Macrocyclization of compounds from solid support using thioesterases
View Patent ↗A method of preparing macrocycles using solid support chemistry and thioesterases is disclosed. Also disclosed are novel macrocycles.
1. A process of preparing a compound of formula (II) comprising
admixing a compound of formula (I) and a thioesterase to form the compound of formula (II),
wherein X 1 is selected from the group consisting of O, NH, and S; X 4 is selected from the group consisting of OH, NH 2 , and SH; X 4 is selected from the group consisting of O, NH, and S; X 5 is independently selected from the group consisting of O, S, NH, and CR 6 ; R 2 and R 6 are each independently selected from the group consisting of hydrogen and C 1-6 alkyl; R 1 , R 3 , and R 4 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkylenearyl, C 1-6 alkyleneheteroaryl, hydroxyC 1-6 alkyl, thioC 1-6 alkyl, C 1-6 alkyleneCO 2 H, C 1-6 alkyleneNH 2 , C 1-6 alkyleneC(O)NH 2 , and C 1-6 alkyleneNH(NH)NH 2 ; R 5 is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; a dashed line indicates an optional cis or trans double bond; Solid Support comprises a polymer or glass substrate; n is 1, 2, 3, 4, 5, 6, or 7; and m is 0 or 1.
2. The process of claim 1 , wherein the thioesterase is selected from the group consisting of cryptophycin thioesterase, erythromycin thioesterase, pikromycin thioesterase, epothilone thioesterase, gramicidin thioesterase, surfactin thioesterase, bryostatin thioesterase, mycolactone thioesterase, rhizoxin thioesterase, tylosin thioesterase, nystatin thioesterase, FK506 thioesterase, tyrocidine thioesterase, daptomycin thioesterase, cyclosporin thioesterase, fengycin thioesterase, bacitracin thioesterase, pristinamycin thioesterase, kynurenine thioesterase, A54145 thioesterase, CDA thioesterase, friulimicin thioesterase, and mixtures thereof.
3. The process of claim 1 , wherein R 3 is C 1-6 alkylenearyl, and aryl is selected from the group consisting of phenyl, 4-hydroxy-3-chlorophenyl, and 4-hydroxyphenyl.
4. The process of claim 1 , wherein R 5 is aryl or heteroaryl.
5. The process of claim 1 , wherein the polymer substrate comprises a polyethylene glycol-acrylamide copolymer.
6. The method of claim 5 , wherein the polymer substrate further comprises an alkylated acylsulfonamide linker.
7. A process of preparing a compound of formula (IV), comprising
admixing a compound of formula (III) and a cryptophycin thioesterase to form a compound of formula (IV):
wherein X 1 is selected from the group consisting of O, NH, and S; X 2 is selected from the group consisting of hydrogen, OC 1-6 alkyl, hydroxyl, and C 1-6 alkyl; X 3 is selected from the group consisting of hydrogen, halo, and C 1-6 alkyl; R 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkylenearyl, C 1-6 alkyleneheteroaryl, hydroxyC 1-6 alkyl, thioC 1-6 alkyl, C 1-6 alkyleneCO 2 H, C 1-6 alkyleneNH 2 , C 1-6 alkyleneC(O)NH 2 , and C 1-6 alkyleneNH(NH)NH 2 ; and Solid Support comprises a polymeric or glass substrate.
8. The process of claim 7 , wherein the cryptophycin thioesterase has a concentration of about 0.1 μmol to about 0.3 μmol.
9. The process of claim 7 , wherein the molar ratio of the compound of formula (IV) to a byproduct compound of formula (V) is at least 2:1,
10. The process of claim 1 , wherein the thioesterase is cryptophycin thioesterase.
11. The process of claim 7 , wherein the polymeric substrate has a loading of about 0.15 to about 0.3 mmol/g.
12. The process of claim 7 , wherein the polymeric substrate comprises a polyethylene glycol-acrylamide copolymer.
13. The process of claim 12 , wherein the polymeric substrate further comprises an alkylated acylsulfonamide linker.
14. The process of claim 13 , wherein the alkylated acylsulfonamide comprises a formula —N(CH 2 CN)SO 2 (CH 2 ) p CONH-polymer substrate, wherein p is 1, 2, 3, 4, 5, 6, 7, or 8.