Chiral biaryls synthesis

In the axially chiral biaryl synthesis via the double [2 - - 2 - - 2] cycloaddition shown in Scheme 9.18, the use of ethyl cyanoformate (69) instead of monoynes furnished the corresponding C2-symmetric axially chiral pyridines 71 with excellent enantios-electivity, although the yield of 71 was low, due to the formation of regioisomeric by-products (Scheme 9.26) [19],... 

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. 

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... 

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 enantioselective complexation technique can also be applied as one step in the reaction sequence, providing chiral substrates for the next step. We will now discuss the example of Gabriel synthesis between potassium phthalimide 41 and alkyl bromide 42, which leads to optically active amines (Scheme 1) [51], Instead of the complicated preparation of chiral alkyl bromides (halides), imides (43), which are reaction intermediates, have been resolved. Upon treatment with hydrazine and KOH, these gave optically active amines. The chiral host (S,S)-(-)-6 or the chiral biaryl host (,S>(-j-40 was used for the effective resolution of the intermediates 43. Racemic mixtures 43a-d were resolved by complex formation with the host (S,S)-(-)-6 in a mixture of diethyl ether and light petroleum. 

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

Dahl BJ, Branchaud BP (2004) Synthesis and characterization of a functionalized chiral biaryl capable of exhibiting unidirectional bond rotation. Tetrahedron Lett 45 9599-9602... 

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>. 

Approaches to the 1,4-dioxocines have been greatly improved during the last decade. Intermolecular condensation with the formation of two C-O bonds is an efficient route to 1,4-dioxocine ring system, particularly in the synthesis of numerous axially chiral biaryls. Intramolecular cyclization with the formation of a C-C bond, particularly by means of the RCM strategy, opened a new avenue in the synthesis of eight-membered 1,4-diheterocines with demonstrated success in the approaches to 1,4-dioxocines with a variable substitution pattern. 

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). ... 

Wang, Q.W., Xiang, L., Song, H.B. et al. (2008) Synthesis of amidolanthanides with new chiral biaryl-based NNO ligands and their use as catalysts for enantioselective hydroamination/cycUzation. Inorganic Chemistry, 47, 4319. 

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]. 

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

Later in 2014, Benhamou et also reported the synthesis of chiral biaryl products using the new bulky chiral PEPPSI pre-catalyst 83 (Figure 10). The combination... 

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. 

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