Cyclorelease

Nicolaou, K. C. Winssinger, N. Pastor, J. Murphy, F. Solid-Phase Synthesis of Macrocyclic Systems by a Cyclorelease Strategy Application of the Stille Coupling to a Synthesis of (.S )-Zearalenone, Angew. Chem. Int. Ed. Eng. 1998, 37, 2534. 

The same authors demonstrated a solid-phase combinatorial synthesis of a muscone library starting from the monomethyl methanephosphonate 96 bovmd to the Merrifield resin. The key steps were the synthesis of the /1-ketophospho-nates 97, introduction of the aldehyde group, which was necessary for the cyclorelease, and final reduction of double bonds in 98 to the modified mus-cones 99 (Scheme 27). 

Fig. 15 Examples of cyclorelease (a) ring-closing metathesis (this reaction afforded several macrocycles, among which we describe only one) and (b) Stille coupling.

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). 

Fig. 16 (a) macrocyclic lactone synthesis by cyclorelease via a sulfur ylide and (b) macrocyclization via intramolecular Suzuki-... 

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. 

In such linkers, the latent bond requires activation before cleavage can occur. Many of the linker units discussed elsewhere in this chapter could be considered safety-catch linker units. For example, photolytic activation described in Section 1.2.4 and cyclorelease discussed in Section 1.2.2 are essentially safety-catch strategies. This section, however, will concentrate on synthetic activation. The first example of such an approach was a sulfonamide linker reported by Kenner et al. in 1971. The sulfonamide 7 is stable to both acidic and basic conditions, making it synthetically valuable. However, alkylation of the nitrogen with, for example, diazomethane or iodoacetonitrile, gave 8, from which substrates (e.g., carboxylic acids 9) could be cleaved under nucleophilic conditions (Scheme 1.4). 

Scheme 7.3 Intramolecular Stille coupling in macrocyclization. (a) Solution-phase synthesis [54]. (b) Solid-phase synthesis by a cyclorelease strategy [55].

Cyclorelease of (d/)-muscone intermediate 306 Supported ketophosphonate 305 (1.0 equiv) was suspended in toluene... 

Nicolaou KC, Winssinger N, Pastor J, Murphy F. Solid-phase synthesis of macrocychc systems by a cyclorelease strategy. Angew. Chem. Int. Ed 1998 37 2534-2537. 

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