Login| Sign Up| Help| Contact|

Patent Searching and Data


Title:
ORTHO SUBSTITUTED CHIRAL PHOSPHINES AND PHOSPHINITES AND THEIR USE IN ASYMMETRIC CATAYLTIC REACTIONS
Document Type and Number:
WIPO Patent Application WO/2002/040491
Kind Code:
A1
Abstract:
3,3'-substituted chiral biaryl phosphine and phosphinite ligands and metal complexes based on such chiral ligands useful in asymmetric catalysis are disclosed. The metal complexes are useful as catalysts in asymmetric reactions, such as, hydrogenation, hydride transfer, allylic alkylation, hydrosilylation, hydroboration, hydrovinylation, hydroformylation, hydroformylation, olefin metathesis, hydrocarboxylation, isomerization, cyclopropanation, Diels-Alder reaction, Heck reaction, isomerization, Aldol reaction, Michael addition, epoxidation, Kinetic resolution and [m+n] cycloaddition. The metal complexes are particularly effective in Ru-catalyzed asymmetric hydrogenation of beta-ketoesters to beta-hydroxyesters and Ru-catalyzed asymmetric hydrogenation of enamides to beta amino acids.

Inventors:
Zhang, Xumu (276 Camelot Lane State College, PA, 16803, US)
Application Number:
PCT/US2001/043779
Publication Date:
May 23, 2002
Filing Date:
November 16, 2001
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
THE PENN STATE RESEARCH FOUNDATION (304 Old Main University Park, PA, 16802, US)
International Classes:
C07B53/00; C07B61/00; C07C45/50; C07C45/72; C07C67/303; C07C67/317; C07C67/343; C07C69/67; C07C231/12; C07C231/18; C07C233/04; C07C303/40; C07C311/16; C07F9/46; C07F9/48; C07F9/50; C07F9/645; C07F9/655; C07F9/6571; C07F9/6574; C07F9/6584; C07F15/00; C07C233/05; C07C233/06; C07C233/47; (IPC1-7): C07F9/06; C07F9/141; C07F9/50; C07F9/535; C07F9/655
Foreign References:
US5312996A1994-05-17
Other References:
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS (COLUMBUS OH, USA); SRIGES, W. ET AL.: "Method for the preparation of optically active trimethylactic acid and its esters", XP002909218, accession no. STN Database accession no. 2001:885409
DATABASE CAPLUS [online] CHEMICAL ABSTRACT, COLUMBUS OH, USA; ZHANG ET AL.: "Synthesis of chiral bisphoshines with tunable bite angles and their applications in asymmetric hydrogenation of .beta.ketoesters", XP002909219, accession no. STN Database accession no. 2000:574233
See also references of EP 1341797A4
Attorney, Agent or Firm:
Greeley, Paul D. (Ohlandt, Greeley Ruggiero & Perle, L.L.P. One Landmark Squar, 10th Floor Stamford CT, 06901-2682, US)
Download PDF:
Claims:
WHAT IS CLAIMED IS:
1. A ligand represented by the formula or its enantiomer: wherein each X and X'is independently selected from the group . consisting of : alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2; wherein each Z and Z1 is independently selected from the group consisting of : alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2; or wherein Z and Z1 together form the bridging group ABAI ; wherein each Z', Z", Zl'and Zi"is independently selected from the group consisting of : H, alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2; or wherein Z'and Z together form the bridging group A'BA; Z'and Z together form a fused cycloaliphatic or aromatic group; Z, and Zl'together form the bridging group Al BIAl' ; and/or Z1 and Zl'together form a fused cycloaliphatic or aromatic group; wherein each A, A', Al and Al'is independently selected from the group consisting of : O, CH2, NH, NR, S, CO and a bond; wherein each B and Bl is independently selected from the group consisting of : linear, branched or cyclic alkylene of 1 to 6 carbon atoms, arylene of 6 to 12 carbon atoms, O, CH2, NH, NR, S, CO, SO2, P (O) R, P (O) OR, POR, SiR2 and a bond; wherein each T is independently selected from the group consisting of : alkyl, substituted alkyl, aryl, substituted aryl, alkoxide, aryloxide, R, R', R", YR', YR", Y'R'and Y"R" ; or wherein two T groups together form an alkylene, arylene, alkylenediamino, arylenediamino, alkelenedioxyl or arylenedioxyl; wherein each T'is independently selected from the group consisting of : alkyl, substituted alkyl, aryl, substituted aryl, alkoxide, aryloxide, R, R', R", YR', YR", Y'R'and Y"R"; or wherein two T'groups together form an alkylene, arylene, alkylenediamino, arylenediamino, alkelenedioxyl or arylenedioxyl; wherein each R, R'and R"is independently selected from the group consisting of : alkyl, substituted alkyl, aryl, aralkyl and alkaryl of 1 to 22 carbon atoms; or wherein two R groups, two R'groups or two R"group together form an alkylene, arelene or substituted arylene group; and wherein each Y, Y'and Y"is independently selected from the group consisting of : O, CHZ, NH, S and a bond between carbon and phosphorus; with the proviso that when the Y group at the 2'position is a bond between carbon and phosphorus, X'is hydrogen.
2. The ligand of claim 1, wherein said substituted alkyl has one or more substituents, each independently selected from the group consisting of : halogen, ester, ketone, carboxylic acid, hydroxy, alkoxy, aryloxy, thiol, alkylthio and dialkylamino.
3. The ligand of claim 1, wherein said alkylene is selected from the group consisting of compounds represented by the formula : (CH2) n, wherein n is an integer in the range of from 1 to 8.
4. The ligand of claim 1, wherein each of said aryl groups optionally has one or more substituents, each independently selected from the group consisting of : halogen, ester, ketone, sulfonate, phosphonate, hydroxy, alkoxy, aryloxy, thiol, alkylthiol, nitro, amino, vinyl, substituted vinyl, carboxylic acid, sulfonic acid and phosphine.
5. The ligand of claim 1, wherein each of said arylene groups optionally has one or more substituents, each independently selected from the group consisting of : halogen, ester, ketone, sulfonate, phosphonate, hydroxy, alkoxy, aryloxy, thiol, alkylthiol, nitro, amino, vinyl, substituted vinyl, carboxylic acid, sulfonic acid and phosphine.
6. The ligand of claim 1, wherein each of said arylene groups is independently selected from the group consisting of : 1,2divalent phenyl, 2,2' divalent1, 1'biphenyl, 2,2'divalent1,1'binaphthyl and ferrocene.
7. The ligand of claim 1, wherein said ligand is a racemic mixture of enantiomers.
8. The ligand of claim 1, wherein said ligand is a nonracemic mixture of enantiomers.
9. The ligand of claim 1, wherein said ligand is one of the enantiomers.
10. The ligand of claim 1, having an optical purity of at least 85% ee. t.
11. The ligand of claim 1, having an optical purity of at least 95% ee.
12. The ligand of claim I, wherein said ligand is selected from the group consisting of compounds represented by the following formulas: wherein each X and X'is independently selected from the group consisting of : alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2; wherein each Z and Z1 is independently selected from the group consisting of: alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2 ; or wherein Z and Z I together form the bridging group ABAi ; wherein each Z', Z", Zl'and Zi"is independently selected from the group consisting of : H, alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2 ; or wherein Z'and Z together form the bridging group A'BA; Z'and Z together form a fused cycloaliphatic or aromatic group; Z) and Zt'together form the bridging group At BiA)' ; and/or Z) and Zl'together form a fused cycloaliphatic or aromatic group; wherein each A, A', Al and Al'is independently selected from the group consisting ouf0, CH2, NH, NR, S, CO and a bond; wherein each B and Bl is independently selected from the group consisting of : linear, branched or cyclic alkylene of 1 to 6 carbon atoms, arylene of 6 to 12 carbon atoms, O, CH2, NH, NR, S, CO, SO2, P (O) R, P (O) OR, POR, SiR2 and a bond; wherein each YR', YR", Y'R'and Y"R"is independently selected from the group consisting of: alkyl, substituted alkyl, aryl, substituted aryl, alkoxide and aryloxide ; or wherein two YR', YR", Y'R'or Y"R"groups together form an alkylene, arylene, alkylenediamino, arylenediamino, alkelenedioxyl or arylenedioxyl; wherein each R, R'and R"is independently selected from the group consisting of : alkyl, substituted alkyl, aryl, aralkyl and alkaryl of 1 to 22 carbon atoms; or wherein two R groups, two R'groups or two R"group together form an alkylene or arelene group; and wherein each Y, Y'and Y"is independently selected from the group consisting of : O, CH2, NH, S and a bond between carbon and phosphorus; with the proviso that when the Y group at the 2'position is a bond between carbon and phosphorus, X'is hydrogen.
13. The ligand of claim 1, wherein said ligand is selected from the group consisting of compounds represented by the following formulas: wherein each X is independently selected from the group consisting of : alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2 ; wherein each X'is independently selected from the group consisting of : hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2 ; wherein each Z and Z, is independently selected from the group consisting of : alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2; wherein each Z', Z", Zz'and Zl"is independently selected from the group consisting of : H, alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2 ; wherein each A, A', A, and Al'is independently selected from the group consisting of : O, CH2, NH, NR, S, CO and a bond; wherein each B and B X is independently selected from the group consisting of : linear, branched or cyclic alkylene of 1 to 6 carbon atoms, arylene of 6 to 12 carbon atoms, O, CH2, NH, NR, S, CO, SO2, P (O) R, P (O) OR, POR, SiR2 and a bond; wherein each R and R'is independently selected from the group consisting of : alkyl, substituted alkyl, aryl, substituted aryl, aralkyl and alkaryl of 1 to 22 carbon atoms, alkoxide and aryloxide; or wherein two R groups or two R'groups together form an alkylene, arelene, alkylenediamino, arylenediamino, alkelenedioxyl or arylenedioxyl groups.
14. The ligand of claim 1, wherein said ligand is selected from the group consisting of compounds represented by the formulas: 'PPhz g C02Et h PPh2 /PP hz I I . rP Ph1 PPhz PPhx .. IPPh2.,. PP ti,. 11., PPh, CH3 3 vPPh2 Xph2 L4 cl OCN S'M 83 NMe2 \ PH Ilk , PPh1 I _PPhi : WPhz I \ WPhz ciOCHz WSIMe3 NMe2 L5 L6 L7 L8 cFb CH3 CH3 P (C6FS) 2 P (pMephenyl), P (3. sd im et h ylp he ny 1) 2 +'P (pMephenY2 % P (3, sd imethylph en yl) 2 L9 Ll0 Ll l L9 LIO L11 ¢4PCy2 XP (sdstBophenyl) 2 CHZ I (POMephenyl) 2 1. 1P (pOMephenyl), .,. P (pOMephenyi) x cH c i L12 L13 L14 L14 CH, CH, cl3 FirCFrphenyljx P (a, sdCFphenyl) z// P (pNMeZphenylh ,. gP (pCF3phenyl) 2.'P (3, 5dCF3phenA) 2 *'CH3 CHa CHa I// CHa L15 L16 L17 P iPr \ \ M SPh // I P r XPOPPhz lc T ¢4oPPh2 XOPPhz Pr // Pr 4ooph, US Ou pr i SPh Pr i L18 Ph L19 Me SPh Lug , Pr Pr L20 L21 : OPPhZ \ : OPPhre,. OPPhx,. OPPh= '\ \ \ \ : //// CONHPh SiMea gpb L22 L24 L25 L26 Oh \ h \ 'OP (CsFs) x OP (pMaPhenyl) Z OP (asdmenylphenY9z ..., OP (CGFS) 2... IOP (pMephenyl) 2.. IOP (3, 5dimethypherTyl) 2 / i I// L. 29 Ph L. 3 Ph l Ph I \ h \ Ph Ph I OPCY2 OP (3, sditBuphenyl) 2 Ph OP (pOMepherryl) 2 L3. L.. *OPCy2. .. L..'OPh. sd'tBuphenyR ! Ph Ph / /h L32 Ph L33 Ph Ph L34 h Ph Ph 'OP (PCFpherryl) 2 OP (, rdrCFaphyly// T OP (pNMe2phenyl) z "OP (pCFPhYD2.. OP (3, 5dCF3pharryl) 2 .... OP (pNMa2phanyl) 2 Ph Ph h L35 L36 L37 IPrwD Ihr h SPh i I ' i <CH2PPh2 vCH2PPh2 t\CH2Pph2 eCHzPPh t>CH2PPh < ; h2 ff2\CH2PPh2 &k*CH2PPh2 .,'CH, PPh, Pu L38 g L40 L41 SPn Pur Pur CONHPH SMe3 SIP o vCH2PPh2 H CHzPPh2 \4CH2PPh2 eCH2PPh2 .,. CH2PPh2.., CH2P Ptl CH2PPh2... CH2PPh2 WSCONHPh ! H2P p // CONHPh S'M//SiPh,, L43 L44 L45 I Ph \ \ h \ Ph CH2p (C6Fs) 2 CH2P (pMephenyi) 2 CH2P (3, 5d me fiylphenyl) 2 .. CH2P (C. 6Fs) 2 CH 2P (pM epheny 02.., C FP (3, 5 dTn ethypnY') 2 // H pu Ph \ \ CH2PC CH2P (3, 5ditBuphenyl) 2 'CH2P (PoMophonyf) 2 \ .,. CHsPCyx . wCHzP (asdrEBrphenyl olé . , I'l L49 L50 L51 h pu Ph I XC (p CF3pherryo2 CH2P (3, 5diCF3phenyl) 2 2P (pNMe2phBrVI) 2 CH 2 P (p CF3Ph en yl) 2 CH 2 P (3 rd C F.p he n y2 L52 L53 L54 geh pu Ph Pu L52 L53 L54 IPrrq iPr \ Ph Me \ \ ( \ \ SPh (//Pr/f NHPPth NHPPhz NHPPh2 'NNPPhx t > NHPPh2 g NHPPh2 ¢ßsNHPPh2 sNHPPh2 L 51 6X ict L55 L56 P+lPr L57 L58 CONHPH SIP h, V vNHPPh2 'NHPP NHPPhx//NHPPhz 'SN H P P N NHPPti2.. NHPPh2 (///// CONHPh SlMe3 WSIPh L59 L60 L61 L62 I I \ \ Ph \ Ph \ Ph N HP (CA F5) 2 NHP (pMephenyi) 2 NH P (3, s drn ethyp he ny2 NH P (C ! Fs) 2 t NhP (pMephenyl) 2 twNHp (3sdnethylsheryl) 2 I//I// Ph Ph Ph Lb3 Lb5 \ h \ Ph \ Ph NHPCyz NHP (, rdf6Bopheny0z I/P NHP (POMephenyn :. NNPCyZ I \ yNHP (adEtBuptterryl) Z : NHP (p0MePherry) : "zut //// L66 Pu oh L67 Ph XN H P (p CF3shenYl) 2gN H P (, 6d FC Frph9nY02 XN HP (pN Me2phenyl) 2 NHP (pNMerphenyl) 2 Ph'LkL L66 L67 ; NHP (pCFrphenyl) 2. NHP (3, sdiCF,pherryl) z L69 Ph Ph Ph Ph I/Ph // Ph L70 L71 OCH, [tCH3 CO2Et wPh H3CO@Ph CFb C02Et h. bc CH3 Ph \ //f/ IbCCl. pPhz PPha hhCC PPh7 L...PPh2 HCC4..."PPh : O'.'PP' H, CO..PPh, I CH3 CH3 LIOI C02Et Ph H3C P h Li osa C tu \ CHa I \ Svte,, \ CH i HzC4CH3 12 SfMe3 tCH TACO. Ip ptv H3CO..PP h2 HC IPPh2 \. H3COttPPhc % I StMe3 L107 CH3 L1040CH3 L 105 L106 OCH3 CH3 CH3 I y I . I HsCO >PPh2 tP (pMrFpherlyl) 2 ° 9 P (3, s dimethykphenyl) 2 YrP Y n H3COsh, : PPh2 °sS"ç (PMe phenyl) 2 oOh, ç (35dImethylpher, yl) 2 LI08/OH'LI 9 CH' CH, LI 0 CL3 w. '//I CHa d PCy='P (,. sdEBuphenyO2/ ''T PfpOMepheny CH3 CH3 k1), CFb . : P (frOMepherryl} oc3 oc L111 L112 L113 \ oCH, ocH MBa/P (PCFaphertyl) x HaCO/F (asdrCFrpheny9z HaCO I/P (PNMe=phenylh HjCO T PfpNMerpheny M02"q (PCF3phenyl) 2 HC,"P (3, sdiCF3pherryl) 2 H, NCO .. (PNMe=pherrylh CF OCH3 OCH3 OCH :) Ll 14 Ll 15 Ll 16 tp iPr Ph Me h 'pur lcB'.. . OPPIIZ OPPra ETOOC OPPE FIC , OPPhz sOPPhZ ,. aPPh= ., PPh2 Pu /Ph I .'I / L117 MA Ph LIl8 Lll9 L120 iPr iPr CONHPH S'Me3 siph3 OPPH ! OPPhz CO OPPt CO/OPPIU OPPh2 XOPPh2 H3COtoPPh2 HsCQ<OPPh2 H3C<opPh2 /I/I \ I/ CONHPh SiMe3 SPh, L121 L122 L 123 L124 Oh IN HaCO OP (CsFs) : Hno OP (pMephenyl HaCO OP (, sdmeihylpherryl) z Fbco""'P (CaFs) 2 H, C'OP (pMephyi) Vi, C,)... IOP (3, sdimelhyphonyiz oc /Ph Ph/Ph L125 L126 L127 h Ph Oh HaCO'OPCyz H3COJ% OP (6dFtBuphenylh <Ph WjCO"r OPfpOMheny H3CO, sOPCy2 H3Co, ="OP (3, sdlt i3vFph6nyi) 2 Ph HC. ; Zz. I Ph I/Ph I/ Ph Ph L129 L130 Ph Ph h H% 3 CO'OP (pCF3pherlyf) 2 H3CO OP (3, schCF3phanY] H3CO OP (pNM"hony42 CO'..'OP (pCF3phenyt) : n, eOs. ...'OP (3. !dCFjpheny)), H, CO.. JL.. <OP (pNMe2pheny)) : Ph Ph Ph Ph L131 Li32 L133 L (33 ip V Pr Ph \ Me \ SPh //iPr/ HsCO HCO CNxPPha CPPt CCIxPPhx r CH2PPTu ffico... CH2PPN H3CO..., CH2PPh2"CH2PPh2... CPPh2 Pu / L134 L135 1pr iPr L136 Me L137 SPh ihr dur N. C H : i A OCH3 >SMe3 ~ SIPhs H, C0, 6,'CHPPh FC"CH2PPh2 HC CH2pPhz Fbc..CH2PPQ /OCH/SiMe ( SiPh, L138 L139 L140 L141 Ph \ Ph /CH2P (CsFsn Ha CH2P (pMephenyl) 2 H3CO/CH2P (3sdmelthylphenyl) 2 .,% CH2P (CaFS) 2 H3CO.... CH ? (PMOPhertYD2 H3CO CH2P (3, sdimethyphenYI) 2 BPh wPh uPh L142 Ll43 L144 Ph Ph Oh Ph \ pu H3CO CH2PCy2 H3C CH2P (dttBuphenyl) 2 H3CO'GH2P (p~OMrrphenyl), H, Co v bç +*CH*Cy2 H3CoK > > cH2p (zl6dlt8uFphenyìk H3C C H2 P (p0 M aph en Yl) 2 Ph Ph L145 L146 (, 147 Ph Ph \ oh h Me2N CHzP (pCFaphanyl) z HCO/CIiP (. sdCFphenyl) a ) HCO r CHzPpNMezphenyth Ph Ph /I f HaCO ; CHaP (rNMerphenyl) x Pu L148 L149 L150 L150 iP iPr \ oh \ \ Me Ph 'PUR i /P r/ H. NHPPh2 NHPPfp HCO NHPPhz MezN NHPPha H, Co NHPPh2..,. NHPPti2 FBCO NHPPh2 Me2... NHPPt, / an L152 L153 L154 L151 iar Pr CONHPH S'Me3 StPh I V NHPPhz H3COtNPPh2 XNHPPh2 H3COtNHPPh2 XNHPPhz N HP H3C°¢E » NHPPh2 twNHPPh2 H3Co¢5sNHPPh2 EPh2 i CONNPh/SiMee SPft LISS L156 Lut57 L158 CC P h Ph i o tJHPPt S6C0 NHP (pMephenyl) W6C0 NHP (a, sdmethylphernyl . : NHPPhx HC ; NhP (Mepherryl) : HCO. NHP (a, sdmelhylphenyl) x / Ph Ph Ph L159 L160 L161 h h Ph I \ I \ I\ NHPCy HCO/NIiP (, sdfEBttpheryl) i H, CO NHP (pOMepherryl) = ..., NHPCY2 H, C"N Vi P (3 rd FlBuph en YI) 2 H r, NliP (pOMephonY)) 2 Fh I/Ph I/Ph L162 L163 L164 Ph NHP(pCFaphenylnNHP (ydiCF3phenyny/ 'N HP (ErN Mezphenyi « _>,.NH P (pC F3phenY Ih 9, NHP (,, ; dlCFph enyl) 2 //i I \ ., Ph Ph/ L165 L166 L167 Lt67 CH3 C02Et Ph oWCH3 0 PPtu O/PPhx 3 P IPPH, ..PP R /CH I/. /. 'coze L198 Ph o p L196 L197 L199 o"f y \ OClil \ Sdvle NMea PPh : PP/PPu O 'PPIu . PPt I . : PPhx p I ; PPhz ; PPhz 112 / Nome1 Laoo ° zoi °cH Co sM, L202 1203 CH3 0 c6 CH3 P (CoF5) 2 P (pM"heriyl) 2 0 P (3, rrdirnothylphanyN .."P (CeFs) 2.."P (PMoPhYQ2 IP (3. sdimethylphonYI) 2 HOCH, 0 0 L204 L205 L206 Gin CHa \ CH PCYz PG. sdtBupherryl) = P (POMephyl) = ..'PCY2., P (FomepherlYD2 W=CHSaipoMePhery9z cHa c i L207 L208 L209 CH3 cb CHEZ °$(PFaphenyx/PinsdCFpherrylk 'PfpNMezphenyfh . L,.. . CF. pny.. .... .. d. CF. pheny. 