Atropisomer syntheses

B. Morgan, A. Zaks, D.R. Dodds, I. Liu, S. Megati, EG. Njoroge, V.M. Girijavallabhan, Enzymatic kinetic resolution of piperidine atropisomers Synthesis of a key intermediate of the farnesyl protein transferase inhibitor SCH66336,1. Org. Chem. 65 (18) (2000) 5451-5459. 

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. 

A methylenation of cyclic carbonates such as 6/4-132 using dimethyltitanocene to give a ketene acetal, followed by a subsequent Claisen rearrangement, allowed the synthesis of medium-ring lactones such as 6/4-133 in good yields these are otherwise difficult to obtain. In this transformation, 6/4-133 is formed as a l l-mix-ture of the two atropisomers 6/4-133a and 6/4-133b (Scheme 6/4.33). The substrate... 

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. 

Couplings can also be carried out by simple nucleophilic substitution reactions of arenechromium tricarbonyls . For example, in the synthesis of biaryl 469, asymmetric lithiation of 463 using in situ silylation provides the complex 466 via 464 and 465. Nucleophilic substitution by the tolyl Grignard 467 yields 468 as a single atropisomer in 68% yield, and decomplexation gives the biaryl 469 in 92% yield (Scheme 184). 

In the following year, Bringmann et al. showed a further application of a biomimetic oxidative coupling of murrayafoline A (7) to the first total synthesis of murrastifoline F (191) (162). This work also includes the resolution of ( + )-murrastifoline F (191), the stereochemical assignment of its atropisomers, and the determination of the enantiomeric ratio present in an authentic root extract of M. homigii. 

Preference will be given to those methods that have proven to be applicable to the stereoselective total synthesis of demanding target molecules, such as naturally occurring biaryls. Of special interest are those methods that allow the optional synthesis of either of the two atropisomers in question. 

For the synthesis of the porphyrin the formate ester of 3j3-hydroxy-5-cholenic acid 179 was coupled via amide bonds to the a,/ ,a,j -atropisomer of meso-tetrakis(o-aminophenyl)-porphyrin 170, using the mixed anhydride... 

Ward, Pelter, and co-workers have documented the efficacy of in situ generated ruthenium tetrakis(trifluoroacetate) (following the work of Robin and Landais) [126, 127] as a useful reagent for the synthesis of a large number of stegane-like molecules [123]. In the transfused butyrolactone series 180, single diastereomers 181 are usually obtained (Scheme 43a). If cis-fused butyrolactones 182 are used as precursors, the biaryl products are formed as a mixture of atropisomers 183 and 184 (Scheme 43b). 

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 aromatic systems, oxazolines can have three different functions (Fig. 4). Firstly, they can be used as protecting groups for carboxylic acids. Secondly, they activate even electron-rich aromatic systems for nucleophilic substitution. Fluorine or alkoxy groups in the ortho position can be substituted by strong nucleophiles such as Grignard reagents. Thirdly, when biaryl compounds with axial chirality are synthesized in these reactions, oxazolines can induce the formation of only one atropisomer with excellent selectivity. These three qualities were all used in the synthesis of 20, a precursor of the natural product isochizandrine [10]. 

Atropisomers should be suited to enantioselec-tive synthesis using thermodynamic control, and Curran has proposed using anilides as prochiral auxiliaries , responding to stereochemistry within... 

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. 

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