Enzymatic Transamination of Cyclopamine Analogs

Abstract

Provided are processes for the synthesis of amino analogues from ketone starting materials.

1 .- 38 . (canceled) 
     
     
         39 . A compound of formula (II): 
       
         
           
           
               
               
           
         
         or a salt thereof 
         made by a process comprising contacting a compound of formula (I): 
       
       
         
           
           
               
               
           
         
         or a salt thereof, an amino donor molecule, and an amine transaminase enzyme in a solution to provide a compound of formula (II) or a salt thereof; 
         wherein: 
         R 1  is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —OR 16 , —C(O)R 16 , —CO 2 R 16 , —SO 2 R 16 , —C(O)N(R 17 )(R 17 ), —[C(R 16 ) 2 ] q —R 16 , —[(W)—N(R 17 )C(O)] q R 16 , —[(W)—C(O)] q R 16 , —[(W)—C(O)] q R 16 , —[(W)—C(O)] q R 16 , —[(W)—SO 2 ] q R 16 , —[(W)—N(R 17 )SO 2 ] q R 16 , —[(W)—C(O)N(R 17 )] q R 17 , —[(W)—O] q R 16 , —[(W)—N(R 17 )] q R 16 , or —[(W)—S] q R 16 ; wherein W is a diradical and q is 1, 2, 3, 4, 5, or 6; 
         each R 2  and R 3  is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, halo, —OR 16 , —OR 16 , —N(R 17 ) 2 , or —SR 16 , or R 2  and R 3  taken together form a double bond or form a group 
       
       
         
           
           
               
               
           
         
         wherein Z is NR 17 , O, or C(R 18 ) 2 ; 
         R 4  is independently H, halo, —OR 16 , —N(R 17 ) 2 , or —SR 16 ; 
         each R 5  and R 6 , is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, —OR 16 , —N(R 17 ) 2 , or —SR 16 ; or R 5  and R 6  taken together with the carbon to which they are bonded form C═O, C═S, C═N—OR 17 , C═N—R 17 , C═N—N(R 17 ) 2 , or form an optionally substituted 3-8 membered ring; 
         each R 7 , R 8 , R 9 , R 10 , R 11 , R 12  and R 13  is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, —OR 16 , —N(R 17 ) 2 , or —SR 16 ; 
         or R 10  and R 11  taken together, or R 11  and R 12  taken together, form a double bond or form a group 
       
       
         
           
           
               
               
           
         
         wherein Z is NR 17 , O, or C(R 15 ) 2 ; 
         each R 14  and R 15  is, independently, H, halo, —OR 16 , —N(R 17 ) 2 , or —SR 16 ; or R 14  and R 15  taken together with the carbon to which they are bonded form C═O or C═S; 
         X is a bond or the group —C(R 19 ) 2 —; wherein each R 19  is, independently, H, alkyl, aralkyl, halo, —CN, —OR 16 , or —N(R 17 ) 2 ; 
         R 16  is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or —[C(R 20 ) 2 ] p —R 21  wherein p is 0-6; or any two occurrences of R 16  on the same substituent are taken together to form a 4-8 membered optionally substituted ring; 
         R 17  is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, —C(═O)R 20 , C(═O)OR 23 , —SO 2 R 20 , —C(═O)N(R 20 ) 2 , or —[C(R 20 ) 2 ] p —R 21  wherein p is 0-6; or any two occurrences of R 17  on the same substituent are taken together to form a 4-8 membered optionally substituted ring; 
         R 18  is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, —CN, —OR 20 , —OSi(R 20 ) 3 , —C(═O)R 20 , —C(═O)OR 20 , —SO 2 R 20  or —C(═O)N(R 20 ) 2 ; 
         R 20  is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or any two occurrences of R 20  on the same substituent are taken together to form a 4-8 membered optionally substituted ring; 
         R 21  is —OR 22 , —N(R 22 )C(═O)R 22 , —N(R 22 )C(═O)OR 22 , —N(R 22 )SO 2 (R 22 ), —C(═O)R 22 N(R 22 ) 2 , —OC(═O)R 22 N(R 22 )(R 22 ), —SO 2 N(R 22 )(R 22 ), —N(R 22 )(R 22 ), —C(═O)OR 22 , —C(═O)N(OH)(R 22 ), —OS(O) 2 OR 22 , —S(O) 2 OR 22 , —OP(═O)(OR 22 )(OR 22 ), —N(R 22 )P(O)(OR 22 )(OR 22 ), or —P(═O)(OR 22 )(OR 22 ); and 
         R 22  is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl; or any two occurrences of R 22  on the same substituent are taken together to form a 4-8 membered optionally substituted ring. 
       
