the chiral rh complex , since the carboxylate anion generated from the substrate and triethylamine has a greater affinity for the metal than the corresponding acid . 9a the enantioselectivity in the hydrogenation was found to be highly dependent on the nature of the rh complex . when a neutral rh complex was used as the catalyst precursor , the optical yield decreased dramatically ( entry 3 ). the highest selectivity ( 96 . 8 %, s ) for the hydrogenation of a - acetoamidocinnanic acid was obtained in thf at 1 atm of h 2 in the presence of triethylamine ( entry 4 ), while changing substrate / catalyst ratio had a small effect on the enantioselectivities ( entry 4 vs 5 ). table 1______________________________________optimization of the asymmetric hydrogenation of α - acetamidocinnamic acid . sup . a # str6 ## # str7 ## - entry solvent et . sub . 3 n (%) ee (%). sup . b______________________________________1 etoh -- 89 . 2 2 etoh 50 93 . 3 3 . sup . c etoh 50 83 . 6 4 clch . sub . 2 ch . sub . 2 cl 50 93 . 4 5 thf 50 96 . 8 6 . sup . d thf 5 95 . 1______________________________________ . sup . a the reaction was carried out at rt under 1 atm of h . sub . 2 for 24 h [ substrate ( 0 . 5 mmol , 0 . 125 m ):[ rh ( cod ). sub . 2 ] bf . sub . 4 : ligand ( 1 ) = 1 : 0 . 01 : 0 . 011 ]. the reaction went in quantitative yield . . sup . b determined by gc using achirasilval iii fsot column on the corresponding methyl ester . the s absolute configuration was determined b comparing the optical rotation with the reported value . . sup . c 0 . 5 mol % [ rh ( cod ) cl ]. sub . 2 was used as the catalyst precursor . . sup . d 0 . 1 mol % [ rh ( cod ). sub . 2 ] bf . sub . 4 / 0 . 11 mol % ligand ( 1 )/ 5 mol % et . sub . 3 n were used . the methology is useful in the asymmetric synthesis of chiral amino acids . tables 2 and 3 show the enantioselectivity of some amino acids obtained by hydrogenation of α -( acylamino ) acrylic acids under an optimum condition . enantioselectivities in this hydrogenation were not sensitive to the substitution pattern on the β - position of the prochiral olefin substrates , where α - benzamidocinnamic acid gave better optical than the corresponding acetoamido derivative . table 2______________________________________asymmetric hydrogenations of dehydroamino acid derivatives # str8 ## # str9 ## # str10 ## entrysubstrate con . % % ee . sup . a______________________________________ 1 100 97 . 5 - 2 100 92 . 6 - 3 100 96 . 8 - 4 100 99 . 0 - 5 100 97 . 0______________________________________ . sup . a % ee determined by gc using chirasilval iii fsot column of the corresponding methyl ester . table 3______________________________________asymmetric hydrogenations of dehydroamino acid derivatives # str16 ## # str17 ## # str18 ## entrysubstrate con . % % ee . sup . a______________________________________ 6 100 99 . 0 - 7 100 98 . 2 - 8 100 92 . 5 - 9 100 91 . 6 - 10 100 92 . 9______________________________________ . sup . a % ee determined by gc using chirasilval iii fsot column of the corresponding methyl ester or by hplc ( oj collumn ) for the corresponding methyl ester , the results are summarized in table 4 . table 4______________________________________asymmetric hydrogenations of methyl ester of dehydroamino acid derivatives # str24 ## # str25 ## # str26 ## - substrate entry ( r ) con . % % ee . sup . a______________________________________1 h 100 76 . 2 - 2 100 78 . 4 - 3 . sup . b 100 60 . 0 - 4 100 75 . 1 - 5 100 80 . 5 - 6 100 70 . 9 - 7 100 85 . 3 - 8 100 79 . 1______________________________________ . sup . a ee determined by gc using chirasilval iii fsot column . sup . b 50 mol % et . sub . 3 n was added table 5__________________________________________________________________________asymmetric hydrogenations of dehydroamino acid derivatives # str34 ## # str35 ## - p -- p = chiral diphenylphosphine (% ee ) substrate dipamp binap chiraphos bppm diop bicp__________________________________________________________________________ 94 r36 ## 67 91 98 73 98 - 95 84 89 91 81 97 - 96 100 99 83 64 99 - 94 79 * 83 86 84 98__________________________________________________________________________ * nhcoph for the asymmetric hydrogenation of imines , rhodium iridium - complexes of bicp are effective . table 6 provides some results on this asymmetric reaction . for an imine substrate , up to 94 % ee has achieved and this is among the highest enantioselectivity obtained with group viii transition metal catalysts coordinated by a chiral phosphine ligand . table 6__________________________________________________________________________ir and rh - catalyzed asymmetric hydrogenation of imines__________________________________________________________________________ # str40 ## # str41 ## phthalimide ( 4 mol %) 100 % con , 93 . 