Asymmetric synthesis of organic compounds

A process for producing a chiral compound of the formula (IV) in a stereoisomeric excess:

• wherein
• R1, R2, R3 and R4 are each independently selected from hydrogen, Ra, hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 Ra;
• and —(CH2)j-heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 Ra;
• or R1 and R3 taken together with the carbon atoms to which they are attached may form a carbocyclic or heterocyclic group, which group is optionally substituted with 1, 2, 3, 4 or 5 Ra;
• R5, R6 and R7 are each independently selected from hydrogen, Ra, hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 Ra;
• and —(CH2)j-heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 Ra;
• or R5 and one of R7 and X, taken together with the carbon atoms to which they are attached, may form a carbocyclic or heterocyclic group, which group is optionally substituted with 1, 2, 3, 4 or 5 Ra;
• X and Y taken together form —C(O)R8, —C(O)OR8, —C(O)NR8R9, —C(O)SR8 or —C(O)SeR8, wherein R8 and R9 are each independently hydrogen or selected from hydrocarbyl and —(CH2)j-heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, oxo, cyano, amino, hydroxy, alkyl and alkoxy;
• or
• X is carbon and Y is oxo;
• and X and R5 taken together with the carbon atoms to which they are attached form a carbocyclic group or a heterocyclic group, either of which is optionally substituted with 1, 2, 3, 4 or 5 Ra;
• each Ra is independently selected from halogen, trifluoromethyl, cyano, nitro, oxo, ═NRb, —ORb, —C(O)Rb, —C(O)N(Rb)Rc, —C(O)ORb, —C(O)SRb, —C(O)SeRb, —OC(O)Rb, —S(O)kRb, —S(O)kN(Rb)Rc, —N(Rb)Rc, —N(Rb)N(Rb)Rc, —N(Rb)C(O)Rc and —N(Rb)S(O)kRb;
• Rb and Rc are each independently hydrogen or selected from hydrocarbyl and —(CH2)j-heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, oxo, cyano, amino, hydroxy, alkyl and alkoxy;
• j is 0, 1, 2, 3, 4, 5 or 6;
• k is 0, 1 or 2;
• and
• the asterisk * designates a chiral center of (R) or (S) configuration;
• wherein the process comprises:
• (i) contacting a compound comprising an alkene bond with a hydrometallating agent of the formula HZrCp2Cl, wherein M comprises a metal, wherein said compound and the hydrometallating agent are contacted under conditions such that they react to form a compound of the formula (II):
• wherein M is ZrCp2Cl;
• and
• (ii) contacting the compound of the formula (II) with a compound of the formula (III):
• wherein the compound of formula (II) and the compound of formula (III) are contacted under conditions such that they undergo an asymmetric 1,4-conjugate addition reaction to form a stereoisomeric excess of a compound of formula (IV), wherein said asymmetric conjugate addition reaction is performed in the presence of a metal catalyst comprising a non-racemic chiral ligand, wherein the metal catalyst comprises copper (I) and the non-racemic chiral ligand is a phosphoramidite ligand.

A process for producing a chiral compound in a stereoisomeric excess, the process comprising:

• (i) contacting a first compound comprising an alkene bond with a hydrometallating agent, wherein the first compound and the hydrometallating agent are contacted under conditions such that the first compound is hydrometallated by said hydrometallating agent;
• and
• (ii) contacting the hydrometallated first compound with a second compound, wherein the second compound comprises a conjugated π-bond system which is capable of undergoing a 1,6-conjugate addition reaction and which has a carbon atom at said 6-position, wherein the hydrometallated first compound and the second compound are contacted under conditions such that they undergo an asymmetric 1,6-conjugate addition reaction in which a carbon atom of said hydrometallated first compound binds to the carbon atom at said 6-position of the second compound, forming a stereoisomeric excess of a compound having a chiral carbon atom at said 6-position, wherein said asymmetric conjugate addition reaction is performed in the presence of a metal catalyst, said metal catalyst optionally comprising a non-racemic chiral ligand;
• wherein:
• the hydrometallating agent is HZrCp2Cl;
• the second compound is an unsaturated carbonyl compound comprising at least two alkene bonds that are conjugated with a carbonyl group;
• the metal catalyst comprises copper (I);
• and
• the non-racemic chiral ligand is a phosphoramidite ligand.

A process for producing a chiral compound of the formula (VI) in a stereoisomeric excess:

• wherein
• R1, R2, R3 and R4 are each independently selected from hydrogen, Ra, hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 Ra;
• and —(CH2)j-heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 Ra;
• or R1 and R3 taken together with the carbon atoms to which they are attached may form a carbocyclic or heterocyclic group, which group is optionally substituted with 1, 2, 3, 4 or 5 Ra;
• R10, R11, R12, R13 and R14 are each independently selected from hydrogen, Ra, hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 Ra;
• and —(CH2)j-heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 Ra;
• or two or more of R10, R11, R12, R13, R14 and X taken together with the carbon atoms to which they are attached, may form a carbocyclic or heterocyclic group, which group is optionally substituted with 1, 2, 3, 4 or 5 Ra;
• X and Y taken together form —C(O)R8, —C(O)OR8, —C(O)NR8R9, —C(O)SR8 or —C(O)SeR8, wherein R8 and R9 are each independently hydrogen or selected from hydrocarbyl and —(CH2)j-heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, oxo, cyano, amino, hydroxy, alkyl and alkoxy;
• or
• X is carbon and Y is oxo;
• and X and one or more of R10, R11, R12, R13 and R14 taken together with the carbon atoms to which they are attached form a carbocyclic group or a heterocyclic group, either of which is optionally substituted with 1, 2, 3, 4 or 5 Ra;
• each Ra is independently selected from halogen, trifluoromethyl, cyano, nitro, oxo, ═NRb, —ORb, —C(O)Rb, —C(O)N(Rb)Rc, —C(O)ORb, —C(O)SRb, —C(O)SeRb, —OC(O)Rb, —S(O)kRb, —S(O)kN(Rb)Rc, —N(Rb)Rc, —N(Rb)N(Rb)Rc, —N(Rb)C(O)Rc and —N(Rb)S(O)kRb;
• Rb and Rc are each independently hydrogen or selected from hydrocarbyl and —(CH2)j-heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, oxo, cyano, amino, hydroxy, alkyl and alkoxy;
• j is 0, 1, 2, 3, 4, 5 or 6;
• k is 0, 1 or 2;
• and
• the asterisk * designates a chiral center of (R) or (S) configuration;
• wherein the process comprises:
• (i) contacting a compound comprising an alkene bond with a hydrometallating agent of the formula HZrCp2Cl, wherein M comprises a metal, wherein said compound and the hydrometallating agent are contacted under conditions such that they react to form a compound of the formula (II):
• wherein M is ZrCp2Cl;
• and
• (ii) contacting the compound of the formula (II) with a compound of the formula (V):
• wherein the compound of formula (II) and the compound of formula (V) are contacted under conditions such that they undergo an asymmetric 1,6-conjugate addition reaction to form a stereoisomeric excess of a compound of formula (VI), wherein said asymmetric conjugate addition reaction is performed in the presence of a metal catalyst, said metal catalyst optionally comprising a non-racemic chiral ligand, wherein the metal catalyst comprises copper (I) and the non-racemic chiral ligand is a phosphoramidite ligand.

A process for producing a chiral compound of the formula (IVa) in a stereoisomeric excess:

• wherein
• R1, R2, R3 and R4 are each independently selected from hydrogen, Ra, hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 Ra;
• and —(CH2)j-heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 Ra;
• or R1 and R3 taken together with the carbon atoms to which they are attached may form a carbocyclic or heterocyclic group, which group is optionally substituted with 1, 2, 3, 4 or 5 Ra;
• R5, R6 and R7 are each independently selected from hydrogen, Ra, hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 Ra;
• and —(CH2)j-heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 Ra;
• or R5 and one of R7 and X, taken together with the carbon atoms to which they are attached, may form a carbocyclic or heterocyclic group, which group is optionally substituted with 1, 2, 3, 4 or 5 Ra;
• R15 and R16 are each independently selected from hydrogen, Ra, hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 Ra;
• and —(CH2)j-heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 Ra;
• X and Y taken together form —C(O)R8, —C(O)OR8, —C(O)NR8R9, —C(O)SR8 or —C(O)SeR8, wherein R8 and R9 are each independently hydrogen or selected from hydrocarbyl and —(CH2)j-heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, oxo, cyano, amino, hydroxy, alkyl and alkoxy;
• or
• X is carbon and Y is oxo;
• and X and R5 taken together with the carbon atoms to which they are attached form a carbocyclic group or a heterocyclic group, either of which is optionally substituted with 1, 2, 3, 4 or 5 Ra;
• each Ra is independently selected from halogen, trifluoromethyl, cyano, nitro, oxo, ═NRb, —ORb, —C(O)Rb, —C(O)N(Rb)Rc, —C(O)ORb, —C(O)SRb, —C(O)SeRb, —OC(O)Rb, —S(O)kRb, —S(O)kN(Rb)Rc, —N(Rb)Rc, —N(Rb)N(Rb)Rc, —N(Rb)C(O)Rc and —N(Rb)S(O)kRb;
• Rb and Rc are each independently hydrogen or selected from hydrocarbyl and —(CH2)j-heterocyclyl, either of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, oxo, cyano, amino, hydroxy, alkyl and alkoxy;
• j is 0, 1, 2, 3, 4, 5 or 6;
• k is 0, 1 or 2;
• and
• the asterisk * designates a chiral center of (R) or (S) configuration;
• wherein the process comprises:
• (i) contacting a compound comprising an alkene bond with a hydrometallating agent of the formula HZrCp2Cl, wherein M comprises a metal, wherein said compound and the hydrometallating agent are contacted under conditions such that they react to form a compound of the formula (II):
• wherein M is ZrCp2Cl;
• and
• (ii) contacting the compound of the formula (II) with a compound of the formula (III):
• and a compound of the formula (VII):
• wherein the compound of formula (II), the compound of formula (III) and the compound of formula (VII) are contacted under conditions such that they undergo an asymmetric 1,4-conjugate addition reaction to form a stereoisomeric excess of a compound of formula (IVa), wherein said asymmetric conjugate addition reaction is performed in the presence of a metal catalyst comprising a non-racemic chiral ligand, wherein the metal catalyst comprises copper (I) and the non-racemic chiral ligand is a phosphoramidite ligand.