1,. ., , CHa CH CH L210 L211 L212 CH3 iP iPr su h \ / TPr Opp OPPh2 opph, OP Ph2 ""L""'"'" / Pu/ Mu L213 L214 Pr L215 L216 '\ CONHPh 0' SiMe /' OPPhz OPPh2 040PPN OPPI, 2 OPPh2 \,., OPPh2 I . ;. OPPhx \,. OPPhz .. OF'Phz . ph WCONHPh ° SlMes 51Phs < L217 t218 Ph h \ h Oh 0/I I/ OP(C F) 2 0% P (pMephenyl) 2 CSOP (3 sdmethylphenyl) > 0"'OP (C5F5... OP (pMephenyN.... OP (3, sdimeliyphenyl) 2 Off.OC L23I L232 Oh h Oh OPCYZ OP (35dkBupheryi) 2 Ph OP (pOMaphenyly OPCY2 OP (35dtBL'phenyt) 2 OP (pOMephenyl) 2 . I Ph Ph L233 L234 L235 Ph Ph Ph Ph Ph OP(p,CFyphY02 OP (3, 5diCF3phonyl) 2 OP (pNMe2pherrjfQ2 T OPfpNMMpheny C oP (pCF3pherlylk Ct^OPf dFCF3pheny02 (sCP (p N Me2sheny42 Ph Ph I/ Ph Ph L236 L237 Ph L238 iP i iPr, Ma pu \ I, IPr I I OWGH2PPh2 ihr CH2PPN CH2PPh2 Cii2PPh2 ChPPh2 GH2PPta Pur L239 L240 L241 Me L242 Ph Pr ip r, iPr iP r CH PP 0 CFt=PPhx 0. CHP .... CFPPh. CHzPPh2 CFi2PPh2 0.CH2PPh2 2 L243oNHPh C ONH Ph L244 L245 L246 Cp Ph \ h Ph CHxPPh CVP (PMephenyl) 2 CH2P (3, sdanethylpherryl) 2 0 CHzP (PMephenyl) 2 CHp (3, sdmehylphenyl) 2 Ph Ph M, Ph Pu h Oh CH2PCY2 CFbP (3. sdtBuphenyl) 2 Ph ... CH2PCY2."CH2P (3, 5dilBuphenyQ ?."CFbP (pOM"hanyl) 2 CC. L252 Ph Ph Ph Ph Ph 'Ph CH2P (pCFsphenyk CH2P (3. SchCF3phenyl) 2 .nCltzP (pCFpherry) z. 'CHxP (, sdHCFphenyln L L254"'"' Ph Ph L253h L254P h Ph LZ55 tp 1pr Ph Me SPh / \ ip f w NHPPha NHPPhr NHPPtI NHPPh N'p L yil 58 L9 Pu /Ph I/// Mu L256 L257 p i P L258 L29 SPh CONHPH SMe3 SPh3 vNH PPh2 v N HP Ph2 eN HP Ph2 wNHPPh2 NHPPN NHPPh2 NHPPh2 % NHPPh2 Ho F L260 L26) L262 L263k P h \ Ph Ph 'NHP (CaFs) x NNP (p. Mepherryl) 2 NHP (, sdmethylpherryl) x NHP (CsFs) 2.. NhP (pMephenyQ ? NHP (mdimetiylphenyl) 2 // Ph L265 Ph L26h Ph Ph Oh NH [4NHP (3, 5dFtB Fphenylk > T NHP (pOMephenyl) 2 INHPCy2 NHPfisditBUpheoyl) 2 ,,. NHP (pOMepherrylJ L267 l. 268 Ph L 69 Ph Ph Ph Ph NHP(pCFphenyl) Z NHP (, sdCFapheryl) z I/ 'NHP (pNMei. phenyx ) > K"sNHp (pcFapheny02 1, *NHP (atsdFCFaophenyl) 2 <1 XPh W>Ph 0t > NHP (pNMe2phenYlk Ph Ph L270 L271 Ph L272 CHa C02Et Ph \. /PPt'I d I/PPh d PPhx PPh= z I : : PPhx C \ :, p, \. : PPhz CO ; PPh : h 301 CH'L302 CE L303 ph L304 i CH3 \ SiMe CHo \ PPhx PPhx C''PPhz H PPhz p \,. PPh= 0 . : PPtu p\ \. : WPfu H . PPh7 ho ."*p Pti, 2 0 FPPh2 CH YPPh2 L305 L306 L307 oCHa \ CH, CHa i PPhx PiPMephenyl) Z d... P (, sdmethyEphenyly c".PPh, c", P (pMePhenYI) 2.... P (3, sd ime thylp he nyl) 2 C. C,. OCHm I CHa CH L309 L310 L312 CF+ I \ CHa / CY2 a'P (3, sdi Btiph en yl) 2 P (pOMepheriyrh tcy2 tP (ssdFBBuphenyl) 2 tO<@pOMe phenylz Ph Y4z (L3I3 Ha I CH L314 L315 C OCIb \ OCH, ocb oh3 0 Me, ; : PPhx.. Phx R \.,. pPh : / CH OG !I OCh6 L316 L317 L318 IPrD tPr me pu h lpf Me Ph \ c ; *, OPPh2 0 P Ph, oppa OPPh2 OPPH, Pu Ph I I "''L320 Jj. L32 ! L322 i a,CONHPH SiMe3 SIPN OPPtu C OPPhz/'p OPPhz OPPhs .OPPh2. 'OPPIIZ0.. OPPh, 00., Opptu . % Oppt L323 L324 L325 L326 w Ph Ph Ph w W OP (CsFse 0 OP (p. Mephenyl) i O OP sdmelfhylphenyl) 2 Swo>Ct°P (c5Fd2 {op (pMephenyl) 2 \ oshB"oP", s4mehyKpheny42 \./ L327 Ph L328 Ph Ph Ph Ph Oh OPCyz C OP (a, sdrtBuphenyl) z F (pOM pherryIx snOPCya p ;. OP (a sdr68uphenyl) z R Ph c Ph"OP (pOMephenyl) 2 /Ph/Ph I/ L330 L 331 L332 P h Ph Ph h Ph OP (pCFaPharryl) x OP CF OP (3sdHCFrphenypa OP (pNMerphenyl) x ot" RO O I ;. OP (, sWCFnpberry) z O ,,. ZIP (pNMe2phenyOx / Ph/ L333 L334 Ph L335 P h iP iPr Ph Y i/dr h [Pr Me Ph (CH2PPh2 o<M2 COt CH2PPh2COtCH2PPh2 zur Ph M e L336 L33, # L338 L339 ocb, $kM e3 sip u i i i 0 CH2P Ph2 Cli2PPh2 0 CtiPptl, CF12PPh2 0."CH2PPh2 CO.. :, CH, PPh,."CH2PPh2 , CHzp Pk OCHa SiMe,, SiPh/ L340 L341 L342 L343 Oh h HxP (CeFs) x' CHzP (pMephenYOx Co H2Piasdimethylphenyi) z .... CH2P (CFs) 2 ,.,..,CHiP (pMephenyl) 2 c 0 CFP (3,5dimethyphonyl), L344 L345 L346 L344Ph L 5 Ph L346 h h h \ oh ) j/0 r CHPtpOMepheny . CH2PCy2 p. CFt2P (, sdEBuphenyl) a \.. CHxP (pOMephenyl) x 347Ph 48 h' Ph L349 h h Ph CHzP (pCFapharryl) z I CFhP (a. sdCFapherryl) x/ , CNzP (p. CFrphenyz O CHiP (p_NMezpheny) z CN '. CHzP (sdrCFaphenYh > ;. P (p NMerphenyl) 2 Ph Ph Ph Ph/ L350 P h L31 L352 iPr Me Ph / TPr i N p ( ;.. NHPPha \ \ (,. NHPPhi 0 , NHPPhx CH . NHPPhx \. Pur / Pu Pur (pur CONHPh \ SiMea gip NH pph 0 N HPP a NHPPh2 NHPPh2 0 NHPPh2 o... NHPPhz"NHPPh2.. NHPPa CO... NHPPh2 L357CONHPh SIMea % 9 Seh Lp L358 Ph \ Ph e w NHPPhz C NHP (pMepherryl) x 0 NHP (sdmethy4pharryl) z R"Ou¢ sNHPPh2 tL>*Nhp (pMephenyl) 2 totNHp (Zsdlmethylphenyl) 2 " /I/ Ph Ph P h Ph Ph Ph Ph P h Ph NHPC. yz l\ NHP (, sdtBuphenyl) z'0 NHP (pOMephenylk NHPCy2 RO NH P (3, sdFtB uphany 1) 2 NHP (pOMephenyl) 2 Ph h Ph \ h Ph \ Ph h Ph 0 NHP (pCF3phony% 0 NHP (3AdiC F3phenyr) 2 tu NHP (pNMe=phenr 0 NHP (pCFpheqyj) z INHP (, % 5dCF3phenyj) 2 . Ph Ph Ph L367 L368 L369 L369 15.
15. The ligand of claim 1, represented by the formula: or wherein each R is independently selected from the group consisting of : alkyl, aryl, substituted alkyl, substituted aryl and SiR3; and wherein each Ar is independently selected from the group consisting of : phenyl, substituted phenyl, aryl and substituted aryl.
16. The ligand of claim 1, represented by the formula :.
17. The ligand of claim 1, represented by the formula:.
18. A catalyst prepared by a process comprising: contacting a transition metal salt, or a complex thereof, and a ligand selected from the group consisting of compounds represented by the formula or its enantiomer: wherein each X and X'is independently selected from the group consisting of : alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2; wherein each Z and Z1 is independently selected from the group consisting of: alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2; or wherein Z and Zi together form the bridging group ABAu ; wherein each Z', Z", Z1' and Z1" is independently selected from the group consisting of : H, alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2 or wherein Z'and Z together form the bridging group A'BA; Z'and Z together form a fused cycloaliphatic or aromatic group; Z and Z,'together form the bridging group Al BlAI'; and/or Z, and Zl'together forrm a fused cycloaliphatic or aromatic group; wherein each A, A', Al and Al'is independently selected from the group consisting ouf0, CH2, NH, NR, S, CO and a bond; wherein each B and B, is independently selected from the group consisting of : linear, branched or cyclic alkylene of 1 to 6 carbon atoms, arylene of 6 to 12 carbon atoms, O, CH2, NH, NR, S, CO, SO2, P (O) R, P (O) OR, POR, SiR2 and a bond; wherein each T is independently selected from the group consisting of : alkyl, substituted alkyl, aryl, substituted aryl, alkoxide, aryloxide, R, R', R", YR', YR", Y'R'and Y"R" ; or wherein two T groups together form an alkylene, arylene, alkylenediamino, arylenediamino, alkelenedioxyl or arylenedioxyl ; wherein each T'is independently selected from the group consisting of : alkyl, substituted alkyl, aryl, substituted aryl, alkoxide, aryloxide, R, R', R", YR', YR", Y'R'and Y"R" ; or wherein two T'groups together form an alkylene, arylene, alkylenediamino, arylenediamino, alkelenedioxyl or arylenedioxyl; wherein each R, R'and R"is independently selected from the group consisting of : alkyl, substituted alkyl, aryl, aralkyl and alkaryl of 1 to 22 carbon atoms; or wherein two R groups, two R'groups or two R"group together form an alkylene or arelene group; and wherein each Y, Y'and Y"is independently selected from the group consisting of : O, CH2, NH, S and a bond between carbon and phosphorus; with the proviso that when the Y group at the 2'position is a bond between carbon and phosphorus, X'is hydrogen.
19. The catalyst of claim 18, wherein said substituted alkyl has one or more substituents, each independently selected from the group consisting of : halogen, ester, ketone, carboxylic acid, hydroxy, alkoxy, aryloxy, thiol, alkylthio and dialkylamino.
20. The catalyst of claim 18, wherein said alkylene is selected from the group consisting of compounds represented by the formula :(CH2) n, where n is an integer in the range of from 1 to 8.
21. The catalyst of claim 18, wherein each of said aryl groups optionally has one or more substituents, each independently selected from the group consisting of : halogen, ester, ketone, sulfonate, phosphonate, hydroxy, alkoxy, aryloxy, thiol, alkylthiol, nitro, amino, vinyl, substituted vinyl, carboxylic acid, sulfonic acid and phosphine.
22. The catalyst of claim 18, wherein each of said arylene groups optionally has one or more substituents, each independently selected from the group consisting of : halogen, ester, ketone, sulfonate, phosphonate, hydroxy, alkoxy, aryloxy, thiol, alkylthiol, nitro, amino, vinyl, substituted vinyl, carboxylic acid, sulfonic acid and phosphine.
23. The catalyst of claim 18, wherein each of said arylene groups is independently selected from the group consisting of : 1, 2divalent phenyl, 2,2' divalent1, I'biphenyl, 2,2'divalent1, 1'binaphthyl and ferrocene.
24. The catalyst of claim 18, wherein said ligand is a racemic mixture of enantiomers.
25. The catalyst of claim 18, wherein said ligand is a nonracemic mixture of enantiomers.
26. The catalyst of claim 18, wherein said ligand is one of the enantiomers.
27. The catalyst of claim 18, having an optical purity of at least 85% ee.
28. The catalyst of claim 18, having an optical purity of at least 95% ee.
29. The catalyst of claim 18, wherein said transition metal is selected from the group consisting of : Ag, Pt, Pd, Rh, Ru, Ir, Cu, Ni, Mo, Ti, V, Re and Mn.
30. The catalyst of claim 18, wherein said transition metal is selected from the group consisting of : Pt, Pd, Rh and Ru.
31. The catalyst of claim 18, wherein said transition metal salt, or complex thereof, is selected from the group consisting of : AgX; Ag (OTf) ; Ag (OTf) 2 ; AgOAc; PtCla ; H2PtCI4 ; Pd2 (DBA) 3; Pd (OAc) 2; PdCl2 (RCN) 2; (Pd (allyl) Cl) 2 ; Pd (PR3) 4 ; (Rh (NBD) 2) X ; (Rh (NBD) CI) 2 ; (Rh (COD) Cl) 2 ; (Rh (COD) 2) X; Rh (acac) (CO) 2 ; Rh (ethylene) 2 (acac); (Rh (ethylene) Cl) 2 ; RhCI (PPh3) 3; Rh (CO) 2Cl2 ; RuHX (L) 2 (diphosphine), RuX2 (L) 2 (diphosphine), Ru (arene) X2 (diphosphine), Ru (aryl group) X2; Ru (RCOO) 2 (diphosphine); Ru (methallyl) 2 (diphosphine); Ru (aryl group) X2 (PPh3) 3; Ru (COD) (COT); Ru (COD) (COT) X; RuX2 (cymen) ; Ru (COD) n ; Ru (aryl group) X2 (diphosphine); RuC12 (COD); (Ru (COD) 2) X; RuX2 (diphosphine); RuCl2 (=CHR) (PR'3) 2 ; Ru (ArH) C12 ; Ru (COD) (methallyl) 2 ; (Ir (NBD) 2Cl) 2 ; (Ir (NBD) 2) X; (Ir (COD) 2Cl) 2; (Ir (COD) 2) X; CuX (NCCH3) 4; Cu (OTf) ; Cu (OTf) 2 ; Cu (Ar) X; CuX; Ni (acac) 2 ; NiX2 ; (Ni (allyl) X) 2 ; Ni (COD) 2; MoO2 (acac) 2; Ti (OiPr) 4; VO (acac) 2 ; MeRe03 ; MnX2 and Mn (acac) 2; wherein each R and R'is independently selected from the group consisting of: alkyl or aryl; Ar is an aryl group; and X is a counteranion.
32. The catalyst of claim 31, wherein L is a solvent molecule and wherein said counteranion X is selected from the group consisting of : halogen, BF4, B (Ar) 4, wherein Ar is fluorophenyl or 3,5ditrifluoromethyl1phenyl, C104, SbF6, PF6, CF3S03, RCOO and a mixture thereof.
33. The catalyst of claim 18, prepared in situ or as an isolated compound.
34. The catalyst of claim 18, wherein said transition metal salt, or a complex thereof is selected from the group consisting of : [Rh (COD) CI] 2, [Rh (COD) 2] X, [Ir (COD) CI] 2, [Ir (COD) 2] X, Rh (acac) (CO) 2, Ni (allyl) X, Pd2 (dba) 3, [Pd (allyl) Cl] 2, Ru (RCOO) 2 (diphosphine), RuX2 (diphosphine), Ru (methylallyl) 2 (diphosphine) and Ru (aryl) X2 (diphosphine), wherein X is selected from the group consisting of : BF4, C104, SbF6, CF3S03, Cl and Br; and wherein said ligand is selected from the group consisting of compounds represented by the formula: (a) wherein each R is independently selected from the group consisting of: alkyl, aryl, substituted alkyl, substituted aryl and SiR3; and wherein each Ar is independently selected from the group consisting of : phenyl, substituted phenyl, aryl and substituted aryl; (b) (c) (d) and a combination thereof.
35. A process for preparation of an asymmetric compound comprising: contacting a substrate capable of forming an asymmetric product by an asymmetric reaction and a catalyst prepared by a process comprising: contacting a transition metal salt, or a complex thereof, and a ligand selected from the group consisting of compounds represented by the formula or its enantiomer: wherein each X and X'is independently selected from the group consisting of : alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2 ; wherein each Z and Z is independently selected from the group consisting of : alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2 ; or wherein Z and Z together form the bridging group ABAI ; wherein each Z', Z", Zl'and ZI"is independently selected from the group consisting of : H, alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (0) (OR) 2 and P (OR) 2, or wherein Z'and Z together form the bridging group A'BA; Z'and Z together form a fused cycloaliphatic or aromatic group; Z, and Zl'together form the bridging group A, B)A)'' ; and/or Z ; and Z ;' together form a fused cycloaliphatic or aromatic group; wherein each A, A', Al and Al'is independently selected from the group consisting of: O, CH2, NH, NR, S, CO and a bond; wherein each B and B, is independently selected from the group consisting of : linear, branched or cyclic alkylene of 1 to 6 carbon atoms, arylene of 6 to 12 carbon atoms, O, CH2, NH, NR, S, CO, SO2, P (O) R, P (O) OR, POR, SiR2 and a bond; wherein each T is independently selected from the group consisting of : alkyl, substituted alkyl, aryl, substituted aryl, alkoxide, aryloxide, R, R', R", YR', YR", Y'R'and Y"R" ; or wherein two T groups together form an alkylene, arylene, alkylenediamino, arylenediamino, alkelenedioxyl or arylenedioxyl ; wherein each T'is independently selected from the group consisting of : alkyl, substituted alkyl, aryl, substituted aryl, alkoxide, aryloxide, R, R', R", YR', YR", Y'R'and Y"R" ; or wherein two T'groups together form an alkylene, arylene, alkylenediamino, arylenediamino, alkelenedioxyl or arylenedioxyl; wherein each R, R'and R"is independently selected from the group consisting of: alkyl, substituted alkyl, aryl, aralkyl and alkaryl of 1 to 22 carbon atoms; or wherein two R groups, two R'groups or two R"group together form an alkylene or arelene group; and wherein each Y, Y'and Y"is independently selected from the group consisting of: O, CH2, NH, S and a bond between carbon and phosphorus; with the proviso that when the Y group at the 2'position is a bond between carbon and phosphorus, X'is hydrogen.
36. The process of claim 35, wherein said asymmetric reaction is selected from the group consisting of : hydrogenation, hydride transfer, allylic alkylation, hydrosilylation, hydroboration, hydrovinylation, hydroformylation, olefin metathesis, hydrocarboxylation, isomerization, cyclopropanation, Diels Alder reaction, Heck reaction, isomerization, Aldol reaction, Michael addition, epoxidation, kinetic resolution and [m+nj cycloaddition wherein m = 3 to 6 and n =2.
37. The process of claim 36, wherein said transition metal is selected from the group consisting of : Ag, Pt, Pd, Rh, Ru, Ir, Cu, Ni, Mo, Ti, V, Re and Mn.
38. The process of claim 36, wherein said asymmetric reaction is hydrogenation and said substrate is selected from the group consisting of : imine, ketone, ethylenically unsaturated compound, enamine, enamide and vinyl ester.
39. The process of claim 36, wherein said asymmetric reaction is a silvercatalyzed asymmetric [3 +2] cycloaddition of an azomethine ylide with a dipolarophile.
40. The process of claim 36, wherein said asymmetric reaction is a palladiumcatalyzed allylic alkylation and said substrate is an allylic ester.
41. The process of claim 36, wherein said asymmetric palladium catalyzed allylic alkylation reaction is a kinetic resolution reaction and said substrate is a racemic allylic ester.
42. The process of claim 36, wherein said asymmetric reaction is hydrogenation, said substrate is a betaketoester, said transition metal is Ru and said asymmetric compound is a betahydroxyester.
43. The process of claim 36, wherein said asymmetric reaction is hydrogenation, said substrate is an enamide, said transition metal is Ru and said asymmetric compound is a beta amino acid.
44. The process of claim 36, wherein said ligand is selected from the group consisting of compounds represented by the formula: (a) wherein each R is independently selected from the group consisting of : alkyl, aryl, substituted alkyl, substituted aryl and SiR3; and wherein each Ar is independently selected from the group consisting of : phenyl, substituted phenyl, aryl and substituted aryl ; (b) (c) (d) and a combination thereof.
45. The process of claim 44, wherein said asymmetric reaction is hydrogenation, said substrate is a betaketoester, said transition metal is Ru and said asymmetric compound is a betahydroxyester.
46. The process of claim 44, wherein said asymmetric reaction is hydrogenation, said substrate is an enamide, said transition metal is Ru and said asymmetric compound is a beta amino acid.
Description:
ORTHO SUBSTITUTED CHIRAL PHOSPHINES AND PHOSPHINITES AND THEIR USE IN ASYMMETRIC CATALYTIC REACTIONS BACKGROUND OF THE INVENTION 1. FIELD OF THE INVENTION The present invention relates to novel chiral ligands derived from 3,3'- substituted biaryl phosphines and phosphinites. More particularly, the present invention relates to transition metal complexes of these chiral phosphine ligands.

