Enzymatic Transamination of Cyclopamine Analogs

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:
• R1 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —OR16, —C(O)R16, —CO2R16, —SO2R16, —C(O)N(R17)(R17), —[C(R16)2]q—R16, —[(W)—N(R17)C(O)]qR16, —[(W)—C(O)]qR16, —[(W)—C(O)]qR16, —[(W)—C(O)]qR16, —[(W)—SO2]qR16, —[(W)—N(R17)SO2]qR16, —[(W)—C(O)N(R17)]qR17, —[(W)—O]qR16, —[(W)—N(R17)]qR16, or —[(W)—S]qR16;
• wherein W is a diradical and q is 1, 2, 3, 4, 5, or 6;
• each R2 and R3 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, halo, —OR16, —OR16, —N(R17)2, or —SR16, or R2 and R3 taken together form a double bond or form a group
• wherein Z is NR17, O, or C(R18)2;
• R4 is independently H, halo, —OR16, —N(R17)2, or —SR16;
• each R5 and R6, is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, —OR16, —N(R17)2, or —SR16;
• or R5 and R6 taken together with the carbon to which they are bonded form C═O, C═S, C═N—OR17, C═N—R17, C═N—N(R17)2, or form an optionally substituted 3-8 membered ring;
• each R7, R8, R9, R10, R11, R12 and R13 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, —OR16, —N(R17)2, or —SR16;
• or R10 and R11 taken together, or R11 and R12 taken together, form a double bond or form a group
• wherein Z is NR17, O, or C(R15)2;
• each R14 and R15 is, independently, H, halo, —OR16, —N(R17)2, or —SR16;
• or R14 and R15 taken together with the carbon to which they are bonded form C═O or C═S;
• X is a bond or the group —C(R19)2—;
• wherein each R19 is, independently, H, alkyl, aralkyl, halo, —CN, —OR16, or —N(R17)2;
• R16 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or —[C(R20)2]p—R21 wherein p is 0-6;
• or any two occurrences of R16 on the same substituent are taken together to form a 4-8 membered optionally substituted ring;
• R17 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, —C(═O)R20, C(═O)OR23, —SO2R20, —C(═O)N(R20)2, or —[C(R20)2]p—R21 wherein p is 0-6;
• or any two occurrences of R17 on the same substituent are taken together to form a 4-8 membered optionally substituted ring;
• R18 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, —CN, —OR20, —OSi(R20)3, —C(═O)R20, —C(═O)OR20, —SO2R20 or —C(═O)N(R20)2;
• R20 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl;
• or any two occurrences of R20 on the same substituent are taken together to form a 4-8 membered optionally substituted ring;
• R21 is —OR22, —N(R22)C(═O)R22, —N(R22)C(═O)OR22, —N(R22)SO2(R22), —C(═O)R22N(R22)2, —OC(═O)R22N(R22)(R22), —SO2N(R22)(R22), —N(R22)(R22), —C(═O)OR22, —C(═O)N(OH)(R22), —OS(O)2OR22, —S(O)2OR22, —OP(═O)(OR22)(OR22), —N(R22)P(O)(OR22)(OR22), or —P(═O)(OR22)(OR22);
• and
• R22 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl;
• or any two occurrences of R22 on the same substituent are taken together to form a 4-8 membered optionally substituted ring.

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:
• R1 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —OR16, —C(O)R16, —CO2R16, —SO2R16, —C(O)N(R17)(R17), —[C(R16)2]q—R16, —[(W)—N(R17)C(O)]qR16, —[(W)—C(O)]qR16, —[(W)—C(O)O]qR16, —[(W)—OC(O)]qR16, —[(W)—SO2]gR16, —[(W)—N(R17)SO2]qR16, —[(W)—C(O)N(R17)]qR17, —[(W)—O]qR16, —[(W)—N(R17)]qR16, or —[(W)S]qR16;
• wherein W is a diradical and q is 1, 2, 3, 4, 5, or 6;
• each R2 and R3 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, halo, —OR16, —OR16, —N(R17)2, or —SR16, or R2 and R3 taken together form a double bond or form a group
• wherein Z is NR17, O, or C(R18)2;
• R4 is independently H, halo, —OR16, —N(R17)2, or —SR16;
• each R5 and R6, is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, —OR16, —N(R17)2, or —SR16;
• or R5 and R6 taken together with the carbon to which they are bonded form C═O, C═S, C═N—OR17, C═N—R17, C═N—N(R17)2, or form an optionally substituted 3-8 membered ring;
• each R7, R8, R9, R10, R11, R12 and R13 is, independently, H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, —OR16, —N(R17)2, or —SR16;
• or R10 and R11 taken together, or R11 and R12 taken together, form a double bond or form a group
• wherein Z is NR17, O, or C(R18)2;
• each R14 and R15 is, independently, H, halo, —OR16, —N(R17)2, or —SR16;
• or R14 and R15 taken together with the carbon to which they are bonded form C═O or C═S;
• X is a bond or the group —C(R19)2—;
• wherein each R19 is, independently, H, alkyl, aralkyl, halo, —CN, —OR16, or —N(R17)2;
• R16 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl or —[C(R20)2]p—R21 wherein p is 0-6;
• or any two occurrences of R16 on the same substituent are taken together to form a 4-8 membered optionally substituted ring;
• R17 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, —C(═O)R20, —C(═O)OR20, —SO2R20, —C(═O)N(R20)2, or —[C(R20)2]p—R21 wherein p is 0-6;
• or any two occurrences of R17 on the same substituent are taken together to form a 4-8 membered optionally substituted ring;
• R18 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, halo, —CN, —OR20, —OSi(R20)3, —C(═O)R20, —C(═O)OR20, —SO2R20 or —C(═O)N(R20)2;
• R20 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl;
• or any two occurrences of R20 on the same substituent are taken together to form a 4-8 membered optionally substituted ring;
• R21 is —OR22, —N(R22)C(═O)R22, —N(R22)C(═O)OR22, —N(R22)SO2(R22), —C(═O)R22N(R22)2, —OC(═O)R22N(R22)(R22), —SO2N(R22)(R22), —N(R22)(R22), —C(═O)OR22, —C(═O)N(OH)(R22), —OS(O)2OR22, —S(O)2OR22, —OP(═O)(OR22)(OR22), —N(R22)P(O)(OR22)(OR22), or —P(═O)(OR22)(OR22);
• R22 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl;
• or any two occurrences of R22 on the same substituent are taken together to form a 4-8 membered optionally substituted ring;
• and
• R23 is —CH3.