Biaryl ether macrocycles

Total synthesis of complex (macrocyclic) natural products using fast and flexible strategies and diversity-oriented synthesis of natural product-like macrocycles are important research topics in our laboratory. The following sections describe the total synthesis of epothilone D and epothilone D5 analogues, DOS of cyclopeptide alkaloid analogues, of biaryl ether macrocycles, and of steroid/peptide hybrid macrocycles, respectively. 

Key components for the synthesis of biaryl ether macrocycles were diisonitriles 98 and 101. The former was synthesized in two steps (61% yield) from commercially available diamine 97 by bisformamide formation and subsequent dehydration with phosphorus oxychloride (Scheme 16). Starting ma-... 

Encouraged by the success of MUMBIs to synthesize biaryl ether macrocycles, we endeavored to combine this methodology with experience in steroid synthesis to obtain very large macrocycles with both peptide and steroid moieties (Fig. 21). These molecules bear no direct resemblance to any known natural products, but they do display a high degree of structural... 

Zhu and coworkers have developed SNAr-based macrocyclization via biaryl ether formation.4 The first example of SNAr-based macrocyclization for synthesis of model carboxylate-binding pocket C-O-D rings of vancomycin was reported in 1994 (Scheme 9.3).10... 

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... 

Scheme 5 Macrocyclic biaryl ether formation by S Ar reaction in synthetic studies towards RP-66453 (25)...

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... 

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... 

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]. 

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... 

Key reactions of the total synthesis of the vancomycin aglycon presented by Nicolaou and coworkers [4-6] are a Suzuki coupling [15] for the synthesis of the M(5-7) unit (Scheme 5) and the triazene method, described recently for the construction of macrocyclic biaryl ethers (Scheme 6) [16]. 

Macrocyclic diarylheptanoids can be derived from their open chain congeners by oxidative phenol coupling resulting in macrocyclic biaiyls or biaryl ethers. Usually they were named after the plant source and can be conveniently classified according to the plant families in which they occur. 

The intramolecular Ullmann condensation was used by D.L. Boqer and co-workers to form the 15-membered macrocyclic ring of the cytotoxic natural product, combretastatin D-2. This compound possesses unusual meta- and paracyciophane subunits, which are also found in a range of antitumor antibiotics. The first approach where the final step was a macrolactonization was unsuccessful, so the researchers chose to form the biaryl ether moiety as the key macrocyciization step. Methyicopper was found to mediate the cyclization and gave moderate yield of the corresponding biaryi ether. Finaiiy boron triiodide mediated demethylation afforded the natural product. 

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.)... 

We will discuss alcohol and ether functionalised NHC first, followed by furan functionalised ones. After a brief glimpse into Bertrand s noncyclic biaryl amino carbenes, we will turn towards macrocyclic, crown ether type examples and finally to NHC bearing a carbonyl group in the sidechain. 

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