The transition metal complexes are useful as catalysts in asymmetric reactions, such as, hydrogenation, hydride transfer, allylic alkylation, hydrosilylation, hydroboration, hydrovinylation, hydroformylation, olefin metathesis, hydrocarboxylation, isomerization, cyclopropanation, Diels-Alder reaction, Heck reaction, isomerization, Aldol reaction, Michael addition, epoxidation, kinetic resolution and [m+n] cycloaddition.

2. DESCRIPTION OF THE PRIOR ART Discovery of new chiral ligands is crucial in developing highly enantioselective transition metal-catalyzed reactions. Many chiral ligands have been made for applications in asymmetric catalysis, however, relatively few of these chiral ligands are commonly used in industry for the synthesis of chiral molecules.

Several chiral ligands having a biaryl backbone are known in the prior art.

These are summarized below:

Among these ligands, BINAP (1) is one of the most frequently used chiral ligands. The axially dissymmetric, fully aromatic BINAP has demonstrated to be highly effective for many asymmetric reactions (Noyori, R. et al. Acc. Chem. Res.

1990,23,345, Ohkuma, T. et al. J. Am. Chem. Soc. 1998,120,13529). Recent results show that partially hydrogenated BINAP with a larger bite angle, H8- BINAP (2), is a better ligand for certain asymmetric reactions due to restriction of conformational flexibility (Zhang X. et al. Synlett 1994,501). Chiral BINAPO (3) was made and it was not effective due to the conformational flexibility (Grubbs, R. et al. Tetrahedron Lett. 1977, 1879). Other axially dissymmetric ligands such as BIPHEMP (4) and MeO-BIPHEP (5) were developed and used for a number of asymmetric reactions (Sclunid, R. et al. Pure & Appl. Chem. 1996, 68, 131 ; Schmide, R. et al. Helv. Chim. Acta, 1988,71,897). However, the present inventor is not aware of any examples of related 3,3' substituted chiral biaryl phosphines, the subject of the present invention, being disclosed in the prior art (Broger, E. A. et al., WO 92/16536 and Broger, E. A. et al., W093/15089).

NAPHOS (6), another example of a prior art compound has been prepared (Tamao, K. et al. Tetrahedron Lett. 1977,1389) and was found to be not effective for asymmetric hydrogenation reaction. The corresponding ligands with the N linker, BDPAB (7) and H8-BDPAB (8) have also been made and tested for asymmetric hydrogenation reactions (Zhang, F. et al. J. Am. Chem. Soc. 1998, 120, 5808).

