Macrocyclic libraries

An 8000-member library of trisamino- and aminooxy-l,3,5-triazines has been prepared by use of highly effective, microwave-assisted nucleophilic substitution of polypropylene (PP) or cellulose membrane-bound monochlorotriazines. The key step relied on the microwave-promoted substitution of the chlorine atom in monochlorotriazines (Scheme 12.7) [35]. Whereas the conventional procedure required relatively harsh conditions such as 80 °C for 5 h or very long reaction times (4 days), all substitution reactions were found to proceed within 6 min, with both amines and solutions of cesium salts of phenols, and use of microwave irradiation in a domestic oven under atmospheric reaction conditions. The reactions were conducted by applying a SPOT-synthesis technique [36] on 18 x 26 cm cellulose membranes leading to a spatially addressed parallel assembly of the desired triazines after cleavage with TFA vapor. This concept was later also extended to other halogenated heterocycles, such as 2,4,6-trichloropyrimidine, 4,6-dichloro-5-nitropyrimidine, and 2,6,8-trichloro-7-methylpurine, and applied to the synthesis of macrocyclic peptidomimetics [37]. 

In the following sections, examples of hydrogen-bonding templates for the synthesis of macrocycles, cages, interlocked species, helicates and for the photochemical reaction of olefins will be discussed. The use of hydrogen-bonding templates in dynamic combinatorial libraries will also be presented. 

The major components are series of homologous trimers, tetramers, and pentamers of the three acids 44-46, along with smaller quantities of dimers, hexamers, and heptamers. Furthermore, the secretion contains several isomers of each oligomer, furnishing a combinatorial library of several hundred macro-cyclic polyamines [51, 52]. Using repeated preparative HPLC fractionation, the most abundant trimeric, tetrameric and pentameric earliest-eluting compounds were isolated. One and two-dimensional H NMR spectroscopic analyses showed that these molecules were the symmetric macrocyclic lactones 48, 49, and 50 (m, n, o, p, q=7) derived from three, four or five units, respectively, of acid 46. Moreover, using preparative HPLC and NMR methods, various amide isomers, such as 53,54, and 55 (Fig. 9) were also isolated and characterized [51,52]. 

Dynamic transacetalization experiments targeting cyclophane formation have also been described by Mandolini and coworkers [34]. Production of a cyclic polyether DCL by direct reaction of triethylene glycol and 4-nitrobenzaldehyde has been reported by Berkovich-Berger and Lemcoff amplification of small macrocyclic members of the library by ammonium ion was observed [35]. With these few examples demonstrating feasibility, we can anticipate increased use of transacetalization in future DCC efforts. 

Wessjohann, L. A. Rivera, D. G. Leon, F. Freezing imine exchange in dynamic combinatorial libraries with Ugi reactions Versatile access to tern-plated macrocycles. Org. Lett. 2007, 9,4733 736. 

Corbett, P. T Sanders, J. K. M. Otto, S. Exploring the relation between amplification and binding in dynamic combinatorial libraries of macrocyclic synthetic receptors in water. Chem. Eur. J. 2008,14, 2153-2166. 

Cousins, G. R. L. Poulsen, S.-A. Sanders, J. K. M. Dynamic combinatorial libraries of pseudo-peptide hydrazone macrocycles. Chem. Commun. 1999, 1575-1576. 

Kay Severin s group has previously investigated the preparation of dynamic combinatorial libraries of metallo-macrocycles for use as sensors for Li+ at physiologically relevant conditions [59]. For example, they have found that ligand 62 and metal complexes 63 undergo a self-assembly process to yield the trimeric complexes depicted in Scheme 4.15 [60]. Mixtures of 64 and... 

Gonzalez-Alverez, A. Alfonso, I. Gotor, V. Highly diastereoselective amplification from a dynamic combinatorial library of macrocyclic oligoimines. Chem. Commun. 2006, 2224-2226. 

Schreiber proposed the Lipschutz method (oxidative coupling of two aryl-Cu(I) moieties) to generate a library of biaryl-containing macrocycles [54]. Biaryl macrocycles were obtained in good to excellent yield where other methods (Pd coupling etc.) failed or gave inferior results (Scheme 4). 

The synthesis of a small library of very large (up to 60-membered) steroid/ peptide hybrid macrocycles has been achieved using double and fourfold Ugi reactions. This type of compound has not previously been described in literature. Neither have multicomponent reactions been used so far to form directly macrocycles of this size. In fact, synthetic macrocycles of this size with this structural complexity are very rare. 

In more recent works, Zhu and coworkers synthesized a variety of para-cyclophanes and biarylether containing macrocycles (14c and d) using a reaction sequence consisting of an Ugi reaction followed by an intramolecular Sj Ar cyclization (Scheme 14) [76-78]. Many linear precursors (14a and b) were achieved with the Ugi reaction by employing varied primary amines. This synthetic planning allowed the introduction of four points of diversity within the resulting scaffolds, thus producing a small library of cyclopeptoids. 

A similar type of compounds, without the nitro group, was achieved by Wessjohann and coworkers (Scheme 15) [79]. Their approach also uses the Ugi reaction to build the linear peptoid intermediates, but a nucleophilic substitution is employed for the ring closure, which is a difficult task with a strained phenolate. A small library of macrocycles with general formula 15a was prepared, including also some 15-membered ansa-cycles (not shown). 

Straightforward, versatile, and generates libraries of macrocyclic pseudo peptides with unprecedent functional and skeletal diversity. For example, natural product-inspired biaryl ether-cyclopeptoid macrocycles were obtained by this methodology [98, 99]. 

Nicolaou, K. C. Pastor, J. Winssinger, N. Murphy, F. Solid Phase Synthesis of Macrocycles by an Intramolecular Ketophosphonate Reaction. Synthesis of a (7//)-Muscone Library, J. Am. Chem. Soc. 1998,120, 5132. 

Takahashi et al.45 used a 4-hydroxybenzenesulfonate linker on Syn-Phase polystyrene Crowns to prepare glucose derivatives and macrocycles (Scheme 20). Displacement of the monosaccharide-supported Crowns 70 with nucleophiles such as azide, iodide, and acetate gave the respective 6-substituted glucose derivatives 71, 72, and 73 in excellent purities and yields. The authors suggest that this methodology could be utilized for the preparation of oligosaccharide libraries. 

A transition-state analogue for an acetal hydrolysis has been used to select and amplify the production of a macrocycle from a dynamic combinatorial library of disulfides in water. The macrocycle gives a modest acceleration of the acetal hydrolysis reaction.6... 

In term of diversity-oriented strategies, multicomponent reactions (MCR) represent an attractive and rapid access to libraries of macrocycles inspired by biologically active natural products. Combined with Passerini and Ugi reactions, M-RCM has already shown promising synthetic potential, as illustrated by the pioneering work of Domling and coworkers [46]. Condensation of isocyanide 69 with carboxylic acid 70 in the presence of paraformaldehyde leads to bis-olefin 71, which is subsequently submitted to RCM in the presence of G1 and titanium isopropoxide to give the 22-membered macrocycle 72 (Scheme 2.27). 

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