Nucleophile, auxiliary

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. ... 

With chiral auxiliaries1,41 a remote chiral moiety is temporarily introduced into the substrate in order to direct the nucleophilic addition diastereoselectively. The chiral auxiliary can be removed from the initial addition product with complete conservation of the chirality of the desired product and also of the chiral auxiliary. The recovered chiral auxiliary can then be reused in further reactions. Therefore, chiral auxiliaries are used to chiralize an a priori achiral carbonyl substrate by the introduction of a covalently bound, but nevertheless easily removable, chiral source. 

Besides high effectiveness in the diastereoselective control of nucleophilic addition reactions, another major goal in the design of chiral auxiliaries is the use of readily available, chiral starting materials. The hexahydro-l//-pyrrolo[l,2-c]imidazole derivatives 9a-e are examples which use the inexpensive amino acid L-proline (7) as starting material. 

J Based on polarimctry. NMR and GC analysis. These results support a uniform stereochemical course of the reaction The nucleophile attacks the Re-face of the SAMP-hydrazone. b Obtained with RAMP (2c) as auxiliary. 

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... 

Chapters 1 and 2 focus on enolates and other carbon nucleophiles in synthesis. Chapter 1 discusses enolate formation and alkylation. Chapter 2 broadens the discussion to other carbon nucleophiles in the context of the generalized aldol reaction, which includes the Wittig, Peterson, and Julia olefination reactions. The chapter and considers the stereochemistry of the aldol reaction in some detail, including the use of chiral auxiliaries and enantioselective catalysts. 

Chapter 1 deals with alkylation of carbon nucleophiles by alkyl halides and tosylates. We discuss the major factors affecting stereoselectivity in both cyclic and acyclic compounds and consider intramolecular alkylation and the use of chiral auxiliaries. 

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. 

There are many reports on the asymmetric addition of nucleophiles to carbon-nitrogen double bonds [6]. However, the majority of these reports are based on substrate control and rely on chiral auxiliaries in imines. Moreover, almost all of these reports are just for aldo-imine cases [7]. 

The problems associated with the use of this classical method in organotin chemistry are essentially due to the fact that the carbon-tin bond can sometimes very easily be cleaved by electrophiles or by nucleophiles. The crucial step is therefore the elimination of the auxiliary group without the cleavage of any of the carbon-tin bonds. This cleavage could for instance not be achieved successfully in the case of /7-(z -propylmethylphenylstannyl)-N,N-dimethylaniline [formula (60) in... 

The first case of the use of amino acids as chiral auxiliaries in nucleophilic addition to triazinones was employed in the reaction of C-nucleophiles with 3-aryl-l,2,4-triazin-5(4 )-ones 16 and A-protected amino acids 17, to form l-acyl-6-Nu-3-aryl-l,6-dihydro-l,2,4-triazin-5(4A)-ones 18 in high diastereomeric excess <06TL7485>. 

Several reviews and research papers discussing the application and extension of this method have appeared.40 For example, Weber et al.41 reported an interesting result in which cerium acted as a counterion in the modified proline auxiliary (SAMEMP 40) for selective addition of organocerium reagents to hydrazones. The initial adduct was trapped with either methyl or benzyl chloro-formate to afford the stable /V-aminocarbonatc 41 (Scheme 2-24). From this example readers can see that this proline chiral auxiliary can be used not only for a-alkylation but also for nucleophilic addition, which is discussed in detail later. 

The following auxiliaries and nucleophiles are often employed for this purpose ... 

To complement the above information, a highly enantioselective synthesis of a-amino phosphonate diesters should be mentioned.164 Addition of lithium diethyl phosphite to a variety of chiral imines gives a-amino phosphonate with good to excellent diastereoselectivity (de ranges from 76% to over 98%). The stereoselective addition of the nucleophile can be governed by the preexisting chirality of the chiral auxiliaries (Scheme 2-63). 

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. 

In the reaction of (R,R)-tartrate allyl-boronate with aldehydes, Si attack of the nucleophile on the carbonyl group has been observed, while Re attack occurs in (S, S )-tartrate allyl-boronate reactions. Thus, an (S )-alcohol is produced preferentially when an (R,R)-allyl reagent is used, and the (R)-product can be obtained from an (S.Sj-reagent. assuming that the R substituent in the aldehyde substrate takes priority over the allyl group to be transferred. In fact, no exceptions to this generalization have yet been found in over 40 well-characterized cases where the tartrate auxiliary controls the stereochemical outcome of the allyl or crotyl transfer.72... 

Scheme 3-56 shows an example of the generation of chiral amines via nucleophilic attack onto an imine substrate in the presence of an external homochiral auxiliary. Moderate ee can be obtained from 161-induced reactions, and moderate to high ee can be expected from 162-induced reactions. For instance, when 161 (R1 = Et, R2 = t-Bu) is involved in the reaction, nucleophilic attack of RLi (R = Me, -Bu. and vinyl) on imine 163 gives product 164 with 81-92%... 

In summary, the reaction of osmium tetroxide with alkenes is a reliable and selective transformation. Chiral diamines and cinchona alkakoid are most frequently used as chiral auxiliaries. Complexes derived from osmium tetroxide with diamines do not undergo catalytic turnover, whereas dihydroquinidine and dihydroquinine derivatives have been found to be very effective catalysts for the oxidation of a variety of alkenes. OsC>4 can be used catalytically in the presence of a secondary oxygen donor (e.g., H202, TBHP, A -methylmorpholine-/V-oxide, sodium periodate, 02, sodium hypochlorite, potassium ferricyanide). Furthermore, a remarkable rate enhancement occurs with the addition of a nucleophilic ligand such as pyridine or a tertiary amine. Table 4-11 lists the preferred chiral ligands for the dihydroxylation of a variety of olefins.61 Table 4-12 lists the recommended ligands for each class of olefins. 

Tetrahydropyrrolo[l,4]oxazine 74, obtained by photoinduced electron-transfer (PET) oxidative activation of substituted prolinol, undergoes nucleophilic substitution of the OH at position C-3 with allyltrimethylsilane in the presence of TiCU (Scheme 8). The reaction was highly stereoselective and produced, after hydrolysis of the resultant amide 75, optically active a-hydroxy acid 76 together with the auxiliary (.S )-prolinol that can be effectively recycled <1998TL7153>. 

We have proposed the concept of electroauxiliary,10 which activates substrate molecules toward electron transfer and controls a reaction pathway that would favor the formation of the desired products. For example, preintroduction of an electroauxiliary such as a silyl group to a carbon a to nitrogen gives rise to selective introduction of a nucleophile on the carbon to which the auxiliary has been attached. The use of a silyl group as electroauxiliary was... 

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