Chiral electron-withdrawing groups

The oxazoline ring of 10 and 11 can be transformed into a variety of functionalities hydrolysis yields a carboxylic acid and regenerates the chiral auxiliary that can be recycled [12]. Alternatively, sequential N-methylation/reduction provides an aldehyde suitable for further transformation. Mild cleavage conditions must be selected to prevent racemization about the Csp —Csp bond. 

Although the substitution pattern of the nucleophile is limited by the presence of an ortho chelating substituent (OMe, 1,3-dioxan-2-yl group, etc.), a wide range of natural products and analogs 

The versatility of the Meyers reaction for the construction of the dibenzocyclooctadiene backbone is amply documented (Fig. 8.2). In particular, lignans (-)-interiotherin A (17) [21], (-)-schizandrin (18), (-)-isoschizandrin (19) [22], and (-)-gomisin E (20) [21] were prepared by this method. The synthetic utility of the Meyers reaction to create the axially chiral biaryl skeletal framework was further displayed by the atroposelective syntheses of natural naphthylisoquinoline alkaloids including (-)-O-methylancistrocladine (21) [23] and (-)-0-methylhamatine (22) [24], among others [25, 26], and by the synthesis of enantiomericaUy pure C -symmetric biphenyl ligand 23 and binaphthyl porphyrin 24 (Fig. 8.3), which have been used as intermediates for the preparation of chiral catalysts for asymmetric reduction and epoxidation [27, 28]. 

FIGURE 8.3 Synthesis of C -symmetric biphenyl ligand 23 and binaphthyl porph5nin 24. 

Although the sulfonamide group exerts a stronger electron-withdrawing effect, it is a less effective activator (entries 11 and 12) however, the axial chirality is induced with higher fidelity [31, 32]. The direction of twist of the binaphthyl axis is again reversed by R (H OMe) permutation. 

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An alkene activated by an electron-withdrawing group—often an acrylic ester 2 is used—can react with an aldehyde or ketone 1 in the presence of catalytic amounts of a tertiary amine, to yield an a-hydroxyalkylated product. This reaction, known as the Baylis-Hillman reaction, leads to the formation of useful multifunctional products, e.g. o -methylene-/3-hydroxy carbonyl compounds 3 with a chiral carbon center and various options for consecutive reactions. 

Epoxides bearing electron-withdrawing groups have been most commonly synthesized by the Darzens reaction. The Darzens reaction involves the initial addition of an ct-halo enolate 40 to the carbonyl compound 41, followed by ring-closure of the alkoxide 42 (Scheme 1.17). Several approaches for inducing asymmetry into this reaction - the use of chiral auxiliaries, reagents, or catalysts - have emerged. 

A 7r-bond can react with various active species, such as the electrophile oxene and its isoelec-tronic species (nitrenes and carbenes) and radicals. A 7r-bond can also react with a nucleophile, when it is conjugated with an electron-withdrawing group. In these reactions O, N, or C atom(s) are transferred from the active species to the olefins, forming two tr-bonds, such as C—O, C—N, and C—C, at the expense of the 7r-bond. If the 7r-bond is prochiral, chiral center(s) are... 

The asymmetric 1,3-dipolar cycloaddition of nitrones (515), possessing an electron-withdrawing group, to allylic alcohols was achieved by using diisopropyl (/ ,/ )-tartrate [(R,R-DIPT)] as a chiral auxiliary. The isoxazolidines (516) and... 

Using a stoichiometric amount of (i ,i )-DIPT as the chiral auxiliary, optically active 2-isoxazolines can be obtained via asymmetric 1,3-dipolar addition of achiral allylic alcohols with nitrile oxides or nitrones bearing an electron-withdrawing group (Scheme 5-53).86a Furthermore, the catalytic 1,3-dipolar cycloaddition of nitrile oxide has been achieved by adding a small amount of 1,4-dioxane (Scheme 5-53, Eq. 3).86b The presence of ethereal compounds such as 1,4-dioxane is crucial for the reproducibly higher stereoselectivity. 

It has to be taken into account that these catalysts are not yet fully developed. Introduction of electron-withdrawing groups is suspected to increase Lewis acidity, which influences activity, and the optimum spacer length may enable formation of chiral polymers, but such variations are synthetically challenging. 

Alkylation at the 6-position can also be achieved with N -unsubstituted 4-pyrimidinones, via a dianion, when there is an electron-withdrawing group also present at the 6-position. Thus, alkylation of the chiral pyrimidinone 514 (At = -chlorophenyl) gave a 54% yield of the enantiomerically pure methyl derivative 516 via the dianion 515 <1999JOC7885>. 

The oxazoline ring acts as an electron-withdrawing group for a substituent at the 2-position. Thus, the ot-protons of a 2-alkyloxazoline exhibit some acidity and can be abstracted by a base. A 2-alkenyloxazoline can be viewed as a masked acrylic acid derivative and is capable of undergoing Michael addition and Diels-Alder reactions. These reactions can often be carried out stereoselectively using a chiral oxazoline. Other types of chiral auxilliaries, most notably oxazolidinones, are also very effective for these types of applications. However, they are outside the scope of this chapter. The discussion in this section will focus on the new developments with oxazolines. 

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