9 % ee h . sub . 2 ( 1000 psi ), toluene , rt - # str42 ## # str43 ## phthalimide ( 4 mol %) 100 % con , 64 . 7 % ee h . sub . 2 ( 1470 psi ), toluene , rt - # str44 ## # str45 ## 100 % con , 60 . 2 % ee__________________________________________________________________________ the rigid fused bicyclic [ 2 . 2 . 1 ] structure represents a new motif in chiral ligand design . changes in the size of the r group on the ring system can modulate the asymmetric induction and high enantioselectivities can be achieved . scheme 3 shows the synthesis of new chiral bicyclic phosphines ( abbreviated as pennphos because it represents a different structure from duphos [ dupont phosphine ] and was made at penn state ). ## str46 ## rhodium complexes with pennphos ligands can be used as catalyts for asymmetric hydrogenation . table 7 lists the asymmetric hydrogenation results for dehydroamino acid derivatives . table 7______________________________________asymmetric hydrogenations of dehyroamino acid derivatives______________________________________ # str47 ## # str48 ## # str49 ## # str50 ## entry substrate con . % % ee . sup . a______________________________________ - 1 100 84 . 3 - 2 100 52 . 8 - 3 100 82 . 7 - 4 100 82 . 3 - 5 100 81 . 9 - 6 100 83 . 5______________________________________ . sup . a % ee determined by gc using chirasilval iii fsot column of the corresponding methyl ester . the rhodium complexes with me - pennphos are very effective for hydrogenation of simple ketones . up to 97 % ee has been obtained with acetophenone , which is the highest enantioselectivity reported in the direct asymmetric hydrogenation of simple ketones with group viii transition metal complexes . table 8 summarizes some results for this study . table 8__________________________________________________________________________asymmetric hydrogenations of simple ketones__________________________________________________________________________ # str57 ## # str58 ## # str59 ## # str60 ## entry substrate catalyst h . sub . 2 pressure con . % % ee__________________________________________________________________________ 1 [ rh ( cod ) cl ]. sub . 2 30 atm 97 96 . 5 - 2 [ rh ( cod ) cl ]. sub . 2 30 atm 70 91 - 3 [ rh ( cod ). sub . 2 ] bf . sub . 4 70 atm 73 79 . 6__________________________________________________________________________ synthesis of another class of chiral cyclic phosphines is illustrated in scheme 4 . the phospha - tricyclic structure is unique and the phosphines are made from chiral 1 , 4 - diols with two rings . tricyclic structure dictates the chiral environment around phosphines and ring size can be changed by varing the chiral diols . both monophosphines and bisphosphines can be made from the straightforward synthetic route . they can be used as ligands for many asymmetric reactions ## str64 ## rhodium complexes with these chiral tricyclic phosphines can be used as catalyts for asymmetric hydrogenation . table 9 lists the asymmetric hydrogenation results for dehydroamino acid derivatives . table 9______________________________________asymmetric hydrogenations of dehyroamino acid derivatives______________________________________ # str65 ## # str66 ## # str67 ## # str68 ## entry substrate con . % % ee . sup . a______________________________________ 1 100 52 . 9 - 2 100 77 . 6______________________________________ . sup . a ee determined by gc using chirasilval iii fsot column of the corresponding methyl ester . the rigid fused bicyclic [ 2 . 2 . 1 ] structure represents a new motif in chiral ligand design . analogous to burk &# 39 ; s systems , changes in the size of the r group on the ring system can modulate the asynimetric induction and high enantioselectivities can be achieved . the present invention provides the syntheses of chiral monophosphines with this fused bicyclic ring structure ( scheme 5 ) and their application in pd - catalyzed asymmetric allylic alkylations . ## str71 ## the ligand synthesis depends on the availability of enantiomerically pure cyclic 1 , 4 - diols . halterman 13 and vollhardt 14 have previously prepared chiral cyclopentadiene derivatives from the chiral diols . 