Processes for the production of polycyclic fused ring compounds

Abstract

The present invention provides processes for the production of polycyclic fused ring compounds. The polycyclic fused ring compounds are produced by protecting a polycyclic fused ring polyol with a bridging silicon-based protecting group and attaching a suitable side chain. Novel polycyclic fused ring compounds and intermediate compounds are also described.

1 . A process for the production of a polycyclic fused ring compound corresponding to Formula (10): 
     
       
         
         
             
             
         
       
       the process comprising treating a polycyclic fused ring polyol with a bridging silicon-based protecting group and a side chain precursor, 
       wherein
 the polycyclic fused ring polyol corresponds to Formula (3): 
 
     
     
       
         
         
             
             
         
       
       
         the bridging silicon-based protecting group corresponds to Formula (4): 
       
     
     
       
         
         
             
             
         
       
       
         the side chain precursor corresponds to Formula (6) 
       
     
     
       
         
         
             
             
         
       
       
         X 2  is alkyl, alkenyl, alkynyl, aryl, heterocyclo, —OX 6 , —SX 7 , or —NX 8 X 9 ; 
         X 3  is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl, or heterocyclo; 
         X 5  is —COX 10 , —COOX 10 , or —CONHX 10 ; 
         X 6  is acyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydrogen, or hydroxy protecting group; 
         X 7  is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group; 
         X 8  is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo; 
         X 9  is an amino protecting group; 
         X 10  is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; 
         G 1 , G 2 , G 3 , and G 4  are independently hydrocarbyl, substituted hydrocarbyl, alkoxy, or heterocyclo; 
         L 1  and L 2  are independently amine, halide, or sulfonate leaving groups; 
         Z is hydrocarbyl, substituted hydrocarbyl, heterocyclo, —[O—Si(Z 10 )(Z 11 )—] n O—, or —O—; 
         Z 10  and Z 11  are hydrocarbyl; 
         n is 1 or 2; and 
         the dashed lines denote the skeletal structure of the polycyclic fused ring polyol. 
       
     
   
   
       2 . A process for the production of a polycyclic fused ring compound corresponding to Formula (12): 
     
       
         
         
             
             
         
       
       the process comprising treating a polycyclic fused ring polyol with a bridging silicon-based protecting group, 
       wherein
 the polycyclic fused ring polyol corresponds to Formula (3): 
 
     
     
       
         
         
             
             
         
       
       and
 the bridging silicon-based protecting group corresponds to Formula (4): 
 
     
     
       
         
         
             
             
         
       
       wherein
 G 1 , G 2 , G 3 , and G 4  are independently hydrocarbyl, substituted hydrocarbyl, alkoxy, or heterocyclo; 
 L 1  and L 2  are independently amine, halide, or sulfonate leaving groups; 
 Z is hydrocarbyl, substituted hydrocarbyl, heterocyclo, —[O—Si(Z 10 )(Z 11 )—] n O—, or —O—; 
 Z 10  and Z 11  are hydrocarbyl; 
 n is 1 or 2; and 
 the dashed lines denote the skeletal structure of the polycyclic fused ring polyol, provided, however, that G 1 , G 2 , G 3 , and G 4  are not branched alkyl when Z is —O—. 
 
     
   
   
       3 . A process for the production of a polycyclic fused ring compound corresponding to Formula (20 R ): 
     
       
         
         
             
             
         
       
       the process comprising treating a polycyclic fused ring compound corresponding to Formula (9 R ): 
     
     
       
         
         
             
             
         
       
       with an alcohol and a base, wherein
 the alcohol has the formula R 10A OH; 
 G 1 , G 2 , G 3 , and G 4  are independently hydrocarbyl, substituted hydrocarbyl, alkoxy, or heterocyclo; 
 R 10A  is hydrocarbyl; 
 R 13  is hydrogen or has the structure 
 
     
     
       
         
         
             
             
         
       
       
         X 2  is alkyl, alkenyl, alkynyl, aryl, heterocyclo, —OX 6 , —SX 7 , or —NX 8 X 9 ; 
         X 3  is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl, or heterocyclo; 
         X 4  is hydrogen or an amino protecting group; 
         X 5  is —COX 10 , —COOX 10 , or —CONHX 10 ; 
         X 6  is acyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydrogen, or hydroxy protecting group; 
         X 7  is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group; 
         X 8  is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo; 
         X 9  is an amino protecting group; 
         X 10  is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; 
         Z is hydrocarbyl, substituted hydrocarbyl, heterocyclo, —[O—Si(Z 10 )(Z 11 )—] n O—, or —O—; 
         Z 10  and Z 11  are hydrocarbyl; 
         n is 1 or 2; and 
         the dashed lines denote the skeletal structure of the polycyclic fused ring compound. 
       
