Role as chiral auxiliary

Hada, K., Watanabe, T., Isobe, T. and Ishikawa, T. (2001) Guanidinium ylides as a new and recyclable source for aziridines and their roles as chiral auxiliaries. Journal of the American Chemical Society, 123, 7705-7706 [Chem. Eng. News, Aug. 13, 32 (2001)]. 

One example of the use of 2D-NMR experiments in conformational analysis is the study of molecular interactions between cinchonidine and acetic acid [26]. These alkaloids are used as chiral auxiliaries in enantioselective hydrogenations, and the enantiomeric excess is dependent on solvent polarity, acetic acid being a good solvent This suggests that protonation and a preferred conformation play a role in achieving high enantioselectivities. With a combination of COSY-experiments, 3J coupling constants and NOESY experiments, it was shown that one conformer is preferred in acidic solutions. 

The optically active arylsulfinylmethylene moiety plays two important roles in asymmetric synthesis of optically active amino acids one is as chiral auxiliary, and the other is as... 

It has been observed that addition of Lewis acids to the free radical allylation improved the chemical yield [101]. When substrates with a chiral auxiliary were subjected to free radical allylation in the presence of a Lewis acid, the desired allylated products were obtained with high stereoselectivity [94 d]. In these reactions the Lewis acid plays a pivotal role in fixing the conformation of radical intermediates. Recently Sibi indicated that an elevated reaction temperature accelerated inversion of the stereochemistry of the radical-centered carbon giving rise to greater diastereoselectivity (Scheme 12.39) [102]. When enantiomerically pure Lewis acids were employed as chiral auxiliaries enantioselective free radical allylation of sulfones [103] and oxazolidinones [104] were realized. In the latter reaction two contiguous chiral centers were generated successfully in a single operation with excellent stereoselectivity via tandem C-C bond formation both enantiomers can be se-... 

The second approach to achieve asymmetric induction used (-)-(li ,3f ,45)-menthol or ( —)-(l/C3/C4S)-8-phenylmenthol as chiral auxiliary in diazenes 13 (Table 2, entries 10 and ll)23. In no case was the induced diastereoselectivity higher than a diastereomeric ratio of 53 47 and thus this route did not prove to be synthetically useful. Obviously, the auxiliary at the end of the tether plays no significant role in determining the direction of coiling of the acyclic chain 23. 

Chiral auxiliaries having Cj symmetry are very useful in asymmetric synthesis [161] and their role as chiral-protective groups of unsaturated carbonyl derivatives have been examined in an attempt to obtain formal enantioselective cycloadditions, as shown in Scheme 33. 

Oxazolidinones are frequently used as chiral auxiliaries in asymmetric transformations, as ligands for metal catalysts, and as precursors to vicinal amino alcohols. These common structural motifs in natural products and pharmaceuticals have spurred interest in the development of methods for their preparation. Espino and Du Bois reported the synthesis of indane-appended oxazolidinone 215 via Rh-catalyzed C-H insertion of carbamate ester 214. A variety of other carbamates was found to be competent substrates for this reaction. The role of magnesium oxide as additive was presumed to be as scavenger of acetic acid generated from the iodinane oxidant. 

The oxazohne substituents play a key role not only as chiral auxiliary but also as precursors of the aldehyde groups in the optically active atropoiso-meric biaryl 56, with a configurationally stable C2 symmetry. 

One of the key pioneers in this area was Solladie, who thoroughly investigated the reactions of chiral sulfoxide carbanions [21], Their diastereoselec-tive additions to ketones and aldehydes are illustrative of the method (Scheme 13.16) [67]. Addition of 104 to cyclohexyl methyl ketone (105) thus furnished adduct 106. The sulfoxide, having fulfilled its role as an auxiliary, is subsequently subjected to reductive cleavage to afford hydroxy ester 107. After transesterification, alcohol 108 was produced in 95 % ee. Despite the numerous years that have transpired since these results were first published, such optically active tertiary alcohols remain otherwise difficult to prepare, a feature that attests to the potential value of chiral sulfoxide anions in asymmetric synthesis. 

These examples and those in Scheme 2.6 illustrate the key variables that determine the stereochemical outcome of aldol addition reactions using chiral auxiliaries. The first element that has to be taken into account is the configuration of the ring system that is used to establish steric differentiation. Then the nature of the TS, whether it is acyclic, cyclic, or chelated must be considered. Generally for boron enolates, reaction proceeds through a cyclic but nonchelated TS. With boron enolates, excess Lewis acid can favor an acyclic TS by coordination with the carbonyl electrophile. Titanium enolates appear to be somewhat variable but can be shifted to chelated TSs by use of excess reagent and by auxiliaries such as oxazolidine-2-thiones that enhance the tendency to chelation. Ultimately, all of the factors play a role in determining which TS is favored. 

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. 

In the asymmetric reduction of ketones, stereodifferentiation has been explained in terms of the steric recognition of two substituents on the prochiral carbon by chirally modified reducing agents40. Enantiomeric excesses for the reduction of dialkyl ketones, therefore, are low because of the little differences in the bulkiness of the two alkyl groups40. In the reduction of ketoxime ethers, however, the prochiral carbon atom does not play a central role for the stereoselectivity, and dialkyl ketoxime ethers are reduced in the same enantiomeric excess as are aryl alkyl ketoxime ethers. Reduction of the oxime benzyl ethers of (E)- and (Z)-2-octanone with borane in THF and the chiral auxiliary (1 R,2S) 26 gave (S)- and (R)-2-aminooctane in 80 and 79% ee, respectively39. 

HF/MeCN as electrolyte. The observed diastereoselectivities are discussed in connection with the chiral auxiliary and the role of the anode [208]. 

Carbohydrates are configurationally stable, easily available in enantiopure forms from the chiral pool, and they show a high density of chiral information per molecular unit. Their polyfunctionality and structural diversity fadhtate their tailor-made modification, derivatization, and structural optimization for a broad spectrum of synthetic applications. While derivatives of various saccharides have already been utilized as versatile starting materials and building blocks for chiral auxiliaries, ligands, and reagents [330] their obvious role as precursors for the... 

The 3-acyl-2(3F/)-oxazolones function as good dienophiles in cycloaddition reactions with cyclic 2,4-dienes such as cyclopentadienes and anthracenes. Thus, the thermal reaction of 3-acetyl-2(37/)-oxazolone with cyclopentadiene and the hexachloro and hexamethyl derivatives gives endo-cycloadducts exclusively. In particular, the chiral cycloadducts 221 and 223 derived from the diastereoselective Diels-Alder reactions of 3-(2-exo-alkoxy-l-apocamphanecarbonyl)-2(3/7)-oxazo-lones with hexamethylcyclopentadiene and 9,10-dimethylanthracene, respectively, are highly useful as chiral 2-oxazolidinone auxiliaries. The conformationally rigid roofed structures play a crucial role in affording excellent chiral induction (Fig. 5.54). 

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