Synthesis of avrainvillamide, stephacidin b, and analogues thereof

Abstract

The syntheses of the natural products, avrainvillamide and stephacidin B, are provided. The α,β-unsaturated nitrone functionality of avrainvillamide and its 3-alkylidene-3H-indole 1-oxide core is shown to covalently and reversibly bond to heteroatom-based nucleophiles. This capability may allow these molecules to bind active site nucleophiles and may provide the basis for designing potent and selective enzyme inhibitors. Both avrainvillamide and its dimer stephacidin B have been reported to exhibit antiproliferative activity, and avrainvillamide has been reported to exhibit antimicrobial activity against multi-drug resistant bacteria. Avrainvillamide has been found to target cytoskeleton-linking membrane protein (CLIMP-63) thereby preventing cells from undergoing mitosis. The invention provides syntheses of these natural products as well as analogs of these natural products and their functional cores. The compounds of the invention may be used in the treatment of diseases such as cancer, autoimmune diseases, and bacterial infection.

1 - 65 . (canceled) 
     
     
         66 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR G ; —C(═O)R G ; —CO 2 R G ; —CN; —SCN; —SR G ; —SOR G ; —SO 2 R G ; —NO 2 ; —N 3 ; —N(R G ) 2 ; —NHC(═O)R G ; —NR G C(═O)N(R G ) 2 ; —OC(═O)OR G ; —OC(═O)R G ; —OC(═O)N(R G ) 2 ; —NR G C(═O)OR G ; or —C(R G ) 3 ; wherein each occurrence of R G  is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;
 wherein two or more substituents may form substituted or unsubstituted, cyclic, heterocyclic, aryl, or heteroaryl structures; 
 wherein R 2  and R 3 , R 4  and R 5 , or R 6  and R 7  may form together ═O, ═NR G , or ═C(R G ) 2 , wherein each occurrence of R G  is defined as above; 
 P is an oxygen protecting group or hydrogen; 
 Nu is hydrogen, —OR Nu , —SR Nu , —C(R Nu ) 3 , or —N(R Nu ) 2 , wherein each occurrence of R Nu  is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; 
 
       
         
           
           
               
               
           
         
         represents a substituted or unsubstituted, cyclic, heterocyclic, aryl, or heteroaryl ring system; and 
         n is an integer between 0 and 4. 
       
     
     
         67 . The compound of  claim 66 , wherein P is hydrogen. 
     
     
         68 . The compound of  claim 66 , wherein P is C 1 -C 6  alkyl. 
     
     
         69 . The compound of  claim 66 , wherein P is an oxygen-protecting group. 
     
     
         70 . The compound of  claim 66 , wherein Nu is —SR Nu . 
     
     
         71 . (canceled) 
     
     
         72 . The compound of  claim 66 , wherein Nu is —OR Nu . 
     
     
         73 . The compound of  claim 66 , wherein Nu is hydrogen. 
     
     
         74 . The compound of  claim 66  of the formula: 
       
         
           
           
               
               
           
         
       
