Applications of Chiral Auxiliaries

Chiral auxiliaries have traditionally been used in the academic and small-scale synthetic arenas. This, in part, has been due to the infancy of chiral auxiliaries themselves in organic synthesis. Many of these chiral substrates have been developed only in the last 10-20 years, and their synthetic utility is only now being realized. Additionally, many chiral auxiliaries are difficult to prepare and handle at large scale. Only recently has their been considerable effort to produce large quantities of the auxiliaries. Another important consideration is the cost of the auxiliary compared with alternate methods such as resolution. The experimental reaction conditions for some of the more common chiral auxiliaries often call for specialized equipment and/or extreme temperature conditions. These factors, to date, have combined to limit the use of chiral auxiliaries on an industrial scale. 

This chapter summarizes the application of chiral auxiliaries at a scale important to the chiral fine chemical business. In addition, and as important, there are numerous cases in which a chiral auxiliary has been used in the early stages of pharmaceutical development and the potential exists for this approach to be used in future work at larger scale. Lastly, there exists a limited number of cases in which the auxiliary exists as part of an active drug. The known industrial applications, the potential applications, and the presence of auxiliaries in active drugs are all addressed. 

By definition, a chiral auxiliary differs from a chiral template in that the auxiliary is capable of being recycled after the desired asymmetric reaction. Hence, chiral 287 

A number of reviews exist on the formation and uses of chiral auxiliaries [1, 3-7]. Some of these auxiliaries, such as oxazolines, can be used on their own or incorporated into chiral ligands for asymmetric transition metal catalyzed synthesis [7]. 

Many chiral auxiliaries are derived from 1,2-amino alcohols [7], including oxazolidinones (1) [7-9], oxazolines (2) [10,11], bis-oxazolines (3) [12,13], oxa-zinones (4) [14], and oxazaborolidines (5) [15-17]. Even the 1,2-amino alcohol itself can be used as a chiral auxiliary [18-22]. Other chiral auxiliary examples include camphorsultams (6) [23], piperazinediones (7) [24], (S)-l-amino-2-(methoxymethyl)-pyrrolidine (SAMP) (8) and (R)-l-amino-2-(methoxymethyl)-pyrrolidine (RAMP) [25], chiral boranes such as isopinocampheylborane (9) [26], and tartaric acid esters (10). Some of these auxiliaries have been used as ligands 

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Upon removal of the auxiliary, an enantioenriched product could be obtained. The application of chiral auxiliary-based methods to Simmons-Smith cyclopropanation not only provided a useful synthetic strategy, but it also served to substantiate earlier mechanistic hypotheses regarding the directing influence of oxygen-containing functional groups on the zinc reagent [6dj. 

The application of chiral auxiliaries is an alternative route to obtain enantiomerically pure compounds. This approach has been frequently used in the total syntheses of natural products like hirsutene [53] and (+)-15-norpentalene [61]. 

In this section, the literature about Diels-Alder reactions will be presented in a conceptual and illustrative way. After a profound introduction dealing with the development of mechanistic understanding of the Diels-Alder reaction, some interesting recent synthetic developments and applications will be presented. The reaction types and fields of interest are structured in such a way that they can be easily linked to ongoing research from the past ten years. Special attention will be paid to the application of chiral auxiliaries and chiral Lewis acids in asymmetric Diels-Alder reactions. 

The 1,3-dipolar cycloadditions of 1,3-dipoles with chiral alkenes has been extensively reviewed and thus only selected examples will be highlighted here. We have chosen to divide this section on the basis of the different types of alkenes rather than on the basis of the type of 1,3-dipole. For 1,3-dipolar cycloadditions, as well as for other reactions, it is important that the chiral center intended to control the stereoselectivity of the reaction is located as close as possible to the functional group of the molecule at which the reaction takes place. Hence, alkenes bearing the chiral center vicinal to the double bond are most frequently apphed in asymmetric 1,3-dipolar cycloadditions. Examples of the application of alkenes with the chiral center localized two or more bonds apart from the alkene will also be mentioned. Application of chiral auxiliaries for alkenes is very common and will be described separately in Section 12.3. 

The application of chiral auxiliary groups which can be removed after the cycloaddition has met with limited success. The chiral auxiliary can be attached to either the ketene or alkene moiety. In a study of dichloroketene cycloadditions with a series of enol ethers 18, to which a chiral alkoxy group is attached, diastereoselectivities ranged from 55 to 90%,n with the choice of chiral auxiliary being crucial to obtaining the desired diastereoselectivity. 

Although this application area is intriguing, the focus of this chapter remains on the broader application of chiral auxiliaries for asymmetric synthesis. 

There are numerous examples where the potential for the application of chiral auxiliaries, once again primarily oxazolidinones, exists for an industrial setting. 

Case Study 6.21 Asymmetric synthesis in crystals - application of chiral auxiliaries... 

Principles and recent applications of chiral auxiliaries 06S1899. 

This book is considered to be a handbook about the application of chiral auxiliaries in selected areas of cycloaddition reactions. We hope it will serve as a useful tool for those working in the field of organic synthesis, e.g. the stereoselective synthesis of cycloalkanes and heterocycles,... 

This compilation embraces a wide variety of subjects, such as solid-phase and microwave stereoselective synthesis asymmetric phase-transfer asymmetric catalysis and application of chiral auxiliaries and microreactor technology stereoselective reduction and oxidation methods stereoselective additions cyclizations metatheses and different types of rearrangements asymmetric transition-metal-catalyzed, organocatalyzed, and biocatalytic reactions methods for the formation of carbon-heteroatom and heteroatom-heteroatom bonds like asymmetric hydroamina-tion and reductive amination, carboamination and alkylative cyclization, cycloadditions with carbon-heteroatom bond formation, and stereoselective halogenations and methods for the formation of carbon-sulfur and carbon-phosphorus bonds, asymmetric sulfoxidation, and so on. 

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