US009777023B2 (12 ) United States Patent ( 10) Patent No. : US 9 ,777 , 023 B2 Mehrkhodavandi et al. ( 45 ) Date of Patent : Oct . 3 , 2017 (54 ) DINUCLEAR INDIUM CATALYSTS AND Douglas et al ( A Highly Active Chiral Indium Catalyst for Living THEIR USE FOR (CO ) Lactide Polymerization , Angew . Chem . Int. Ed . 2008 , 47 , 2290 2293 ) . * OF CYCLIC International Search Report, International Application No . PCT/ (75 ) Inventors : Parisa Mehrkhodavandi, Vancouver CA2012 /050331 , entitled " Catalysts and Methods for Cyclic (CA ) ; Insun Yu , Vancouver (CA ) ; J . (Co ) Polymerization , and and Products ” , Inter national filing date : May 18 , 2012 , Date of Communication : Aug . Alberto Acosta -Ramirez , Whites Lake 20 , 2012 . (CA ) Written Opinion of the International Searching Authority , Interna tional Application No . PCT /CA2012 / 050331, entitled “ Catalysts ( 73 ) Assignee: University of British Columbia , and Methods for Cyclic Ester (Co ) Polymerization , and Polymer and Vancouver, British Columbia (CA ) Copolymer Products ” , International filing date : May 18 , 2012 , Date ( * ) Notice : Subject to any disclaimer , the term of this of Communication : Aug . 20 , 2012 . patent is extended or adjusted under 35 International Preliminary Report on Patentability, International Application No. PCT/ CA2012 /050331 , entitled " Catalysts and U . S . C . 154 ( b ) by 42 days . Methods for Cyclic Ester ( Co )Polymerization , and Polymer and (21 ) Appl . No. : 14 / 118 , 433 Copolymer Products ” , International filing date : May 18 , 2012 , Date of Communication : Oct. 2 , 2013 . (22 ) PCT Filed : May 18 , 2012 Acosta - Ramirez , A ., et al ., “ Synthesis and structural studies of chiral indium ( III ) complexes supported by tridentate ( 86 ) PCT No .: PCT/ CA2012 / 050331 diaminophenol ligands” , Inorg. Chem ., vol . 49 (12 ), pp . 5444 -5452 , 2010 . $ 371 ( c ) ( 1 ) , Douglas, A . F ., et al. , “ A highly active chiral indium catalyst for (2 ), (4 ) Date: Jul. 21 , 2014 living lactide polymerization ” , Angew . Chem . Int. Ed ., vol . 47 ( 12 ) , ( 87 ) PCT Pub . No. : WO2012 / 155275 pp . 2290 - 2293 , 2008 . Osten , K . M ., et al. , “ Effects of ligand tuning on dinuclear indium PCT Pub . Date : Nov . 22 , 2012 catalysts for lactide polymerization ” , Dalton Trans. , vol . 41 ( 26 ) , pp . 8123 -8134 , Mar. 8 , 2012 . (65 ) Prior Publication Data Othman , N . , et al. , “ Thermoheological and mechanical behavior of polylactide and its enantiometric diblock and blends” , US 2015 /0038651 A1 Feb . 5, 2015 Polymer , vol . 53 ( 12 ), pp . 2443 - 2452 , Apr. 18 , 2012 . Xu , C . , et al. , “ Highly Controlled immortal polymerization of Related U . S . Application Data B -butyrolactone by a dinuclear indium catalyst ” , Chem . Commun ., vol. 48 (54 ) , pp . 6806 -6808 , May 16 , 2012 (60 ) Provisional application No .61 / 487 ,626 , filed on May Campbell , E . J . and Nguyen , S . T. , “ Unsymmetrical Salen - Type 18 , 2011 . Ligands: High Yeild Synthesis of Salen - Type Schiff Bases Contain ing Two Different Benzaldehyde Moieties " , Tetrahedron Letters , Foreign Application Priority Data 42 : 1221 - 1225 ( 2001 ) . ( 30 ) Hiki, S ., et al. , “ Synthesis and Characterization of Hydroxy - Termi nated [RS ]- poly ( 3 -hydroxybutyrate ) and its Utilization to Block May 18 , 2011 ( CA ) 2740821 Coplolymerization With L - Lactide to Obtain a Biodegradable Ther (51 ) Int. Ci. moplastic Elastomer " , Polymer , 41 :7369 - 7379 (2000 ) . C08G 63 /84 (2006 .01 ) (Continued ) CO7F 5 / 00 ( 2006 .01 ) C08G 63/ 82 ( 2006 .01 ) Primary Examiner — Gregory Listvoyb B01J 31/ 22 (2006 . 01) (74 ) Attorney, Agent, or Firm — Hamilton , Brook , Smith (52 ) U . S . CI. & Reynolds, P . C . CPC ...... C07F 5 /006 (2013 . 01 ) ; C08G 63 /823 ( 2013 .01 ) ; C08G 63/ 84 ( 2013 .01 ) ; B01J (57 ) ABSTRACT 31/ 2243 (2013 .01 ) ; B01J 2531 /0216 (2013 .01 ) ; Provided are novel dinuclear indium catalysts of formula B01J 2531 / 0238 ( 2013 .01 ) ; BOIJ 2531/ 33 ( A ) that are capable of living and immortal ring opening ( 2013 .01 ) polymerization and copolymerization of cyclic ester mono ( 58 ) Field of Classification Search mers for the preparation of biodegradable and CPC ...... C07F 5 / 006 ; CO8G 63 / 84 copolymers , in particular polyesters . Also disclosed are See application file for complete search history . polymerization methods and polymer products . These dinuclear indium catalysts allow less costly , highly reactive References Cited living polymerization of cyclic ester monomers with pos (56 ) sible high turn over rates and /or substantial stereo -chemical FOREIGN PATENT DOCUMENTS and microstructure control. WO WO 2012/ 155275 A1 11 /2012 ( A ) OTHER PUBLICATIONS L - In In — 12 Hsieh et al ., “ Indium complexes incorporating bidentate substituted L ' In Xinh pyrrole ligand : Synthesis , characterization , and ring -opening polymerization of e -caprolactone ” , Inorg . Chim , Acta , vol. 359 , Issue 2 , pp . 497 - 504 , Jan . 2006 . * USPTO structure search , Jan . 2016 . * 12 Claims, 15 Drawing Sheets US 9, 777 ,023 B2 Page 2

( 56 ) References Cited

OTHER PUBLICATIONS Holbach , M . , et al. , “ A Practical One - Pot Synthesis of Enantiopure Unsymmetrical Salen Ligands” , J . Org . Chem . Note , 71: 2903- 2906 ( 2006 ) . Ovitt , T .M . and Coates, G . W ., “ Steroselective Ring -Opening Polymerization of rac -Lactide with a Single - Site , Racemic Alumi num Alkoxide Catalyst: Synthesis of Teroblock Poly ( lactic acid ) ” , J . Polym Scie A : Poly Chem , 38 : 4686 - 4692 ( 2000 ) . Mehrkhodavandi, P ., et al ., “ Highly Active Catalysts for Ring Opening Polymerization of Lactide .” Paper presented at the CSC National Conference , Hamilton , Ontario , (May 30 - Jun . 3 , 2009 ) . Mehrkhodavandi, P . , et al . , “ Dinuclear Indium Catalysts for Enatioselective Polymerization of Lactide. ” Presented at the Inor ganic Gordon Research Conference , University of British Colum bia, ( Jun . 20 -26 , 2010 ). Woo , E . M . and Chang , L ., “ Crystallization and Morphology of Sterocomplexes in Nonequimolar Mixtures of poly ( L -lactic acid ) with excess poly ( D - lactic acid ) ” , Polymer, 52 :6080 -6089 (2011 ) . Dauth , A . and Love, J. A . , “ Synthesis and Reactivity of 2 - Azametal lacyclobutanes ” , Dalton Trans. , 41: 7782 - 7791 (2012 ) . Extended European Search Report for EP12785681. 3 , “ Dinuclear Indium Catalysts and Their Use for (Co ) Polymerization of Cyclic Esters ” , dated Jul. 15 , 2015 . Mehrkhodavandi, P ., et al ., “ Chiral Indium Catalysts for Controlled Polymerization of Lactide ” , presented at the Canadian Society for Chemistry ( CSC ) National Conference , University of British Columbia , Toronto , Canada, (May 30 - Jun . 2 , 2010 ) , 22 pages . * cited by examiner U . S . Patent Oct . 3 , 2017 Sheet 1 of 15 US 9 , 777 ,023 B2

3 .000

2 .500 v = - 3. 8095x + 7. 7017 R = 0 .9966 2 . 000

In([e-CL]/TMB) 1 . 500

1 . 000 #tTTTTTTTTr - * 0 .500

0 .000 0. 00 0 . 10 0. 20 0 .30 0 .40 0 .50 0 .60 0 .70 0 .80 t ( h )

FIGURE 1 Patent Oct. 3 , 2017 Sheet 2 of 15 US 9 ,777 ,023 B2 Hy

e 19831.55 1.51 11,46 11.5001.3148 88682 gg -26 ??? - = XXXX 0 sowe w o 0920- ABAWAPIPPY 2 . 26 2 . 15 3 .5529 912520 .41 TTTTTTTTTTT EUWT TTr amp moment per 3 . 0 2 . 5 20 1 . 5 10 Chemical Shift (ppm ) FIGURE 2 U . S . Patent Oct . 3 , 2017 Sheet 3 of 15 US 9 ,777 ,023 B2

16.5 movementsespompoms.17

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FIGURE 2 ctd . U . S . Patent Oct. 3 , 2017 Sheet 4 of 15 US 9 ,777 , 023 B2

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FIGURE 3 ctd . U . S . Patent Oct. 3 , 2017 Sheet 6 of 15 US 9 ,777 , 023 B2

me

15 RelativeRIintensity cosessensor

10 11 12 13 14 15 16 17 18 19 20 Time of elution (min )

FIGURE 4 U . S . Patent Oct. 3 , 2017 Sheet 7 of 15 US 9 ,777 , 023 B2

FIGURE 5 U . S . Patent Oct. 3 , 2017 Sheet 8 of 15 US 9 ,777 , 023 B2

OR FEGIR 19202 H4ne N1 N30

FIGURE 6 U . S . Patent Oct. 3 , 2017 Sheet 9 of 15 US 9 ,777 , 023 B2

[ (NNO + Bu )InCl ] z( u -OEt ) ( IL -CI ) 400000 .

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FIGURE 7 U . S . Patent Oct . 3 , 2017 Sheet 10 of 15 US 9 ,777 ,023 B2

80000 [( NNHO )Inl ] 2 ( ll -OEt ) (u -I )

.

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40000 . - Mn gmol- 1 30000 .

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10000 .

0 ...... L 100 200 300 400 500 Equiv . lactide ?

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FIGURE 9 U . S . Patent Oct. 3 , 2017 Sheet 12 of 15 US 9 , 777 ,023 B2

120000 Cam [ (NNHO ) In (I ) (dL -OEt ) lz 100000 in.

.www 80000

. 60000 . dowBeograduco- .www

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i

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FIGURE 10 U . S . Patent Oct . 3 , 2017 Sheet 13 of 15 US 9 ,777 , 023 B2

• 1st 100 equiv 2nd 100 equiv oCGo: (tawlga]uy

??????????????????????????? 0 1000 2000 3000 4000 5000 6000 7000 Time ( s )

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FIGURE 11 U . S . Patent Oct . 3, 2017 Sheet 14 of 15 US 9 ,777 ,023 B2

1 . 2

Refractiveindex

of 14 15 16 17 18 19 20 Elution time (min )

FIGURE 12 U . S . Patent Oct 3 , 2017 Sheet 15 of 15 US 9 , 777, 023 B2

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:

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02 4

0 16 17 18 19 20 21 22 23 24 Elution time (min )

FIGURE 13 US 9 ,777 ,023 B2 DINUCLEAR INDIUM CATALYSTS AND A first embodiment of the present invention is a catalyst THEIR USE FOR (CO ) POLYMERIZATION represented by structural formula ( A ) : OF CYCLIC ESTERS CROSS -REFERENCE ( A ) This application is the U . S . National Stage of Interna 1 ' — In In — L? ; tional Application No . PCT /CA2012 /050331 , filed May 18 , 2012 , which designates the U . S . , published in English , and claims the benefit of U .S . Provisional Application No . 10 61 /487 ,626 , filed May 18 , 2011 and claims priority under 35 wherein Land L are each independently a tridentate ligand U .S .C . $ $ 119 or 365 (c ) to Canadian Application No . 2, 740 , represented by structural formula (B ): 821, filed May 18 , 2011, the entireties of which are incor porated herein . 15 (B ) BACKGROUND OF THE INVENTION R ?

Polymers prepared by cyclic ester polymerization and z copolymerization such as poly ( lactone )s and poly ( lactide )s are interesting polymer systems in that they typically are 20 biodegradable and bioassimilable . In addition , a number of R - N obro monomers used to produce these polymers can be produced from biomass using enzyme technology or living organisms such as yeast. Poly ( lactic acid ) (PLA ) , produced by ring -opening 25 mu polymerization (ROP ) of lactide (LA ) , is a leading biode gradable and biocompatible polyester with wide - ranging applications . Several well - defined Lewis acid catalysts have been developed for this reaction ; prominent among them are metal alkoxides based on aluminum , zinc , and rare -earth 30 r . metals , as well as organocatalysts . These known systems or a stereoisomer thereof; have successfully addressed one or more important factors each R ' independently is - ( C - C ) alkyl; in the ROP of LA , such as activity and catalyst toxicity . Yl is 0 - R or OH ; Enantioselectivity , in particular , has garnered much atten - y2 is O _ RO OH . CI. Br. or 1: tion , and catalysts with exquisite control over PLA tacticity 35 have been reported . Nevertheless , in most cases examples of each Ró independently is – ( CZ- C ) alkyl; highly selective catalysts that exhibit site control remain n is 0 to 4 ; confined to aluminum salen complexes , which have low each R and R² is independently a - Hor ( C7 - C Jalkyl; or reactivity and functional- group tolerance . Rl and R2 together with the carbon atoms to which they There is a need for improved catalysts for the living 40 are bonded form a ( C - - C - )cycloalkyl ring , optionally polymerization and copolymerization of cyclic ester mono substituted with up to two groups selected independently mers . Improved catalysts can be , for example , less costly or from (CZ -C4 ) alkyl , ( C , - C4) alkoxy, phenyl, CF3, highly reactive providing high turnover rates , enhanced - F , - Cl, Br, and — I; stereochemical control or enhanced microstructure control, for example , by way of block copolymer self assembly and 4515 R * is - H or ( C7 - C3) alkyl; precise control over block ratio . Other desirable character each X is independently an anionic ligand ; and istics of improved catalysts include reduced toxicity , increased functional- group tolerance , increased stability or the ability to produce high molecular weight polymers and or a stereoisomer of the catalyst represented by structural copolymers , particularly , with narrow molecular weight 50 formula (A ); distribution . There is further a need for polymers andand provided that when L and L ? are both represented by copolymers produced with such improved catalysts, specifi structural formula : cally ; there is a need for biodegradable polymers and copolymers with controlled microstructure . This background information is provided for the purpose 55 of making known information believed by the applicant to be of possible relevance to the present invention . No admis sion is necessarily intended , nor should be construed , that any of the preceding information constitutes prior art against the present invention . 60 H - N SUMMARY OF THE INVENTION The invention relates to indium catalysts , a process for num polymerization of cyclic ester monomers using the indium 65 catalysts and the polymers and copolymers prepared by the t - Bu * t - Bu process . US 9 ,777 ,023 B2 then the catalyst is not represented by structural formula : foam a first polymer block of the block copolymer ; and ( b ) polymerizing a second cyclic estermonomer , different from the first cyclic ester monomer , with a catalyst represented by (P1 ) structural formula ( A ) or a stereoisomer thereof under 5 conditions suitable for ring -opening polymerization of the L ! — In In — L ? , second cyclic ester monomer to form a second polymer block of the block copolymer . In a particular embodiment, the first cyclic ester monomer and the second cyclic ester monomer are independently represented by structural for (P2 ) mula ( I ) . A fourth embodiment of the present invention is a poly L ! — In In — L ? , mer prepared by a process comprising polymerizing a cyclic ester monomer such as the cyclic ester monomer represented 15 by structural formula ( I ) with a catalyst represented by structural formula ( A ) or a stereoisomer thereof under conditions suitable for ring -opening polymerization of the ( P3 ) cyclic ester monomer, provided that when the tridentate ligands L ' and L are represented by the following structural L - In - -612Cl In — L? , or 20 formula :

(P4 )

