Asymmetric carbon-carbon-bond-forming reactions catalyzed by bifunctional cinchona alkaloids

A compound represented by formula IV:

• wherein, independently for each occurrence:
• R represents a substituted or unsubstituted alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, heterocycloalkyl, —C(═O)-atkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, —C(═O)-heteroaralkyl, —C(═O)-heterocycloalkyl, —C(═S)N(H)-alkyl, —C(═S)N(H)-alkenyl, —C(═S)N(H)-alkynyl, —C(═S)N(H)-aryl, —C(═S)N(H)-aralkyl, —C(═S)N(H)-heteroaryl, —C(═S)N(H)-heteroaralkyl, —C(═S)N(H)-heterocyclic, or —C(═S)N(H)-heterocycloalkyl;
• R1 represents a substituted or unsubstituted alkyl or alkenyl;
• R2 and R3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R4 represents hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R5 represents H or lower alkyl;
• n is an integer from 0 to 6 inclusive;
• and
• m is an integer from 0 to 8 inclusive.

A method of preparing a chiral, non-racemic β-cyano ketone, chiral, non-racemic β-keto ester, chiral, non-racemic β-cyano ester or chiral, non-racemic 1,3-diketone, comprising the step of:

• reacting a prochiral β-cyano ketone, prochiral β-keto ester, prochiral β-cyano ester, or prochiral 1,3-diketone with an electron-deficient alkene in the presence of a catalyst;
• thereby producing a chiral, non-racemic β-cyano ketone, chiral, non-racemic β-keto ester, chiral, non-racemic β-cyano ester or chiral, non-racemic 1,3-diketone;
• wherein said catalyst is represented by formula III:
• wherein, independently for each occurrence:
• R represents a substituted or unsubstituted alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, heterocycloalkyl, —C(═O)-atkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, —C(═O)-heteroaralkyl, —C(═O)-heterocycloalkyl, —C(═S)N(H)-alkyl, —C(═S)N(H)-alkenyl, —C(═S)N(H)-alkynyl, —C(═S)N(H)-aryl, —C(═S)N(H)-aralkyl, —C(═S)N(H)-heteroaryl, —C(═S)N(H)-heteroaralkyl, —C(═S)N(H)-heterocyclic, or —C(═S)N(H)-heterocycloalkyl;
• R1 represents a substituted or unsubstituted alkyl or alkenyl;
• R2 and R3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R4 represents hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R5 represents H or lower alkyl;
• n is an integer from 0 to 6 inclusive;
• and
• m is an integer from 0 to 8 inclusive.

A method of preparing a chiral, non-racemic β- cyano ketone, chiral, non-racemic β-keto ester, chiral, non-racemic β-cyano ester or chiral, non-racemic 1,3-diketone, comprising the step of:

• reacting a prochiral β-cyano ketone, prochiral β-keto ester, prochiral β-cyano ester, or prochiral 1,3-diketone with an electron-deficient alkene in the presence of a catalyst;
• thereby producing a chiral, non-racemic β-cyano ketone, chiral, non-racemic β-keto ester, chiral, non-racemic β-cyano ester or chiral, non-racemic 1,3-diketone;
• wherein said catalyst is represented by formula IV:
• wherein, independently for each occurrence:
• R represents a substituted or unsubstituted alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, heterocycloalkyl, —C(═O)-atkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, —C(═O)-heteroaralkyl, —C(═O)-heterocycloalkyl, —C(═S)N(H)-alkyl, —C(═S)N(H)-alkenyl, —C(═S)N(H)-alkynyl, —C(═S)N(H)-aryl, —C(═S)N(H)-aralkyl —C(═S)N(H)-heteroaryl, —C(═S)N(H)-heteroaralkyl, —C(═S)N(H)-heterocyclic, or —C(═S)N(H)-heterocycloalkyl;
• R1 represents a substituted or unsubstituted alkyl or alkenyl;
• R2 and R3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R4 represents hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R5 represents H or lower alkyl;
• n is an integer from 0 to 6 inclusive;
• and
• m is an integer from 0 to 8 inclusive.

A method of kinetic resolution comprising the step of:

• reacting a prochiral β-cyano ketone, prochiral β-keto ester, prochiral β-cyano ester, or prochiral 1,3-diketone with an electron-deficient alkene in the presence of a catalyst;
• thereby producing a chiral, non-racemic β-cyano ketone, chiral, non-racemic β-keto ester, chiral, non-racemic β-cyano ester or chiral, non-racemic 1,3-diketone;
• wherein said catalyst is represented by formula III:
• wherein, independently for each occurrence:
• R represents a substituted or unsubstituted alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, heterocycloalkyl, —C(═O)-atkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, —C(═O)-heteroaralkyl, —C(═O)-heterocycloalkyl, —C(═S)N(H)-alkyl, —C(═S)N(H)-alkenyl, —C(═S)N(H)-alkynyl, —C(═S)N(H)-aryl, —C(═S)N(H)-aralkyl, —C(═S)N(H)-heteroaryl, —C(═S)N(H)-heteroaralkyl, —C(═S)N(H)-heterocyclic, or —C(═S)N(H)-heterocycloalkyl;
• R1 represents a substituted or unsubstituted alkyl or alkenyl;
• R2 and R3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R4 represents hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R5 represents H or lower alkyl;
• n is an integer from 0 to 6 inclusive;
• and
• m is an integer from 0 to 8 inclusive.

