Asymmetric synthesis of organic compounds

1. 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 1,4-conjugate addition reaction and which has a carbon atom at said 4-position, wherein the hydrometallated first compound and the second compound are contacted under conditions such that they undergo an asymmetric 1,4-conjugate addition reaction in which a carbon atom of said hydrometallated first compound binds to the carbon atom at said 4-position of the second compound, forming a stereoisomeric excess of a compound having a chiral carbon atom at said 4-position, wherein said asymmetric conjugate addition reaction is performed in the presence of a metal catalyst comprising a non-racemic chiral ligand;

wherein:

the hydrometallating agent is HZrCp 2 Cl;

the second compound is an α,β-unsaturated carbonyl compound;

the metal catalyst comprises copper (I); and

the non-racemic chiral ligand is a phosphoramidite ligand.

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

wherein

R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, R a , hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R a ; and —(CH 2 ) j -heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R a ;

or R 1 and R 3 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 R a ;

R 5 , R 6 and R 7 are each independently selected from hydrogen, R a , hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R a ; and —(CH 2 ) j -heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R a ;

or R 5 and one of R 7 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 R a ;

X and Y taken together form —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —C(O)SR 8 or —C(O)SeR 8 , wherein R 8 and R 9 are each independently hydrogen or selected from hydrocarbyl and —(CH 2 ) 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 R 5 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 R a ;

each R a is independently selected from halogen, trifluoromethyl, cyano, nitro, oxo, ═NR b , —OR b , —C(O)R b , —C(O)N(R b )R c , —C(O)OR b , —C(O)SR b , —C(O)SeR b , —OC(O)R b , —S(O) k R b , —S(O) k N(R b )R c , —N(R b )R c , —N(R b )N(R b )R c , —N(R b )C(O)R c and —N(R b )S(O) k R b ;

R b and R c are each independently hydrogen or selected from hydrocarbyl and —(CH 2 ) 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 HZrCp 2 Cl, 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 ZrCp 2 Cl; 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.

3. A process according to claim 2 , wherein said compound comprising an alkene bond is a compound of the formula (I):

4. A process according to claim 2 , wherein R 1 is hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R a .

5. A process according to claim 2 , wherein R 3 is hydrogen or hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R a .

6. A process according to claim 2 , wherein R 1 and R 3 taken together with the carbon atoms to which they are attached form, in the compounds of formulae (II) and (IV), cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 R a .

7. A process according to claim 2 , wherein R 2 and R 4 are each hydrogen.

8. A process according to claim 2 , wherein the chiral compound is produced in an enantiomeric excess or a diastereomeric excess.

9. A process according to claim 2 , wherein the process further comprises formulating a product comprising the chiral compound or converting the chiral compound into a product.

10. 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 HZrCp 2 Cl;

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.

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

wherein

R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, R a , hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R a ; and —(CH 2 ) j -heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R a ;

or R 1 and R 3 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 R a ;

R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from hydrogen, R a , hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R a ; and —(CH 2 ) j -heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R a ;

or two or more of R 10 , R 11 , R 12 , R 13 , R 14 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 R a ;

X and Y taken together form —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —C(O)SR 8 or —C(O)SeR 8 , wherein R 8 and R 9 are each independently hydrogen or selected from hydrocarbyl and —(CH 2 ) 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 R 10 , R 11 , R 12 , R 13 and R 14 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 R a ;

each R a is independently selected from halogen, trifluoromethyl, cyano, nitro, oxo, ═NR b , —OR b , —C(O)R b , —C(O)N(R b )R c , —C(O)OR b , —C(O)SR b , —C(O)SeR b , —OC(O)R b , —S(O) k R b , —S(O) k N(R b )R c , —N(R b )R c , —N(R b )N(R b )R c , —N(R b )C(O)R c and —N(R b )S(O) k R b ;

R b and R c are each independently hydrogen or selected from hydrocarbyl and —(CH 2 ) 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 HZrCp 2 Cl, 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 ZrCp 2 Cl; 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.

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

wherein

R 1 , R 2 , R 3 and R 4 are each independently selected from hydrogen, R a , hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R a ; and —(CH 2 ) j -heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R a ;

or R 1 and R 3 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 R a ;

R 5 , R 6 and R 7 are each independently selected from hydrogen, R a , hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R a ; and —(CH 2 ) j -heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R a ;

or R 5 and one of R 7 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 R a ;

R 15 and R 16 are each independently selected from hydrogen, R a , hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R a ; and —(CH 2 ) j -heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R a ;

X and Y taken together form —C(O)R 8 , —C(O)OR 8 , —C(O)NR 8 R 9 , —C(O)SR 8 or —C(O)SeR 8 , wherein R 8 and R 9 are each independently hydrogen or selected from hydrocarbyl and —(CH 2 ) 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 R 5 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 R a ;

each R a is independently selected from halogen, trifluoromethyl, cyano, nitro, oxo, ═NR b , —OR b , —C(O)R b , —C(O)N(R b )R c , —C(O)OR b , —C(O)SR b , —C(O)SeR b , —OC(O)R b , —S(O) k R b , —S(O) k N(R b )R c , —N(R b )R c , —N(R b )N(R b )R c , —N(R b )C(O)R c and —N(R b )S(O) k R b ;

R b and R c are each independently hydrogen or selected from hydrocarbyl and —(CH 2 ) 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 HZrCp 2 Cl, 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 ZrCp 2 Cl; 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.