Total synthesis of salinosporamide a and analogs thereof

Abstract

The present application relates to certain compounds and to methods for the preparation of certain compounds that can be used in the fields of chemistry and medicine. Specifically, described herein are methods for the preparation of various compounds and intermediates, and the compounds and intermediates themselves. More specifically, described herein are methods for synthesizing Salinosporamide A and its analogs that includes forming a compound of formula (VIII).

1 . A method of preparing a compound of formula (VI) comprising:
 (a) reacting acetoacetic acid with a compound of formula (I) to form a compound of formula (III-2):   
       
         
           
           
               
               
           
         
         (b) alkylating the compound of formula (III-2) with allyl bromide and forming a compound of formula (V) via an intramolecular aldol reaction: 
       
       
         
           
           
               
               
           
         
       
       and
 (c) dehydrating the compound of formula (V) to form a double bond between C-2 and C-3 and give a compound of formula (VI): 
 
       
         
           
           
               
               
           
         
         wherein: R 1  is selected from the group consisting of hydrogen, an unsubstituted or substituted C 1-6  alkyl, and an unsubstituted or substituted aryl; and R 2  is selected from the group consisting of hydrogen, an unsubstituted or substituted C 1-6  alkyl, an unsubstituted or substituted aryl, and an unsubstituted or substituted arylalkyl. 
       
     
     
         2 . The method of  claim 1 , wherein the compound of formula (V) has a structure and a stereochemistry selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         3 . A method of preparing a compound of formula (VI) comprising:
 (a) reacting acetoacetic acid with a compound of formula (I) to form a compound of formula (III-2), and   
       
         
           
           
               
               
           
         
       
       and
 (b) reacting the compound of formula (III-2) with allyl bromide and formingform a compound of formula (VI) via an intramolecular aldol 
 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of hydrogen, an unsubstituted or substituted C 1-6  alkyl, and an unsubstituted or substituted aryl; and R 2  is selected from the group consisting of hydrogen, an unsubstituted or substituted C 1-6  alkyl, an unsubstituted or substituted aryl, and an unsubstituted or substituted arylalkyl. 
       
     
     
         4 . A method of preparing a compound of formula (VI) comprising:
 (a) adding diketene to a compound of formula (I) to form a compound of formula (III-2);   
       
         
           
           
               
               
           
         
         (b) alkylating the compound of formula (III-2) with allyl bromide to form a compound of formula (V) via an intramolecular aldol reaction; and 
       
       
         
           
           
               
               
           
         
         (c) dehydrating the compound of formula (V) to form a compound of formula (VI) to form a double bond between C-2 and C-3 and give a compound of formula (VI): 
       
       
         
           
           
               
               
           
         
         wherein: R 1  is selected from the group consisting of hydrogen, an unsubstituted or substituted C 1-6  alkyl, and an unsubstituted or substituted aryl; and R 2  is selected from the group consisting of hydrogen, an unsubstituted or substituted C 1-6  alkyl, an unsubstituted or substituted aryl, and an unsubstituted or substituted arylalkyl. 
       
     
     
         5 . The method of  claim 4 , wherein the compound of formula (V) has a structure and a stereochemistry selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         6 . A method of preparing a compound of formula (VI) comprising:
 (a) adding diketene to a compound of formula (I) to form a compound of formula (III-2); and   
       
         
           
           
               
               
           
         
         (b) alkylating the compound of formula (III-2) with allyl bromide forming a compound of formula (VI) via an intramolecular aldol condensation reaction: 
       
       
         
           
           
               
               
           
         
         wherein: R 1  is selected from the group consisting of hydrogen, an unsubstituted or substituted C 1-6  alkyl, and an unsubstituted or substituted aryl; and R 2  is selected from the group consisting of hydrogen, an unsubstituted or substituted C 1-6  alkyl, an unsubstituted or substituted aryl, and an unsubstituted or substituted arylalkyl. 
       
     
     
         7 . A compound of formula (VI-A): 
       
         
           
           
               
               
           
         
         wherein: R 1  is selected from the group consisting of hydrogen, an unsubstituted or substituted C 1-6  alkyl, and an unsubstituted or substituted aryl; and R 2  is selected from the group consisting of hydrogen, an unsubstituted or substituted C 1-6  alkyl, an unsubstituted or substituted aryl, and an unsubstituted or substituted arylalkyl. 
       
     
     
         8 . The compound of  claim 7 , wherein R 1  is an unsubstituted or substituted C 1-6  alkyl; and R 2  is an unsubstituted or substituted C 1-6  alkyl. 
     
     
         9 . The compound of  claim 8 , wherein R 1  is t-butyl. 
     
     
         10 . The compound of  claim 8 , wherein R 2  is methyl. 
     
     
         11 . A method of preparing the compound of  claim 7  comprising a dehydrating a compound of formula (Va-A) to form a compound of formula (VI-A). 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of hydrogen, an unsubstituted or substituted C 1-6  alkyl, and an unsubstituted or substituted aryl; and R 2  is selected from the group consisting of hydrogen, an unsubstituted or substituted C 1-6  alkyl, an unsubstituted or substituted aryl, and an unsubstituted or substituted arylalkyl.