13 - 14 halterman 13 has synthesized chiral diols 1 and 2 from the inexpensive starting materials p - xylene and p - diisopropylbenzene , respectively . the synthesis employed birch reduction , followed by asymmetric hydroboration and recrystallization to 100 % ee . conversion of the optically pure diols to the corresponding mesylates proceeds cleanly . nucleophilic substitution by li 2 pph on the chiral dimesylates 3 and 4 generated the corresponding bicyclic phosphines , which were trapped by bh 3 . th to form the air - stable boron - protected monophosphines 5 and 6 , respectively . deprotection with a strong acid produces the desired products [ 7 , ( 1r , 2s , 4r , 5s )-(+)- 2 , 5 - dimethyl - 7 - phenyl - 7 - phosphabicyclo [ 2 . 2 . 1 ] heptane ; 8 , ( 1r , 2r , 5r )-(+)- 2 , 5 - diisopropyl - 7 - phenyl - 7 - phosphabicyclo -[ 2 . 2 . 1 ] heptane ] in high yields . pd - catalyzed allylic alkylation was utilized to test the effectiveness of these new monophosphines as chiral ligands . although many palladium complexes of multidentate phosphine and nitrogen ligands are excellent catalysts for this reaction , 15 palladium complexes of simple chiral monophosphines are normally not effective . 15 however , pd - catalyzed allylic alkylation with the new monophosphine 7 gave excellent enantioselectivities and conversions ( table 10 ), comparable to the best results ( 99 % ee ) reported to date . 15 table 10__________________________________________________________________________palladium - catalyzed asymmetric allyclic alkylation with chiral monophosphines . sup . a__________________________________________________________________________ # str72 ## # str73 ## # str74 ## # str75 ## entry l *[ pd ] [ pd ]: l * nu additive time ( h ) yield (%) % ee . sup . b__________________________________________________________________________ 1 7 pd . sub . 2 ( dba ). sub . 3 1 : 2 . 2 ch . sub . 2 ( co . sub . 2 me ). sub . 2 -- 1 . 5 96 74 ( r ) 2 7 pd ( oac ). sub . 2 1 : 2 . 2 ch . sub . 2 ( co . sub . 2 me ). sub . 2 -- 4 . 0 98 72 ( r ) 3 7 [ pd ( c . sub . 3 h . sub . 5 ) cl ]. sub . 2 1 : 1 . 1 ch . sub . 2 ( co . sub . 2 me ). sub . 2 -- 5 . 0 97 60 ( r ) 4 7 [ pd ( c . sub . 3 h . sub . 5 ) cl ]. sub . 2 1 : 2 . 2 ch . sub . 2 ( co . sub . 2 me ). sub . 2 -- 2 . 0 93 95 ( r ) 5 7 [ pd ( c . sub . 3 h . sub . 5 ) cl ]. sub . 2 1 : 3 . 3 ch . sub . 2 ( co . sub . 2 me ). sub . 2 -- 1 . 5 96 96 ( r ) 6 7 [ pd ( c . sub . 3 h . sub . 5 ) cl ]. sub . 2 1 : 2 . 2 ch . sub . 2 ( co . sub . 2 me ). sub . 2 2 . 8 % agbf . sub . 4 1 . 0 80 97 ( r ) 7 7 [ pd ( c . sub . 3 h . sub . 5 ) cl ]. sub . 2 1 : 2 . 2 ch . sub . 2 ( co . sub . 2 me ). sub . 2 2 . 8 % licl 2 . 0 95 96 ( r ) 8 7 [ pd ( c . sub . 3 h . sub . 5 ) cl ]. sub . 2 1 : 2 . 2 ch . sub . 2 ( come ). sub . 2 -- 2 . 0 99 & gt ; 97 . sup . c ( r ) 9 7 [ pd ( c . sub . 3 h . sub . 5 ) cl ]. sub . 2 1 : 2 . 2 ch ( nhac )( co . sub . 2 et ). sub . 2 -- 2 . 0 95 & gt ; 99 . 5 . sup . d ( s ) 10 8 [ pd ( c . sub . 3 h . sub . 5 ) cl ]. sub . 2 1 : 2 . 2 ch . sub . 2 ( co . sub . 2 me ). sub . 2 -- 3 . 5 99 78 ( r ) __________________________________________________________________________ . sup . a the reaction was carried out under n . sub . 2 using 1 , 3diphenyl - 2 - propenyl acetate , nu ( nucleophile ) ( 300 mol %), bsa ( bis ( trimethylsilyl ) acetamide ) ( 300 mol %), koac ( 2 mol %), toluene , [ pd ] 1 . 4 mol % and l *. . sup . b % ee was measured by hplc using a chiralcel od column , and the absolute configuration was determined by comparing the optical rotation with literature values . . sup . c % ee was measured by comparing the optical rotation with literatur values . . sup . d % ee was measured by hplc using a chiracel oj column . ruthenium complexes with chiral phosphines are excellent catalysts for the asymmetric hydrogenation of beta keto - esters . table 11 lists the results based on ru - bicp catalytic system . table 11______________________________________asymmetric hydrogenations of beta - keto ester # str76 ## # str77 ## # str78 ## entry temp catalyst h . sub . 2 pressure con . % % ee______________________________________1 65 ° c . ru ( bicp ) br . sub . 2 1 atm 97 82 2 40 ° c . ru ( bicp ) br . sub . 2 5 atm 95 76 3 50 ° c . ru ( bicp ) cl . sub . 2 5 atm 43 84______________________________________ unless otherwise indicated , all reactions were carried out under nitrogen . thf and ether were freshly distilled from sodium benzophenone ketyl . toluene and 1 , 4 - dioxane were freshly distilled from sodium . dichloromethane and hexane were freshly distilled from cah 2 . methanol was distilled from magnesium and cah 2 . reactions were monitored by thin - layer chromatography ( tlc ) analysis . column chromatography was performed using em silica gel 60 ( 230 - 400 mesh ). 