Lewis Acids and Chiral Auxiliaries

In the latter example, chelation with Lewis acid (ZnCl2 OEt2 [35] and MgBr2 OEt2 [36]) was done to lock the two carbonyls present on the molecule into a cM-oid conformation and to force the alkyl group on the planar radical to 

8-Phenylmenthylalcohol has been widely employed as a chiral auxiliary in diastereoselective reactions [39]. Essential to achieving good diastereoselectivity in radical additions are proper rotamer distributions with respect to the 0=C-C=C bond and successful shielding of the alkene Ti-face. The conformation of the acrylate in this scenario exists as an equilibrium mixture of s-cis and s-trans isomers [40]. Reports indicate that the acrylate can be fixed in the s-trans conformation in the presence of Lewis acid [41]. 

The addition of BF3-OEt2 was shown to promote 1,4-addition of the stannyl radical through an s-trans conformation, giving the optically active (7 )-)5-stannyl 

4 Lewis Acid-Mediated Diastereoselective Radical Reactions 

These selected examples show the importance of Lewis acid in diastereoselective radical reactions. Complexation with Lewis acid, in an endocyclic manner or by using extremely bulky metal complexes such as MABR or MAD, reduces the conformational flexibility of intermediate radicals resulting in an improved facial bias. Lewis acid has been shown to effectively enhance facial selectivity by making a temporary ring a to the radical, thus mimicking the exocyclic effect. Radical reactions involving chiral auxiliaries have also benefited from the use of Lewis acid. 

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Scheme 11. Acyclic stereocontrol in radical reactions Lewis acid and chiral auxiliaries...

Scheme 12. Lewis acid and chiral auxiliary oxazolidinones. Atom transfer radical addition and radical polymerization reactions...

Camphor-derived sulfonamide can also permit control of enantioselectivity by use of additional Lewis acid. These chiral auxiliaries can be used under conditions in which either cyclic or noncyclic TSs are involved. This frequently allows control of the syn or anti stereoselectivity.143 The boron enolates give syn products, but inclusion of SnCl4 or TiCl4 gave excellent selectivity for anti products and high enantioselectivity for a range of aldehydes.145... 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

Novel bidentate chiral Lewis acids derived from 1.8-naphthalenediylbis(dichloroborane) and modified amino acids as chiral auxiliary have been successfully utilized as effective catalysts for the asymmetric Diels-Alder reaction of a,[ -unsaturated aldehydes. The enantioselectivity is highly sensitive to the kind of chiral amino acids. Moderate enantioselectivity was obtained with the tryptophan-derived ligand for the endo adduct, but amino acids without aromatic groups... 

A potential method for the preparation of novel amino acids via the highly selective addition of radicals to the glyoxylic oxime derivative of Oppolzer s camphor sultam (88) has been reported.181 Both Lewis acid and non-Lewis acid-mediated reaction conditions for the addition of alkyl radicals generated from alkyl iodides and Et3B/Bu3SnH were examined. A new chiral auxiliary based upon (R,R)-2,5-diphenylpyiTolidine has been used in the addition of phenylthiyl radicals to unsaturated methacrylamides. The selectivity was found to be better than that reported for the structurally related 2,5-dimethylpyrrolidine derivative.182... 

The mechanism depicted portrays the rationale for the enantioselectivity and high reaction rates, which are influenced only by the CBS catalyst. This catalyst is a combination of both a Lewis acid and a chiral auxiliary ... 

In the crossed aldol reaction between acetaldehyde and propiophenone, two chirality centres are created and consequently, four stereoisomers will be produced. Compounds A and B are enantiomers of each other and can be described with the stereo descriptor u. Similarly, C and D are enantiomers and are /-configured. Since both starting materials are achiral, without the use of a chiral base or chiral auxiliary, racemates will be produced. Likewise the choice of base, the addition of a Lewis acid and the reaction conditions used to form the enolate can control which diastereomer is preferentially formed. If the Z enolate is formed, the u product is the preferred product, whilst the E enolate yields predominately the / product. 