     
   
   
       4 . The process of  claim 3  further comprising treating a polycyclic fused ring compound corresponding to Formula (20 R ) with an acylating agent to produce a compound corresponding to Formula (20 R10 ): 
     
       
         
         
             
             
         
       
       wherein
 R 10  is acyl. 
 
     
   
   
       5 . A polycyclic fused ring compound corresponding to Formula (9 R13 ): 
     
       
         
         
             
             
         
       
       wherein
 G 1 , G 2 , G 3 , and G 4  are independently hydrocarbyl, substituted hydrocarbyl, alkoxy, or heterocyclo; 
 R 13  is hydrogen, hydroxy protecting group, a metal, comprises ammonium, or has the structure 
 
     
     
       
         
         
             
             
         
       
       
         X 2  is alkyl, alkenyl, alkynyl, aryl, heterocyclo, —OX 6 , —SX 7 , or —NX 8 X 9 ; 
         X 3  is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl, or heterocyclo; 
         X 4  is hydrogen or an amino protecting group; 
         X 5  is —COX 10 , —COOX 10 , or —CONHX 10 ; 
         X 6  is acyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydrogen, or hydroxy protecting group; 
         X 7  is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group; 
         X 8  is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo; 
         X 9  is an amino protecting group; 
         X 10  is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; 
         Z is hydrocarbyl, substituted hydrocarbyl, heterocyclo, —[O—Si(Z 10 )(Z 11 )—] n O—, or —O—; 
         Z 10  and Z 11  are hydrocarbyl; 
         n is 1 or 2; and 
         the dashed lines denote the skeletal structure of the polycyclic fused ring compound, provided, however, G 1 , G 2 , G 3 , and G 4  are not branched alkyl when Z is —O—. 
       
     
   
   
       6 . A polycyclic fused ring compound corresponding to Formula (20 R10 ): 
     
       
         
         
             
             
         
       
       wherein
 G 1 , G 2 , G 3 , and G 4  are independently hydrocarbyl, substituted hydrocarbyl, alkoxy, or heterocyclo; 
 R 10  is hydrogen or acyl; 
 R 10A  is hydrocarbyl; 
 R 13  is hydrogen or has the structure 
 
     
     
       
         
         
             
             
         
       
       
         X 2  is alkyl, alkenyl, alkynyl, aryl, heterocyclo, —OX 6 , —SX 7 , or —NX 8 X 9 ; 
         X 3  is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl, or heterocyclo; 
         X 4  is hydrogen or an amino protecting group; 
         X 5  is —COX 10 , —COOX 10 , or —CONHX 10 ; 
         X 6  is acyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydrogen, or hydroxy protecting group; 
         X 7  is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group; 
         X 8  is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo; 
         X 9  is an amino protecting group; 
         X 10  is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; 
         Z is hydrocarbyl, substituted hydrocarbyl, heterocyclo, —[O—Si(Z 10 )(Z 11 )—] n O—, or —O—; 
         Z 10  and Z 11  are hydrocarbyl; 
         n is 1 or 2; and 
         the dashed lines denote the skeletal structure of the polycyclic fused ring compound. 
       
     
   
   
       7 . The process of  claim 1  wherein
 Z is —(CH 2 ) y —, —[O—Si(Z 10 )(Z 11 )—] n O—, or —O—;   n is 1 or 2;   y is a positive integer from about 1 to about 4; and   Z 10  and Z 11  are alkyl.   
   
   
       8 . The process of  claim 7  wherein
 G 1 , G 2 , G 3 , and G 4  are independently alkyl, aryl, heteroaryl, or cycloalkyl.   
   
   
       9 . The process of  claim 8  wherein
 G 1 , G 2 , G 3 , and G 4  are independently methyl, ethyl, ethenyl, phenyl, or cyclopentyl.   
   
   
       10 . The process of  claim 7  wherein
 L 1  and L 2  are independently halide leaving groups.   
   
