Use of a Chiral Auxiliary

Introduction of a chiral auxihary into the silyl group of silyl enolates has been attempted [109-111]. The enantioselectivity of the reaction with binaphthyl-based silyl enolate 44 is, however, rather low [109]. Denmark et al. have reported that en-oxysilacyclobutane 45, bearing a chiral auxihary, adds to aldehydes without any catalyst to give the corresponding adducts with high diastereo- and diastereoface-selectivity [111]. 

We will give two examples, one involving the formation of a covalent bond, and the other the formation of an ion pair. 

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Scheme 211 Asymmetric synthesis of vinylaziridines by use of a chiral auxiliary.

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. 

Use of a chiral auxiliary on the allene results in excellent control of product stereochemistry. For example, epoxidation of allene 179 in the presence of furan leads to 180 in 80% yield (Eq. 13.61). The ratio of endo to exo isomers was 96 4 [69]. 

The use of a chiral auxiliary to induce stereochemical selectivity in the 3-aza -oxa-Cope rearrangement of O-aryl oximes 142 was reported by Citivello and Rapoport ... 

The use of a chiral auxiliary group on the ketene iminium salt permits the enantioselective synthesis of cyclobutanones. These salts offer a wider scope for asymmetric induction than ketenes since there are two substituents on the nitrogen of these salts which are not present on the oxygen of ketenes. Use of a chiral amide 8 or a geminal ehloroenaminc 10 permits the enantioselective synthesis of cyclobutanones 9 and 11. respectively, with enantiomeric excesses ranging from 55-97%. ... 

The original racemic patents described the use of resolution to give a chiral oxirane, such as 25, as an intermediate or the use of a chiral auxiliary (20) to produce the salmeterol enantiomers. Alkylation of chiral amine 20 with 2-benzyloxy-5-(2-bromo-acetyl)-benzoic acid methyl ester, followed by diastereoselective reduction of the ketone with lithium borohydride furnished intermediate 21 after chromatographic separation of the diasteromers. Removal of the benzyl group and the chiral auxiliary was... 

A chiral auxiliary is a temporary chiral group on a molecule that directs the stereochemical outcome of a reaction on another part of the molecule. Almost all synthetic routes involving chiral auxiliaries follow three steps (1) covalently attach the auxiliary to the molecule, (2) perform the reaction that forms the new stereocenter, and (3) remove the auxiliary. Under this model, use of a chiral auxiliary adds two steps to a synthesis because the auxiliary must be added and removed. Additional steps in a synthetic scheme require additional time, increase cost, and decrease the overall yield. Despite these disadvantages, chiral auxiliaries are fairly common in drug synthesis. 

Atorvastin (Lipitor, 13.40) is a cholesterol-lowering drug that has been synthesized as a single enantiomer through use of a chiral auxiliary (Scheme 13.6).16 Ester 13.36 contains the auxiliary, a chiral alcohol. Deprotonation of the ester forms an enolate (13.37). The enolate then attacks an aldehyde. The asymmetry of the stereocenter on the auxiliary causes the reaction to favor stereoisomer 13.38 over 13.39. Several recrystallizations are required to obtain 13.38 in high enantiomeric excess. Cleavage of the auxiliary from 13.38 and further manipulations of the side-chain afford atorvastin. 

Figure 10.10 The synthesis of 2R-methylbutanoic acid, illustrating the use of a chiral auxiliary. The chiral auxiliary is 2S-hydroxymethyltetrahydropyrrole, which is readily prepared from the naturally occurring amino acid proline. The chiral auxiliary is reacted with propanoic acid anhydride to form the corresponding amide. Treatment of the amide with lithium diisopropyla-mide (LDA) forms the corresponding enolate (I). The reaction almost exclusively forms the Z-isomer of the enolate, in which the OLi units are well separated and possibly have the configuration shown. The approach of the ethyl iodide is sterically hindered from the top (by the OLi units or Hs) and so alkylation from the lower side of the molecule is preferred. Electrophilic addition to the appropriate enolate is a widely used method for producing the enantiomers of a-alkyl substituted carboxylic acids...

There are many problems associated with carrying out asymmetric synthesis at scale. Many asymmetric transformations reported in the literature use the technique of low temperature to allow differentiation of the two possible diastereoisomeric reaction pathways. In some cases, the temperature requirements to see good asymmetric induction can be as low as -100°C. To obtain this temperature in a reactor is costly in terms of cooling and also presents problems associated with materials of construction and the removal of heat associated with the exotherm of the reaction itself. It is comforting to see that many asymmetric catalytic reactions do not require the use of low temperature. However, the small number of robust reactions often leads development chemists to resort to a few tried and tested approaches, namely chiral pool synthesis, use of a chiral auxiliary, or resolution. In addition, the scope and limitations associated with the use of a chiral catalyst often result in a less than optimal sequence either because the catalyst does not work well on the necessary substrate or the preparation of that substrate is long and costly. Thus, the availability of a number of different approaches helps to minimize these problems (Chapter 2). 

Many pericyclic reactions are stereospecific and, because they have to be run at temperatures higher than ambient, are very robust. It is somewhat surprising that there are very few examples of pericyclic reactions being run at scale, especially in light of our understanding of the factors that control the stereochemical course of the reaction either through the use of a chiral auxiliary or catalyst (Chapter 26). 

As with another class of compounds, the scale of synthesis and time required at the research stage before product can be made influence which method is finally used. At small scale, a plethora of methods exist to prepare amino acids, in addition to isolation of the common ones from natural sources. The majority of these small-scale reactions rely on the use of a chiral auxiliary or template. At larger scale, asymmetric hydrogenation and biocatalytic processes come into their own. For the amino acids approaching commodity chemical scales, biological approaches, either as biocatalytic or total fermentation, provide the most cost-efficient processes. 

