Biaryl-containing

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). 

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]. 

Third, the procedure described above has been applied to the preparation of various biaryls containing hetero-aromatic rings (Entries 15-17, 19, 20). Although the number of papers reporting the use of the Ni- or Pd-catalyzed procedure for aryl-aryl coupling 1s still small, the synthesis of steganone by Raphael and his co-workers is demonstrative of its synthetic potential. 

It is not possible to prepare biaryls containing a free carboxyl group directly by the diazo reaction. No biaryl is formed when (a) diazotized aniline and sodium benzoate, (b) diazotized anthranilic acid and aqueous sodium benzoate, or (c) diazotized anthranilic acid and benzene are used as components in the reaction.13 On the other hand, the reaction proceeds normally if methyl benzoate is used in reaction (a) or when methyl anthranilate replaces the anthranilic acid in (b) and in (c). The success of the diazohydroxide reaction appears to lie in the ability of the non-aqueous liquid to extract the reactive diazo compound from the aqueous layer.4 However, esters and nitriles can be prepared from esters of aromatic amino acids and cyanoanilines and also by coupling with esters of aromatic acids, and from the products the acids can be obtained by hydrolysis. By coupling N-nitrosoacetanilide with ethyl phthalate, ethyl 4-phenylphthalate (VIII) is formed in 37% yield. 

Spring DR, Krishnan S, Blackwell HE, Schreiber SL, Diversity-oriented synthesis of biaryl-containing medium rings using a one bead/one stock solution platform, J. Am. Chem. Soc., 124 1354-1363, 2002. 

The oxidative coupling of phenols has been known since the 19 th century, but seminal studies carried out by Pummerer [1-8], who identified a phenolic radical as an intermediate of the reaction, initiated the modern age of mechanistic understanding in this area. It was then demonstrated that this radical mechanism also occurs in Nature, to produce complex biaryl-containing phenolics [9, 10]. 

The efficiency of HRP for the coupling of iodotyrosine derivatives has also been studied by Eickhoff) who extended the chemistry to include the formation of biaryl linkages between small peptides in low yields (5-6 %) [30]. Biaryl-containing peptide libraries were also prepared by HRP oxidative coupling of appropriate phenolic precursors. 

Phase-switching strategy was applied to the multistep synthesis of isoxazolines 45-47. The approach exploits the boronic acid functionality as a phase-tag which can be easily immobilized on diethanolaminomethyl polystyrene (DEAM-PS) resin and then released by treatment with wet THF. Each reaction step was carried out in solution and the products were purified by addition of the scavenging resin, followed by filtration, washing of the supported material, hydrolytic release and evaporation. Finally, the boronic acid could be used to introduce additional substituents on the molecule. For example, 46 was converted into the biaryl-containing isoxazoline 47 by a Suzuki cross-coupling reaction <07JCO193>. 

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. 

Synthesis of biaryls containing one or two ortho substituents (Sect. C). 

Synthesis of chiral atropisomeric biaryls containing three or four ortho substituents (Sect. D). 

C. SYNTHESIS OF BIARYLS CONTAINING ONE OR TWO ORTHO SUBSTITUENTS VIA Pd- OR Ni-CATALYZED ARYL-ARYL COUPLING... 

TABLE 8. Pd- or Ni-Catalyzed Aryl-Aryl Coupling Providing Biaryls Containing One Ortho Substituent"... 

Examples of the synthesis of biaryls containing two aryl groups, each of which contains one ortho snbstituent, seem to be rather rare. In the synthesis of magnolol and ( )-monoterpenyhnagnolol shown in Scheme Zn was reported to be more satisfactory than Sn. The latter reaction was reported to be accompanied by double bond migration to significant extents. 

D. SYNTHESIS OF BIARYLS CONTAINING THREE OR FOUR ORTHO SUBSTITUENTS... 

Biaryls containing three or four ortho substituents are discrete from the others in that they can exist as persistent atropisomers that are chiral. There are even a number of natural products containing such chiral biaryl moieties including michellamines A and B and vancomycin. These compounds provide some of the ultimately chal-... 

Some representative examples of the synthesis of biaryls containing just one ortho substituent are shown in Table 8. The product yields are generally in the range of 70-100%, and Mg, Zn, B, and Sn are commonly used. Thus, one ortho substituent does not generally exert significant steric effects detrimental to the desired CTOSS-coupling. Somewhat surprisingly, even those substituents that can chelate metals, such as COOMe " and have been... 

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