Synthesis of oligoketides

Abstract

Facile methods for preparing diketide and triketide thioesters are disclosed. The resulting thioesters may be used as intermediates in the synthesis of desired polyketides, and may contain functional groups which ultimately reside in side chains on the resulting polyketide and thus can be used further to manipulate the polyketide so as form derivatives. The polyketides produced may also be tailored by glycosylation, hydroxylation and the like. New polyketides and their derivatives and tailored forms are thereby produced.

1 . A method to prepare a diketide or triketide thioester which method comprises 
 a) treating a benzoxazolone derivative of said diketide or triketide with the salt of a thiol anion from which the thioester is to be formed so as to form the thioester of said diketide or triketide; or    b) treating a 2-oxazolidinone derivative of said diketide or triketide with the lithium salt of a thiol anion from which the thioester is to be formed in the presence of sufficient Lewis acid to reduce the basicity of the thiol anion so as to form the thioester of said diketide or triketide.    
     
     
         2 . The method of  claim 1  wherein said thioester is an N-acyl cysteamine thioester.  
     
     
         3 . The method of  claim 1  wherein the Lewis acid is trimethylammonium.  
     
     
         4 . A diketide or triketide thioester prepared by the method of any of claims  1 - 3 .  
     
     
         5 . A method to prepare a polyketide which method comprises treating a polyketide synthase (PKS) enzyme complex with the diketide or polyketide thioester of  claim 4  under conditions wherein said polyketide is formed.  
     
     
         6 . The method of  claim 5  wherein said PKS is contained in a cell.  
     
     
         7 . The method of  claim 5  wherein said polyketide has the lactone backbone structure of 6-dEB.  
     
     
         8 . A polyketide prepared by the method of any of claims  5 - 7 .  
     
     
         9 . The polyketide of  claim 8  which contains a functional group in a side chain at position 13 of the lactone.  
     
     
         10 . The polyketide of  claim 9  wherein the functional group is a double bond, a triple bond, a halo group, an azide, an ester, an alcohol, or an aromatic nucleus.  
     
     
         11 . The polyketide of  claim 10  wherein the functional group is a double bond, a halo group, an azide, or an aromatic nucleus.  
     
     
         12 . The polyketide of  claim 8  which contains a functional group at a side chain coupled to the 12 position of the lactone.  
     
     
         13 . The polyketide of  claim 12  wherein said functional group is a double bond.  
     
     
         14 . A method to prepare a tailored polyketide which method comprises treating the polyketide of  claim 8  with tailoring enzymes.  
     
     
         15 . The method of  claim 14  wherein the tailoring enzymes are contained in a cell.  
     
     
         16 . A tailored polyketide prepared by the method of  claim 15 .  
     
     
         17 . The tailored polyketide of  claim 16  which comprises hydroxylation or glycosylation.  
     
     
         18 . A method to prepare a derivatized polyketide or tailored polyketide which method comprises contacting the polyketide of any of claims  9 - 13  or tailored polyketide of  claim 16  or  17  with a suitable reagent compatible with said functional group.  
     
     
         19 . A derivatized polyketide or tailored polyketide prepared by the method of  claim 18 .  
     
     
         20 . The method of  claim 1  wherein said diketide or triketide comprises 2-methyl-3-hydroxy substituents.  
     
     
         21 . The method of  claim 20  wherein said diketide or triketide substituents have syn chirality.  
     
     
         22 . The method of  claim 21  wherein said diketide or triketide is selected from the group consisting of 
 2-methyl-3-hydroxyhexanoyl;  
 2-methyl-3-hydroxy-4-pentenoyl;  
 2-methyl-3-hydroxybutanoyl;  
 2-vinyl-3-hydroxypentanoyl; and  
 2,4-dimethyl-3,5-dihydroxyheptanoyl.  
 
     
     
         23 . The method of  claim 1  wherein said diketide or triketide is selected from the group consisting of 
 (2S,3R)-2-methyl-3-hydroxyhexanoyl;  
 (2S,3R)-2-methyl-3-hydroxy-4-pentenoyl;  
 (2S,3R)-2-methyl-3-hydroxybutanoyl;  
 (2S,3R)-2-vinyl-3-hydroxypentanoyl;  
 (2S,4S,5R)-2,4-dimethyl-5-hydroxy-3-oxoheptanoyl;  
 (2S,3S,4S,5R)-2,4-dimethyl-3,5-dihydroxyheptanoyl; and  
 (4S,5R)-4-methyl-5-hydroxy-2-heptenoyl.  
 
     
     
         24 . A method to synthesize a derivative of at least a triketide containing stereochemically pure chiral centers at at least positions 2 and 5 which method comprises 
 treating a stereochemically controlled diketide derivative having a chiral center at position 2 of said diketide with an aldehyde in the presence of tin(II) triflate and titanium tetrachloride so as to maintain the chirality at position 2 and provide control of the chirality at position 5.    
     
     
         25 . The method of  claim 24  wherein said sterically controlled diketide is a derivative of 2-oxazolidinone.  
     
     
         26 . A method to synthesize an oligoketide thioester on a solid support, which method comprises 
 (1) reacting an N-acyl-2-imidazolidinone coupled to said solid support with an aldehyde or acyl moiety under conditions whereby said aldehyde or acyl moiety couples to a position α to a carbonyl in the acyl group of the 2-imidazolidinone;    (2) optionally repeating step (1); and    (3) cleaving the resulting oligoketide from the solid support by reaction with a salt of a thiol anion, thus providing an oligoketide thioester.    
     
     
         27 . The method of  claim 26  wherein the salt is a lithium salt, and/or 
 wherein said cleaving is performed in the presence of a Lewis acid.  
 
     
     
         28 . A method to synthesize an oligoketide thioester on a solid support, which method comprises 
 (1) reacting an N-acyl benzoxazolone coupled to said solid support with an aldehyde under conditions whereby said aldehyde couples to a position α to a carbonyl in the acyl group of the benzoxalozone;    (2) optionally repeating step (1); and    (3) cleaving the resulting oligoketide from the solid support by reaction with a salt of a thiol anion, thus providing an oligoketide thioester.    
     
     
         29 . A method to synthesize a racemic mixture of diketides which method comprises treating an N-acyl derivative of a benzoxazolone with an aldehyde under conditions wherein said aldehyde couples to a position alpha to the carbonyl in the acyl group thereby obtaining a racemic mixture of diketides coupled to said benzoxazolone.  
     
     
         30 . The tailored polyketides of  claim 16  selected from the group consisting of those of Examples 17B and 17C.  
     
     
         31 . The derivatized polyketide or tailored polyketide of  claim 19  which is selected from the group consisting of the polyketides of Examples 16A, 16B, 18 and 24.