Macrocyclizations on solid supports

Walters, M. A. Macrocyclization on solid support using Heck reaction. Chemtracts 1998,11,291-296. 

Hiroshige, M. Hauske. J.R. Zhou, P. Palladium-mediated macrocyclization on solid support and its applications to combinatorial synthesis. J. Am. Chem. Soc. 1995, 117. 11590-11591. 

Akal997 Akaji, K. and Kiso, Y, Macrocyclization on Solid Support using Heck Reaction, Tetrahedron Lett., 38 (1997) 5185-5188. 

As stated above, several supramolecular motifs such as hydrogen-bonding, donor-acceptor, or metal-ligand interactions have been used to promote the organization of Pcs in solution. Somehow different, and probably to some extent more complex, is the case when such organization is sought on solid supports, as in this latter case the interactions between the macrocycles and the surface itself should also be taken into account. 

An impressive example is the first macrocyclization performed on solid supports by Zhou and coworkers [22] starting from aryliodide 17, which gave the desired compound 18 under remarkably mild conditions in exceptionally high purity and yield (Scheme 14.5). 

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. 

B.ii.c. Intramolecular Heck Reactions. The main advantage of intramolecular Heck reactions on solid support is the pseudodilution of the starting material leading to an increase of the yield. The first use of this was reported in 1995 for the synthesis of 20- to 24-membered macrocyclic ring systems (Scheme 3). ... 

Pernerstorfer J, Schuster M, Blechert S. Cyclisation/cleavage of macrocycles by ring-closing metathesis on solid support-conformational studies. Chem. Commun. 1997 1949-1950. 

In addition to the success just described with the well-known named processes, a number of other macrocyclization reactions mediated by palladium complexes have been reported. The first of these approaches exploits the established chemistry of palladium Jt-allyl complexes for use in activation towards reaction with nucleophiles. This reaction was employed by Harran et al. as a critical step in the construction of a series of macrocycles such as 116 via 115) designed to significantly reduce the peptidic character of known active peptides (Scheme 11.14). " The approach tolerates a variety of functionality, including alcohols, amides, thioethers and selected heteroaromatics, and was also successfully conducted on solid support. 

A promising approach to this topic is the development of biocompatible solid phase attachment systems for macrocycles that allow on-bead enzymatic and chemical modification [4]. While making use of recent developments in polymeric support for resins, we endeavored in constructing a new linker system, which allows easy attachment of macrocycles to the solid phase, simple organic or enzymatic reactions, and cleavage from solid support under mild conditions [98]. 

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 3-12 Macrocyclization achieved on a solid support. = A PdCOAc), PPh, Bu NCl, DMF/EtjN/water (9 1 1), rt, overnight [125].

The metathesis concept on a solid support has been extended to so-called crossmetathesis, whereby one of the reacting alkenes is attached to the solid support and a terminal alkene is present in solution [138], During metathesis, this terminal alkene becomes immobilized on the resin. The reaction conditions were optimized in such a way that the possible formation of macrocycles could be prevented. The allyl-dimethylsilyl polystyrene 116 used in the reaction was synthesized according to Scheme 55. After metathesis, terminal alkenes 117 are released by scission of the Si-C bond mediated by appropriate nucleophiles (Sakurai conditions). 

Some chiral starting materials containing more than two hydroxy groups have been used for the syntheses of macrocycles. Tetraols, for example, can react at two hydroxy functions, leaving the other hydroxy functions to bond the product to solid supports or on ion-selective electrodes (Bogatskii et al.,... 

Methods 0-6, 0-7, and 0-8 are simple procedures for preparing the polyaza macrocycles with reactive secondary amine groups in the ring or on pendant alkyl groups or a hydroxy group on a ring carbon atom. These reactive functional groups allow these macrocycles to be further reacted to add other species or to be attached to a solid support. 

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