25 L ! — In n — . H - N 30 mi A second embodiment of the present invention is a method comprising polymerizing a cyclic ester monomer t - Bu t - Bu , with a catalyst represented by structural formula ( A ) or a 35 stereoisomer thereof under conditions suitable for ring and the catalyst is represented by structural formula (P1 ) , opening polymerization of the cyclic ester monomer. (P2 ), (P3 ) or (P4 ), then the cyclic ester monomer is not The catalyst is represented by structural formula A , L ' and L -lactide , D -lactide ,meso - lactide or rac - lactide . L ’ are each independently a tridentate ligand represented by A fifth embodiment of the present invention is a block structural formula (B ) , provided that when the tridentate 40 copolymer. The block copolymer is prepared by a process ligands Land L2 are represented by the following structural comprising: ( a ) polymerizing a first cyclic ester monomer formula : such as the cyclic ester monomer represented by structural formula ( 1 ) with a catalyst represented by structural formula 45 ( A ) or a stereoisomer thereof under conditions suitable for ring -opening polymerization of the first cyclic ester mono mer to form a first polymer block of the block copolymer ; and (b ) polymerizing a second cyclic ester monomer such as mo the cyclic ester monomer represented by structural formula 50 ( 1 ) , different from the first cyclic ester monomer, with a - N catalyst represented by structural formula ( A ) or a stereoi somer thereof under conditions suitable for ring - opening polymerization of the second cyclic ester monomer to form min a second polymer block of the block copolymer . 55 t - Bu * t - Bu BRIEF DESCRIPTION OF THE DRAWINGS The foregoing will be apparent from the following more and the catalyst is represented by structural formula (P1 ) , particular description of example embodiments of the inven ( P2 ), (P3 ) or ( P4) , then the cyclic ester monomer is not 60 tion , as illustrated in the accompanying drawings in which L -lactide , D - lactide, meso -lactide or rac - lactide . like reference characters refer to the same parts throughout A third embodiment of the present invention is copoly - the different views . The drawings are not necessarily to merization method for preparing a block copolymer . The scale , emphasis instead being placed upon illustrating method comprises ( a ) polymerizing a first cyclic ester mono - embodiments of the present invention . mer with a catalyst represented by structural formula ( A ) or 65 FIG . 1 shows the relative concentration of c -caprolactone a stereoisomer thereof under conditions suitable for ring - against time in the polymerization of e -caprolactone with opening polymerization of the first cyclic ester monomer to [( NNO )InCl ] 2 ( u - OEt) ( u - C1) . US 9 ,777 ,023 B2 FIG . 2 shows the ' H NMR of the block copolymer images are not superimposable , most commonly because L - lac -b - f- BBL . they contain an asymmetrically substituted carbon atom that FIG . 3 shows the ' H NMR of the block copolymer acts as a chiral center . " ” means one of a pair of BBL -b - f- BBL . molecules that are mirror images of each other and are not FIG . 4 shows the GPC elution diagram of poly ( L -lac - b - 5 superimposable . Diastereomers are stereoisomers that are rac- lac ) ( left peak ) and its first block , poly ( rac- lac ). not related as mirror images , most commonly because they FIG . 5 shows the molecular structure of contain two or more asymmetrically substituted carbon [( NN , Bu) Inl] 2( u -OEt ) 2 obtained by single - crystal X - ray atoms. “ R ” and “ S ” represent the configuration of substitu diffraction . ents around one or more chiral carbon atoms. When a chiral FIG . 6 shows the molecular structure of [ (NN Bu ) 10 center is not defined as Ror S . either a pure enantiomer or Inl ]2 (u -OH ) ( u -OEt ) , obtained by single -crystal X -ray dif a mixture of both configurations is present. fraction . FIG . 7 shows the observed poly ( lactide ) (PLA ) M , (v ) More specifically , " stereoisomers ” of the catalysts as and molecular weight distribution ( o ) as function of added referred to herein , include the below " cis ” and “ trans ” rac - lactide for f (NN _ O , , ) InC1 ] ( u -C1 ) ( u -OEt ) 15 stereoisomers , as well as and diastereomers ( M , = number averaged molecular weight, thereof, (note that for simplicity only the co -ordinate bond PDI= polydispersity index ) . ing N , N and O atoms of the tridentate ligands are shown ) : FIG . 8 shows the observed poly ( lactide) (PLA ) M , ( v ) and molecular weight distribution ( o ) as function of added rac -lactide for [ (NN , OBU ) Inl] 2 ( u - OH ) ( u -OEt ) (Mr = number 20 Ny2vN N Y2 averaged molecular weight, PDI= polydispersity index ) . n — N N FIG . 9 shows the observed poly ( lactide ) (PLA ) M ,, ( v ) n and molecular weight distribution ( o ) as function of added YI rac - lactide for [( NN ,OBwInl ] (u -OH )( u - OEt) (Mn = number " cis " trans " averaged molecular weight, PDI= polydispersity index ). 25 FIG . 10 shows the observed poly ( lactide ) (PLA ) M , ( v ) and molecular weight distribution ( o ) as function of added “ Racemate ” or “ ” means a compound of rac - lactide for [( NN , Ome) Inl] ( u -OEt ) 2 (Mn = number aver equimolar quantities of two enantiomers , wherein such aged molecular weight, PDI= polydispersity index ). mixtures exhibit no optical activity ; i. e . , they do not rotate FIG . 11 shows in part ( a ), top , a plot of Ln ( [BBL ] ) versus 30 the plane of polarized light. time for two sequential additions of 100 equiv of [BBL ]/ [ 1 ] in CD , CN at 60 .6° C ., and in part ( b ) , bottom , the GPC The compounds of the invention may be prepared as traces of the polymers produced by 20 consecutive additions individual isomers by either isomer specific synthesis or of 200 equiv . of [ BBL ]/ [ 1 ] in THF at 25° C . resolved from an isomeric mixture . FIG . 12 shows a GPC elution diagram for polymers 35 When the stereochemistry of a disclosed compound is produced by iROP with a dinuclear Indium catalyst of named or depicted by structure , the named or depicted rac -LA with ethanol . stereoisomer is at least 60 % , 70 % , 80 % , 90 % , 99 % or 99 . 9 % FIG . 13 shows a GPC elution diagram for polymers pure relative to the other stereoisomers , for example , by produced by iROP of L - LA with MePEG114 by a dinuclear weight or as determined by spectroscopic analysis . When a Indium catalyst. 40 single enantiomer is named or depicted by structure , the depicted or named enantiomer is at least 60 % , 70 % , 80 % , DETAILED DESCRIPTION OF THE 90 % , 99 % or 99. 9 % by weight optically pure . Percent INVENTION optical purity by weight is the ratio of the weight of the Dinuclear Indium Catalysts enantiomer that is present divided by the combined weight The catalysts of the present invention can be described by of the enantiomer that is present and the weightof its optical structural formula ( A ) . They are initiator and catalyst com isomer . plexes for the ring -opening polymerization of cyclic esters The tridentate ligands L ' and L2 can be different chemical as described herein . Each tridentate ligand bonds with one groups , different stereoisomers , different enantiomers , or the indium metal ion via one covalent bond between 0 and In 50 same enantiomers. Typically, when Land L ’ are the same and two co -ordinate ( dative covalent) bonds between N and chemical group , they are also the same enantiomer . For In ; these three bonds are indicated by the “ _ ” between L ? example , for a ligand with two asymmetric centers, the and In , and between L´ and the other In , for example , in catalyst typically is of (RR ,RR ) and /or (SS , SS ) form . structural formula ( A ) . These same bonds are also indicated as three “ _ ” extending from N , N , and O , respectively , in 55 A sixth embodiment of the present invention is a catalyst the structural formulas for the tridentate ligands, for represented by structural formula ( A ) , or a stereoisomer example , structural formula ( B ) . Additionally , each Yl is thereof: bridged between the two In by bonds indicated by “ _ ” . Further, each ligand X is bonded with one In . With regard to the bridging ligands Y and Y ? , when the group is a 0 - R 60 ( A ) or OH , it is to be understood that the oxygen atom partici pates in the bonding . 11 - Ina1 x2IX - L2, The invention also includes various isomers and mixtures of catalysts . Certain of the catalysts of the present invention may exist in various stereoisomeric forms. Stereoisomers 65 are compounds which differ only in their spatial arrange - wherein L ' and L are each independently a tridentate ligand ment. Enantiomers are pairs of stereoisomers whose mirror represented by structural formula ( B ) : 7 US 9 ,777 ,023 B2 (C1 ) R77 R7 w

m R3 - N R3 - N yern ww mi

(R *) n (C2 )

Values and alternative values for the variables in struc tural formula ( A ) and ( B ) are provided in the following paragraphs . It is understood that the invention encompasses RP all combinations of the substituent variables defined herein . 20 Each R ' is independently — (CZ -C4 ) alkyl . Alternatively , both R ’ are the same — (CZ -C4 ) alkyl. In yet another alter native , both R ' are methyl , ethyl or propyl. In yet another mm alternative , both R ' propyl. YlisO Ró or OH . Alternatively , Yl is OCH , CH , or OH . 25 Py In yet another alternative , Yl is OCH CHz . Y2 is O - R “ , OH , CI, Br, or I. Alternatively, Y2 is ( D1) OCH CH3, OH , CI, Br, or I . Each Rº independently is – ( C . - C . ) alkyl . Alternatively , 30 both Rº independently are (C , -C . ) alkyl. In yet another alternative, both Rºare OCH CHz. n is 0 to 4 . Alternatively , mal n is 0 to 2 . In yet another alternative , n is 2 . RUN Each R ' and R ’ is independently a Hor — (CZ -C4 ) alkyl; or R1 and R2 together with the carbon atoms to which they 35 are bonded form a (C5 - C7) cycloalkyl ring , optionally sub stituted with up to two groups selected independently from mo — (C1 - C4 )alkyl , (C1 - C4 ) alkoxy , phenyl , CF3, — F , - Cl, Br, and — I . Alternatively , R and R2 are — H ; or R ? and R2 together with the carbon atoms to which they are 40 bonded form a cyclohexyl ring, optionally substituted with (D2 ) up to two groups selected independently from (C1 -C4 ) alkyl, (C2 -C4 ) alkoxy, CF3, F , Cl, Br, or — I. In yet another alternative, R ' and R² are H ; or RP and R2 together with the carbon atoms to which they are bonded 43 form a cyclohexyl ring. R - N Ris - H or - ( C , - CZ ) alkyl . Alternatively , Rºis - H or m methyl. Each X is independently an anionic ligand . Alter natively , each X is independently ( C1- C4) alkoxy, BF4, PF . , wa acetate , acetylacetonate , trifluoroacetate , F , C1, or I. In yet another alternative , each X is independently Cl, Br or I. In yet another alternative , both X are C1, Br or I. R4 R4 Each R4 independently is (C1 - C5) alkyl. Alternatively , each R * is independently methyl , ethyl, n -propyl , isopropyl, 55 (D3 ) n -butyl , isobutyl , sec -butyl , or tert -butyl . In yet another alternative , each R4 is independently methyl or tert- butyl ( i . e . , t -butyl or tBu ) . In yet another alternative , n is 2 , and one R4 is in para position to the phenol hydroxyl and is methyl or tert -butyl and one R * is ortho position to the 60 - N phenol hydroxyl and is tert -butyl . In a 1st specific embodiment, the catalyst of the present invention is represented by structural formula ( A ) , or a stereoisomer thereof, and Land L ' are each independently a tridentate ligand represented by structural formula (C1 ) , 65 (C2 ), (D1 ) , ( D2 ) , (D3 ), (E1 ) or (E2 ), or a stereoisomer R4 thereof: US 9 , 777, 023 B2 10 - continued - continued ( 51 ) ( E5a ) R ,

H - N * IIIiiii* — 10 – – N – H 10 infli

1 TRA? 15 ( 52) R

IIIII 20 ( 3 ) H – -N –

25 - In

" RP ; and values and alternative values for the remainder of the 30 R R?????? variables are as described for the sixth embodiment. In a 2nd specific embodiment, the catalyst of the present invention is represented by structural formula ( E3a) , ( E4a ), 35. ( E5a ), ( C3) , ( C3t ), ( D4) , ( D5) or ( D6) : ( C3t) CR4 ( E3a)

40

- In - X V*?? H In – – – – H -IIiiiuY 45 –

: ?

50 R? - R 4 R ( E4a ) RR , ( D4) 55

,•situti H N - H 11 Xiv : SXYI •till •JIiii -

-- ? 4 P - US 9 , 777 ,023 B2 12 - continued -continued (D5 ) ( F4a ) R4 - R4,

N1 III 2 0 . . X In - 11till*** * lliu 10 11111111 X1 — N — H encom -o

R4 V R4, 15 Po

20 ( DO ) P RY (D5 )

25

T111 1111111** Xinin - In 111111*** Xvin 30 111nn. R6 RA RS P 35 R4 R4

40 wherein Y2 is OCH CH3, OH , C1, Br or I, and values and (D6 ) alternative values for the remainder of the variables are as described for the sixth embodiment. P R4; In a 3rd specific embodiment , the catalyst of the present 45 invention is represented by structural formula (E3a ), ( E4a ) , (D5 ) or (DC ): 11 1* Xm . In 50 111111"

(E3a )

55 R $

O

H - N - InLX In — N — H 11111111 60 and values and alternative values for the remainder of the 0- variables are as described for the sixth embodiment. In a 4th specific embodiment, the catalyst of the present invention is represented by structural formula ( A ), or a R 65 stereoisomer thereof, and L ' and L2 are each independently R4 Px V R4, a tridentate ligand represented by structural formula (C1 ) , (D1 ) , or ( E1 ), or a stereoisomer thereof: US 9 , 777 ,023 B2 13 14 -continued (D2 )

5 R3 - N R3 — N ma 10

( Rºn P4 R4R4 ; 15 (D1 ) and values and alternative values for the remainder of the variables are as described in the sixth embodiment. In a 6th specific embodiment , the catalyst of the present 20 invention is represented by structural formula ( A ) , or a stereoisomer thereof, and L ' and L are each independently - N a tridentate ligand represented by structural formula (D3 ) or mm (E2 ) , or a stereoisomer thereof: 25 ( D3 ) (R4 ) n

(E1 ) 1111111**.

m mm min ww (E2 )

P R4 ; and values and alternative values for the remainder of the # H - N vi variables are as described in the sixth embodiment. In a 5th specific embodiment, the catalyst of the present invention is represented by structural formula ( A ) , or a stereoisomer thereof, and L ' and L are each independently 50 a tridentate ligand represented by structural formula (C2 ) or R4 R4 (D2 ) , or a stereoisomer thereof: and values and alternative values for the remainder of the (C2 ) 55 variables are as described in the sixth embodiment. In a seventh embodiment , the catalyst is represented by min structural formula R3 - N (P1 ) ma L ' — Inn — L ?,

P4 Py US 9 , 777 ,023 B2 15 16 -continued - continued (P2 ) ( P11 ) TILIL ! — In - In - L ? , L ! — In BrBr In — 12 or

(P3 ) 10 (P12 ) TO 11 - In - In - L ”,

11 - In A In - L2; (P4 ) 15

L -II - In In L ?, or a stereoisomer thereof; 20 wherein L ' and L are each independently a tridentate ligand represented by structural formula (C1 ) , (D1 ) , or (E1 ) , or a stereoisomer thereof. ( P5) Br 25 L ! — In BramyIn — L2 (C1 )

R3 - N TO worn L - In BrBr In — L

(P7 ) (D1 ) L ! — In ILIn — L ?- , OF (P8 ) R - N 11 - In - CICl- In - L2. nun

(E1 )

L In Br In — L ?,

H - N (P10 ) 60 min L ! — In In — L ?, R4 R4 ;

65 and values and alternative values for the remainder of the variables are as described in the sixth embodiment. US 9 , 777, 023 B2 17 18 In a 7th specific embodiment, the catalyst of the present -continued invention is the one of the seventh embodiment, wherein it is further provided thatLand L2 are not both represented by (C5 ) structural formula : 5

CI - In CI In

H - N

mi ( C5t )

t - Bu t - Bu

In an eight embodiment, the catalyst is represented by structural formula (C4 ), (C4t ) , (C5 ), (C5t ) , (E6 ) , ( E7 ) or o29 ( E8 ) : 30

( C4) 35

( E6 ) InCI In - 40 CI .

o

N - In In - N - H . 45 11111 Cli!

50 (C4t ) Me v t - Bu t - Bu Me,

( E7) 55

60 H - N - In Tv In - N - H 11111***

65 MeA t t - Bu t -BuV Bu Me, US 9 , 777 ,023 B2 19 20 - continued - continued ( E8 ) (P4 )

5 11 - In In L2.

10 H — .12 1 111 - N - H 10 In a tenth embodiment, the catalyst of the present inven tion is the one of the sixth embodiment, the 1st specific 15 embodiment, the 2nd specific embodiment, the 3rd specific embodiment, the 4 specific embodiment, the 5th specific embodiment, or the 6th specific embodiment, wherein it is further provided that when L ' and L ? are both represented by structural formula : 20 In a ninth embodiment, the catalyst of the present inven tion is the one of the sixth embodiment, the 1st specific embodiment, the 2nd specific embodiment, the 3rd specific embodiment, the 4th specific embodiment, the 5th specific embodiment, or the 6th specific embodiment, wherein it is 25 further provided that when Land L ? are both represented by structural formula : H - N 30 mi

35 t - Bu t - Bu , H — N — mu then the catalyst is not represented by structural formula : 40 t - Bu * tt - Bu Bu , (P1 ) then the catalyst is not represented by structural formula : 4515 L ' - In - ClC - In - 12

@(P1 )

Il - In - In - L ? , 50 (P2 )

11 - Ino I - In - Lº, (P2 ) 55 n ci L ! — In In — 12,

Ô (P3 ) (P3 ) C 11 — In cin — L , or L ' - In - C1- In — L ?, op TO US 9 , 777 ,023 B2 21 22 - continued - continued (P11 ) (P4 ) om L ' - InMe Bry In — L ? , or L' - < -- In — l? ,

( P12 )

11 - In In - L2. Br ( P5) Br Li - In Br - In - L ?,

A 7th specific embodiment is a catalyst composition com 20 prising a catalyst represented by structural formula ( F ): ( P6 ) t -Bu (F ) 25 But- Br L ' - In - Br. In - L ?,

( P7) HH — N — n - N - H

on I L ' - InC [ In - L2

t - Bu V tt - Bu ( P8 ) in at least 80 % purity . More typically , the composition 40 comprises the catalyst represented by structural formula ( F ) in at least 90 % purity . Even more typically , the composition CI comprises the catalyst represented by structural formula ( F ) L ' - In C1 - In — 12, in at least 95 % purity . An gth specific embodiment is a catalyst composition 45 comprising a catalyst represented by structural formula (F1 ) :

( P9 ) (F1 ) t - Bu t - Bu

50

L ' - In Br In - Br- In - L2L ., 1111lllll***

In 55 H - N

( P10 ) +1111N H 60 t - Bu * t - Bu L ' - In - C CI- In - L ? in at least 80 % purity . More typically , the composition comprises the catalyst represented by structural formula (F1 ) 65 in at least 90 % purity . Even more typically , the composition comprises the catalyst represented by structural formula (F1 ) in at least 95 % purity, US 9 ,777 ,023 B2 23 24 Agth specific embodiment is a catalyst composition com wherein prising a catalyst represented by structural formula (F2 ): m is 1 to 4 ; Q is CH2 - , - C (HRM ) — , or - C ( R " R " ) ; each Z is independently — CH , — , - O , C O ) , (F2 ) 5 - C (HRM ) , or C ( R " R " ) ; and each R " is i ) — ( C , -Cs )alkyl optionally substituted with t -Bu t - Bu hydroxyl , - ( C1 - C3) alkoxy or – O – ( C1 -C3 ) alkenyl, or ii ) ( C , - C5 )alkenyl ; or a stereoisomer thereof. The ring - opening polymerization of a cyclic ester mono 10 mer to form a polymer or polymer block of a copolymer is performed under suitable conditions , that is any condition | | In NSH under which the cyclic ester monomer is polymerized by the 1101 catalyst to form a polymer or polymer block of a copolymer . More particularly , suitable conditions can include polymer 15 izing in a suitable solvent system , that is a single solvent or a solvent mixture . Suitable solvent systems allow the cata lyst and the cyclic ester monomer to be in solution in at least t - Bu * t - Bu part of the solvent system , and include but are not limited to toluene , THF, CH , C1, , acetonitrile , chlorobenzene, ether, in at least 80 % purity . More typically , the composition 20 chloroform . The ring - opening polymerization can also be comprises the catalyst represented by structural formula (F2 ) performed without solvent, for example , as neat polymer ization in liquid or molten monomer. Additionally , suitable at least 90 % purity . Even more typically , the composition conditions include suitable temperatures. Typically , the tem comprises the catalyst represented by structural formula (F2 ) perature should at least be high enough for the solvent in at least 95 % purity . 25 system to be a liquid . More typically , the temperature is “ Purity ” as referred to herein with regard to catalyst between 0° C . and 110° C ., even more typically , between 20° compositions, refers to purity as determined by 1H NMR C . and 100° C . Even further, suitable conditions include spectroscopy in solution . suitable catalyst concentration , typically , from 0 . 1 - 5 mM . Polymerization and Copolymerization Methods A plurality of different cyclic ester monomers can be The dinuclear indium complexes as described in the 30 polymerized at the same time, or during different times of previous section are initiators and catalysts of the ring the entire polymerization process. With regard to the below opening polymerization of cyclic ester monomers . It has embodiments directed to polymerization and copolymeriza been found that these complexes can facilitate living ring tion methods , steps ( a ) , (b ) , and optionally ( c ) can occur at opening polymerization . Accordingly , the below described the same time , overlap in time, or can be separate in time . polymerization methods can be living ring opening polym - 35 Further, with regard to the copolymerization methods erization including copolymerization methods . described in below embodiments , the first cyclic ester mono Suitable cyclic ester monomers include , but are not lim mers can be polymerized in a solvent or solvent system and ited to cyclic ester monomers represented by the following the second cyclic ester monomer is added to the solvent or structural formula ( I ) : solvent system ( either directly or in a second miscible 40 second solvent ) . If the second cyclic ester monomer is added before the first cyclic ester monomer is substantially polym erized but after the first cyclic ester monomer has been polymerized to form a first polymer block , typically, both cyclic ester monomers will be polymerized at the same time 45 resulting in a copolymer block (which can be random Q + Z )mi copolymer block ) , that is , the resulting copolymer includes at least the first polymer block covalently bonded to the wherein copolymer block . m is 1 to 4 ; The ring -opening polymerization methods of the present Q is CH - , - C (HRM ) — , or — C (R " R " ) ; 50 invention can be living polymerization methods, that is , each Z is independently - CH2 , - O , CEOPo ) , polymerizing steps can be living polymerizing steps in the C (HRM ) — or - C (RMRM ) — ; and each R " is i) — (C1 methods disclosed herein . Cs )alkyl optionally substituted with hydroxyl, ( C , - CZ ) Typically , in living polymerization cyclic esterter momonomer alkoxy or – O (C1 - C3 ) alkenyl , 11 ) — (C1 -C5 Jalkenyl, or is polymerized at very low polymer chain termination rates iii ) (C7 - C3) X " wherein XM = F , C1, Br, or I; 55 ( i. e ., the ability of the growing polymer chains to terminate or a stereoisomer thereof. is substantially removed ) . The result can be that the polymer Alternatively , suitable cyclic ester monomers include, but chains grow at a more constant rate ( compared to traditional are not limited to cyclic ester monomers represented by the chain polymerization ) and the polymer chain lengths remain following structural formula ( I ) : very similar ( i. e ., they have a very low polydispersity index ) . 60 The ring - opening polymerization methods of the present invention can further be immortal ring opening polymeriza tion methods, that is , polymerizing steps can be immortal polymerizing steps in the methods disclosed herein . FO Typically , in immortal ring opening polymerization Q + Z ) m ; 65 ( PROP ) of a cylic ester monomer , external nucleophiles act as both initiators and chain transfer agents in conjunction with a catalyst. The result can be that catalytic productivity US 9 ,777 ,023 B2 25 26 is enhanced and metal contamination of polymers signifi - catalyst under conditions suitable for ring -opening polym cantly reduced in comparison to classic living systems, erization of the cyclic ester monomer , wherein the catalyst while the polymer chain end is functionalized with the is as described in any one of the embodiments 6 to 10 , or as chosen chain transfer agent . in any one of the specific embodiments 1 to 9 , provided that A description of further polymerization and copolymer - 5 when the tridentate ligands L ' and L ? are represented by ization embodiments follows below . structural formula : Polymerization Methods An 11th embodiment of the present invention is a method comprising polymerizing a cyclic ester monomer with a catalyst under conditions suitable for ring - opening polym erization of the cyclic ester monomer, wherein the catalyst Z is as described in any one of the embodiments 6 to 10 , or as in any one of the specific embodiments 1 to 9 , provided that when the tridentate ligands L ' and L ? are represented by H - N structural formula : 15 WM

t - Bu t - Bu 20 H - N and the catalyst is represented by structural formula :

