Analogs of discodermolide and dictyostatin-1, intermediates therefor and methods of synthesis thereof

Abstract

A compound of the following structure: 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, 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 —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 (CH 2 ) p where p is an integer in the range of 4 to 12, —(CHR k1 ) y1 (CHR k2 ) y2 (CHR k3 ) y3 (CHR k4 ) y4 (CHR k5 ) y5 C(R s1 )═C(R s2 )C(R s3 )═C(R s4 )—, —(CHR k1 ) y1 (CHR k2 ) y2 (CHR k3 ) y3 (CHR k4 ) y4 (CHR k5 ) y5 CH(R s1 )CH(R s2 )C(R s3 )═C(R s4 )—, —(CHR k1 ) y1 (CHR k2 ) y2 (CHR k3 ) y3 (CHR k4 ) y4 (CHR k5 ) y5 C(R s1 )═C(R s2 )CH(R s3 )CH(R s4 )—, —(CHR k1 ) y1 (CHR k2 ) y2 (CHR k3 ) y3 (CHR k4 ) y4 (CHR k5 ) y5 CH(R s1 )CH(R s2 )CH(R s3 )CH(R s4 )—, wherein y1 and y2 are 1 and y3, y4 and y5 are independently 0 or 1, R k1 , R k2 , R k3 , R k4 and R k5 are independently H, CH 3 , or OR 2a , and R s1 , R s2 , R s3 , and R s4 are independently H or CH 3 , wherein R 2a 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 ; and R 5 is H or OR 2b , wherein R 2b is H, an alkyl group, an aryl 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 .- 3 . (canceled)  
   
   
       4 . A compound of the following structure  
     
       
         
         
             
             
         
       
       wherein R 1  is H, an alkyl group, an aryl group, an alkenyl group, an alkynyl group, or a halogen atom;  
       R 2  and R 2d  are independently H, 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, —H 2 CH(CH 3 )—, —CH═CH—, —CH═C(CH 3 )—, or —C═C—;  
       R 4  is (CH 2 ) p  where p is an integer in the range of 4 to 12, —(CHR k1 ) y1 (CHR k2 ) y2 (CHR k3 ) y3 (CHR k4 ) y4 (CHR k5 ) y5 C(R s1 )═C(R s2 )C(R s3 )═C(R s4 )—, (CHR k1 ) y1 (CHR k2 ) y2 (CHR k3 ) y3 (CHR y4 ) y4 (CHR k5 ) y5 CH(R s1 )CH(R s2 )C(R s3 )C(R s4 ), —(CHR k1 ) y1 (CHR k2 ) y2 (CHR k3 ) y3 (CHR y4 ) y4 (CHR k5 ) y5 C(R s1 )═C(R s2 )CH(R s3 )CH(R s4 )—, —(CHR k1 ) y1 (CHR k2 ) y2 (CHR k3 ) y3 (CHR k4 ) y4 (CHR k5 ) y5 CH(R s1 )CH(R s2 )CH(R s3 )CH(R s4 )—, wherein y1 and y2 are 1 and y3, y4 and y5 are independently 0 or 1, R k1 , R k2 , R k3 , R k4  and R k5  are independently H, —CH 3 , or OR 2a , and R s1 , R s2 , R s3 , and R s4  are independently H or CH 3 , wherein R 2a  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 ; and  
       R 5  is H or OR 2b , wherein R 2b  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 ; and  
       R 10  is H or alkyl.  
     
   
   
       5 . The compound of  claim 4  with the following stereostructure, or its enantiomer  
     
       
         
         
             
             
         
       
       wherein R 1  is alkenyl; R 2  is H; R 2d  is H, OC(O)CH 3  or OC(O)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 CH(CH 3 ) or CH═C(CH 3 );  
       and R 4  is —(CHR k1 ) y1 (CHR k2 ) y2 (CHR k3 ) y3 (CHR k4 ) y4 (CHR k5 ) y5 C(R s1 )═C(R s2 )C(R s3 )═C(R s4 )— wherein y1-y4 are 1, y5 is 0, R k1  and R k3  are OH, R k2  is H, R k4  is CH 3 , R s1 , R s2 , R s3  and R s4  are H, R 5  is OH; and R 10  is H or alkyl.  
     
