Main-group metal-based asymmetric catalysts and applications thereof

A stereoselective nucleophilic addition process which comprises:

• combining a chiral or prochiral π-bond-containing substrate represented by general formula 1 and a nucleophile represented by NuY in the presence of a chiral, non-racemic catalyst to produce a stereoisomerically enriched product 2, wherein said chiral, non-racemic catalyst comprises a chiral tetradentate ligand having at least one Schiff base nitrogen complexed with a main-group metal atom from group 2, 12, 13, or 14;
• maintaining the combination under conditions appropriate for said chiral, non-racemic catalyst to catalyze a stereoselective nucleophilic addition reaction between said chiral or prochiral π-bond-containing substrate and said nucleophile, and said process is represented by:
• wherein
• R, R′, and R″ represent, independently for each occurrence, hydrogen, alkyl, alkenyl, alkynyl, thioacyl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, heteroalkyl, amidine, acetal, ketal, aryl, heteroaryl, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, —C(O)R10, —C(O)OR10, —C(O)SR10, —OC(O)R10, —SC(O)R10, —C(O)N(R11)2, —N(R12)C(O)N(R12)2, —N(R12)C(S)N(R12)2, or —(CH2)m—R80;
• R10 represents independently for each occurrence H, alkyl, alkenyl, or —(CH2)mR80;
• R11 represents independently for each occurrence H, alkyl, alkenyl, —(CH2)m—R80, —C(O)alkyl, —C(O)alkenyl, —C(O)alkynyl, or —C(O)(CH2)m—R80;
• or two instances of R11 are taken together with the N atom to which they are attached to form a heterocycle having from 4 to 8 atoms;
• R12 represents independently for each occurrence H, alkyl, or aralkyl;
• X is selected from the group consisting of C(R)2, O, S, Se, and NR″;
• Y is selected, independently for each occurrence, from the group consisting of H, Li, Na, K, Mg, Ca, B, Al, Cu, Ag, Ti, Zr,Si(R)3, and Sn(R)3;
• and
• Nu is selected from the group consisting of conjugate bases of weak Bronsted acids and carbanions;
• R80 represents independently for each occurrence an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m represents independently for each occurrence an integer in the range 0 to 8 inclusive;
• and
• said chiral, non-racemic catalyst is represented by general formula 100:
• wherein
• Z1, Z2, Z3 and Z4 each represent a Lewis base;
• the C1 moiety, taken with Z1, Z3 and M, and the C2 moiety, taken with Z2, Z4 and M, each, independently, form a heterocycle;
• R1, R2, R′1 and R′2 each, independently, are absent or represent a covalent substitution with an organic or inorganic substituent permitted by valence requirements of the electron donor atom to which it is attached;
• R40 and R41 each independently are absent, or represent on or more covalent substitutions of C1 and C2 with an organic or inorganic substituent permitted by valence requirements of the ring atom to which it is attached;
• or any two or more of R1, R2, R′1, R′2, R40 and R41 taken together form a bridging substituent;
• with the proviso that C1 is substituted at at least one site by R1, R′1 or R41, and C2 is substituted at at least one site by R2, R′2 or R40, and at least one of R1, R′1 and R41 is taken together with at least one of R2, R′2 and R40 to form a bridging substituent so as to provide Z1, Z2, Z3 and Z4 as tetradentate;
• M represents a main-group metal atom from Group 2, 12, 13, or 14;
• A represents a counterion or a nucleophile;
• and
• wherein each of R1, R2, R′1, R′2, R40, and R41 are selected to provide at least one stereogenic center in said tetradentate ligand.