(P1 ) 25 L - I CI ! In - 12 t - Bu * t - Bu C1 and the catalyst is represented by structural formula : 30 1 (P2 ) (P1 ) L ! — In - In - L ? , L ' — ín C - In - L , 35

(P3 ) (P2 ) 40 L ! — In - InIn -- 12L , or 11 — In I ,In L2

45 ( P4)

@(P3 )

Li - In Y In - L ?, L ' In - In - L ?, or 50

(P4 )

55 then the cyclic ester monomer is not L - lactide, D - lactide , meso - lactide or rac - lactide. 11 - In - In - L ” , The cyclic ester monomer is represented by the following structural formula ( I ) : 60

then the cyclic ester monomer is not L - lactide , D -lactide , - 0 meso - lactide or rac - lactide . 65 QtZ) m A 12th embodiment of the present invention is a method comprising polymerizing a cyclic ester monomer with a US 9 , 777 ,023 B2 28 wherein -continued m is 1 to 4 ; (P2 ) Q is CH - , - C (HR " ) , or C ( R " R " ) ; each Z is independently - CH2- , - O , CEO ) , L ' — 1n - In - La , - C (HRM ) — , or C ( R " R " ) ; and 5 each R " is i ) ( C -C5 ) alkyl optionally substituted with hydroxyl , ( C , - CZ )alkoxy or O (C7 -C3 ) alkenyl, ii ) (C .- Cs) alkenyl , or iii ) (C7 -C3 ) Xi wherein XM = F , CI, Br, or I ; (P3 ) or a stereoisomer thereof; 10 provided that (i ) no more than one Z is 04 , ( ii ) no more than one Z is C ( O ) - , ( iii ) at least one carbon ring L ' In - In - L ?, or atom is between any two oxygen ring atoms, ( iv ) at least aa0 one carbon ring atom is between any two - C ( O ) - 15 groups, and ( v ) at least one of any three consecutive ring ( P4) members is _ CH , — , - C (HRM ) , or C ( R " R " ) . In a more particular embodiment, the cyclic ester mono mer is represented by the following structural formula (I ) : 20 L - In I Im In - L ?

- 0 Q + Z ) m ; 25 then the cyclic ester monomer is not L - lactide, D -lactide , wherein meso - lactide or ac - lactide . m is 1 to 4 ; The cyclic ester monomer is a di- lactone represented by Q is CH2 - , - C (HRM ) , or — C (R " R " ) ; 30 structural formula ( II ) or a lactone represented by structural each Z is independently — CH , — , - 04 , - C ( O ) - , formula (III ): C (HRM ) — , or — C (R ” R ” ) — ; and each R " is i) (C2 -C3 ) alkyl optionally substituted with hydroxyl, ( C , -CZ ) alkoxy or — O - ( C , - CZ) alkenyl , or ii ) ( C - C5) alkenyl. A 13th embodiment of the present invention is a method comprising polymerizing a cyclic ester monomer with a catalyst under conditions suitable for ring -opening polymerization of the cyclic ester mono mer, wherein the catalyst is as described in any one of the embodiments 6 to 10 , or as in any one of the specific 4010 embodiments 1 to 9 , provided that when the tridentate O= ligands L ' and L2 are represented by structural formula : ( III)

=O

45

1 wherein p is 1 or 2 ; nim 50 g is 2 to 5 ; each z is independently CH - C (HRM ) , or - C (R " R " ) — ; and each R " is i) (C1 - C5 )alkyl optionally substituted with t - Bu t - Bu hydroxyl, — ( C , -CZ ) alkoxy or - 0 (C , - CZ )alkenyl , ii ) 55 ( C -C5 )alkenyl , or iii) (C1 - C5 ) X " wherein X " = F , CI, Br, or I ; and the catalyst is represented by structural formula : or a stereoisomer thereof. In a more particular embodiment , the cyclic ester mono mer is represented by the following structural formula (I ) : ci (P1 ) 60 Il - In - CLYC - In - L ?,

QtZm US 9 ,777 , 023 B2 30 wherein The cyclic ester monomer is represented by structural m is 1 to 4 ; formula : Q is CH - , - C (HR " ) , or - C ( R " R " ) ; each Z is independently - CH2- , - O , CEO ) , C (HRM ) — , or C ( R " R " ) — ; and each R " is i ) ( C -C5 ) alkyl optionally substituted with (IV ) hydroxyl, - C , -CZ ) alkoxy or – O – (C -C3 )alkenyl , or ii ) ( C , -C5 ) alkenyl . A 14th embodiment of the present invention is a method comprising polymerizing a cyclic ester monomer with a 10 catalyst under conditions suitable for ring -opening polym erization of the cyclic ester monomer , wherein the catalyst is as described in any one of the embodiments 6 to 10 , or as in any one of the specific embodiments 1 to 9 , provided that when the tridentate ligands L and L are represented by 15 structural formula :

(VI ) H

?

t - Bu t- - Bu and the catalyst is represented by structural formula : ( VII)

ci (P1 ) L ! — In C1 In - L2 ( VIII )

( P2) 11 - In In - L , ( IX )

o , or

(P3 ) • L - InCI In - L ?, or

(P4 ) 55

or a stereoisomer thereof. An 15th embodiment of the present invention is a method - - n - L? comprising polymerizing a cyclic ester monomer with a catalyst under conditions suitable for ring -opening polym erization of the cyclic ester monomer , wherein the catalyst is as described in any one of the embodiments 6 to 10 , or as 65 in any one of the specific embodiments 1 to 9 , provided that then the cyclic ester monomer is not L - lactide , D -lactide , when the tridentate ligands L ' and L are represented by meso - lactide or rac - lactide . structural formula : US 9 , 777 ,023 B2 32 -continued ( P7)

L ' - In - In - L , H - N

mm 10 (P8 )

t - Bu ? t - Bu and the catalyst is represented by structural formula : 15 11 - In - C C - IN 12.

( P1) CI 20 ( P9) L - In CiCI - -- In - 12

Ll - In - Bry 25 \ Br In — 12 (P2 ) -6 Li - In In - L ? , 30 ( P10 )

Ll - In - In - L ?, (P3 ) 35 TO L ' — In In — L ?, ( P11 ) 40 OE (P4 ) Il - In -. BrBra In — L ?, or

45 Li -JI In I - In - L2. (P12 )

50 L ! — InLI In — L ? , ( P5 ) Br Ll - In - Br In — 12 Br- 55 then the cyclic ester monomer is not L - lactide, D - lactide, meso - lactide or rac - lactide. ( P6 ) A 16th embodiment of the present invention is a method comprising polymerizing a cyclic ester monomer with a Br catalyst under conditions suitable for ring -opening polym Li - In Br In — 12, erization of the cyclic ester monomer , wherein the catalyst is as described in any one of the embodiments 6 to 10 , or as 65 in any one of the specific embodiments 1 to 9 , provided that when the tridentate ligands L and L2 are represented by structural formula : US 9 , 777 ,023 B2 33 34 -continued (P8 )

H - N L ! — In In — L? ,

mm 10 (P9 )

t - Bu ? t - Bu and the catalyst is represented by structural formula : 15 L - In Br 1 In — L ,

20 ( P10 ) 11 — In Ci In - L ?, H L ' — In In — L? ,

25 ( P11 ) Il - In LI- I - In - 12 L ! — inIn BranBr In — L ?, or 30 09

( P12 ) L ! — Inn — L ? , 35 TOA L ' — In In — L ? ,

40

1 '- In In - L2 then the cyclic ester monomer is not L - lactide, D - lactide, meso - lactide or rac - lactide . The cyclic ester monomer is represented by the following 45 structural formula ( I ) : (P5 ) Br Br \ LiL ' - In Brin — L ? , 50 O + )m wherein m is 1 to 4 ; R is CH - , - C (HR " ) , or - C ( R " R " ) ; L - inIn Br In — each Z is independently CH2 - , - O - , CEO , C (HR " ) — , or - C (R " R " ) — ; and 60 each R " is i) – ( C , - C3) alkyl optionally substituted with (P7 ) 60 eachhydroxyl , – ( C1- C3) alkoxy or - 0 (C7 -C3 ) alkenyl , ii ) ( C , - C5) alkenyl , or iii ) (C2 -C3 ) X " wherein X " = F , CI, - In I . Br, or I ; ( In— , or a stereoisomer thereof; 65 provided that ( i ) no more than one Z is — O , (ii ) no more than one Z is C ( O ) - , ( iii ) at least one carbon ring atom is between any two oxygen ring atoms , ( iv ) at least US 9 ,777 ,023 B2 35 36 one carbon ring atom is between any two - CEO ) — - continued groups, and ( v ) at least one of any three consecutive ring (P3 ) members is CH2 - , C ( HRM ) — , or C ( R " R " ) . In a more particular embodiment, the cyclic ester mono 5 1 mer is represented by the following structural formula (I ) : 1 ' - In ci 0 (P4 )

Q + Z )mi 11- In I 1 In - L ? wherein m is 1 to 4 ; Q is CH , C (HR ” ) , orC ( R " R " ) ; each Z is independently _ CH , , - O , C O ) , (P5 ) C (HR " ) — , or - C ( R " R " ) ; and 20 each R " is i ) ( C , -Cs ) alkyl optionally substituted with 11 - In - BrB -- In — L? hydroxyl , - (C1 - C3) alkoxy or — O - ( C - C3) alkenyl, or ii ) (C1 - C5 ) alkenyl. A 17th embodiment of the present invention is a method 25 comprising polymerizing a cyclic ester monomer with a (P6 ) catalyst under conditions suitable for ring -opening polym erization of the cyclic ester monomer, wherein the catalyst is as described in any one of the embodiments 6 to 10 , or as Il - In Br In — L . in any one of the specific embodiments 1 to 9 , provided that 30 Br when the tridentate ligands L and L ’ are represented by structural formula : (P7 )

L —Inn — 12 OT win (P8 )

O mi Ll- In - Cl LC1 In — 12, t -Bu t- Bu and the catalyst is represented by structural formula : (P9 )

( P1) L ' - In - Br Ll - In - C In — 12 Br 02

( P10 ) ( P2 ) TO L ' - In I In - L ?, Lliki ' - In In - L ” , US 9, 777 ,023 B2 37 38 - continued each R " is i ) ( C -C5 ) alkyl optionally substituted with (P11 ) hydroxyl, (C , -C3 ) alkoxy or – O – (C , -CZ ) alkenyl , or ii ) (C1 - Cs) alkenyl . 11 _ Br ! 5 An 18th embodiment of the present invention is a method L - In" Br - In - L2, or comprising polymerizing a cyclic ester monomer with a catalyst under conditions suitable for ring -opening polym erization of the cyclic ester monomer, wherein the catalyst is as described in any one of the embodiments 6 to 10 , or as in any one of the specific embodiments 1 to 9 , provided that (P12 ) 10 when the tridentate ligands L and L2 are represented by structural formula : L !— INI In — 12

15 then the cyclic ester monomer is not L - lactide, D -lactide , 20 meso - lactide or rac - lactide . The cyclic ester monomer is a di- lactone represented by structural formula ( II ) or a lactone represented by structural formula ( III ) : mim 25 tt - Bu o t - Bu and the catalyst is represented by structural formula : 30 ( Z )p ; (P1 ) SOOS ( III) 35 -C7 11 - Ini 21 In — L ?,

40 wherein p is 1 or 2 ; (P2 ) q is 2 to 5 ; each z is independently – CH2 C (HR " ) — , or 45 L ' - In myIn — 12 - C ( R " R " ) ; and each R " is i) (C1 - C5) alkyl optionally substituted with hydroxyl, ( C , -C3 ) alkoxy or 0 (C1 - C3 )alkenyl , ii ) ( C1- C5 )alkenyl , or iii) (C7 -C3 ) X " wherein XM = F , CI, Br, or I ; 50 (P3 ) or a stereoisomer thereof. In a more particular embodiment, the cyclic ester mono mer is represented by the following structural formula ( I ) : L ' - In - In - L ? , 55

? (P4 )

Q + Z )m ; L ' - In - In - L ? , wherein m is 1 to 4 ; Q is CH - , C (HRM ) — , or C ( R ” R ” ) ; each Z is independently CH , — , - 0 - , CE ) , C (HRM ) — , or C ( R " R " ) — ; and US 9, 777 , 023 B2 39 ? 40 - continued - continued ( PS ) (P12 )

r ? ?Br II - net, n LP , II - (- I I - In - L2

?10 ( P6 ) then the cyclic ester monomer is not L - lactide , D -lactide , meso- lactide or rac- lactide . . L! - - - - The cyclic ester monomer is represented by structural HOmBOH 15 formula : (IV ) (PT ) 20 L !- - in - L2, 25 ?? * ( P8 ) ?=

30 ? L - C1C?A?I2

35

(P9 ) 40

il| -i Br BTBr On - L2. 45 71)(A

( P10) SO HO?16 Il - in - C1C In - L2. 55 O , or

( P11 ) 8 HO? 60

L - in -? By Br, On" - L , or

66 or a stereoisomer thereof. US 9 ,777 , 023 B2 41 Copolymerization Methods (b ) polymerizing a second cyclic ester monomer, different A 19th embodiment of the present invention is a copoly from the first cyclic ester monomer , with a catalyst under merization method for preparing a block copolymer , com conditions suitable for ring - opening polymerization of the prising: second cyclic ester monomer to form a second polymer ( a ) polymerizing a first cyclic ester monomer with a catalyst 5 block of the block copolymer. under conditions suitable for ring -opening polymerization The catalyst for step ( a ) and ( b ) is independently as of the first cyclic ester monomer to form a first polymer described in any one of the embodiments 6 to 10 , or as in any block of the block copolymer; and one of the specific embodiments 1 to 9, and the first cyclic ( b ) polymerizing a second cyclic ester monomer , different ester monomer and the second cyclic ester monomer are from the first cyclic ester monomer, with a catalyst under 10 independently a di- lactone represented by structural formula conditions suitable for ring - opening polymerization of the second cyclic ester monomer to form a second polymer ( II) or a lactone represented by structural formula ( III) : block of the block copolymer . The catalyst for step (a ) and ( b ) is independently as described in any one of the embodiments 6 to 10 , or as in any 15 ( II ) one of the specific embodiments 1 to 9 , and the first cyclic ester monomer and the second cyclic ester monomer are independently represented by structural formula (I ) : ( Z !) p ; å NO @

- 0 (III )

Q + Ž )mi @ wherein m is 1 to 4 ; Q is CH - , - C (HRM ) , or — C (R " R " ) ; wherein each Z is independently - CH2 - , - 04 , - C ( O ) - , 30 p is 1 or 2 ; - C (HRM ) — , or C ( R " R " ) — ; and q is 2 to 5 ; each R " is i) - ( C , -C5 ) alkyl optionally substituted with each zi is independently CH , — , - C (HRM ) , or hydroxyl, ( C , -CZ ) alkoxy or O ( C , - CZ) alkenyl , ii) ( C , -C5 ) alkenyl, or iii ) (C7 -C3 ) X ” wherein X " = F , C1, - C (R ” R ” ) — ; and Br, or I ; each R " is i ) ( C -C5 ) alkyl optionally substituted with or a stereoisomer thereof; hydroxyl, - (C7 -C3 ) alkoxy or - 0 ( C , - CZ) alkenyl , ii ) provided that (i ) no more than one Z is 04 , ( ii ) no more ( C , - C Jalkenyl, or iii ) (C7 -C3 ) X ” wherein X " = F , C1, than one Z is CC- 0 ) - , ( iii) at least one carbon ring Br, or 1 ; atom is between any two oxygen ring atoms, ( iv ) at least or a stereoisomer thereof. one carbon ring atom is between any two - C ( O ) - 4040 1In a more particular embodiment, the cyclic ester mono groups, and ( y ) at least one of any three consecutive ring mer is represented by the following structural formula ( 1 ) : members is CH - , - C ( HRM ) — , or C ( R " R " ) . In a more particular embodiment, the cyclic ester mono mer is represented by the following structural formula (1 ) : 45 - 0