   
       11 . The process of  claim 1  wherein the bridging silicon-based protecting group is selected from the group consisting of 1,3-dichlorotetramethyldisiloxane; 1,5-dichlorohexamethyltrisiloxane; 1,7-dichlorooctamethyltetrasiloxane; 1,3-dichloro-1,3-diphenyl-1,3-dimethyldisiloxane; 1,3-dichlorotetraphenyldisiloxane; 1,3-divinyl-1,3-dimethyl-1,3-dichlorodisiloxane; 1,1,3,3-tetracyclopenyldichlorodisiloxane; 1,2-bis(chlorodimethylsilyl)ethane; 1,3-bis(chlorodimethylsilyl)propane; 1,6-bis(chlorodimethylsilyl)hexane; and 1,8-bis(chlorodimethylsilyl)octane. 
   
   
       12 . The process of  claim 1  wherein the polycyclic fused ring polyol treated with the bridging silicon-based protecting group corresponds to Formula (13): 
     
       
         
         
             
             
         
       
       wherein
 R 1  is hydrogen, acyl, or together with R 2  or R 14  forms carbonate, acetal, or ketal; 
 R 2  is hydrogen, acyl, or together with R 1  or R 4  forms carbonate, acetal, or ketal; 
 R 4  is hydrogen, acyl, or together with R 2  forms carbonate, acetal, or ketal; and 
 R 14  is hydrogen, hydroxy, acyl, or together with R 1  or R 2  forms carbonate, acetal, or ketal. 
 
     
   
   
       13 . The process of  claim 1  wherein the polycyclic fused ring polyol treated with the bridging silicon-based protecting group is 10-DAB (23): 
     
       
         
         
             
             
         
       
     
   
   
       14 . The process of  claim 3  wherein the polycyclic fused ring compound treated with the alcohol and the base corresponds to Formula (19): 
     
       
         
         
             
             
         
       
       wherein
 R 1  is hydrogen, acyl, or together with R 2  or R 14  forms carbonate, acetal, or ketal; 
 R 2  is hydrogen, acyl, or together with R 1  or R 4  forms carbonate, acetal, or ketal; 
 R 4  is hydrogen, acyl, or together with R 2  forms carbonate, acetal, or ketal; and 
 R 14  is hydrogen, hydroxy, acyl, or together with R 1  or R 2  forms carbonate, acetal, or ketal. 
 
     
   
   
       15 . The process of  claim 14  wherein the polycyclic fused ring compound treated with the alcohol and the base corresponds to Formula (29): 
     
       
         
         
             
             
         
       
     
   
   
       16 . The compound of  claim 5  wherein the polycyclic fused ring compound corresponds to Formula (19): 
     
       
         
         
             
             
         
       
       wherein
 R 1  is hydrogen, acyl, or together with R 2  or R 14  forms carbonate, acetal, or ketal; 
 R 2  is hydrogen, acyl, or together with R 1  or R 4  forms carbonate, acetal, or ketal; 
 R 4  is hydrogen, acyl, or together with R 2  forms carbonate, acetal, or ketal; and 
 R 14  is hydrogen, hydroxy, acyl, or together with R 1  or R 2  forms carbonate, acetal, or ketal. 
 
     
   
   
       17 . The compound of  claim 16  wherein the polycyclic fused ring compound corresponds to Formula (29): 
     
       
         
         
             
             
         
       
     
   
   
       18 . The compound of  claim 6  wherein the polycyclic fused ring compound corresponds to Formula (30 R ): 
     
       
         
         
             
             
         
       
       wherein
 R 1  is hydrogen, acyl, or together with R 2  or R 14  forms carbonate, acetal, or ketal; 
 R 2  is hydrogen, acyl, or together with R 1  or R 4  forms carbonate, acetal, or ketal; 
 R 4  is hydrogen, acyl, or together with R 2  forms carbonate, acetal, or ketal; and 
 R 14  is hydrogen, hydroxy, acyl, or together with R 1  or R 2  forms carbonate, acetal, or ketal. 
 
     
   
   
       19 . The compound of  claim 18  wherein the polycyclic fused ring compound corresponds to Formula (40 R ): 
     
       
         
         
             
             
         
       
     
   
   
       20 . The process of  claim 1  wherein
 X 2  is —OX 6 ;   X 3  is phenyl;   X 5  is —COOX 10  or —COX 10 ;   X 6  is hydrogen or hydroxy protecting group; and   X 10  is tert-butyl or phenyl.   
   
   
       21 - 24 . (canceled)