Wadsworth-Emmons reaction macrocyclization

Intramolecular condensation of phosphonate carbanions with carbonyl groups carried out under conditions of high dilution have been utilized in macrocycle syntheses. Entries 7 and 8 show macrocyclizations involving the Wadsworth-Emmons reaction. Entries 9 to 11 illustrate the construction of new double bonds in the course of a multistage synthesis. The LiCl/amine conditions are used in Entries 9 and 10. 

Other examples of Ugi reactions combined with RCM have been described in the literature. Hebach and Kazmaier reported the synthesis of conformationally fixed cyclic peptides [70] and Beck and Domling synthesized biaryl-containing natural product-like macrocycles using this method [41]. The same group also reported combination of Passerini and Horner-Wadsworth-Emmons reactions to obtain butenolides [67] and another variation for the combinatorial synthesis of thiazoles [69]. 

To date long-chain phosphonylated aldehydes (n > 10) have been prepared exclusively as precursors for the synthesis of 11- to 17-membered macrocycles via intramolecular Homer-Wadsworth-Emmons reactions (Scheme 5.63). This widely used cyclization step provides the best method for preparing macrocycles. 

In the last steps of the total syntheses, ester 474 was converted into aldehyde 475 in four steps with an overall yield of 65%. Macrocyclization was possible via a Horner-Wadsworth-Emmons reaction and precursor 476 for roridin E (378) and baccharin B5 (379) was obtained. The final step in the synthesis of roridin E (378) was the isomerization of the double bond. 

Diphenyl phosphite-ester-aldehyde substrates (83) undergo a Z-selective intramolecular Homer-Wadsworth-Emmons (HWE) reaction to give macrocyclic ene-lactones (84). Terminal placement of the ester in the substrate gives a macrocyclic alkene with... 

Floreancig and co-workers communicated the synthesis of (+)-dactylolide in 2005. The key step of Floreancig s synthesis involved an asymmetric vinylogous Mu-kaiyama-aldol reaction and an intramolecular Prins cyclization of the acetal bearing substrate. The macrocyclization of the synthesis was achieved by Honer-Wadsworth-Emmons olefination as demonstrated by the Smith group in the first total synthesis of (+)-zampanolide (Schemes 2.55, 2.56). 

Muscone (40) is a sex pheromone of the musk deer and a chemical component of cosmetics. A 12-member library of racemic muscone analogs was synthesized by Nicolaou et al.," who anployed a cyclorelease method on solid support to form the macrocycle scaffold (Figure 11.17). A phosphonate-functionalized resin loaded on encoded SMART microreactors 36 was coupled to olelinic esters 35 to form the p-ketophosphonates 37. Sorting and cross olefin metathesis of 37 with two alkenols followed by oxidation with Dess-Martin reagent gave aldehydes 38. An intramolecular ketophosphonate-aldehyde condensation (Homer-Emmons-Wadsworth reaction) of 38 caused smooth cyclorelease of macrocyclic enones 39. Parallel solution-phase chemistry completed the sequence. 

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