E Q + Z )mi - 0 50 wherein OZ) m ; m is 1 to 4 ; Q is CH2 - , C (HR " ) , or C ( RD mpm" R " ) ; wherein each Z is independently CH2 , 0 , C O ) , m is 1 to 4 ; - C (HR " ) , or - C (R " R " ) — ; and Q is CH - , - C (HR " ) , or C (R " R " ) ; 55 each R " is i) (C1 - C5) alkyl optionally substituted with each Z is independently — CH , — , - 04 , C40 ) , hydroxyl, ( C - CZ) alkoxy or 0 ( C -CZ ) alkenyl, or C (HRM ) — , or C ( R " R " ) — ; and ii ) ( C / - C5) alkenyl. each R " is i) (C1 - C5 )alkyl optionally substituted with 21st embodiment of the present invention is a copoly hydroxyl, — (C7 -C3 ) alkoxy or – O – ( C7 -C3 ) alkenyl, or merization method for preparing a block copolymer , com ii ) — (C1 - C5 )alkenyl . 60 prising : A 20 + embodiment of the present invention is a copoly - ( a ) polymerizing a first cyclic ester monomer with a catalyst merization method for preparing a block copolymer, com under conditions suitable for ring -opening polymerization prising : of the first cyclic ester monomer to form a first polymer ( a ) polymerizing a first cyclic ester monomer with a catalyst block of the block copolymer , and under conditions suitable for ring - opening polymerization 65 ( b ) polymerizing a second cyclic ester monomer , different of the first cyclic ester monomer to form a first polymer from the first cyclic ester monomer, with a catalyst under block of the block copolymer ; and conditions suitable for ring -opening polymerization of the US 9 ,777 , 023 B2 43 44 second cyclic ester monomer to form a second polymer conditions suitable for ring -opening polymerization of the block of the block copolymer. second cyclic ester monomer to form a second polymer The catalyst for step (a ) and ( b ) is independently as block of the block copolymer . described in any one of the embodiments 6 to 10 , or as in any The catalyst for step ( a ) and ( b ) is independently as one of the specific embodiments 1 to 9 , and the first cyclic 5 described in any one of the embodiments 6 to 10 , or as in any ester monomer and the second cyclic ester monomer are one of the specific embodiments 1 to 9 , and the first cyclic independently represented by structural formula : ester monomer is lactide, D - lactide , L - lactide, meso - lactide , rac -lactide , B -butyrolactone , or 4 - (but - 3 - en - 1 -yl ) oxetan - 2 one ; and the second cyclic ester monomer is lactide , D -lac (IV ) 10 tide , L - lactide ,meso - lactide, rac- lactide, B -butyrolactone , or 4 - ( but- 3 - en - 1 - yl) oxetan - 2 -one . A 23rd embodiment of the present invention is a copoly merization method as described in the 19th embodiment , further including ( c ) polymerizing a third cyclic ester monomer, different from the first and second cyclic ester monomer , with a =O catalyst under conditions suitable for ring -opening (V ) polymerization of the third cyclic ester monomer to form O= a third polymer block of the block copolymer ; and 20 wherein the catalyst for step ( c ) is independently as described in any one of the embodiments 6 to 10 , or as in any one of the specific embodiments 1 to 6 . ( VI) A 24th embodiment of the present invention is a copoly merization method as described in the 20th embodiment, further including ( c ) polymerizing a third cyclic ester monomer, different from the first and second cyclic ester monomer , with a catalyst under conditions suitable for ring - opening polymerization of the third cyclic ester monomer to form 30 a third polymer block of the block copolymer , and wherein the catalyst for step ( c ) is independently as described in any one of the embodiments 6 to 10 , or as in any one of the specific embodiments 1 to 6 . A 25th embodiment of the present invention is a copoly 35 merization method as described in the 21st embodiment, further including ( c ) polymerizing a third cyclic ester monomer , different from the first and second cyclic ester monomer , with a (VIII ) catalyst under conditions suitable for ring - opening 40 polymerization of the third cyclic ester monomer to form a third polymer block of the block copolymer , and wherein the catalyst for step ( c ) is independently as described in any one of the embodiments 6 to 10 , or as in (IX ) any one of the specific embodiments 1 to 6 . 45 A 26th embodiment of the present invention is a copoly merization method as described in the 23rd embodiment , O , or further including ( c ) polymerizing a third cyclic ester monomer , different from the first and second cyclic ester monomer, with a ( X ) 50 catalyst under conditions suitable for ring - opening polymerization of the third cyclic ester monomer to form a third polymer block of the block copolymer; and wherein the catalyst for step ( c ) is independently as described in any one of the embodiments 6 to 10 , or as in 55 any one of the specific embodiments 1 to 6 . A further embodiment of the present invention is a polymerization method of anyone of the preceding embodi or a stereoisomer thereof. ments, wherein a high ratio of chain transfer agent to A 22nd embodiment of the present invention is a copoly - dinuclear Indium catalyst is provided . Typically the chain merization method for preparing a block copolymer , com - 60 transfer agent is an alcohol, polyester or polyether. Suitable prising : alcohols are RnOH , where Rn is any alkyl chain , including (a ) polymerizing a first cyclic ester monomer with a catalyst straight and branched alkyl chains. In one example , the under conditions suitable for ring -opening polymerization alcohol is ethanol. In alternative examples , the alcohol is of the first cyclic ester monomer to form a first polymer HO (CH , OH , THO ( CH2) , l . (CH ) and [HO (CH ) L ( C ) as block of the block copolymer ; and 65 well as other star shaped multiols . Polyesters can also be ( b ) polymerizing a second cyclic ester monomer, different used , such as, for example , (OH -terminated PLA ) or from the first cyclic ester monomer , with a catalyst under HO (CH2O ) OH . A specific , non - limiting example of a suit US 9 ,777 ,023 B2 45 46 able polyether is mPEG . A “ high ratio ” as referred to herein , polymer block can be prepared by ROP of a rac - lactide (i .e ., typically , refers to a ratio that supports immortal polymer racemic mixture of L - LA and D -LA ) . ization . Typically , suitable ratios of chain transfer agent to Block copolymers that can be prepared from cyclic ester dinuclear Indium catalyst are between about 1 and 1000 , monomers using the catalysts and methods of the present between about 1 and 500 , between about 1 and 100 , between 5 invention include but are not limited to di- block copolymers about 1 and 50 ; between about 1 and 20 ; between about 1 and tri- block copolymers (e . g. , A - B -C or A -B - A type ), and 10 ; or between about 1 and 4 . particularly , A -B - A tri -block type copolymers . Polymers and Copolymers The polymers and polymer blocks of block copolymers Using the processes of the present invention as described prepared from a racemic cyclic ester monomer , can be in the previous section , polymers including copolymers, andod 10 iso -enriched ,more particularly , they can be characterized by particularly , block copolymers , can be prepared from cyclic a Pm value ofmore than about 0 . 5 , more than about 0 .53 , or ester monomers as described herein . more than about 0 . 6 ; alternatively , polymers and polymer In the embodiments described herein , a polymer can be a blocks of block copolymers of the present invention can be homopolymer or a copolymer. Typically, the copolymers are characterized by a P value between 0 .53 and 0 .62 . block copolymers . More typically , the copolymers are di 15 Polymers and polymer blocks of block copolymers pre block or tri- block copolymers . pared from an enantiopure cyclic ester monomer can be In particular embodiments the polymer, and more particu isotactic . For example , isotactic PLA was prepared by ROP larly , block copolymer is a thermoplastic and biodegradable of L -LA using the methods of the present invention . polymer . Also , typically , the polymers and block copolymers of the A “ homopolymer ” as referred to herein , is a polymer that 20o present invention are characterized by a polydispersity index is prepared by the ring -opening polymerization of a single of between 1 . 0 and 1 . 5 , more typically, between 1 . 0 and type of cyclic ester monomer, for example , D - lactide . 1 . 35 , and even more typically , between 1 . 0 and 1 . 2 . A “ copolymer ” as referred to herein , is a polymer that is Also , typically, the number average molecular weight of prepared by the ring -opening polymerization of at least two the polymers and block copolymers of the present invention different cyclic ester monomers . “ Different ” in this context 25 is between“ Polydispersity about 10index kDa (andPDI 300) ” as kDa referred. to herein . is requires that the cyclic ester monomers differ at least ste - calculated as the weight average molecular weight divided reochemically , for example, one cyclic ester monomer can be L -lactide and the other D - lactide . For example , the ROP by the number average molecular weight of the polymer. of lactide, or more particularly , a racemic mixture of L - lac - theA presentdescription invention of embodiments fo 11. of further embodiments of tide and R - lactide prepares a copolymer. the present invention follows. The catalysts as described herein can exhibit isoselectivity 30 A 27 " " embodiment of the present invention is a polymer in the ROP of cyclic ester monomers leading to “ iso prepared by the method as described in the 11 th embodi enriched ” polymers or iso - enriched polymer blocks in a ment. block copolymer . A 28th embodiment of the present invention is a polymer An “ iso - enriched ” polymer as referred to herein , is a , prepared by themethod as described in the 12th embodiment . polymer , in which the polymer molecules exhibit on average 35 A 29th embodiment of the present invention is a polymer more meso tetrads than racemo tetrads. prepared by the method as described in the 13th embodiment . A measure to characterize the extent of iso - enrichment is A 30th embodiment of the present invention is a polymer Pm , that is , the conditional probability that a monomer prepared by the method as described in the 14th embodiment. insertion gives rise to the formation of a meso Mmm( ) A 31st embodiment of the present invention is a polymer tetrad . Values for P , provided in the Examples described 40 prepared by the method as described in the 15 " embodiment. herein were experimentally obtained from NMR measure A 32nd embodiment of the present invention is a polymer ments using the ratios of peaks in the spectrum of the prepared by themethod as described in the 16th embodiment . homonuclear decoupled proton NMR spectroscopy which A 33 " embodiment of the present invention is a polymer shows peaks corresponding to different tetrads . In accor - prepared by the method as described in the 17th embodiment. dance with accepted literature data ( JACS, 2002 , 124 , 1316 ) 45 A 34th embodiment of the present invention is a polymer the ratio of the peaks indicated the Pm or probability ofmeso prepared by the method as described in the 18th embodiment. linkages in the polymers . A 35th embodiment of the present invention is a block An “ isotactic ” polymer as referred to herein , is charac - copolymer prepared by the copolymerization method as terized by a Pm value of about 1 , that is , an isotactic polymer described in the 19th embodiment, wherein in step ( a ) a first substantially only contains polymer molecules in which all 50 polymer block of the block copolymer is prepared , and in structural units have the same orientation , for example , step ( b ) a second polymer block of the block copolymer is isotactic PLA : prepared . A 36th embodiment of the present invention is a block copolymer prepared by the copolymerization method as 55 described in the 20th embodiment, wherein in step ( a ) a first polymer block of the block copolymer is prepared , and in step ( b ) a second polymer block of the block copolymer is prepared . 311111111 111111111 A 36th embodiment of the present invention is a block 60 copolymer prepared by the copolymerization method as A “ block copolymer ” as referred to herein , is a copolymerlymer described in the 2121st embodiment, wherein in step ( a ) a first that comprises at least two different polymer blocks . “ Dif - polymer block of the block copolymer is prepared , and in ferent” in this context requires that each polymer block is step ( b ) a second polymer block of the block copolymer is polymerized from a different cyclic ester monomers , prepared . wherein the cyclic ester monomers differ at least in their 65 A 37th embodiment of the present invention is a block stereochemical composition , for example , a first polymer copolymer prepared by the copolymerization method as block can be prepared by ROP of L - lactide and a second described in the 22nd embodiment, wherein in step ( a ) a first US 9 ,777 ,023 B2 47 48 polymer block of the block copolymer is prepared , and in The teachings of all patents , published applications and step (b ) a second polymer block of the block copolymer is references cited herein are incorporated by reference in their prepared . entirety . A 38th embodiment of the present invention is a block Catalyst Synthesis copolymer prepared by the copolymerization method as 5 The dinuclear indium catalysts of the present invention described in the 23rd embodiment, wherein in step (a ) a first can be synthesized using the methods and methods analo polymer block of the block copolymer is prepared , in step gous to the ones described below . ( b ) a second polymer block of the block copolymer is The formula “ [ (NNR30R4 ) InX ] 2( u - Y )( u - Yl) ” as used prepared , and in step ( c ) a third polymer block of the block 10 hereinherein , denotes catalystscatalysts reprrepresented by structural formula copolymer is prepared . ( A ) in which both tridentate ligands are represented by the A 39th embodiment of the present invention is a block following structural formula : copolymer prepared by the copolymerization method as described in the 24th embodiment, wherein in step ( a ) a first polymer block of the block copolymer is prepared , in step 15 ( b ) a second polymer block of the block copolymer is prepared , and in step ( c ) a third polymer block of the block w copolymer is prepared . A 40th embodiment of the present invention is a block copolymer prepared by the copolymerization method as 20 R3 - - N described in the 25th embodiment , wherein in step ( a ) a first polymer block of the block copolymer is prepared , in step ( b ) a second polymer block of the block copolymer is mi prepared , and in step ( c ) a third polymer block of the block copolymer is prepared . 25 A 41st embodiment of the present invention is a block RO v tBu copolymer prepared by the copolymerization method as described in the 26th embodiment, wherein in step ( a ) a first If Y and Y2 are the same, the formula can shortened to polymer block of the block copolymer is prepared , in step “ [ (NN R30R4) InX ]_ ( u - Y ? ) ” . The formula “ I ( TH?NNR3ORA ) ( b ) a second polymer block of the block copolymer is » InX ] ( u - Y2) (u - Y ! )” as used herein , denotes catalysts repre prepared , and in step ( c ) a third polymer block of the block sented by structural formula ( A ) in which both tridentate copolymer is prepared . ligands are represented by the following structural formula : A 42nd embodiment of the present invention is a polymer or block copolymer composition of any one of the polymers or copolymers described in the preceding embodiments , in which the polymer or copolymer , respectively , is at least 80 % , more typically , is at least 85 % , and even more typi cally , is at least 90 % pure by weight . RUN min Further Definitions 40 “ Alkyl” means an optionally substituted saturated ali phatic branched or straight- chain monovalent hydrocarbon radical having the specified number of carbon atoms . Thus , mi " ( C - C . ) alkyl ” means a radical having from 1 -6 carbon atoms in a linear or branched arrangement. " ( C , -C6 ) alkyl ” 45 R v tButBu includes methyl, ethyl, propyl, butyl, pentyl and hexyl. Further, each of the listed alkyls includes the branched - chain monovalent hydrocarbon , e . g. , butyl includes n -butyl , sec If “ NNORA " is recited, R3 is H unless it is clear from the butyl, iso -butyl and tert -butyl . context that R * is not H . " Cycloalkyl” means a saturated aliphatic cyclic hydrocar- 50 The following Table provides an overview of exemplary bon ring . Thus, “ C3- C , cycloalkyl” means a hydrocarbon dinuclear indium catalysts suitable for the ring opening radical of a ( 3 - 7 membered ) saturated aliphatic cyclic hydro - polymerization of cyclic ester monomers : carbon ring . A C3 -C , cycloalkyl includes , but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. 55 Example 1 [( NN OBU ) InBr] 2( u - Br) (u -OEt ) Example 2 [ (NN , OBU ) Inl ]2 ( u - 1) ( u -OEt ) " Alkenyl” as used herein refers to a hydrocarbon back Example 3 [ (NNHO :Bu ) InI( u -OH ) ] 2 bone radical, having the number of carbon atoms falling Example A4 [ (NN , Ome) InCl] 2 ( u - Cl) ( u -OEt ) within the specified range . For example , (C2 -C3 ) alkenyl Example A5 [ ( NN OMe) In1] 2 ( u - I ) ( u -OEt ) , and means that a hydrocarbon radical is attached that may [ (NN Ome) Inl] 2 ( u - OEt) 2 contain anywhere from 2 to 3 carbon atoms with the 60 Example B2 [ (NN , Ome) Inl] 2 ( u -OEt ) remaining valence filled in by hydrogen atoms unless speci Example B3B4 [ (NN , OBU ) Inl Inl] 2 (u u -OEt ) 2 fied otherwise . The term also includes each permutation as Example C1 [ (NNHxBu ) Inl] 2( u -OH ) (u -OEt ) Example C2 [ (NN Ome) Inl] 2 ( u -OH ) ( u -OEt ) though it were separately listed . Thus, (C2 -C3 ) alkenyl Example D [( TH -NN MEDBU )InCl ] 2 ( u -C1 ) ( -OEt ) , and includes ethenyl, 1 -propenyl and 2 -propenyl . [ ( TH - NNMeme) InCl ] z (u -C1 )( u -OEt ) Examples and Experimental Section 65 A description of example embodiments of the invention Example E [( NNMexBu ) In ( Cl) ] 2 ( u - C1) ( u -OEt ) follows. US 9 , 777 ,023 B2 49 50 EXAMPLES 138. 2 , 136 .8 , 126 .2 , 125. 9 , 118 .8 , 53 .4 , 51. 2 , 38 .3 , 36 .0 , 34 . 5 , 32 . 5 , 31 . 7 , 31 . 2 , 30 . 4 , 24 . 8 , 24 . 7 , 22 . 2 , 27 . 7 . EI- LRMS Unless otherwise indicated , all air and /or water- sensitive (m /z ) [ M + ] 634 . Anal . Calcd ( found ) for C25H39Brz reactions were carried out under dry nitrogen using either an InN20 : C , 47 . 30 (47 .29 ) ; H , 6 . 15 (6 . 13 ) ; N , 4 .42 ( 4 .41 ) MBraun glovebox or standard Schlenk line techniques. 5 (note : DACH is diaminocyclohexane ). NMR spectra were recorded on a Bruker Avance 400 . Synthesis of {[ (NN , OBU )InBr ] 2 (u -Br ) ( u - OEt) } : A 25 mL MHz spectrometer. 1H NMR chemical shifts are reported round - bottom flask was charged with complex (NN , OxBu ) in ppm versus residual protons in deuterated solvents as InBr2 ( 0 . 100 g , 0 . 16 mmol) dissolved in 5mL of toluene . A follows: 8 7 .27 CDC12 , 8 7 . 16 C6D6 , 85. 32 CD C1z . solution of NaOEt ( 0 .011 g , 0 . 16 mmol) in 5 mL of toluene 13C { H } NMR chemical shifts are reported in ppm 10 was added dropwise to this mixture . After stirring the versus residual 13C in solvents as follows: 8 77 . 2 CDC12, 8 reaction mixture for 2 h at room temperature , NaBr forma 128 . 4 CDa, 8 54 . 0 CD , C1 , . Diffraction measurements for tion was observed . The salt was removed by filtration X - ray crystallography were made on a Bruker X8 APEX II through glass filter paper, and the remaining yellow solution diffractometer with graphite -monochromated Mo Ka radia - was evaporated to dryness . The residue was washed with tion . 15 pentane and dried for 2 h in vacuo to yield the { [ (NN , Bu ) Solvents (pentane , THF, toluene, dichloromethane , and InBr ] 2 (u -Br )( u -OEt ) } complex as a white powder ( 0 .071 g , diethyl ether) were degassed and dried using 3 Å molecular 70 % yield ) . ' H NMR (400 MHz, CD2C12) : 8 7 .20 ( 1H , d , sieves in an MBraun Solvent Purification System . THF was J = 4 Hz, ArH ) , 6 . 80 ( 1H , d , J = 3 Hz, ArH ) , 4 .81 ( 1H , d , J = 12 further dried over sodium benzophenone ketyl and distilled Hz, HN — CHH — Ar ) , 4 .40 ( m , 1H , OCHHMe) , 4 . 19 (1H , under Ny. CD , C1, and CDC1 , were dried over Cat , and 20 m , OCHHMe) , 3 .72 ( 1H , d , J = 12 Hz, NH - CHHAr ), 2 . 55 degassed through a series of freeze -pump - thaw cycles .CD (3H , s, NMeMe ), 2. 48 (2H , m , CHN (Me ) , and CHNH ) , 1 . 89 was dried over sodium and degassed using a series of (3H , s , NMeMe) , 1 . 85 (4H , in , CH2 – of DACH ) , 1 .43 freeze -pump - thaw cycles . InC1z , InBrz , Inlz, and In (Me ) ; (9H , s, t- Bu ), 1 .41 (2H , t J= 8 Hz , OCH CH3) , 1 .27 (11H , s , were purchased from Strem Chemicals and used without t - Bu and m , — CH , — of DACH ) , 1 . 07 ( 2H , m , - CH , — of further purification . For the enantiopure catalyst, ( + ) - trans - 25 DACH ) . 13C { ' H } NMR ( 100 . 64 MHz, CD2C1 ) : 8 163 . 3 , 1 , 2 -diaminocyclohexane was resolved using Jacobsen ' s 138 . 7 , 136 . 7 , 129 . 5 , 125 . 8 , 120 . 0 , 67 . 4 , 61 . 2 , 50 . 6 , 45 . 7 , method (Larrow , J. F .; Jacobsen , E . N . ; Gao , Y .; Hong, Y . P .; 38 . 1 , 35 . 8 , 34 . 3 , 32 . 1 , 30 . 3 , 26 . 4 , 25 .4 , 25 . 3 , 22 . 4 , 19 . 9 . Nie , X . Y .; Zepp , C . M ., J . Org. Chem . 1994, 59 , 1939 - 1942 ) EI- LRMS ( m / z ) : 554 ( M + - In (NNO ) (Br ) 2 (OEt ) ) , 634 ( M + ) and then carried forward through the same procedures as — In — (NNO ) Br( OET ) ). Anal . Calcd ( found ) for used for the rac - catalyst . Benzyl potassium was synthesized 30 C48H23BrzIn N403: C , 46 . 70 ( 46 .72 ) ; N , 4 .50 ( 4 . 34 ) ; H , using a modified literature procedure using n - butyllithium 6 .70 (6 .69 ) . ( Aldrich ) , potassium tert -butoxide ( Alfa Aesar ) , and toluene (Schlosse , M . ; Hartmann , J . Angew . Chem . , Int. Ed . Engl. Example 2 1973 , 12 , 508 -509 ) . All other compounds were obtained from Aldrich and used without further purification . The 35 Synthesis of Catalyst Complex [( NN , Bu) Inl] 2( u literature preparation of H NNGO (Mitchell , J . M . ; Finney, OEt) N . S . Tetrahedron Lett . 2000 , 41 , 8431 - 8434 ) was modified as follows: the imine was recrystallized from warm acetoni- Synthesis of (NN , OBJ ) Inly : A similar procedure to that trile , and the proligand was recrystallized from acetonitrile for complex (NN , OrBu) InBr2 (see Example 1) was used when it was formed . K (NN , O ) was prepared according to 40 using Inlz (0 .171 g, 0 .34 mmol ) and KNN , {Bu ( 0 .130 g , procedures described in Labourdette, G .; Lee, D . J .; Patrick , 0 .34 mmol) . The reaction was stirred at room temperature B . O . ; Ezhova , M . B . ; Mehrkhodavandi, P . Organometallics for 2 h , and then KI formation was observed . The salt was 2009 , 28 , 1309 - 1319 . removed by filtration through glass filter paper, and the remaining yellow solution was evaporated to dryness . Example 1 45 (NN , OBInl , was obtained as a yellow powder ( 0 . 235 g ; 95 % yield ) . 'NMR ( 400 MHz, CD , C12 ) : 8 7 . 26 ( 1H , d , J = 3 Synthesis of catalyst complex [ (NN , OBU) InBr] 2 ( u Hz, ArH ) , 6 .88 ( 1H , d , J = 3 Hz, ArH ) , 4 . 13 ( 1H , t , J = 12 Hz, Br) ( u -OEt ) RANCH CHy ), 3. 97 ( 1H , d , J = 15 Hz, NH – CH2 – Ar) , 2 .78 (2H , m ,NCH of DACH ), 2 .62 (3H , s, NMeMe) , 2 .46 , Synthesis of (NN , Bu ) InBrz : A solution of K ( NN , O ) 50 ( 3H , s , NMeMe) , 1 . 91 (4H , m , CH2 - of DACH ) , 1 . 44 ( 0 . 112 g , 0 .29 mmol) in 5 mL of THF was added dropwise ( 9H , s , t - Bu ), 1 ,33 (2H , in , - CH2- of DACH ) , 1 . 28 ( 9H , to a solution of InBr3 ( 0 . 105 g , 0 . 29 mmol) in 5 mL of THF. S, t -Bu ) , 1 . 27 ( 2H , m , _ CH , — of DACH . 13C ( 1H } NMR The reaction was stirred at room temperature for 2 h , and the ( 100 .64 MHz , CD2C1 ) : 8 163 . 5 , 139 . 9 , 136 . 9 , 126 . 0 , 125 . 9 , formation of KBr was observed . The salt was removed by 118 .8 , 53. 5 , 51. 2 , 38 . 5 , 36 . 2 , 34 . 5 , 32. 5 , 31. 8 , 31 . 3 , 30. 6 , filtration through glassfilter paper, the remaining yellow - 55 24 . 9 , 24 . 8 , 22. 1, 21 .8 . EI- LRMS ( m / z ) [M +] : 728 . Anal. orange solution was evaporated to dryness, and the residue Calcd ( found ) for C25Hz, 1 , InN20 : C , 41 . 20 41 . 15 ) ; H , 5 . 36 was dried 2 h in vacuo . Complex (NN , 0 . R . ) InBr , was ( 5 . 35 ) ; N , 3 . 84 ( 3 . 81 ) . obtained as a yellow crystalline solid ( 0 . 155 g ; 83 % yield ). Synthesis of { [( NN ,OBU ) Inl] 2 (u - OEt) } : The same pro Suitable crystals for X -ray diffraction were grown by slow cedure to prepare { [ (NN ,OBU ) InBr ] 2 ( u - Br) ( u -OEt ) } in diffusion of pentane in a CH2C12 solution of the complex , 60 Example 1 was followed using (NN ,OB , ) Inl, ( 0 . 080 g , 0 . 11 ( NN , OxBu ] InBrz. ' H NMR (400 MHz, CD , C1 ) : 87 .27 ( 1H , mmol) dissolved in 5 mL of toluene and NaOEt (0 .008 g , d , J = 3 Hz, ArH ) , 6 . 88 ( 1H , d , J = 3 Hz, ArH ) , 4 . 15 ( 1H , triplet , 0 . 11 mmol ) in 5 mL of toluene . The reaction was stirred at R N - CH - CH2) , 4 .06 ( 1H , d , J = 12 Hz , NH - CH2 - Ar) , room temperature for 12 h , and then Nal formation was 2 .71 (3H , S , N (Me ) (Me ) ), 2 .60 (2H , m , CHNH and observed . The salt was eliminated by filtration through glass CHNMez) , 2 .48 (3H , s , N (Me ) (Me ) ) , 1 . 95 (6H , CH2 – of 65 filter paper, and the yellow solution was evaporated to DACH ) , 1 .43 ( 9H , s , t - Bu ) , 1 . 28 (11H , s , t -Bu and m , CH2 dryness. The residue was washed with pentane , and of DACH ). 13C { ' H } NMR ( 100 .64 MHz, CD2C12 ): d 163 . 5, { [( NN , Bu ] InI] 2 (u - 1) ( u -OEt ) } was obtained as a white US 9 ,777 ,023 B2 51 :52 powder , which was dried for 2 h in vacuo ( 0 .051 mg; 68 % -continued yield ) . 1H NMR ( 400 MHz, CD , C12 ) : 8 7 .22 (1H , J = 4 Hz , ArH ) , 6 . 80 ( 1H , d , J = 3 Hz , ArH ) , 4 .84 (1H , d , J = 12 Hz , HN — CHH — Ar ) , 4 .40 m , 1H , OCHHMe) . 4 .21 ( 1H , m , OCHHMe ), 3 .75 ( 1H , d , J = 12 Hz, NH - CHH — Ar ) , 3 . 43 5 ( 1H, d , J = 12 Hz , CHNH) , 2 . 66 ( 2H , m , CH? ofDACH) , D 2 .56 ( 3H , s , NMeMe) , 2 .48 , ( 1H , m , CHN (Me ) , ) , 1 . 92 (3H , t -Bu 2 NaOET s , NMeMe) , 1 . 83 (2H , m , - CH2 - of DACH ) , 1 .44 ( 9H , s , + 111 toluene, 16 h t - Bu ) , 1 . 41 ( 2H , t J = 8 Hz , OCH , CH ) , 1 . 28 ( 11H , s , t -Bu and In 1X m , - CH2 - of DACH ) , 1 . 14 ( 2H , m , - CH — of DACH ) . 13C { { H } NMR ( 100 . 64 MHz, CD , C1, ) : 8 163. 2 , 138 . 9 , N X 136 . 7 , 126 . 8 , 124 . 5 , 119 . 9 , 67 . 3 , 62. 0 , 50 . 3 , 46 . 0 , 38 . 1 , 35 . 7 , 34 . 3 , 32 . 2 , 30 . 3 , 26 . 2 , 25 . 5 , 26 . 3 , 22 . 7 , 19 . 6 . EI- LRMS ( m / z ) (NNOR ) INX2 602 ( M + - In (NNO )( I) , (OEt ) ) , 728 (M + - In ( NNO )I | R = t- Bu , X = C1 ( 1 ) (OEt )) . Anal. Calcd ( found ) for C48Hg313In2N2O3 : C , 41. 91 is R = Me, X = Cl ( 2 ) . I ( 3 ) (41 . 92 ) ; H , 6 .03 (6 .05 ) ; N , 4 . 10 ( 4 . 12 ) . N - 11111 Example 3 Synthesis of Catalyst Complex [ (NN , Bw )InI ( u 20 H Xin - N - H OH ) ]2 [( NN , OBU ) InI( u -OH ) ] z: {[ (NN ,OBU )Inl ] 2 ( u -I ) (u -OEt ) } as prepared in Example 2 was removed from the inert 25 atmosphere and exposed to moist air for 24 h , to yield the t- Bu air - and moisture - stable u - OH dinuclear complex t - Bú [ (NN , Bw) InI( u -OH ) ] 2 in quantitative yield . Suitable crys [( NNOR ) InX ]2 ( u - X )( u -OEt ) tals for X - ray diffraction were grown by slow diffusion of R = t- Bu , X = C1 ( 4 ) Et 0 in a CH2Cl2 solution of [ (NN , OBW) InI( u - OH ) ] 2 . ' H 30 R = Me, X = CI (5 ). I (6 ) NMR ( 300 MHz, CDC1z ) : 8 7 .23 ( 1H , d , J = 3 Hz, Ar) , 6 .78 ( 1H , d , J = 3 Hz, Ar) , 4 .77 ( 1H , d , J = 15 Hz, NCHHAr ) , 3 . 87 ( 1H , b , OH ) , 3 .73 (1H , d , J = 6 Hz, NCHHAr ) , 3 .37 ( 1H , d , The chiral diaminophenol proligands H (NN , OR) where R J = 9 Hz, CHNH ) , 2 .68 ( 1H , m CHNMe2 ) , 2 .54 (3H . s . is a para -methyl or t -butyl substituent on the phenol group NMeMe) 2 . 20 (3H , m , CH2 of DACH ) , 1 . 93 (3H , S , 35 were synthesized according to the method described in NMeMe) . 1 . 81 ( 2H . m . CH , of DACH ). 1. 58 (2H . m . CH . Douglas et al. , Angew . Chem . Int . Ed . 2008 , 47 , 2290 - 2293 . of DACH ) , 1 . 47 ( 9H , s . t- Bu ). 1 . 27 ( 9H . s . t- Bu ). 1 . 08 (2H . Dihalide complexes bearing these ligands, (NN . O . R . ) InX , m , CH , of DACH ) . 13C { ' H } NMR (100 MHz, CDC1z ): 8 ( X = C1 ( 1 )) and (NN Ome) InX2 ( X = C1 (2 ), I (3 ) ), were 164 .2 , 139. 8 , 137. 8 , 127. 3 , 125. 1 , 121. 2, 65 . 9, 53 . 1, 51. 9 , prepared by addition of the potassium salts of the ligands to 51. 2 , 44. 3 , 38. 7 , 36 . 2 , 34 . 9 , 32 . 7 , 31. 6 , 31. 4 , 31. 2 , 25. 5 , 25 .4 , * ' the appropriate indium trihalide . Both , racemic and enantio 22 . 1 . Anal. Calcd ( found ) for C34H 00N O In I2 : C , 46 .70 pure H (NNOR ) can be used in the syntheses described (46 .32 ); H , 7. 19 (7 . 18 ), N , 4 .10 (4 . 11 ) . below . Addition of 2 equiv NaOEt to complexes 1 - 3 , forms the mixed bridge alkoxy -halide complexes [( NN OBU ) Example A 45 InX ] (u - X ) (u -OEt ) ( X = C1 (4 )) and ( (NN , Ome) InX ] (u - X ) Synthesis of Dinuclear Indium Complexes of the (u -OEt ) ( X = C1 ( 5 ) , I (6 )) . Type [( NN , R ) InX ]2 ( u - X )( u -OEt ) Example A1

