Auxiliary controlled stereoselectivity

Selective labelling of the two diastereotopic methyl groups of i-leucine (144) has enabled their fates during secondary metabolic reactions to be elucidated [66]. Moreover, in the context of protein interactions, differentiation of the leucine pro-R and pro-S methyl groups in protein NMR spectra allows molecular recognition phenomena to be studied [67]. Recently, efficient routes to both forms of Relabeled leucine, based on application of an auxiliary-controlled stereoselective conjugate addition reaction (Scheme 6.27) have been described [68]. Thus, starting... 

Scheme 6.27. Auxiliary-controlled stereoselective cuprate addition as the key step for the construction of both diastereomeric forms of [5-"q-leucine 144.

Weymann, M, Schultz-Kukula, M, and Kunz, H, Auxiliary-controlled stereoselective enolate protonation enantioselective synthesis of cis and trans annulated decahydroquinoline alkaloids. Tetrahedron Lett., 39, 7835-7838. 

Although examples of auxiliary-controlled stereoselective BelluS-Claisen rearrangements have appeared in the literature, the Lewis acid-mediated enantioselective version is a more attractive alternative for practitioners. MacMillan and Yoon have reported that the nonracemic Lewis acid complex 262 efficiently promotes an enantioselective Bellu -Claisen rearrangement with formation of amide 263 in good yield and with excellent selectivity. ... 

With Reagent-Controlled Stereoselectivity With Auxiliary Control... 

As is the case for aldol addition, chiral auxiliaries and catalysts can be used to control stereoselectivity in conjugate addition reactions. Oxazolidinone chiral auxiliaries have been used in both the nucleophilic and electrophilic components under Lewis acid-catalyzed conditions. (V-Acyloxazolidinones can be converted to nucleophilic titanium enolates with TiCl3(0-/-Pr).320... 

In this section an approach is discussed whereby absolute configurational assignment is based on auxiliary- or reagent-controlled stereoselective key reactions. The stereochemical outcome of the reaction used for the assignment must be predictable, from either the absolute configuration of the auxiliary or the reagent, by a rule or (better) a well-defined model of the transition state220. 

In the cases where auxiliary- or reagent-controlled stereoselectivity is employed for the assignment of absolute configurations, it must always be considered that the normal stereochemical outcome of the particular reaction may be reversed depending on both the structure of the starting material and/or the reaction conditions. Some examples are discussed ... 

Until recently only a few examples of stereoselective alkylation reactions of localized carban-ions which proceed under auxiliary control have been reported. The reason is obviously to be found in the difficulty of generating such carbanions having no additional stabilization and, if generated, in the low nucleophilicity of these strongly basic reagents. 

The approach of using chiral auxiliaries to control stereoselectivity has been investigated by a number of groups. Curran et al. (89JA9238) noted that development of chiral auxiliaries in these systems is a particular... 

In addition to being an efficient chiral controller in a number of stereoselective transformations of chiral acrylates, (i.e. the Diels-Alder reaction, the conjugate reduction, the asymmetric dihydroxylation, and the nitrile oxide cycloaddition ) the bomanesultam (11) has been shown to be an exceptionally efficient chiral auxiliary for stereoselective aldol condensations (eqs eq 3 and eq 4). Depending upon the reaction conditions, A -propionylsultam can produce either the syn or anti aldol product with an excellent diastereoselectivity, Furthermore, good diastereoselectiv-ities are also observed for the corresponding acetate aldol reaction (eq 5), ... 

The alkylation of enolates constitutes a very powerful method for the formation of C-C bonds. Several methods have been developed in order to control the stereoselectivity of this process. First applications of carbohydrate auxiliaries in stereoselective alkylations of ester enolates were described by Heathcock et al. [152] in 1981. 

Keywords Stereogenic reactions. Mechanism control. Substrate and reagent control. Stereoselectivity, Simple diastereoselectivity, exo-endo-Diastereoselectivity, Double stereodifferentiation, Chiral catalysts, Chiraphor and catalaphor. Hybrid catalysts. Chiral auxiliary... 

Other chiral catalysts have also been developed that do not fall into the families shown in Fig. 3 [25-30], but to date they tend to give low enantioselectivities and will not be discussed in this chapter. In addition, chiral auxiliaries are sometimes utilized instead of or in addition to chiral catalysts to control stereoselectivity [31-34], but this is becoming increasingly less popular as the catalysts become more selective. 

Scheme 3.15. Controlled stereoselective enolate formation and asymmetric alkylation of a second generation camphor ester enolate chiral auxiliary [75].

In Sj reactions, substrate and reagent combine to form a diastereomeric transition state. In the case of auxiliary-controlled reactions, the asymmetric induction is promoted by a chiral element temporarily linked to the arene or the nucleophile. The ideal chiral auxiliary has to fulfill several requirements (i) it must be easily available in both enantiomeric forms to permit selective synthesis of both enantiomers, (ii) it must induce good stereoselectivity, (iii) the diastereomeric products must be easily separated, and (iv) cleavage of the chiral auxiliary must provide the requisite enantiomer in high yield without racanization. Additionally, an efficient work-up to allow easy recovay of expensive chiral auxiliaries is highly desirable. Most chiral auxiliaries are either natural products (alcohols, amino acids, carbohydrates, etc.) or derived from natural products. 

Of all the chiral auxiliaries that have been studied so far, a-pinene-based allylboranes have proven to be one of the most effective, inexpensive, and versatile reagents based on high optical purity observed for the product homoallylic alcohols. " a-Pinene is highly inexpensive and readily obtained from pine trees. Both enantiomers of a-pinene are available in nature (-)-a-pinene is more common in Europe, and the (+)-a-isomer is found in North American pine trees. Moreover, a-pinene-based allylboranes were found to exhibit excellent levels of reagent-controlled stereoselectivity in their reaction with a wide variety of chiral and achiral aldehydes. These factors greatly simplify the synthetic design of complex natural products as the requisite chiral centers can be... 

As an extension of the Evans aldol reaction, the so-called Evans-Mettemich variation [17] adds two polyketide units to the growing polyketide chain (Scheme 2.114). It should be pointed out that here not the chiral auxiliary controls the stereoselectivity but the a-chiral center, which in turn was previously generated by addition to the Evans propionate. Using different metals and reaction conditions, three out of four possible stereoisomers can be generated and subsequent reduction of the keto carbonyl group can construct an additional chiral alcohol (vide infra). 

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