       wherein each occurrence of R 1  is independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR A ; —C(═O)R A ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; —N(R A ) 2 ; —NHC(═O)R A ; —NR A C(═O)N(R A ) 2 ; —OC(═O)OR A ; —OC(═O)R A ; —OC(═O)N(R A ) 2 ; —NR A C(═O)OR A ; or —C(R A ) 3 ; wherein each occurrence of R A  is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;
 R 6  is selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR F ; —C(═O)R F ; —CO 2 R F ; —CN; —SCN; —SR F ; —SOR F ; —SO 2 R F ; —NO 2 ; —N 3 ; —N(R F ) 2 ; —NHC(═O)R F ; —NR F C(═O)N(R F ) 2 ; —OC(═O)OR F ; —OC(═O)R F ; —OC(═O)N(R F ) 2 ; —NR F C(═O)OR F ; or —C(R F ) 3 ; wherein each occurrence of R F  is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; 
 R 7  is selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR G ; —C(═O)R G ; —CO 2 R G ; —CN; —SCN; —SR G ; —SOR G ; —SO 2 R G ; —NO 2 ; —N 3 ; —N(R G ) 2 ; —NHC(═O)R G ; —NR G C(═O)N(R G ) 2 ; —OC(═O)OR G ; —OC(═O)R G ; —OC(═O)N(R G ) 2 ; —NR G C(═O)OR G ; or —C(R G ) 3 ; wherein each occurrence of R G  is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; 
 R 8  and R 9  are independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR H ; —C(═O)R H ; —CO 2 R H ; —CN; —SCN; —SR H ; —SOR H ; —SO 2 R H ; —NO 2 ; —N 3 ; —N(R H ) 2 ; —NHC(═O)R H ; —NR H C(═O)N(R H ) 2 ; —OC(═O)OR H ; —OC(═O)R H ; —OC(═O)N(R H ) 2 ; —NR H C(═O)OR H ; or —C(R H ) 3 ; wherein each occurrence of R H  is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; 
 R 10  and R 11  are independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR J ; —C(═O)R J ; —CO 2 R J ; —CN; —SCN; —SR J ; —SOR J ; —SO 2 R J ; —NO 2 ; —N 3 ; —N(R J ) 2 ; —NHC(═O)R J ; —NR J C(═O)N(R J ) 2 ; —OC(═O)OR J ; —OC(═O)R J ; —OC(═O)N(R J ) 2 ; —NR J C(═O)OR J ; or —C(R J ) 3 ; wherein each occurrence of R J  is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; 
 R 12  is selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR L ; —C(═O)R L ; —CO 2 R L ; —CN; —SCN; —SR L ; —SOR L ; —SO 2 R L ; —NO 2 ; —N 3 ; —N(R L ) 2 ; —NHC(═O)R L ; —NR L C(═O)N(R L ) 2 ; —OC(═O)OR L ; —OC(═O)R L ; —OC(═O)N(R L ) 2 ; —NR L C(═O)OR L ; or —C(R L ) 3 ; wherein each occurrence of R L  is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; 
 R 13  and R 14  are independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR M ; —C(═O)R M ; —CO 2 R M ; —CN; —SCN; —SR M ; —SOR M ; —SO 2 R M ; —NO 2 ; —N 3 ; —N(R M ) 2 ; —NHC(═O)R M ; —NR M C(═O)N(R M ) 2 ; —OC(═O)OR M ; —OC(═O)R M ; —OC(═O)N(R M ) 2 ; —NR M C(═O)OR M ; or —C(R M ) 3 ; wherein each occurrence of R M  is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; 
 R 15  is selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR P ; —C(═O)R P ; —CO 2 R P ; —CN; —SCN; —SR P ; —SOR A ; —SO 2 R P ; —NO 2 ; —N 3 ; —N(R P ) 2 ; —NHC(═O)R P ; —NR P C(═O)N(R P ) 2 ; —OC(═O)OR P ; —OC(═O)R P ; —OC(═O)N(R P ) 2 ; —NR P C(═O)OR P ; or —C(R P ) 3 ; wherein each occurrence of R P  is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; 
 wherein two or more substituents may form substituted or unsubstituted, cyclic, heterocyclic, aryl, or heteroaryl structures; 
 wherein R 6  and R 7 , R 8  and R 9 , R 13  and R 14 , and one R 12  and another R 12  may form together ═O, ═NR G , or ═C(R G ) 2 , wherein each occurrence of R G  is defined as above; 
 X is O, S, C(R X ) 2 , or NR X , wherein R X  is hydrogen, a protecting group, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety, 
 Z is O, S, or NR Z , wherein R Z  is hydrogen, a protecting group, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety, or OR Z′ , wherein R Z′  is hydrogen, a protecting group, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety; 
 P is an oxygen-protecting group or hydrogen; 
 Nu is hydrogen, —OR Nu , —SR Nu , —C(R Nu ) 3 , or —N(R Nu ) 2 , wherein each occurrence of R Nu  is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; 
 the dashed line represents the presence or absence of a bond; 
 m is an integer between 0 and 6, inclusive; and 
 n is an integer between 0 and 2, inclusive. 
 
