Chiral biaryls asymmetric synthesis

Axially chiral biaryls are found widely in the key structure of useful chiral ligands and catalysts [1] and biologically active compounds [2], The conventional method for their catalytic asymmetric synthesis is based on an asymmetric cross-coupling approach [3], As a conceptually new approach to axially chiral biaryls, asymmetric aromatic ring construction via transition-metal-catalyzed [2 - - 2 + 2] cycloaddition has recently appeared [4], In 1999, Sato et al. reported two types of nickel-catalyzed [2-1-2-1-2] cycloaddition for the synthesis of functionalized biaryls [5], One was the cycloaddition of aryl-substituted monoyne 1 with acetylene, leading to biaryl 2 (Scheme 9.1), and the other was the cycloaddition of aryl-substituted 1,6-diyne 3 with acetylene, leading to biaryl 4 (Scheme 9.2) [5],... 

The first catalytic 1,4-addition of diethylzinc to 2-cyclopentenone with over 90% ee was described by Pfaltz and Escher, who used phosphite 54 with biaryl groups at the 3,3 -positions of the BINOL backbone.46 Chan and co-workers achieved high enantioselectivity in the same reaction (up to 94% ee) by using chiral copper diphosphite catalyst (R,R,R)-41 48,48a 48d Hoveyda and co-workers used ligand 46 to realize excellent enantiocontrol (97% ee) in the 1,4-additions of 2-cyclopentenones,52 which may be used in the practical asymmetric synthesis of some substituted cyclopentanes (including prostaglandins). 

Axial Chirality. For a system with four groups arranged out of the plane in pairs about an axis, the system is asymmetric when the groups on each side of the axis are different. Such a system is referred to as an axial chiral system. This structure can be considered a variant of central chirality. Some axial chiral molecules are allenes, alkylidene cyclohexanes, spiranes, and biaryls (along with their respective isomorphs). For example, compound 7a (binaphthol), which belongs to the class of biaryl-type axial chiral compounds, is extensively used in asymmetric synthesis. Examples of axial chiral compounds are given in Figure 1-5. 

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. 

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... 

The potassium enolate generated from 23 is regarded as an enantiomeric atropisomer. Recently non-biaryl atropisomers have been receiving more attention in asymmetric synthesis.19 Most of them employ atropisomers that are configurationally stable at room temperature, while attention in this chapter is focused on asymmetric reactions that proceed via chiral nonracemic enolate intermediates that can exist only in a limited time. An application of configurationally stable atropisomeric amide to a chiral auxiliary for stereoselective alkylation has been reported by Simpkins and co-workers (Scheme 3.10).20... 

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>. 

The other primary application of asymmetric Grignard coupling reactions has been in the synthesis of axially chiral binaphthyl and biphenyl derivatives. Hayashi performed a binaphthyl synthesis (equation 6) in 95% ee using a nickel catalyst and ligand (7), a P-O chelating analog to (3). For a similar synthesis of chiral biaryls (equation 7) ligand, (8) was found to yield the most successful results (93% ee). ... 

Asymmetric synthesis of chiral biaryls is a very attractive notion, since some such compounds, e.g., BINAP, have served as useful chiral ligands. In this sense, the synthesis of (/ )-2,2 -dimethyl-l,r-binaphthyl in 63% yield and in 83% ce using Br2Ni(PPFOMe) as a catalyst is noteworthy L175] (Scheme 1-48). 

Another noteworthy development is an asymmetric synthesis of chiral biaryls by a Pd-catalyzed enantioselective aryl-aryl coupling reaction of prochiral 2,6-bis(triflyloxy)biaryls [62], Using Cl2Pd[(53-Phephosl as a chiral catalyst, the first phenylation of l-[2,6-bis(triflyloxy)phenylJnaphthalene with PhMgBr proceeds in 85% ee. As might be expected, the minor enantiomer is the more reactive of the two in the second phenylation. This leads to a kinetic resolution, and the desired monophenylated enantiomer can be obtained in 93% ee. Similarly favorable enantioselective alkynylation results have also been reported [180]. 

Of the various possible asymmetric cross-coupling reactions, (1) asymmetric alkylation with secondary alkylmetals, (2) asymmetric biaryl synthesis, and (3) asymmetric allylation with allylic electrophiles have been most extensively studied with chiral Ni and Pd complexes [166]. The initial study in this area was reported as early as 1974 by Kumada and his co-workers, but only a meager range of 8-15% ee was reported [167]. By the end of the 1970s, however, the cross-coupling reaction had been sufficiently developed so that its application to the asymmetric synthesis was already practically attractive, as indicated by an asymmetric total sythesis of (R)-(—)-a-curcumene in five steps in 66% ee and 34% overall yield shown in Scheme 1-47 [168]. 

Kelly, T. R., Li, Q., Bhushan, V. Intramolecular biaryl coupling asymmetric synthesis of the chiral B-ring diol unit of pradimicinone. 

Q1. 2,2 -Binaphthol (54) is a chiral biaryl that is used in asymmetric synthesis. Determine the configuration of the enantiomer shown in 54. 

Scheme 4.14. Asymmetric synthesis of biaryls (a) binaphthyls using a chelating oxazoline [149] (b) biphenyls using a chelating oxazoline [150] (c) biphenyls using a nonchelating oxazoline [151] (d) binaphthyls using a chiral leaving group [153].

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