Macrocycles solid-phase method

The group of Grieco has presented a method for efficiently performing macrocy-clizations on a solid phase (Scheme 7.31) [48]. The preparation of the macrocyclic peptides required several standard transformations, which are not described in detail herein. The final intramolecular nucleophilic aromatic substitution step was carried out under microwave irradiation at 50 °C in a dedicated CombiCHEM system (see Fig. 3.9) utilizing microtiter plates in a multimode batch reactor. The cycli-zation product was obtained in good yield after a reaction time of 10 min and sub-... 

A novel concept for the synthesis of macrocyclic peptidomimetics 262, which incorporate heteroaromatic units, was reported (Scheme 39). This method involves sequential SNAr reactions of orthogonally protected amino groups of peptides and other linear oligomers on halogenated heterocycles such as 2,4,6-trichloro[l,3,5]triazines. The scope of this novel solid-phase approach was evaluated systematically by means of the SPOT-synthesis methodology on planar cellulose membranes <2000JC0361>. 

To complete this short treatment on solid-phase synthesis, let us be mention the efforts made by several groups to obtain methods that allow a cyclorelease (also called cyclative cleavage) of the macrocycle, in other words, the cyclization reaction and the release from the polymer support occur simultaneously. The methods developed so far involve the metathesis reaction (Fig. 15a) the Stille coupling (Fig. ISb) and sulfur ylides (Fig. 16a). 

This combination of solid-phase peptide synthesis followed by TE-mediated macrocyclization mimics the function of NRPSs, in which a peptide chain is first elongated and then cleaved and often cyclized. The applicability of this approach for the discovery of NCEs is apparent established synthetic combinatorial methods could be employed in concert with the enzymatic machinery of the NRPS. In the case of the tyroddine A Ubrary, two analogs were discovered that displayed both improved antibiotic activity and a better in vitro therapeutic index (human erythrocytes vs. Gram positive/negative bacteria) relative to the parent tyroddine A. 

As described in Section 11.7.1, palladium (0) chemistry has been found particularly well-suited for constructing macrocyclic structures and, hence, applications for libraries have also been pursued. Indeed, as already noted, one of the first macrocyclic library efforts actually used the Heck reaction for solid phase construction of small collections of 20- to 24-membered semi-peptidic macrocycles (299, Figure 11.26, site of ring closure and chemistry indicated). In addition, modest-sized libraries of RGD mimic macrocycles (300) ° and macrosphelide analogues (301) were prepared using palladium-catalysed cyclocarbonylation on resin. This particular method proved to be tolerant of a variety of functional groups, including halides, ethers, ketones and esters. 

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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