Synthesis of cantharidin

Abstract

The invention provides synthetic methods for the preparation of cantharidin and analogs thereof. In one aspect, the invention provides an improved Diels-Alder cycloaddition to generate a key intermediate en route to cantharidin and analogs thereof. In yet another aspect, the invention describes a new palladium-mediated carbonylation providing another key intermediate en route to cantharidin and analogs thereof. In addition to synthetic methods, present invention also provides compounds (i.e., intermediates) useful in the synthesis of cantharidin and analogs thereof. Compounds provided herein may have biological activity, and therefore may be used in the treatment of diseases or conditions (e.g., infectious diseases and skin conditions).

1 . A method of preparing Compound (1): 
       
         
           
           
               
               
           
         
         the method comprising reacting Compound (2): 
       
       
         
           
           
               
               
           
         
         with furan;
 wherein the reaction is carried out in the absence of a Lewis acid; and 
 wherein the reaction is carried out at around atmospheric pressure. 
 
       
     
     
         2 . The method of  claim 1 , wherein the reaction is carried out in the absence of added acid. 
     
     
         3 - 6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein the reaction is carried out in the absence of a Brønsted acid. 
     
     
         8 . The method of  claim 1 , wherein the reaction is carried out at a pressure of approximately 1 atm. 
     
     
         9 . The method of  claim 1 , wherein the reaction is carried out in the absence of added acid and in the absence of increased pressure. 
     
     
         10 . The method of  claim 1 , wherein the reaction is carried out in a solvent. 
     
     
         11 - 16 . (canceled) 
     
     
         17 . The method of  claim 1 , wherein the reaction is carried out in the absence of solvent. 
     
     
         18 - 21 . (canceled) 
     
     
         22 . The method of  claim 1 , wherein the reaction is carried out at a temperature below 100° C. 
     
     
         23 . The method of  claim 22 , wherein the reaction is carried out at approximately room temperature. 
     
     
         24 - 29 . (canceled) 
     
     
         30 . The method of  claim 1 , wherein furan is present in greater than 1 equivalent relative to the amount of Compound (2) in the reaction mixture. 
     
     
         31 . The method of  claim 30 , wherein the ratio of Compound (2) to furan in the reaction mixture is from 1:4 to 1:5. 
     
     
         32 . (canceled) 
     
     
         33 . The method of  claim 1 , wherein the Compound (1) is formed in exo/endo ratio of about 70:30 to 99:1. 
     
     
         34 - 36 . (canceled) 
     
     
         37 . The method of  claim 33 , wherein the exo/endo ratio is about 98:2. 
     
     
         38 . The method of  claim 1 , wherein Compound (1) is isolated in greater than 50% yield. 
     
     
         39 - 46 . (canceled) 
     
     
         47 . The method of  claim 1  further comprising a step of hydrogenating Compound (1) to yield Compound (3): 
       
         
           
           
               
               
           
         
       
     
     
         48 - 49 . (canceled) 
     
     
         50 . The method of  claim 47  further comprising a step of reducing Compound (3): 
       
         
           
           
               
               
           
         
         to yield cantharidin: 
       
       
         
           
           
               
               
           
         
       
     
     
         51 - 53 . (canceled) 
     
     
         54 . A method of preparing a compound of Formula (IV): 
       
         
           
           
               
               
           
         
         the method comprising reacting a compound of Formula (III): 
       
       
         
           
           
               
               
           
         
         in the presence of furan, wherein:
 n is 0, 1, 2, 3, 4, or 5; 
 each instance of R 3  is independently hydrogen, halogen, —CN, —NO 2 , —N 3 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfinyl, —OR O , —N(R N ) 2 , or —SR S ; 
 each instance of R O  is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; 
 each instance of R N  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group; or optionally two R N  on the same nitrogen are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; and 
 each instance of R S  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group. 
 
       
     
     
         55 - 98 . (canceled) 
     
     
         99 . A method of preparing a compound of Formula (I): 
       
         
           
           
               
               
           
         
         the method comprising reacting a compound of Formula (II): 
       
       
         
           
           
               
               
           
         
         in the presence of palladium, carbon monoxide, and a reagent of the formula R 2 OH; 
         wherein:
 X 1  is halogen, optionally substituted sulfonate, or optionally substituted phosphonate; 
 R 1  and R 2  are independently optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or an oxygen protecting group. 
 
       
     
     
         100 - 134 . (canceled) 
     
     
         135 . A compound of Formula (II): 
       
         
           
           
               
               
           
         
         wherein:
 X 1  is halogen, optionally substituted sulfonate, or optionally substituted phosphonate; 
 R 1  is optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or an oxygen protecting group. 
 
       
     
     
         136 - 142 . (canceled) 
     
     
         143 . The compound of  claim 135 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         144 - 155 . (canceled)