Thiol Protecting Group

Abstract

The present invention relates to the use of a compound comprising a moiety of formula (I) as a reagent for protecting a thiol group in a thiol compound wherein X, X′ and Y are as defined herein. The protecting group methodology of the present invention allows straightforward and selective protection of thiol groups. Cleaving of the thiol group to regenerate the thiol functional group is also facile and controllable. The present invention further provides an analogous protecting group methodology directed to protection of disulfide groups.

1 . A process, which comprises:
 (i) reacting a thiol compound with a compound comprising a moiety of formula (I)   
       
         
           
           
               
               
           
         
       
       wherein X and X′ are the same or different and each represents oxygen, sulfur or a group of formula ═NR 1 , in which R 1  is hydrogen, hydroxyl, C 1-6  alkyl or phenyl, and Y is an electrophilic leaving group,
 thus producing a compound having a protected thiol group; and 
 (ii) subsequently deprotecting said protected thiol group; 
 and wherein at least one step is carried out after step (i) and before step (ii) which comprises effecting a chemical transformation on a functional group carried by the thiol compound that is not the protected thiol group, under conditions to which the protected thiol group is chemically inert, but to which a thiol group would be chemically reactive. 
 
     
     
         2 . A process according to  claim 1 , wherein said compound comprising a moiety of formula (I) is a compound of formula (Ia) 
       
         
           
           
               
               
           
         
       
       wherein:
 X and X′ are the same or different and each represents oxygen, sulfur or a group of formula ═NR 1 , in which R 1  is hydrogen, hydroxyl, C 1-6  alkyl or phenyl; 
 Y is an electrophilic leaving group; 
 R 2  represents a hydrogen atom or a group IG; 
 either:
 R 3  and R 3 ′ are the same or different and each represents a hydrogen atom or a group IG; or 
 R 3  and R 3 ′ together form a group of formula —N(R 33′ ), wherein R 33′  represents a hydrogen atom or a group IG; or 
 R 3  and R 3 ′ together form a group of formula —N(R 33′ )—N(R 33′ )—, wherein each R 33′  is the same or different and represents a hydrogen atom or a group IG; and 
 
 each group IG is the same or different and represents a moiety which is a C 1-20  alkyl group, a C 2-20  alkenyl group or a C 2-20  alkynyl group, which is unsubstituted or substituted by one or more halogen atoms and in which (a) 0, 1 or 2 carbon atoms are replaced by groups selected from C 6-10  arylene, 5- to 10-membered heteroarylene, C 3-7  carbocyclylene and 5- to 10-membered heterocyclylene groups, and (b) 0, 1 or 2 —CH 2 — groups are replaced by groups selected from —O—, —S—, —S—S—, —C(O)—, —NH— and —N(C 1-6  alkyl)-groups, wherein: 
 (i) said arylene, heteroarylene, carbocyclylene and heterocyclylene groups are unsubstituted or substituted by one or more substituents selected from halogen atoms and C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylthiol,
 —N(C 1-6 alkyl)(C 1-6  alkyl) and nitro groups; and 
 
 (ii) 0, 1 or 2 carbon atoms in said carbocyclylene and heterocyclylene groups are replaced by —C(O)— groups. 
 
     
     
         3 . A process according to  claim 1 , wherein Y is a halogen atom or a triflate, tosylate, mesylate, N-hydroxysuccinimidyl, N-hydroxysulfosuccinimidyl, C 1-6  alkylthiol, 5- to 10-membered heterocyclylthiol, C 6-10  arylthiol, C 3-7  carbocyclylthiol, —OC(O)CH 3 , —OC(O)CF 3 , phenyloxy, —NR x R y R z   +  or —PR x R y R z   +  group, in which R x , R y  and R z  are the same or different and are selected from hydrogen atoms and C 1-6  alkyl and phenyl groups. 
     
     
         4 . A process Use according to  claim 3 , wherein Y is a halogen atom or a C 1-6  alkylthiol, 5- to 10-membered heterocyclylthiol, C 6-10  arylthiol or C 3-7  carbocyclylthiol group. 
     
     
         5 . A process according to  claim 1 , wherein X and X′ each represent oxygen. 
     
