Asymmetric quaternary centre

Nair and co-workers have demonstrated NHC-catalysed formation of spirocyclic diketones 173 from a,P-unsaturated aldehydes 174 and snbstitnted dibenzylidine-cyclopentanones 175. Where chalcones and dibenzylidene cyclohexanones give only cyclopentene products (as a result of P-lactone formation then decarboxylation), cyclopentanones 175 give only the spirocychc diketone prodncts 173 [73]. Of particular note is the formation of an all-carbon quaternary centre and the excellent level of diastereoselectivity observed in the reaction. An asymmetric variant of this reaction has been demonstrated by Bode using chiral imidazolium salt 176, obtaining the desymmetrised product with good diastereo- and enantioselectivity, though in modest yield (Scheme 12.38) [74],... 

As an extension of this work, these authors have applied this catalyst system to vinylogous asymmetric Mukaiyama-type aldol reactions, involving silyl vinyl ketene acetals and pyruvate esters. These reactions afforded the corresponding y,5-unsaturated a-hydroxy diesters with quaternary centres in high yields and enantioselectivities of up to 99% ee (Scheme 10.25). It was shown that the presence of CF3CH2OH as an additive facilitated the turnover of the catalyst. 

An efficient way to create, enantioselectively, all-carbon quaternary centres, by the unprecedented asymmetric conjugate addition of Grignard reagents to enones has been developed using a copper catalyst and a chiral diaminocarbene ligand of the corresponding salt (19) or (20).87... 

The asymmetric Heck reaction is catalysed by enantiomerically pure palladium catalysts formed with chelatingbiphosphines, especially BINAP, and this has proved an effective method for the synthesis of sterically constrained carbon centres, including quaternary centres. This chapter concludes with a brief discussion of enantioselective alkylmetallations using Grignard and organoaluminium species, which have proved useful in the diastereo- and enantioselective synthesis of polyene systems. 

The asymmetric epoxidation of acyclic )S,)3-disubstituted o, )3-enones in acetonitrile, by peracetic acid and catalysed by an iron complex in which Fe(OTf)2 was coordinated by two 2-[l-(l-naphthyl)-2-naphthyl]-l,10-phenanthroline ligands (35) (R = m-xylyl), to the corresponding Q ,j8-epoxyketones with yield up to 88% and up to 92% ee was achieved. The epoxy ketone was further converted to functionalized )8-keto-aldehydes with an all-carbon quaternary centre." The transfer hydrogenation of acetophenone to 1-phenylethanol in isopropanol in the absence of added base was catalysed by a five-coordinated Fe(II) complex (36) and certain analogues. ... 

A chiral aluminium Lewis acid catalyst composed of Me3Al and 3,3 -bis-(trimethylsilyl)-BINOL has been reported to promote catalytic asymmetric ring expansion of cyclohexanone with a-substituted a-diazoacetates to give seven-membered rings with an all-carbon quaternary centre (Scheme 70). ... 

Despite impressive progress that has been achieved in the asymmetric hydrovinylation of styrene and its derivatives, the asymmetric hydrovinylation of (a-alkylvinyl)arenes, which has a potential for being a novel methodology for the construction of chiral all-carbon quaternary centres, has not been well documented. In this context, Zhou et aL reported in 2006 the first... 

The value of the method lies in the fact that quaternary centres are fairly difficult to make asymmetrically by other methods. Once again, the diastereofacial selectivity derives from the cyclic chelate structure of the enolate alkoxide, though the exact nature of the species is as yet unclear. A useful feature is that the opposite enantiomer of the product can readily be obtained by simply reversing the order of the two alkylation steps. 

It is worth mentioning that other methodologies for the asymmetric silyl addition to a,p-unsaturated systems [116] do not allow the formation of quaternary centres. 

Asymmetric conjugate addition of dialkyl or diaryl zincs for the formation of all carbon quaternary chiral centres was demonstrated by the combination of the chiral 123 and Cu(OTf)2-C H (2.5 mol% each component). Yields of 94-98% and ee of up to 93% were observed in some cases. Interestingly, the reactions with dialkyl zincs proceed in the opposite enantioselective sense to the ones with diaryl zincs, which has been rationalised by coordination of the opposite enantiofaces of the prochiral enone in the alkyl- and aryl-cuprate intermediates, which precedes the C-C bond formation, and determines the configuration of the product. The copper enolate intermediates can also be trapped by TMS triflate or triflic anhydride giving directly the versatile chiral enolsilanes or enoltriflates that can be used in further transformations (Scheme 2.30) [110],... 

It was unusual to find that both enantiomers had similar activity in vitro, but these are relatively planar molecules in which the asymmetric centre is well separated from the basic end group, so there is close coincidence of the key recognition sites of the indole nucleus, carbonyl function and basic imidazole nitrogen atom. The quaternary derivative (20) of ondansetron retained activity (RVN p 2 8.4), suggesting that the imidazole ring is pro-tonated in the binding interaction with the receptor. 

The first examples of catalytic asymmetric conjugate addition of alkylzinc reagents to trisubstituted nitroalkenes, such as PhC(Me)=CHN02, leading to the formation of nitroalkanes bearing a quaternary carbon stereogenic centre, have been reported. Reactions are promoted by the readily available amino acid-based phosphine (211)... 

Meyers and Devine [196] have used the first one formation of the enethiolate with LDA and addition of an allylic bromide provided the kete-ne aminothioacetal. In other cases this compound is usually not observed, but here, due to steric hindrance, it was detected, and the facility of the rearrangement, as compared to the oxygen series, was illustrated by the fact that it required only stirring at room temperature to occur. An excellent stereoselectivity of 91 9 was achieved for this creation of two new asymmetric centres, including one or even two quaternary ones. The synthetic value was demonstrated by the transformation into enantiopure cyclohexenones. 

In a major development of RCM methodology, it has been found that chiral Mo complexes e.g. 4, offer vastly superior ee than conventional Ru catalysts in the conversion of achiral vinyl alkadienyl ethers into dihydropyrans. The enantioselective synthesis of tertiary carbon stereogenic centres proceeds with typical ee of 80 - 90% while such asymmetric RCMs generate quaternary carbon stereogenic centres with even higher ee (Scheme 4) <06JA5153>. 

The tetrahedral geometry is found most commonly at a normal sp carbon centre. However, it may be found in other situations. For example, there is no need for the chiral centre to be a carbon atom, i.e. other tetravalent asymmetrical centres such as a quaternary ammonium salt would suffice. In passing, it ought to be noted that there needs only to be a very small difference in the four groups in order for optical activity to arise. This may be illustrated by the isotopically labelled sulphone, R1R2S180160, which is optically active. 

The asymmetric Heck reaction can be used to synthesise quaternary carbon centres. During studies towards the synthesis of 3,3-disubstituted oxindoles. Overman and coworkers have shown how the use of silver salts can change the sense of asymmetric induction of the cyclised product. Thus, the iodide (10.131) can be converted into the product (10.132) with the (S)-enantiomer predominating, when the reaction is run in the presence of silver salts. In the absence of silver salts, the (J )-enantiomer is the major product. 

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