A method of kinetic resolution comprising the step of:

• reacting a prochiral β-cyano ketone, prochiral β-keto ester, prochiral β-cyano ester, or prochiral 1,3-diketone with an electron-deficient alkene in the presence of a catalyst;
• thereby producing a chiral, non-racemic β-cyano ketone, chiral, non-racemic β-keto ester, chiral, non-racemic β-cyano ester or chiral, non-racemic 1,3-diketone;
• wherein said catalyst is represented by formula IV:
• wherein, independently for each occurrence:
• R represents a substituted or unsubstituted alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic, heterocycloalkyl, —C(═O)-atkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, —C(═O)-heteroaralkyl, —C(═O)-heterocycloalkyl, —C(═S)N(H)-alkyl, —C(═S)N(H)-alkenyl, —C(═S)N(H)-alkynyl, —C(═S)N(H)-aryl, —C(═S)N(H)-aralkyl, —C(═S)N(H)-heteroaryl, —C(═S)N(H)-heteroaralkyl, —C(═S)N(H)-heterocyclic, or —C(═S)N(H)-heterocycloalkyl;
• R1 represents a substituted or unsubstituted alkyl or alkenyl;
• R2 and R3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R4 represents hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R5 represents H or lower alkyl;
• n is an integer from 0 to 6 inclusive;
• and
• m is an integer from 0 to 8 inclusive.

A compound represented by formula III:

• wherein, independently for each occurrence:
• R represents —C(═O)-aryl, —C(═O)-aralkyl, or —C(═O)-heterocyclic;
• R1 represents a substituted or unsubstituted alkyl or alkenyl;
• R2 and R3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R4 represents hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R5 represents lower alkyl;
• n is an integer from 0 to 6 inclusive;
• and
• m is an integer from 0 to 8 inclusive.

A compound represented by formula IV:

• wherein, independently for each occurrence:
• R represents C(═O)-aryl, —C(═O)-aralkyl, or —C(═O)-heterocyclic;
• R1 represents a substituted or unsubstituted alkyl or alkenyl;
• R2 and R3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R4 represents hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R5 represents lower alkyl;
• n is an integer from 0 to 6 inclusive;
• and
• m is an integer from 0 to 8 inclusive.

A method of preparing a chiral, non-racemic β-cyano ketone, chiral, non-racemic β-keto ester, chiral, non-racemic β-cyano ester or chiral, non-racemic 1,3-diketone, comprising the step of:

• reacting a prochiral β-cyano ketone, prochiral β-keto ester, prochiral β-cyano ester, or prochiral 1,3-diketone with an electron-deficient alkene in the presence of a catalyst;
• thereby producing a chiral, non-racemic β-cyano ketone, chiral, non-racemic β-keto ester, chiral, non-racemic β-cyano ester or chiral, non-racemic 1,3-diketone;
• wherein said catalyst is represented by formula III:
• wherein, independently for each occurrence:
• R represents —C(═O)-aryl, —C(═O)-aralkyl, or —C(═O)-heterocyclic;
• R1 represents a substituted or unsubstituted alkyl or alkenyl;
• R2 and R3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R4 represents hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R5 represents lower alkyl;
• n is an integer from 0 to 6 inclusive;
• and
• m is an integer from 0 to 8 inclusive.

A method of preparing a chiral, non-racemic β-cyano ketone, chiral, non-racemic β-keto ester, chiral, non-racemic β-cyano ester or chiral, non-racemic 1,3-diketone, comprising the step of:

• reacting a prochiral β-cyano ketone, prochiral β-keto ester, prochiral β-cyano ester, or prochiral 1,3-diketone with an electron-deficient alkene in the presence of a catalyst;
• thereby producing a chiral, non-racemic β-cyano ketone, chiral, non-racemic β-keto ester, chiral, non-racemic β-cyano ester or chiral, non-racemic 1,3-diketone;
• wherein said catalyst is represented by formula IV:
• wherein, independently for each occurrence:
• R represents C(═O)-aryl, —C(═O)-aralkyl, or —C(═O)-heterocyclic;
• R1 represents a substituted or unsubstituted alkyl or alkenyl;
• R2 and R3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R4 represents hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R5 represents lower alkyl;
• n is an integer from 0 to 6 inclusive;
• and
• m is an integer from 0 to 8 inclusive.

A method of kinetic resolution comprising the step of:

• reacting a prochiral β-cyano ketone, prochiral β-keto ester, prochiral β-cyano ester, or prochiral 1,3-diketone with an electron-deficient alkene in the presence of a catalyst;
• thereby producing a chiral, non-racemic β-cyano ketone, chiral, non-racemic β-keto ester, chiral, non-racemic β-cyano ester or chiral, non-racemic 1,3-diketone;
• wherein said catalyst is represented by formula III:
• wherein, independently for each occurrence:
• R represents —C(═O)-aryl, —C(═O)-aralkyl, or —C(═O)-heterocyclic;
• R1 represents a substituted or unsubstituted alkyl or alkenyl;
• R2 and R3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R4 represents hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R5 represents lower alkyl;
• n is an integer from 0 to 6 inclusive;
• and
• m is an integer from 0 to 8 inclusive.

A method of kinetic resolution comprising the step of:

• reacting a prochiral β-cyano ketone, prochiral β-keto ester, prochiral β-cyano ester, or prochiral 1,3-diketone with an electron-deficient alkene in the presence of a catalyst;
• thereby producing a chiral, non-racemic β-cyano ketone, chiral, non-racemic β-keto ester, chiral, non-racemic β-cyano ester or chiral, non-racemic 1,3-diketone;
• wherein said catalyst is represented by formula IV:
• wherein, independently for each occurrence:
• R represents C(═O)-aryl, —C(═O)-aralkyl, or —C(═O)-heterocyclic;
• R1 represents a substituted or unsubstituted alkyl or alkenyl;
• R2 and R3 represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R4 represents hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aralkyl, heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine, carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether, ketone, aldehyde, or ester;
• R5 represents lower alkyl;
• n is an integer from 0 to 6 inclusive;
• and
• m is an integer from 0 to 8 inclusive.