Meyers synthesis of biaryls

The Meyers synthesis of biaryls Preparation of biphenyl-2-carboxylic acid (543) [40)... 

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... 

Table 1. The yields and enantioselectivity in the Meyers synthesis of biaryl 608 from oxazolines bearing the chiral leaving group [26]...

Meyers has also reported the use of chiral oxazolines in asymmetric copper-catalyzed Ullmann coupling reactions. For example, treatment of bromooxazoline 50 with activated copper powder in refluxing DMF afforded binaphthyl oxazoline 51 as a 93 7 mixture of atropisomers diastereomerically pure material was obtained in 57% yield after a single recrystallization. Reductive cleavage of the oxazoline groups as described above afforded diol 52 in 88% yield. This methodology has also been applied to the synthesis of biaryl derivatives. 

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. 

The Ullmann reaction has been employed in the syntheses of numerous symmetrical natural compounds and biaryl ligands. With Meyers synthesis of mastigophorene A (not shown), a representative example is outlined in Equation 12.18-3, Scheme 12.18 [74]. 

Retrosynthetic analysis of 5 and 6 yielded ketone 7 as pivotal intermediate. A key reaction for the synthesis of 7 was the auxiliary-controlled, di-astereoselective biaryl coupling of a phenyl magnesium bromide (from 8 or 9) with aryloxazoline 10 (Scheme 1). This coupling strategy was developed in the Meyers laboratory [12] and previously applied to the enantioselective synthesis of other naturally occurring biaryl lignans, such as steganone [13]. 

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... 

This synthesis resolved one of the issues encountered in the Meyers synthesis, i. e. the epimerization of configurationally labile intermediates, since in this case the rotation around the biaryl axis is precluded by the presence of the bulky chromium tricarbonyl group. 

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. 

The first asymmetric intermolecular synthesis of 0-methylancistrocladine (2) involved the use of a Meyers biaryl coupling, successfully utilised in the earlier synthesis of dehydroancistrocladine (66), to construct the biaryl linkage atropisomer-selectively (ref. 60,61). It was envisaged that 2 could arise from the acetamide 102 which in turn could be derived from biaryl 103 (Scheme 14). A coupling between the Grignard reagent 104 and chiral oxazoline 105 could then provide 103 stereospecifically. This approach required the synthesis of chiral oxazoline 105 which is outlined in Scheme 15 and begins with the nitrile 71 available in three steps from 1,5-diacetoxynaphthalene (see Scheme 8). 

Meyers et al. have reported an asymmetric synthesis of (-)-steganone (179) in which formation of the biaryl bond represents the first stage in the synthesis of the eight membered ring (scheme 69) [155]. They have also used their oxazoline-mediated coupling approach to carry out asymmetric syntheses of (-)-schizandrin and (-)-isoschizandrin [156]. 

Somewhat between diastereoselective and enantioselective approaches is the Cram s synthesis involving the oxazolines with chiral alkoxide leaving groups [26]. In this manner, bromine in oxazoline 596 was substituted with sodium alkoxides, derived from readily available natural alcohols such as menthol (597), fenchyl alcohol (598), bomeol (599), quinine (600), and quinidine (601) to give the respective chiral oxazolines 602-606, Scheme 10. The Meyers reaction of oxazolines 602-606 and 1-naphthylmagnesium bromide (608) was effected at low temperatures (-42 °C) affording the expected biaryl 609 with respective chiral induction. 

The versatility of the Meyers reaction for the construction of the dibenzocyclooctadiene backbone is amply documented (Fig. 8.2). In particular, lignans (-)-interiotherin A (17) [21], (-)-schizandrin (18), (-)-isoschizandrin (19) [22], and (-)-gomisin E (20) [21] were prepared by this method. The synthetic utility of the Meyers reaction to create the axially chiral biaryl skeletal framework was further displayed by the atroposelective syntheses of natural naphthylisoquinoline alkaloids including (-)-O-methylancistrocladine (21) [23] and (-)-0-methylhamatine (22) [24], among others [25, 26], and by the synthesis of enantiomericaUy pure C -symmetric biphenyl ligand 23 and binaphthyl porphyrin 24 (Fig. 8.3), which have been used as intermediates for the preparation of chiral catalysts for asymmetric reduction and epoxidation [27, 28]. 

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