Macrolactonization procedures

The resin-bound trienes 83 (Scheme 11) were prepared in a similar fashion to the solution-phase studies (Sect. 2.2.2) and underwent tandem RCM resin-cleavage to liberate four macrolactones 84a,b and 85a,b in a combined yield of 52%. Although, as expected, a large amount of initiator 3 was required to effect this transformation, the procedure constituted a novel and efficient route to the epothilones which paved the way for the generation of a library of epothilone analogs. The library synthesis was achieved using the recently developed SMAR-I9 microreactors (SMART=single or multiple addressable radiofrequency tag) [25] (Scheme 12). 

Macrocycles are often not easy to form, especially when they include many substituents. The applied procedure to synthesize macrolactones was introduced by Yamaguchi and co-workers and has since been used extensively.21 First the acid is transformed into the mixed anhydride 26. Refluxing the anhydride in toluene will yield the desired macrocycle. The attack of the alcohol at the trichlorobenzoic acid carbonyl moiety is not favored because of steric hindrance by the chlorine substituents ortho to the acid. Therefore the ring is closed selectively. Usually in macrocyclizations high dilution conditions are applied, too, in order to avoid intermolecular reactions. 

The discontinuous process for preparing macrolactones described in the text is impractical. Instead of this process one uses a continuous method with a syringe pump one adds a solution of the hydroxycarboxylic acid very slowly—that is, in the course of hours or days—into a small flask, which contains >1 equivalent of the activator and, if necessary, just enough triethylamine to neutralize any released HCl.The rate at which the acid is added is regulated such that it is equal to or smaller than the lactonization rate. This procedure is called working under pseudo-high dilution. At the end of the... 

In the classical procedure, the mixed anhydride is formed in THF in the presence of NEts. After filtration of NEtsHCl and evaporation of the solvent, the mixed anhydride is diluted in toluene and slowly added by syringe pump to a highly diluted solution of DMAP in toluene at 80 °C or under reflux/ The mixed anhydride is attacked by DMAP with formation of a cationic intermediate which forms the macrolactone by nucleophilic attack of the hydroxyl group. The mode of action is depicted below. The reaction proceeds with retention of the configuration at C-co. 

Although Bu2SnO is a powerful catalyst for cyclization of co-hydroxy and co-amino carboxylic acids [294], treatment of co-hydroxy trifluoroethyl esters with Bu jSnOMe catalysis resulted in macrolactonization and/or diolide formation in different ratios, depending on chain lengths and reaction conditions (Scheme 12.166) [295]. In this reaction inter- and/or intramolecular transesterification occurred between trifluoroethyl esters and alkoxytrialkyltin generated by rapid exchange of the alkoxytin catalyst with the terminal alcohol. By use of this procedure as a final key step a 12-membered macrocyclic otonecine diester was obtained (Scheme 12.167) [296]. 

Boden and Keck [53] developed a practical method for macrolactonization by treatment with DCC and DMAP in the presence of DMAP-HCl the original esterification procedures using DCC and DMAP or 4-pyrrolidinopyridine were reported by Neises and Steglich [54] and Hassner and Alexanian [55] independently. This method worked very efficiently for the macrolactonization (92% yield) in the total synthesis of cytovaricin (196) (see Scheme 29 later in this chapter). 

Leighton s synthetic strategy is shown in Scheme 43. Side chain 200 was introduced by the Still-modified (Z)-selective Honer-Emmons reaction forming the C2 -C3 double bond. Macrolactonization leading to 201 was carried out by using the Yamaguchi procedure, and C17 asymmetric carbon was constructed by alkenylzinc addition to an aldehyde in 202. The 2,6-trans-tetrahyderopyran was synthesized by the Hosomi-Sakurai reaction to a lactol. 

Macrolides. - The Steglich esterification procedure (DCC-DMAP) can be applied to the macrolactonization of u>-hydroxy-acids if, in addition, an excess of the hydrochloride salt of DMAP is... 

Interested in facilitating access to the macrolactone, we also explored the macrolactonization by employing the Shiina s procedure [191-193] (Scheme 2.81). To this end, the seco-acid 2.359 of the aldehyde 2.333 was independently prepared and subjected to Shiina s MNBA macrolactonization reaction conditions. The reaction smoothly proceeded to provide the macrolactone 2.332 in 81 % yield. At this point, we hypothesized that the result was most likely due to the gem-disubstituent effect induced by the TBS-protected cyanohydrin functionality. As mentioned, in the previous syntheses of (+)-dactylolide, several attempts for the macrolactonization of the structurally related substrates without the cyanohydrin group either failed to afford the corresponding macrolactone or resulted in low to modest yields (21 8 %) under various macrolactonization conditions, suggesting that the TBS-protected cyanohydrin in our substrate appears to have a noticeable effect in the NHC-catalyzed oxidative macrolactonization. 

Chapter Synthesis of 12- to 16-Membered-Ring Lactones is dedicated to the synthesis of 12- to 16-membered ring lactones. In this chapter, M. Kalesse and M. Cordes present an overview of the macrocyclization of seco-acids as well as new effective procedures to access 12- to 16-membered ring lactones such as ringclosing metatheses of alkynes and olefins. The authors also report the use of ketene sources and benzodioxinones to produce macrocyclic lactones. Nitrile oxide-olefin cycloaddition, intramolecular C-H oxidative macrolactonization, and Yamaguchi and Mukaiyama macrocyclization as well as macrolactonization via thioester or using phosphorus reagents are described. 

Hydroxy acids H0-(CH2)n-C02H with n>3 react with DEAD and TPP to afford the corresponding lactones. This procedure can be utilized in the preparation of macrolide antibiotics and related compounds. Macrolactonization by the use of DEAD-TPP depends on the reaction conditions and the structure of the seco acids. Thus dropwise addition of the hydroxy acid (18) over a period of 10 h to a mixture of DEAD (7.7 equiv) and TPP (7.5 equiv) affords the lactone (19) in 59% yield as well as the unwanted di-lactide (20) in a yield of <1%. On the other hand, the reaction of... 

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