SUMMARY OF THE INVENTION The present invention includes a ligand represented by the formula or its enantiomer : wherein each X and X'is independently selected from the group consisting of : alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2; wherein each Z and Zl is independently selected from the group consisting of : allcyl, aryl, substituted allcyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2; or wherein Z and Z1 together form the bridging group A-B-A1 ; wherein each Z', Z", Z1'and Zi"is independently selected from the group consisting of: H, alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2 ; or wherein Z'and Z together form the bridging group A'-B-A; Z'and Z together form a fused

cycloaliphatic or aromatic group; Z1 and Zl'together form the bridging group Al- B1-Al'; and/or Z1 and Zl'together form a fused cycloaliphatic or aromatic group; wherein each A, A', A1 and Ai'is independently selected from the group consisting of : O, CH2, NH, NR, S, CO and a bond ; wherein each B and B1 is independently selected from the group consisting of : linear, branched or cyclic alkylene of 1 to 6 carbon atoms, arylene of 6 to 12 carbon atoms, O, CH2, NH, NR, S, CO, SO2, P (O) R, P (O) OR, POR, SiR2 and a bond; wherein each T is independently selected from the group consisting of : alkyl, substituted alkyl, aryl, substituted aryl, alkoxide, aryloxide, R, R', R", YR', YR", Y'R'and Y"R" ; or wherein two T groups together form an alkylene, arylene, alkylenediamino, arylenediamino, alkelenedioxyl or arylenedioxyl; wherein each T'is independently selected from the group consisting of : allcyl, substituted alkyl, aryl, substituted aryl, allcoxide, aryloxide, R, R', R", YR', YR", Y'R'and Y"R" ; or wherein two T'groups together form an alkylene, arylene, allcylenediamino, arylenediamino, alkelenedioxyl or arylenedioxyl; wherein each R, R'and R"is independently selected from the group consisting of : allcyl, substituted alkyl, aryl, arallcyl and alkaryl of 1 to 22 carbon atoms; or wherein two R groups, two R'groups or two R"group together form an alkylene or arelene group; and wherein each Y, Y'and Y"is independently selected from the group consisting of: O, CH2, NH, S and a bond between carbon and phosphorus; with the proviso that when the Y group at the 2'position is a bond between carbon and phosphorus, X'is hydrogen.

The present invention further includes a catalyst prepared by a process, which includes: contacting a transition metal salt, or a complex thereof, and a ligand according to the present invention.

The present invention still further includes a process for preparation of an asymmetric compound including: contacting a substrate capable of forming an

asymmetric product by an asymmetric reaction and a catalyst prepared by a process including: contacting a transition metal salt, or a complex thereof, and a ligand according to the present invention.

The metal complexes are useful as catalysts in asymmetric reactions, such as, hydrogenation, hydride transfer, allylic alkylation, hydrosilylation, hydroboration, hydrovinylation, hydroformylation, olefin metathesis, hydrocarboxylation, isomerization, cyclopropanation, Diels-Alder reaction, Heck reaction, isomerization, Aldol reaction, Michael addition, epoxidation, kinetic resolution and [m+n] cycloaddition. The metal complexes are particularly effective in Ru-catalyzed asymmetric hydrogenation of beta-ketoesters to beta- hydroxyesters and Ru-catalyzed asymmetric hydrogenation of enamides to beta amino acids.

DETAILED DESCRIPTION OF THE INVENTION The present invention includes 3,3'-substituted chiral biaryl phosphines and phosphinites and related ligands for applications in asymmetric catalysis.

Introduction of 3,3'-substituted groups can restrict the rotation of substituents adjacent to the phosphines. Control of orientations of these groups around the phosphine can lead to effective chiral induction for asymmetric reactions. Metal complexes of these phosphines, phosphinites and related non-C2 symmetric ligands with ortho substitution are useful for a large variety of asymmetric reactions. A number of chiral ligands can be made having the desired structure in which the 3,3' positions are substituted, with the proviso that at least one ortho position is occupied by a group other than H atom.

In the non-C2 symmetric ligands, ortho substituted groups play an important role for asymmetric catalysis. The 3,3' substituted chiral biaryl phosphines, phosphinites and related ligands of the present invention are

described below. An important feature of these ligands is that at least one of the 3 and 3'positions must be occupied by a group other than hydrogen.

The ligands are represented by the formula: wherein each X and X'is independently selected from the group consisting of : alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2; wherein each Z and Z1 is independently selected from the group consisting of: alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2; or wherein Z and Z1 together form the bridging group A-B-Al ; wherein each Z', Z", Zl'and Zi"is independently selected from the group consisting of : H, alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2; or wherein Z'and Z together form the bridging group A'-B-A; Z'and Z together form a fused cycloaliphatic or aromatic group; Z1 and Z1'together form the bridging group Ai- B1-Al'; and/or Z1 and Zl'together form a fused cycloaliphatic or aromatic group; wherein each A, A', A1 and Ai'is independently selected from the group consisting of : O, CH2, NH, NR, S, CO and a bond; wherein each B and B1 is independently selected from the group consisting of : linear, branched or cyclic alkylene of 1 to 6 carbon atoms, arylene of 6 to 12

carbon atoms, O, CH2, NH, NR, S, CO, SO2, P (O) R, P (O) OR, POR, SiR2 and a bond; wherein each T is independently selected from the group consisting of : alkyl, substituted alkyl, aryl, substituted aryl, alkoxide, aryloxide, R, R', R", YR', YR", Y'R'and Y"R" ; or wherein two T groups together form an alkylene, arylene, alkylenediamino, arylenediamino, alkelenedioxyl or arylenedioxyl ; wherein each T'is independently selected from the group consisting of : alkyl, substituted alkyl, aryl, substituted aryl, alkoxide, aryloxide, R, R', R", YR', YR", Y'R'and Y"R" ; or wherein two T'groups together form an alkylene, arylene, alkylenediamino, arylenediamino, alkelenedioxyl or arylenedioxyl; wherein each R, R'and R"is independently selected from the group consisting of : alkyl, substituted alkyl, aryl, aralkyl and alkaryl of 1 to 22 carbon atoms; or wherein two R groups, two R'groups or two R"group together form an alkylene or arelene group; and wherein each Y, Y'and Y"is independently selected from the group consisting of : O, CH2, NH, S and a bond between carbon and phosphorus; with the proviso that when the Y group at the 2'position is a bond between carbon and phosphorus, X'is hydrogen. Preferably the alkylene group includes compounds represented by the formula :- (CH2)"-, wherein n is an integer in the range of from 1 to 8. The present invention also includes the corresponding enantiomer of each of the above ligands.

The substituted alkyl group can have one or more substituents and each substituent can independently be halogen, ester, ketone, carboxylic acid, hydroxy, alkoxy, aryloxy, thiol, alkylthio or dialkylamino. The aryl groups can optionally have one or more substituents, each of which can independently be halogen, ester, ketone, sulfonate, phosphonate, hydroxy, alkoxy, aryloxy, thiol, alkylthiol, nitro, amino, vinyl, substituted vinyl, carboxylic acid, sulfonic acid or phosphine. The arylene groups optionally can have one or more substituents, each of which can independently be halogen, ester, ketone, sulfonate, phosphonate, hydroxy, alkoxy, aryloxy, thiol, alkylthiol, nitro, amino, vinyl, substituted vinyl, carboxylic acid,

sulfonic acid or phosphine. Preferably, each of the arylene groups can be 1,2- divalent phenyl, 2,2'-divalent-1, 1'-biphenyl, 2,2'-divalent-1, 1'-binaphthyl or ferrocene, i. e., a-Fc-group.

In a preferred embodiment, the present invention includes compounds represented by the following formulas:

wherein each X and X'is independently selected from the group consisting of : alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2 ; wherein each Z and Zl is independently selected from the group consisting of : alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2; or wherein Z and Z1 together form the bridging group A-B-Al ; wherein each Z', Z", Zl'and Zi"is independently selected from the group consisting of : H, alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2; or wherein Z'and Z together form the bridging group A'-B-A; Z'and Z together form a fused cycloaliphatic or aromatic group; Zl and Z1' together form the bridging group AI- B1-A1'; and/or Zl and Zl'together form a fused cycloaliphatic or aromatic group; wherein each A, A', Al and Al'is independently selected from the group consisting of : O, CH2, NH, NR, S, CO and a bond; wherein each B and Bl is independently selected from the group consisting of : linear, branched or cyclic alkylene of 1 to 6 carbon atoms, arylene of 6 to 12 carbon atoms, O, CH2, NH, NR, S, CO, SO2, P (O) R, P (O) OR, POR, SiR2 and a bond; wherein each YR', YR", Y'R'and Y"R"is independently selected from the group consisting of: alkyl, substituted alkyl, aryl, substituted aryl, alkoxide and aryloxide; or wherein two YR', YR", Y'R'or Y"R"groups together form an alkylene, arylene, alkylenediamino, arylenediamino, alkelenedioxyl or arylenedioxyl; wherein each R, R'and R"is independently selected from the group consisting of : alkyl, substituted alkyl, aryl, aralkyl and alkaryl of 1 to 22 carbon atoms; or wherein two R groups, two R'groups or two R"group together form an alkylene or arelene group; and

wherein each Y, Y'and Y"is independently selected from the group consisting of : O, CH2, NH, S and a bond between carbon and phosphorus; with the proviso that when the Y group at the 2'position is a bond between carbon and phosphorus, X'is hydrogen.

In another preferred embodiment, the present invention includes compounds represented by the following formulas:

wherein each X is independently selected from the group consisting of : alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2 ; wherein each X'is independently selected from the group consisting of : hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2; wherein each Z and Zi is independently selected from the group consisting of : allcyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2; wherein each Z', Z", Zl'and Zi"is independently selected from the group consisting of : H, alkyl, aryl, substituted alkyl, substituted aryl, OR, SR, NR2, COOR, halide, SiR3, P (O) R2, P (O) (OR) 2 and P (OR) 2; wherein each A, A', Al and A1'is independently selected from the group consisting of : O, CH2, NH, NR, S, CO and a bond; wherein each B and B, is independently selected from the group consisting of : linear, branched or cyclic alkylene of 1 to 6 carbon atoms, arylene of 6 to 12 carbon atoms, O, CH2, NH, NR, S, CO, S02, P (O) R, P (O) OR, POR, SiR2 and a bond; wherein each R and R'is independently selected from the group consisting of : alkyl, substituted alkyl, aryl, substituted aryl, aralkyl and alkaryl of 1 to 22 carbon atoms, alkoxide and aryloxide; or wherein two R groups or two R'groups together form an alkylene, arelene, alkylenediamino, arylenediamino, alkelenedioxyl or arylenedioxyl groups.

The ligands of the present invention can be a racemic mixture of enantiomers. Preferably, the ligand is a non-racemic mixture of enantiomers, and more preferably, the ligand is one of the enantiomers. Preferably, the ligand has an optical purity of at least 85% ee, and more preferably, the ligand has an optical purity of at least 95% ee.

