Chiral auxiliaries, and

Enantioselective aldoi condensation by means of a chiral auxiliary and boron enolates... 

Dithiane 1-oxide derivatives as chiral auxiliaries and asymmetric building blocks for organic synthesis 980PP145. 

These early studies on zinc carbenoids provide an excellent foundation for the development of an asymmetric process. The subsequent appearance of chiral auxiliary and reagent-based methods for the selective formation of cyclopropanes was an outgrowth of a clear understanding of the achiral process. However, the next important stage in the development of catalytic enantioselective cyclopropanations was elucidation of the structure of the Simmons-Smith reagent. 

The landmark report by Winstein et al. (Scheme 3.6) on the powerful accelerating and directing effect of a proximal hydroxyl group would become one of the most critical in the development of the Simmons-Smith cyclopropanation reactions [11]. A clear syw directing effect is observed, implying coordination of the reagent to the alcohol before methylene transfer. This characteristic served as the basis of subsequent developments for stereocontrolled reactions with many classes of chiral allylic cycloalkenols and indirectly for chiral auxiliaries and catalysts. A full understanding of this phenomenon would not only be informative, but it would have practical applications in the rationalization of asymmetric catalytic reactions. 

Clearly it is advantageous to be able to use achiral starting materials and a chiral reagent to induce an asymmetric reaction, thus obviating the need to attach and remove a chiral auxiliary and permitting the recovery and reuse of the chiral reagent. 

Further reactions of allyl organometallics with a-alkoxyaldimines 1, prepared from (S)-2-(methoxymcthoxy)propionaldehyde and (R)- and (S)-l-phenylethylamine, illuminate the difference in the influence of the nitrogen chiral auxiliary and the x-alkoxy center7. 

Amidoalkylation of silyl enol ethers with /V-acyliiiiiiiium ions containing camphanoyl-derived acyl functions (see Appendix) as the chiral auxiliary leads to optically active 2-substituted piperidine derivatives with moderate to high diastereoselectivity, depending on the chiral auxiliary and the cnol ether82 99. The auxiliary is removed by hydrolysis with base or acid. 

Various chiral auxiliaries and catalysts have been developed that allow diastereoface-and enantioface-selective Michael additions. 

As shown in scheme 1, (S)-amide 2 (ref. 4) obtained from ethyl ester of (S)-proline, chiral auxiliary and 2-substituted-2-propenoic acids 1 are bromolactonized with N-bromosuccinimide (NBS)-DMF, followed by hydrolysis with 6N-HC1 to afford (S)-4. The results are summarized in Table 1. 

J. Seyden-Penne, in Chiral Auxiliaries and Ligands in Asymmetric Synthesis, John Wiley and Sons, New York, 1995. 

Among the most useful carbonyl derivatives are (V-acyloxazolidinones, and as we shall see in Section 2.3.4, they provide facial selectivity in aldol addition reactions. l,3-Thiazoline-2-thiones constitute another useful type of chiral auxiliary, and they can be used in conjunction with Bu2B03SCF3,44 Sn(03SCF3)2,45 or TiCl446 for generation of enolates. The stereoselectivity of the reactions is consistent with formation of a Z-enolate and reaction through a cyclic TS. 

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... 

The following cycloaddition reactions involve chiral auxiliaries and proceed with a good degree of diastereoselectivity. Provide a rationalization of the formation of the preferred product on the basis of a TS. 

The synthesis in Scheme 13.47 was also based on use of a chiral auxiliary and provided the TBDMS-protected derivative of P-D lactone in the course of synthesis of the macrolide portion of the antibiotic 10-deoxymethymycin. The relative stereochemistry at C(2)-C(3) was obtained by addition of the dibutylboron enolate of an A-propanoyl oxazolidinone. The addition occurs with syn anti-Felkin stereochemistry. 

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. 

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. 

Having demonstrated a practical and reliable method to access 2-arylpyrrolidines in high enantioselectivity, we felt that a noteworthy extension of this methodology would lie in its application to bis-arylated products 27, providing a rapid and efficient approach to enantiopure C2-symmetric 2,5-diarylpyrrolidines, which have been identified as valuable chiral auxiliaries and chiral ligand manifolds [29]. Towards this end, substrate 26a was subjected to the standard arylation conditions, which produced 2,5-diphenyl-N-Boc-pyrrolidine 27 in a 96 4 diastereomeric ratio, and 57% isolated yield (s-BuIi/TMEDA produced 27 in lower d.r. (66 34) and yield (42%)), as depicted in Scheme 8.13. 