     
         6 . A process according to  claim 2 , wherein IG represents a moiety which is an unsubstituted C 1-6  alkyl group, C 2-6  alkenyl group or C 2-6  alkynyl group, in which (a) 0 or 1 carbon atom is replaced by a group selected from phenylene, 5- to 6-membered heteroarylene, C 5-6  carbocyclylene and 5- to 6-membered heterocyclylene groups, wherein said phenylene, heteroarylene, carbocyclylene and heterocyclylene groups are unsubstituted or substituted by one or two substituents selected from halogen atoms and C 1-4  alkyl and C 1-4  alkoxy groups, and (b) 0, 1 or 2 —CH 2 — groups are replaced by groups selected from —O—, —S—, —C(O)—, —NH— and —N(C 1-6  alkyl)-groups. 
     
     
         7 . A process according to  claim 6 , wherein IG represents a moiety which is an unsubstituted C 1-6  alkyl group, in which (a) 0 or 1 carbon atom is replaced by a group selected from unsubstituted phenylene, 5- to 6-membered heteroarylene, C 5-6  carbocyclylene and 5- to 6-membered heterocyclylene groups, and (b) 0 or 1 —CH 2 — groups are replaced by groups selected from —O—, —NH— and —N(C 1-6  alkyl)-groups. 
     
     
         8 . A process Use according to  claim 6 , wherein IG represents an unsubstituted C 1-6  alkyl or phenyl group. 
     
     
         9 . A process according to  claim 2 , wherein R 3 , R 3′  and R 33 ′ each represent a group IG. 
     
     
         10 . A process according to  claim 2 , wherein said compound of formula (Ia) is a compound of formula (Ib) 
       
         
           
           
               
               
           
         
       
       wherein X, X′, Y, R 2  and R 33′  are all as defined in to  claim 2 . 
     
     
         11 . A process Use according to  claim 10 , wherein:
 X and X′ each represent an oxygen atom;   R 33′  represents a hydrogen atom or a C 1-6  alkyl group;   Y represents a halogen atom; and   R 2  represents a hydrogen atom or a C 1-6  alkyl group.   
     
     
         12 . A process according to  claim 1 , wherein the thiol compound is cysteine or a peptide or protein comprising at least one cysteine residue. 
     
     
         13 . (canceled) 
     
     
         14 . A process according to  claim 1 , wherein said step of deprotecting said protected thiol group is effected by reacting the protected thiol group with a reagent that is capable of acting as a nucleophile in a conjugate addition reaction. 
     
     
         15 . A process according to  claim 14 , wherein said reagent is a phosphine compound or a thiol. 
     
     
         16 . A process according to  claim 15 , wherein said reagent is tris(2-carboxyethyl)phosphine, 1,2-ethanedithiol, glutathione, 2-mercaptoethanol or dithiothreitol. 
     
     
         17 . A compound of formula (II) 
       
         
           
           
               
               
           
         
       
       wherein X, X′, R 2 , R 3′  and R 3′  are all as defined in  claim 2 , Q is a carboxyl group or a protected carboxyl group and Q′ is an amine group or a protected amine group;
 with the proviso that said compound of formula (II) is not  14 C—N-ethylmaleimide-S-cysteine or  14 C—N-ethylmaleimide-S-N-acetyl-cysteine. 
 
     
     
         18 . A compound according to  claim 17 , wherein Q is a carboxyl group and Q′ is a protected amine group. 
     
     
         19 . A process, which comprises:
 (i) reacting a disulfide group in a disulfide compound with a compound comprising a moiety of formula (III)   
       
         
           
           
               
               
           
         
       
       wherein X and X′ are the same or different and each represents oxygen, sulfur or a group of formula ═NR 1 , in which R 1  is hydrogen, hydroxyl, C 1-6  alkyl or phenyl, and Y and Y′ are the same or different and each represents an electrophilic leaving group,
 thus producing a compound having a protected disulfide group; and 
 (ii) subsequently deprotecting said protected disulfide group; 
 and wherein at least one step is carried out after step (i) and before step (ii) which comprises effecting a chemical transformation on a functional group carried by the disulfide compound that is not the protected disulfide group, under conditions to which the protected disulfide group is chemically inert, but to which a disulfide group would be chemically reactive. 
 
     
     
         20 . A process according to  claim 19 , wherein said compound comprising a moiety of formula (III) is a compound of formula (Ma) 
       
         
           
           
               
               
           
         
       
       wherein X, X′, Y, R 3  and R 3′  are all as defined in  claim 2  and Y′ is a further group Y, each group Y being the same or different. 
     
     
         21 . (canceled)