Illudin analogs, uses thereof, and methods for synthesizing the same

Abstract

This invention provides illudin derivatives, intermediates, preparation methods, pharmaceutical compositions and uses thereof. Specific examples include novel synthetic routes to prepare illudin derivatives and an illudin derivative having a positive optical rotation, which has therapeutic value.

What is claimed: 
     
         1 . A process for synthesizing compounds having the formula (III): 
       
         
           
           
               
               
           
         
       
       wherein Ri, R 2  and R 3  are independently (C1-C4) alkyl, methyl, or hydroxyl, comprising the steps of
 selecting a cyclopentenone having an alcohol group; 
 protecting the alcohol group; 
 reacting the protected cyclopentenone with a diazoketone to form a cycloadduct; and reducing the cycloadduct. 
 
     
     
         2 . The method according to  claim 1 , wherein the cyclopentenone of step a is selected from the group consisting of substituted cyclopentenones. 
     
     
         3 . The method according to  claim 1 , wherein the cleaving of the oxy group is achieved through the use of a suitable acid or base. 
     
     
         4 . The process according to  claim 1 , wherein the diazoketone is derived from a diazo compound and a ketone. 
     
     
         5 . The process of  claim 1 , wherein R1, R2, and R3 are each independently selected from (C1-C4) alkyl groups. 
     
     
         6 . The process of  claim 1 , further comprising oxidizing the cleaved cycloadduct to obtain hydroxyureamethylacylfulvene (+). 
     
     
         7 . The method according to  claim 6 , further comprising isolating hydroxyureamethylacylfulvene (+) after step g) using standard purification techniques. 
     
     
         8 . A method for synthesizing enantiopure acylfulvene, hydroxymethyl acylfulvene (HMAF), and hydroxyureamethylacylfulvene (UMAF) utilizing an enzymatic resolution of Compound 9 (Scheme 5). 
       
         
           
           
               
               
           
         
       
     
     
         9 . A method of synthesizing hydroxyureamethylacylfulvene (+) comprising the steps of:
 a) selecting a cyclopentenone having an alcohol group;   b) protecting the alcohol group of the selected cyclopentenone;   c) reacting the protected cyclopentenone with a diazoketone to form a cycloadduct;   d) Reducing the cycloadduct obtained in step c;   e) Alkylating a ketone group of the reduced cycloadduct;   f) Cleaving an oxy group of the alkylated cycloadduct; and   g) Oxidizing the cleaved cycloadduct to obtain hydroxyureamethylacylfulvene (+).   
     
     
         10 . The method according to  claim 9 , wherein the cyclopentenone of step a is selected from the group consisting of substituted and unsubstituted cyclopentenones. 
     
     
         11 . The method according to  claim 9 , wherein the protecting group used in step b is selected from the group consisting of acetyl, benzyl, tert-butyldimethylsilyl (TBDMS), and tert-butoxy carbonyl groups. 
     
     
         12 . The method according to  claim 9 , wherein the cleaving of the oxy group in step f is achieved through the use of a suitable reagent, such as an acid or base. 
     
     
         13 . The method according to  claim 9 , wherein the alkylating agent used in step 5 is selected from the group consisting of alkyl halides, alkyl sulfonates, and alkyl tosylates. 
     
     
         14 . The method according to  claim 9 , wherein the alkylating agent of step e) is an alkyl halide. 
     
     
         15 . The method according to  claim 9 , further comprising isolating hydroxyureamethylacylfulvene (+) after step g by standard purification techniques.