SYNTHESIS OF AXIALLY CHIRAL BIARYLS

Apart from enantio- and diastereoselective synthesis, binaphthols as the widely used chiral auxiliaries have been obtained in optically pure form by several method 

Miyano s approach was effective also in the synthesis of ( )-6,6 -dinitrodiphenic acid (556) from 3-nitro-2-halobenzoic acids 557 or 558, via diesters 559 and 560, derived from (Ti)-binaphthol (4), in moderate yield and good optical purity, 80-85% d.e. [14], 

Beside reductive dehalogenation side-products, the Miyano s method led to the formation of dimer such as 561, as a product of intermolecular Ullmann coupling of 

Using other chiral 1,2-diols such as 1,2-diphenyl-1,2-ethanediol or 2,3-butanediol, the Lipshutz approach allows to rich very high diastereoselectivity [19]. Among reactions that have been used in the diastereoselective synthesis of unsymmetrical axially chiral biaryls, beside Ullmann and Lipshutz reactions, are the Suzuki-Miyaura and Meyers synthesis of biaryls. 

However, in the Suzuki-Miyaura reaction of relatively simple, enantiomerically pure, both naphthyl bromides and naphthylboronic acids gave diastereomeric mixtures, indicating rather low diastereoselectivity [21]. More important access to axially chiral biaryls is the Meyers approach in its diastereoselective version [22-25]. It was foimd that oxazolines, derived from readily available amino alcohol 585 [22], underwent the Meyers synthesis of biaryls giving the expected biaryls in high d.e. s [23-25]. Thus l-methoxynaphthyl-2-carboxamide (586) was activated with triethyloxonium tetrafluoroborate to 587, which reacted with 585 to give the oxazoline 588. The latter 

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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... 

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... 

Uemura and Kamikawa have presented a review on the stereoselective synthesis of axially chiral biaryls utilizing planar chiral (arene)chromium complexes [44]. 

In the asymmetric synthesis of axially chiral biaryls, the formation of two C-O bonds is the key step in the etherification of 2,2, 6,6 -tetrahydroxybiphenyl 187 (Scheme 21). Sequential etherification of the biaryl 187 with 1,4-di-O-benzyl-L-threitol 188 under the Mitsunobu conditions afforded the monoether 189. After deprotection of the /-butyldimethylsilyl (TBDMS) group with Bu4NF, the intermediate alcohol was again subjected to the Mitsunobu reaction in situ. The intramolecular cyclization proceeded smoothly to give 190 in high yield (for R= Bn, m.p. 138-139°C) <2000JOC1335>. 

Bringmann G, Price Mortimer AJ, Keller PA, Gresser MJ, Gamer J, Breuning M (2005) Atroposelective synthesis of axially chiral biaryl compounds. Angew Chem Int Ed 44 5384-5427... 

An alternative to the Meyers or Cram oxazoline methods is the use of 2-menthoxybenzoates for the synthesis of axially chiral biaryls. Treatment of the ester 34 with Grignard reagent 35 provides the (M)-biphenyl 36 in 94% e.e (ref. 23). However, poor enantioselectivities were observed in cases where an ortho chelating substituent on the Grignard reagent was absent. 

A review by Bringmann, Breuning et al. (05AG(1E)5384) entitled Atroposelective synthesis of axially chiral biaryl compounds contains a few examples of heteroaromatic compounds but methodologically it is of... 

The atroposelective synthesis of axially chiral biaryls via configurationally unstable, lactone-bridged biaryls 02JOM(661)31. 

An alternate approach to the asymmetric synthesis of axially chiral biaryls has been developed based on the nickel-catalysed Kumada cross coupling of dibenzothiophenes. Cleavage of the carbon—sulfur bond of achiral dibenzoth-iophene (10.25) with the nickel catalyst generated from ligand (10.26) leads to the... 

Enantioposition-selective asymmetric cross-coupling has also been successfully applied to the synthesis of axially chiral biaryl molecules (Scheme 11).155],[56] Reaction of the achiral ditriflate 52 with 2 equiv of phenyhnagnesium bromide in the presence of lithium bromide and 5 mol % of PdCl2[(5)-phephos (10b)] at -30 °C for 48 h gave an 87% yield of the monophenylation product (S)-53, which is 93% ee, and a 13% yield of diphenylation product 54. The enantiomeric purity of the monophenylation product... 

The efficacy and the chiral leaving group-induced enantioselectivity in the Meyers synthesis of axially chiral biaryls of some selected examples are given in the Table 1. 

Enantioselective synthesis of axially chiral biaryls include all approaches where the starting material is achiral and the chirality is induced by an influence of chiral catalyst or reagent. Among enantioselective reactions that have been successfully used in the synthesis of axially chiral biaryls are the Kharasch reaction [34-36], Suzuki-Miyaura reaction [37,38], oxidative phenolic coupling mediated by copper complexes... 

Enantioselective as well as diastereoselective synthesis of axially chiral biaryls is the subject of a rapidly growing interest, due to its role as a crucial motif in a great number of drag candidates, chiral polymers, chiral auxiliaries, catalysts, etc. 

Scheme 2-40. Synthesis of axially chiral biaryls via asymmetric cyclotrimerization.

The transition metal-catalyzed [2+2+2] cycloaddition has been applied to the atroposelective biaryl synthesis. The first example is the chiral cobalt(I) complex-catalyzed [2+2+2] cycloaddition of aryl-diynes with nitriles to produce axially chiral arylpyridines [19a]. Subsequently, the enantioselective synthesis of axially chiral biaryl phosphine oxides has also been achieved (Scheme 21.16) [19b]. 

Chapter 7 - Miscellaneous methods for synthesis of biaryls. Pages 241-291 Chapter 8 - Synthesis of axially chiral biaryls. Pages 293-320 Subject index. Pages 321-349... 

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