Processes for the synthesis of five and six membered heterocyclic rings
View Patent ↗The present invention provides processes for the synthesis of five and six membered rings. In particular, the present invention provides processes for the synthesis of five and six membered rings in alkaloids.
1. A process for the preparation of a compound of Formula (IIa):
the process comprising:
(a) contacting a compound of Formula (Ia), with an alcohol and a proton donor having a pKA of less than 0 to form a reaction mixture, wherein a molar ratio of the proton donor to compound of Formula (Ia) is from about 1:1 to about 20:1, and wherein the compound of Formula (Ia) is of the following structure:
(b) heating the reaction mixture to form a compound of Formula (IIa), wherein:
A is {—}O{—} and is a member of a five-membered heterocyclic ring;
R 1 , R 2 , and R 3 are each independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, {—}OH, {—}NH 2 , {—}SH, {—}SR 111 , {—}OR 111 , and {—}N(R 111 ) 2 ;
R 4 is selected from the group consisting of {—}OH, {—}SH, {—}NH 2 , {—}NHR 112 , {—}N(OH)R 112 , {—}P(OH) 2 , {—]P(OH)R 112 , {—}B(OH) 2 , {—}B(OH)R 112 , and {—}Si(OH)(R 112 ) 2 ;
R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b , are each independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, {—}OH, {—}NH 2 , {—}SH, {—}SR 111 , {—}OR 111 , and {—}N(R 111 ) 2 ; provided that any of R 6a and R 6b , R 7a and R 7b , R 8a and R 8b , may together form a moiety selected from the group consisting of {═}O, {═}S, and {═}NR 111 ;
R 9 , R 10a , R 10b , R I4 , R I5a , R I5b , R I6a , R I6b , and R I7 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and {—}OR 112 ;
R 111 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;
R 112 is selected from the group consisting of {—}H, hydrocarbyl, and substituted hydrocarbyl; and
carbons attached to R groups selected from the group consisting of R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 10a , R 10b , R 15a , R 15b , R 16a , and R 16b may optionally form a carbon-carbon double bond with each other or an adjacent carbon.
2. The process of claim 1 , wherein the reaction mixture further comprises an aprotic solvent and a water scavenger, the alcohol comprises an alkoxy, and the reaction mixture is heated to a temperature of about 20° C. to about 120° C.
3. The process of claim 1 , wherein the reaction mixture is heated to a temperature of about 20° C. to about 120° C. for a period of time sufficient to convert a substantial portion of the compound having Formula (Ia) to a mixture of intermediates comprising ketal derivatives.
4. The process of claim 3 , wherein the ketal derivative comprises a moiety or ring structure selected from the group of compounds of any of Formulas (III), (IIIb), (IIIc), and (IIId):
wherein:
B is selected from the group consisting of halogen, {—}OH, {—}OR 20 , {—}SH, and {—}SR 20 ;
R 20 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl; and
R 516 and R 517 are independently selected from the group consisting of {—}OH, {—}OR 20 , {—}SH, and {—}SR 20 .
5. The process of claim 3 , wherein the ketal derivative comprises a moiety or ring structure selected from the group of compounds of any of Formulas (IV), (IVa), (IVc), and (IVd):
wherein:
R 518 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl.
6. The process of claim 3 , wherein the reaction mixture is heated to a temperature of about 60° C. to about 120° C. for a period of time sufficient to convert a substantial portion of the mixture of intermediates comprising ketal derivatives to a mixture of intermediates comprising enol ether derivatives.
7. The process of claim 6 , wherein the enol ether derivative comprises a moiety or ring structure selected from the group of compounds of any of Formulas (V), (Va), (Vb), (Vc), (Vd), (VI), (VIa), (VIb), (VIc), and (VId):
wherein:
B is selected from the group consisting of halogen, {—}OH, {—}OR20, {—}SH, and {—}SR21;
R 21 is selected from the group consisting of {—}H, hydrocarbyl, and substituted hydrocarbyl;
R 514 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl; and
R 515 is selected from the group consisting of O, S, and NR 21 .
8. The process of claim 6 , wherein the enol ether derivative comprises a moiety or ring structure selected from the group of compounds of any of Formulas (VII), (VIIa), (VIIb), (VIIc), and (VIId);
wherein:
R 518 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl.
9. The process of claim 6 , wherein the alcohol is removed from the reaction mixture after the formation of the mixture of intermediates comprising enol ether derivatives; and the reaction mixture is maintained at a temperature of about 60° C. to about 120° C. for a period of time sufficient to convert a substantial portion of the mixture of intermediates comprising enol ether derivatives to the compound of Formula (IIa).
10. The process of claim 1 , further comprising subjecting the compound of Formula (IIa) to hydrolysis to form a compound of Formula (VIIIa):
wherein:
A is {—}O{—} and is a member of a five-membered heterocyclic ring;
R 1 , R 2 , and R 3 are each independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, {—}OH, {—}NH 2 , {—}SH, {—}SR 111 , {—}OR 111 , and {—}N(R 111 ) 2 ;
R 5 , R 7a , R 7b , R 8a , and R 8b , are each independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, {—}OH, {—}NH 2 , {—}SH, {—}SR 111 , and {—}(OR 111 , and {—}N(R 111 ) 2 ; provided that any of R 7a and R 7b , R 8a and R 8b , may together form a moiety selected from the group consisting of {═}O, {═}S, and {═}NR 111 ;
R 9 , R 10a , R 10b , R 14 , R 15a , R 15b , R 16a , R 16b , and R 17 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and {—}OR 112 ;
R 111 is selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl;
R 112 is selected from the group consisting of {—}H, hydrocarbyl, and substituted hydrocarbyl; and
carbons attached to R groups selected from the group consisting of R 7a , R 7b , R 8a , R 8b , R 10a , R 10b , R 15a , R 15b , R 16a , and R 16b may optionally form a carbon-carbon double bond with each other or an adjacent carbon.
11. The process of claim 1 , wherein the optical activity of the compound of Formula (IIa) is selected from the group consisting of (+), (−), and combinations of both; and the configuration of the chiral carbons C-5, C-13, C-14, and C-9 of the compound of comprising Formula (IIa) may be selected from the group consisting of RRRR, RRSR, RRRS, RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, SSSR, SSRS, and SSSS; provided, however, that the C-15 and the C-16 carbons are both either on the alpha face of the molecule or the beta face of the molecule.
12. The process of claim 1 wherein the weight/weight ratio of alcohol to compound Formula (Ia) is from about 0.5:1 to about 10:1.