   
   
       6 . The compound of  claim 5  wherein R 1  is —CH═CH 2 , and R 2d  is H, OC(O)CH 3  or OC(O)NH 2 .  
   
   
       7 . A compound of the following structure:  
     
       
         
         
             
             
         
       
       wherein R 1  is H, an alkyl group, an aryl group, an alkenyl group, an alkynyl group, or a halogen atom;  
       R 2  and R 2d  are independently H, 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, —H 2 CH(CH 3 )—, —CH═CH—, —CH═C(CH 3 )—, or —C≡C—;  
       R 5  is H or OR 2b , wherein R 2b  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 11a  and R 11b  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 11a  and R 11b  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 12  is a halogen atom, CH 2 OR 2c , CHO, CO 2 R 10 , CH═CHCH 2 OR 2c , CH═CHCHO, wherein R 2c  is H, an alkyl 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.  
     
   
   
       8 . A compound of  claim 7  with the following stereostructure, or its enantiomer  
     
       
         
         
             
             
         
       
       wherein R 1  is alkenyl; R 2d  is H, OC(O)CH 3  or OC(O)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 CH(CH 3 ) or CH═C(CH 3 );  
       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 4 OCH 3 ) or C(CH 3 ) 2 ; R 12  is a halogen atom, CH 2 OR 2c , CHO, CO 2 R 10 , CH═CHCH 2 OR 2c , CH═CHCHO, wherein R 2c  is H, an alkyl 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.  
     
   
   
       9 . The compound of  claim 8  wherein R 1  is —CH═CH 2 , R 2d  is H, —OC(O)CH 3  or —OC(O)NH 2 , and R 12  is —CH 2 OH, —CHO or —CO 2 R 10 .  
   
   
       10 . A compound having the following structure:  
     
       
         
         
             
             
         
       
       wherein R 2  is H, 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 5  is H or OR 2b , wherein R 2b  is H, an alkyl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , or COR e ;  
       R 11a  and R 11b  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 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 alkoxyarly group;  
       R 12  is a halogen atom, CH 2 OR 2c , CHO, CO 2 R 10 , CH═CHCH 2 OR 2c  or CH═CHCHO, CH═CHCO 2 R 10 , wherein R 2c  is H, an alkyl 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.  
     
   
   
       11 . The compound of  claim 10  with the following stereostructure, or its enantiomer  
     
       
         
         
             
             
         
       
       R 2  is H; R 3  is CH 2 CH(CH 3 ) or CH═C(CH 3 ); 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 4 OCH 3 ) or C(CH 3 ) 2 ; 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, 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 H or together form a portion of a six-membered acetal ring containing C(H)(p-C 6 H 4 OCH 3 ) or C(CH 3 ) 2 .  
     
   
   
       12 . A compound having the following formula  
     
       
         
         
             
             
         
       
       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, 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, —H 2 CH(CH 3 )—, CH═CH—, —CH═C(CH 3 )—, or —C≡C—;  
       R 11a  and R 11b  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 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, an alkyl 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.  
     
   
   
       13 . The compound of  claim 12  with the following stereostructure, or its enantiomer  
     
       
         
         
             
             
         
       
       wherein R 3  is CH 2 CH(CH 3 ) or CH═C(CH 3 ); 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 4 OCH 3 ) or C(CH 3 ) 2 ; 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, 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 H or together form a portion of a six-membered acetal ring containing C(H)(p-C 6 H 4 OCH 3 ) or C(CH 3 ) 2 .  
     
