Lactones high dilution method

Macrolides. Steliou, Hanessian, and co-workers- have prepared lactones and lactams in moderate to excellent yield by treatment of ro-hydroxy or ru-amino carboxylic acids with catalytic amounts of di-r -butyltin oxide in refluxing mesitylcne or xylene in a Dean-Stark apparatus for 12 24 hours. The method has the advantage of high dilution, since the tin reagent is regenerated continuously. As expected, yields arc low for medium-sized rings. 

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. 

Macrocyclic lactones. Ireland and Brown1 have adapted the Eschenmoser contraction of sulfides to a synthesis of five- and six-membered lactones. An example is formulated in equation (I). A hydroxy thioamide is esterified to give a chloro ester, which is then treated in sequence with Nal and phosphine 1. The method can also be used for preparation of macrocyclic lactones under high-dilution... 

Cyclization of the methanesulfonate of 12-hydioxydodecanoic acid in toluene with aqueous sodium bicarbonate and a 1% cross-linked, DF 0.04, (polystyrylmethyl)tri-n-butylphosphonium ion phase transfer catalyst gave 66% yield (1321. However, the concentration of substrate in the final reaction mixture was 2.3 mM, no higher than in most high dilution experiments. A more promising method is solid-liquid phase transfer catalysis. A 0.1M suspension of the potassium salt of 12-bromododecanoic acid in toluene containing 2.5 Mm tetra-n-butylammonium bromide was heated at 90 °C to give 95% of the 13-membered lactone (Equation 32) (1331. Effective concen-... 

Lactone Formation. Long-chain hydroxy acids can, by this method, be converted into lactones (eq 3). Of note is the observation that even macrocyclic lactones can be formed in high yields without high dilution or other catalysts. 

Macrolactonization. When a carboxylic acid is treated with 2,2 -dipyridyl disulfide in the presence of Triphenylphosphine, the corresponding 2-pyridinethiol ester is formed. Corey and Nicolaou have developed an efficient method for the synthesis of macrocyclic lactones based on these 2-pyridinethiol esters. When an m-hydroxy thiolester is heated in refluxing xylene under high dilution conditions (10 M, typically accomplished with syringe pump techniques), macrolactonization occurs, liberating triphenylphosphine oxide and pyridinethione. The reaction is quite general and is believed to proceed by a double activation mechanism in which the basic 2-pyridinethiol ester simultaneously activates both the hydroxy and the carboxylic acid moieties with a single proton transfer. It has been shown that the cyclization rate is not affected by the presence of acids, bases, or any of the possible reaction contaminants. ... 

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