A review was published covering recent progress in the stereoselective synthesis of piperidines <00S1781>. Routes described in detail include those derived from the chiral-pool, chiral auxiliaries, and catalytic asymmetric methodology. 

An alternative synthesis of nonracemic a-amino stannanes is outlined in equation 3777. The diastereomeric stannanes, obtained by sequential lithiation and stannylation of the starting nonracemic piperidinooxazoline, can be separated by chromatography. Subsequent removal of the chiral auxiliary and N-methylation completes the synthesis. 

The application of a chiral auxiliary or catalyst, in either stoichiometric or catalytic fashion, has been a common practice in asymmetric synthesis, and most of such auxiliaries are available in homochiral form. Some processes of enantiodifferentiation arise from diastereomeric interactions in racemic mixtures and thus cause enhanced enantioselectivity in the reaction. In other words, there can be a nonlinear relationship between the optical purity of the chiral auxiliary and the enantiomeric excess of the product. One may expect that a chiral ligand, not necessarily in enantiomerically pure form, can lead to high levels of asymmetric induction via enantiodiscrimination. In such cases, a nonlinear relationship (NLE) between the ee of the product and the ee of the chiral ligand may be observed. 

In 1986, Puchot et al.104 studied the nonlinear correlation between the enantiomeric excess of a chiral auxiliary and the optical yield in an asymmetric synthesis, either stoichiometric or catalytic. Negative NLEs [(—)-NLEs] were observed in the asymmetric oxidation of sulfide and in [.S ]-proline-mediated asymmetric Robinson annulation reactions, while a positive NLE [(+)-NLEs]... 

Novel bicyclic imidazo-oxazaphosphinines have been synthesized in high diastereoselectivity by Marsault and Just <1996TL977>. In the first step, iV-tritylimidazole 209 was lithiated and, subsequently, treated with (.S )-propylcnc oxide as a chiral auxiliary and acetic acid to give the intermediate 210, which was reacted with alkyl dichlorophos-phite to yield the ring-closed product 211 as a single diastereomer (Scheme 33). Extension of these approaches for further derivatives 212 has also been published <1998NN939>. 

High asymmetric induction by amphiphilic dendrimers was reported by Rico-Lattes and co-workers [32]. These water-soluble but THF-insoluble dendrimers (e.g. 22, Scheme 23) consist of useful, readily available chiral auxiliaries and can be used in the homogeneous (when H20 is the solvent) or heterogeneous (in the case of THF as the reaction medium) catalyzed reduction of prochiral aromatic... 

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. 

Brimble and coworkers172 reported the asymmetric Diels-Alder reactions between quinones 265 bearing a menthol chiral auxiliary and cyclopentadiene (equation 73). When zinc dichloride or zinc dibromide was employed as the Lewis acid catalyst, the reaction proceeded with complete endo selectivity, but with only moderate diastereofacial selectivity affording 3 1 and 2 1 mixtures of 266 and 267 (dominant diastereomer unknown), respectively. The use of stronger Lewis acids, such as titanium tetrachloride, led to the formation of fragmentation products. Due to the inseparability of the two diastereomeric adducts, it proved impossible to determine which one had been formed in excess. 

Taguchi and coworkers175 studied the Lewis acid catalyzed asymmetric Diels-Alder reactions of chiral 2-fluoroacrylic acid derivatives with isoprene and cyclopentadiene. When a chiral l,3-oxazolidin-2-one and diethylaluminum chloride were used as the chiral auxiliary and the Lewis acid catalyst, respectively, a de of 90% was observed for the reaction with isoprene. The reaction with cyclopentadiene afforded a 1 1 mixture of endo and exo isomers with de values of 95% and 96%, respectively. The endo/exo selectivity was improved by using 8-phenylmenthol as the chiral auxiliary. Thus, the reaction... 

Murray and colleagues199 developed some 2,5-diketopiperazines as new chiral auxiliaries and examined their asymmetric induction in the Diels-Alder reactions of their A-acryloyl derivatives with several dienes. Some of their results with dienophile 320 have been summarized in Table 19 (equation 89). When the benzyl group on 320 was substituted by an isopropyl or /-butyl group, the diastereofacial selectivity dropped dramatically. It was proposed that tv-tt stacking between the phenyl group and the electron-poor double bond provided a more selective shielding of one face of the double bond in this special case. 

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