Intermediates and methods for making zearalenone macrolide analogs

Abstract

Disclosed herein are methods and intermediates useful in the preparation of macrolides, e.g., compounds of formula (IV) wherein R 1 -R 12 are as defined herein.

1 . A method for making a compound of formula (VII): 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are each independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 3-6  unconjugated alkenyl and C 3-6  unconjugated alkynyl: 
         R 3  is a first aromatic ring containing oxygen protecting group; 
         R 5  and R 6  are each independently selected from the group consisting of hydrogen, halogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  alkoxy, phenyl and benzyl, wherein the phenyl or benzyl are substituted with 0, 1, 2, or 3 substituents independently selected from halogen, hydroxyl, C 1-3  alkyl, and NH 2 ; or R 5  and R 6  are taken together with the carbons on which they are attached to form a 5-6 membered unconjugated carbocyclic ring; 
         R 11  and R 12  are each independently selected from the group consisting of hydrogen and a base stable oxygen protecting group; or R 11  and R 12  are taken together to form a 5 membered heterocyclyldiyl of structure (a): 
       
       
         
           
           
               
               
           
         
         R 13  is a second aromatic ring containing oxygen protecting group; and 
         wherein R 19  and R 20  are each independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy and phenyl, or R 19  and R 20  together represent a fluorenyl moiety of structure (b): 
       
       
         
           
           
               
               
           
         
         comprising reacting a compound of formula (I): 
       
       
         
           
           
               
               
           
         
         wherein R 4  is selected from the group consisting of hydrogen and a base stable oxygen protecting group; 
         with a compound of formula (II): 
       
       
         
           
           
               
               
           
         
         wherein X is a halogen; 
         under suitable basic conditions, such that a compound of formula (V) is formed: 
       
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are each independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 3-6  unconjugated alkenyl and C 3-6  unconjugated alkynyl; 
         R 3  is selected from the group consisting of hydrogen and a base stable oxygen protecting group; 
         R 5  and R 6  are each independently selected from the group consisting of hydrogen, halogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  alkoxy, phenyl and benzyl, wherein the phenyl or benzyl are substituted with 0, 1, 2, or 3 substituents independently selected from halogen, hydroxyl, C 1-3  alkyl, and NH 2 ; or R 5  and R 6  are taken together with the carbons on which they are attached to form a 5-6 membered unconjugated carbocyclic ring; 
         R 11  and R 12  are each independently selected from the group consisting of hydrogen and a base stable oxygen protecting group; or R 11  and R 12  are taken together to form a 5 membered heterocyclyldiyl of structure (a): 
       
       
         
           
           
               
               
           
         
         wherein R 19  and R 20  are each independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy and phenyl, or R 19  and R 20  together represent a fluorenyl moiety of structure (b): 
       
       
         
           
           
               
               
           
         
       
       and
 R 13  is selected from the group consisting of hydrogen and a base stable oxygen protecting group; and 
 converting the compound of formula (V) into a compound of formula (VII). 
 
     
     
         2 . The method of  claim 1 , wherein the suitable basic conditions comprise a base selected from the group consisting of a C 1-6  alkyl lithium, a potassium C 1-6  alkoxide, a potassium C 4-6  t-alkoxide, sodium hydroxide, sodium hydride, ammonia, dimethylsulfoxide sodium salt and sodium hexamethyldisilylamide. 
     
     
         3 . The method of  claim 2 , wherein the base comprises a C 1-6  alkyl lithium. 
     
     
         4 . The method of  claim 1 , wherein the compound of formula (V) is produced in substantially pure form without the use of chromatography in the production of the compound of formula (V). 
     
     
         5 . The method of  claim 1 , wherein the compound of formula (VII) is crystalline. 
     
     
         6 - 11 . (canceled) 
     
     
         12 . A method for making a compound of formula (IV): 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are each independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 3-6  unconjugated alkenyl and C 3-6  unconjugated alkynyl; 
         R 5  and R 6  are each independently selected from the group consisting of hydrogen, halogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  alkoxy, phenyl and benzyl, wherein the phenyl or benzyl are substituted with 0, 1, 2, or 3 substituents independently selected from halogen, hydroxyl, C 1-3  alkyl, and NH 2 ; or R 5  and R 6  are taken together with the carbons on which they are attached to form a 5-6 membered unconjugated carbocyclic ring; 
         R 7  is selected from the group consisting of hydrogen and —OR a  wherein R a  is hydrogen or a base stable oxygen protecting group; 
         R 8  is selected from the group consisting of hydrogen and —OR g  wherein R g  is hydrogen or a base stable oxygen protecting group; 
         R 9  is selected from the group consisting of hydrogen, halogen, —OR b , C 1-6  alkyl, C 3-6  unconjugated alkenyl, C 3-6  unconjugated alkynyl, C 1-6  haloalkyl, —SR d  and 
         —NR e R f  wherein R b  is hydrogen or a base stable oxygen protecting group, wherein R d  is selected from the group consisting of hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  heteroalkyl, 5-7 membered heteroaryl comprising 1, 2 or 3 heteroatoms, and C 5-7  aryl and wherein R e  and R f  are each independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  heteroalkyl, 5-7 membered heteroaryl comprising 1, 2 or 3 heteroatoms, and C 5-7  aryl or a base stable nitrogen protecting group; 
         R 10  is selected from the group consisting of hydrogen, halogen, —OR c , C 1-6  alkyl, C 3-6  unconjugated alkenyl, C 3-6  unconjugated alkynyl, C 1-6  haloalkyl and C 1-6  alkoxy, wherein 
         R c  is hydrogen or a base stable oxygen protecting group; and 
         R 11  and R 12  are each independently selected from the group consisting of hydrogen and a base stable oxygen protecting group; or R 11  and R 12  are taken together to form a 5 membered heterocyclyldiyl of structure (a): 
       