1 h nmr were recorded on bruker ace 200 , wp 200 , am 300 and wm 360 spectrometers . chemical shifts are reported in ppm downfield from tetramethylsilane with the solvent resonance as the internal standard ( cdcl 3 , δ 7 . 26 ppm ). 13 c , 31 p and 1 h nmr spectra were recorded on brnker am 300 and wm 360 or varian 200 or 500 spectrometers with complete proton decoupling . chemical shifts are reported in ppm downfield from tetramethylsilane with the solvent resonance as the internal standard ( cdcl 3 , δ 77 . 0 ppm ). optical rotation was obtained on a perkin - elmer 241 polarimeter . ms spectra were recorded on a kratos mass spectrometer ms 9 / 50 for lr - ei and hr - ei . gc analysis were carried on helwett - packard 5890 gas chromatograph with a 30 - m supelco β - dex ™ or r - 225dex ™ column . hplc analysis were carried on waters ™ 600 chromatograph with a 25 - cm chiralcel od column . compound 3 was synthesized by asymmetric hydroboration of bi - 1 - cyclopentenlyl using (+)- monoisopinocampheylborane ((+)- ipcbh 2 ) according to the literature procedure ( brown , h . c . ; jadhav , p . k ., mandal , a . k . j . org . chem . 1982 , 47 , 5074 ). the absolute configuration of the diol was assigned based on the asymmetric hydroboration of trisubstituted olefins ( e . g . methylcyclopentene ) using (+)- ipcbh 2 . 1 h nmr ( cdcl 3 , 300 mhz ) δ 4 . 04 ( br , 2 h ), 3 . 84 ( m , 2 h ), 2 . 02 ( m , 2 h ), 1 . 66 - 1 . 22 ( m , 10 h ), 1 . 21 ( m , 2 h ); 13 c nmr δ 78 . 6 , 52 . 2 , 33 . 6 , 29 . 2 , 20 . 5 ; ms m / z 170 ( m + , 0 . 35 ), 152 , 134 , 108 , 95 , 84 , 68 ; hrms calcd for c 10 h 18 o 2 : 170 . 1307 ( m + ); found : 170 . 13 15 . to a solution of ( 1r , 1 &# 39 ; r )- bicyclopentyl -( 2s , 2 &# 39 ; s )- diol ( 0 . 8 g , 4 . 65 mmol ) and triethylamine ( 1 . 68 ml , 12 . 09 mmol ) in ch 2 cl 2 ( 30 ml ) was added dropwise a solution of methanesulfonyl chloride ( 0 . 76 ml , 9 . 92 mmol ) in ch 2 cl 2 ( 2 ml ) at 0 ° c . the reaction mixture was stirred at 0 ° c . for 30 min , and at rt for 2 h , then quenched by saturated aqueous ammonium chloride solution ( 25 ml ). the aqueous layer was extracted with ch 2 cl 2 ( 3 × 20 ml ) and the combined organic solution was dried over na 2 so 4 . after evaporation of the solvent , a white solid was obtained , which was used directly for the next step . 1 h nmr ( cdcl 3 , 200 mhz ) δ 5 . 01 ( m , 2h ), 3 . 04 ( s , 6 h ), 2 . 17 ( m , 2 h ), 2 . 15 - 1 . 65 ( m , 10 h ), 1 . 43 - 1 . 52 ( m , 2 h ); 13 c nmr δ 86 . 8 , 48 . 2 , 38 . 4 , 32 . 8 , 27 . 4 , 22 . 5 . diphenylphosphine ( 1 . 25 ml , 7 . 0 mmol ) in thf ( 80 ml ) was cooled to - 78 ° c . to this solution , n - buli in hexane ( 4 . 1 ml , 6 . 6 mmol ) was added via syringe over 5 min . the resulting orange solution was warmed to rt and stirred for 30 min . after cooling the mixture to - 78 ° c ., ( 1r , 1 &# 39 ; r , 2s , 2 &# 39 ; s )- 1 , 1 &# 39 ;- bicyclopentyl - 2 , 2 &# 39 ;- diol bismesylate ( 1 . 01 g , 3 . 1 mmol ) in thf ( 20 ml ) was added over 20 min . the resulting orange solution was warmed to rt and stirred overnight . the white suspension solution was hydrolyzed with saturated aqueous nh 4 cl solution . the aqueous layer was extracted with ch 2 cl 2 ( 2 × 20 ml ). the combined organic solution was dried over anhydrous na 2 so 4 . after removal of the solvents under reduced pressure , the residue was dissolved in ch 2 cl 2 ( 50 ml ), then treated with bh 3 . thf ( 10 ml , 10 mmol ) at rt and the mixture was stirred overnight . the reaction mixture was added to nh 4 cl aqueous solution , and extracted with ch 2 cl 2 ( 2 × 50 ml ). the combined organic solution was dried over anhydrous na 2 so 4 . after evaporation of the solvent under reduced pressure , the residue was subjected to column chromatography on silica gel , eluting with ch 2 cl 2 / hexane ( 1 : 5 ) and then ch 2 cl 2 / hexane ( 2 : 3 ) affording the product as a white solid . yield : 0 . 36 g ( 21 %). 1 h - nmr ( cdcl 3 ) δ 7 . 80 - 7 . 30 ( m , 20 h , ph ), 2 . 55 - 2 . 35 ( m , 2 h , chp ( bh 3 ) ph 2 ), 1 . 95 - 1 . 35 ( m , 14 h , ch 2 and ch ), 1 . 7 - 0 . 5 ( broad , 6 h , bh 3 ). 31 p - nmr ( cdcl 3 ): δp = 17 . 5 ( br ). 13 c - nmr ( cdcl 3 ) δ 133 . 43 ( d , 2 j ( pc )= 8 . 5 hz , c ortho ), 132 . 25 ( d , 2 j ( pc )= 8 . 5 hz , c ortho ), 132 . 