50 Synthesis of 6 -tert -butyl - 2 - { N - [ 2 - ( N , N -dimethyl ) Scheme 1 . aminocyclohexyl] salicaldimino } - 4 - methylphenol (H2NN , Ome) 55 The H2NN , Ome proligand was synthesized according to the method described in Douglas et al. , Angew . Chem . Int . y * t --Bu 1 ) KCH Ph Ed . 2008 , 47, 2290 -2293 . ( 78 % yield after recrystallization toluene in acetonitrile ). ' H NMR (300 MHz, CD ,C1 , ) : 8 6 . 98 ( 1H , NH OH 2 ) InX3 sod, J = 3 Hz, ArH ) , 6 . 70 ( 1H , d , J = 3 Hz, Ara ), 3 . 98 ( 1H , d , THF J = 12Hz, NH - CH2 - Ar ), 3 .78 ( 1H , d , J = 12 Hz, NH CH?Ar) , 3 . 51 (1H , br. S ., NH?) , 2 .40 - 2 .30 (1H , m , N - CH = CH , of DACH ), 2 .25 (3H , s, Ar - CH3) , 2. 20 (6H , s , - N - (CH3 ) 2 ) 1 . 83 - 1 . 80 ( 2H , m , N - CH = CH , and H (NNOR ) 65 CH2 of DACH ) , 1 .71 - 1 .60 ( 1H , m , CH2- of R = t - Bu or Me DACH ), 1 .42 (9H , Ar - (CH3 ) 3 ), 1. 24 - 1. 11 (4H , m , CH , — of DACH ) . US 9 ,777 , 023 B2 53 54 Example A2 1 . 86 - 1 .99 (1H , m , — CH — of DACH ), 1. 82 ( 1H , br. m , CH , — of DACH ) , 1 . 39 9H , Ar - ( CH3) 3 ) , 1 . 01 - 1 . 31 (6H , Synthesis of [ (NN , Ome) InCl2 ] m , - CH2 - of DACH and O - CH2 - CH3) ; 13C { {H } NMR (101 MHz, CD2C12 ) 8 163 .2 (Ar C ), 139 .9 (Ar C ), 130 .6 (Ar A suspension of InC12 (239 mg, 1 .08 mmol) in THF ( 3 ml) 5 C - H ) , 128 . 6 ( Ar C - H ) , 123 . 3 ( Ar C ) , 120 . 0 ( Ar C ) , 65. 3 was added dropwise to a slurry solution of KHNN , O in ( N - CH2 - Ar) , 63 .0 ( 0 CH2 CH3) , 53 . 2 ( N - CH THF ( 10 ml) , which was produced by reacting the equimolar CH?) , 50. 8 (N CH2CH2 ) , 44 . 6 ( N ( CH3) 2) , 38 . 5 amount ofH2NN , One (309 mg, 0 . 97 mmol ) and benzylpo - ( N (CH2 ) ,) , 35 .5 ( Ar - C (CH3 ) 2) , 31. 5 ( Ar - CH ,) , 30 . 2 tassium ( 126 mg, 0 .97 mmol) in Toluene ( 30 ml) . The ( Ar - C ( CH3) 3 ) , 25 . 4 CH2 - of DACH ) , 25 . 2 ( CH2 mixture was stirred for 12 h at room temperature. A white 10 of DACH ) , 22 .4 ( CH , — of DACH ) , 20 . 9 ( CH , — of solid was filtered through Celite . The pale yellow filtrate was DACH ), 19 . 8 ( 0 CH2CH3) . concentrated under vacuum . An off- white solid was precipi tated out of solution by adding ether ( 5 ml) to the concen Example A5 trated filtrate . The desired product was obtained on a glass frit and dried in vacuo for few hours . Recrystallization with 15 Synthesis of [ (NN , Ome) Inl] 2 ( 4 - 1) ( u -OEt ) and a mixture solution of THF and ether at room temperature afforded yellow crystals. (380 mg, 76 % ) H NMR ( 400 [( NN , Ome) Inl ] , (u -OEt ) 2 MHz, CD2C12 ) : 87. 04 (IH , d , J = 2 . 0 Hz, ArH ) , 6 .68 ( 1H , d , J = 1 . 7 Hz, ArH ), 4 . 46 ( 1H , d , J = 12. 6 Hz, NH - CH2 - Ar) , 3 .97 ( 1H , dd , J = 12 . 5 , 6 . 7 Hz, NH - CH2 Ar) , 2 .73 - 2 .82 20 ( 1H , m , N - CH = CH2of DACH ), 2 .71 ( 3H , s , Ar - CH3) , 2 .63 - 2 .61 ( 1H , m , N = CH - CH , of DACH ) , 2 .54 ( 1H , br . S ., CH2 - of DACH ) , 2 .38 - 2 .48 (1H , m , CH2 – of DACH ) , 2 .27 ( 3H , s , - N - (CH3 ) 2 ) , 2 .21 (3H , s , Ar - CH3) , 1 . 94 - 2 . 04 ( m , 1H , CH2- of DACH ), 1 .78 - 1 . 94 (2H , in , 25 Bu 2 NaOE - CH2— of DACH ), 1 . 40 ( 9H , Ar - ( CH3) 3 ) , 1 . 18 - 1 .29 toluene , 16 h (3H , m , CH2 - of DACH ) ; 13C { 'H } NMR ( 101 MHz, CD C12 ) 6 Anal. Calcd . For C20H33C12InN20 : C 47 .74 ; H InilllI 6 .61 ; N 5 .57 . Found : C 47 .48 ; H 6 .60 ; N 5 .51 . 30 Example A3 Synthesis of [( NN , me) In12 ] H — N — 11 — N — H A suspension of Inlz (973 mg, 1 . 96 mmol) in THF (3 ml) 35 x was added dropwise to a slurry solution of KHNN , OM (700 mg, 1 . 96 mmol) in THF (20 ml) , which was produced by reacting the equimolar amount of H ,NN , Ove and benzyl potassium in toluene . The mixture was stirred for 12 h at room temperature. A white solid was filtered through Celite . 40 Bu Bu The pale yellow filtrate was concentrated under vacuum . An off -white solid was precipitated out of solution by adding ether (10 ml) to the concentrated filtrate . The desired product Bu was obtained on a glass frit and dried in vacuo for few hours . ( 965 mg, 72 % ) 45 Example A4 Synthesis of [( NN , Ome) InC1] 2 (u -C1 ) ( u -OEt ) H - N Tuin NH- 50 A solution of NaOEt (20 mg, 0 . 30 mmol) in toluene ( 1 .5 - 11 | | | ml) was added dropwise to a stirring suspension of [ (NN , Ome) InC12 ] ( 150 mg, 0 . 30 mmol) in toluene ( 3 ml) at room temperature . The reaction mixture was stirred for 12 h . Bu The white precipitate was filtered through Celite , to collect 55 the pale yellow filtrate. All volatiles were removed in vacuo , and ether (5 ml) was added to the residue . The desired Two equivalents of NaOEt (61 . 3 mg, 0 . 90 mmol) in off - white solid was precipitated out of solution . The product toluene ( 6 ml) were added dropwise to a stirring suspension was collected on a glass frit and dried in vacuo for few hours of [ (NN , OmInI ] ( 309. 4 mg, 0 . 45 mmol) in toluene ( 8 ml) ( 140 . 8 mg, 93 % ) . ' H NMR ( 400 MHz, CD , C12 ) : 86 . 99 ( 1H , 60 at room temperature after both of the solutions were stirred br. S . , 6 .60 ( 1H , br. S ., ArH ) , 4 .91 (1H , d , J = 13 . 5 Hz, for 5 minutes separately . The reaction mixture was stirred NH - CH2 - Ar ) , 4 .25 - 4 .45 ( 1 H , m ,0 CH , — CHZ) , 3 .72 for 16 h . The white precipitate was filtered through a glass ( 1H , dd , J = 1 . 7 , 13. 6 Hz, NH - CH2 - Ar ), 2 . 86 ( 1H , td , filter paper , to collect the pale yellow filtrate . All volatiles J = 3 . 1 , 11 . 3 Hz , N - CH = CH2 ), 2 .73 - 2 .74 ( 1H , br. m , were removed in vacu . A THF solvent ( ca . 2ml) was added - CH2- of DACH ) , 2 .66 ( 3H , S , - N (CH3 ) 2 ) , 2 . 52 - 2 . 63 65 to the residue , and acetonitrile ( ca . 5 ml) was added to ( 1H , m , N - CH - CH2) , 2 .48 - 2 . 50 ( 1H , m , - CH2- of separate [ (NN , Ome) Inl] 2 ( u - I) ( u -OEt ) and ( (NN , Ome) Inl] 2 DACH ), 2 . 18 (3H , s, Ar - CH3 ), 2 .03 (3H , S, - N (CH3 ) 2 ), (u -OEt ) 2 . The solution was filtered through a fine frit to US 9 ,777 ,023 B2 55 56 collect the filtrate for [ (NN , Ome) Inl] 2 (u - I) ( u -OEt ) , and the -continued white solid for [ (NN , Omee ) Inl] 2 (u -OEt ) 2 . The solvent from the collected filtrate was removed under vacuum and washed Bu with acetonitrile ( 2x1 ml) . The off -white solid was dried under vacuum to obtain [ (NN ,Ome ) Inl] 2 ( u - I ) ( u - OEt) . 5 ( [( NN , Ome) Inl] 2 (u - I) ( u -OEt ) : 100 .5 mg, 35 % yield ; com plex 7 : 39 . 5 mg, 14 % yield ) ' H NMR (400 MHz, CD2C1_ ) : 8 7 .00 ( 1H , d , J = 1 . 9 Hz, ArH ), 6 .63 ( 1H , d , J = 1 . 9 Hz, ArH ) , H - N - N - H 4 . 79 - 4 . 86 (1H , m , NH CH , Ar ) , 4 . 15 - 4 . 41 ( 1 H , m , O CH , CH3) , 3 .65 - 3 . 77 ( 1H , m , NH - CH2 - Ar ) , 3 .41 10 ( 1H , d , J = 10 . 8 Hz, N - CH = CH , ) , 2 .60 - 2 . 72 ( 1H , m , N - 1111 N - CH = CH2) , 2 . 57 ( 3H , S , - N ( CH3) 2 ), 2 .51 - 2 . 55 ( 1H , m , - CH2 - of DACH ) , 2 . 46 ( 1H , td , J = 3 . 2 , 11. 4 Hz, CH Bu of DACH ), 2 .20 (3H , s , Ar - CH3) , 1 . 96 (3H , s , - N (CH3 ) 2 ), 15 1 .84 ( 1H , t , J = 12 . 1 Hz , CH2 – of DACH ), 1. 43 (9H , Ar - (CH3 ) 3 ), 1 .37 (2H , t, J = 12 . 1 Hz , O CH2CH3) , A suspension of KOEt (24 . 5 mg, 0 .29 mmol ) in toluene ( 4 1 . 05 - 1 . 33 ( 4H , m , — CH , - of DACH ) ; ' ' C { ' H } NMR ( 101 ml) were added dropwise to a stirring suspension of racemic MHz, CD , C1, ) 8 63 . 4 ( Ar C ) , 139 .7 ( Ar C ) , 130 . 5 ( Ar (NN O ) Inl , l ( 100 mg, 0 . 14 mmol) in toluene (6 ml) at C - H ) , 128 . 4 Ar C – H ) , 122 . 9 ( Ar C ), 120 . 3 ( Ar C ) , 67. 4 20 room temperature after both of the solutions were stirred for ( N - CH2 - Ar ), 61. 9 ( 0 CH2CH3) , 53. 2 ( N — CH - 5 minutes separately . As soon as the addition was finished , CH2) , 50 . 0 (N - CH - CH2) , 46 .0 (N (CH3 ) 2 ), 38 .1 the pale yellow color of the reaction mixture was turned to ( N (CH3 ) 2) , 35 .3 (Ar - C (CH3 ) 3 ), 31 .2 ( Ar - CH3) , 30 .4 white , and the white solid was filtered through a glass filter ( Ar - C ( CH3) 3 ) , 25 . 4 ( CH2 - of DACH ) , 25 . 2 ( CH2 – paper to collect the colorless filtrate . All volatiles were of DACH ) , 22 .6 ( CH , - of DACH ) , 20 . 9 ( CH , - of 25 removed in vacuo to dryness . A THF solvent ( ca . 1ml) was added to the residue , and acetonitrile ( ca . 2 ml) was added DACH ) , 19 . 5 ( 0 _ CH2CH3) . to precipitate a white solid out of solution . The solution was Example A6 decanted off , and the solid was washed with acetonitrile ( 2x1 ml) and dried under vacuum to obtain [ (NN , Ou ) 30 Inl] 2 ( u -OEt ) as a white solid . ' H NMR ( 400 H MHzMe ), Synthesis of [ (NN , Ome) InBr] 2 (u - Br) (IL - OED ) CD2C12 ) : 86 . 98 ( 1H , br. S ., ArH ), 6 .59 (1H , br. s ., ArH ), 5 .08 nilar ( 1H , d , J = 13 . 3 Hz, NH - CH2 - Ar ), 3 .62 - 3 .83 (2H , m , [ (NN , Ome) InBr] 2 ( u -Br )( u -OEt ) can be prepared similar 0 CH, CH?, NHCH?Ar) , 2 .69 (1H , br. S. , to the methods described in Example 1 except that the N - CH = CH , ) , 2 .64 ( 4H , br. s . , _ CH , - of DACH , [ (NN , Ome ) InBrz ] is used which can be prepared similar to 35 - N (CH2 ) , ) , 2 .55 - 2 .47 (1H , m , N - CH - CH , ) , 2 . 48 - 2 . 50 the method of Example A2. ( 1H , m , - CH2 0 ofDACH ) , 2 . 18 (3H , s , Ar - CHZ) , 2 . 06 Examples B (3H , S , - N (CH3 ) 2 ) , 1 .97 (1H , br. s ., - CH2- of DACH ) , 1 . 76 - 1 . 90 (2H , in , - CH2 - of DACH ) , 1 .41 ( 1H , br. s ., _ CH , — of DACH ) , 1 . 39 ( 9H , Ar - (CH2 ) 2 ) , 1 .05 - 1 . 23 Synthesis of Dinuclear Indium Complexes of the 40 (6H , m , _ CH , — of DACH andO CH , CH , ) ; 13C { H } Type [( NN OR) InX ] 2( u - OEt )2 with R = Me or t -Bu NMR ( 151 MHz, CD , C12 ) d 163 .5 ( Ar C ) , 139. 7 (Ar C ) , and X = C1, Br, or I 130 . 4 ( Ar C - H ) , 128 . 4 ( Ar C - H ) , 122 . 4 ( Ar C ) , 120 . 0 ( Ar Example B1 C ) , 68. 3 ( N - CH2 - Ar ), 60 . 8 ( 0 _ CH2 CH3) , 52 .6 (N CH CH ), 51 .4 (NCH CH ) , 49. 9 ( N ( CH?) ) , 45 40 . 0 ( N (CH2 ) , ) , 35 . 3 ( Ar - C ( CH2) 2 ) , 31 . 1 ( Ar - CHZ ), 30 . 4 Synthesis of [( NN , Ome ) Inl] 2( u -OEt ) 2 ( Ar - C ( CH3) 3 ) , 25 . 4 CH - of DACH ) , 25 . 1 ( CH The [ (NN , Ome) Inl] 2 (u -OEt ) , complex was prepared as of DACH ) , 23 . 3 ( CH , - of DACH ), 20. 9 ( CH2- of described in Example A5 . DACH ) , 19 . 7 ( 0 _ CH2 CH3) . Example B2 50 Example B3 Synthesis of [ (NN , Ome) Inl ]2 (u -OEt ) 2 Synthesis of [ (NN ,OBU ) Inl ] 2 (u -OEt ) 2

