Substituted 3-hydroxy-delta-lactones from epoxides

Abstract

Catalysts and methods for the carbonylation of epoxides to substituted 3-hydroxy-δ-lactones and β-lactones are disclosed.

1 . A method comprising the steps of:
 reacting an epoxide of formula:   
       
         
           
           
               
               
           
         
         
           wherein: 
           n is an integer between 0 and 3, inclusive; 
         
         R a , R b , R c , R d  and each R group are independently hydrogen; halogen; C 1  to C 20  alkyl; C 2  to C 20  alkenyl; C 2  to C 20  alkynyl; up to a C 16  carbocycle; up to a C 16  heterocycle; —C(R 13 ) z H (3-z) ; or a polymer chain; or
 two or more of R a , R b , R c , R d , or R groups may be taken together with intervening atoms to form one or more optionally substituted rings optionally containing one or more heteroatoms, and any of R a , R b , R c , R d , and R may optionally be further substituted with one or more X groups; 
 
         P′ is hydrogen or a hydroxyl protecting group; 
         each occurrence of X is independently halogen; a phosphorus-containing moiety, —OR 10 ; —OC(O)R 13 ; —OC(O)OR 13 ; —OC(O)NR 11 R 12 ; —CN; —CNO; —C(O)R 13 ; —C(O)OR 13 ; —C(O)NR 11 R 12 ; —C(R 13 ) z H (3-z) ; —NR 11 C(O)R 10 ; —NR 11 C(O)OR 10 ; —NCO; —NR 12 SO 2 R 13 ; —S(O) x R 13 ; —S(O) 2 NR 11 R 12 ; —NO 2 ; —N 3 ; —(CH 2 ) k R 14 ; —(CH 2 ) k —Z—R 14 ; and —(CH 2 ) k —Z—(CH 2 ) m —R 14 ; 
         R 10  at each occurrence can be independently selected from the group consisting of: hydrogen; —C(R 13 ) z H (3-z) ; C 1  to C 12  alkyl; C 2  to C 12  alkenyl; C 2  to C 12  alkynyl; up to a C 12  carbocycle; up to a C 12  heterocycle; —S(O) 2 R 13 ; —Si(R 15 ) 3 ; and a hydroxyl protecting group; 
         R 11  and R 12  at each occurrence can be independently selected from the group consisting of: hydrogen; C 1  to C 12  alkyl; C 2  to C 12  alkenyl; C 2  to C 12  alkynyl; and —C(R 13 ) z H (3-z) ; 
         R 11  and R 12 ; when both present, can optionally be taken together with the atom to which they are attached to form an optionally substituted 3- to 10-membered ring, optionally containing one or more additional heteroatoms; 
         R 13  at each occurrence can be independently selected from the group consisting of: hydrogen; halogen; C 1  to C 12  alkyl; C 2  to C 12  alkenyl; C 2  to C 12  alkynyl; up to a C 12  carbocycle; or up to a C 12  heterocycle; 
         R 14  at each occurrence can be independently selected from the group consisting of halogen; —OR 10 ; —OC(O)R 13 ; —OC(O)OR 13 ; —OC(O)NR 11 R 12 ; —CN; —CNO; —C(R 13 ) z H (3-z) ; —C(O)R 13 ; —C(O)OR 13 ; —C(O)NR 11 R 12 ; —NR 11 C(O)R 13 ; —NR 11 C(O)OR 10 ; —NR 11 SO 2 R 13 ; —NCO; —N 3 ; —NO 2 ; —S(O) x R 13 ; —SO 2 NR 11 R 12 ; up to a C 12  heterocycle; and up to a C 12  carbocycle; 
         R 15  at each occurrence can be independently selected from the group consisting of: C 1  to C 6  alkyl; C 2  to C 6  alkenyl; C 2  to C 6  alkynyl; and up to C 12  substituted or unsubstituted carbocycle; 
         Z is a divalent linker and can be selected from the group consisting of: —(CH═CH) a —; —(CH≡CH) a —; —C(O)—; —C(═NOR 11 )—; —C(═NNR 11 R 12 )—; —O—; —N(R 11 )—; —N(C(O)R 13 )—; —S(O)—; a polyether; and a polyamine;
 a can be 1, 2, 3, or 4; 
 k can be an integer from 1 to 8 inclusive; 
 m can be an integer from 1 to 8 inclusive; 
 x can be 0, 1, or 2; and 
 z can be 1, 2, or 3; 
 