A method for catalyzing a stereoselective nucleophilic addition reaction which comprises:

• combining a chiral or prochiral π-bond-containing substrate represented by formula 1 and a nucleophile represented by NuY in the presence of a chiral, non-racemic catalyst to produce a stereoisomerically enriched product 2, wherein said chiral catalyst comprises a chiral tetradentate ligand complexed with a main-group metal atom from Group 2, 12, 13, or 14;
• and
• maintaining the combination under conditions appropriate for said chiral, non-racemic catalyst to catalyze a stereoselective nucleophilic addition reaction between said π-bond-containing substrate and said nucleophile, and said process is represented by:
• wherein
• R, R′, and R″ represent, independently for each occurrence, hydrogen, alkyl, alkenyl, alkynyl, thioacyl, alkylthio, imine, phosphoryl, phosphonate, phosphine, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, heteroalkyl, amidine, acetal, ketal, aryl, heteroaryl, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, —C(O)R10, —C(O)OR10, —C(O)SR10, —OC(O)R10, —SC(O)R10, —C(O)N(R11)2, —N(R12)C(O)N(R12)2, —N(R12)C(S)N(R12)2, or —(CH2)m—R80;
• R10 represents independently for each occurrence H, alkyl, alkenyl, or —(CH2)mR80;
• R11 represents independently for each occurrence H, alkyl, alkenyl, —(CH2)m—R80, —C(O)alkyl, —C(O)alkenyl, —C(O)alkynyl, or —C(O)(CH2)m—R80;
• or two instances of R11 are taken together with the N atom to which they are attached to form a heterocycle having from 4 to 8 atoms;
• R12 represents independently for each occurrence H, alkyl, or aralkyl;
• X is selected from the group consisting of C(R)2, O, S, Se, and NR″;
• Y is selected, independently for each occurrence, from the group consisting of H, Li, Na, K, Ma, Ca, B, Al, Cu, Ag, Ti, Zr, Si(R)3 and Sn(R)3;
• Nu is selected from the group consisting of conjugate bases of weak Bronsted acids and carbanions;
• R80 represents independently for each occurrence an unsubstituted or substituted aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• m represents independently for each occurrence an integer in the range 0 to 8 inclusive;
• and
• said chiral, non-racemic catalyst is represented by general formula 100:
• wherein
• Z1, Z2, Z3 and Z4 each represent a Lewis base;
• the C1 moiety, take with Z1, Z3 and M, and the C2 moiety, taken with Z2, Z4 and M, each, independently, form a heterocycle;
• R1, R2, R′1 and R′2 each, independently, are absent or represent a covalent substitution with an organic or inorganic substituent permitted by valence requirements of the electron donor atom to which it is attached;
• R40 and R41 each independently are absent, or represent on or more covalent substitutions of C1 and C2 with an organic or inorganic substituent permitted by valence requirements of the ring atom to which it is attached;
• or any two or more of R1, R2, R′1, R′2 R40 and R41 taken together form a bridging substituent;
• with the proviso that C1 is substituted at at least one site by R1, R′1 or R41 and C2 is substituted at at least one site by R2, R′2 or R40, and at least one of R1, R′1 and R41 is taken together with at least one of R2, R′2 and R40 to form a bridging substituent so as to provide Z1, Z2, Z3 and Z4 as tetradentate;
• M represents a main-group metal atom from Group 2, 12, 13, or 14;
• A represents a counterion or a nucleophile;
• and
• each of R1, R2, R′1, R′2, R40 and R41 are selected to provide at least one stereogenic center in said tetradentate ligand.

A method for synthesis of stereoisomerically enriched chiral compounds, comprising reacting a prochiral or chiral π-bond-containing substrate with a nucleophile in the presence of a chiral, non-racemic catalyst, and under conditions wherein said chiral catalyst catalyzes a stereoselective nucleophile addition reaction between said π-bond-containing substrate and said nucleophile, to produce a product which is stereoisomerically-enriched relative to a racemic mixture produced—in the case of a prochiral π-bond-containing substrate—or to the 1:1 ratio of diastereoisomers produced—in cases wherein the π-bond-containing substrate is chiral—in the absence of said chiral catalyst;

