Biaryls, chiral

Diphosphines with one (167) or two (165) stereogenic phosphorus atoms were prepared from enantiomerically pure 164 and could be separated into single diastereomers by column chromatography and/or recrystallisation. It was found that the phosphorus atoms epimerised upon heating, reducing the number of diastereomers and sometimes giving a single isomer. 

The protected ligand 180 was obtained as a single diastereoisomer in 25% yield by oxidative coupling of lithiated 179. Desulfurisation with hexa-chlorodisilane afforded the desired ligand in 90% yield. Remarkably, the ligand is stable in air for days in spite of being quite electron rich. 

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. 

---

A chiral axis is present in chiral biaryl derivatives. When bulky groups are located at the ortho positions of each aromatic ring in biphenyl, free rotation about the single bond connecting the two rings is inhibited because of torsional strain associated with twisting rotation about the central single bond. Interconversion of enantiomers is prevented (see Fig. 1.16). 

The hydrogenation of allylic alcohols and a,/>-unsaluraled acids leads to products with a very high synthetic potential, and both transformations were used quite early for industrial applications. In both cases Ru complexes with axially chiral biaryl ligands (binap analogues) are the catalysts of choice. Here, we will dis-... 

Preparation of the chiral biphenyls and binaphthyls with high enantiose-lectivity can be achieved via substitution of an aromatic methoxyl group with an aryl Grignard reagent using oxazoline as the chiral auxiliary.38 Schemes 8-10 and 8 11 outline the asymmetric synthesis of such chiral biaryl compounds. 

Another method for synthesizing chiral biaryls is the substrate-controlled... 

Lipshuz et al.42 have developed a new approach to the chiral biaryls mediated by cyanocuprate. The diastereoselective coupling depends on the proper choice of the tether (Scheme 8-13). 

Van Leeuwen s studies using diphosphite ligands 2 and 18 indicated that the stability and catalytic performance of the [RhH(CO)2(diphosphite)] species depends strongly on the configuration of the 2,4-pentanediol ligand backbone and the chiral biaryl phosphite moieties. Thus, for example, ligands 2b, 2d and 2m, which form well defined stable bis-equatorial (ee)... 

A simple, commercially available chiral alcohol, a,a,a a -tetraaryl-l,3-dioxo-lane-4,5-dimethanol (TADDOL, 7a), catalyzes the hetero- and carbo-Diels-Alder reactions of aminosiloxydienes with aldehydes and a-substituted acroleins to afford the dihydropyrones and cyclohexenones, respectively, in good yields and high enan-tioselectivities. More recently, it was reported that axially chiral biaryl diols 7b and 7c were more highly effective catalysts for enantioselective hetero-Diels-Alder reactions (Scheme 12.5). ... 

The axially chiral biaryl 4-DMAP 32 developed by Spivey [117-127] is relatively readily prepared but only provides modest levels of selectivity for the KR of aryl alkyl ec-alcohols < 30 at -78 °C over 8-12 h or < 15 at room temperature in 20 min (Table 4) [119],... 

Maruoka has found that simple alcohols can also be used in the oxy-Michael reaction [107], Using the axially chiral biaryl catalyst 67 (1 mol%) the conjugate addition of methanol, ethanol and aUyl alcohol to a, 3-unsaturated aldehydes was examined (Scheme 29). Despite moderate yields (55-83%) and enantioselectivities (16-53% ee), the high activity of this catalyst suggests that further optimisation... 

However, a more exciting application of this reaction is the oxazoline-directed synthesis of axially chiral biaryls. The oxazoline system not only activates the ortho-methoxy group for nucleophilic displacement but also determines the stereochemical outcome of the reaction. This provides a convenient method for the introduction of axial-chirality. Meyers group continues their earlier lead on this subject with reports of the stereoselective synthesis of tetrasubstituted biphenyls 391,392 examples are shown in Table 8.29 (Scheme 8.154). The best... 

The method of choice for the prefixation of the aromatic halves is the very practicable esterification reaction. This type of bridge ideally fulfills the requirements demanded easy formation, high thermal stability, good electronic coupling conditions, and, finally, facile cleavage by saponification or reduction. The chiral biaryls are thus obtained as biscarboxylic acids or bisbenzyl alcohols, respectively. 

Substituted dibenzothiophenes 156 react with Grignard reagents to give products of the thiophene ring cleavage. With a chiral Ni catalyst, axially chiral biaryl compounds 157 can be obtained in high enantioselectivities (equation 93) . ... 

F.2.2. Asymmetric Cross-Coupling of Aryl Grignard Reagents Forming Axially Chiral Biaryls... 

Despite growing importance of axially chiral biaryls as chiral auxiliaries in asymmetric synthesis, direct synthetic methods accessing to the enantiomerically enriched biaryls from achiral precursors are still very rare, Application of asymmetric cross-coupling to construction of the chiral biaryls is one of the most exciting strategies to this goal. The reported application... 

Three types of reaction systems have been designed and applied for the enantioposition-selective asymmetric cross-coupling reactions so far. First example is asymmetric induction of planar chirality on chromium-arene complexes [7,8]. T vo chloro-suhstituents in a tricarhonyl("n6-o-dichlorobenzene)chromium are prochiral with respect to the planar chirality of the 7t-arene-metal moiety, thus an enantioposition-selective substitution at one of the two chloro substituents takes place to give a planar chiral monosubstitution product with a minor amount of the disubstitution product. A similar methodology of monosuhstitution can be applicable to the synthesis of axially chiral biaryl molecules from an achiral ditriflate in which the two tri-fluoromethanesulfonyloxy groups are enantiotopic [9-11]. The last example is intramolecular alkylation of alkenyl triflate with one of the enantiotopic alkylboranes, which leads to a chiral cyclic system [12], The structures of the three representative substrates are illustrated in Figure 8F.1. 

The ferrocenylphosphine-nickel catalysts are also applied to asymmetric synthesis of axially chiral biaryl compounds through the cross-coupling reaction. Although initial attempts to this... 

---