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US 11,377,396 B2Granted
Enantioselective synthesis of α-quaternary Mannich adducts by palladium-catalyzed allylic alkylation
AssigneeCalifornia Institute of Technology
InventorsBrian M. Stoltz, Yoshitaka Numajiri, Beau P. Pritchett, Koji Chiyoda
Life of this patent
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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.
Claims12
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),
- —OR14, —SR14, or —NR14R15;
- 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;
- R1a and R1b 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), —OR14, —SR14, or —NR14R15;
- R2 and R3 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;
- R4, R5, R6, R7, R8, R9, R10, and R11 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
- R14 and R15 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.
14 more elements
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),
- —OR14, —SR14, or —NR14R15;
- 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;
- R1a and R1b 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), —OR14, —SR14, or —NR14R15;
- R2 and R3 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;
- R4, R5, R6, R7, R8, R9, R10, and R11 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
- R14 and R15 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;
- wherein the compound of Formula (Ia) is Compound VII:
16 more elements
Dependencies are inferred from the claim text.