08 ( d , 1 j ( ph )= 50 . 0 hz , c ipso ), 130 . 67 ( d , 4 j ( pc )= 2 . 1 hz , c para ), 130 . 57 ( d , 4 j ( pc )= 2 . 1 hz , c para ), 129 . 71 ( d , 1 ( pc )= 56 . 5 hz , c ipso ), 128 . 39 ( d , 3 j ( pc )= 9 . 4 hz , c meta ), 128 . 29 ( d , 3 j ( pc )= 9 . 1 hz , c meta ), 46 . 28 ( dd , j ( pc )= 2 . 1 and 4 . 8 hz , c 1 , 1 &# 39 ;), 36 . 26 ( d , 1 j ( pc )= 30 . 6 hz , c 2 , 2 &# 39 ;), 31 . 19 ( ch 2 ), 29 . 52 ( ch 2 ), 22 . 51 ( ch 2 ); ms m / z 520 ( 8 . 95 ), 506 ( 3 . 55 ), 429 ( 19 . 10 ), 321 ( 100 ), 253 ( 7 . 45 ), 185 ( 26 . 64 ), 108 ( 43 . 68 ), 91 ( 11 . 99 ), 77 ( 6 . 88 ), hrms cacld for c 28 h 31 p 2 ( m + - b 2 h 6 - ph ): 429 . 1901 , found : 429 . 1906 . to a solution of the above borane complex of the phosphine ( 0 . 24 g , 0 . 45 mmol ) in ch 2 cl 2 ( 4 . 5 ml ) was added tetrafluoroboric acid - dimethyl ether complex ( 0 . 55 ml , 4 . 5 mmol ) dropwise via syringe at - 5 ° c . after the addition , the reaction mixture was allowed to warm slowly to rt , and stirred for 20 h . the mixture was diluted with ch 2 cl 2 , and neutralized with saturated aqueous nahco 3 solution . the aqueous layer was extracted with ch 2 cl 2 . the combined organic solution was washed with brine , followed by water , and dried over na 2 so 4 . evaporation of the solvent gave the pure phosphine . yield : 0 . 21 g ( 93 %). 1 h nmr ( cdcl 3 , 360 mhz ) δ 7 . 52 - 7 . 27 ( m , 20 h ), 2 . 53 ( m , 2 h ), 2 . 27 ( m , 2 h ), 1 . 93 ( m , 2 h ), 1 . 72 ( m , 2 h ), 1 . 70 - 1 . 43 ( m , 8 h ); 13 c nmr ( cdcl 3 ) δ 139 - 127 ( ph ), 45 . 9 ( d , j = 12 . 1 hz ), 45 . 8 ( d , j = 12 . 0 hz ), 40 . 34 ( d , j = 14 . 0 hz ), 30 . 9 ( m ), 23 . 8 ( m ); 31 p nmr ( cdcl 3 ) δ - 14 . 6 . this phosphine was fully characterized by its borane complex . to a solution of [ rh ( cod ) 2 ] bf 4 ( 5 . 0 mg , 0 . 012 mnmol ) in thf ( 10 ml ) in a glovebox was added chiral ligand 1 ( 0 . 15 ml of 0 . 1 m solution in toluene , 0 . 015 mmol ), and et 3 n ( 0 . 087 ml , 0 . 62 mmol ). after stirring the mixture for 30 min , the dehydroamino acid ( 1 . 2 mmol ) was added . the hydrogenation was performed at rt under 1 atm of hydrogen for 24 h . the reaction mixture was treated with ch 2 n 2 , then concentrated in vacuo . the residue was passed through a short silica gel column to remove the catalyst . the enantiomeric excesses were measured by gc using a chirasil - val iii fsot column . the absolute configuration of products was determined by comparing the observed rotation with the reported value . all reactions went in quantitative yield with no by - products found by gc . to phenylphosphine ( 3 . 0 ml , 27 . 3 mmol ) in tbf ( 200 ml ) was added n - buli ( 34 . 5 ml of a 1 . 6 m solution in hexane , 55 mmol ) via syringe at - 78 ° c . over 20 min . then the orange solution was warmed up to rt and stirred for 1 hr at rt . to the resulting orange - yellow suspension was added a solution of ( 1s , 2s , 4s , 5s )- 2 , 5 - dimethylcyclohexane - 1 , 4 - diol bis ( methanesulfonate ) ( 3 , 8 . 25 g , 27 . 5 mmol ) in thf ( 100 ml ) over 15 min . after the mixture was stirred overnight at rt , the pale - yellow suspension was hydrolyzed with saturated nh 4 cl solution . the mixture was extracted with ether ( 2 × 50 ml ), and the combined organic solution was dried over anhydrous sodium sulfate . after filtration , the solvents were removed under reduced pressure . the residue was dissolved in methylene chloride ( 100 ml ), treated with bh 3 . thf ( 40 ml of a 1 . 0 m solution in thf , 40 mmol ) and the mixture was stirred overnight . it was then poured into saturated nh 4 cl solution and extracted with ch 2 cl 2 ( 3 × 50 ml ). the combined organic solution was dried over anhydrous na 2 so 4 and filtered , the solvent was removed on reduced pressure . the residue was subjected to chromatography on silicon gel column , eluted with hexanes / ch 2 cl 2 ( 4 : 1 ) affording the product as a white solid . yield : 1 . 95 g ( 31 %). [ α ] 25 d =+ 59 . 5 ° ( c 1 . 07 , chcl 3 ). 1 h - nmr ( cdcl 3 ) δ 7 . 60 - 7 . 30 ( m , 5 h , c 6 h 5 ), 2 . 60 - 2 . 40 ( m , 2 h , chp ( bh 3 ) ph ), 2 . 15 - 2 . 05 ( m , 1 h , ch ), 2 . 04 - 1 . 80 ( m , 4 h , ch 2 ), 1 . 65 - 1 . 50 ( m , 1 h , ch ), 1 . 32 ( d , 3 j ( hh )= 6 . 5 hz , 3 h , ch 3 ), 0 . 59 ( d , 3 j ( hh )= 6 . 7 hz , 3 h , ch 3 ), 1 . 6 - 0 . 2 ( br , bh 3 ); 13 c - nmr ( cdcl 3 ) δ 131 . 74 ( d , 2 j ( pc )= 7 . 3 hz , c ortho ), 130 . 56 ( d , 1 j ( pc )= 43 . 9 hz , c ipso ), 129 . 92 ( d , 4 j ( pc )= 2 . 