High-dilution methods macrocycle syntheses

Hexen-l-yn-3-one, 1-methoxy spiroanellation with, 74 Hexonamides, TV-alkyl- aqueous suspensions various micellar aggregates, 352-353 L-Hexoses total synthesis, 264-265 2-Hexulosides by redox glycosylation , 272 High-dilution methods macrocycle syntheses by, 145-146, 240-241, 329, 338 Hindrance, steric. See Steric hindrance Hippuric acid See Glycine, iV-bcnzoyl-HMDS. See Silanamine,. .. 

The intramolecular version for synthesizing cyclic and polycyclic compounds offers a powerful synthetic method for naturally occurring macrocyclic and polycyclic compounds, and novel total syntheses of many naturally occurring complex molecules have been achieved by synthetic designs based on this methodology. Cyclization by the coupling of an enone and alkenyl iodide has been applied to the synthesis of a model compound of l6-membered car-bomycin B 162 in 55% yield. A stoichiometric amount of the catalyst was used because the reaction was carried out under high dilution conditions[132]. 

In the course of experiments directed at the synthesis of open-chained equivalents of macrocyclic polyethers (see Chap. 7), Rasshofer and Vogtle found that 9 or its derivatives were formed rather than the desired compounds . Although the yields obtained by this method are modest, the facts that the reaction is conducted without the use of high dilution and in one-pot recommend it. 

Shortly after their first report of all-oxygen bridged cryptands, Dietrich, Lehn and Sauvage reported incorporation of sulfur in the strands. The experimental methods used were essentially similar to those applied in the syntheses of the parent cryptands. As in previous cases, a diacyl chloride was condensed with a diamine under high dilution conditions. In this case, however, the diamine contained sulfur atoms rather than oxygen. The synthesis of compound 5 was accomplished in two stages as illustrated below in Eq. (8.3). The first cyclization step affords the macrocyclic amine in 55% yield. The macrobicyclic product (5) is formed in 25% yield from the monocyclic diamine and the acid chloride. 

Trost and coworkers137 have reported the polymer-supported palladium catalyzed cyclization of 1, l-bis(phenylsulfonyl)epoxyalkene 235 which gives cycloalkanes 236 and 237 in a 2 1 ratio (equation 143). This method has proven useful for the synthesis of macrocyclic compounds under neutral conditions without using high dilution technique. Temperature and concentrations are critical. The best results are achieved if a reaction mixture of 0.1-0.5 m is added to a preheated (at 65 °C) suspension of the catalyst. 

The saturated aza-oxa crown ethers were first synthesised as intermediates in the synthesis of the nitrogen cryptands.1 The reaction conditions used for the formation of these macrocycles involved the high-dilution technique. In this versatile method, a diamine and a diacid chloride are simultaneously added in the presence of triethylamine to a large volume of solvent, usually toluene, over an extended period of time. The major product from such a reaction is the [1+1] cyclised product, although the [2+2] adduct can often be isolated as well, in low yield. Whilst this method is still sometimes used,2,3 particularly for cryptand synthesis (Chapter 5), it has been superseded by methods that are more convenient and which proceed under medium dilution. 

Durette et al. [74] have achieved the total synthesis of the hexadepsipeptide antibiotic L-156,602 128) using the mixed phosphonic anhydride method as key macrolactamization step. As shown in Scheme 43, treatment of the linear depsipeptide 126 with n-propylphosphonic anhydride and DMAP in dichloro-methane at high dilution afforded the macrocycle 127 in more than 57% yield. 

The Mukaiyama reagent, l-methyl-2-chloropyridinium iodide (28), is also suitable for macrolactamization [85]. Jones et al. [86] achieved the first total synthesis of the important immunosupressant (-)-FK-506 (151) using the Mukaiyama method as a key cyclization step. As shown in Scheme 50, the unstable amino acid 149 was treated with 28 under high dilution to give the macrocycle 150 in... 

The low affinity of sulfur for alkali metal ions, however, renders template effects of less consequence in the synthesis of polythia macrocycles. Thus, the competition between cycli-zation and linear polymerization is more statistically defined, with cyclization kinetically favored only at high dilution 64,65,66). Consequently, most of the synthetic methods for the synthesis of polythia rings involve high-dilution techniques coupled with relatively long reaction times. Historically, the study of the coordination chemistry of macrocyclic thioethers has been hindered by difficulties in the synthesis of the free ligands. The synthesis of [BJaneSa, first reported by Ochrymowycz and co-workers in 1977 101), illustrates this well. 

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... 

The synthesis of podand hosts is conceptually relatively straightforward and is generally achieved using conventional synthetic methods such as ether, sulfide or amide bond formation however, the synthesis of macrocycles is a little more challenging and is accomplished by one or both of two general procedures, i.e. high-dilution synthesis and template synthesis. 

The template method for the general synthesis of macrocycles holds considerable promise an example of this approach is the preparation of macrolide (77) from the crown ether complex (76). Yields are up to 70% although high-dilution techniques are still required as some degree of intermolecular complexation occurs. One problem with this particular method is the removal of water from the parent hydroxy-thioester crown ether, which is converted into (76) using KOBu. ... 

High-dilution conditions for the intramolecular application of the malonic ester synthesis to the preparation of macrocyclic diesters have been reported yields between 9 and 50% are obtained. Dialklacyl phosphonates provide a new method for the acetylation of enolates including the sodium enolate of diethyl malonate. An alternative method for the generation of diester enolates involves the reductive a-deacetoxylation of an a-acetoxy diester (Scheme 30). The... 

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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