Selected examples of the chiral ligands according to the present invention are represented by the following formulas: CH3 C02Et Ph PPh2 /I I , .. ' Phz PPhz PPhz PPhz -IPPh2., PP h2,,, PPh 2 CH3 r COzEt L2 C I O H3 SiM e,, N Mex \ I \ I I \ PPh2 P Ph2 P Ph2 PPh2 ll-PP h2,. NPPh2 _,. IPP h2 _. % PPh2 ,. CI I/OCHs/SiMes I/NMez L5 L6 L7 L8 ¢gCH3 aCH3 CH3 P (C6F5) 2 P (p-Me-phenyl) 2 P (3, -dim ethyl-phenyl) 2 ,.. P (CGFs) 2-.,-% P (p-Me-phenYI) 2 (3, 5-dimethyl-ph enyl) 2 9 L10 L11 L CH, CH3 CH3 f 3 vPC h vP (3, s-di-t-Bu-phenyl) z P (p-OMe-phenyl) 2 _, PC yz., ' (s s-d i-t-Bu-ph en yl) 2 Ilk"-t /CHa/ CHs I/ L12 L13 L14 cFb L14 CH3 I CH'CH3 P(pCFs-phenyl) z P (3s-di-CF3-phenyl) Z I// T P (p-NMerpheny)) 2 e . L. P (p-CF3-pheny)) 2. .. ..,.-''P (3, s-di-CF3-pheny)) 2,... /CHs/CH3 I// CHUS CH3 L15 L16 L17 p iPr SPh /iP r ( OPPh2 PPh, OPPh2 OPPh2 hz ;. OPPYri \ \ (OPPhZ : 'OPPha ; OPPhz W. \. Me SPh L18 Ll9 p Pr L20 L21 I \ CONNPh \ SiMes \ \ SiPM i I i /OPPhx I/OPPhz I//OPPhz OPPhz \. \ : iOPPhx :. OPPhx ,, OPPh2 ,.. PPhz /CONHPh//SiMe3 /SiPtxs L22 L24 L25 L26 Ph Ph Ph i i 'OP (CsFs) x -OP (p-Mphenyl) 2 OP (3, s-dimethyl-phenyl) 2 L IOP (c6F5) 2... OP (p-Me-phenyl) 2.., OP (,, -dimethyl-phenyi) L29 Ph L30 Ph L31 Ph Ph Ph OPCy2/OP (3, s-di-t-Bu-phenyl) 2 I/ T OP (p-OMe-pheny)) 2 .. IOPCY2.. OP (3, s-di-t-Bu-phenyl) 2 .. OP (p-OMe-phenyl) z /i /i Ph Ph Ph /OP (p-CF3-phenyl) 2 OP (3, s-di-CF3-phenyl) x,/ 2 'OP (p-NM ez-phen yl) a (. OP (p-CF3-phenyl) Z : OP (a, s-t1i-CFe-phenyl) a \ ( ;. OP (pNMe2-phenyl) 2 I /// Ph Ph,/ ph L35 L36 L37 ! pur Pu Me I in r SPI CHaPPha/// CHZPPhz CHzPPhx (. CHZPPha-CNxPPhz . CH2PPhz , CH2PPh2 Ph p CH2PPh2 L38 g L40 M8 L41 SPh iPr SiMe3 \ CONNPh I SiMe3 I /CHzPPhz//CHzPPha//CHZPPhz//CHzPPhz t CH2PPh2, I,, CH2P Ph2 ICH PPh.., CH2PPh2 //// LA2 ONHPh L, 43 SiMe,, J SiPh3 L424 L45 L45 Oh /. i I// i HaPsFs) z CHzP (p-Me-pheny!) z CH2P (3s-dimethyl-phenyl) z , : CHxP (CsFs) z I ;. CHaP (pMe-phenyl) a ,"CHZP (3, sdimethyl-phenyl) Z //, i/ L46 'L48 Ph L47 Ph / L46 L48 oh Ph Ph Ph CH2PC CH2P (3, 5-di-t-Bu-phenyl) 2 'CHaP (p-OM e-pheny I) 2 CH2P Cy C H2 P (3, s-di-t-B u-p he n yl) 2 . CH2P (p-OMe-phenyl) 2 / Ph w L49 Lh I// Ph Ph Ph Ph t CH2P (p-CF-phenyl) 2 CH2P (3, s-dkCF3-phenyi) 2 'CN z P (p-NMez-ph e nyl) 2 . .., .--CH2P (p-CF3-phen) 2... .. jCH2P (3s-d !-CF3-pheny !) 2 i /Ph I// ph L52 L54 iP iPr \ Ph Me \ \ I \ SPh NHPPh2 I//TPr//// NH P Ph 2 NHPPh2 NH PP h2 (4 , ; NNPPha ; NNPPhz,.. NHPPh2 (NHPPh2 I \ \ \ //Ph I// I// L55 L57 Me SPh Ph i CONHPH SiMe3 SIP h3 I V POP NHPPhz g NHPPh2 f"NHPPh2 g+]"tNHpph2 f NHPPh2 ".'tu CONHPh Simas S ! P113 L59 L60 L61 Ph I \ Ph \ Ph Ph Ph Ph NHP (C6FS) 2 NHP (p-Me-phenyl) 2 NHP (3, s-dimethyphenyl) 2 , NHP (CsFs) z I :. NhP (p-Me-phenyi) 2 I \ \,,,. NHP ( s-dimethyl-phenyl) z //Ph/L64 Ph//Ph Pu pu \ Ph \ Ph Ph /NHPCya//NHP (3, sdi-EBu-phenyl) Z NHP (p-OMe-phenyl) 2 ..., NNHPCyz N H (NHP (3s-di-t-Bu-phenyl) 2 Ph Ph //Ph Ph I// L66 L67 Ph L68 \ oh NHP(p-CFs-phenyl) z NNP (3, -di-CF3-phenyl) Z I// 'NHP (p-NMe2-phenyl) 2 NHP ;. NHP (p-CFa-phenyl) z ,.. NHP (a, s-di-CFa-phenyl) x L69 Ph Ph Ph '//I/ Ph Ph// L69 Ph L70 L71 Oc :, | C H3 CO2Et Ph H3 COPh HaCd'.'PPhz PPh2 H3Cd PPh2 t"-PPh2 H3co<) <. : 8PPh2 z°+j". *PPh2 H3COg ; PPh2 H C 0 ., P P L 00 CH3 L O1 OZEt Ph H3C ph L1 2 L103pcH3 C H,.." \ CNa \ SiMe, \ CHa i H3Cd"PP H3C4CH3 D SiMe3 tCH3 H3CO *'.-p pfl2 H3CO..... pp t.... PP h2 H3C 9Ph2 H3CC) CH3 SiMe3 CH3 HQ40CH3 L105' L106 L107 OCH3 I/. I/ HaCO pp 0 p(p-Me-phenyl) 2 . P (3, s-dimethyl-phenyl) 2 H3C...-IPPh2 0... T (p-Me-phenyl) 2-'P (3 5-d imethyl-phenyl) 2 /OCH3/CNa' CN3 L108 L109 L110 CH, CH3 CHa "T'P (p-OMe-pheny)) ; P (p-OMe-phenyl) 2 p . : PCy2 ,. rP (ss-di-t-Bu-phenyl) a \.,. P (p-OMphenyl) Z /CHa I/CHa I/ L111 L112 CH3 L113 Oc3 OCH3 MetP/P (p-CFa-phenyl) x HaCO 1/P (3s-di-CF3-phenyl) 2 H3C0 I/P (p-NMe2-phenyl) 2 HaCO 1 Pfp-NMe-pheny Mez ; : P (p-CF3-phenyl) 2 H3C ... P (3, 5-di-CF3-phenyl) a CH3 OCH3 OCH3 CH3 OCHa I/ LOCHS Ll 14 L115 L116 r fY? TY fY" ip~ Pr Oh /iPr/ 0 PP 112 OPP 112 ETOOC OP PQ H3COttoPPh2 se$ vOpPh2 EtOOCt0o'OPPh2 'pur Ph I ( Me I/ L117 L119 L120 L 118 ipr iP r CONHPh SiMe I \ SiPYr,,. i OPPh2 H3O OPPh2 H3CO/OPPh2 H3C OPPh2 .. OPPh2 H3C OPPh2 H3C. 1OPPh2 H3CO.-OP Ph2 /I/li / CONHPh SiMea SiPha L121 L122 L123 L124 Ph \ Ph Ph OP (CeFs) 2 HaC I/OP (p-Me-phenyl) 2 H3CO I/OP (s, s-dimethyl-phenyl) 2 H3 C otOP (C3 F6) 2 H3 C tvOp (p-M e phenylh H3CO_tk OPf 3, 6-dimexh yi-phenyl) 2 zu Ph ph Ph L125 L126 L127 Ph Oh Ph HsCO OPCyz H3CO OP (36-di-t-Bu-phenyl) a H3CO'OP (p-OMe-phenyl) 2 H3CO A. wopcy2 H3CO w s"IOP (3, 6-di-t-Bu-phenyl) 2 Ph Ph Ph/Ph I/ L128 L129 L130 Ph Ph Oh H3C0/pp (p-CFa-phenyl) x H3p/OP (a, s-di-CFa-phenyl) x HaCO I/OP (p-NMe1-phenyl) Z H3CO.. OP (p-CF3-phenyl) 2 H3CO OP (3, 5-dCF3-phenyl) 2 H3C OP (p-NMe2-phenYi) 2 ils Oh L131 L132 L133 in ihr Ph \ M e \ SPh OiPr CH2PPh2 H3CO CH2PP 112 CH2PPh2 CH2PPN H3 CO. ICH2PPIV H3CO.., CH2PPh2 CH2PPh2.., CH2PPh2 . Pr /Ph I/I/Me/ L134 L135 Pr L136 L137 SPh iPr iPr 00 H3 SiM e3 SiP h, H3C0/CH2PPha N3CO'CH2PPh2 H3CO/CH2PPhz H3/cH2PPh2 H3COs}"-CH2PPh2 H3CO. CH2PPh2 H3CO CH2PPh2 H3COß CH2PPh2 OCH3/SiMea SiPFu L138 L139 L140 L141 Ph I \ Ph Ph i I/ CH2P (C6F5) 2 CH2P (p-Me-phenyl) 2 H3CO CH 2 P (3, 5-d ! me thyl-ph en YI) 2 ;. CH2P (C6Fs) 2 H3pC.., CH2P (p-Me-phenyl) 2 H3CO , : CH2P (3, s-dimethyl-phenyl) 2 pu Ph L142 L143 L144 ph Ph Oh H3C0'CHZPCy2 HaCO'CHZP (3s-di-t-Bu-phenyl) 2/ HaCO'CH2P (p-OMe-phenyl) Z 3 CH 2P CY2 H3C C H2 P (3, 5- di-t-B U-phenyl) : H3C .. CH2P (p-OMa-phenyl) 2 Ph/Ph I/ L145 L146 L147 Ph Oh Pu oh Me2N CH2P (p-CF3-phenyl) 2 H3CO CH2P (3, g-di-CF3-Phenyl H, CO CH2P (p-NMe2-phenyl) 2 Me2N. CH2P (p-CFs-phenyl) z HsGO'CNzP (p-NMez-phenyl) 2 Ph Ph Ph HsCO ,: CNxP (p-NMerphenyl) z Ph Ph/ L 148 L 149 Ph L150 PrW Pr Ph Me Ph \ i iP r/ H3Co) NHPPh2) tNHP) Ph2 H3Co) 7NHPPh2 Me2N7NHPPh2 H3COtsNHPPh2 th2 H3Cou¢>\NHPPh2 Me2g NHpPh2 'Pr Pu pu L151 L152 L153 Me L154 iPr iPr \ CONHPh SiMe I \ SiPh3 NHP2 H3C0 NHPPh2 NHPPh2 H3CO NHPPh2 H3Cot. NHPPh2 % \sNHpPh2 H3CotNHPPh2 tNHPPh2 I/,/ P h Ph Ph L155 L156 L157 L158 P h Ph Ph NHPPha HaCO NHP (p-Me-phenyl) z CO NHP (a, s-dimethyl-phenyl) z NH PPh2 H3C N hP (p-M e-p he ny 1) 2 HC0 N H P (3, 5-d im e thyl-ph en yl) 2 Ph P h P h L159 L160 L161 Ph Ph Ph \ I\ \ NHPCY2 HsCO/NHP (3, 5-di-bBu-phenyl) 2 HsCO/NNP (p-OMe-phenyl) 2 :, ,,,, NHP (3, -di-t-Bu-phenyl) 2 H3C... INHP (p-OML-phenYI) 2 /ph I/Ph I/Ph Po Ph Ph Ph L162 L163 L164 NHP (p-CF3-phenyl) z (3s rP 1'42 NHP (p-NMeZ-phenyl) z .. NHP (p-CF3-phenyl) x. NHP (3, 5-di-CF3-phenyl) 2 INHP (p-NMe2-phenyi) 2 /Ph//Ph// Ph L165 L166 L167 \ CHa \ COzEt Ph //I/ PP hz P Phz P Phz O/PPha . 'PPhz I \ :., PPhz I ., PPhZ., PPhx L196 3 CO2Et tL198 Ph °°tl L196 L197 L199 OCH3 C SiMe, NMez I i PPh2 P Ph, pptv PP 112 0 \/ L200 L201 L202 L203 L202 L203 CHa Cp CH3 CHs P (C6 F5) 2 0 P (p-Me-phenyl) 2 0 P (3, s-d im ethyl-pheny 1) 2 ,. : P (C6F5) 2.., P (p-Me-phenyl) 2 .., P (3, s-d imethyl-phen YI) 2 Ns Chl3 O/CHg L204 L205 L206 CH3 CH, //\ CHa PC P (ss-dt-Bu-phenyl) 2 P (p-OMe-phenyl) Z ,.,. N'Cya ,,. P (3, s-di-t-Bu-phenyl) x ,,. P (p-OMe-phenyl) 2 CHa CHs L207 L208 L209 CH3 \ CN3 CH3 P (p-CFa-phenyl) x Ptas-dCF3-phenyl) 2 'P (p-N Me2-p henyl) 2 . ..-Pfp-CFa-pheny)) . J-....'P (3. s-di-CF3-pheny !) 2 C"3/C. H3 L210 L211 CH3 L212 ip ! Pr Ph Me SPI /I iPr , OPPH-Opp , 0 OPP h2 OP Ph2 ,. OP Phx ;. OPPhz OP Ph2."OPPh2 0 OPPh2. OPPh2 -0 "Opp' L213 Me sPh L213 P2 i iPr L'15 L216 I CONHPH 0 SiMe3 si Pfb I OPPhz 0 OPPhZ OPPhz v-OPPhx , OPPhZ I , ;. OPPhz', ;. OPPhz , : 'Phz / WCONHPh ° SiMs3 9>SiPh3 < L217 , l g L219 Ph Ph P h / i I/ OP (CeFs) z OP (p-Me-phenyl) a OP ( s-dimethyl-phenyl) 2 0 OP (p-M e-p h en YI) 2 0 P (3, 5-di m e th yl-ph en YI) 2 L230 Ph Ph Ph Ph P h Hep h Pin /OPCyz/OP (a, s-di-t-Bu-phenyl) a I/ 'OP (p-OMphenyl) 2 XOPCy2 XOP (3 s-di-t-Bu-phenyl) 2 XOP (p-OMe-phenyl) 2 Ph I Ph L233 L234 L235 Ph Ph Ph Ph Ph OP (p-CF3-phenyl) p I OP (a, s-di-CFs-phenyl) z OP (p-N Mez-pheny I) z OP (p-CF3-phenyl) 2 OP (3, 5-dkCF3-phenyl) 2 I \ I \ \,. OP (p-NMe2-phenylz Ph I/ L236 L237 L238 L238 iPt-yiPr Me pu Ph Me Ph 'CHzPPhz CHZPPha CHzPPha CNZPPh2 .. CHzPPha,. CHaPP hz .,, CH2PPh2 /'Pr Oh L239 L240 L241 Me L ¢2 Ph Ihr ihr / Ihr ihr CONHph CH2PPh2 CH2PPC CH2PPIV .... CH2PPh2 H2PPh2... ICH2PPh2 < 0..., CH2PPh2 L243ONHPh 24sime, 45 siPn3 L246 W W 0 CHzPPhx'CH2P (p-Me-phenyl) 2 C H2 s-dimethyl-phenyl) 2 gsCH2PPh2 cjCH2P (p-Me-phenyl) 2 OaCH2P (3, s-dime6hyl-phenyl) 2 L247 Ph L248 Ph L249 Ph Ph Ph Ph CH2PCY2 C H2 P (3, s-dHt-BU-phenyl) z I/ T CH2P (P-OMe-pheny !) 2 O CH2PCy2 oaCH2P (3, 5-di-t-Bu-phenyl) 2 (g\. CH2P (p-OMe-phenyl) 2 I L250 Ph L251 L252 Ph Ph Ph Ph Ph Ph I CH2P (p-CF3-phenyl) 2 I CH2P (3, s-di-CF3-phenyl) 2 C Hz P (p-N Mez-p heny I) z , CHZP (p-CF3-phenyl) Z : CHaP (s, s-di-CFa-phenyl) a -CH2P (p C (: 'P h Ph L253 L254 L255 Ph L255 ip P » | P r Ph \ Me \ SPh /I iPr NHPPhh NHPPha NHPPha NHPPhZ XNHPPh2 3tNHPJPh2 OWNHPPh2 XNHPPh2 p Ph [ I/ L256 L257p ; Pr L258M8 L259 SPh I CONHPh \ SiMea \ SiPha NH p eNHPPh2 vNHPPh2 eNHPPh2 vNHPPh2 NH PP h2 NHPPh2 NHPPh2,, NH PPh2 CONHPh/SiMes L260 L261 L262 L263 L263 P h \ Ph Ph NHP (CsFs) x-NHP (p-Me-phenyl) Z NHP (a, s-dimethyl-phenyl) x (2CNHP (C6F6) 2 L NhP (p-Me phenyl) 2 tNHP (3, 6-dime6hyl-phenyl) 2 I L2sa P"L2 5 Ph L26 h Ph Ph Oh i NHPCyx NHP (s, s-di-t-Bu-phenyl) a I/ 'NHP (p-OMe-phenyl) 2 r. NHPCyz .,,. NHP (3, s-di-t-Bu-phenyl) 2 \ ; . NHP (p-OMe-pheny ) z P h P h Ph l \ Ph l Ph Ph NHP(p-CF3-phenyl) 2 NHP (a, s-di-CFa-phenyl) z 'NHP (p-NMerphenyl) x % NH P (p-C F3-p he ny 1) 2...-NHP (3, s-di-CF3-phenYI) 2 N H P (p-NM e2-ph e nyl) 2 ,,. NHP (p-NMez-phenyl) z Ph I/ tT7t"'Ph L270"''L272 CH3'CO, Et Ph Ph . IPPh2 C p tl2 C'PPh2 ; : PPhz C,, PP,. PPhz p .. PPhz / L301CH3 L302 Et L303 Ph L304 i CH3 '\ SiMe3 CHa W PPh2 p PI, 2 Ph2 0"-'PPI12 0. 11"'-'PP 112, IPPh2 CNa I I I/SiMea L308 L305 L306 L307 L308 OCH3 CH3 o||/CH3 / \ 0 P Me-hen I P P Y 1s P (ss-dimethy4phenyl) x . P (p-Me-phenyl) z < P (a, s-dimethyl-phenyl) 2 C. C.. CH3/C. H3/C"J L309 L310 L312 CNs CH3 CH3 P CY2 P (3, 5-di-l-Bu-phenyl) 2 P (p-0 M e-p he ny 1) 2 ,. : PCyz C,. P (s, s-di-t-Bu-phenyl) 2 c I c I c , L313 H3 I CHa L313 L314 > C H3 CH3 OCH3 OCH3 Cyme PPh2 '0'PPh2 e 0 I \ 'RO CH3 OCH3 OCH3 L316 L317 L318 in, ihr Me Ph P r PPh2 :. OPPhx G.. OPPhz ., OPPh2...-OPPh2 Eo.. IOPPh2 'Pr Ph I I / Pu mye ihr ihr i CONHPh \ SiMe3 SiPhr,, 0 0 OPPh2 0 OPPh2 0 OPPh2 / t<°>tdOPPh2 tOPPht <o>doPPh2 \ ONß OPPht CONHPh SiMe3 SiPh3 > L323 L324 L325 L326 Ph \ Ph \ Ph I i OP (CsFs) z C OP (p-Me-phenyl) 2 CO OP (3s-dimethyl-phenyl) 2 0.... OP (p-Me-phenyl) 2 OP (3, 5-dimethyphenY]) 2 L327 Ph L328 Ph L329 Ph Ph Ph Ph OPCy2 OP (3, s-di-t-Bu-phenyl) 2 I/ T OP (p-OMe-phenyt) 2 ; OPCyz 0 , : OP (a, s-di-tBu-phenyl) z R c. OP (p-OMe-phenYI) 2 Ph/Ph I/ L330 L331 L332 Ph L332 P h Oh Ph Ph CO OP (p-CFs-pherryl) z q/ p ;, OP (pCF3-phenyl) Z P (3$-di-CFa-phenyl) z OP (p-NMez-phenyl) z \ O 9 s,-OP (p-C F3-phenY92 t\ O ; OP (a, s-di-CFa-phenyl) x 0 ,, 'P (P-NMe2-phenyl) 2 RO 0... OP (3,5-di-CF3-phenYI) 2 0 L333 L334 Ph L335 Ph in Me Ph T OiPr CO/CNZPPh2 Go CHzPPhz C CHxPPhzCO CHsPPhx cl2 pu I/ L336 L338 Me L339 Ph L3r ; p r SiM es \ SiP M OCH3 p CHzPPhz '0 CH2PPh= 0 CNzPPha 0 CN2PPh2 < 0 CH2PPh2 c'CH2PPh2 oo.."CH2PPh2.,. ICH2P Ph2 /,///w SiM L340 L341 g L343" L340 L341 L342 L343 \ i i CNzP (C6F5) 2'0 CHzP (p-Me-phenyl) z C CHZP (as-dimethyV-phenyl) Z ... CH2P (C6F5) 2 0... CH2P (p-Me-phenYll) : Ph ,,.-Ph Ph L344 h L345 Ph L346 h Ph Ph Ph 0 CH2PCy2 CO CH2P (3s-di-t-Bu-phenyl) z 2 0 CH2P (p-OMe-phenyl) 2 . CH2PCy2 p (. CH2P (3. s-di-t-BU-phenyI) 2 pu pu L347" p. L349 Ph Pn I 'CHzP (p-CFa-phenyl) a \ Q CHxP (a, s-di-CFa-phenyl) z CO CH2P (p-NMeZ-phenyl) z NH 'NxP (p-CFa-phenyl) z, CH P-d ,, z (35 i-CF3-phenyl) 2 ', CH2P (p-NMe-phenyl) Z I/ Ph Ph I350 L351 L352 iP i iPr mye Oh \ Tir/ w w O NHPPhz NNPPh2 C NHPPhZ NH NHPPha c % NHPPli2 0.., NHPPh NHPPh2 N'p, L 36 L353 L355 Me L3 6 Ph L354iPr i iPr w CONHPh \ SiMes SiPhx, / W NHPPh NHPPhz 0 NHPPhz z NHPPh2 outNHPPh2"'NHP Ph2.,. INHPPli2 0"., NHPPh2 R I / L57CONHPh SiMe3 L359 SiPhs Ph P h Ph I Ph \ Ph NNPPhz NHP (p-Me-phenyl) Z O NHP (3, 5-dimethyl-phenyl) 2 Ft* c 0 N HP (3, s-dimethyl-phenyl) 2 , L361Ph I362 Ph L363 Ph Ph Ph Ph NHPCY2 NHP (3, s-di-t-Bu-phenYD2 NHP (p-OMe-phenYI) 2 o>4> NHPCy2 RO <NHP (3, s-di-t-Bu-phenyl) 2 <sNHP (p-oMe-phenyl) 2 Fla I L364 L365 L366 Ph Ph Ph NHP (p-CF3-phenyl) Z O I/NHP (ss-di-CFa-phenyl) 2 NHP (p-NMe2-phenyl) 2 P h Ph P h , . NHP (p-NMea-phenyl) z L367 L368 L369 L368 L369