     
     
         75 - 78 . (canceled) 
     
     
         79 . A method of preparing a product of formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR G ; —C(═O)R G ; —CO 2 R G ; —CN; —SCN; —SR G ; —SOR G ; —SO 2 R G ; —NO 2 ; —N 3 ; —N(R G ) 2 ; —NHC(═O)R G ; —NR G C(═O)N(R G ) 2 ; —OC(═O)OR G ; —OC(═O)R G ; —OC(═O)N(R G ) 2 ; —NR G C(═O)OR G ; or —C(R G ) 3 ; wherein each occurrence of R G  is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;
 wherein two or more substituents may form substituted or unsubstituted, cyclic, heterocyclic, aryl, or heteroaryl structures; 
 wherein R 2  and R 3 , R 4  and R 5 , or R 6  and R 7  may form together ═O, ═NR G , or ═C(R G ) 2 , wherein each occurrence of R G  is defined as above; and 
 n is an integer between 0 and 4; 
 
       the method comprising steps of:
 coupling a compound of formula: 
 
       
         
           
           
               
               
           
         
       
       wherein R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are as defined above and X is a halogen, 
       with a compound of formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1  and n are defined as above and Y is a halogen, boronic acid (—B(OH) 2 ), boronic ester, or organoborane; under suitable condition to form the product. 
     
     
         80 . The method of  claim 79 , wherein R 4  or R 5  is not hydrogen. 
     
     
         81 . The method of  claim 79 , wherein at least one of R 2 , R 3 , R 6 , and R 7  is not methyl. 
     
     
         82 . The method of  claim 79 , wherein at least one occurrence of R 1  is not hydrogen. 
     
     
         83 . The method of  claim 79 , wherein the coupling is performed in the presence of an organometallic catalyst. 
     
     
         84 . The method of  claim 83 , wherein the coupling is performed in the presence of a palladium catalyst. 
     
     
         85 . The method of  claim 84 , wherein the catalyst is selected from the group consisting of Pd(OAc) 2  and Pd 2 dba 3 . 
     
     
         86 . The method of  claim 79 , wherein X is I. 
     
     
         87 . The method of  claim 79 , wherein Y is Br or —B(OH) 2 . 
     
     
         88 - 106 . (canceled) 
     
     
         107 . A method of treating a proliferative disease, the method comprising steps of:
 administering a therapeutically effective amount of a compound of the formula:   
       
         
           
           
               
               
           
         
       
       wherein R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are independently selected from the group consisting of hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR G ; —C(═O)R G ; —CO 2 R G ; —CN; —SCN; —SR G ; —SOR G ; —SO 2 R G ; —NO 2 ; —N 3 ; —N(R G ) 2 ; —NHC(═O)R G ; —NR G C(═O)N(R G ) 2 ; —OC(═O)OR G ; —OC(═O)R G ; —OC(═O)N(R G ) 2 ; —NR G C(═O)OR G ; or —C(R G ) 3 ; wherein each occurrence of R G  is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;
 wherein two or more substituents may form substituted or unsubstituted, cyclic, heterocyclic, aryl, or heteroaryl structures; 
 wherein R 2  and R 3 , R 4  and R 5  or R 6  and R 7  may form together ═O, ═NR G , or ═C(R G ) 2 , wherein each occurrence of R G  is defined as above; 
 
       
         
           
           
               
               
           
         
         represents a substituted or unsubstituted, cyclic, heterocyclic, aryl, or heteroaryl ring system; and 
         n is an integer between 0 and 4; to a patient suffering from a proliferative disease. 
       
     
     
         108 . The method of  claim 107 , wherein the proliferative disease is cancer. 
     
     
         109 . The method of  claim 107 , wherein the proliferative disease is an inflammatory disease. 
     
     
         110 - 113 . (canceled)