Enzymatic Transamination of Cyclopamine Analogs
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 .