• wherein the π-bond-containing substrate is represented by the general formula 1, the nucleophile is represented by NuY, and the product of the subject process is represented by 2:
• wherein
• R, R′, and R″ represent, independently for each occurrence, hydrogen, alkyl, alkenyl, alkynyl, thioacyl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, heteroalkyl, amidine, acetal, ketal, aryl, heteroaryl, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, —C(O)R10, —C(O)OR10, —C(O)SR10, —OC(O)R10, —SC(O)R10, —C(O)N(R11)2, —N(R12)C(O)N(R12)2, —N(R12)C(S)N(R12)2, or —(CH2)m—R80;
• R10 represents independently for each occurrence H, alkyl, alkenyl, or —(CH2)mR80;
• R11 represents independently for each occurrence H, alkyl, alkenyl, —(CH2)m—R80, —C(O)alkyl, —C(O)alkenyl, —C(O)alkynyl, or —C(O)(CH2)m—R80;
• or two instances of R11 are taken together with the N atom to which they are attached to form a heterocycle having from 4 to 8 atoms;
• R12 represents independently for each occurrence H, alkyl, or aralkyl;
• X is selected from the group consisting of C(R)2, O, S, Se and NR″;
• Y is selected, independently for each occurrence, from the group consisting of H, Li, Na, K, Mg, Ca, B, Al, Cu, Ag, Ti, Zr, Si(R)3, and Sn(R)3;
• Nu is selected from the group consisting of conjugate bases of weak Bronsted acids and carbanions;
• R80 represents independently for each occurrence an unsubstituted or substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle;
• and
• m represents independently for each occurrence an integer in the range 0 to 8 inclusive;
• and
• the chiral catalyst is represented by the general formula:
• wherein
• the substituents R1, R2, Y1, Y2, X1, X2, X3 and X4 each, independently, represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, phosphoryl, phosphonate, phosphine, silyl, ether, thioether, sulfonyl, selenoether, ester, —C(O)R10, —C(O)OR10, —C(O)SR10, —OC(O)R10, —SC(O)R10, —C(O)N(R11)2, or —(CH2)m—R7;
• or any two or more of the substituents taken together form a carbocyle or heterocycle ring having from 4 to 8 atoms in the ring structure, with the proviso that at least one of R1, Y1, X1 and X2 is covalently bonded to at least one of R2, Y2, X3 and X4 to provide the β-iminocarbonyls to which they are attached as a tetradentate ligand, and at least one of Y1 and Y2 is a hydrogen;
• R7 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle;
• R10 represents independently for each occurrence H, alkyl, alkenyl, or —(CH2)mR80;
• R11 represents independently for each occurrence H, alkyl, alkenyl, —(CH2)m—R80, —C(O)alkyl, —C(O)alkenyl, —C(O)alkynyl, or —C(O)(CH2)m—R80;
• or two instances of R11 are taken together with the N atom to which they are attached to form a heterocycle having from 4 to 8 atoms;
• m represents independently for each occurrence zero or an integer in the range of 1 to 8;
• M represents the main-group metal atom from Group 2, 12, 13, or 14;
• A represents a counterion or a nucleophile;
• and
• wherein each of R1, R2, Y1, Y2, X1, X2, X3 and X4, are selected such that the catalyst is asymmetric.

A method of realizing a stereoselective addition of a nucleophile to a prochiral or chiral π-bond-containing substrate, wherein the π-bond-containing substrate is represented by the general formula 1, and the nucleophile is represented by NuY, to give a product represented by 2:

• wherein
• R, R′, and R″ represent, independently for each occurrence, hydrogen, alkyl, alkenyl, alkynyl, acyl, thioacyl, alkylthio, imine, phosphoryl, phosphonate, phosphine, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, heteroalkyl, amidine, acetal, ketal, aryl, heteroaryl, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, —C(O)R10, —C(O)OR10, —C(O)SR10, —OC(O)R10, —SC(O)R10, —C(O)N(R11)2, —N(R12)C(O)N(R12)2, —N(R12)C(S)N(R12)2, or —(CH2)m—R80;
• R10 represents independently for each occurrence H, alkyl, alkenyl, or —(CH2)mR80;
• R11 represents independently for each occurrence H, alkyl, alkenyl, —(CH2)m—R80, C(O)alkyl, —C(O)alkenyl, —C(O)alkynyl, or —C(O)(CH2)m—R80;
• or two instances of R11 are taken together with the N atom to which they are attached to form a heterocycle having from 4 to 8 atoms;
• R12 represents independently for each occurrence H, alkyl, or aralkyl;
• X is selected from the group consisting of C(R)2, O, S, Se and NR″;
• Y is selected, independently for each occurrence, from the group consisting of H, Li, Na, K, Mg, Ca, B, Al, Cu, Ag, Ti, Zr, Si(R)3 and Sn(R)3;
• and
• Nu is selected from the group consisting of conjugate bases of weak Bronsted acids and carbanions;
• R80 represents independently for each occurrence an unsubstituted or substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle;
• m represents independently for each occurrence an integer in the range 0 to 8 inclusive;
• and
• which method comprises reacting said π-bond-containing substrate with said nucleophile in the presence of at least a catalytic amount of a chiral tetradentate metallosalenate catalyst represented by the general formula 106:
• wherein
• each of the substituents R1, R2, R3, R4, R5, Y1, Y2, X1, X2, X3, X4, X5, X6, X7, and X8, independently, represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, thiol, amine, imine, phosphoryl, phosphonate, phosphine, silyl, ether, thioether, sulfonyl, selenoether, —C(O)R10, —C(O)OR10, —C(O)SR10, —OC(O)R10, —SC(O)R10, —C(O)N(R11)2, or —(CH2)m—R7;
• R5 is hydrogen, alkyl, alkenyl, alkynyl, alkoxyl, silyloxy, amino, thiol, amine, imine, amide, phosphoryl, phosphonate, phosphine, silyl, ether thioether, sulfonyl, selenoether, —C(O)—, —C(O)O—, —C(O)S—, —OC(O)—, or —SC(O)—;
• or any two or more of the substituents taken together form a carbocycle or heterocycle having from 4 to 10 atoms in the ring structure;
• R7 represents independently for each occurrence aryl, cycloalkyl, cycloalkenyl, heterocycle, or polycycle;
• R10 represents independently for each occurrence H, alkyl, alkenyl, or —(CH2)mR7;
• R11 represents independently for each occurrence H, alkyl, alkenyl, —(CH2)m—R80, —C(O)alkyl, —C(O)alkenyl, —C(O)alkynyl, or —C(O)(CH2)m—R80, or two instances of R11 are taken together with the N atom to which they are attached to form a heterocycle having from 4 to 8 atoms;
• m represents independently for each occurrence zero or an integer in the range of 1 to 8;
• M represents a main-group metal atom from Groups 2, 12, 13, or 14;
• A represents a counterion or a nucleophile;
• and
• if R5 is absent, at least one of R1 and R2 is taken together with at least one of R3 and R4 to form a bridging substituent, and each of the substituents of 106 are selected such that the salenate is asymmetric.

A method of resolving enantiomers from a racemic mixture of a chiral π-bond-containing substrate, or a racemic mixture of a chiral nucleophile having general formulas 1 and NuY, respectively:

