Chiral compounds auxiliary removal

It is often possible to convert an achiral compound to a chiral compound by (1) addition of a chiral group (2) running an asymmetric synthesis, and (3) cleavage of the original chiral group. An example is conversion of the achiral 2-pentanone to the chiral 4-methyl-3-heptanone (50). In this case, >99% of the product was the (5) enantiomer. Compound 49 is called a chiral auxiliary because it is used to induce asymmetry and then is removed. 

Chiral templates can be considered a subclass of chiral auxiliaries. Unlike auxiliaries that have the potential for recycle, the stereogenic center of a template is destroyed during its removal. Although this usually results in the formation of simple by-products that are simple to remove, the cost of the template s stereogenic center is transferred to the product molecule. Under certain circumstances, chiral templates can provide a cost-effective route to a chiral compound (Chapter 25). Usually, the development of a template is the first step in understanding a specific transformation and the knowledge gained is used to develop an auxiliary or catalyst system. 

Even if the resolution of an amino acid is relatively easy, the synthesis of a racemic mixture when only one enantiomer is desired is wasteful, because half of the product cannot be used. Recently, considerable effort has been devoted to the development of methods that produce only the desired enantiomer by so-called asymmetric synthesis. As was discussed in Chapter 7, one enantiomer of a chiral product can be produced only in the presence of one enantiomer of another chiral compound. In some asymmetric syntheses a chiral reagent is employed. In others a compound called a chiral auxiliary is attached to the achiral starting material and used to induce the desired stereochemistry into the product. The chiral auxiliary is then removed and recycled. 

For the diastereoselective hetero Diels-Alder reaction of carbonyl compounds using removable chiral auxiliaries, intensive studies of the uncatalyzed... 

But there are, of course, disadvantages. Chiral auxiliaries must be attached to the compound under construction, and after they have done their job they must be removed. The best auxiliaries can be recycled, but even then there are still at least two unproductive steps in the synthesis. We may have given the impression that successful asymmetric synthesis is made possible by joining any chiral compound to the substrate. This is very far from the truth. Discovering successful chiral auxiliaries requires painstaking research and most potential chiral auxiliaries give low ees in practice. More efficient may be chiral reagents, or, best of all, chiral catalysts, and it is to these that we turn next. 

As we have seen, the Diels-Alder reaction can be both stereoselective and regioselective. In some cases, the Diels-Alder reaction can be made enantioselective Solvent effects are important in such reactions. The role of reactant polarity on the course of the reaction has been examined. Most enantioselective Diels-Alder reactions have used a chiral dienophile (e.g., 199) and an achiral diene,along with a Lewis acid catalyst (see below). In such cases, addition of the diene to the two faces of 199 takes place at different rates, and 200 and 201 are formed in different amounts. An achiral compound A can be converted to a chiral compound by a chemical reaction with a compound B that is enantiopure. After the reaction, the resulting diastereomers can be separated, providing enantiopure compounds, each with a bond between molecule A and chiral compound B (a chiral auxiliary). Common chiral auxiliaries include chiral carboxylic acids, alcohols, or sultams. In the case illustrated, hydrolysis of the product removes the chiral R group, making it a chiral auxiliary in this reaction. Asymmetric Diels-Alder reactions have also been carried out with achiral dienes and dienophiles, but with an optically active catalyst. Many chiral catalysts... 

The oxazoline 184 provides an attractive approach to lactacystin as it is a protected form of 3-hydroxyleucine. The other half of the molecule was made in the LeukoSite synthesis by a very different method the alkylation of an Evans chiral auxiliary. This was chosen partly because they wished to vary the alkyl group on the pyrrolidone ring and we use the propyl compound as example. The phenylalanine derived oxazolidinone 193 (chapter 27) was acylated and then the titanium enolate of 194 was alkylated to give 195 with very high selectivity and the chiral auxiliary removed to give the simple acid 196. 

In reaction A of Fig. 3, a very cheap chiral auxiliary such as pseudoephedrine is able to control the steric course of an alkylation reaction in a highly efficient fashion [14]. Remarkably, auxiliary removal is possible in different conditions, thus opening access to several classes of virtually enantiomerically pure compounds from the same precursor. 

Enolate alkylations can be carried out stereoselectively to give enantiomerically enriched a-alkyl carbonyl compounds. Particular success has been achieved with the aid of chiral auxiliaries, enantiomerically pure chiral compounds that can be attached to the carbonyl group to control the direction of substitution at the a carbon, then removed to leave the desired a-alkyl carbonyl compound with high enantioselectivity. 

A -sulfinyl chiral auxiliaries have been used to prepare enantiopure tetrahydro-P-carbolines and tetrahydroisoquinolines in good yields under mild reaction conditions. Both enantiomers of V-p-toluenesulfinyltryptamine 46 could be readily prepared from the commercially available Andersen reagents.Compound 46 reacted with various aliphatic aldehydes in the presence of camphorsulfonic acid at -78 °C to give the A-sulfinyl tetrahydro-P-carbolines 47 in good yields. The major diastereomers were obtained after a single crystallization. Removal of the sulfinyl auxiliaries under mildly acidic conditions produced the tetrahydro-P-carbolines 48 as single enantiomers. 

A nice and convergent approach to both compounds makes use of RCM to form the 5-membered building block 71, which mimics the carbohydrate part of the nucleosides. The necessary diene precursor 69 is readily assembled via Evans aldol chemistry. RCM then affords the ring in almost quantitative yield (69->70), leaving the chiral centers and the free hydroxyl group intact. Removal of the chiral auxiliary by reductive cleavage, attachment of the base by means of jt-allylpalladium chemistry, and a final deprotection step complete these highly efficient syntheses [46]. 

Cycloaddition of enantiomerically pure a-chloro nitroso compounds derived from steroids and carbohydrates (e.g. 158, equation 102) proceeds with considerable stereoselectivity. Final removal of the chiral auxiliary results in Af-unsubstituted cyclic hydroxylamines of high ee. 

The compound 37 is called a chiral auxiliary because it is used to induce asymmetry and then removed. 

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