Methods for enantioselective allylic alkylation of esters, lactones, and lactams with unactivated allylic alcohols

Patent metadata

Field	Value
Publication number	US-10358422-B2
Application number	US-201816177926-A
Country	US
Kind code	B2
Filing date	Nov 1, 2018
Priority date	Nov 1, 2017
Publication date	Jul 23, 2019
Grant date	Jul 23, 2019

Abstract

The present disclosure provides methods for enantioselective synthesis of cyclic and acyclic α-quaternary carboxylic acid derivatives via nickel-catalyzed allylic alkylation.

First claim

We claim:

1. A method of synthesizing a pharmaceutical agent comprising preparing a compound of Formula (IX):

comprising:
treating a compound of Formula (I)

with a compound of Formula (II) that is Formula (IIa) or Formula (IIb)

in an organic solvent
in the presence of a complex formed by contacting a Ni(0) source with a ligand L;
wherein:
X is O or N-PG;
PG is a protecting group selected from benzyl, tosyl, benzoyl, Boc, methyl, and phenyl;
R 1 is methyl or ethyl;
R 2 is H, methyl, aralkenyl, aryl, or hetaryl;
R 8 and R 9 are each H, or R 8 and R 9 , taken together with the carbon atoms to which they are attached, form an aryl or heteroaryl ring;
is a single bond when R 8 and R 9 are each H, and
when R 8 and R 9 , taken together with the carbon atoms to which they are attached, form an aryl or heteroaryl ring;

L is selected from (R)-BINAP, (R)-H 8 -BINAP, (R)-Segphos, and (R)-P-phos;
the Ni(0) source is Ni(COD) 2 ; and
the organic solvent is toluene, diethyl ether, methyl t-butyl ether (MTBE), tetrahydrofuran (THF), or dioxane, or a mixture thereof.

2. The method of claim 1 , wherein:
X is O;
R 1 is ethyl;
R 2 is H;
the organic solvent is toluene, diethyl ether, MTBE, THF, or dioxane; and
the reaction temperature is 0° C., −10° C., or 23° C.

3. The method of claim 2 , wherein R 8 and R 9 are each H and the organic solvent is diethyl ether.

4. The method of claim 3 , wherein 10 mol % Ni(COD) 2 and 12 mol % of ligand are used.

5. The method of claim 3 , wherein the reaction temperature is 0° C., the ligand is (R) -P-phos, and 5 mol % Ni(COD) 2 and 6 mol % of ligand are used.

6. The method of claim 2 , wherein:
R 8 and R 9 are each H;
10 mol % Ni(COD) 2 and 12 mol % of ligand are used;
the reaction temperature is 23° C.; and
the organic solvent is toluene, MTBE, THF, or dioxane.

7. The method of claim 1 , wherein:
X is O;
the compound of Formula (II) is a compound of Formula (IIb);
10 mol % of Ni(COD) 2 and 12 mol % of L are used;
L is (R)-P-phos; and
the organic solvent is diethyl ether.

8. The method of claim 7 , wherein
R 2 is H;
R 8 and R 9 are each H; and
the reaction temperature is −10° C.

9. The method of claim 7 , wherein
R 1 is ethyl;
R 2 is H;
R 8 and R 9 combine to form a phenyl ring including the carbon atoms to which R 8 and R 9 are attached; and
the reaction temperature is −10° C.

10. The method of claim 7 , wherein
R 1 is ethyl;
R 2 is Ph, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 3,5-dimethylphenyl, 2-naphthyl, 2-methoxyphenyl, 2-furyl, 2 -thienyl, methyl, or styryl;
R 8 and R 9 are each H; and
the reaction temperature is 10° C.

11. The method of claim 1 , wherein X is N-PG, PG is benzoyl, R 1 is ethyl, R 2 is H, R 8 and R 9 are each H, and:
i. 10 mol % Ni(COD) 2 and 12 mol % L are used, the organic solvent is 2:3 toluene:MTBE, reaction temperature is 10° C., and L is (R)-H 8 -BINAP; or
ii. 10 mol % Ni(COD) 2 and 12 mol % L are used, the organic solvent is 2:3 toluene:MTBE, reaction temperature is 10° C., and L is (R)-Segphos; or
iii. 10 mol % Ni(COD) 2 and 12 mol % L are used, the organic solvent is 2:3 toluene:MTBE, reaction temperature is 10° C., and L is (R)-P-phos; or
iv. 5 mol % Ni(COD) 2 and 6 mol % L are used, the organic solvent is 2:3 toluene:MTBE, reaction temperature is 10° C., and L is (R)-P-phos; or
v. 10 mol % Ni(COD) 2 and 12 mol % L are used, the organic solvent is 2:3 toluene:diethyl ether, reaction temperature is 10° C., and L is (R)-P-phos; or
vi. 10 mol % Ni(COD) 2 and 12 mol % L are used, the organic solvent is toluene, reaction temperature is 10° C., and L is (R)-P-phos; or
vii. 10 mol % Ni(COD) 2 and 12 mol % L are used, the organic solvent is THF, reaction temperature is 10° C., and L is (R)-P-phos; or
viii. 10 mol % Ni(COD) 2 and 12 mol % L are used, the organic solvent is 2:3 toluene:MTBE, reaction temperature is 23° C., and L is (R)-P-phos.

12. The method of claim 1 , wherein X is N-PG, PG is benzoyl, R 8 and R 9 are each H, L is (R)-P-phos, 10 mol % Ni(COD) 2 and 12 mol % L are used, the compound of Formula (II) is a compound of Formula (IIa), the organic solvent is 2:3 toluene:MTBE, and:
i. reaction temperature is 10° C., R 1 is methyl, and R 2 is H; or
ii. reaction temperature is 30° C., R 1 is ethyl, and R 2 is phenyl.

13. The method of claim 1 , wherein:
X is N-PG;
PG is benzoyl;
R 1 is ethyl;
R 2 is phenyl;
R 8 and R 9 are each H;
L is (R)-P-phos;
10 mol % of Ni(COD) 2 and 12 mol % of L are used;
the organic solvent is 2:3 toluene:MTBE; and:
i. the compound of Formula (II) is a compound of Formula (IIa) and reaction temperature is 10° C.; or
ii. the compound of Formula (II) is a compound of Formula (IIb) and reaction temperature is 10° C.; or
iii. the compound of Formula (II) is a compound of Formula (IIa) and reaction temperature is 30° C.; or
iv. the compound of Formula (II) is a compound of Formula (IIb) and reaction temperature is 30° C.

Assignees

• Stoltz Brian M
• Ngamnithiporn Aurapat
• Jette Carina I
• Bachman Shoshana
• Virgil Scott C
• Lackner Sebastian
• California Inst Of Techn

Inventors

• Stoltz Brian M
• Ngamnithiporn Aurapat
• Jette Carina I
• Bachman Shoshana
• Virgil Scott C
• Lackner Sebastian

Classifications

• C07D309/32

  having two double bonds between ring members or between ring members and non-ring members · CPC title

• C07D309/30

  Oxygen atoms, e.g. delta-lactones · CPC title

• C07D211/86 Primary

  Oxygen atoms · CPC title

• C07D409/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D407/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title