Process Involving Cross Metathesis of Olefins

Abstract

A method of forming a macrocyclic musk compound comprising the steps of: — i) cross-metathesizing a first olefin and a second olefin in the presence of a homogeneous transition metal catalyst comprising an alkylidene ligand, to form a statistical mixture of a hetero-dimer intermediate of said first and second terminal olefin, and homo-dimers ii) separating the hetero-dimer from the statistical mixture of hetero- and homo-dimers iii) and cyclizing the hetero-dimer intermediate to form the macrocyclic musk compound.

1 . A method of forming a macrocyclic musk compound comprising the steps of: —
 i) cross-metathesizing a first olefin and a second olefin in the presence of a homogeneous transition metal catalyst comprising an alkylidene ligand, to form a statistical mixture of a hetero-dimer intermediate of said first and second terminal olefin, and homo-dimers 
 ii) separating the hetero-dimer from the statistical mixture of hetero- and homo-dimers 
 iii) and cyclizing the hetero-dimer intermediate to form the macrocyclic musk compound. 
 
     
     
         2 . A method according to  claim 1  wherein the first olefin has the formula (I) 
       
         
           
           
               
               
           
         
         wherein
 OR 2  is a protected hydroxyl group, which is selected from: an alkyl ether group; an ester group; a silyl ether group; and a carbonate group; 
 R 3  is H or methyl; and, 
 n is an integer from 1-8 
 
       
     
     
         3 . A method according to  claim 1 , wherein the second olefin has the formula 
       
         
           
           
               
               
           
         
         wherein:
 R 7  is branched or non-branched alkyl moiety containing 1 to 5 carbon atoms, and 
 m is an integer from 1 to 10. 
 
       
     
     
         4 . A method according to  claim 1 , wherein the hetero-dimer has the formula 
       
         
           
           
               
               
           
         
       
     
     
         5 . A method according to  claim 1 , wherein the hetero-dimer has the formula 
       
         
           
           
               
               
           
         
       
     
     
         6 . A method according to  claim 1 , wherein the hetero-dimer has the formula 
       
         
           
           
               
               
           
         
       
     
     
         7 . A method according to  claim 1 , wherein the first olefin and second olefin are reacted in a 1:x molar ratio to produce a ratio of hetero-dimer:first homo-dimer:second homo-dimer of 2x:1:1x 2 . 
     
     
         8 . A method according to  claim 1 , wherein the hetero-dimer is formed in admixture with a protected alcohol homo-dimer and a carboxylic acid ester homo-dimer. 
     
     
         9 . A method according to  claim 8  wherein the mixture of protected alcohol hetero-dimer and each carboxylic acid ester homo-dimer is formed in a molar ratio of 2:1:1. 
     
     
         10 . A method according to  claim 1 , wherein the hetero-dimer is separated from the homo-dimers by distillation at a temperature of 100 to 220 degrees centigrade and a pressure of 1 to 10 mbar. 
     
     
         11 . A method according to  claim 1 , wherein the homo-dimers are recycled by metathesis with ethylene to regenerate the first and second olefins. 
     
     
         12 . A method according to  claim 11  wherein the homo-dimers are treated with ethylene gas at a pressure of 1 bar to 20 bar. 
     
     
         13 . A method according to  claim 1 , wherein the hetero-dimer is cyclised by trans-esterification. 
     
     
         14 . A method according to  claim 13  wherein, if the hetero-dimer contains a protected alcohol group, it is first de-protected by hydrolysis before being subjected to cyclisation by tran-esterification. 
     
     
         15 . A method of forming E/Z 9-ambrettolide according to the method according to  claim 1 . 
     
     
         16 . A method of forming E/Z 9-ambrettolide according to  claim 15 , wherein the E/Z ratio is from 80.20 to 90:10. 
     
     
         17 . A method according to  claim 16  wherein the E/Z ratio is 85:15. 
     
     
         18 . A method according to  claim 1 , wherein the catalyst is a molybdenum or tungsten catalyst containing an alkylidene ligand. 
     
     
         19 . A method according to  claim 1 , wherein the catalyst is a compound according to the formula: 
       
         
           
           
               
               
           
         
         wherein
 M=Mo or W; R 1  is aryl, heteroaryl, alkyl, or heteroalkyl; which may be substituted; 
 R 2  and R 3  can be the same or different and each is hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, or heteroaryl; which may be substituted; 
 R 5  is alkyl, alkoxy, heteroalkyl, aryl, aryloxy, heteroaryl, silylalkyl, silyloxy, which may be substituted; and 
 R 4  is a residue R 6 —X—, wherein
 X═O and R 6  is aryl, which may be substituted; or 
 X═S and R 6  is aryl, which may be substituted; or 
 X═O and R 6  is (R 7 , R 8 , R 9 )Si; wherein R 7 , R 8 , R 9  are alkyl or phenyl, which may be substituted; or 
 X═O and R 6  is (R 10 , R 11 , R 12 )C, wherein R 10 , R 11 , R 12  are independently selected from phenyl, alkyl; which may be substituted; 
 
 
         or,
 R 4  and R 5  are linked together and are bound to M via oxygen. 
 
       
     
     
         20 . E/Z 9-ambrettolide formed according to a method according to  claim 1 . 
     
     
         21 . The hetero-dimer of the formula: 
       
         
           
           
               
               
           
         
         wherein:
 OR 2  is a protected hydroxyl group, selected from: an alkyl ether group; an ester group; a silyl ether group; or a carbonate group; 
 R 3  is H or methyl; 
 n is an integer from 1-8; and, 
 R 7  is a branched or non-branched alkyl moiety containing 1 to 5 carbon atoms 
 
       
     
     
         22 . The hetero-dimer according to  claim 21  having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The hetero-dimer according to  claim 21  or  claim 22  having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         24 . E/Z Nirvanolide formed according to a method according to  claim 1 . 
     
     
         25 . The hetero-dimer according to  claim 21  having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The hetero-dimer according to  claim 25  having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         27 . A method according to  claim 3 , wherein:
 R 7  is methyl or ethyl.   
     
     
         28 . A method according to  claim 3 , wherein:
 m is 7.