Atropisomer syntheses enantiomerically

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. 

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... 

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. 

Third, the diastereotopic facial selectivity between the olefin and the ketyl is determined by the biaryl stereochemistry. This stereocontrol element, set earlier via a kinetic resolution of racemic lactone ( )-28, provided an enantiomerically enriched atropisomer (98% ee) that was carried throughout the synthesis without loss of stereochemical integrity. 

The synthesis of chiral racemic atropisomeric pyridines by cobalt-catalyzed [2 + 2 + 2] cycloaddition between diynes and nitriles was reported in 2006 by Hrdina et al. using standard CpCo catalysts [CpCo(CO)2, CpCo(C2H4)2, CpCo(COD)] [34], On the other hand, chiral complexes of type II were used by Gutnov et al. in 2004 [35] and by Hapke et al. in 2010 [36] for the synthesis of enantiomerically enriched atropisomers of 2-arylpyridines (Scheme 1.18). This topic is described in detail in Chapter 9. It is noteworthy that the 2004 paper contains the first examples of asymmetric cobalt-catalyzed [2 - - 2 - - 2] cycloadditions. At that time, it had been preceded by only three articles dealing with asymmetric nickel-catalyzed transformations [37]. Then enantioselective metal-catalyzed [2 -i- 2 - - 2] cycloadditions gained popularity, mostly with iridium- and rhodium-based catalysts, as shown in Chapter 9. 

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