0 hz , c para ), 128 . 44 ( d , 3 j ( pc )= 8 . 6 hz , c meta ), 43 . 07 ( d , 1 j ( pc )= 30 . 5 hz , chp ( bh 3 ) ph ), 40 . 85 ( d , 1 j ( pc )= 31 . 6 hz , chp ( bh 3 ) ph ), 36 . 27 ( ch 2 ), 36 . 67 ( d , 3 j ( pc )= 13 . 5 hz , ch 2 ), 35 . 91 ( d , 2 j ( pc )= 3 . 5 hz , ch ), 34 . 65 ( d , 2 j ( pc )= 9 . 8 hz , ch ), 20 . 78 ( ch 3 ) 20 . 53 ( ch 3 ); 31 p - nmr ( cdcl 3 ) δ 36 . 3 ( d , broad , 1 j ( pb )= 58 . 8 hz ); hrms calcd for c 14 h 22 bp : 232 . 1552 ( m + ); found : 232 . 1578 ; c 14 h 19 p : 218 . 1224 ( m + - bh 3 ); found : 218 . 1233 . using the same procedure as in the preparation of 5 . yield : 0 . 33 g ( 50 %). [ α ] 25 d =+ 25 . 5 ° ( c 1 . 02 , chcl 3 ). 1 h - nmr ( cdcl 3 ) δ 7 . 55 - 7 . 30 ( m , 5 h , c 6 h 5 ), 2 . 85 - 2 . 70 9 ( m , 2 h chp ( bh 3 ) ph ), 2 . 30 - 2 . 20 ( m , 1 h , ch ), 2 . 18 - 2 . 00 ( m , 1 h , ch ), 1 . 95 - 1 . 65 ( m , 4 h , ch 2 ), 1 . 40 - 1 . 20 ( m , 2 h , ch ), 1 . 03 ( d , 3 j ( ph )= 6 . 5 hz , ch 3 ), 0 . 87 ( d , 3 j ( ph )= 6 . 7 hz , ch 3 ), 0 . 85 ( d , 3 j ( ph )= 7 . 4 hz , ch 3 ), 0 . 53 ( s , broad , 3 h , ch 3 ), 1 . 5 - 0 . 2 ( broad , bh 3 ); 13 c - nmr ( cdcl 3 ) δ 131 . 19 ( d , 2 j ( pc )= 8 . 3 hz , c ortho ), 130 . 71 ( d , 1 j ( pc )= 45 . 2 hz , c ipso ), 129 . 97 ( d , 4 j ( pc )= 2 . 5 hz , c para ), 128 . 45 ( d , 3 j ( pc )= 9 . 5 hz , c meta ), 50 . 30 ( d , 2 j ( pc )= 2 . 1 hz , ch ), 48 . 77 ( d , 2 j ( pc )= 9 . 7 hz , ch ), 38 . 27 ( d , 1 j ( pc )= 30 . 5 hz , chp ( bh 3 ) ph ), 36 . 81 ( ch 2 ), 36 . 71 ( d , 1 j ( pc )= 31 . 5 hz , chp ( bh 3 ) ph ), 34 . 73 ( d , 3 j ( pc )= 13 . 7 hz , ch 2 ), 31 . 92 ( chme 2 ), 31 . 12 ( chme 2 ), 22 . 41 ( ch 3 ), 21 . 55 ( ch 3 ), 20 . 73 ( ch 3 ), 20 . 10 ( ch 3 ); 31 p - nmr ( cdcl 3 ) δ 36 . d ( d , broad , 1 j ( pb )= 51 . 4 hz ). to a solution of corresponding borane complex of the phosphine ( 5 , 1 . 0 g , 4 . 31 mmol ) in ch 2 cl 2 ( 22 ml ) was added tetrafluoroboric acid - dimethyl ether complex ( 2 . 63 ml , 21 . 6 mmol ) dropwise via a syringe at - 5 ° c . after the addition , the reaction mixture was allowed to warm up slowly , and stirred at rt . after 20 h , 31 p nmr showed the reaction was over , it was diluted by ch 2 cl 2 , neutralized by saturated nahco 3 aqueous solution . the aqueous layer was extracted with ch 2 cl 2 . the combined organic solution was washed with brine , followed by water , and then dried over na 2 so 4 . evaporation of the solvent gave a pure phosphine product , which was confirmed by nmr . yield : 0 . 9 g ( 96 %). [ α ] 25 d =+ 92 . 5 ° ( c 2 . 3 , toluene ); 1 h nmr ( cdcl 3 , 360 mhz ) δ 7 . 38 - 7 . 34 ( m , 2h ), 7 . 26 - 7 . 21 ( m , 2h ), 7 . 19 - 7 . 16 ( m , 1h ), 2 . 60 - 2 . 54 ( m , 2h ), 1 . 89 - 1 . 62 ( m , 5h ), 1 . 44 - 1 . 42 ( m , 1h ), 1 . 16 ( d , j = 6 . 12 hz , 3h ), 0 . 55 ( d , j = 6 . 95 hz , 3h ); 13 c nmr ( cdcl 3 ) δ 138 . 68 ( d , j = 29 . 3 hz ), 131 . 42 ( d , j = 13 . 0 hz ), 127 . 88 ( d , j = 2 . 35 hz ), 126 . 57 ( s ), 47 . 34 ( d , j = 13 . 5 hz ), 45 . 26 ( d , j = 10 . 2 hz ), 39 . 21 ( d , j = 6 . 7 hz ), 39 . 21 ( d , j = 5 . 3 hz ), 38 . 74 ( d , j = 6 . 7 hz ), 34 . 69 ( d , 17 . 2 hz ), 22 . 37 ( d , j = 7 . 8 hz ), 21 . 52 ( s ); 31 p nmr ( cdcl 3 ) δ - 7 . 29 . using the same procedure as in the preparation of 7 . yield : 1 . 0 g ( 95 . 5 %). [ α ] 25 d =+ 43 . 9 ° ( c 1 . 2 , toluene ); 1 h nmr ( cdcl 3 , 360 mhz ) δ 7 . 35 - 7 . 30 ( m , 2h ), 7 . 24 - 7 . 14 ( m , 3h ), 2 . 94 - 2 . 85 ( m , 2h ), 1 . 76 - 1 . 53 ( m , 5h ), 1 . 25 - 1 . 14 ( m , 2h ), 1 . 06 ( d , j = 7 . 77 hz , 3h ), 0 . 95 - 08 . 0 ( m , 1h ), 0 . 87 ( dd , j = 3 . 77 hz , 7 . 89 hz , 6 h ), 0 . 49 ( d , j = 9 . 30 hz , 3h ); 13 c nmr ( cdcl 3 ) δ 138 . 83 ( d , j = 30 . 49 hz ), 130 . 69 ( d , j = 12 . 2 hz ), 127 . 71 ( d , j = 2 . 87 hz ), 126 . 45 ( s ), 53 . 38 ( d , j = 6 . 34 hz ), 48 . 63 ( d , j = 17 . 06 hz ), 41 . 97 ( d , j = 13 . 4 hz ), 40 . 51 ( d , j = 9 . 96 hz ), 37 . 60 ( d , j = 11 . 09 hz ), 37 . 39 ( d , j = 9 . 74 hz ), 33 . 03 ( d , 6 . 11 hz ), 31 . 86 ( s ), 21 . 89 ( s ), 21 . 78 ( s ), 21 . 23 ( s ), 20 . 40 ( s ); 31 p nmr ( cdcl 3 ) δ - 7 . 49 . the procedures are exemplified by the experiments carried out with ligand 7 in toluene . to a stirring solution of [ pd 2 ( η 3 - c 3 h 5 ) 2 cl 2 ] ( 3 . 0 mg , 0 . 008 mmol ) in toluene ( 1 . 5 ml ) was added ligand 7 ( 0 . 36 ml of 0 . 1 m solution in toluene , 0 . 036 mmol ) under a nitrogen atmosphere . after 30 mins , racemic 1 , 3 - diphenyl - 1 - acetoxypropene ( 150 mg , 0 . 