Chiral auxiliary based approaches

The nucleophilic addition to imines bearing a chiral auxiliary is an extremely reliable, 

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The powerful influence of an oxygen substituent on the rate and stereoselectivity of cyclopropanation augured well for the development of a chiral auxiliary based approach to asymmetric synthesis [54]. The design of the chiral auxiliary would take into account ... 

A chiral auxiliary-based approach has been developed for the preparation of chiral, non-racemic cyclopropyhnethylamines that are not protected with electron-withdrawing groups. The cyclopropanation of ally he tertiary amines bearing a -hydroxide occurred... 

Substantial progress has also been made in the chiral auxiliary-based approach to an enantioselective intermolecular Pauson-Khand reaction. Initial studies utilizing alkynes substituted with fra s-2-phenylcyclohexanol produced cyclopentenones with low drs, however, the diastereomers were easily separable... 

A number of chiral auxiliary-based approaches for the Simmons-Smith cyclo-propanation have been reported and many of them offer the advantage of producing enantiomerically pure cyclopropyl derivatives after the cleavage of the... 

Far from being industrially viable, this synthesis showed that a chiral auxiliary-based approach to the drug was possible, and very recently an alternative and much more attractive route has been reported by DSM [53]. This is described in Fig. 14. 

Shu Kobayashi of the University of Tokyo found Organic Lett. 2008,10, 807) that the conjugate addition of 25 to 24 mediated by a chiral Ca catalyst proceeded with high enantiocontrol at both of the newly formed stereogenic centers, to give 26. In a chiral auxiliary based approach, Dennis C. Liotta foimd J. Org. Chem. 2008, 73,1264) that condensation of 27 with 28 gave predominantly just two of the possible four diastereomeric azetines. Alkylation of the cis diastereomer, followed by benzoylation and hydrolysis, then delivered the a-quatemary 3-amino acid derivative 29 as a single enantiomerically-pure diastereomer. 

Oxaziridine 206 has been utilized in combination with several chiral auxiliary-based approaches to effect diastereoselective a-hydroxylations of enolates [23, 24, 118]. A striking example using chiral oxazolidinones was reported by Evans and is depicted in Equation 20 [119]. In the course of devel-... 

Derivatives of the Oppolzer sultam [32] may be employed in a general, chiral auxiliary-based approach to stereoselective synthesis of substituted cyclopropanes. In this context, Hacksell carried out a study in which unsaturated substrates such as 30 were converted into the corresponding cyclopro-... 

Another chiral auxiliary-based approach was documented by Davies (Equation 5) [8, 34]. These studies involved diazo compounds that incorporate vinyl and C=0 substitution and revealed that these stable carbene precursors participate in a variety of useful transformations, including diastereoselective cydopropanations. Importantly, Davies found that the cydopropanations with 33, in contrast with those of their simpler diazoacetate counterparts, are highly diastereoselective. The reaction with styrene and chiral diazo compound 33 is representative treatment of styrene with 33 in the presence of a simple Rh catalyst resulted in the formation of product 34 with high asymmetric induction dr 98.5 1.5) and in 84% yield. In this example, the panto-lactone auxiliaiy is a convenient, readily available chiral alcohol. 

A chiral auxiliary-based approach utilizing oxazepinediones has been reported by Trost [108]. The reaction between 142 and 143 in the presence of Pd(OAc)2/P(Ot-Pr)j furnished cycloadduct 144 in 85% yield (Scheme 18.25). The optically pure cyclopentanone 145 was obtained after hydrolytic cleavage of the auxiliary and was converted into the anticancer agent rocagla-mide (146). 

Only few chiral auxiliary-based approaches are available that provide general access to optically active [2 + 2]-photocycloaddition products. One notable example is the approach using unsaturated bicyclic lactams reported by Meyers (Scheme 18.39) [147]. Irradiation of 234 in the presence of ethylene gas afforded cycloadduct 235 in 94 6 dr and 93 % yield. This cyclobutane intermediate could be readily converted into grandisol (236) after removal of the chiral auxiliary. 

Stereochemical Control Through Chiral Auxiliaries. Another approach to control of stereochemistry is installation of a chiral auxiliary, which can achieve a high degree of facial selectivity.124 A very useful method for enantioselective aldol reactions is based on the oxazolidinones 10,11, and 12. These compounds are available in enantiomerically pure form and can be used to obtain either enantiomer of the desired product. 