• wherein
• R, R′,and R″ represent, independently for each occurrence, hydrogen, alkyl, alkenyl, alkynyl, thioacyl, alkylthio, imine, phosphoryl, phosphonate, phosphine, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, heteroalkyl, amidine, acetal, ketal, aryl, heteroaryl, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, —C(O)R10, —C(O)OR10, —C(O)SR10, —OC(O)R10, —SC(O)R10, —C(O)N(R11)2, —N(R12)C(O)N(R12)2, —N(R12)C(S)N(R12)2, or —(CH2)m—R80;
• R10 represents independently for each occurrence H, alkyl, alkenyl, or —(CH2)mR80;
• R11 represents independently for each occurrence H, alkyl, alkenyl, —(CH2)m—R80, —C(O)alkyl, —C(O)alkenyl, —C(O)alkynyl, or —C(O)(CH2)m—R80;
• or two instances of R11 are taken together with the N atom to which they are attached to form a heterocycle having from 4 to 8 atoms;
• R12 represents independently for each occurrence H, alkyl, or aralkyl;
• X is selected from the group consisting of C(R)2, O, S, Se and NR″;
• Y is selected, independently for each occurrence, from the group consisting of H, Li, Na, K, Mg, Ca, B, Al, Cu, Ag, Ti, Zr, Si(R)3, and Sn(R)3;
• and
• Nu is selected from the group consisting of conjugate bases of weak Bronsted acids and carbanions;
• R80 represents independently for each occurrence an unsubstituted or substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle;
• and
• m represents independently for each occurrence an integer in the range 0 to 8 inclusive;
• the method comprising contacting said racemic mixture of the π-bond-containing substrate (1) or racemic mixture of the nucleophile with an achiral nucleophile or π-bond-containing substrate, respectively, able to react with the racemic substrate in the presence of a chiral catalyst having the form:
• in which
• Z1, Z2, Z3 and 4 each represent a Lewis base;
• the C1 moiety, taken with Z1, Z3 and M, and the C2 moiety, taken with Z2, Z4 and M, each, independently, form a heterocycle;
• R1, R2, R′1 and R′2 each, independently, are absent or represent a covalent substitution with an organic or inorganic substituent permitted by valence requirements of the electron donor atom to which it is attached,
• R40 and R41 each independently are absent, or represent one or more covalent substitutions of C1 and C2 with an organic or inorganic substituent permitted by valence requirements of the ring atom to which it is attached,
• or any two or more of the R1, R2, R′1, R′2 R40 and R41 taken together form a bridging substituent;
• with the proviso that C1is substituted at at least one site by R1, R′1 or R41, and C2 is substituted at at least one site by R2, R′2 or R40, and
• at least one of R1, R′1 and R41 is taken together with at least one of R2, R′2 and R40 to form a bridging substituent so as to provide Z1, Z2, Z3 and Z4 as a tetradentate;
• M represents a main-group metal atom from Group 2, 12, 13, or 14;
• A represents a counterion or a nucleophile;
• and
• wherein each R1, R2, R′1, R′2, R40 and R41 are selected to provide at least one stereogenic center in said tetradentate ligand, under conditions wherein one enantiomer of the racemic π-bond-containing substrate or racemic nucleophile reacts with an achiral nucleophile or π-bond-containing substrate, respectively, in a nucleophilic addition leaving the other enantiomer of the racemic substrate substantially unchanged.

A method of providing a chiral, non-racemic α-amino nitrile, comprising reacting a prochiral or chiral imine with hydrogen cyanide, or a surrogate thereof, in the presence of a chiral, non-racemic catalyst such that a chiral, non-racemic α-amino nitrile is formed, wherein the chiral, non-racemic catalyst comprises an asymmetric tetradentate ligand complexed with a main-group metal atom from group 2, 12, 13, or 14;

• said complex having rectangular planar or rectangular pyramidal geometry, and said chiral, non-racemic catalyst is represented by general formula 100:
• wherein
• Z1, Z2, Z3 and Z4 each represent a Lewis base;
• the C1 moiety, taken with Z1, Z3 and M, and the C2 moiety taken with Z2, Z4 and M, each, independently, form a heterocycle;
• R1, R2, R′1 and R′2 each, independently, are absent or represent a covalent substitution with an organic or inorganic substituent permitted by valence requirements of the electron donor atom to which it is attached;
• R40 and R41 each independently are absent, or represent one or more covalent substitutions of C1 and C2 with an organic or inorganic substituent permitted by valence requirements of the ring atom to which it is attached;
• or any two or more of R1, R2, R′1, R′2, R40 and R41 taken together form a bridging substituent;
• with the proviso that C1 is substituted at at least one site by R1, R′1, or R41, and C2 is substituted at at least one site by R2, R′2 or R40, and at least one of R1, R′1 and R41 is taken together with at least one of R2, R′2and R40 to form a bridging substituent so as to provide Z1, Z2, Z3 and Z4 as tetradentate;
• M represents a main-group metal atom from Group 2, 12, 13, or 14;
• A represents a counterion or a nucleophile;
• and
• each of R1, R2, R′1, R′2, R40, and R41 are selected to provide at least one stereogenic center in said tetradentate ligand.