60 mmol ) was added . then the solution was allowed to be stirred 30 mins . n , o - bis ( trimethylsiyl ) acetamide ( 0 . 44 ml , 1 . 8 mmol ), dimethyl malonate ( 0 . 21 ml , 1 . 8 mmol ) and potassium acetate ( 3 mg , 0 . 03 mmol ) were added in this order . the reaction was monitored by tlc ( eluent : hexane / ethyl acetate = 10 / 1 ). after 1 . 5 hrs , tlc showed the reaction was over . after the solvent was evaporated in vacuo , column chromatography on silica gel ( eluent : hexane / ethyl acetate = 10 / 1 ) of the residue yielded the pure product : yield : 190 mg , 97 . 7 %. the optical purity was determined to be 95 . 5 % ee by bplc ( daicel chiralcel od column , 1 ml / min , hexane / 2 - propanol = 99 / 1 ). to a solution of chloro ( 1 , 5cyclooctadiene ) iridium ( i ) dimer ( 2 mg , 0 . 003 mmol ) in toluene ( 4 ml ) was added a solution of bicp in toluene ( 0 . 1 m , 71 ul , 0 . 0071 mmol ), the resulting solution was stirred in glovebox for 30 min . then phthalimide ( 3 . 5 mg , mmol ) was added and the reaction mixture was stirred for another 30 min before 2 , 3 , 3 - trimethylindolenine ( 96 ul , 0 . 6 mmol ) was added . the reaction tube was placed in an autoclave , pressurized with hydrogen to 1000 psi after several exchange with hydrogen , and stirred at rt for 65 h . conversion ( 97 . 8 %) and enantiomeric excess ( 92 . 2 %) were determined by gc ( a capillary column : γ - dex - 225 ). to the suspension of nah ( 8 . 0 g , 333 mmol ) in thf ( 200 ml ), cooled to 0 ° c ., was added 1 , 2 - diphosphinobenzene ( 4 . 0 ml , 30 . 4 mmol ), followed by hmpa ( 80 ml ). the resulting orange suspension was stirred at 0 ° c . for 1 h . ( 1s , 2s , 4s , 5s )- 2 , 5 - dimethylcyclohexane - 1 , 4 - diol dimesolate ( 18 . 3 g , 60 . 9 mmol ) in thf ( 150 ml ) was added over 20 min . the resulting orange - red suspension was stirred at rt for 3 . 5 days , hydrolyzed with nacl - h 2 o and then extracted with hexane ( 2 × 100 ml ). the combined organic solution was dried over na 2 so 4 . after filtration , the solvents were removed under reduced pressure . the residue was subjected to chromatography on silica gel column , eluted with hexane . yield : 3 . 0 g ( 27 . 5 %). 1 h - nmr ( cdcl 3 ): δ h = 7 . 25 - 7 . 10 ( m , 2 h , aromatic ), 7 . 08 - 6 . 95 ( m , 2 h , aromatic ), 3 . 21 ( d , broad , 2 h , 2 j ( ph )= 14 . 5 hz , pch ), 2 . 58 ( d , broad , 2 h , 2 j ( ph )= 13 . 4 hz , pch ), 1 . 90 - 1 . 60 ( m , 12 h ), 1 . 55 - 1 . 35 ( m , 2 h ,), 1 . 17 ( d , 6 h , 3 j ( hh )= 6 . 3 hz , ch 3 ), 0 . 60 ( d , 6 h , 3 j ( hh )= 6 . 3 hz , ch 3 ). ch . 13 c - nmr ( is out of first order , cdcl 3 ): δ c = 143 . 94 , 143 . 66 , 143 . 48 , 143 . 20 , 131 . 05 , 131 . 00 , 130 . 93 , 126 . 33 , 46 , 24 , 46 . 20 , 46 , 17 , 46 . 13 , 45 . 92 , 45 . 69 , 45 . 61 , 45 . 38 , 40 . 17 , 40 . 05 , 39 . 89 , 39 . 73 , 39 . 61 , 39 . 52 , 39 . 33 , 39 . 29 , 39 . 26 , 34 . 76 , 34 . 61 , 34 . 51 , 34 . 41 , 34 . 26 , 22 . 69 , 22 . 65 , 22 . 61 , 20 . 82 . 31 p - nmr ( cdcl 3 ): δ p =- 7 . 3 ppm . 1 , 2 - diphosphinobenzene ( 0 . 4 ml , 3 . 04 mmol ) and nah ( 0 . 9 g , 37 . 5 mmol ) were mixed in thf ( 50 ml ) and cooled to 0 ° c . hmpa ( 8 . 5 ml , 49 mmol ) was added . the resulting orange suspension was stirred at 0 ° c . for 1 h and then ( 1s , 2s , 4s , 5s )- 2 , 5 - dimethyl - cyclohexane - 1 , 4 - diol dimesolate ( 2 . 17 g , 6 . 08 mmol ) in thf ( 40 ml ) was added over 10 min . the resulting orange - red suspension was stirred at rt for 3 days . after cooled to 0 ° c ., it was hydrolyzed with nacl - h 2 o , and extracted with hexane ( 2 × 50 ml ). the combined organic solution was dried over na 2 so 4 and filtered . the solvents were removed under reduced pressure . the residue was subjected to chromatography on silica gel column , eluted with hexane . yield : 0 . 6 g ( 42 %). 1 h - nmr ( cdcl 3 ): δ h = 7 . 20 - 7 . 10 ( m , 2 h , aromatic ), 7 . 05 - 6 . 90 ( m , 2 h , aromatic ), 3 . 38 ( d , broad , 2 h , 2 j ( ph )= 14 . 2 hz , pch ), 2 . 85 ( d , broad , 2 h , 2 j ( ph )= 13 . 5 hz , pch ), 1 . 85 - 1 . 45 ( m , 12 h ), 1 . 30 - 1 . 08 ( m , 4 h ), 1 . 03 ( d , 6h , 3 j ( hh )= 6 . 4 hz , ch 3 ), 0 . 96 ( d , 6h , 3 j ( hh )= 5 . 6 hz , ch 3 ), 0 . 86 ( d , 6h , 3 j ( hh )= 6 . 5 hz , ch 3 ), 0 . 47 ( s , 6 h , ch 3 ). 13 c - nmr ( is out of first order , cdcl 3 ): δ c = 143 . 97 , 143 . 62 , 143 . 56 , 143 . 50 , 143 . 45 , 143 . 09 , 130 . 96 , 130 . 90 , 130 . 86 , 126 . 11 , 54 . 10 , 54 . 06 , 54 . 03 , 48 . 65 , 48 . 56 , 48 . 46 , 42 . 