The use of a chiral auxiliary or group on the dienophile can provide for face selectivity. High endo-exo selectivities have been achieved with bicyclic adducts, together with high asymmetric induction. Chiral dienophiles can be classified as either type I or type II reagents (Figure 26.1).4... 

A serendipitous use of a chiral auxiliary in atrop-selective biaryl bond formation has recently been published by Kita and co-workers [39, 137]. With diaryl substrate 201, which is related to precursors of the ellagitannins (see Section 14.6.1), PIFA-mediated oxidative coupling did not lead to the expected ellagitannin structure 202 (Scheme 50). Rather surprisingly, this reaction proceeds with intermolecular Ar-Ar bond formation. The chiral glucose framework efficiently transfers stereochemical information, but not in a intramolecular closure. 

Enantiomerically pure Diels-Alder adducts of Ceo were prepared by Tsuji and co-workers by use of a chiral auxiliary in the diene component and separation of the diastereoisomeric intermediates.385 The starting material for the diene component was a cyclic cyclopentenone acetal (224, Scheme 1.21) derived from L-threitol, reacting via its cyclopentadiene-containing enol ether isomer.385,386 The diastereoisomeric products 225 and 226, formed without significant diastereoselectivity, were isolated as the acetals, separated and subsequently hydrolyzed to afford the enantiomeric ketones (+)-227 and (—)-227. NOE measurements allowed the determination of the absolute configuration of the diastereoisomeric intermediates 225 and 226 and, therefore, also of the enantiomeric ketones (+)-(R,R)-227 and (—)-(S,S)-227 (Scheme 1.21).385... 

Subsequent effort by various groups was dedicated to improvement of the scheme to provide an efficient synthesis of chiral 14, via chemical [49] or enzymatic resolution [50] or, as inTagawa s synthesis (Scheme 16.13), the use of a chiral auxiliary [51]. A procedure to recycle the otherwise wasted (J ,J )-diastereoisomer of 16 via conversion to the mesylate of mt-17 and inversion with CsOAc was also reported [52], as well as a variant to obtain the desired enantiomer via Sharpless dihydroxylation [53]. 

Like their ubiquitous 0(O-acetal relatives, N, 0-acetals can exceed the narrow bounds of passive protection and participate in synthetic operations of far greater significance. Wc will illustrate the point by the enantioselective a-alkylation of proline [Scheme 8.163]357 360 without the use of a chiral auxiliary. The procedure is another example of the self-regeneration of stereocentres and begins... 

Synthesis of Unnatural (S)-Proline Derivatives. The condensation of pivaladehyde with (S)-proline yields stereoselec-tively, after lithiation and reaction with an electrophile, the hi-cyclic compound (28), which is a versatile educt for the synthesis of many a-suhstituted proline analogs (29) (eq 12). The reactions proceed via the formation of a chiral lithium enolate without the use of a chiral auxiliary (self-reproduction of chirality). The reaction with a variety of electrophiles cis to the t-Bu group yields a plethora of a-substituted (5)-proline derivatives (29). A limitation of this strategy is the acetal cleavage of some substituted products (28). ... 

Studies in the nineteen-eighties revealed that some Maimich-type reactions of imines with silyl enolates can be controlled with high diastereoselectivity, and that use of a chiral auxiliary enables highly enantioselective synthesis of -aminocarbo-nyl compounds [186]. Some Lewis acids, for example TMSOTf and zinc halides, were also found to be effective in catalytic quantities [187-190] although the original method requires a stoichiometric amount of TiCU [185]. In the last decade, further progress has been made by development of new acid catalysts. 

By use of a chiral auxiliary, diastereoselective aziridination could also be achieved [69]. Reaction of chiral N-enoylbornane[10,2]sultams with N-aminophthalimide in the presence of lead tetraacetate in CH2CI2 proceeded smoothly and afforded excellent yields of the corresponding N-phthalimidoaziridines with high diastereomeric excess (Scheme 13.48) [69a]. 

With non-stabilized enolates the radical reaction does not occur spontaneously but can be effectively initiated by triethylborane. The use of a chiral auxiliary group on the enolate leads to perfluoroalkylation products with reasonably good diastereomeric excesses (Scheme 2.105). 

We have already seen how relative stereocontrol may be achieved in aldol reactions at the positions labelled 1 and 2 in 194 (chapters 4 and 27). One of these chiral centres is formed from the aldehyde electrophile and the geometry of the double bond of the enolate determined whether we got anti or syn geometry (chapters 4 and 21). The absolute stereochemistry at these centres could be controlled by a variety of methods (chapters 23-29), including the use of a chiral auxiliary (chapter 27). 

Asymmetric induction in the aza-annulation reaction through the use of a chiral auxiliary was pioneered by d Angelo and coworkers in their work with 456. Even though annulation was not accomplished with the use of methyl crotonate, crotonyl cyanide produced an equimolar mixture of 458 and 459 in moderate yield (Scheme 36).112 Both 458 and 459 reflect regioselective Michael addition at the most substituted cx-carbon. The vicinal methyl substituents that resulted from aza-annulation were oriented in a cis relationship. 

One could envision the generation of the asymmetric center of a-aminonitrile 17 in one of two possible modes, not considering approaches using resolutions techniques. The first mode is more traditional and employs the use of a chiral auxiliary as part of the imine. The second takes advantage of the great strides made in asymmetric catalysis, whether mediated by transition metals or by the more recent organocatalysts. 

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