55 t - Bu

60 Bu 2 KOET t - Bu 2 NaOEt toluene, 16 h O toluene , 2 h In111111 In111111 US 9 ,777 ,023 B2 57 58 - continued -continued , t - Bu Bu t - Bus BuBun 11

In 111 T H Tinn. N - H 10 titi V t - Bu Nr. t - Bu Bu A 25 mL round bottom flask was charged with a solution 15 Bu of NaOEt (56 mg, 0 . 84 mmol) in 5 mL of toluene . A solution of [( NN , Ome) Inl2 ] ( 300mg , 0 .42 mmol) dissolved in 10 mL FIG . 5 shows the molecular structure of [ (NN , OBW) of toluene was added dropwise to this mixture . After stirring Inl ] 2 ( u -OEt ) 2 obtained by single - crystal X -ray diffraction . It the reaction mixture for 2 h at room temperature . Nal 20 shows two octahedral indium centres bridged by two ethox formation was observed . The salt was removed by filtration ide ligands and both cyclohexyl diamine groups in the dimer through glass filter paper and the remaining yellow solution have the same ( R , R ) stereochemistry . The molecular struc was evaporated to dryness . The residue was washed with ture is depicted with ellipsoids at 50 % probability and most pentane and dried for 2 h in vacuo to yield complex 5 as a H atoms as well as solvent molecules omitted for clarity . white powder (208 mg. 76 % vield ). 1 H NMR (400 MHz. 25 Selected bond lengths ( A ): In1- 11 ( 2 . 8068 ( 3 ) ), In1 -01 CD , C1, ) : 8 7 . 20 ( 1H , d , J = 3 Hz, ArH ), 6 .75 ( 1H , d , J = 3 Hz, ( 2 .082 ( 2 ) ) , In1 - 02 ( 2 . 163( 2 )) , Inl- N1 ( 2 .275 ( 2 ) ) , Inl -N2 ArH ) , 5 . 10 ( 1H , d . 2 ) , v = 12 Hz. HN - CHH — Ar ) , 4 . 33 ( m . ( 2 . 381 ( 3 ) . Selected bond angles ( ) :01 - In1 -02 ( 91 . 22 ( 8 ) ) , 1H . OCHMe) , 3 . 78 ( 1H . m . OCHHMe ), 3 .73 ( 1H , d . J = 12 01- In1 -02 ( 163. 88 ( 8 ) , 01- In1 -11 ( 92 .77 ( 6 ) ) , 01- Inl -N1 Hz , NH - CHH — Ar) , 2 .64 (3H , s , NMeMe ), 2 .62 ( 2H , in , (85 . 06 ( 8 ) ) , 01- In1 - N2 ( 94 . 93 ( 9 ) ) , N1- In1 -N2 (75 .97 ( 9 ) ) , CHN ( Me) , and CHNH) , 2 . 04 ( 3H, s , NMeMe) , 1 . 90 ( 4HHm, m , 30 N2 - In1 -02 ( 98 .69 ( 9 ) ) , Ni — In1- 11 ( 171 .11 (6 ) ) , In1 -02 - In1? - CH2 - of DACH ) , 1 . 41 ( 9H , s , t -Bu ), 1 . 26 ( 11H , s , t - Bu ( 105 .84 ( 8 ) ). and m , — CH — of DACH ) , 1. 21 ( 2H , t J = 8 Hz, It has been surprisingly found , that [ (NN , OBU) Inl] 2 OCH2CH3) ,1 .18 (2H , in , CH , — of DACH ). 13C { H } ( u - OEt ) , is resistant to dissociation in solution under a NMR ( 100 .64 MHz, CD , C1, ) : 13C { H } NMR ( 100 .64 variety of conditions, including in the presence of a strong MHz , CD2C1_ ) : 163. 2 (Car ) , 138. 8 (Car ) , 136 . 0 (Car ) , 35 base such as pyridine. 126 . 8 (CH4r ), 124 . 4 (CH4r ) , 119 . 5 (Car ) , 67 . 3 (CHNMez ) , The bisalkoxy bridged dinuclear Indium catalysts of the 60 . 8 ( OCH CH3) , 52 . 7 (NCH , Ar ), 50 . 3 (CHNCH Ar ), 45 . 7 present invention with X = C1 or Br can be synthesized ( NMeMe) , 39 .9 (NMeMe ) , 35 .5 (CH2 - DACH ) , 34 .7 according to methods analogous to the ones described (CMez ), 32 . 1 (CMez ), 31. 1 (CMez ) , 30 . 5 (CMez ), 25 .6 10 above . (CH2 - DACH ) , 25 .2 (CH2 - DACH ), 23 .2 (CH2 - DACH ), 19. 9 (OCH CH3 ). Elemental analysis calc . ( found ) for Examples C C50H3612In N404: C . 46 .44 (46 .41 ) , N . 4 .33 (4 .34 ) , H . 6 .65 Synthesis of Dinucicar Indium Complexes of the ( 6 .60 ) . Type [( NN , OR) InX ]2 (u - OH )( u -OEt ) with R =Me or 45 t -Bu and X = C1, Br, or I Example B4 Example C1 Synthesis of [( NN , Bu )Inl ] 2 ( u -OEt ) , Synthesis of [( NN ,OBU ) Inl] ,( u -OH ) (u -OEt ) 50 The [ (NN ,OBU ) Inl] 2 ( u - OEt) , complex was also prepared A 25 mL round bottom flask was charged with a solution following the method of Example B3 but using THF and of [ (NNOBJ . ) Inl] ( u -OEt ) , (250 mg, 0 . 19 mmol) in 10 mL stirring for 16 h as schematically shown below : CH _ C12 , and then water (3 . 5 ul , 0 . 19 mmol) was added to the solution . The reaction was stirred for 1 h and after that 55 the mixture was evaporated to dryness in vacuo . The residue Bu was washed with diethyl ether and dried for 2 h in vacuo , to yield [ (NNOBU ) Inl ] 2 (u - OH ) ( u -OEt ) as a white powder. Suitable crystals for X -ray diffraction were grown by slow diffusion on diethyl ether in a CH , C1, solution of the 60 complex ( 204 . 1 mg, 85 % yield ) . ' H NMR (400 MHz, Bu 2 NaOEt CD , C1 ) : 8 7 . 20 ( 1H , d , J = 3 Hz, ArH ) , 6 . 78 (1H , d , J = 3 Hz , THF , 16 h ArH ) , 4 .82 ( 1H , d , 2J41. 4 = 12 Hz, HN - CHH — Ar ), 4 .39 ( m , IN 0 .5H , OCHHMe) , 4 . 20 ( 0 .5H , m , OCHHMe) , 3 .74 ( 1H , d , InHI J = 12 Hz , NH CHH — Ar ), 3 .69 ( 1H , OH ), 3 .43 ( 1H , m NI 65 CHN ( Me) ), 2 . 62 (1H , m , CHNH ) , 2 . 55 ( 3H , s , NMeMe) , 2 .47 (2H , m , CH2 – of DACH ) , 1 .91 ( 3H , s , NMeMe) , 1 . 84 (4H , m , _ CH , - of DACH ) , 1 .43 ( 9H , s , t - Bu ) , 1 .27 US 9 ,777 ,023 B2 59 60 ( 11H , s , t -Bu and m , - CH2 - of DACH ) , 1 .15 ( 2H , t Example D 3JH - H = 6 Hz, OCH CH3) , 1 . 07 ( 2H , m , - CH2 - of DACH ) . 13C { H } NMR ( 100 .64 MHz, CD , C12 ): 8 163 . 2 (ca ), 138 .9 (Cm ), 136 . 7 (CA ) , 126 . 8 (CH4 ) , 124 . 5 ( CHAT) , 119 . 9 (Car ) , Synthesis of [ (TH -NN MEDBW ) InCl] z (u -C1 ) (u -OEt ) 67. 3 (OCH _ C13 ) , 62 . 0 (CHNMez ) , 53 . 3 (CHNCH , Ar ), 50 . 3 5 and [ (TH -NNyelme ) InCl] 2( u -Cl ) ( u -OEt ) (NCH Ar) 46 . 0 (NMeMe ) , 38 . 1 (NMeMe ) , 34. 3 (CMez ) , 32. 1 (CMez ) , 31. 1 (CMez ) , 30 . 5 (CMez ), 26 .4 (CH2 DACH ) , 25 . 4 (CH -DACH ) , 25 . 3 ( CH - DACH ), 22 . 4 ( CH2- DACH ) , 19 . 9 ( OCH CH3) . Elemental analysis caic . ( found ) for C48Hg413In ,N404 : C . 45. 46 (45 .13 ), N . 4 .43 ( 4 .40 ), H . 6 .64 ( 6 .69 ) . FIG . 6 shows the molecular structure of [ (NNO /BW ) Inl] 2 ( u - OH ) ( u -OEt ) , obtained by single -crystal X - ray diffraction . (C4 ) FIG . 6 shows a dinuclear complex where both indium 15 centres are in a distorted octahedral geometry. The NNO ligands are bound to the metal center infac - fashion and only the homo -chiral ( R , R / R , R ) -[ ( NNO (Bu ) Inl] z ( u -OH ) (u -OEt ) is observed . The molecular structure is depicted with ellipsoids at 50 % probability and most H atoms as well as solvent 20 molecules omitted for clarity . Selected bond lengths ( Å ) : In1 -01 ( 2 . 180 ( 3 ) ), In2- 01 ( 2 .211 ( 3 ) ) , In1- 02 (2 . 142( 3 )) , In2 -02 ( 2 . 146 ( 3 ) ) , In1 - 03 ( 2 .090 ( 3 ) ) , In1 -N3 ( 2 . 336 ( 4 ) ) , Inl -N4 ( 2 . 273 ( 4 ) ) , In1 - 12 ( 2 . 8030 ( 4 ) ) , In2 - 11 ( 2 .7923 ( 4 ) ) , In2 -04 (2 .099 (5 )) , In2 -N1 (2 . 338 (9 )) , In - N2 ( 2 .265 (5 ) ). Selected bond angles (* ) : 01- In1 -02 ( 92. 49 ( 12 ) ) , N3- In1- 12 ( 96 . 20 ( 10 )) , N3 - In1- O3 ( 103. 29 ( 14 )) , N1 - In2 - 11 (98 .20 ( 15 ) ) , N1- In2 - 04 ( 100 . 14 ( 5 ) ) , 01- In2 -02 : 74 .58 ( 12 )) , Inl 01- In2 ( 103 . 26 (13 )) , In1 -02 - In2( 106 .90 (14 ) ), O2 - In1 -03 30 ( 165 .62 ( 12 ) ) . ( C4t ) Example C2 35 Synthesis of [ (NN , Ome) Inl] 2 ( u -OH ) (u -OEt ) The complex [( NN , Ome) Inl] 2( u -OH )( u -OEt ) was pre

2. pared as shown below : $

Bu #

1 . 0 H2O - N - N - H THF , 16 h 50 Nr

Bu (C5 ) 55

In - N NH 60 ooo

- Bu Bu

1 or US 9 ,777 ,023 B2 61 62 - continued -continued ( C5t ) OH O t - Bu

NH2 t - Bu

NH3Cl C In t - Bu

? * t - Bu

OH 20 The proligand for the synthesis of catalyst (C5 ) was NH?Cl prepared as described in Williams et al. , J . AM . CHEM . SOC . 2003 , 125 , 11350 -11359 , and the catalyst (C5 ) pre 1. Et3N pared according to methods analogous to the preparation of 25 2 . > 10 equiv CH20 , [ (NNO (Bu ) InCl] 2 (u -Cl ) (u -OEt ) as described above. The NaONBH ; catalyst (C4 ) can be prepared in an analogous manner. t - Bu Example E 30 Synthesis of the Dinuclear Indium Catalysts of the * t - Bu Type [ ( NNMe Bu) In ( Cl) ] z (u - Cl) ( u - OEt) NCH OH The catalyst represented by structural formula (D7 ) 35 N (CH3 ) 2