02 , 41 . 96 , 41 . 24 , 41 . 20 , 41 . 18 , 41 . 14 , 37 . 94 , 37 . 77 , 37 . 60 , 37 . 46 , 33 . 29 , 33 . 27 , 33 . 24 , 31 . 69 , 23 . 45 , 23 . 40 , 23 . 35 , 22 . 22 , 20 . 97 , 20 . 54 , 31 p - nmr ( cdcl 3 ): δ p =- 8 . 7 ppm . 1 , 2 - diphosphinobenzene ( 0 . 20 ml , 1 . 52 mmol ) and nah ( 0 . 40 g , 16 . 7 mmol ) were mixed in thf ( 50 ml ) and cooled to 0 ° c . hmpa ( 4 . 3 ml , 25 mmol ) was added . the resulting orange suspension was stirred at 0 ° c . for 1 h and then treated with ( 1r , 1 &# 39 ; r , 2s , 2 &# 39 ; s )- 1 , 1 &# 39 ;- bicyclopentyl - 2 , 2 &# 39 ;- diol bismesylate ( 0 . 993 g , 3 . 04 mmol ) in thf ( 40 ml ). the resulting orange - red suspension was stirred at rt for 20 h , pale orange - yellow suspension formed . after cooled to 0 ° c ., it was hydrolyzed with nacl - h 2 o , and extracted with hexane ( 2 × 50 ml ). the combined organic solution was dried over na 2 so 4 and filtered . the solvents were removed under reduced pressure . the residue was subjected to chromatography on silica gel column , eluted with hexanelether ( 40 : 1 . 5 ). yield : 0 . 42 g ( 67 %). 1 h - nmr ( cdcl 3 ): δ h = 7 . 50 - 7 . 30 ( m , 2 h , aromatic ), 7 . 25 - 7 . 10 ( m , 2 h , aromatic ), 3 . 15 - 2 . 95 ( m , 2 h , pch ), 2 . 85 - 2 . 70 ( m , 2 h , pch ), 2 . 50 - 2 . 30 ( m , 4 h , ch ), 2 . 05 - 1 . 00 ( m , 24 h , ch 2 ). 13 c - nmr ( is out of first order , cdcl 3 ): δ c = 144 . 03 , 143 . 98 , 130 . 16 , 130 . 12 , 130 . 08 , 127 . 50 , 53 . 64 , 52 . 97 , 44 . 72 , 44 . 66 , 44 . 60 , 43 . 07 , 32 . 64 , 32 . 01 , 31 . 86 , 31 . 68 , 30 . 58 , 26 . 47 , 25 . 41 , 25 . 36 , 25 . 31 . 31 p - nmr ( cdcl 3 ): δ p = 9 . 6 ppm . in a glovebox , a schlenk reaction bottle was charged with a given amount of rh catalyst precursor and me - pennphos in a ratio of 1 . 1 mol ligand per 1 mol rh and 10 ml of the given solvent ( dried and degassed ), the resulting orange - yellow solution was stirred at rt for 20 min . then substrate ( 1 mmol , sub / cat = 100 ) was added . the nitrogen atmosphere was exchanged to h 2 by flashing the schlenk with h 2 . the reaction mixture was then stirred at rt and 1 atm h 2 for a certain period of time . the reaction solution was passed through a short silica gel , washed with ether . the conversion and ee were measured by gc analysis on chirasil - val iii column . the absolute configuration was determined by measuring the rotation of product and comparing with the corresponding standard values . in a glovebox , a reaction bottle was charged with [ rh ( cod ) cl ] 2 ( 2 . 5 mg , 0 . 0101 mmol ) and me - pennphos ( 3 . 7 mg , 0 . 0103 mmol ), and meoh ( 10 ml , dried and degassed ), the resulting orange - yellow solution was stirred at rt for 30 min . then ketone substrate ( 1 mmol , substrate / catalyst = 100 ) was added . the reaction solution was then placed in an autoclave . the nitrogen atmosphere was exchanged to h 2 by flashing the autoclave with h 2 ( 10 to 20 atm ). the autoclave was pressurized to a certain atmosphere of h 2 . the reaction mixture was then stirred at rt for a given period of time . the reaction solution was then passed through a short silica gel , washed with ether . the conversion and ee were measured by gc analysis on chiral β - dex 120 column . the absolute configuration was determined by measuring the rotation of product and comparing with the corresponding standard values . bicp ( 0 . 01 mol ) and ru ( cod )( 2 - methylallyl ) 2 ( 0 . 01 mol ) were placed in a 10 ml schlenk tube and the vessel was purged with argon . 2 ml of anhydrous acetone were added . to this suspension was added methanolic hbr ( 0 . 11 ml of a 0 . 29 m solution ) and the suspension was stirred 30 min at rt . the solvent was thoroughly evaporated under vacuum and the ru ( bicp ) br 2 obtained was used immediately . the solution of appropriate substrate ( 1 mmol ) in degassed solvent ( 2 ml ) was placed in a 10 ml schlenck tube and degasses by 3 cycles of vacuum / argon . this mixture was added to the catalyst ( 1 %) in a glass vessel and placed under argon in 300 ml stainless steel autoclave . the argon atmosphere was replaced with hydrogen . the hydrogenations were run under the reaction conditions given the solvent was removed under pressure . conversion and ee are determined by chiral gc column β - dex 120 and γ - dex 225 . the above examples illustrate the present invention and are not intended to limit the invention in spirit or scope . 1 . 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