   
   
       14 . A compound having the following formula  
     
       
         
         
             
             
         
       
       wherein R 2  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 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 11a  and R 11b  are independently H, an alkyl group, and aryl 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 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, 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;  
       R 16  is H or alkyl; and  
       R 17  is CH 2 OR 2f , CHO, CO 2 R 10 , 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 .  
     
   
   
       15 . The compound of  claim 14  with the following stereostructure, or its enantiomer  
     
       
         
         
             
             
         
       
       wherein R 2  is H, an alkyl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , or COR e , 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 4 OCH 3 ) or C(CH 3 ) 2 .  
     
   
   
       16 . A compound having the following formula  
     
       
         
         
             
             
         
       
       wherein R 1  is H, an alkyl group, an aryl group, an alkenyl group, an alkynyl group, or a halogen atom;  
       R 2 , R 2d  and R 2e  are independently H, 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 5  is H or OR 2b , wherein R 2b  is H, an alkyl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , or COR e ;  
       q is an integer in the range of 2 to 5;  
       R 18  is H, and R 19  is hydroxy, alkoxy or —SR z , wherein R z  is an alkyl group or an aryl group, or R 18  and R 19  taken together are ═O.  
     
   
   
       17 . The compound of  claim 16  with the following stereostructure, or its enantiomer  
     
       
         
         
             
             
         
       
     
   
   
       18 . The compound of  claim 17  where wherein R 1  is a CH═CH 2  and R 3  is (Z)-CH═CH—, or —CH 2 CH 2 —.  
   
   
       19 . A compound having the following structure  
     
       
         
         
             
             
         
       
       R 11a  and R 11b  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 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 alkoxyarly group;  
       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 20  is CH 2 OR 2g , CHO, CO 2 R 10 ; wherein R 2g  is H, an alkyl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , or COR e , and wherein R 10  is H or alkyl; and  
       R 21  is a halogen atom, CH 2 OR 2c , CHO, CO 2 R 10a , CH═CHCH 2 OR 2c , CH═CHCHO or CH═CHCO 2 R 10 , wherein R 2c  is H, an alkyl group, a benzyl group, a trityl group, —SiR a R b R c , CH 2 OR d , or COR e , and wherein R 10a  is H or alkyl.  
     
   
   
       20 . The compound of  claim 19  with the following stereostructure, or its enantiomer  
     
       
         
         
             
             
         
       
     
   
   
       21 . The compound of  claim 20  where 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 4 OCH 3 ) or C(CH 3 ) 2 .  
   
   
       22 . The compound of  claim 21  wherein R 1  is CH═CH 2 , and R 21  is CH 2 OH, CHO or CO 2 R 10 .  
   
   
       23 . A compound having the following formula  
     
       
         
         
             
             
         
       
       wherein R 13  is H or an alkyl group, R 14  is H, an alkyl group, an aryl group or an alkoxyaryl group, and R 22  is a halogen atom or —P(Ar) 3 X, wherein X is a counteranion selected from the groups halide, tetrafluoroborate, hexafluorophosphate and sulfonate, provided that when R 13  and R 14  are methyl groups, X is not I.  
     
   
   
       24 . A compound of  claim 23  provided that when R 13  and R 14  are alkyl groups, X is not halogen.  
   
   
       25 . The compound of  claim 23  with the following stereostructure, or its enantiomer  
     
       
         
         
             
             
         
       
       wherein R 13  is H or an alkyl group, and R 14  is H, an alkyl group, an aryl group or an alkoxyaryl group, R 22  is a halogen atom or —P(Ar) 3 X, wherein X is a counteranion selected from the groups halide, tetrafluoroborate, hexafluorophosphate and sulfonate, provided that when R 13  and R 14  are methyl groups, X is not I.  
     
   
   
       26 . The compound of  claim 25  wherein R 13  is H, R 14  is aryl, and R 22  is P(C 6 H 5 ) 3 X.  
   
   
       27 . The compound of  claim 25  wherein R 14  is C 6 H 4 -p-OCH 3 .  
   
   
       28 .- 33 . (canceled)