         with carbon monoxide (CO) in the presence of a catalytically effective amount of a catalyst of the formula:
   [Lewis acid] u+ {[QT(CO) v ] s- } t    II
 
 wherein: 
 Q is any ligand or set of ligands and need not be present; 
 T is a transition metal; 
 s is an integer from 1 to 4 inclusive; 
 t is a number such that t multiplied by s equals u; 
 u is an integer from 1 to 6 inclusive; and 
 v is an integer from 1 to 9 inclusive; 
 
         to produce a compound of the formula: 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The method of  claim 1 , wherein P′ is hydrogen. 
     
     
         3 . The method of  claim 1 , wherein R, R c , and R d  are hydrogen. 
     
     
         4 . The method of  claim 1 , wherein the epoxide is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein p is an integer between 1 and 4, inclusive. 
     
     
         5 . The method of  claim 1 , wherein the epoxide is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein p is an integer between 1 and 4, inclusive. 
     
     
         6 . The method of  claim 1 , wherein the epoxide is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein p is an integer between 1 and 4, inclusive. 
     
     
         7 . The method of  claim 1 , wherein the epoxide is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 1 , wherein the epoxide is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein m is an integer between 0 and 10, inclusive. 
     
     
         9 . The method of  claim 1 , wherein the epoxide is of the formula: 
       
         
           
           
               
               
           
         
       
       wherein m is an integer between 0 and 10, inclusive. 
     
     
         10 . The method of  claim 1 , wherein the epoxide is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 10 , wherein P′ is hydrogen. 
     
     
         12 . The method of  claim 10 , wherein X is a halogen. 
     
     
         13 . The method of  claim 10 , wherein X is chlorine. 
     
     
         14 . The method of  claim 1 , wherein the epoxide is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 1 , wherein the epoxide is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 15 , wherein P′ is hydrogen. 
     
     
         17 . The method of  claim 15 , wherein R 10  is a suitable protecting group or hydrogen. 
     
     
         18 . The method of  claim 17 , wherein R 10  is a silyl protecting group. 
     
     
         19 . The method of  claim 18 , wherein R 10  is tert-butyldimethylsilyl. 
     
     
         20 - 43 . (canceled) 
     
     
         44 . A method comprising steps of:
 reacting an epoxide of formula S-Ia′:   
       
         
           
           
               
               
           
         
       
       wherein:
 P′ is hydrogen or a hydroxyl protecting group; 
 Q′ is selected from the group consisting of: hydrogen; halogen; (a) C 1  to C 20  alkyl; (b) C 2  to C 20  alkenyl; (c) C 2  to C 20  alkynyl; (d) up to a C 16  carbocycle; (e) up to a C 16  heterocycle; and (f) —C(R 13 ) z H (3-z) ; or 
 Q′ is selected from the group consisting of a core of a statin molecule, a precursor to the core of a statin molecule, or a derivative of the core of a statin molecule; 
 with carbon monoxide (CO) in the presence of a catalytically effective amount of a catalyst of the formula:
   [Lewis acid] u+ {[QT(CO) v ] s- } t    II
 
 wherein: 
 Q is any ligand or set of ligands and need not be present; 
 T is a transition metal; 
 s is an integer from 1 to 4 inclusive; 
 t is a number such that t multiplied by s equals u; 
 u is an integer from 1 to 6 inclusive; and 
 v is an integer from 1 to 9 inclusive; 
 
 to produce a compound of the formula S-I′: 
 
       
         
           
           
               
               
           
         
       
     
     
         45 - 73 . (canceled)