Corey-Nicolaou lactonization

Corey procedure 243 Corey lactone 68 ff., 72 f. Corey-Nicolaou... 

The Buszek (—)-octalactin A synthesis is notable for its useage of the Corey-Nicolaou thiopyridyl ester7 protocol for saturated eight-mem-bered lactone construction. Prior to this synthesis, no eight-membered lactone ring had ever been prepared in high yield from the cyclisation of a saturated hydroxy carboxylic acid precursor. This reaction therefore broke important new ground in the arena of complex natural product synthesis. 

Lactone ring expansion. The lithio derivative from this sulfoxide (LDA) reacts with lactones to form adducts which on further treatment with KH and then r-BuLi are transformed into ketenes. Acidification regenerates lactones of one size larger. This reaction sequence works well for expansion of 5- and 6-membered lactones. For the synthesis of macrolides, it is necessary to quench the ketene with pyridine-2-thiol and use the Corey-Nicolaou method to effect reclosure of the lactone ring. 

A variety of specialized reagents have been developed for macrolactonization reactions. Two of the more important are the Corey-Nicolaou reagent, 2,2 -dipyridyl disulfide (232)10 jjjg Mukaiyama reagent, which is 2-chloro-l-methylpyridinium iodide (233). A number of related reagents have been developed, including imidazole disulfide 234 [2,2 -dithio-(4-ferf-butyl-l-isopropylimidazole)]l 2 and imidazole 235 [N-(trimethylsilyl)imidazole].l 3 All of these reagents are effective for the cyclization of co-hydroxy acids, as shown in Table 6.1. For comparison, available cyclization results with DEAD and 234 are included. In this table, a hydroxy acid is converted to a lactone (219). 

Inspection of Table 6.1 suggests that the Mukaiyama reagent gives better yields of lactone with simple ou-hydroxy acids than the Corey-Nicolaou reagent. Offer an explanation that accounts for this observation. 

COREY-NICOLAOU-GERLACH Macrolactonization 2-Pyridinethiol a reagent in the synthesis of large ring lactones. 

Corey-Nicolaou S-Pyridyl Ester Lactonization Method... 

In principle, all that remained to do to reach erythronolide (2) was to deprotect the Ci3 hydroxyl group of 62, conduct the macrolactonization, remove the acetonides, and carry out an oxidation state adjustment at C9. Of course this was easier said than done. The macrolactonization turned out to be very difficult. The Woodward group degraded Erythromycin A (1) to 17 thiopy-ridyl ester substrates, only three of which underwent lactonization under the Corey-Nicolaou conditions. Two of these derivatives gave low yields, but 63 cyclized to 64 in good yield. This effort established that (1) the 5-configuration was essential at C9 and (2) the C3-C5 and C9-C11 diol units had to be protected as cyclic acetals. Based on this information, carbamate-acetal 65 was eventually prepared Ifom the natural product and found to cyclize to 66 in 70% yield. Thus, to complete a total synthesis, it was necessary to convert w-acetorude 62 to 65, and move 66 forward to erythromycin A (1). 

Table 5 shows the yields of the lactones 56 obtained by an intramolecular cycli-zation of the -halogeno carboxylic acids 55 using ceaum ions. The yields are compared to those obtein l by Corey and Nicolaou [2] using the pyridinethiol procedure. 

Table 5. Yields of the lactones 56 and of the dilides 57 according to the cesium method [51] and according to the method of Corey and Nicolaou [2]...

The modified Corey-Nicoiaou macroiactonization was applied for the construction of the BCD ring system of brevetoxin A by K.C. Nicolaou and co-workers. The dihydroxy dicarboxylic acid substrate was subjected to a one-pot bis-lactonization. After the formation of the bis-2-pyridinethiol ester, the lactonization was conducted at low substrate concentration (0.013 M) in toluene at reflux temperature. 

Corey, E. J., Nicolaou, K. C., Melvin, L. S., Jr. Synthesis of novel macrocyclic lactones in the prostaglandin and polyether antibiotic series. 

Esters and lactones. Swiss chemists have used a procedure similar to that of Corey and Nicolaou (5, 260) for preparation of esters and lactones, but they carry out the reaction in the presence of 1 eq. of AgBp4 or AgC104. Coordination of an S-2-pyridylthiocarboxylate with silver ion permits rapid esterification at 20° in a few minutes. If the silver salt is omitted in the example cited, the yield of ester is only 5% after 7 days at 20°. 

Corey EJ, Nicolaou KC (1974) An Efficient and Mild Lactonization Method for the Synthesis of Macrolides. J Am Chem Soc 96 5614... 

Corey and Nicolaou used the S-pyridyl ester [19], which was generated by Mukaiyama thioester formation using 2,2 -dipyridyl disulfide and PPhj [20], as an activated precursor for lactonization. In 1976, they first accomphshed the total synthesis of some macrolide molecules including recifeioUde (15), as shown in Scheme 5.1 [21]. 

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. ... 

---