Atropisomeric amides

L. H. Lithiation and stereoselective transformations of 3-aroyl-2,2,4,4-tetramethyloxazoli-dines, a new class of add-labile atropisomeric amides. Synlett 2002, 290-294. 

Desymmetrisation of the enantiotopic methyl groups of 432 with a chiral lithium amide base leads to atropisomeric amides in good enantiomeric excess.186... 

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... 

Enantioselective lithiation can be used to introduce and control new elements of planar or of axial chirality. The principal classes of compounds displaying these stereochemical features are ferrocenes, arenechromium tricarhonyl complexes, biaryls, atropisomeric amides and al-lenes. Methods for the enantioselective lithiation of these compound classes, relying on either substrate (chiral auxihary) or reagent (chiral base) control will be reviewed. 

As with atropisomeric biaryls, axial chirality in atropisomeric amides maybe introduced by stereochemical control in the atroposelective reactions of planar chiral complexes [115]. Enantioselective lithiation was reported in this context by Uemura, who showed that the achiral complexes 195,198,201 and 204 are de-protonated enantioselectively by treatment with chiral lithium amide bases (Scheme 50) [116-118]. The stereogenic C-C and C-N axes in these compounds are orientated such that the larger NR2 and acyl groups, respectively, are directed away from the chromium. A range of chiral lithium amides was investigated, and by careful selection it was possible to obtain products 196,199,202 and 205... 

Dai et al. [55] reported the only example of P,0 ligands applied to the asymmetric Mizoroki-Heck reaction. The atropisomeric amide-derived ligands 88 were applied to the reaction of phenyl triflate (2) and 2,3-dihydrofuran (1). Conversions were low (<30%) in all cases, although moderate enantioselectivity was observed (52% ee, ligand 88a). 

Dai, W.-M., Yeung, K.K.Y. and Wang, Y. (2004) The first example of atropisomeric amide-derived P,0-ligands used for an asymmetric Heck reaction. Tetrahedron, 60, 4425-30. 

In 2004, Walsh s group developed L-proline-catalysed aldol reactions of atropisomeric amides sueh as benzamides and naphthamides. " The DKR process simultaneously established the stereoehemistry of the atropisomeric amide chiral axis and a stereogenic centre, providing high enantioselectivities, as shown in Scheme 2.101. 

Scheme 2.101 L-Proline-catalysed DKRs of atropisomeric amides.

Attempts to induce asymmetry in the cyclisation of 57 using the chiral lithium amides, which had worked well with simple benzamides, were frustrated by the inherent chirality, at low temperature, of the naphthamide itself. This feature is common to all 2-substituted tertiary aromatic amides, which may become atropisomeric at low temperature due to slow rotation about the Ar-CO bond.48 We therefore sought to... 

Direct synthesis of atropisomeric benzamides and anilides from prochiral precursors has been reported using chiral-amide-mediated deprotonation of 2,6-dimethyl-substituted ben-zamide and anilide chromium complexes. A screening of amides revealed that (R,R) 3 was the most selective in the deprotonation of the benzylic methyl groups (Scheme 51)92 94. 

An early attempt to exploit the atropisomerism inherent in aromatic amides [8] drew inspiration from the suggestion that the orientation of nicotinamide s C = O bond was fundamental to the stereoselectivity of hydride transfer to or from NADH [9]. Ohno and his co-workers managed... 

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. 

Crotonates bearing an atropisomeric 1-naphthamide moiety can be reacted in a Sml2-mediated reductive coupling with a variety of aldehydes to yield enantiomerically enriched 7-butyrolactones. The crotonate derived from 2-hydroxy-8-methoxy-Tnaphthamide reacted with pentanal to afford the highest ee of >99% in a combined yield of 90% with a cisltrans-mt o of 90 10. The chiral crotonate can also be linked to a Rink amide resin with the C-8 oxygen, and in the solid-phase reaction the same level of axial-to-central chirality transfer was obtained (Equation 103) <2006JOC2445>. 

The final neutral palladium(II) complex with the amide functionalised carbene hgand features two six membered metallacycles, just as the cationic not yet deprotonated one does. The amine nitrogen atom has four substituents (H, Pd and two C). Since the two metallacycles can adopt two distinct conformations that slowly flip into each other for steric reasons, the nitrogen atom appears chiral due to atropisomerism despite its overall C -symmetry. The deprotonated complex lacks this feature, clearly visible in the respective NMR spectra. 

In a number of amides, thioamides, and related systems, rotation about the single bond is hindered, and distinct geometric isomers can be observed and even isolated. This type of geometric isomerism is referred to as atropisomerism and results from resonance contributions by the nitrogen atom that imparts significant double bond character to the system, thus slowing rotation. Such is the case for the thioamide aldose... 

The reaction of tetrachlorophthaloyl dichloride with ammonia gives two atropisomeric tetrachloroterephthaldiamides, depending upon whether the ammonia is in dry ethyl ether (amide-a) (Bandres, 1975) or in aqueous concentrated solution (amide-P) (Taratiel, 1980). It has been found that for the reaction in ether the primary product is actually amide-P which is gradually converted into amide-a. Such isomerization also takes place around 270°C. Amide-a is assumed to be the anti isomer (75). In this case, the energy barrier is due to steric repulsions between the two o-chlorine pairs... 

Atropisomerism was demonstrated in 379. It arose from aryl-C=0 and amide rotations. The rotation about the N-p5u-azolyl-aryl bond was not blocked (09BMCL1767). 

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]. 

Atropisomerization of the C-amide bond can be suppressed by introducing a bulky f-butyl group in the naphthalene by an S Ar reaction. Addition of crystals of (+)-l 15/116 to f-BuLi in cold toluene provides with good ee s the naphthalene derivatives 117/118 of undetermined absolute configuration. Kinetic resolutions of racemic amines were also performed using the provisional chiral molecular conformation derived from chiral crystals [94]. Despite the attractive features of these examples, planning of absolute asymmetric S Ar transformation remains a difficult task since only about 10% of achiral substrates crystallize in a chiral fashion. 

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