     
     
         40 . A compound of formula (III): 
       
         
           
           
               
               
           
         
         or salt thereof 
         made by a process comprising contacting a compound of formula (I): 
       
       
         
           
           
               
               
           
         
         or a salt thereof, an amino donor molecule, and an amine transaminase enzyme in a solution to provide a compound of formula (II): 
       
       
         
           
           
               
               
           
         
         or a salt thereof; 
         further comprising contacting a compound of formula (II) or a salt thereof with a sulfonylating agent that is methanesulfonyl chloride or methanesulfonyl anhydride to provide a compound of formula (III) or salt thereof; 
         wherein: 
         R 1  is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —OR 16 , —C(O)R 16 , —CO 2 R 16 , —SO 2 R 16 , —C(O)N(R 17 )(R 17 ), —[C(R 16 ) 2 ] q —R 16 , —[(W)—N(R 17 )C(O)] q R 16 , —[(W)—C(O)] q R 16 , —[(W)—C(O)O] q R 16 , —[(W)—OC(O)] q R 16 , —[(W)—SO 2 ] g R 16 , —[(W)—N(R 17 )SO 2 ] q R 16 , —[(W)—C(O)N(R 17 )] q R 17 , —[(W)—O] q R 16 , —[(W)—N(R 17 )] q R 16 , or —[(W)S] q R 16 ; wherein W is a diradical and q is 1, 2, 3, 4, 5, or 6; 
         each R 2  and R 3  is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, halo, —OR 16 , —OR 16 , —N(R 17 ) 2 , or —SR 16 , or R 2  and R 3  taken together form a double bond or form a group 
       
       
         
           
           
               
               
           
         
       
       wherein Z is NR 17 , O, or C(R 18 ) 2 ;
 R 4  is independently H, halo, —OR 16 , —N(R 17 ) 2 , or —SR 16 ; 
 each R 5  and R 6 , is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, —OR 16 , —N(R 17 ) 2 , or —SR 16 ; or R 5  and R 6  taken together with the carbon to which they are bonded form C═O, C═S, C═N—OR 17 , C═N—R 17 , C═N—N(R 17 ) 2 , or form an optionally substituted 3-8 membered ring; 
 each R 7 , R 8 , R 9 , R 10 , R 11 , R 12  and R 13  is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, —OR 16 , —N(R 17 ) 2 , or —SR 16 ; 
 or R 10  and R 11  taken together, or R 11  and R 12  taken together, form a double bond or form a group 
 
       
         
           
           
               
               
           
         
         wherein Z is NR 17 , O, or C(R 18 ) 2 ; 
         each R 14  and R 15  is, independently, H, halo, —OR 16 , —N(R 17 ) 2 , or —SR 16 ; or R 14  and R 15  taken together with the carbon to which they are bonded form C═O or C═S; 
         X is a bond or the group —C(R 19 ) 2 —; wherein each R 19  is, independently, H, alkyl, aralkyl, halo, —CN, —OR 16 , or —N(R 17 ) 2 ; 
         R 16  is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or —[C(R 20 ) 2 ] p —R 21  wherein p is 0-6; or any two occurrences of R 16  on the same substituent are taken together to form a 4-8 membered optionally substituted ring; 
         R 17  is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, —C(═O)R 20 , —C(═O)OR 20 , —SO 2 R 20 , —C(═O)N(R 20 ) 2 , or —[C(R 20 ) 2 ] p —R 21  wherein p is 0-6; or any two occurrences of R 17  on the same substituent are taken together to form a 4-8 membered optionally substituted ring; 
         R 18  is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, —CN, —OR 20 , —OSi(R 20 ) 3 , —C(═O)R 20 , —C(═O)OR 20 , —SO 2 R 20  or —C(═O)N(R 20 ) 2 ; 
         R 20  is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; or any two occurrences of R 20  on the same substituent are taken together to form a 4-8 membered optionally substituted ring; 
         R 21  is —OR 22 , —N(R 22 )C(═O)R 22 , —N(R 22 )C(═O)OR 22 , —N(R 22 )SO 2 (R 22 ), —C(═O)R 22 N(R 22 ) 2 , —OC(═O)R 22 N(R 22 )(R 22 ), —SO 2 N(R 22 )(R 22 ), —N(R 22 )(R 22 ), —C(═O)OR 22 , —C(═O)N(OH)(R 22 ), —OS(O) 2 OR 22 , —S(O) 2 OR 22 , —OP(═O)(OR 22 )(OR 22 ), —N(R 22 )P(O)(OR 22 )(OR 22 ), or —P(═O)(OR 22 )(OR 22 ); 
         R 22  is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl; or any two occurrences of R 22  on the same substituent are taken together to form a 4-8 membered optionally substituted ring; and 
         R 23  is —CH 3 .