Metal catalyzed dearomative 1,2-carboamination
Described herein is the development of an arenophile-mediated, nickel-catalyzed dearomative trans-1,2-carboamination protocol. A range of readily available aromatic compounds was converted to the corresponding dienes using Grignard reagents as nucleophiles. This strategy provided products with exclusive trans-selectivity and high enantioselectivity was observed in case of benzene and naphthalene. The utility of this methodology was showcased by controlled and stereoselective preparation of small, functionalized molecules. A concise synthesis of (+)-pancratistatin and (+)-7-deoxypancratistatin from benzene using an enantioselective, dearomative carboamination strategy has been achieved. This approach, in combination with the judicious choice of subsequent olefin-type difunctionalization reactions, permits rapid and controlled access to a hexasubstituted core. Finally, minimal use of intermediary steps as well as direct, late stage C-7 hydroxylation provides both natural products in six and seven operations.
1. An urazole compound of Formula I:
or the enantiomer thereof;
wherein
R 1 is alkyl, alkenyl, aryl, or heteroaryl;
R 2 , R 3 and R 6 are each independently H, D, halo, alkyl, cycloalkyl, OR A , N(R A ) 2 , aryl, heteroaryl, or R 2 and R 3 taken together form a ring wherein the ring is unsaturated or aromatic;
R 4 is H, alkyl, or cycloalkyl;
R 5 is H, alkyl, cycloalkyl, or aryl;
each R A is independently H, alkyl, cycloalkyl, C(═O)R B , aryl, or heteroaryl; and
each R B is independently H, OH, halo, alkyl, aryl, heteroaryl, or N(R A ) 2 , wherein N(R A ) 2 is not recursive with C(═O)R B ;
wherein each alkyl, cycloalkyl, alkenyl, aryl, and heteroaryl is optionally substituted with one or more substituents.
2. The urazole compound of claim 1 wherein the stereochemistry of the urazole compound is (S,R) or (R,S).
3. The urazole compound of claim 1 wherein R 4 is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, or phenyl wherein phenyl is optionally substituted, and R 6 is H or D.
4. The urazole compound of claim 3 wherein R 1 is aryl.
5. The urazole compound of claim 1 wherein R 1 is aryl, and R 2 , R 3 and R 6 are H or D.
6. A composition comprising an urazole compound of claim 1 and a solvent.
7. A composition comprising a transition metal catalyst, a bidentate ligand, an organometallic nucleophile, and a cycloadduct of an aromatic substrate and a 1,2,4-triazoline-3,5-dione.
8. A method to prepare a compound of Formula I:
or the enantiomer thereof;
wherein
R 1 is alkyl, alkenyl, aryl, or heteroaryl;
R 2 , R 3 and R 6 are each independently H, D, halo, alkyl, cycloalkyl, OR A , N(R A ) 2 , aryl, heteroaryl, or R 2 and R 3 taken together form a ring wherein the ring is unsaturated or aromatic;
R 4 and R 5 are each independently H, alkyl, cycloalkyl, or aryl;
each R A is independently H, alkyl, cycloalkyl, C(═O)R B , aryl, or heteroaryl; and
each R B is independently H, OH, halo, alkyl, aryl, heteroaryl, or N(R A ) 2 , wherein N(R A ) 2 is not recursive with C(═O)R B ;
wherein each alkyl, cycloalkyl, alkenyl, aryl, and heteroaryl is optionally substituted with one or more substituents;
comprising carrying out an arenophile-mediated dearomative 1,2-carboamination of an aromatic substrate.
9. The method of claim 8 wherein:
a) irradiating a mixture of an aromatic substrate and a compound of Formula X forms a dearomatized cycloadduct;
b) contacting the dearomatized cycloadduct with a transition metal catalyst and an organometallic nucleophile forms a carboaminated organometallic; and
c) quenching the carboaminated organometallic forms the dearomatized trans-1,2-carboaminated product of claim 8 ;
wherein Formula X is:
wherein R 4 is H, alkyl, cycloalkyl, or aryl.
10. The method of claim 9 wherein the aromatic substrate is an optionally substituted aryl substrate and the transition metal catalyst comprises a chiral ligand.
11. A method to prepare an urazole compound of Formula I:
or the enantiomer thereof;
wherein
R 1 is alkyl, alkenyl, aryl, or heteroaryl;
R 2 , R 3 and R 6 are each independently H, D, halo, alkyl, cycloalkyl, OR A , N(R A ) 2 , aryl, heteroaryl, or R 2 and R 3 taken together form a ring wherein the ring is unsaturated or aromatic;
R 4 and R 5 are each independently H, alkyl, cycloalkyl, or aryl;
each R A is independently H, alkyl, cycloalkyl, C(═O)R B , aryl, or heteroaryl; and
each R B is independently H, OH, halo, alkyl, aryl, heteroaryl, or N(R A ) 2 , wherein N(R A ) 2 is not recursive with C(═O)R B ;
wherein each alkyl, cycloalkyl, alkenyl, aryl, and heteroaryl is optionally substituted with one or more substituents;
comprising:
a) irradiating a mixture of an aromatic substrate and a compound of Formula X:
wherein R 4 is H, alkyl, cycloalkyl, or aryl;
b) contacting the mixture with a transition metal catalyst and an organometallic nucleophile; and
c) quenching the mixture;
thereby forming the dearomatized trans-1,2-carboaminated compound of Formula I by cycloaddition and transition metal catalyzed dearomative carboamination of an aromatic substrate.
12. The method of claim 11 wherein the transition metal catalyst is a nickel catalyst.
13. The method of claim 12 wherein the nickel catalyst comprises a chiral phosphine ligand.
14. The method of claim 13 wherein the chiral phosphine ligand comprises ferrocene.
15. The method of claim 11 wherein the nucleophile comprises a Grignard reagent.
16. The method of claim 11 wherein the mixture is irradiated with visible light.
17. The method of claim 11 wherein the mixture is quenched with an alkylating agent.
18. The method of claim 11 wherein R 1 is aryl, R 4 is (C 1 -C 6 )alkyl, and R 6 is H or D.
19. The method of claim 11 wherein the dearomatized trans-1,2-carboaminated compound is enantiomerically enriched.
20. The method of claim 11 wherein the urazole compound is an urazole compound of Formula II:
or the enantiomer thereof;
wherein R 4 and R 5 are each independently H or (C 1 -C 6 )alkyl; and
wherein a compound of Formula II is used for an organic synthesis of a pancratistatin.