The present invention also includes a catalyst prepared by a process comprising contacting a transition metal salt, or a complex thereof, and a ligand according to the present invention. The catalyst may be prepared in situ or as an isolated compound.

The catalyst of the present invention can be a racemic mixture of enantiomers. Preferably, the catalyst is a non-racemic mixture of enantiomers, and more preferably, the catalyst is one of the enantiomers. Preferably, the catalyst has an optical purity of at least 85% ee, and more preferably, the catalyst has an optical purity of at least 95% ee.

Suitable transition metals for the preparation of the catalyst include Ag, Pt, Pd, Rh, Ru, Ir, Cu, Ni, Mo, Ti, V, Re and Mn.

As mentioned above, the catalyst can be prepared by contacting a transition metal salt or its complex and a ligand according to the present invention.

Suitable transition metal salts or complexes include the following: AgX; Ag (OTf) ; Ag (OTf) 2 ; AgOAc; PtC12 ; H2PtCl4 ; Pd2 (DBA) 3; Pd (OAc) 2 ; PdCl2 (RCN) 2 ; (Pd (allyl) Cl) 2; Pd (PR3) 4; (Rh (NBD) 2) X; (Rh (NBD) C1) 2; (Rh (COD) Cl) 2; (Rh (COD) 2) X; Rh (acac) (CO) 2; Rh (ethylene) 2 (acac); (Rh (ethylene) 2Cl) 2; RhCl (PPh3) 3; Rh (CO) 2Cl2 ; RuHX (L) 2 (diphosphine), RuX2 (L) 2 (diphosphine), Ru (arene) X2 (diphosphine), Ru (aryl group) X2; Ru (RCOO) 2 (diphosphine); Ru (methallyl) 2 (diphosphine) ; Ru (aryl group) X2 (PPh3) 3; Ru (COD) (COT); Ru (COD) (COT) X; RuX2 (cymen); Ru (COD) n ; Ru (aryl group) X2 (diphosphine); RuC12 (COD) ; (Ru (COD) 2) X; RuX2 (diphosphine); RuCl2 (=CHR) (PR'3) 2; Ru (ArH) Cl2 ; Ru (COD) (methallyl) 2 ;

(Ir (NBD) 2Cl) 2; (Ir (NBD) 2) X; (Ir (COD) 2Cl) 2 ; (Ir (COD) 2) X; CuX (NCCH3) 4; Cu (OTf) ; Cu (OTf) 2 ; Cu (Ar) X; CuX; Ni (acac) 2; NiX2 ; (Ni (allyl) X) 2; Ni (COD) 2; Mo02 (acac) 2 ; Ti (OiPr) 4 ; VO (acac) 2; MeRe03 ; MnX2 and Mn (acac) 2; wherein each R and R'is independently selected from the group consisting ouf. alkyl or aryl; Ar is an aryl group; and X is a counteranion.

In the above transition metal salts and complexes, L is a solvent and the counteranion X can be halogen, BF4, B (Ar) 4 wherein Ar is fluorophenyl or 3,5- di-trifluoromethyl-1-phenyl, C104, SbF6, PF6, CF3SO3, RCOO or a mixture thereof- In another aspect, the present invention includes a process for preparation of an asymmetric compound using the catalysts described above. The process includes the step of contacting a substrate capable of forming an asymmetric product by an asymmetric reaction and a catalyst according to the present invention prepared by contacting a transition metal salt, or a complex thereof, and a ligand according to the present invention.

Suitable asymmetric reactions include asymmetric hydrogenation, hydride transfer, allylic alkylation, i. e., palladium-catalyzed allylic alkylation of an allylic ester, hydrosilylation, hydroboration, hydrovinylation, hydroformylation, olefin metathesis, hydrocarboxylation, isomerization, cyclopropanation, Diels-Alder reaction, Heck reaction, isomerization, Aldol reaction, Michael addition; epoxidation, kinetic resolution, i. e., palladium-catalyzed allylic alkylation of a racemic allylic ester, and [m+n] cycloaddition wherein m = 3 to 6 and n = 2, i. e., silver-catalyzed asymmetric [3 +2] cycloaddition of an azomethine ylide with a dipolarophile.

Preferably, the asymmetric reaction is hydrogenation and the substrate to be hydrogenated is an ethylenically unsaturated compound, imine, enamine, enamide, vinyl ester or a ketone, including a ketone such as a beta-ketoester.

In the case of beta-ketoesters and enamides, the use of Ru as the transition metal to produce an asymmetric beta-hydroxyester and beta amino acid, respectively, is preferred, particularly when the ligand is a compound represented by one of the following formulas: wherein each R is independently selected from the group consisting of : alkyl, aryl, substituted alkyl, substituted aryl and SiR3 ; and wherein each Ar is independently selected from the group consisting of : phenyl, substituted phenyl, aryl and substituted aryl;

or a combination thereof.

The detailed description of ligand synthesis and asymmetric reactions thereof is provided below.

General procedures All reactions and manipulations were performed in a nitrogen-filled glove box or using standard Schlenk techniques. THF and toluene were dried and distilled from sodium-benzophenone ketyl under nitrogen. Methylene chloride was distilled from CaH2. Methanol was distilled from Mg under nitrogen. (R, R)- BDNPB was made a solution of 1 Omg/ml in toluene before use. Column chromatography was performed using EM silica gel 60 (230-400 mesh). 1H, 13C and 31p NMR were recorded on Bruker WP-200, AM-300, and AMX-360 spectrometers. Chemical shifts were reported in ppm down field from tetramethylsilane with the solvent resonance as the internal standard. Optical rotation was obtained on a Perlcin-Elmer 241 polarimeter. MS spectra were recorded on a KRATOS mass spectrometer MS 9/50 for LR-EI and HR-EI. GC analysis was carried on Helwett-Packard 6890 gas chromatography using chiral capillary columns. HPLC analysis was carried on Waters 600 chromatography.

Ligand Synthesis

Ligand Synthesis Several chiral ligands have been prepared and used for asymmetric hydrogenation reactions. Scheme 1 shows the synthesis of these ligands. The starting material, enantiomerically pure BINOL can be converted to many chiral phosphines and phosphinites (lla-L20, llb-L18, llc-L31, 11d and 15-L38).

3,3'-disubstituted BINOL was prepared from (S)-BINOL according to known literature methods (Cox, P. J. et al. Tetrahedron Lett. 1992,33,2253; Simonsen, K. B. et al. J Org. Chem. 1998,63,7536). R R I w w I I Ila : R=Me, Ar=Ph OH OH nBuLi, TEF OPAr2 llb: R=Ph, Ar=Ph su oH OH Elr2pC1 FAr llc: R=3,5-Me? C6H4, Ar2PCI Ar = Pli R R lld : R=Ph, Ar= (10) 11 3, 5-Me2C6H4, 10a:R=Me 10b : R=Ph 10c : R = 3, 5-Me2C6H4 Ph Ph Ph NBS, CC14, reflu au eOH 2) NiC12 (dppp), MeMgBr MPh cH2sr -) I- CH2Br Mu 12 13 Ph Oh Ph lob 12 h 13 Ph 10b 12 13 1 CH2C) DiDtjTi-n ? LICL DAF CH2CI nBuLi CH2PPh2 Pu pu 14 Ph 14 15 Scheme 1. Ligand Synthesis Chiral bisphosphinite ligands (lla-L20, llb-L18, llc-L31, 11d) were made through reaction of chlorodiaryl phosphine with the corresponding chiral diols (lOa-lOc) in high yields. Chiral bisphosphine 15 was made from 3,3'- diphenyl-2,3'dihydroxyl-1,1'-binaphthyl (lOb) in a few steps. Compounds 12-14 5 were synthesized according to a reported procedure (Xiao, D. et al. Org. Lett.

1999,1,1679). Representative examples can be synthesized by a variety of methods. Several such methods suitable for use in the synthesis of chiral 3,3'disubstituted bisaryl phosphines, are described below: ExamplesofLigand Synthesis Li Me L i Me BuLi orLDA ., % POR2 ,. PORZ ..... POR2. POR : li mye M e LAH or sil ane POR2 . POR2/i I \ \ PRx Wul 4 PR2 Ar (OH) 2, SuzukiCoupling Ar tv Me Ar Ar A PORi'PRZ POR2 LAH or sil ane *, *P R2 Ar Air ruz 1) LDA or BuLi i I R Cu R ppR > z Ja gI POR2 POR2 2) 12 resolved |R 9 R LAH or si lane R R'=OCH3, Ph, etc. ..,.. PRZ LOCH3 OCH3 H, CO Me H 3 COD C u 1 1) BuLi HCO POR2 H3C0 PORZ-> H, CO 1. pOR2 2) Mel H3CON POR2 POR2 resolved H3C0 Me OCH, H3CO OCH3 CH3 Juli, 12 H3CO H3 CO'Ar H3CO P OR2 H, Co POR2 LAH or silane 2 ArB (OH) 2, Suzuki Coupling-) 0- Product H3C POR2 H3CO-'P 0 R2 R= Ph substituted H, o i H3co Ar Aryl, Cy oralkyl CH3 CH3 group

EXAMPLE 1 Synthesis of a 3, 3'-Disubstituted Chiral BINOL (lOb) (R)-2,2'-Bismethoxymethoxy-1,1'-binaphthyl To a THF (200 ml) solution of NaH (5. 52 g, 230 mmol) was added (R)- BINOL (28. 6g, 100 mmol) solution in THF (50 ml) under nitrogen at zero temperature, after 30 min, chloromethyl methyl ether (17. 09 ml, 225 mmol) in 30 ml THF was added dropwise. The mixture was stirred overnight at room temperature. 3 ml water was added carefully to destroy the excess NaH, and filtered to remove the inorganic salt. The solution was passed a silica gel plug (hexane/ethyl acetate = 1/1) to give pure product (97% yield).

(R)-3,3'-diiodo-2,2'-Bismethoxymethoxy-1,1'-binaphthyl

To a solution of (R)-2,2'-Bismethoxymethoxy-1,1'-binaphthyl (37.4g, 100mmol) in diethyl ether (400 ml) was added n-BuLi (100 ml, 2.5 M in hexane, 250 mmol) at room temperature under nitrogen, the mixture was stirred for 3 hours, then was cooled to 0°C, 200 ml THF was added, after 10 min, a solution of iodine (300 mol, 76.2g) in THF (60 ml) was added dropwise. The mixture was allowed to warm to room temperature over 4 hours. 100 ml saturated Na2S03 aqueous was added to destroy the excess iodine, then extracted with ethyl acetate, organic phase was washed with 100 ml saturated Na2S03, 3X100 ml water, dried over sodium sulfate and evaporated. The residue was purified by a silica gel column eluted with (hexane/ethyl acetate = 7/1) to give product as a yellow solid (80% yield, contain 5-7% monoiodo-substituted product).

(R)-3,3'-diphenyl-2,2'-Bismethoxymethoxy-1,1'-binaphthyl To a solution of (R)-3,3'-diiodo-2,2'-Bismethoxymethoxy-1, 1'-binaphthyl (90 mmol, 56.3g) and phenylboronic acid (25.2 g, 225 mmol) in THF 800 ml, was added Pd (PPh3) 4 (2.3 g, 2 mmol) and degassed 1M K2CO3 aqueous solution (400 ml, 400 mmol). The reaction mixture was heated at reflux for 20 hours. The mixture was extracted with ethyl acetate, and combined organic layer was washed with brine. Evaporation of the solvent gave a yellow solid (47g). The residue was used to next step without other purification.

Ph Ph + OMOM EtOH, HCI 9 OH z TOMTOM DCM, Reflux OH Ph \ Ph (R)-3,3'-diphenyl-1,1'-binaphthol To a solution of (R)-3,3'-diphenyl-2,2'-Bismethoxymethoxy-l, l'binaphthyl (47 g) in a mixture solvent of 200 ml DCM and 500 ml EtOH was added concentrated HCl (90 ml). The reaction mixture was heated at reflux under nitrogen for 16 hours. The volatile components were removed under reduced pressure, and the residue was purified by column chromatography on silica gel (DCM/hexanes=4/6) to give the product (25.2 g, 57.6 mmol, 64% yield for two steps) EXAMPLE 2 Alternative Route for the Synthesis of a 3,3'-Disubstituted Chiral BINOL (lOb) (S)-2,2'-Dimethoxy-1,1'-dinaphthyl To a solution of (S)-2,2'-dihydroxy-1,1'-dinaphthyl (100g, 349.7 mmol) in 1000ml 95% EtOH was added dimethyl sulfate (93.1ml, 981.7 mmol, 2.8eq.) and followed by dropwise addition of a solution of NaOH (175g) in 300ml H20.

After the addition, the resulting system was heated to reflux for 3 h, and then cooled. The reaction mixture was filtered, the precipitate was collected and

washed with 10% aqueous NaOH (3x150 ml), and recrystallized from toluene (reflux to dissolve into 700 ml toluene, then let it stay at 0 °C overnight) to yield 84.1g white crystal product (S)-2,2'-dimethoxy-1, 1'-dinaphthyl (yield = 76.6%).

1H-NMR (CDCl3) : 87. 985 (d, J=9. OHz, 2H, Ar-H), 7.875 (d, J=8. 1Hz, 2H, Ar-H), 7.468 (d, J=9. OHz, 2H, Ar-H), 7.300-7.326 (t, 2H, Ar-H), 7.199-7.218 (t, 2H, Ar- H), 7.118 (d, J=8. lHz, 2H, Ar-H), 3.773 (s, 6H,-OCH3).

