Asymmetric catalytic decarboxylative alkyl alkylation using low catalyst concentrations and a robust precatalyst

Patent metadata

Field	Value
Publication number	US-10106479-B2
Application number	US-201615081157-A
Country	US
Kind code	B2
Filing date	Mar 25, 2016
Priority date	Mar 27, 2015
Publication date	Oct 23, 2018
Grant date	Oct 23, 2018

Abstract

This invention provides efficient and scalable enantioselective methods that yield 2-alkyl-2-allylcycloalkyanone compounds with quaternary stereogenic centers. Methods include the method for the preparation of a compound of formula (I):

comprising treating a compound of formula (II) or (III):

with a palladium (II) catalyst under alkylation conditions.

First claim

What is claimed is:

1. A method for the preparation of a compound of formula (Ia):

comprising treating a compound of formula (IIa) or (IIIa):
or a salt thereof;

with a Pd(II) catalyst, wherein the Pd(II) catalyst is used in an amount from about 0.02 mol % to about 1 mol % relative to the compound of formula (IIa) or of formula (IIIa), and
wherein, as valence and stability permit,
R 1 represents substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, or halo;
R 2 , R 3 , R 4 , R 5 , R 12 , R 13 , R 14 , and R 15 are independently selected for each occurrence from hydrogen, and alkyl;
W represents —NR 6 —;
B, D, and E independently for each occurrence represent, as valence permits, CR 7 R 8 , C(O) or CR 7 ;
R 6 represents hydrogen or optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, 5- to 10-membered heteroaryl, (5- to 10-membered heteroaryl)alkyl, alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)heteroaryl, —C(O)—(5- to 10-membered heteroaryl)alkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(heteroaryl), or —C(O)O—(5- to 10-membered heteroaryl)alkyl;
R 7 and R 8 each independently represent hydrogen, hydroxyl, halogen, nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, (5- to 10-membered heteroaryl)alkyl, (3- to 10-membered heterocyclyl)alkyl, 3- to 10-membered heterocyclyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, ether group, thioether group, ester group, amido, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, or acylamino;
each occurrence of independently represents a double bond or a single bond as permitted by valence; and
m and n are integers wherein the sum of m and n is 2;
wherein each heteroaryl or heterocyclyl comprises 1 to 4 heteroatoms selected from N, O, and S;
wherein substituents on the alkyl, haloalkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, cycloalkenyl, (3- to 10-membered heterocyclyl)alkyl, 3- to 10-membered heterocyclyl, alkoxy, or amino are selected from a halogen group, hydroxyl, carboxyl, alkoxycarbonyl, formyl, acyl, thioester group, thioacetate group, thioformate group, alkoxy, phosphate group, phosphonate group, phosphinate group, amino, amido, amidine group, imine group, cyano, nitro, azido, sulfhydryl, mercaptoalkyl, sulfate group, sulfonate group, sulfamoyl, sulfonamido, sulfonyl, 5- to 10-membered heterocyclyl, aralkyl, aromatic group, and 5- to 10-membered heteroaromatic group.

2. A method for the preparation of a compound of formula (Ia):

comprising treating a compound of formula (IVa) or (Va) or a salt thereof:

with a compound of formula (X):

 and
a Pd(II) catalyst, wherein the Pd(II) catalyst is used in an amount from about 0.02 mol % to about 1 mol % relative to the compound of formula (IVa) or of formula (Va), and
wherein, as valence and stability permit,
R 1 represents substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, or halo;
R 2 , R 3 , R 4 , R 5 , R 12 , R 13 , R 14 , and R 15 are independently selected for each occurrence from hydrogen, and alkyl;
W represents —NR 6 ;
B, D, and E independently for each occurrence represent, as valence permits, CR 7 R 8 , C(O) or CR 7 ;
R 6 represents hydrogen or optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, (5- to 10-membered heteroaryl)alkyl, alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)heteroaryl, —C(O)—(5- to 10-membered heteroaryl)alkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(heteroaryl), —C(O)O—(5- to 10-membered heteroaryl)alkyl;
R 7 and R 8 each independently represent hydrogen, hydroxyl, halogen group, nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, (5- to 10-membered heteroaryl)alkyl, (3- to 10-membered heterocyclyl)alkyl, 3- to 10-membered heterocyclyl, alkenyl, alkynyl, cyano, carboxyl, sulfate group, amino, alkoxy, arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, mercaptoalkyl, ether group, thioether group, ester group, amido, thioester group, carbonate group, carbamate group, urea group, sulfonate group, sulfone group, sulfoxide group, sulfonamide group, acyl, acyloxy, or acylamino;
or any two occurrences of R 6 , R 7 , and R 8 on adjacent W, B, D, or E groups, taken together with the intervening atoms, form an optionally substituted aryl, 5- to 10-membered heteroaryl, cycloalkyl, cycloalkenyl, 3- to 10-membered heterocyclyl, or (3- to 10-membered heterocyclyl)alkenyl group;
each occurrence of independently represents a double bond or a single bond as permitted by valence;
m and n are integers each independently selected from 0, 1, and 2;
R a represents optionally substituted alkyl, aryl, or alkoxyl; and
X represents a halide group, carbonate group, sulfonate group, acetate group, or carboxylate group;
wherein each heteroaryl or heterocyclyl comprises 1 to 4 heteroatoms selected from N, O, and S;
wherein substituents on the alkyl, haloalkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, (cycloalkyl)alkyl, cycloalkyl, cycloalkenyl, (3- to 10-membered heterocyclyl)alkyl, 3- to 10-membered heterocyclyl, alkoxy, or amino are selected from a halogen group, hydroxyl, carboxyl, alkoxycarbonyl, formyl, acyl, thioester group, thioacetate group, thioformate group, alkoxy, phosphate group, phosphonate group, phosphinate group, amino, amido, amidine group, imine group, cyano, nitro, azido, sulfhydryl, mercaptoalkyl, sulfate group, sulfonate group, sulfamoyl, sulfonamido, sulfonyl, 3- to 10-membered heterocyclyl, aralkyl, aromatic group, and 3- to 10-membered heteroaromatic moiety.

3. The method of claim 1 , wherein at least two adjacent occurrences of B, D, and E are —CR 7 —.

4. The method of claim 1 , wherein R 6 represents, independently for each occurrence, hydrogen or optionally substituted alkyl, aralkyl, (5- to 10-membered heteroaryl)alkyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)O(alkyl), —C(O)O(aryl), or —C(O)O(aralkyl).

5. The method of claim 1 , wherein R 2 , R 3 , R 4 , R 5 , R 12 , R 13 , R 14 , and R 15 are each hydrogen.

6. The method of claim 1 , wherein R 1 represents unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aryl, (5- to 10-membered heteroaryl)alkyl, 5- to 10-membered heteroaryl, or halo.

7. The method of claim 1 , wherein the Pd(II) catalyst is selected from Pd(OC(O))R c ) 2 , Pd(OAc) 2 , PdCl 2 , Pd(PhCN) 2 Cl 2 , Pd(CH 3 CN) 2 Cl 2 , PdBr 2 , Pd(acac) 2 , [Pd(allyl)Cl] 2 , Pd(TFA) 2 , and pre-formed Pd(II)-ligand complex;
wherein R c is optionally substituted alkyl, alkenyl,

Assignees

• California Inst Of Techn

Inventors

• Stoltz Brian M
• Marziale Alexander N
• Craig Robert A
• Duquette Douglas
• Kim Kelly E
• Liniger Marc
• Numajiri Yoshitaka

Classifications

• C07C49/683

  having unsaturation outside the aromatic rings · CPC title

• C07C2601/20

  the ring being twelve-membered · CPC title

• C07C45/65 Primary

  by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups · CPC title

• C07C2602/10

  the other ring being six-membered, e.g. tetraline · CPC title

• B01J31/04

  containing carboxylic acids or their salts {(B01J31/0277 - B01J31/0298 take precedence; multi-metal carboxylate complexes like Pd (II) acetate, i.e. Pd3 (OAc) 6 or Cr(II)acetate, i.e. Cr2(OAc)4 B01J31/2226)} · CPC title