Enantioselective synthesis of α-quaternary Mannich adducts by palladium-catalyzed allylic alkylation

Patent metadata

Field	Value
Publication number	US-11377396-B2
Application number	US-201916579382-A
Country	US
Kind code	B2
Filing date	Sep 23, 2019
Priority date	Dec 18, 2014
Publication date	Jul 5, 2022
Grant date	Jul 5, 2022

Abstract

This invention provides enantioenriched Mannich adducts with quaternary stereogenic centers and novel methods of preparing the compounds. Methods include the method for the preparation of a compound of formula (I):comprising treating a compound of formula (II):with a transition metal catalyst under alkylation conditions.

First claim

What is claimed is:

1. A method comprising treating a compound of formula (IIa):

with a transition metal catalyst under alkylation conditions, thereby preparing a compound of formula (Ia):

wherein, as valence and stability permit, A, B, C, and D each independently represent, as valence permits, NR′, CR″R′″, C(O), O, S, CR″, or N; provided that no two adjacent occurrences of A, B, C, and D are NR′, O, S, or N;
R′ 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 14 , —SR 14 , or —NR 14 R 15 ;

R″ and R′″ 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, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, or acylamino;
or any two occurrences of R′, R″, and R′″ on adjacent A, B, C, or D 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, wherein the sum of m and n is 1, 2, 3, or 4;
R 1a and R 1b each independently represent 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 14 , —SR 14 , or —NR 14 R 15 ;

R 2 and R 3 each independently represent hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl, alkylamino, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl;
R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently selected for each occurrence from hydrogen, hydroxyl, halogen, nitro, alkyl, alkenyl, alkynyl, cyano, carboxyl, sulfate, amino, alkoxy, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, arylalkoxy, heteroaralkyl, (cycloalkyl)alkyl, and (heterocycloalkyl)alkyl; and
R 14 and R 15 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,
wherein the compound represented by formula (Ia) has about 70% ee or greater.

2. The method of claim 1 , wherein the transition metal catalyst comprises a transition metal selected from palladium, nickel, and platinum.

3. The method of claim 1 , wherein the transition metal catalyst further comprises a chiral ligand.

4. The method of claim 1 , wherein the compound represented by formula (Ia) has about 80% ee or greater.

5. The method of claim 1 , wherein the compound represented by formula (Ia) has about 85% ee or greater.

6. The method of claim 1 , wherein the compound represented by formula (Ia) has about 90% ee or greater.

7. The method of claim 1 , wherein in the compound of Formula (Ia),
A is NR′, B and C are each CR″R′″, and D is O, or A is O, B and C are each CR″R′″, and D is NR′;

m and n are each 1.

8. The method of claim 1 , wherein in the compound of Formula (Ia),
one of A, B, C, and D is NR′ and the remaining of A, B, C, and D are each CR″R′″;

m and n are each 1.

9. The method of claim 1 , wherein further comprising converting the compound of Formula (Ia) to an isonitramine or sibirinine.

10. The method of claim 9 , wherein the method comprises a carbonyl reduction reaction.

11. The method of claim 9 , wherein the method comprises a hydroboration reaction.

12. A method comprising treating a compound of formula (IIa):

with a transition metal catalyst under alkylation conditions, thereby preparing a compound of formula (Ia):

wherein, as valence and stability permit, A, B, C, and D each independently represent, as valence permits, NR′, CR″R′″, C(O), O, S, CR″, or N; provided that no two adjacent occurrences of A, B, C, and D are NR′, O, S, or N;
R′ 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 14 , —SR 14 , or —NR 14 R 15 ;

R″ and R′″ 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, alkylamino, alkylthio, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, ether, thioether, ester, amide, thioester, carbonate, carbamate, urea, sulfonate, sulfone, sulfoxide, sulfonamide, acyl, acyloxy, or acylamino;
or any two occurrences of R′, R″, and R′″ on adjacent A, B, C, or D 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, wherein the sum of m and n is 1, 2, 3, or 4;
R 1a and R 1b each independently represent 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 14 , —SR 14 , or —NR 14 R 15 ;

R 2 and R 3 each independently represent hydrogen or substituted or unsubstituted alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl, (cycloalkyl)alkyl, cycloalkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, alkenyl, alkynyl, alkylamino, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or thioalkyl;
R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are eac

Assignees

• California Inst Of Techn

Inventors

• Stoltz Brian M
• Numajiri Yoshitaka
• Pritchett Beau P
• Chiyoda Koji

Classifications

• C07D211/74

  Oxygen atoms · CPC title

• C07C2601/08

  the ring being saturated · CPC title

• C07D265/32

  with oxygen atoms directly attached to ring carbon atoms · CPC title

• C07D211/76

  attached in position 2 or 6 · CPC title

• C07C233/76

  having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms · CPC title