Analogs of dictyostatin, intermediates therefor and methods of systhesis thereof

Abstract

Dictyostatin and its analogs show great promise as new anticancer agents. The present invention provides dictyostatin analogs, synthetic intermediates for the synthesis of dictyostatin analogs, and synthetic methods for the synthesis of such analogs and intermediates. Dictyostatin analogs can have the following structure or its enantiomer wherein R 1 is H, an alkyl group, an aryl group, an alkenyl group, an alkynyl group, or a halogen atom; R 2 is H, a protecting group, an alkyl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , or COR e ; R a , R b and R c are independently an alkyl group or an aryl group; R d is an alkyl group, an aryl group, an alkoxylalkyl group, —R i SiR a R b R c or a benzyl group, wherein R i is an alkylene group; R e is an alkyl group, an allyl group, a benzyl group, an aryl group, an alkoxy group, or —NR g R h , wherein R g and R h are independently H, an alkyl group or an aryl group; R 3 is (CH 2 ) n where n is and integer in the range of 0 to 5, —CH 2 CH(CH 3 ), —CH═CH—, —CH═C(CH 3 ), or —C≡C—; R 4 is wherein R 23a is H, a protecting group, an alkyl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , or COR e , R 23b is H, a protecting group, an alkyl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , or COR e , or R 23a and R 23b together form a portion of six-membered acetal ring incorporating CR t R u ; R t and R u are independently H, an alkyl group, an aryl group or an alkoxyaryl group; and R 5 is H or OR 2b , wherein R 2b is H, a protecting group, an alkyl group, an aryl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , or COR e ; provided that the compound is not dictyostatin 1.

1 . A compound having the following formula, or its enantiomer 
       
         
           
           
               
               
           
         
         R 2  is H, a protecting group, an alkyl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , or COR e ; 
         R a , R b  and R c  are independently an alkyl group or an aryl group; 
         R d  is an alkyl group, an aryl group, an alkoxylalkyl group, —RSiR a R b R c  or a benzyl group, wherein R i  is an alkylene group; 
         R e  is an alkyl group, an allyl group, a benzyl group, an aryl group, an alkoxy group, or —NR g R h , wherein R g  and R h  are independently H, an alkyl group or an aryl group; 
         R 3  is (CH 2 ), where n is and integer in the range of 0 to 5, —CH 2 CH(CH 3 )—, —CH═CH—, —CH═C(CH 3 )—, or —C≡C—; 
         R 11a  and R 11b  are independently H, a protecting group, an alkyl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , COR e , or R 11a  and R 11b  together form a portion of six-membered acetal ring containing CR t R u ; 
         R t  and R u  are independently H, an alkyl group, an aryl group or an alkoxyaryl group; 
         R 12  is a halogen atom, CH 2 OR 2c , CHO, CO 2 R 10 , CH═CHCH 2 OR 2c , CH═CHCHO or CH═CHCO 2 R 10 , wherein R 2c  is H, a protecting group, an alkyl group, an aryl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , or COR e , and R 10  is H or alkyl; and 
         R 14a  and R 14b  are independently H, an alkyl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , COR e , or R 14a  and R 14b  together form a six-membered ring containing CR v R w , wherein R v  and R w  are independently H, an alkyl group, an aryl group or an alkoxyaryl group. 
       
     
     
         2 . The compound of  claim 1  with the following stereostructure, or its enantiomer 
       
         
           
           
               
               
           
         
         wherein R 3  is CH 2 CH(CH 3 )CH 2 CH 2 , CH═CH, or CH═C(CH 3 ); and R 11a  and R 11b  are H or together form a portion of a six-membered acetal ring containing C(H)(p-C 6 H 40 CH 3 ) or C(CH 3 ) 2 . 
       
     
     
         3 . A compound having the following formula, or its enantiomer 
       
         
           
           
               
               
           
         
         wherein X is H, NCH 3 (OCH 3 ), or a leaving group; 
         R 11  is H, a protecting group, an alkyl group, and aryl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , or CORE, 
         R t  and R u  are independently H, an alkyl group or an aryl group; 
         R 12  is a halogen atom, CH 2 OR 2c , CHO, CO 2 R 10 , CH═CHCH 2 OR 2c , CH═CHCHO or CH═CHCO 2 R 10 , wherein R 2c  is H, a protecting group, an alkyl group, an aryl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , or COR e , and R 10  is H or alkyl. 
       
     
     
         4 . A process for reacting a first compound of the following formula, or its enantiomer 
       
         
           
           
               
               
           
         
         wherein R 2  a protecting group, an alkyl group, an aryl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , or COR e ; 
         R a , R b  and R c  are independently an alkyl group or an aryl group; 
         R d  is an alkyl group, an aryl group, an alkoxylalkyl group, —R i SiR a R b R c  or a benzyl group, wherein R i  is an alkylene group; 
         R e  is an alkyl group, an allyl group, a benzyl group, an aryl group, an alkoxy group, or —NRGR h  wherein R g  and R h  are independently H, an alkyl group or an aryl group; 
         R 16  is H or alkyl; and 
         R 17  is CH 2 OR 2f , CHO, CO 2 R v , wherein R 2f  is H, an alkyl group, an aryl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , or COR e ; 
         R 25 CH═CX 2 , C≡CH or C═CSiR a R b R; 
         X is Cl, Br or I with a second compound of the following formula, or its enantiomer 
       
       
         
           
           
               
               
           
         
         wherein X is NCH 3 (OCH 3 ), or a leaving group; 
         R 11  an alkyl group, and aryl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , COR e ; 
         R 12  is a halogen atom, CH 2 OR 2c , CO 2 R v , CH═CHCH 2 OR 2c  or CH═CHCO 2 R v , wherein R 2c  is an alkyl group, an aryl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , or COR e , and R v  is alkyl, comprising metalation of the first compound and addition of the second compound to produce a compound of the following formula, or its enantiomer 
       
       
         
           
           
               
               
           
         
         wherein R 24  is C≡C.