Biaryl atropisomers

The use of diazodicarboxylates has been recently explored in Cinchona alkaloid catalyzed asymmetric reactions. Jprgensen [50] reported the synthesis of non-biaryl atropisomers via dihydroquinine (DHQ) catalyzed asymmetric Friedel-Crafts ami-nation. Atropisomers are compounds where the chirality is attributed to restricted rotation along a chiral axis rather than stereogenic centers. They are useful key moieties in chiral ligands but syntheses of these substrates are tedious. 

The first use of non-biaryl atropisomers as chiral ligands in metal-catalyzed reactions was reported with ligand 21 [83] (Fig. 2). The allylic alkylation of 19 gave 20 in good enantioselectivity (90% ee) although in moderate yield (60%). Comparable results (89-99% yield, 90.2-94.7% ee) were obtained with 22 which possesses only axial chirality [84],... 

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... 

Non-Biaryl Atropisomers New Classes of Chiral Reagents, Auxiliaries and Ligands ... 

These reactions, and other successful resolutions (both classical [20, 21] and on chiral stationary phase [8, 22, 23]) of atropisomeric aromatic amides means that this class of non-biaryl atropisomers are now available enantiomerically enriched. 

The search for a general synthesis of enantio-merically pure non-biaryl atropisomers has been given added impetus by the discovery [26, 27] that the absolute configuration of some atropiso-meric amides affects their biological activity. The enantiomeric atropisomers 21 and 22 (Scheme 13) differed in activity at the tachykinin NK, receptor by a factor of 6-13, with 21 being the more active. Atroposelectivity must now be an important new consideration in drug synthesis. 

The optical activity of the tri- and tetra-orr/zo substituted biaryls (atropisomers) is a consequence of the chiral axis, present in this structure. The configuration R- or S-) of these compounds is matched according to the Cahn-Ingold-Prelog (CIP) system and an additional sequence rule Near groups precede far groups. An example with 2-chloro-6-methoxy-2 -nitro-6 -carboxy-l,T-biphenyl (9) is illustrative. Figure 2 ... 

SCHEME 1334. DKR of biaryl atropisomers via organocatalytic asymmetric bromination. 

Gustafson J, Lim D, MUIct SJ (2010) Dynamic kinetic resolutirai of biaryl atropisomers via peptide-catalyzed asymmetric bnnninatiotL Scitaice 328 1251—1255... 

Ortho-substituted aromatic amides show atropisomerism as a result of the perpendicular orientation of the aryl and amide moieties. The non-biaryl atropisomers readily undergo racemization through rotation about the aryl-amide bond, indicating the possibility of DKR. For example, (S)-proline mediated addition of acetone to 2-formyl naphthamide gave a 2 1-5.5 1 diastereoisomer mixture with the optical purity of the major anti-isomer ranging from 86% to 91% ee (Scheme 5.24) [72]. 

In addition, the last fifteen years have seen families of atropisomers based on structures other than biaryls come forward as potential new sources of such structures, and atropisomeric anilides, benzamides and naphthamides have been used as chiral ligands, catalysts, auxiliaries and various starting materials. Indeed, a number of non-biaryl atropisomers have been successfully investigated for DKR. 

Despite the prevalence and importance of atropisomerism in organic structures, the field of asymmetric catalysis has not yet recorded extensive success in the development of catalysts, which control this stereochemical feature. Indeed, catalytic reactions of this nature are presently rare and only modest atropi-somer selectivity has been observed. In this context. Miller s group recently developed the DKR of biaryl atropisomers via peptide-catalysed asymmetric bromination. The reaction proceeded via an atropisomer-selective electrophilic aromatic substitution reaction using a simple bromination reagent such as A7-bromophthtalimide. As shown in Scheme 5.27, a series of chiral bromi-nated biaryl compounds could be prepared with excellent enantioselectivities of... 

The important work by Clayden s group dealing with the asymmetric synthesis of either biaryl or non-biaryl atropisomers has not been included in this chapter, since the authors assumed that these reactions evolved through dynamic thermodynamic resolution processes most of the time. 

Scheme 35.30 Novel non-biaryl atropisomers via asymmetric F-C amination.

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