The virtue of performing the PKR in an enantioselective manner has been extensively elaborated during the last decade. As a result, different powerful procedures were developed, spanning both auxiliary-based approaches and catalytic asymmetric reactions. For instance, the use of chiral N-oxides was reported by Kerr et al., who examined the effect of the chiral brucine N-oxide in the intermolecular PKR of propargylic alcohols and norbornadiene [59]. Under optimized conditions, ee values up to 78% at - 60 °C have been obtained (Eq. 10). Chiral sparteine N-oxides are also able to induce chirality, but the observed enantioselectivity was comparatively lower [60]. 

A general synthesis of a-chiral ketones with essentially 100% ee is based on the utilization of boronic esters. These esters can be prepared by asymmetric hydroboration of prostereogenic olefins and subsequent removal of the chiral auxiliary. Two approaches to a-chiral ketone formation are known ... 

Ketiminium salts have been shown to participate readily in [2-r 2]-cyclo-additions with olefins [35]. Ghosez reported a classic in this area, involving the use of prolinol-derived ketiminium species (Scheme 18.28) [122]. Treatment of a-chloroenamine 172 with ZnCl2 facilitated chloride abstraction under mild conditions to yield an intermediate ketiminium salt 173. The reactive cumulene participated in a diastereoselective cycloaddition with cyclo-pentene to afford the chiral ketone 174 (> 97 % ee), after hydrolytic removal of the auxiliary. These diastereoselective [2 2]-cycloadditions of Ghosez provide a rare example of a chiral auxiliaiy-based approach to chiral cyclobutanones. 

A nice and convergent approach to both compounds makes use of RCM to form the 5-membered building block 71, which mimics the carbohydrate part of the nucleosides. The necessary diene precursor 69 is readily assembled via Evans aldol chemistry. RCM then affords the ring in almost quantitative yield (69->70), leaving the chiral centers and the free hydroxyl group intact. Removal of the chiral auxiliary by reductive cleavage, attachment of the base by means of jt-allylpalladium chemistry, and a final deprotection step complete these highly efficient syntheses [46]. 

In recent years, for analytical purposes the direct approach has become the most popular. Therefore, only this approach will be discussed in the next sections. With the direct approach, the enantiomers are placed in a chiral environment, since only chiral molecules can distinguish between enantiomers. The separation of the enantiomers is based on the complex formation of labile diastereoisomers between the enantiomers and a chiral auxiliary, the so-called chiral selector. The separation can only be accomplished if the complexes possess different stability constants. The chiral selectors can be either chiral molecules that are bound to the chromatographic sorbent and thus form a CSP, or chiral molecules that are added to the mobile phase, called chiral mobile phase additives (CMPA). The combination of several chiral selectors in the mobile phase, and of chiral mobile and stationary phases is also feasible. 

Darzens reaction of (-)-8-phenylmethyl a-chloroacetate (and a-bromoacetate) with various ketones (Scheme 2) yields ctT-glycidic esters (28) with high geometric and diastereofacial selectivity which can be explained in terms of both open-chain or non-chelated antiperiplanar transition state models for the initial aldol-type reaction the ketone approaches the Si-f ce of the Z-enolate such that the phenyl ring of the chiral auxiliary and the enolate portion are face-to-face. Aza-Darzens condensation reaction of iV-benzylideneaniline has also been studied. Kinetically controlled base-promoted lithiation of 3,3-diphenylpropiomesitylene results in Z enolate ratios in the range 94 6 (lithium diisopropylamide) to 50 50 (BuLi), depending on the choice of solvent and temperature. ... 

The preceding reactions illustrate control of stereochemistry by aldehyde substituents. Substantial effort has also been devoted to use of chiral auxiliaries and chiral catalysts to effect enantioselective aldol reactions.71 72 Avery useful approach for enantioselective aldol condensations has been based on the oxazolidinones 1-3, which are readily available in enantiomerically pure form. 

A special case of asymmetric induction using chiral auxiliaries has been reported for the alkylation of /1-keto esters94,106. In this approach the reaction proceeds in a diastereoselective manner via a base-catalyzed opening of the corresponding chiral 1.2-cyclohexanedioxy or 1,2-cyclohep-tanedioxy acetal, e g., acetal 50. 

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