The iT-face differentiation in favor of adducts (443) was more pronounced with increasing amounts of the Lewis acid and at lower reaction temperatures (cf. entries 3/4 and 8/9). The cooperative effect of chiral auxiliaries at the diene and at the dienophile units is exemplified by the double diastereoface selective addition presented in entry 2. Particularly noteworthy is the outstanding ir-face selectivity, observed in the [4 + 2) cycloaddition of juglone (445). Removal of the prosthetic group fiom adducts (443) was accomplished via hydrogenolysis or allylic displacement, as illustrated by the key step (447) (448) of a synAesis of enantiomerically emiched (+)-ibogamine (Scheme 105). ... 

This type of reaction attracted broad interest when it was discovered that high regioselectivity can also be effected with organoaluminum compounds and other nucleophiles in the presence of Lewis acids and that by employing chiral cyclic acetals (from optically active 1,2- or 1,3-diols) diastereoselective transformations can be realized. - Such reactions are synthetically very valuable when considering that the overall process represents an enantioselective Michael addition, where the chiral auxiliary can be recycled (Scheme 39). ... 

Since the middle of the 198O s remarkable progress has been achieved in the development of asymmetric aldol reactions of silyl enolates. In the beginning of this evolution, chiral auxiliary-controlled reactions were extensively studied for this challenging subject [106]. As new efficient catalysts and catalytic systems for the aldol reactions were developed, much attention focused on catalytic enantiocontrol using chiral Lewis acids and transition metal complexes. Thus, a number of chiral catalysts realizing high levels of enantioselectivity have been reported in the last decade. 

The first use of removable chiral auxiliaries in the ene reaction of a carbonyl group was reported with the oxoacetate esters of 2-(l-methylethyl)-5-methylcyclohexanol, although the level of control was not of practical value,8. Both the level and the sense of stereochemical direction were found to vary with the Lewis acid and the solvent. Both this reaction and the later more effective examples are illustrated in Table 4. 

An early variant of the Nazarov cyclization119 employed an alkoxycarbonyl substituent and Lewis acid catalysis to facilitate the reaction. The cyclizations were described as temperamental", but did demonstrate the capability to facilitate the cyclization and control the site of the alkene in the cyclized product. For example, cyclization of the a,a -dienone 7 is promoted by the action of trimethylsilyl iodide to afford the /i-keto ester 8 in 48% yield. No studies in stereoinduction have been reported, but, given the recent advances in the design of chiral Lewis acids and the efficient chiral auxiliaries for the reactions of carboxylic acid esters, these substrates are potentially suitable candidates for such studies. 

The recent explosion in the development of asymmetric strategies for organic synthesis has fostered investigations into the discovery of methods for enantioselective and diastereoselective Diels-Alder reactions. Some early forays into this field focused on the use of chiral auxiliaries covalently attached to one of the reaction partners however, nearly all recent investigations have centered on developing chiral catalysts. The multitude of new catalysts spans the range of Lewis acids and Bronsted acids and bases as well as metal-based and organic molecules. 

Asymmetric Diels-Alder reactions using a dienophile containing a chiral auxiliary were developed more than 20 years ago. Although the auxiliary-based Diels-Alder reaction is still important, it has two drawbacks - additional steps are necessary, first to introduce the chiral auxiliary into the starting material, and then to remove it after the reaction. At least an equimolar amount of the chiral auxiliary is, moreover, necessary. After the discovery that Lewis acids catalyze the Diels-Alder reaction, the introduction of chirality into such catalysts has been investigated. The Diels-Alder reaction utilizing a chiral Lewis acid is truly a practical synthetic transformation, not only because the products obtained are synthetically useful, but also because a catalytic amount of the chiral component can, in theory, produce a huge amount of the chiral product. 

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