Biaryl-containing macrocycles

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). 

In the laboratory of J. Zhu, the synthesis of the fully functionalized 15-membered biaryl-containing macrocycle of RP 66453 was accomplished. One of the key steps in their approach was Corey s enantioselective alkylation of a glycine template with a structurally complex biaryl benzyl bromide. This benzyl bromide was prepared from the corresponding benzyl mesylate via the Finkelstein reaction using lithium bromide in acetone. 

A novel macrocyclization reaction was developed based on a domino Miyaura boration intramolecular Suzuki crosscoupling sequence in the laboratory of J. Zhu. " This strategy was applied in the synthesis of biaryl-containing macrocycles. The diiodide substrate was dissolved in degassed DMSO, and then the catalyst and the base were added. Successful macrocyclization required extensive experimentation, and the authors determined that the concentration and the nature of the base were the two most important factors. Interestingly, potassium carbonate is not suitable as a base in the Miyaura boration, since it tends to give biaryl by-products, but in this particular macrocyclization reaction it proved to be completely ineffective because the reaction failed to take place. 

Boisnard, S., Carbonnelle, A.-C., Zhu, J. Studies on the Total Synthesis of RP 66453 Synthesis of Fully Functionalized 15-Membered Biaryl-Containing Macrocycle. Org. Lett. 2001,3, 2061-2064. 

Other examples of Ugi reactions combined with RCM have been described in the literature. Hebach and Kazmaier reported the synthesis of conformationally fixed cyclic peptides [70] and Beck and Domling synthesized biaryl-containing natural product-like macrocycles using this method [41]. The same group also reported combination of Passerini and Horner-Wadsworth-Emmons reactions to obtain butenolides [67] and another variation for the combinatorial synthesis of thiazoles [69]. 

Cristau P, Vors JP, Zhu JP (2001) A rapid access to biaryl ether containing macrocycles by pairwise use of Ugi 4CR and intramolecular SNAr-based cycloetherification. Org Lett 3 4079 82... 

As for the biaryl ether containing macrocycles, an array of bioactive macrocycles with an endo aryl-aryl bond exist in nature. A new palladium catalyzed reaction has been recently developed in which bis(pinacolato)diborane(4) mediated the process to reach such a structural motif. The reaction consists of a domino process involving a Miyaura s arylboronic ester synthesis and an intramolecular Suzuki-coupling. Synthesis of a bicyclic A-B-O-C ring system of RP-66453 273, a neurotensine receptor antagonist, with an endo aryl-aryl and an endo aryl-aryl ether bond was described (Scheme 53).141... 

From Alnus species i.e. varieties of alder, containing also a large variety of open chain diarylheptanoids (7-21), some biaryl type macrocyclic compounds have also been isolated. In Alnus japonica Steud. indigeneous in Japan Nomura et al. found four diphenols of this kind. The constitution of alnuson (80) and alnusoxide (81) was elucidated in 1975 (20), while alnusdiol (82) and its oxidation product, alnusonol (83) were characterized in 1981 (17). It was observed that 81 could only be isolated from the dried plant and may be therefore an artefact. Alnusdiol was optically active and therefore a trans-diol but its absolute configuration remained unknown. 

Compounds 80 and 93 were reisolated by Sawa and his cowoikers from C. cordata along with a new biaryl type macrocyclic diarylheptanoid (84) containing an unusual diol acetonide function. 

In an alternative synthesis, a two-step sequence involved an Ugi four-component reaction and an intramolecular nucleophilic aromatic substitution to provide rapid access to biaryl-ether-containing macrocycles in solution phase and solid phase (Figure 11.34). 55 Using isonitriles, aldehydes, amines, and carboxylic acids as inputs for the Ugi reaction, dipeptides 70 were formed. Upon cyclization of 70 with K2CO3 in DMF, macrocycles 71 with four points of diversity were obtained. Moreover, the presence of the nitro group allowed the introduction of further structural variation. In the solid-phase synthesis, the Ugi condensation used isonitriles attached to a Wang resin. 

FIGURE 11.34 Synthesis of natural product-like biaryl-ether-containing macrocycles. (From Cristau, R, Vors, J.P., and Zhu, J., Rapid and diverse route to natural product-like biaryl ether containing macrocycles, Tetrahedron, 59, 7859, 2003.)... 

The most prominent application of the Ru-arene chemistry has been for the preparation of biaryl ethers in the syntheses of portions of vancomycin,467 ristocetin (Equation (127)),462,468-473 and teicoplanin (see also Section 10.14.1.2).474-476 Additional applications477-479 have included the syntheses of the macrocyclic biaryl ether-containing compounds K-13480,481 and OF4949-III,481,482 several macrocyclic depsipeptides,483,484 and poly(phenylene oxide) polymers.485... 

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... 

Macrocyclic diarylheptanoids can be derived from linear ones by oxidative cyclization. This is supported by the fact that in all of the biaryl type representatives the aryl-aryl bond is in meta position relative to both ends of the seven-carbon chain, while in those containing a diarylether bond a meta,para bridging can be identified. This substitution pattern corresponds to activation of the position ortho to the phenolic hydroxy group. Biosynthesis of cyclic diarylheptanoids was investigated by Inoue et al. (84). They fed [1- C] and... 

Uses of bases of this type, such as DBU and DBN have been reviewed [15] and more recently they have been used as stoichiometric bases in the synthesis of 2H-isoindoles [ 16],biaryl thioethers [17],phthalocyanines [18] and the related macrocyclic compounds [18], 2,4-dioxo-l,2,3,4-tetrahydroquinazolines [19], dihydro alanine-containing peptides [20] and [[pyrazolylmethyl)amino]-propyl azepinones and -pyrrolidinones [21]. Chiral DBU/DBN-related molecules have also been synthesized which were fovmd to be useful as catalysts in an asymmetric Michael reaction [22]. 

A boronic acid ester, which contains an aryl iodide moiety attached by an appropriate tether, can act as an inttamolecular arylation agent. Thns, Li and Burgess developed a polymer-bound precursor, which by a biaryl coupling ensning cleavage fnmished a macrocyclic constrained /3-tum peptide mimic (Scheme... 

A macrocyclic triangular trinuclear Pt complex composed of an optically active biaryl group and cis-dialkynylplatinum(ii) group 851 has been prepared. The macrocycle containing Ti at the binaphthyl group shows high catalytic activity toward asymmetric addition of diethylzinc to aldehydes. 

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