Chiral auxiliaries nucleophilic substitution

Chiral oxazolines developed by Albert I. Meyers and coworkers have been employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon-carbon bonds. For example, metalation of chiral oxazoline 1 followed by alkylation and hydrolysis affords enantioenriched carboxylic acid 2. Enantioenriched dihydronaphthalenes are produced via addition of alkyllithium reagents to 1-naphthyloxazoline 3 followed by alkylation of the resulting anion with an alkyl halide to give 4, which is subjected to reductive cleavage of the oxazoline moiety to yield aldehyde 5. Chiral oxazolines have also found numerous applications as ligands in asymmetric catalysis these applications have been recently reviewed, and are not discussed in this chapter. ... 

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. 

Chapter 2 provided a general introduction to the a-alkylation of carbonyl compounds, as well as the enantioselective nucleophilic addition on carbonyl compounds. Chiral auxiliary aided a-alkylation of a carbonyl group can provide high enantioselectivity for most substrates, and the hydrazone method can provide routes to a large variety of a-substituted carbonyl compounds. While a-alkylation of carbonyl compounds involves the reaction of an enolate, the well known aldol reaction also involves enolates. 

Chiral oxazolines employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon-carbon bonds. 

The synthesis of substituted cysteines can be accomplished via Michael addition reactions,]67124-126] by nucleophilic displacement,]127] from racemic thiazolines,]128] via aziridine ring opening,]129 and by asymmetric synthesis using a chiral auxiliary.]130] The details for some of these methods are described. 

In contrast to classical Meerwein arylations, non-activated alkenes are well suited for this reaction type for two reasons. First, due to the relatively slow formation of azo compounds by addition of aryl radical 49 to 48, this undesired pathway cannot compete successfully with the attack of 49 on the alkene to give radical adduct 50. Second, a nucleophilic alkyl radical 50 arises from the addition step, which is effectively trapped by electrophilic salt 48 to give azo compound 51. As a result of several improvements, the methodology is now applicable for a wide range of polar to non-polar alkenes with almost no restrictions on the substitution pattern of the diazonium salt [101, 102]. Moderate diastereoselectivities have been obtained in first attempts with chiral auxiliaries [103]. The azo compounds accessible, such as 51, can be converted to carboamination products 52 by hydrogenation and to various other heterocycles. 

An interesting example of stereoselective coupling of an aromatic radical with a nucleophile is found in the reaction of 1-iodonaphthalene with the imide anion 12, containing a chiral auxiliary. In this reaction the diasteromeric isomers of the substitution compound are formed (Sch. 17) [87]. This reaction is highly dependent on the metal counter ion used. All the ions studied [Li, Na, K, Cs, Ti(IV)] are selective, but the highest stereoselection is reached with Li at low temperature (—78°) and with Ti(IV) (ca. 99% de) [87]. 

Chiral Auxiliary. (/ ,/ )-( ) has been used as a chiral auxiliary to direct the stereochemistry of addition of a nucleophile to an acrylate moiety. Almost complete stereoselectivity is achieved in the addition of cyclopentanecarboxylic acid lithium dianion to the a-substituted acrylate substrate (eq 14). This methodology allows stereochemical control at the a-position of a p-amino ester and thus complements the methodology described above for the stereoselective formation of p-substituted p-amino esters. 

Other auxiliary nucleophiles can be used in combination with DCC. The most important ones include 7-aza-l,2,3-benzotriazol-l-ol (7, HOAt)f l and 3-hydroxy-l,2,3-benzotriazin-4(3//)-one (8, HODhbt) which will be described in the section concerning the fragment condensation (Section 4.3.2.2). The use of isolated 3-hydroxy-l,2,3-benzotriazin-4(3//)-ones (8, HODhbt)f l will be discussed under active esters, (Section 4.3.3.1.5). The use of HOAt in peptide chemistry has been discussed by Carpino.f It decreases the time course of coupling reactions, reduces the loss of chiral integrity, and provides a visual indication, yellow to colorless, of the reaction endpoint in solution. HOAt was shown to be a superior coupling additive in both solutiont and solid-phase synthesesf when compared with HOBt. HOAt can be used as a direct substitute for HOBt. Furthermore, HOAt like HOBt is compatible with a variety of activation methods. The performance of HOAt derivatives was compared... 

The Michael-type addition reaction of nucleophilic reagents with chirally modified a,jff-substituted carbonyl compounds constitutes the established methodology for the preparation of y9-substituted carbonyl compounds. The disadvantage of this type of asymmetric Michael reaction is the loading and disloading process of the chiral auxiliary on the Michael acceptor. However, this type of the reaction has been well documented to give the adduct with a high level of diastereoselectivity [83, 84]. 

Takemoto, Y, Yoshikawa, N., and Iwata, C., Utility of diene-tricarbonyliron complexes as mobile chiral auxiliaries. Highly diastereoselective 1,5-nucleophilic substitution with 1,2-migration of the l c(( ())i moiety, J. Chem. Soc., Chem. Commun., 631, 1995. 

JR)- and (S)-binaphthols 1.44 [230-235] have sometimes been used as chiral auxiliaries. Examples include reduction of y-ketoester 1.45 [236], nucleophilic substitution of binaphthol ethers (G = binaphthol) 1.46, by organomagnesium reagents, organocuprate additions to binaphthol monodnnamates [237], and alkylations of arylacetic or crotonic esters [238,239]. 

The addition of carbon radicals to carbon-carbon double bonds is, perhaps, the single most important radical transformation [3]. This reaction is discussed elsewhere in this volume, but, because of the importance of addition reactions in the development of the use of chiral auxiliaries, a few background comments are made here. Typical carbon radicals are nucleophilic and undergo reaction more readily with electron-deficient than with electron-rich compounds. For alkene addition reactions, therefore, substitution of electron-withdrawing groups on the alkene increases the rate of radical addition relative to the unsubstituted parent compound. 

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