Lactone Formation from Hydroxycarboxylic Acids

On the other hand, the rate of formation of the undesired acyclic (mono/oligo/poly)esters is d [tetrahedral precursor of acyclic ester] 

If one divides Equation 6.17 by Equation 6.18, the expression on the left side of the equals sign corresponds approximately to the yield ratio of the lactone and the mixture of the acyclic esters, oligo- and polyesters. Taking this into account, one obtains as a new equation the following  

From Equation 6.19 it follows that the lower the concentration of the activated acid, the higher the selectivity with which the lactone is produced versus the acyclic ester, oligo- and polyesters. Macrolactones are therefore produced in very dilute ( 1 pmol/L) solutions. 

For work on a 1 -mole scale one would thus have to use a 1.000-liter flask to activate and then lactonize the entire ft)-hydroxycarboxylic acid. Of course, it is much more practical to work in a smaller reaction vessel. However, one must also not exceed the mentioned concentration limit of 1 pmol/L. Therefore, one can introduce only as much of the carboxylic acid in this smaller reaction vessel at a time so that its concentration does not exceed 1 pmoEL. Subsequently, one would have to activate this amount of acid and would then have to wait until it is lactonized. After that additional acid would have to be added and then activated, and so on. A more practical alternative is shown in Side Note 6.3. 

The process for preparing macrolactones described in the text is impractical. Instead of this process one uses a continuous method with a syringe pump a solution of the hydroxycar-boxylic acid is added very slowly—that is, in the course of hours or days—i nto a small flask, which contains 1 equivalent of the activator and, if necessary, just enough triethylamine to neutralize any released HC1. The rate at which the acid is added is regulated such that it is equal to or smaller than the lactonization rate. This is called pseudo high dilution. At the end of the reaction the lactone solution can be relatively concentrated, e. g., 10 mmoEL, at least 10,000 times more concentrated than without the use of this trick. 

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With the aid of this reagent, a method has been developed for the synthesis of peptides [76]. It proceeds under mild conditions and largely without racemization. The combination of reagents provides a method for the synthesis of macrolides (macrocyclic lactones) from long-chain co-hydroxycarboxylic acids, as demonstrated by the formation of pentadecanolide from 15-hydroxypentadecanoic acid [77]. 

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