Biaryl moiety

The Stille reaction has developed as a popular protocol for the formation of C-C bonds due to the air- and moisture-stability as well as functional group compatibility of organotin compounds. Together with the Suzuki-Miyaura coupling it is one of the most powerful methods for the synthesis of molecules containing unsymmetrical biaryl moieties. However, despite its efficiency, this versatile reaction has slowly been displaced by other procedures that avoid the use of highly toxic organostannanes. 

The focus of this paper is on the preparation of biaryl moieties which are commonly present in a wide variety of pharmaceutically active compounds. Two different and practical approaches to synthesize the biaryl substructure will... 

Nature has an abundance of biologically interesting and pharmaceutically active natural products possessing the biaryl moiety. Synthetic chemists have thus devised a number of different methods to assemble the biaryl functionality. 

Conserved aromatic residues are likely to interact with the biaryl moiety... 

The reaction is quite sensitive to the chiral ligand used. Diphosphines with an axially disymmetric biaryl moiety in the backbone give the best results. The effectiveness of p-Tol-BINAP as ligand, for example, is similar to that of BINAP. The related atropisomeric ligand BIPHEMP can also be used [9]. Among chiral aliphatic diphosphines tested, CyDIOP, which only differs from DIOP in the type of P-substituents, also gives satisfactory results. 

Further modification of the benzilidene moiety of 78 by isopropoxystyrene gives a highly robust complex 79, which can be easily recovered by silica gel chromatography after RCM [70]. A similar phosphine-free recyclable complex with a biaryl moiety 80 proved to be more active than 76 and 79 the relative reactivity order is 79<78<80 [71]. 

In biaryl-substituted isoxazoline derivatives (13-14) [75], a biaryl moiety was designed to interact with the S4 aryl-binding domain of the FXa active site, hi this case, hydrophilicity was found to be the most important term (Eq. 10) [72]. 

Diarylheptanoids constitute a distinct group of natural plant metabolites characterized by two aromatic rings linked by a linear seven-carbon aliphatic chain. They may be divided into two subgroups, i.e. open chain and macrocyclic diarylheptanoids. In the latter the aromatic rings are connected to form a diarylether or a biaryl moiety. 

The first total synthesis of three naturally occurring cyclophane derivatives belonging to the turriane family of natural products was also described by A. Furstner et al These natural products have a sterically hindered biaryl moiety and saturated as well as unsaturated macrocyclic tethers. Stereoselective entry to this class of compounds is possible using RCAM followed by Lindlar reduction of the resulting cycloalkynes. 

During the total synthesis of the proteosome inhibitor TMC-95A by S.J. Danishefsky et al., the biaryl moiety of the compound was assembled in good yield by the Suzuki cross-coupling of an aryl iodide and an arylboron intermediate. ... 

The main difficulties associated with constructing the biaryl moiety as a single atropisomer early in the synthesis lies within the arene substitution pattern. The thermal isomerization barrier for a steganone precursor that carries only three ortho substituents is extremely sensitive to the exact identity of those substituents. Specifically, when one of the three groups (e.g., a formyl moiety) adds only a small amount to the inversion barrier and a second substituent (e.g., a methoxy group) is also relatively small, the barrier to inversion renders the biaryl stereochemically labile even at 0 For example, at least one of... 

For several years Hallberg has used MW-promoted reactions for optimization of different types of aspartyl protease inhibitors [7]. The Suzuki-Miyaura coupling was recently used to introduce biaryl moieties in cyclic sulfonamide HIV-1 protease inhibitors. A series of sixteen reactions were performed with fair to moderate yields and the reaction times were, in all examples except two, limited to only 5 min... 

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-... 

Figure 3.1 Important natural products and chiral reagents containing axially chiral biaryl moieties.

The conclusion of this section is that the introduction of P-stereogenic centres into chiral biaryl moieties is still a synthetic challenge, which remains to be addressed. 

In 2001, the synthesis of novel ferrocenyl ligands combining a chiral ferrocene unit with an axially chiral biaryl moiety was also described by Bring-mann s group (Scheme 5.50). ... 

The behavior of the substituted bisphenol 29 and bisnaphthol 30 derivatives show what influence the biaryl moiety has. Complexes [RhH(CO)2(phosphine-phosphite)] have been used as catalysts in the asymnietric hydroformylation of styrene. 

Biaryl moieties are ubiquitous in natural products and pharmaceuticals [45]. Consequentially, efficient and direct synthetic protocols for the formation of biaryl molecules are highly desirable. The earliest report of chelate-assisted C-H arylation from 1998 describes the use of Wilkinson s catalyst [RhCl(PPh3)3] for the ortho-C-H functionahzation of 2-arylpyridines with tetraphenylstan-nane (Scheme 23.13) [46]. Monoarylated products can be obtained by using a blocking group on one of the ortho positions on the pyridine moiety of the substrate (13) that prevents arylation of the second ortho-C-H bond. In the absence of a blocking substituent in the substrate 14, diarylated products are formed. 

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