( D7) POLYMERIZATION EXAMPLES Example : Polymerization of rac -lactide The asymmetrically bridged complexes [ (NN , Ome) oog InCl] ( u -Cl ) ( u - OEt ), [ (NN , Ove ) Inl] ( u - OEt) , and [ (NN , Ome) Inl] 2 ( u -OH ) ( u - OEt) as well as symmetrically bridged complex [ (NNÇOX ) Inl] ( u -OEt ) , were used as initiators and catalysts for the ring opening polymerization of racemic lactide (rac -LA , i . e . , racemic mixture of D -lac tide ( D -LA ) and L - lactide ( L -LA ) ) . The reactions, moni 50 tored by ' H NMR spectroscopy at 25° C . showed approxi mately 90 % conversion of 200 equiv of rac -LA to PLA in 30 minutes, with slight variations in rate depending on the initiator. In all cases, an induction period was observed which varied subtly (3 to 8 min ) with the electronic differ ( as racemic mixture of (RR ,RR ) and (SS , SS ) ) was prepared455 ences in the various complexes. After this period , the according to methods analogous to the one described in polymerization reactions were first- order in catalyst and LA Example A4 with proligand prepared according to the fol concentrations with similar rate constants within experimen lowing scheme, and analogously to methods described in tal error , giving an overall second - order rate law for con Organometallics , 2009, 28 (5 ) , 1309- 1319 : sumption of LA ( rate = k [ catalyst ] [LA ] ) ( Table 1 ) . It is 60 believed that that the catalyst in all cases is the dinuclear species behaving as one initiator. NH2 NMR Scale Polymerization of rac - lactide with Indium 1 . 5M HCI Complexes for Kinetic Experiments Ether In a teflon sealed NMR tube, 0 .50 mL of the indium NH2 65 complex in CD , C1, ( 0 .0048 M , 0 .0024 mmol) was added to a solution of rac - lactide ( 66 mg; 0 . 47 mmol) and an internal standard 1, 3 ,5 - trimethoxybenzene (5 mg; 0 .03 mmol) in US 9 , 777 ,023 B2 63 64 0 .48 mL of CD , C12 . This mixture was immediately cooled 30 umol) in ACN - dz ( deuterated acetonitrile ; 1 . 0 mL ) . Then in liquid nitrogen . The NMR tube was waimed to room E - caprolactone ( E - CL , 100 .7 UL , 200 eqv. ) was added to the temperature before it was inserted into the instrument solution . The tube was taken out of the glove box and ( 400MHz Avance Bruker Spectrometer) . The polymeriza immediately placed in a Bruker AV 300 NMR spectrometer tion was then monitored to ca . 95 % conversion . 5 for in - situ monitoring with temperature being maintained at The following rate constants were observed : 50 . 8° C . The change of the relative concentration of E - CL over time is shown in FIG . 1 . The observed rate was found to be first order to monomer concentration , and has the value Entry Catalyst kabs (s - 1) k (M - 's - 1 ) as indicated in row “ 1 ” of Table 1 . In a further experiment, 10 1a [ (NNO -BU ) InCI) ] z ( u -OEt ) (u - Cl) 0 .0023 1 .15 ( + 0 .27 ) the procedure as described in this Example was followed , 2a [( NNO Me) InI) ] z (u -OEt ) ( u -I ) 0 .0034 1 .70 ( 0 .22 ) however , the temperature during in - situ monitoring was 3 [( NNOMe ) InI( u - OEt) ]2 0 .0014 2 .80 ( + 0 .56 ) maintained at 40 .3° C . The observed rate was found to be 4 " [ (NNOYINI ) ( u -OEt ) ( u -OH ) 0 .0036 1 .67 ( + 0 . 14 ) first order to monomer concentration , and has the value as indicated in row “ 2 ” of Table 1 . All the reaction were carried out in an NMR scale Polymerization of 4 - ( but- 3 - en - 1 - yl) oxetan - 2 -on (f - BBL with 200 equiv of LA at 25° C . and followed to 90 % 1) with [ In (NNO )] 2( u -OEt ) (u -CI ) 0conversion . 114 M . ( catalyst? . “ [LA ] == 00 .46 00057 M . Min[ catalyst ?DCI ] = 0. ., 0023 1. 3, 5 -M trimethoxy ; b [LA ]= - f- BLL - 1 was prepared according to Organic Letters 2006 , benzene ( TMB ) was used as internal standard . The value of . Vol. 8 , No. 17 , 3709 - 3712 . kobs was determined from the slope of the plots of In { [LA ] In a glove box , a Teflon - sealed NMR tube was charged [ TMB ] ) vs . time. with a solution of [ In (NNO ) , ( u -OEt ) ( u -Cl ) obtained as Large - scale Polymerization of rac - lactide described above ( 4 . 5 umol) and TMB ( trimethoxybenzene , In a typical experiment, 129 . 3 mg of rac - lactide ( 0 . 92 30 umol) in ACN - d? (deuterated acetonitrile ; 1 . 0 mL ) . Then mmol) was dissolved in 3 mL of CH ,C1 , in a vial and stirred 25 4 - (but - 3 -en - 1 -yl ) oxetan - 2 - on ( f -BLL - 1, 100 UL , 200 eqv. ) using a magnetic stir bar . To this solution ImL of a stock was added to the solution . The tube was taken out of the solution of one of the above indicated indium complexes in glove box and immediately placed in a Bruker AV 300 NMR CH , C1, was added ( 0 . 0046 M ; 0 .0046 mmol) . The reaction spectrometer for in - situ monitoring with temperature being was allowed to proceed for 16 h and then concentrated to maintained at 61 . 5° C . The observed rate was found to be dryness. A sample of the residue was dissolved in CDC1, to 30 first order to monomer concentration , and has the value as be analyzed by 1H NMR spectroscopy to determine con indicated in row “ 3 ” of Table 1 . version . The resulting polymeric material was dissolved in a minimum amount of CH , Cl , and added to cold wet metha TABLE 1 nol (0° C ., 7 mL ) . The polymer crashed out of solution , and Polymerization of E - CL and f- BBL - 1° was isolated by centrifugation . The supernatant was 35 - decanted off and the polymer was dried under high vacuum temp [cat ] KbKobs for 2 h . The resulting polymer was then analyzed by NMR entry monomer Solvent (°C . )a (mmol / L ) [ M ] /[ cat ] (* 10 -5s - ) ( Nuclear Magnetic Resonance ) and GPC (Gel Permeation 1 E - CL ACN -dz 50 . 8 4 . 6 200 105 . 8 Chromatography ) . E - CL ACN -dz 40 . 3 4 . 6 200 45 . 5 FIG . 7 shows the observed poly ( lactide ) (PLA ) ( v ) and 40 3 f - BBL - 1 ACN -dz 61. 5 1 . 6 200 5 . 0 molecular weight distribution ( o ) as functions of added rac -lactide for [ (NN , OBU ) InCl] z (u - C1) ( u -OEt ) beThe 62 reactions .4° C . by were80 % monitoredethylene glycolin - situ inon DMSO Bruker - do AV. 300 . The temperature is calibrated to ( M , = number averaged molecular weight, "Rates were first order to monomer concentration . PDI= polydispersity index ). The line indicates calculated Mn values based on the LA : catalyst ratio . The ability to obtain 45 Polymerization with (CS ) PLA across a wide molecular weight range with low PDI Rae -LA was polymerized with catalyst (C5 ) . The values is a direct result of the unusually stable nature of this observed polymerization rate was kon = 0 .000024 s - 1 with catalyst and the lack of termination mechanisms. It is [LA ] /[ Cat ] = 200 . The tacticity of the obtained polylactide believed that this living behavior may be a direct result of polymer is atatic (P = Pm = 0 .49 ) . the dinuclear nature of the catalyst. 50 Block Copolymerization Examples FIGS . 8 , 9 and 10 show the observed poly (lactide ) ( PLA ) The block copolymers in Table 2 have been prepared M , (v ) and molecular weight distribution ( o ) as functions of added rac - lactide for [ (NN , OBU ) In ] 2 (u - I ( u -OEt ) , using the catalyst [ (NN OBW) InC1] z (u -OEt ) (u - Cl) obtained [ (NN , OBw ) Inl] 2 ( u -OH )( u -OEt ) and [( NN , Ome) Inl] , (u as described in Example above. OEt ) , respectively ( M , = number averaged molecular 55 weight, PDI= polydispersity index ). The line indicates cal TABLE 2 culated M , values based on the LA : catalyst ratio . Block copolymersa The bisethoxy bridged catalyst , [( NN , Me) Inl] 2 (u -OEt ) 2 has been found to exhibit a faster rate of polymerization (see Mn,GPC entry 3 in above table ). 60 Entry M , M2 Equivalent Mntheo. (kDa ) (kDa ) PDI 1 Rac -lac L - lac 650 + 800 208. 4 162 .7 1 . 069 Example: Polymerization of e -caprolactone with 2 Rac - lac L - lac 156 + 800 149 . 2 156 . 9 1 . 050 3 L - lac Rac - lac 755 + 288 150 . 2 163 . 3 1 . 087 [ In ( NN , O ) ] 2 ( u - OEt) ( u -Cl ) 4 L - lac Rac - lac 516 + 516 148 .6 163. 2 1. 083 5 L - lac Rac - lac 288 + 743 147 .8 165 . 6 1 . 058 In a glove box , a Teflon - sealed NMR tube was charged 65 vauAWNA6 Rac - lac BBL 200 + 200 46 . 0 41. 5 1 . 065 with a solution of [( NNO )InCl ] 2 ( u -OEt )( u - Cl) obtained as 7 L - lac BBL 200 + 200 41. 4 described above ( 4 . 5 umol) and TMB ( trimethoxybenzene , US 9 ,777 ,023 B2 65 66 Catalyst 1 has been found to show remarkable activity and TABLE 2 -continued control during polymerization , allowing for formation of Block copolymersa diblock polymers . Addition of high ratios of alcohols to the dinuclear Indium catalyst has been found to lead to fast Mn,GPC 5 chain transfer and immortal polymerization . Entry M Þ M Equivalent Mntheo. ( kDa ) (kDa ) PDI 5 At room temperature , of 200 equivalents 8 L -lac f- BBL - 1 100 + 20 17 .6 25 . 5 1. 203 of BBL in THF reach full conversion in one hour. There is 9 BBL f - BBL - 1 100 + 20 10 . 8 15 . 8 1 .005 a significant solvent effect at room temperature: kob , THF - d , These reactions were run in DCM except entry 9 , which was done in THF. Second ( 2 .9x10 - 4 5 - 1 ) > CD2C12 (6 . 1x10 -5 s - 1 )- CD2CN (5 .5x10 -5 monomer was added directly into polymerization solution after the first monomer was fully s - ? ) > > toluene ( rate not measurable at room temperature ) . converted . Heating might be needed when polymerizing BBL and f - BBL - 1 . " My means the first monomer . However, heating the reactions to 60° C . increases the rates " The left and right numbers mean the equivalent of My and Myrespectively . significantly and allows all reactions to reach full conversion in under 4 hours . With regard to entry 1 in Table 2 , that is , the block All PHB samples produced with complex 1 were atactic . copolymerization of L - lac ( i . e . , L - lactide ) and rac -lac ( i . e . , There is good agreement between calculated and experi racemic lactide ) , a Strauss flask was charged with a solution 15 mental M ,, for [BBL ]: [ 1 ] ratios of up to 5000 . PHB samples of [ (NN 0 ByInCl] ( u -OET ) ( u -C1 ) ( 16 . 6 umol) in dichlo romethane in a glove box . Then L - lac ( 1 .81 g ) was dissolved of greater than 300 kDa with low PDIs have been isolated : and transferred into the flask while stirring . After overnight stirring , a small amount of solution was pipetted out and % M , ( calc ) Mn (GPC ) quenched with 2 drops of HC1/ Et20 , which is used as a 20 Entry BBL ]: [ 1 ] Conva g mol - 1 g mol- 1 PDIC parallel sample to check the properties of the first block . 200 > 99 17260 20400 1 .02 Then rac - lac (0 .69 g ) was added to the rest solution in the 400 > 99 34480 36700 1 .06 flask . Then it was stirred overnight again to allow the second 600 > 99 51700 58820 1 . 07 monomer to be fully converted . After that , it was quenched 800 >99 68920 91480 1 .07 with 0 .5 ml HC1/ Et20 . Conversion was measured by com - 25 1000 > 99 86140 82090 1 .07 paring the relative integration of methine hydrogen peaks in 2000 > 99 172230 135000 1 .05 DovauAWNA 3000 > 99 258320 202000 1 .05 polymer and monomer . The block copolymer was precipi tated by adding cold methanol and washed with cold metha 4000 > 99 344410 256200 1 . 05 nol three times . Then the block copolymer was dried under 5000 96 413280 314700 1 .04 vacuum to constant weight. "Monomer conversion , determined by ' H NMR spectroscopy . The block copolymers of entries 2 to 9 in Table 2 , were 30 Mn cale = [BBL ] ] [ 1 ] x BBL conversion x MBBL + MEOh. All reactions were carried out in THF at 25° C . for 21 h . prepared analogously as described above for entry 1 . Determined by GPC -LALLS dn /dc = 0 . 067 mL/ g ) . FIG . 2 shows the ' H NMR of L -lac - b - f -BBL - 1 (Entry 8 , Table 2 ) , purified polymer. 600 MHz. Monitoring the iROP of BBL in CD2CN at60° C . by ' H FIG . 3 shows the 1 H NMR of BBL -b - f - BBL - 1 ( Entry 9 , NMR spectroscopy shows first order polymerization of Table 2 ), purified polymer. 600 MHz. 35 monomer to 90 % conversion . FIG . 4 shows the GPC elution diagram of poly ( L - lac - b Two consecutive polymerizations of 100 equivalents of rac - lac ) (left peak , Mn = 163. 3 kDa, Entry 3 in Table 2 ) and BBL with complex 1 on the NMR scale resulted in two first its first block poly (rac - lac ) ( right peak , Mn = 124 . 4 kDa) . order plots , with the second addition showing a slightly lower rate than the initial addition as can be seen in FIG . 11 . Example : Immortal Ring - opening Polymerization of 40 FIG . 11 ( a ) shows a plot of Ln ( [BBL ]) versus time for two B -butyrolactone sequential additions of 100 equiv of [BBL ]/ [ 1 ] in CD CN at 60 .6° C . [ 1 ] = 0 .0045 M , [BBL ] = 0 .45 M . FIG . 11 (6 ) shows The dinuclear Indium catalyst [ [ (NN , OBU) InC1] 2 (u -OET ) GPC traces of the polymers produced by 20 consecutive ( u - Cl) (see also Examples A ; hereinafter in this example additions of 200 equiv . of [BBL ]/ [ 1 ] in THF at 25° C . further denoted as “ 1 ” ) was used for the ring opening 45 [ 1 ] = 0 . 0045 M , [ BBL ] = 0 . 90 M . 1st addition , dashed line polymerization of the cyclic ester B - butyrolactone to form (M , = 20 .4 kDa, PDI= 1 . 02 ) . 2nd addition , solid line the biodegradable polyester poly (hydroxybutyrate ) (PHB ): (Mr = 42 .8 kDa , PDI = 1. 05 ) .

N 11011

H - N N — H

- t- Bu Ó ttBut- - Bu t- - Bu tt- - Bú Bu

n [( NNOR )InCl ] 2 ( u -Cl ) ( u -OEt ) (1 )