(S)-3, 3'-Bis (dihydroxyborane)-2,2'-Dimethoxy-1,1'-dinaphthyl Under N2, in a 500 ml Schlenk flask were placed 300 ml of dry t-butyl- methyl ether and TMEDA (14.4 ml, 95.5 mmol, 3equiv). To this solution was added 2.5M n-BuLi in hexane (39.5 ml, 98.7 mmol, 3.1 equiv), the resulting solution was stirred for 30 min. at room temperature, solid (S)-2,2'-dimethoxy- 1, 1'-dinaphthyl (lOg, 31.8mmol) was added in one portion under N2 flow, the reaction system was stirred at room temperature for 3hrs. The resulting brown slurry was cooled to-78°C, and B (OEt) 3 (33.9 ml, 197.5 mmol, 6.2equiv) was dropwise introduced over a period of 15min. The reaction system was allowed to warm room temperature and was left stirring overnight. The reaction was quenched with 150ml aqueous 1M HCl solution, and was stirred for another 2 h.

The phase was separated, the organic phase was washed with aqueous 1M HCl solution (3 x 100mL) and saturated aqueous NaCl solution (3 x 100 ml), and dried over Na2S04. The solvent was removed, and the resulting white solid were recrystallized twice from 70ml toluene (reflux to dissolve into 700ml toluene, then let it stay at 0 °C overnight, and recrystallization once can't remove by-product completely) to give the product (S)-3, 3'-Bis (dihydroxyborane)-2,2'-Dimethoxy- 1, 1'-dinaphthyl 9.3 3 g (Yield = 73.3 %). 1 H-NMR (Acetone-d6): 6 8.556 (s, 2H, Ar- H), 8.041 (d, J=8. 1Hz, 2H, Ar-H), 7.454 (t, 2H, Ar-H), 7.335 (t, 2H, Ar-H), 7.112 (d, J=8. 1 Hz, 2H, Ar-H), 3.773 (s, 6H,-OCH3). lH-NMR shows that toluene is very difficult to remove completely, but there is no any influence on the secondary reaction.

(S)-3,3'-Diphenyl-2, 2'-dimethoxy-1, 1'-dinaphthyl In a 50ml Schlenk flask were placed (S)-3, 3'-bis (dihydroxyborane)-2,2'- dimethoxy-1, l'-dinaphthyl (1. 206 g, 3 mmol), Ba (OH) 2.8H20 (2.739g, 8.7mmol, 2.9 equiv), and Pd (PPh3) 4 (183 mg, 0.15 mmol, 5% mol), the reaction system was evacuated and filled with N2 for three times, 1, 4-dioxane (18ml), H20 (8ml), and bromobenzen (1. 89ml, 18mmol, 6eq.) were added. The reaction system was heated under reflux for 24 hrs under N2 and cooled to room temperature. The 1,4-dioxane was removed, and the resulting mixture was redissolved into 100ml CH2C12, and washed with aqueous 1M HCl solution (3x 50 ml) and saturated aqueous NaCI solution (2 x 50 ml), and dried over Na2S04. The solvent was removed to yield crude product (S)-3, 3'-diphenyl-2, 2'-dimethoxy-l, 1'-dinaphthyl 1.513 g as orange syrup.

This intermediate was not isolated and was used directly in the final step.

(S)-3,3'-Diphenyl-2, 2'-dihydroxy-l, l'-dinaphthyl (lOb) The crude product diphenyl-2,2'-dimethoxy-1,1'-dinaphthyl (1.513g, approximately 3mmol) was dissolved into 80 ml dry CH2C12, and cooled to-78°C, BBr3 (1.5 ml) was added in 10 min., and the reaction system was stirred for 18 h at room temperature. The resulting slight brown solution was cooled to 0°C, and 200 ml H20 was added carefully. The phase was separated, and the organic phase was washed with H20 (5 x 80 ml) and saturated aqueous NaCl solution (2 x 50 ml), and dried over Na2S04. The solvent was removed, and the resulting solid was recrystallized from 10 ml MeOH to yield (S)-lOb as white-gray powder (overall yield of coupling and deprotection steps, 61.8%).

'H-NMR (CDCl3) : 88. 029 (s, 2H, Ar-H), 7.929 (d, J= 7.9Hz, 2H, Ar-H), 7.741 (dd, 4H, J= 7.9 1. 4Hz Ar-H), 7.499 (t, 4H, Ar-H), 7.376-7.434 (m, 4H, Ar- H), 7.325 (td, 2H, J= 7.9 1.3Hz Ar-H), 7.250 (t, 2H, Ar-H), 5.364 (br, 2H,-OH).

EXAMPLE 3 Synthesis of a 3,3'-Disubstituted Chiral Phosphinite, (R)-3, 3'-diphenyl-2, 2'- bisdiphenylphosphinooxy-1,1'-binaphthyl (11b) To a solution of (R)-3, 3'-diphenyl-1, 1'-binaphthol (876 mg, 2 mmol) in 20 ml THF at-78°C was added n-BuLi (2.8 ml, 4.5 mmol) dropwise, the mixture was warmed to room temperature and stirred for 30 min, then cooled to-78°C, Ph2PCl (0.9 ml, 5 mmol) was added via syringe, then warmed to room temperature and stirred overnight. The THF was removed under reduced pressure, the residue was purified by basic A1203 (EtOAc/Hexane/Et3N = 90/8/2) to give pure product (1.41 g, 87% yield).

'H-NMR (CD2C12, 360 MHz) 6.80-7.20 (m, 24H), 7.35-7.48 (m, 12H), 7.50-7.65 (m, 4H).). 3IP-NMR (CD2C12, 360 MHz) 112.78.). 13C-NMR (CD2Cl2, 360 MHz) 124-150 (m). [a] D20=114. 7 (c, 0.38, CHC13). MS: 203 (100), 387 (65), 439 (48), 807 (50). HRMS C56H41O2P2 807. 2566 Cal.: 807.2582.

EXAMPLE 4 General Procedure for Catalytic Asymmetric Hydrogenation of Enamides In a glove box, the Rh-phosphine complex was made in situ by mixing Rh (COD) 2PF6 (3.7 mg, 0.008 mmol) and a chiral phosphine ligand (0.8 ml. of 1 Qmg/mL ligand in toluene, 0.012 mmol) in 19.2 ml of CH2C12. The mixture was

stirred for 30 min. Then 2.5 ml of this solution was transferred to a 10 ml vial with an enamide substrate (0.1 mmol).

The hydrogenation was performed at room temperature under 20 psi of hydrogen pressure for 24 h. The hydrogen was released carefully and the reaction mixture was passed through a silica gel plug eluted with EtOAc. The enantiomeric excess was measured by GC or HPLC using a chiral GC or HPLC column without further purification. The absolute configuration of products was determined by comparing the sign of optical rotation with the reported data.

EXAMPLE 5 Results of Asymmetric Hydrogenation of Enamides To examine the effectiveness of new chiral ligands, hydrogenation of a typical dehydroamino acid derivative and an enamide was carried out. The results are summarized in Table 1. The 3,3'disubstituted bisphosphinite ligands (lla-d) are more effective than BINAPO (3) for asymmetric hydrogenation.

In the similar way, the 3,3'-disubstituted bisphosphine 15 is a better ligand for Rh-catalyzed asymmetric hydrogenation than NAPHOS (6).

We conclude that introduction of 3,3' substituted groups can restrict the rotation of phenyl groups adjacent to phosphines and therefore a well-defined chiral pocket around the transition metal is formed. The conformational rigidity is crucial for achieving high enantioselectivity for a number of asymmetric reactions.

Table 1. Rh (I) -catalyzed asymmetric hydrogenation Substrate jHAc NHAc Ligand COOMe Ph I entry 1 0 P P h2 73% ee 28% ee OPPh2 BINAPO 3 C H3 entry2 + H OPPh "OPPh2 95 % ce 67% ee Pu Ph entry 3 {Ph OPPh llb 99 % ee 94% ee Ph2 ils Ph oh entry 4 p Ar OPAr2 ilc 95% ee 89% ee = Ph Ar entry 5 \ \ pPPh2 lld 93% ee 90% ee COD entry 6 'CH2PPh2 54% ee H2PPh2 NAPHOS 6 Ph i entry 7 XCH2PPh2 99% ee 82% ee , CH2PPh215 Ph The reaction was carried out at rt under 3atm of H2 for 12 h in 3ml of THF with complete conversion (S/C = 100). Ar = 3, 5-Me2C6H4

EXAMPLE 6 Asymmetric Hydrogenation of Beta-keto Esters A number of beta-ketoesters can be reduced in high ee's using a Ru- 3,3'substituted BINAPO (lld) compound as the catalysts. Particularly, the R group is aryl, hetereoaryl, substituted aryl, alkyl and substituted alkyl species.

These reactions can be carried out at low pressure and low temperature, which shows advantages over the reaction carried out with Ru-BINAP complex (90 atm, 90 °C).

Asymmetric Hydrogenation Ar O 0 0. 5 mol% [Ru (Cymene) CI2] 2 I 0 0 OHO cx PPh2 R » OEt 1 mol% 11c R4OEt MQPPh2 6atm H2 inEtOH wAr R=alkyl or ayl 6 atm H2, in EtOH Ar 50 OC OHO OHO Ar = ci Ph » OEt wOEt 3, 5-Me2C6H3 98% ee 11 c EXAMPLE 7 Asymmetric Synthesis of Beta-Amino Acids Synthesis of Starting Material 3-Acetamido-3-Aryl-2-Propenoates and 3- Acetamido-3-hetero-Aryl-2-Propenoates Typical procedure: The starting material methyl 3-acetamido-3-phenyl-2- propenoate can be conveniently synthesized from cheap acetophenone in three steps according to known literature procedure in good yields. The literatures are Zhu, G.; Zhen, Z.; Zhang, X. J. Org. Chem. 1999,64,6907-6910; Krapcho, A. P.; Diamanti, J. Org. Synth. 1973,5,198-201.'H-NMR (CDC13,360 MHz) 8 (Z

isomer) 2.17 (s, 3H), 3.77 (s, 3H), 5.29 (s, 1H), 7.37-7.45 (m, 5H) ; (E isomer) 2.38 (s, 3H), 3.77 (s, 3H), 6.65 (s, 1H), 7.37-7.45 (m, 5H).

An Effective New Way to Make Enamides NHCOR" O O R"CONH2, Ho n ROOC R'+H) ROR Reflux E/Z mixture R', R"= alkyl, substituted alkyl, aryl, substituted aryl, hetereoaryl R = alkyl, aryl Alternatively, 3-acetamido-3-aryl-2-propenoates and 3-Acetamido-3- hetero-aryl-2-propenoates can be prepared through a new route by reacting acetamide with the corresponding beta-keto esters. A related example is demonstrated by Tschaen et al. J Org. Cliem. 1995,60,4324. The typical procedure involves addition of the corresponding beta keto-ester, an acetamide or other amide such as enamide, Amberlyst 15 or other acid catalysts in toluene. The mixture was heated at reflux for some hours with removal of water using a Dean- Stark trap. The end product was obtained after evaporating the solvent.

Asymmetric Hydrogenation of methyl 3-acetamido-3-phenyl-2-propenoate A dry Schlenk tube is charged with [Ru (cymene) Cl2] 2 (1.53 mg, FW = 612,0.0025 mmol), chiral ligand 3,3'-diphenyl-xylyl BINAPO (lld, 4.82 mg, FW = 918, 0.0053 mmol), and then is evacuated and filled with argon. DMF (must be degassed by freeze-thaw cycles) (1 ml) is introduced under stream of argon. The solution is stirred at 100 °C for 10 min under argon, giving a clear reddish brown solution. The reaction mixture is cooled and concentrated at 1 mmHg at 50 °C with vigorous stirring and then at 0.1 mmHg for 1 h to give a reddish brown solid, which is used as hydrogenation catalyst.

To a solution of above catalyst in EtOH/DCM (4 ml, 3/1) in a glove box was added substrate methyl 3-acetamido-3-phenyl-2-propenoate (109 mg, 0.5 mmol). The hydrogenation was performed at 50 °C under 78 psi of hydrogen for 15 hours (not be optimized). The bomb was then cooled to room temperature and hydrogen carefully released. The solvent was removed and the residue dissolved in ether. The ether solution was washed with water and brine and dried over sodium sulfate. The ether solution was passed through a short silica gel column and concentrated to dryness to give pure products methyl 3-acetamido-3-phenyl- 2-propanoate (known compound, see: Zhu, G.; Zhen, Z.; Zhang, X. J. Org. Chem.

1999,64,6907-6910 (Rh/Duphos and BICP, 65% ee); Lubell, W. D.; Kitamura, M.; Noyori, R. Tetrahedron : Asymmetry 1991,2,543 (Ru/BINAP, poor ee)). 1H- NMR (CDC13, 360 MHz) 8 1.92 (s, 3H), 2.76-2.83 (m, 2H), 3.53 (s, 3H), 5.34 (m, 1H), 6.65 (br, 1H), 7.18-7.27 (m, 5H). Chiral GC Condition: Chiral Select-1000 column (dimensions 15m X 0.25 mm (i. d.)). Carrier gas: He (1 ml/min), 180 °C, isothermal; (S) ti = 11.68 min; (R) t2 = 12. 04 min.

AsymmetricHydrogenation Product Ligand 0 0-/ oh A-OMe MeOOC Ph NHAc [), jLjL pAr E/Z mixture MeOOC PAr2 Para Ph 0.5mol% [Ru (Cymene) CI2] 2 ', NHAc Ar=3, 5-Me2C6H3 1 mol% Ligand MeOOC Ar 6atmH2, inEtOH 99% ee 11d 99% ee 11 d 50°C Ph Ar = Ph, Py, aryl, heteroaryl, subtituted aryl (r PPh2 °PPh2 98% ee PPh2 98% ex Ph 11b

EXAMPLE 8 Asymmetric Allylic Alkylation Using 3,3'disubstituted BINAPO as ligands, the Pd-catalyzed asymmetric allylic alkylation can be carried out and some results are listed below: Pd-Catalyzed asymmetric allylic substitution Ee values are determined by chiral HPLC (OJ Column H/IPA = 95/5)

EXAMPLE 9 Asymmetric Allylic Alkvlation with nitrogen nucleophile Using 3,3'disubstituted BINAPO as ligands, Pd-catalyzed asymmetric allylic alkylation with nitrogen nucleophiles can be carried out and some results are listed below: Pd-Catalyzed asymmetric allylic substitution

Ee values are determined by chiral HPLC (OJ Column H/IPA = 85/15) EXAMPLE 10 Synthesis of 3, 3'-disubstituted biaryl phosphines (-)- (3, 3'-diphenyl- 4, 4',5,5',6,6'-hexamethoxybiphenyl-2,2'diyl) bis (diphenylphosphine) 16 17 18 19 20 24

OC H3 OCH3 H sC0 Ph H3C0 Ph (-)-DTTA, i-PrOH /HSiCl3, NBu3 > > H3CO P (O) Ph2 Xylene-H3CO Pph2 25 3/2 HsCOPh H, CO-\Ph OC H3 OCH3 OCH3 25 26

Synthesis of 4-bromo-2,6-dimethoxy-phenol 17 To a 2 liter flask equipped with a magnetic stirrer, thermometer, and nitrogen inlet, was added 77g (0.5 mol) of pyrogallol 1, 3-dimethyl ether, 5.8 ml of MeOH, and 750ml of CH2Cl2. To this solution was added 126mg (5mmol) of NaH (95%). The solution was stirred while cooling to-45°C with a dry-ice acetone bath. 94g (0.53mol) of powdered N-bromosuccinimide was added rapidly.

The reaction mixture was then stirred for lhour at-35°C, heated to room temperature over next 30min, and finally refluxed for 30min. The CH2C12 was removed under reduced pressure and the residue solidified. The tan solid was broken up and stirred well with 1 liter of ether. This was filtered and the residue was washed well with ether. The ether was evaporated under reduced pressure to yield a tan solid. The solid was placed in a 5 liter flask with 3 liters of ligroin (bp: 90-110°C) and heated with stirring to 80°C. The hot solution was decanted from the brown oil and the hot yellow solution was allowed to cool at room temperature for 3hr. The white needles was filtered off and dried to yield 74g (63%) of 17.

