Site-specific isotopic labeling of 1,4-diene systems

Abstract

Methods for preparing isotopically modified 1,4-diene systems from non-isotopically modified 1,4-dienes involve selective oxidation of one or more bis-allylic position(s), or the preparation of isotopically modified 1,4-diene systems via trapping pi-allylic complexes with a source of deuterium or tritium. Such methods are useful for preparing isotopically modified polyunsaturated lipid including polyunsaturated fatty acids and polyunsaturated fatty acid derivatives.

What is claimed is: 
     
         1 . (canceled) 
     
     
         2 . A composition comprising a deuterated polyunsaturated fatty acid or an ester thereof comprising:
 a 1,4-polyene system comprising three or more cis double bonds separated from each other by a bis-allylic methylene group and having a mono-allylic methylene group flanking the 1,4-polyene system;   said fatty acid composition comprising on average more than about 80 percent replacement of hydrogen with deuterium at the bis-allylic sites; and   deuteration at the mono-allylic sites provided that said deuteration comprises on average less than about 35 percent replacement of hydrogen with deuterium at the mono-allylic sites.   
     
     
         3 . The composition of  claim 2 , wherein said fatty acid or ester thereof has an isotopic load of deuterium of greater than 15% said isotopic load being based on the total number of hydrogen/deuterium atoms in said polyunsaturated fatty acid. 
     
     
         4 . The composition of  claim 2 , wherein said fatty acid or ester thereof has an isotopic load of deuterium of greater than 25% said isotopic load being based on the total number of hydrogen/deuterium atoms in said polyunsaturated fatty acid. 
     
     
         5 . The composition of  claim 2 , wherein said fatty acid or ester thereof is an omega 3 fatty acid. 
     
     
         6 . The composition of  claim 2 , wherein said fatty acid or ester thereof is an omega 6 fatty acid or ester thereof. 
     
     
         7 . The composition of  claim 2 , wherein said fatty acid or ether thereof is an omega 9 fatty acid or ester thereof. 
     
     
         8 . The composition of  claim 2 , wherein said fatty acid or ester thereof comprises at least about 90 percent replacement of hydrogen with deuterium at the bis-allylic sites. 
     
     
         9 . The composition of  claim 8 , wherein said fatty acid or ester thereof comprises no more than about 20 percent replacement of hydrogen with deuterium at the mono-allylic sites. 
     
     
         10 . The composition of  claim 2 , wherein said fatty acid or ester thereof is naturally occurring. 
     
     
         11 . The composition of  claim 2 , wherein said fatty acid or ester thereof is arachidonic acid or an ester thereof. 
     
     
         12 . The composition of  claim 11 , wherein the said arachidonic acid or ester thereof comprises at least about 10 percent replacement of hydrogen with deuterium at the mono-allylic sites. 
     
     
         13 . The composition of  claim 2 , wherein said fatty acid or ester thereof is eicosapentaenoic acid or ester thereof. 
     
     
         14 . The composition of  claim 2 , wherein said fatty acid or ester thereof is docosahexaenoic acid or ester thereof. 
     
     
         15 . The composition of  claim 14 , wherein said docohexanenoic acid or ester thereof comprises at least about 5 percent replacement of hydrogen with deuterium at the mono-allylic sites. 
     
     
         16 . The composition of  claim 2 , wherein said fatty acid or ester thereof is linolenic acid or ester thereof. 
     
     
         17 . The composition of  claim 2 , wherein said fatty acid or ester thereof is represented by the formula: 
       
         
           
           
               
               
           
         
         where R 1  is hydrogen or C 1 -C 10  alkyl; 
         R 2  is —OH, —OR 3 , —SR 3 , phosphate or —N(R 3 ) 2 ; 
         each R 3  is independently selected from C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 10  cycloalkyl, C 6 -C 10  aryl, 4-10 membered heteroaryl, 3 to 10 membered heterocyclic ring; 
         n is an integer from 3 to 10; and 
         p is an integer from 1 to 10. 
       
     
     
         18 . The composition of  claim 2 , wherein said fatty acid ester is a monoglyceride, a di-glyceride or a triglyceride, or an ethyl ester.