un B - Butyrolactone poly (hydroxybutyrate ) (BBL ) - the( PHB ) US 9 ,777 ,023 B2 68 Repeating this experiment on a larger scale (consecutive using standard Schlenk line techniques. A Bruker Avance additions of 200 equiv BBL ) resulted in PHB with M , 300 MHz or 400 MHz spectrometer was used to record ' H corresponding to 400 enchained units . and 13C spectra . A Bruker Avance 600 MHz spectrometer Polymerization reactions were also carried out from 22 to was used to acquire homonuclear decoupled ' H { H } spec 72° C ., and activation parameters were obtained from the 5 tra of polylactide . ' H NMR chemical shifts are given in ppm resulting Eyring plot (AH * = 58 (4 ) kJmol -? , AS + = 86 ( 13 ) JK - I versus residual protons in deuterated solvents as follows: 8 mol- 1 . 7 . 27 CDC12 . 13C NMR chemical shifts are given in ppm Catalyst 1 is believed to undergo exchange with added versus residual 13C in solvents as follows: 8 77 .23 CDC12 . alcohol. Complex 1 was dissolved in neat dry methanol at Molecular weights and polydispersity indices were deter room temperature for 16 h , followed by removal of the 10 mined by triple detection gel permeation chromatography solvent. The analogous methoxy complex was formed . The using a Waters liquid chromatograph equipped with a Waters reaction of 1 with two or ten equivalents of dry ethanol was 515 HPLC pump, a Waters 717 plus autosampler , Waters monitored for 24 h by ‘ H NMR spectroscopy (25° C . , Styragel columns ( 4 .6x300 mm ) HR5E , HR4 and HR2, a CDC13 ) . The spectra remain essentially unchanged during Waters 2410 differential refractometer , a Wyatt tristar this period , suggesting that the rate of exchange is faster than 15 miniDAWN laser light scattering detector and a Wyatt the NMR timescale . ViscoStar viscometer. A flow rate of 0 . 5 mL /min was used A two - component catalytic system composed of complex and samples were dissolved in tetrahydrofuran ( THF ) (ca . 2 1 and a chain transfer agent, such as ethanol or mPEG , leads mg/ mL ) . The measurements were carried out at laser wave to the immortal ring opening polymerization of BBL : length of 690 nm , at 25° C . The data were processed using 20 the Astra software provided by Wyatt Technology Corp . A differential scanning calorimeter (DSC ) Q1000 ( TA Instru ments ) was employed to measure the glass transition (T ) [ In ] ( 1 ) : nROH and melting ( Tn ) temperatures. R = CH3CH2, n = 2 - 10 Materials . THF were taken from an IT Inc . solvent OS R = CH3( OCH2CH2 ) 7 , n = 2 - 100 25 purification system with activated alumina columns and BBL degassed before use . CH2Cl2 was refluxed with CaH2, dis tilled and degassed before use . EtOH , CDC1z were dried over CaH2, transferred under vacuum and degassed through 1 [ In ] freeze -pump - thaw cycles before use . DL - , L - and D - lactide ROL O1 30 were donated by Purac Biomaterials and recrystallized twice RO -PHB - [ In ] in toluene . Beta -butyrolactone , purchased from Aldrich , was stirred with CaH , for 48 hours , distilled under vacuum , degassed through freeze - pump - thaw cycles and kept in the The molecular weights of the resulting polymers were freezer at - 30° C . The catalyst [( NN ,OBU ) InCl] 20Et) ( u - Cl) found to be consistent with theoretical values and molecular ,35 (also referred to in this Example as catalyst or complex 1 ) weight distributions are uniformly low ( see the following was prepared as described in Example A4 . Table which shows the results for iROP of BBL with EtOH Synthesis of triblock copolymers . Complex 1 (22 . 7 mg, and mPEG , i. e . , monomethylated poly ( ethylene glycol) . " ) . 0 .0206 mmol) was dissolved in CH2Cl2 and transferred to a round bottom flask . While stirring , a solution of L -LA in [BBL ] / [ROH ] Mn. the Mn expt 40 CH C12 (1 . 267 g, 8 .80 mmol) was added slowly . The polym Entry ROH [ 1] g mol- 1 g mol - 1 PDI erization was allowed to stir for a few hours and then a 1000 / 0 / 1 86140 82890 1 . 07 solution of the second monomer rac -LA ( 0 . 966 g , 6 .71 EtOH 1000 / 2 / 1 28740 28340 1 .01 mmol) in CH2Cl2 was added to the reaction . The polymer EtOH 1000 / 4 / 1 17260 16770 1 .01 ization was allowed to stir overnight and a solution of the EtOH 4000 / 10 / 1 31350 44020 1 .01 45 third monomer D -LA ( 1 . 267 g , 8 . 80 mmol) in CH , Cl , was MPEG 1000 / 2 / 1 28950 27970 1 .01 added to the reaction mixture . The reaction was allowed to vauAWNA mPEG 1000 / 4 / 1 17510 17070 1 .02 mPEG 10000 / 20 / 1 40920 36090 1 .01 stir overnight and then quenched with acidic Et 0 ( 0 . 5 mL mPEG 10000 / 100 / 1 8360 7570 1 .03 of 1. 5 M HCl in Et20 ). A few drops of the mixture were removed to check conversion and the remaining mixture was "Conversions Experiments: entriesin THF 1, - 21°7 100 C .%, , 16entry h , [ 18 ]94 = %0 .;0018M mPEG . =entries CH3( OCH1 -6 21 , CH2 h , ) entries 7 - OH 7 - 8 46 h . 50 concentrated under vacuum and the polymer was precipi My cale = [BBL ] / ([ ROH ] + [I ] ) BBL conversion x MBBL + MROH . All reactions were tated with cold MeOH . The resulting polymer was washed carried out in THF at 250 C . for 21 h . My cale = [BBL ] / ( [ROH ] + [ 1 ]) * BBL conversion MBBL + MROH : with cold MeOH (3x3 mL ) and dried under vacuum . The Determined by GPC -LALLS for PHB and MPEG -CO -PHB , dn /dc = 0. 067 and 0 .063 mLLig/ g polymer was then redissolved in dry CH2Cl2 , a thermal respectively .) stabilizer ( TNPP, 35 . 0 mg ) was added and the solvent was In particular, polymerization of 10000 equivalents of BBL 55 removed under vacuum overnight. Parallel experiments of in the presence of 100 equivalents of mPEG proceeds in a the synthesis of only the first block and the first two block highly controlled manner ( M , the 8 . 36 kDa, M , 55 7 .57 polymers were carried out under the same condition to get kDa) (see , entry 8 in the above ). These results indicate that information of the molecular weight of each block . both ethanol and a longer chain alcohol function well as Immortal polymerization of rac -LA with 1 in the presence chain transfer agents and confirm the robustness of catalyst 60 of ethanol. A 20 mL scintillation vial vas charged with a 1 in the presence of large quantities of protic additives. stirring bar and a 0 . 25 mL solution of 1 in CH C1, (0 .0182 M , 0 .0045 mmol) . 13 . 4 uL of ethanol in CH ,C1 , ( 0 .685 M , Example : Immortal Ring -opening Polymerization of 0 . 0092 mmol ) was added to the stirring catalyst solution . Lactide Subsequently , rac -LA (654 mg, 4 . 5 mmol) was dissolved in 65 CH C1, and slowly added in to the stirring solution . The General consideration . All the air and moisture sensitive total volume of the solution was around 4 mL . The reaction manipulations were carried out in an MBraun glove box or was stirred overnight and then quenched with acidic Et , US 9 ,777 ,023 B2 70 (0 . 5 mL of 1 . 5 M HCl) . A few drops of the reaction mixture representing the number of units of ethylene oxide in the were removed to test conversion with ' H NMR spectros molecule) resulted in well -defined polymers with low PDIs copy. The remaining reaction mixture was dried under (see below Table 3 , entries 1 - 5 ) . The molecular weights of vacuum and dissolved in a minimum amount of CH , C1, and the resulting polymers were much lower than those in the the polymer was precipitated with cold methanol . The 5 situation without MePEG , . As the amount of MePEG , used supernatant was decanted off and the polymer was then increases , the molecular weights of the polymers produced washed with cold methanol ( 1x3 mL ) and dried under decreases . The experimental molecular weights fit the theo vacuum overnight. retical values very well, proving that in the short chain Immortal polymerization of L -LA with 1 in the presence MePEG , the hydroxy group is active enough to perform of MePEG - 7 . A 20 mL scintillation vial vas charged with a 10 chain transfer with the growing polymer chain during the stirring bar and a 0 . 90 mL solution of 1 in CH , C1 , ( 0 . 00309 polymerization . M , 0 .00278 mmol) . 44 .7 uL of MePEG , in CH , C1, ( 0 .0622 M , 0 . 00278 mmol) was added to the stirring catalyst solu tion . Subsequently , rac -LA (401 mg, 2 .78 mmol) was dis TABLE 3 solved in CH2Cl2 and slowly added in to the stirring solu - 15 Polymerization of L -LA with different equivalent ofMePEG tion . The total volume of the solution was around 5 mL . The reaction was stirred overnight and then quenched with acidic [LA ]/ [ROH ] | Mn, theo Mn, expt Et20 ( 0 . 5 mL of 1 . 5 M HCI) . A few drops of the reaction Entry ROH [1 ] Conv . (kDa ) (kDa ) PDI mixture were removed to test conversion with ? H NMR 1 MePEG , 1000 /0 / 1 98 141. 15 144 . 2 1 .06 spectroscopy . The remaining reaction mixture was dried 20 MePEG7 1000 / 1 / 1 99 71 . 305 72 . 41 1 . 04 MePEG7 1000 / 2 / 1 99 47. 53 49 .54 1 . 03 under vacuum and dissolved in a minimum amount of MePEG , 1000 / 3 / 1 98 35 .295 39 . 14 1 . 02 CH2Cl , and the polymer was precipitated with cold metha MePEG , 1000 / 4 / 1 99 28 . 52 % 29 .79 1 .02 nol. The supernatant was decanted off and the polymer was MePEG114 1000 / 5 / 1 >99 33 . 80 31. 90 1 . 14 OvaAWNE MePEG 114 520 / 5 / 1 >99 20 .00 23. 36 1 . 46 then washed with cold methanol ( 1x3 mL ) and dried under 25 MePEG14 500 / 10 / 1 > 99 12 . 20 15 . 95 2 . 30 vacuum overnight. 25 9 MePEG 250 / 10 / 1 > 99 8 .60 10 . 01 2 .21 Immortal polymerization of rac -LA with 1 in the presence of MePEG114 . A round bottom flask was charged with 1 in " All the experiments were done in CH2Cl2 at 25° C . CH _ C12 (73 .5 mg, 0 .0668 mmol) and MePEG114 in THF bCalculated from : My = MWLA * [LA ]/ ( [ 1 ] + [MePEG7 ] ) * Conv . + 350 g /mol . ( 1 .67 g , 0 . 334 mmol) . The mixture was allowed to stir for " Calculated from : M , = MW LA * [ LA ]/ [ MePEG114 ] Conv. + 5000 g /mol . half an hour and dried under vacuum . CH2Cl2 was added to 30 In the experiments of iROP of LA with higher molecular dissolve the dry residue again . While stirring, rac -LA in weight MePEG ( M , = 5000 g /mol , denoted as MePEG 14 CH ,C1 , ( 5 . 00 g , 34 . 7 mmol) was added slowly to the with the subscript 114 representing the number of units of solution . The reaction was allowed to stir overnight and then ethylene oxide in the molecule ) ( Table 3 , entries 6 - 10 ), 1 was quenched with acidic Et, 0 ( 0 . 5 mL of a 1 .5 M HCl in Et O ). A few drops of the reaction mixture were removed to 35 was stirred with MePEG 114 for 30 min and pumped down to check conversion with ' H NMR spectroscopy . The remain dryness to remove the generated ethanol. Therefore the ing mixture was dried under vacuum and dissolved in a amount of initiating group equals the amount ofMePEG114 . minimum amount of CH , C1, and the polymer was precipi The molecular weights of the resulting polymers were close tated in 1 : 1 Et , O /hexane . The supernatant was decanted off to the theoretical values . PDI values are higher with shorter and the polymer was washed with 1 : 1 Et , O /hexane ( 3x313 40 chain PLA segments in the copolymers , likely due to the mL ) and dried under vacuum overnight . larger PDI of the commercially available MePEG 1114 itself . Different equivalents of EtOH (based on the amount of Since MePEG 114 is not as monodispersed as the homopo catalyst 1 ) were used in the iROP of lactide. The molecular lymers made with our living catalyst, the incorporation of weight decreased as more EtOH was added . GPC traces of MePEG 114 increases the PDI of the copolymers. As the PLA the resulting polymers ( see FIG . 12 : from left to right, the 45 block gets longer , the differences of the copolymer chain peaks correspond to entry 1 , entry 2 , entry 3 , entry 4 and lengths caused by MePEG4114 become less significant, thus entry 5 in Table 2 below ) showed narrow molecular weight resulting in a lower PDI. Another possible reason accounting distribution for all of the product polymers . The PDI value for the high PDI is that THF is not a good solvent for this and Pm remain similar to those in the absence of the alcohol, copolymer. Long chain PEG is not soluble in THF, which is making iROP an attractive way to decrease catalyst usage 50 the same situation for copolymers containing MePEG 114 . and scale up polymerization . Also , copolymers might form aggregates in THF, which can be detected by the light scattering detector ofGPC , although TABLE 2 no peaks were observed from the refractive index detector, due to low concentrations ( see FIG . 13 ; from left to right, the Polymerization of rac -LA with different equivalents of EtOH 55 peaks correspond to entry 6 , entry 7 , entry 8 and entry 9 in Mn. theb Mnexpt Table 3 respectively . Entrya [EtOH ]/ [1 ] Conv. (kDa ) (kDa ) PDI POM Example : fBBL - 1 and fBBL - 2 144 . 0 109 . 4 1 . 02 0 . 57 98 72 . 0 75 . 53 1 . 03 0 .60 48 . 0 48 . 29 1 .02 0 .60 60 Functionalized four membered lactones fBBL - 1 and AWNAu 98 36 .0 33 . 46 1 .01 0 .58 fBBL - 2 were synthesized by carbonylation of epoxide com AWNHO 28 . 8 30 . 79 1 .01 0 . 59 pounds . ( John W . Kramer, Emil B . Lobkovsky, and Geoffrey W . Coates ORGANIC LETTERS 2006 Vol. 8 , No . 17 " All the experiments were done in CH2Cl2, with 5 . 0 mg catalyst , [rac -LA ]/ [ 1 ] = 1000 . 3709 - 3712 ) bCalculated from : M ., , = MW LA * [LA ]/ ( [ 1 ] + [ EtOH ] ) > Conv. . 65 fBBL - 1 and fBBL - 2 were used in the ring - opening Immortal ROP of LA with low molecular weight MePEG polymerization using dinuclear Indium catalysts of the pres ( M , = 350 g /mol , denoted as MePEG , with the subscript 7 ent invention as shown in below scheme. US 9 , 777 ,023 B2 e (B ) R2 RN??? CH , CN, 60° C . f - BBL - 1 R3 - Nminporn met CI f -BBL - 2 (R ) each R ' independently is (CZ -C4 ) alkyl; Yl is o Ró or OH ; Y2 is O - R " , OH , C1, Br, or I ; 20 each Rº independently is - (CZ -C6 ) alkyl; n is 0 to 4 ; each R1 and R2 is independently a - Hor — (CZ -C4 ) alkyl; or R1 and R2 together with the carbon atoms to which 25 they are bonded form a (C3 - C , )cycloalkyl ring , option ally substituted with up to two groups selected inde pendently from (C1 - C4) alkyl , (C , -C4 ) alkoxy , phe nyl, — CF3, - F , - Cl, Br, and — I ; R is H or (C2 -C3 )alkyl ; 30 each X is independently an anionic ligand ; and each R4 independently is – (C , -C5 ) alkyl ; or a stereoisomer thereof; and All publications , patents and patent applications men provided that when the tridentate ligands L and L2 are tioned in this Specification are indicative of the level of skill 35 represented by structural formula of those skilled in the art to which this invention pertains and are herein incorporated by reference to the same extent as if each individual publication , patent, or patent application was specifically and individually indicated to be incorporated by reference . 40 m While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that various H - N changes in form and details may be made therein without 15 departing from the scope of the invention encompassed by w the appended claims.

What is claimed is : t - Bu t - Bu 1. A method comprising polymerizing a cyclic ester 30 monomer with a catalyst represented by structural formula and ( a ) each X is Cl, and Y1 is 0 (C2 )alkyl , then Y2 ( A ) or a stereoisomer thereof under conditions suitable for is 0 - R ", OH , Br, or 1; (b ) each X is I , and Ylis ring - opening polymerization of the cyclic ester monomer : - O - (C2 ) alkyl, then Y2 is O - R ", OH , CI, or Br, wherein Rº is C -alkyl , Cz- alkyl , C4- alkyl , 55 - Cz- alkyl , or Co - alkyl; or ( c ) each X is Cl, and Yl is OH , then Y2 is O - R " , C1, Br, or I ; ( A ) and wherein the cyclic ester monomer is optionally repre sented by structural formula ( 1) 1L ! —- InLX 2 In - 13 L 6060 - 0 65 wherein L ' and L2 are each independently a tridentate QtZ ) m ; ligand represented by structural formula (B ): US 9 ,777 ,023 B2 73 74 wherein each R " is i ) ( C - C5) alkyl optionally substituted with m is 1 to 4 ; hydroxyl, - C , -CZ ) alkoxy or — O - C , -CZ ) alkenyl , or Q is CH C (HR " ) , orC ( R " R " ) ; ii ) C1- C5 ) alkenyl; each Z is independently CH2 – , 0 , 040) , - C (HR " ) , or _ C ( R " R " ) — ; and or a stereoisomer thereof. each R " is i ) ( C , -C3 ) alkyl optionally substituted with 3 . The method of claim 2 , wherein each X is indepen hydroxyl, ( C ,- C3 ) alkoxy or O C -C3 ) alkenyl, dently Cl, Br, or I. or ii) — (C -C3 )alkenyl ; 4 . The method of claim 2 , wherein L and L ? are each or a stereoisomer thereof ; independently a tridentate ligand represented by structural provided that (i ) no more than one Z is 0 , ( ii ) no formula more than one Z is C40 ) , ( iii ) at least one carbon ring atom is between any two oxygen ring atoms, (iv ) at least one carbon ring atom is between any two - C ( O ) - groups , and ( v ) at least one of any 16 ( E1) three consecutive ring members is CH2 — , - C (HR " ) , or C ( R " R " ) . 2 . The method of claim 1 , wherein the cyclic ester monomer is represented by structural formula (I ) : 20 H - N win mm ( + 2 ) mi 25 RA wherein m is 1 to 4 ; Q is - CH2 - , C (HRM ) — , or C (R " R " ) — 30 each Z is independently CH2 – , 0 % , CEO) , C ( HR " ) — , or C ( R " R " ) — ; and (E2 ) each R " is i ) (C7 -C3 ) alkyl optionally substituted with hydroxyl, – (C2 -C3 ) alkoxy or - O - ( C - C3) alkenyl, or ii ) — (C , - C5 )alkenyl ; 35 or a stereoisomer thereof; provided that ( i ) no more than one z is – O ( ii ) no noun more than one Z is C40 ) , ( iii ) at least one H - N carbon ring atom is between any two oxygen ring atoms, ( iv ) at least one carbon ring atom is between any 404 two C ( O ) - groups, and (v ) at least one of any min three consecutive ring members is CH2 - , C ( HR " ) — , or C ( R " R " ) — ; or wherein the cyclic R ester monomer is represented by structural formula ( II ) 45 or (III )

( 11) or a stereoisomer of the tridentate ligand represented by 50 structural formula El or E2. 5 . The method of claim 2 , wherein the catalyst is repre ON sented by structural formula ( A ): 55 ( III) ( A )

L ' - In X VanL — 1 ? ;

wherein p is 1 or 2 ; q is 2 to 5 ; 65 each z is independently CH , C (HR " ) , or wherein L ' and L are each independently a tridentate C (RMRM ) — ; and ligand represented by structural formula ( B ): US 9 , 777 ,023 B2 75 76 ( B ) (D1 ) RI mo R3 - N ma muna mm O

( R * ) n each R ' independently is ( C , -C4 ) alkyl; Ylis 0 ( C . - C . )alkyl or OH ; (D2 ) Y ? is 0 (C1 - C6 ) alkyl , OH , CI, Br, or I ; n is 0 to 4 ; 20 each R and R² is independently - H or (C1 - C4) alkyl; or R and R² together with the carbon atoms to which they are bonded form a (C3 - C , ) cycloalkyl ring , option w ally substituted with up to two groups selected inde pendently from – (C , -C4 ) alkyl , — (C2 -C4 ) alkoxy , phe nyl, CF3, — F , Cl, Br, and — I; w R? is - H or ( C , -C3 ) alkyl; each X is independently an anionic ligand; and R px each R * independently is (C1 - C5 ) alkyl; 30 or a stereoisomer of the catalyst represented by structural formula (A ); provided that when L and L2 are both represented by (D3 ) structural formula 1112

m ? - N

P im 24 or a stereoisomer of the tridentate ligand represented by structural formula D1 , D2 or D3 ; or t - Bu t - Bu Bu wherein L ' and L2 are each independently a tridentate ligand represented by structural formula and ( a ) each X is Cl, and Yl is 0 — (C2 ) alkyl, then Y2 is 50* 0 ( C , Jalkyl , 0 (C3 ) alkyl, 0 (C4 ) alkyl, 0 ( C3) alkyl , O ( C6 )alkyl , Br, or I ; ( b ) each X is I, and Y ' is - O - (C2 ) alkyl, then Y2 is 0 (C1 ) alkyl, 0 - (C3 ) alkyl , O ( C2) alkyl, 0 (C3 ) alkyl, O ( C ) alkyl, C1, 55 or Br; (c ) each X is Br, and Yl is O - (C2 ) alkyl, then (E1 ) Y ? is 0 — ( C Jalkyl, 0 (C3 ) alkyl, 0 ( C4 )alkyl , 0 (C3 )alkyl , O ( C . )alkyl , Cl, or I; ( d ) each X is C1, and Yl is OH , then Y2 is 0 ( C / - C ) alkyl, Cl, Br, or I ; ( e ) each X is Br, and Yl is OH then Y2 is O C . -C .) 60 H — N alkyl, Cl, Br, or I; or ( f) each X is I, and Yl is OH , then Y2 is O ( C . - C . )alkyl , C1, Br, or I . 6 . The method of claim 5 , wherein each X is indepen dently Cl, Br, or I . min 7 . The method of claim 6 , wherein L ' and L are each 65 independently a tridentate ligand represented by structural R formula US 9 , 777 ,023 B2 77 78 - continued - continued ( E2 ) ( X )

10 w or a stereoisomer thereof. 9 . The method of claim 1 , wherein : R4 R4 i ) the tridentate ligand is chiral, and (a ) conditions are 15 provided for the polymerizing to exert enantiomorphic or a stereoisomer of the tridentate ligand represented by site control; ( b ) the polymerizing results in an iso structural formula El or E2 . enriched polymer ; or (c ) both (a ) and (b ) ; 8 . The method of claim 1 , wherein the cyclic ester ii ) the polymerizing is substantially first order in catalyst monomer is a dilactone or a lactone represented by structural and monomer concentrations ; or formula 20 iii) the polymerizing is living polymerizing. 10 . The method of claim 1 , wherein it is further provided that when L and Lº are both represented by structural (IV ) formula 25

8

=O

H - N O= 7 mi

t - Bu t - Bu

6 and the catalyst is represented by structural formula

5 BE (P5 ) - Br L ' - In Br In — 12,

4

(P6 ) 3 OG 11- In - Bry In — 1 ?,

( IX ) 60 (P7 )

O . or Il- noIn In — L ?, 65 US 9 , 777 ,023 B2 79 80 -continued - continued (P11 ) (P4 ) H . Il- In - BrBrony In - L ? , or L' - m < - In — ?

( P12 )

Il - In In - 12 ( P5)

Ll - In - Br Br In - L? ,

20 then the cyclic ester monomer is not L -lactide , D -lactide , meso - lactide or rac - lactide . 11 . A polymer prepared by process comprising polymer ( P6 ) izing a cyclic ester monomer with a catalyst represented by structural formula (A ) or a stereoisomer thereof under conditions suitable for ring -opening polymerization of the Br L ' - In Br In - L2 cyclic ester monomer:

30 ( A ) > L ' - In In — L ? ; TO L ' — In In - L ? , wherein L ' and LP are each independently a tridentate 35 ligand represented by structural formula ( B ) : IO (P8 ) ( B ) PORTR2 L' - m < C In — ?, watan win ( P9 )

R * ) n L ' - InBr Y In — 12 , each R ' independently is ( C1- C4 )alkyl ; Y is 0 - R or OH ; 55 Y2 is ( R " , OH , CI, Br, or I; each R independently is (C ,- C .) alkyl; n is 0 to 4 ; ( P10 ) each R ' and R ’ is independently a - Hor — ( C - C4) alkyl; or R1 and R2 together with the carbon atoms to which 60 they are bonded form a (C5 - C7) cycloalkyl ring , option 11 - In - Cl ally substituted with up to two groups selected inde ci- In - L2 pendently from — ( C1 -C4 ) alkyl, ( C , - C4) alkoxy, phe nyl, – CF3, - F , - C1, — Br, and — I ; R * is - H or — ( C , -CZ ) alkyl; 65 each X is independently an anionic ligand ; and each R + independently is – (C1 - C5) alkyl; or a stereoisomer thereof; and US 9 ,777 , 023 B2 provided that when the tridentate ligands L and L2 are represented by structural formula

H - N - wanan mim

t - Bu * t - Bu and ( a ) each X is C1, and Yl is – O – (C2 ) alkyl , then Y2 is O R , OH , Br, or I; ( b ) each X is I , and Yl is - O - ( C , Jalkyl, then Y2 is O - R " , OH , CI, or Br, . wherein Róis — C ,- alkyl, Cz- alkyl, C4 -alkyl , “ - Cz- alkyl, or — Co -alkyl ; or ( c ) each X is Cl, and Y ! is — OH , then Y2 is O _ R " , C1, Br, or I. 12 . The polymer of claim 11 , wherein he polymer is iso - enriched , and , optionally , has a Pm value between 0 .53 and 0 .62 , or is characterized by a polydispersity index of less than 1 . 5 . * * * * *