       
         
           
           
               
               
           
         
         wherein R 19  and R 20  are each independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy and phenyl, or R 19  and R 20  together represent a fluorenyl moiety of structure (b): 
       
       
         
           
           
               
               
           
         
         comprising reacting a compound of formula (I): 
       
       
         
           
           
               
               
           
         
         wherein R 3  is selected from the group consisting of hydrogen and a base stable oxygen protecting group; and 
         R 4  is selected from the group consisting of hydrogen and a base stable oxygen protecting group; 
         with a compound of formula (II): 
       
       
         
           
           
               
               
           
         
         wherein X is a halogen; and 
         R 13  is selected from the group consisting of hydrogen and a base stable oxygen protecting group; 
         under suitable basic conditions to form a compound of formula (V): 
       
       
         
           
           
               
               
           
         
         converting the compound of formula (V) into a compound of formula (VII): 
       
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are each independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 3-6  unconjugated alkenyl and C 3-6  unconjugated alkynyl: 
         R 3  is a first aromatic ring containing oxygen protecting group; 
         R 5  and R 6  are each independently selected from the group consisting of hydrogen, halogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  alkoxy, phenyl and benzyl, wherein the phenyl or benzyl are substituted with 0, 1, 2, or 3 substituents independently selected from halogen, hydroxyl, C 1-3  alkyl, and NH 2 ; or R 5  and R 6  are taken together with the carbons on which they are attached to form a 5-6 membered unconjugated carbocyclic ring; 
         R 11  and R 12  are each independently selected from the group consisting of hydrogen and a base stable oxygen protecting group; or R 11  and R 12  are taken together to form a 5 membered heterocyclyldiyl of structure (a): 
       
       
         
           
           
               
               
           
         
         R 13  is a second aromatic ring containing oxygen protecting group; and 
         wherein R 19  and R 20  are each independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy and phenyl, or R 19  and R 20  together represent a fluorenyl moiety of structure (b): 
       
       
         
           
           
               
               
           
         
       
       and
 converting the compound of formula (VII) to a compound of formula (V), wherein R 13  is H; and 
 reacting the compound of formula (V) with a compound of formula (III): 
 
       
         
           
           
               
               
           
         
         wherein Y is a halogen or —O—SO 2 CF 3 ; 
         under suitable basic conditions, such that a compound of formula (IV) is formed. 
       
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 12 , wherein the compound of formula (IV) is produced in substantially pure form without the use of chromatography in the production of the compound of formula (IV). 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 12 , wherein R 1  is hydrogen. 
     
     
         17 . The method of  claim 12 , wherein R 2  is hydrogen. 
     
     
         18 . The method of  claim 12 , wherein R 5  is selected from the group consisting of hydrogen and C 1-6  alkyl. 
     
     
         19 . The method of  claim 12 , wherein R 6  is selected from the group consisting of hydrogen and C 1-6  alkyl. 
     
     
         20 . The method of  claim 12 , wherein R 5  is hydrogen or methyl. 
     
     
         21 . The method of  claim 12 , wherein R 6  is hydrogen or methyl. 
     
     
         22 . The method of  claim 12 , wherein R 7  is hydrogen or hydroxyl. 
     
     
         23 . The method of  claim 12 , wherein R 8  is hydrogen or hydroxyl. 
     
     
         24 . The method of  claim 12 , wherein R 9  is —NR e R f  and wherein R e  and R f  are each independently hydrogen, C 1-6  alkyl, or a base stable nitrogen protecting group. 
     
     
         25 . The method of  claim 24 , wherein R e  is C 1-6  alkyl and R f  is hydrogen or a base stable nitrogen protecting group. 
     
     
         26 . The method of  claim 24 , wherein R e  is methyl or ethyl. 
     
     
         27 . The method of  claim 12 , wherein R 10  is hydrogen. 
     
     
         28 . The method of  claim 12 , wherein R 11  and R 12  are taken together to form a 5 membered heterocyclyldiyl of structure (a): 
       
         
           
           
               
               
           
         
         wherein R 19  and R 20  are each independently selected from the group consisting of C 1-6  alkyl. 
       
     
     
         29 . (canceled) 
     
     
         30 . The method of  claim 12 , wherein the compound of formula (VII) has the structure: 
       
         
           
           
               
               
           
         
         wherein R 3  is selected from benzoyl or benzyl, wherein the benzoyl or benzyl are each substituted with 0, 1, 2 or 3 substituents independently selected from —OH, —O(C 1-4 alkyl), —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , amides, —OCO(C 1-4 alkyl) and (C 1-4 alkyl); 
         R 13  is 
       
       
         
           
           
               
               
           
         
       
       and
 wherein R 14 , R 15 , R 16 , R 17 , and R 18  are each independently selected from the group consisting of H, NO 2 , —NH 3   + , —COH, —CO(C 1-4  alkyl), —COCl, —COOH, —COO(C 1-4  alkyl), —NR 3   + , —SO 3 H, nitrile, —CF 3  and halogen, wherein at least one of R 14 , R 15 , R 16 , R 17 , and R 18  is selected from the group consisting of NO 2 , —NH 3   + , —COH, —CO(C 1-4  alkyl), —COCl, —COOH, —COO(C 1-4  alkyl), —NR 3   + , —SO 3 H, nitrile, —CF 3  and halogen and the other of R 14 , R 15 , R 16 , R 17 , and R 18  are hydrogen. 
 
     
     
         31 . The method of  claim 12  wherein the compound of formula (VII) is: