Compositions and methods for acylating lactams
This disclosure provides methods for intermolecular enantioselective C-acylation of lactams with quaternary stereogenic centers by applying a chiral Ni catalyst. The methods comprise treating a lactam with a chiral Ni catalyst, an aryl nitrile, and an aryl halide.
1. A method for the preparation of a compound of formula (Ia):
comprising treating a compound of formula (IIa):
or a salt thereof;
with a complex formed by contacting Ni(COD) 2 with a chiral ligand;
an aryl nitrile;
an aryl halide; and
a base;
wherein, as valence and stability permit,
R 1 represents hydrogen or optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)heteroaryl, —C(O)heteroaralkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(heteroaryl), —C(O)O(heteroaralkyl), —S(O) 2 (aryl), —S(O) 2 (alkyl), —S(O) 2 (haloalkyl), —OR 10 , —SR′, or —NR 10 R 11 ;
R 2 represents substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aryl, heteroaralkyl, heteroaralkenyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, alkoxy, amino, or halo;
R 3 represents substituted or unsubstituted aryl;
B and D independently for each occurrence represent, as valence permits, O, S, NR 4 , CR 5 R 6 , C(O), CR 5 , or N; provided that no two adjacent occurrences of N, B and D are NR 4 , O, S, or N;
E represents CR 5 R 6 , C(O) or CR 5 ;
R 4 represents hydrogen or optionally substituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, alkynyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)heteroaryl, —C(O)heteroaralkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(heteroaryl), —C(O)O(heteroaralkyl), —S(O) 2 (aryl), —S(O) 2 (alkyl), —S(O) 2 (haloalkyl), OR 10 , —SR 10 , or —NR 10 R 11 ;
R 5 and R 6 each independently represent hydrogen, hydroxyl, halogen, nitro, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, aryloxy, arylalkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, haloalkyl, ether, thioether, ester, amido, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, or acylamino;
or any two occurrences of R 1 , R 4 , R 5 , and R 6 on adjacent N, B, D, or E groups, taken together with the intervening atoms, form an optionally substituted aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl 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; and
R 10 and R 11 are independently selected for each occurrence from hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, and alkynyl.
2. The method of claim 1 , wherein the sum of m and n is 0, 1, 2, or 3.
3. The method of claim 1 , wherein each occurrence of B, D, and E is independently —CR 5 R 6 —, or —CR 5 —, or —C(O)—.
4. The method of claim 1 , wherein E is —CR 5 R 6 —; and the sum of m and n is 0.
5. The method of claim 4 , wherein
R 1 is selected from optionally substituted alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)heteroaryl, —C(O)heteroaralkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(heteroaryl), —C(O)O(heteroaralkyl), and —S(O) 2 (aryl);
R 5 is selected from hydrogen, hydroxyl, halogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl, amino, alkoxy, aryloxy, alkylamino, amido, and acylamino; or
R 1 and the occurrence of R 5 on E are taken together to form an optionally substituted heteroaryl, heterocycloalkyl, or heterocycloalkenyl group.
6. The method of claim 1 , wherein the compound of formula (I) is represented by formula (Ib):
and
the compound of formula (II) is represented by formula (Ilb):
7. The method of claim 6 , wherein
R 1 is selected from optionally substituted alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkenyl, —C(O)alkyl, —C(O)aryl, —C(O)aralkyl, —C(O)heteroaryl, —C(O)heteroaralkyl, —C(O)O(alkyl), —C(O)O(aryl), —C(O)O(aralkyl), —C(O)O(heteroaryl), —C(O)O(heteroaralkyl), and —S(O) 2 (aryl);
R 5 is selected from hydrogen, hydroxyl, halogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl, amino, alkoxy, aryloxy, alkylamino, amido, and acylamino; or
R 1 and R 5 on E are taken together to form an optionally substituted heteroaryl, heterocycloalkyl, or heterocycloalkenyl group.
8. The method of claim 1 , wherein R 2 represents substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aryl, heteroaralkyl, heteroaralkenyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, or halo.
9. The method of claim 1 , wherein the complex is present in an amount from about 0.1 mol % to about 20 mol % relative to the compound of formula (II).
10. The method of claim 1 , wherein the chiral ligand is an enantioenriched phosphine ligand.
11. The method of claim 1 , wherein the chiral ligand is used in an amount from about 0.5 mol % to about 50 mol % relative to the compound of formula (IIa).
12. The method of claim 1 , wherein the aryl nitrile is an optionally substituted benzonitrile or a naphthonitrile.
13. The method of claim 1 , wherein the treating a compound of formula (IIa) further comprises treating with a lithium salt.
14. The method of claim 1 , wherein the treating a compound of formula (IIa) is in the presence of toluene, tetrahydrofuran, dioxane, methyl tert-butyl ether, dimethoxyethane, or a mixture of toluene and tetrahydrofuran.
15. The method of claim 1 , whereby the compound of formula (Ia) is enantioenriched.
16. The method of claim 1 , wherein:
B, D, and E are each independently CR 5 R 6 , C(O), or CR 5 ;
R 1 represents an optionally substituted cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; and
R 2 represents substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aryl, heteroaralkyl, heteroaralkenyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl, or heterocycloalkyl.
17. The method of claim 1 , wherein:
B, D, and E are each independently CR 5 R 6 , C(O), or CR 5 ;
R 1 represents an optionally substituted cycloalkyl, (cycloalkyl)alkyl, aryl, or aralkyl; and
R 2 represents substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aryl, (cycloalkyl)alkyl, or cycloalkyl.
18. The method of claim 6 , wherein:
R 1 represents an optionally substituted cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl;
R 2 represents substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aryl, heteroaralkyl, heteroaralkenyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl, or heterocycloalkyl; and
R 5 and R 6 are hydrogen.
19. The method of claim 6 , wherein:
R 1 represents an optionally substituted cycloalkyl, (cycloalkyl)alkyl, aryl, or aralkyl;
R 2 represents substituted or unsubstituted alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aryl, (cycloalkyl)alkyl, or cycloalkyl; and
R 5 and R 6 are hydrogen.
20. The method of claim 6 , wherein the compound of formula (Ib) is selected from:
or a salt thereof.