Ref.-J Org. Chem. Vol. 50,1985,1099.

Synthesis of 3,4,5-trimethoxybromobenzene 18 A mixture of 74g (0.32mol) of 4-bromo-2,6-dimethoxy-phenol 17 and 32g (0. 8mol) of NaOH in 850ml of H2O was cooled to 10°C and 45ml (0.48mmol) of dimethyl sulfate was added. The mixture was refluxed for 3h and an equal amount of dimethyl sulfate (total 0.96mol) was then added. The mixture was refluxed for another 3h. Upon cooling overnight, the gray product solidified and was filtered off and dissolved in 1.21 of ether. The ether solution was filtered to remove insoluble impurity and washed sequentially with 5% NaOH solution (200ml), water (2 X 200mL), and brine (200mL). The ether phase was dried over

Na2S04 to give a off-white solid, which was recrystallized in hexane (300ml) to give 62. 3g (79%) of 18.

Synthesis of (3,4,5-trimethoxyphenyl) diphenylphosphine 19 To a solution of 3, 4,5-trimethoxybromobenzene 18 (62.3g, 0.25mol) in dry THF (200ml) was added BuLi solution (169ml, 1.6M in hexane, 0.27mol) dropwise at-78°C within 45min. The resulting beige-colored suspension was stirred for an additional Ih at-78°C. Then PPh2CI (61g, 0.277mol, 49.7ml) was added dropwise. The addition was complete within 2h. The resulting yellow solution was allowed to warm to 0°C within 2h and quenched by addition of NH4Cl solution (200ml). The organic layer was separated, washed with brine (250ml), dried (Na2S04), filtered, and evaporated. The solid was recrystallized from methanol to give 69.5g (80%) of 19.

Ref. : Helvetica Chimica Acta Vol. 74,1991,370-389 Synthesis of 3,4,5-trimethoxyphenyl) diphenylphosphine oxide 20 To a suspension of 19 (69.5g, 0.2mmol) in MeOH (500 ml) was added dropwise 30% H202 (24.5g, 0.215mol) at 0°C. The resulting clear solution was stirred at ambient temperature for lh. Then it was treated with sat. Na2S03 solution (75 ml) and IN HCl solution (50 ml). The mixture was concentrated under reduced pressure to remove the MeOH. The solid residue was dissolved in CH2C12 (300ml), washed with water (2x200 ml) and brine (200 ml), dried over Na2S04, and evaporated. To the resulting white solid was added 300ml hexane and the resulting suspension was stirred vigorously at room temperature.

Filtration of the white solid powder gave 67.2g (0.182mol, 91%) of pure 20.

Ref : Helvetica Chimica Acta Vol. 74,1991,370-389

Synthesis of (2-iodo-3,4,5-trimethoxyphenyl) diphenylphosphine oxide 21 To a solution of (i-Pr) 2NH (31.88ml, 23.02g, 0.227mol) in dry THF (200ml) was added n-BuLi solution (125ml, 1.6M in hexane, 0.2mol) dropwise at -78°C. The addition was complete within 15min. After stirred at 0°C for 10min, the LDA solution was re-cooled to-78°C. It was then added via cannula to a flask containing a solution of 20 (67.2g, 0.182mol) in dry THF (200ml) over 20min. During the addition, the mixture was turned reddish-brown, and eventually a beige suspension was formed. After the reaction mixture was stirred for an additional 15min at-78°C, a solution of I2 (50.6g, 0.2mol) in THF (200ml) was added dropwise. The addition was complete in 3h. A reddish-brown viscous paste was formed at the end of the addition. Then, the cooling bath was removed, and the mixture was allowed to warm to 0°C to form a clear red solution. The mixture was quenched by the addition of a Na2S203 solution (12g in 100ml H20).

The solution was concentrated to remove THF. The residue was dissolved in 300ml of CH2Cl2, washed with water (2 x 200 ml) and brine (200ml), dried over Na2S04, and evaporated. The brown paste was recrystallized in EtOAc (100ml) to give 55g (62%) of 21.

Ref : Helvetica Chimica Acta Vol. 74,1991,370-389 Synthesis of (2-phensl-3v495-trimethoxvphenyl) diphenylphosphine oxide 22 To a 2 liter Schlenk flask was added (2-iodo-3,4,5-trimethoxyphenyl) diphenylphosphine oxide 21 (30g, 61mmol), phenylboronic acid (l l. lg, 91mmol), and degassed THF (800ml). A solution of degassed saturated K2CO3 (400ml) was added afterwards. The whole mixture was degassed with nitrogen for an additional l Omin. Then, Pd (PPh3) 4 (1.22mmol, 1.4g) was added in the solution through one portion. The mixture was stirred at reflux under nitrogen for 24hrs.

In situ 31PNMR showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove THF and 400ml of CH2Cl2 was

then added. The CH2Cl2 layer was washed with water (200ml) and brine (200ml), dried over Na2S04, and evaporated. The solid residue was recrystallized from EtOAc (100ml) to give off-white product 22 (23g). The mother liquid was passed through a silica gel column to give another 4g of product 22. The total yield was 98%.

Synthesis of (2-iodo-6-phenyl-3,4,5-trimethoxyphenyl) diphenylphosphine oxide 23 To a solution of (2-phenyl-3,4,5-trimethoxyphenyl) diphenylphosphine oxide 22 (26.5g, 59.7mmol) in dry THF (500ml) was added t-BuLi (47.7ml, 1.5M in pentane, 71.6mmol) dropwise at-90°C. The addition was complete within 2hrs. The solution was allowed to warm to-78°C and stirred for an additional 3h. Then a solution of 12 in THF (100ml) was added dropwise at this temperature. The addition was complete in 2h. The resulting dark solution was allowed to warm to room temperature and stirred overnight. A solution of Na2S203 (12g in 100ml H20) was added. The resulting yellow solution was concentrated under reduced pressure. To the residue was added 500ml of CH2Cl2.

The CH2Cl2 layer was washed with water (1 OOml) and brine (1 OOml), dried over Na2S04, and evaporated. The residue was recrystallized from EtOAc (100ml) to give a pure brown solid 23 (24g). The mother liquid was passed through a silica gel column to give another 5g of product. The total yield is 85%.

Synthesis of (RS)-(3, 3'-dipheny1-4, 4', 5, 5', 6, 6'-hexamethoxvbiphenvl-2, 2'- diyl) bis (diphenylphosphine oxide) 24 A mixture of (2-iodo-6-phenyl-3,4,5-trimethoxyphenyl) diphenylphosphine oxide 23 (7.4g, 12.6mmol), Cu powder (252mmol, 16g, activated by I2 treatment), and DMF (200ml) was stirred at 155°C for lhr. The cold mixture was evaporated to dryness at the rotor evaporator at 70°C. The residue was treated for a few min with CH2C12 (200ml). The solid was removed by filtration and washed with

CH2C12 (200ml). The combined filtrate was washed with sat. NH4Cl solution (2 X 100mL), dried over Na2S04, and evaporated. The residue was crystallized from EtOAc (100ml) to give 5g (90%) of white product 24.

Resolution of (3,3'-diphenyl-4,4', 5, 5', 6, 6'-hexamethoxybiphenyl-2,2'- diyl) bis (diphenylphosphine oxide) 25 To a mixture of (RS)- (3, 3'-diphenyl-4,4', 5,5', 6,6'-hexamethoxybiphenyl- 2,2'-diyl) bis (diphenylphosphine oxide) 24 (2.3g, 2.5mmol) and (-)-DTTA (- 0.966g, 2.5mmol) was added 40ml of i-PrOH. The resulting slurry was heated to reflux to get a clear solution. Then it was cooled slowly to room temperature and stirred overnight. The salt of (-)-25 and (-)-DTTA was obtained as white powder through filtration (ee: 95%). The salt was recrystallized one more time from 25ml i-PrOH and l. lg of solid was obtained. The solid was dissolved in 50ml of CH2Cl2, washed with 3N NaOH (2x 50ml) and water (3x 50mL), dried over Na2S04, and evaporated. The solid (97.7%, 0.86g) was recrystallized from acetone to give enantiomerically pure product 25 (0.69g, 60%, ee>99.5%).

Synthesis of (-)-(3, 3'-diphenyl-4, 4', 5, 5', 6, 6'-hexamethoxybiphenyl-2, 2'- diyl) bis (diphenylphosphine) 26.

To a solution of (-)- (3, 3'-diphenyl-4,4', 5, 5', 6, 6'-hexamethoxybiphenyl- 2,2'-diyl) bis (diphenylphosphine oxide) 25 (700mg, 0.79mmol, resolved from (-)- DTTA), tributylamine (6.5ml, 27.3mmol), and xylene (100 ml) was added HSiCl3 (1.72 ml, 17mmol) dropwise at 0°C. The reaction was stirred at reflux for 2days.

Some precipitates came out during the course. After cooled down, the reaction mixture was quenched with 30% degassed NaOH solution (20ml) in an ice-water bath. The resulting solution was kept at 60°C for lh. The organic phase was transferred into another Schlenk flask through cannula. The water phase was re- washed with CH2C12 (30ml*2). The combined organic phase was washed with water (50 ml), dried over Na2S04, and evaporated under reduced pressure. The

resulting yellow residue was dissolved in CH2C12 (10 ml) and passed through a basic A1203 column to give a pure white solid 26 (400 mg, 59%).

EXAMPLE 11 Synthesis of 2,2'- (diphenylphosphanyl)-3,6,3', 6'-tetramethoxybiphenyl 27 28 OCH3 OCH3 (-)-DTTA,i-PrOH H3CO4P (O) Ph2 HSiC13, NBu3 H3CovPph > > 2 H3C0 P (O) Ph Xylene H3C0 PPh2 pCH3 OCHg 31 32

(2,5-Dimethoxyphenyl) diphenylphosphine oxide At-78°C, 2.5M n-BuLi in hexane (48mL, 0.12mol) was slowly added to a solution of 1-Bromo-2, 5-dimethoxybenzene (27,25g, 0.115mol) in THF (250mL) causing the solution to become dark yellow (solid suspension). The reaction mixture was stir at this temp for about 30 minutes, following by addition of

diphenylchlorophosphine (21.5 ml, 0.12 mol). During the addition, control the temp below-50°C (add slowly). The resulting yellow solution was allowed to warm up to room temp (take about two hours). The saturated NH4Cl solution (200 ml) was added and reaction mixture form two layers. The organic layer was washed with brine (2x 1 OOmL) and dried (Na2S04). The solvent was removed under vacuum to give a white solid.

Add MeOH (200mL) to the resulting white solid to form suspension. At 0°C, 33% H202 (14ml, 0.13mol) was slowly added to above MeOH suspension.

The addition process takes about 20 minutes and the solid vanished promptly after all H202 was added. The mixture was allowed to stir for one hour at 0°C, follow by adding saturated NaHS03 solution (15ml) and stir for 30 minutes (the KI- Starch paper was applied here to make sure all peroxide was reduced). The solvent was removed under vacuum to give a white solid. The resulting solid was dissolved in CH2Cl2 (200mL) and was washed with water (150mL) and brine (150mL), dried (Na2S04). The solvent was also removed under vacuum to give a white solid. The crude product was treated with hot hexane (2x 1 OOmL) (to remove trace amount of impurity) to give pure product (28,37.3g, 95.8%).

(3,6-Dimethoxy-2-iodophenyl) diphenylphosphine oxide A solution of LDA (6mmol) 1.5M in pentane was slowly added to the phosphine oxide (28,1.69g, 5mmol) in THF (60mL) at 100°C. The resulting dark yellow solution (solid suspension) was allowed to warm up to-78°C (take 30 minutes) and then stirred 3.5 hours at this temp. during which time the white solid precipitated. Solid I2 (1.78g, 7mmol) was added against a counter flow of N2 to the anion in THF at-78°C. The reaction was allowed to come to 0°C and quenched with Na2S203 aq. solution (l OmL). The solvent was removed under vacuum and the residue was extracted with CH2C12 (50mL), washed with water (50mL), brine (50ml) and dried (Na2S04). The solvent was removed and the brown oil residue was treated with EtOAc (1 OmL) (to wash out most of the color

impurities, the product form white solid in EtOAc). Then the vacuum filtration gives the white solid (29, l. 0g, 43%) 2,2'- (Diphenylphosphinoyl) 3,3', 6,6'-tetramethoxybiphenyl Copper powder (320mg, 5mmol) was added to a solution of the iodide (29, 116mg, 0.25mmol) in DMF (lOmL) and the reaction mixture heated to reflux for 8 hours. During the reflux, white solid formed along the wall of flask. The mixture was treated under vacuum to remove most of the solvent (before it cooled). The residue was extracted with CH2C12 (20mL) and washed with water (2xlOmL), brine (lOmL) and dried (Na2S04). The solvent was removed under vacuum and the resulting solid was washed with EtOAc (2mL) to give a white solid (30,70mg, 83%).

Resolution of 2, 2'-(diphenylphosphinoyl) 3,3', 6,6'-tetramethoxybiphenyl (-) DTTA (0.579g, 1. 5mmol) was added to diphosphine oxide (30,0.674g, I mmol) in EtOH (29mL) solution (at this time, DTTA can not dissolve in EtOH solution). The reaction mixture was heated up to reflux until all solid suspension was completely dissolved (take about 20 minutes). The resulting solution was allowed to stir overnight until crystal formed. The mixture was filtrated under vacuum and washed with cold EtOH (5mL). The resulting solid (0.405g, 75.1%) was added to CH2C12 (20mL) and NaOH (20mL, 10% aq.) solution for about 5 minutes, and the entire insoluble solid disappeared. The organic layer was washed with water (2xlOmL), brine (lOmL) and dried (Na2S04). The solvent was removed under vacuum to give a white solid (31,99.3% ee).

2,2'-Diphenylphosphanyl-3,6,3', 6'-tetramethoxybiphenyl HSiCl3 (542mg, 0.4mL) and NBu3 (1.48g, 1. 9mL) were added to diphosphine oxide (31,70mg, 0.1 mmol) in xylene (5mL) solution under N2

atmosphere. The reaction mixture was heated to reflux for 3 hours. The mixture was allowed to cool down to room temp. Then the degassed NaOH aq. solution (10%, 5mL) was added to reaction mixture at 0°C and stir for one hour. The organic layer was washed with degassed water (2#10mL), NH4Cl aq. solution (lOmL), brine (lOmL) and dried (Na2S04). The solvent was removed under vacuum to give a pale yellow solid. After a short plug (silica gel, elute with CH2C12 : Hexane=1 : 1), the solvent was evaporated under vacuum to give a white solid (still not pure white, a little bit pale yellow color) (32,50mg, 75%).

EXAMPLE 12 Asymmetric Hydrogenation of Enamides Facilitated by Rh-Complexes with (-) (3, 3'-diphenyl-4, 4', 5, 5', 6, 6'-hexamethoxybiphenyl-2, 2'-diyl) bis- (diphenylphosphine) (26) Rh-complexes with (-) (3,3'-diphenyl-4,4', 5, 5', 6,6'- hexamethoxybiphenyl-2,2'-diyl) bis (diphenylphosphine) (26) are good catalysts for hydrogenation of enamides. Introduction of 3,3'substituted groups have some effects on enantioselectivity of asymmetric hydrogenation of enamides.

Cyclic enamides can be hydrogenated with good enantioselectivity.

Rh-Catalyzed Asymmetric Hydrogenation OMe Substrate Catalyst Me0 Ph NHAc 1 mol% [Rh (COD) 2] PF6 MeO4PPh2 1 98% ee z + 1. 1 mol% Ligand igand = Me0 PPh2 N HAN 3 atom H2 MeO Ph 99% ee OMe

The present invention has been described with particular reference to the preferred embodiments. It should be understood that the foregoing descriptions and examples are only illustrative of the invention. Various alternatives and modifications thereof can be devised by those skilled in the art without departing from the spirit and scope of the present invention. Accordingly, the present invention is intended to embrace all such alternatives, modifications, and variations that fall within the scope of the appended claims.