Solid-phase macrocycle synthesis

Scheme 10 Solid-Phase Macrocyclization Approaches for Lanthionine Peptide Synthesis (A) Macrocyclization from Preformed Lanthionine Derivatives (B) Macrocyclization from Precursors...

Scheme 13 Solid-Phase Peptide Synthesis of an Enkephalin Analogue by Macrocyclization of Cysteine and Dehydroalaninel271...

Figure 12 A solid-phase total synthesis of the antimycobacterial cyclodepsipeptide kaha-lalide A. The synthesis relies on the Kenner safety-catch linker for attachment to the peptide backbone, followed by macrocyclative cleavage of the linear depsipeptide...

The isolated TE domain from the tyrocidine (tyc) NRPS has recently been shown to catalyze the macrocyclization of unnatural substrates to generate a variety of cyclic peptides. In conjunction with standard solid-phase peptide synthesis, Walsh and coworkers demonstrated a broad substrate tolerance for peptidyl-N-acetylcysteamine thioesters by the tyrocidine TE [41,42], Cyclization of peptide analogs, where individual amino acids were replaced with ethylene glycol units, was observed with high efficiency. In addition, hydroxyacid starter units were readily cyclized by the isolated TE domain to form nonribosomal peptide-derived macrolactones. More recently, Walsh and coworkers have demonstrated effective cyclization of PEGA resin-bound peptide/polyketide hybrids by the tyrocidine TE domain [43], Utilization of a pantetheine mimic for covalent attachment of small molecules to the resin, serves as an appropriate recognition domain for the enzyme. As peptide macrocyclizations remain challenging in the absence of enzymatic assistance, this approach promises facile construction of previously unattainable structures. 

Akaji, K. Teruya. K. Akaji, M. Aimoto. S. Synthesis of cyclic RGD derivatives via solid phase macrocyclization using the Heck reaction. Tetrahedron 2001. 57. 2293-2303. 

FIGURE 2.10 A solid-phase total synthesis of kahalalide A. The Kenner safety-catch sulfonamide linker was employed for backbone amide attachment. After assembly of the hnear peptide, safety-catch activation resulted in macrocyclative cleavage from the resin. 

FIGURE 4,16 Isolated NRPS TEs can catalyze die macrocyclization of NRPs such as tyrocidine A. The TycC TE tolerates structural changes at the positions of tyrocidine A diat are shaded gray, (a) Conventional NRP macrocyclization following NRPS-mediated elongation, (b) Chemical synthesis of the 10-mer acyclic peptide followed by activation as the thioester SNAC for macrocyclization by the isolated TycC TE. (c) Installation of the linker on PEGA resin, followed by solid-phase peptide synthesis and deprotection to yield the immobilized acyclic NRP. The TycC TE accepts the resin-bound peptide as a substrate for macrocyclization. 

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. 

Finally, by introducing the aryl halide into the isocyanide component, as in 96, various macrocyclic peptidomimetics containing a nonsymmetrical endo biaryl ether bridge have been synthesized [89-91]. Aryl nucleophilic substitution also takes place in this case under standard base-promoted conditions. The synthesis was also carried out on solid phase. Selected examples are shown in Fig. 19, but also a... 

This total synthesis is the first of three preparations of macrocycles that will be described (epothilone A, zearalenone, and muscone). All feature cycli-zation/release strategies that involve carbon-carbon bond formation.18 These efforts illustrate how the research on supported syntheses of highly complex structures has inspired the use of creative linker strategies for attachment to a solid phase. 

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. 

High loading can, however, be an inconvenience if resin-bound substrates are able to react with themselves (e.g. during olefin cross-metathesis or macrocyclizations), or if bi- or polyfunctional, unprotected reagents are to be used in solid-phase synthesis. 

Acceptor-substituted haloarenes have been successfully used to O-arylate phenols by aromatic nucleophilic substitution (Table 7.14). The most common arylating agents are 2-fluoro-l-nitroarenes, 2-halopyridines, 2-halopyrimidines, and 2-halotriazines. When sufficiently reactive haloarenes are used, the reaction proceeds smoothly with either the arylating agent or the phenol linked to the support. The thallium(III) nitrate catalyzed arylation of phenols with aryl iodides has been used for macrocycli-zations on solid phase [184], Burgess and co-workers have developed a solid-phase synthesis of 3-turri mimetics based on ring-closure by aromatic nucleophilic substitution (Entry 4, Table 7.14 see also Table 10.5). Phenols, alkylamines, and thiols have been successfully used as nucleophiles for this type of macrocyclization [185],... 

Scheme 25. Solid-phase synthesis of macrocyclic /3-turn mimetics.

Kool reported the synthesis of macrocyclic nucleotide-hybrid compounds (215a-h), putative inhibitors of the HCV polymerase, polymerase C NS5B. The compounds were prepared by solid phase synthesis on controlled pore glass. 

Nicolaou presented a synthesis of 18- and 20-membered macrocycles 125 from solid-phase-bound phosphonate 121. Condensation with ester 122 produced the intermediate 123, which was converted to the cyclization precursors 124 in a five-step sequence. Reaction of 124 with K2CO3 gave the macrocycles 125 in yields of 58% and 62%, respectively (Scheme 33) [49]. 

Nicolaou. K.C.. Pastor. J.. Winssinger, N., and Murphy. E, Solid phase synthesis of macrocycles by an intramolecular ketophosphonate reaction. Synthesis of a ((//)-muscone library, J. Am. Chem. Soc., 120, 5132. 1998. 

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