Reversible chiral auxiliaries, asymmetric

Carbohydrates have found widespread use as chiral auxiliaries in asymmetric Diels-Al-der reactions156. A recent example is a study conducted by Ferreira and colleagues157 who used carbohydrate based chiral auxiliaries in the Lewis acid catalyzed Diels-Alder reactions of their acrylate esters 235 with cyclopentadiene (equation 66). Some representative results of their findings, including the ratios of products 236 and 237, have been summarized in Table 9. The formation of 236 as the main product when diethylaluminum chloride was used in dichloromethane (entry 3) was considered to be the result of an equilibrium between a bidentate and monodentate catalyst-dienophile complex. The bidentate complex would, upon attack by the diene, lead to 236, whereas the monodentate complex would afford 236 and 237 in approximately equal amounts. The reversal of selectivity on changing the solvent from dichloromethane to toluene (entry 2 vs 3) remained unexplained by the authors. 

The optical yield was found to be very sensitive to structural modifications of the achiral agent. For example, use of the more bulky FV or Bu substituents in the 3,5-positions of phenol resulted in lower optical yields. In some cases a reversal of the sense of asymmetric induction was observed. Systematic variation of reaction conditions using the best achiral component, 3,5-xylenol, established that optimum results were obtained in ether solvent at about - 15°C. There was also a minor but definite influence of the rate of addition of ketone as well as an effect of concentration on optical yield, with a slower rate being advantageous. The results of reduction of aryl alkyl ketones are shown in Table 9, along with comparative results of reduction with similar chiral auxiliary reagents. 

Like an enzyme, an asymmetric catalyst binds its substrate, performs a reaction, and releases the product three steps. Chiral auxiliaries have three analogous steps attach, react, and cleave. The advantage of an asymmetric catalyst over an auxiliary is that binding to the substrate is reversible and involves weak, intermolecular forces instead of covalent bonds. Binding and release of the substrate occur in the same reaction vessel as the stereocenter-forming reaction. 

The intermolecular Diels-Alder reaction between the dibromoenone (111) and dienes (112) provides access to bicyclo[5.4.0]undecane systems (113) that are common core structures of many natural products (Scheme 32).118 The alio-threonine-derived O-(/ -biphenyl carbonyl oxy)-/i-phenyloxazaborolidi none catalyses the enan-tioselective Diels-Alder reaction of acyclic enones with dienes.119 The reversal of facial selectivity in the Diels-Alder cycloaddition of a semicyclic diene with a bro-moenone was induced by the presence of the bromo substituent in the dienophile.120 Mixed Lewis acid catalyst (AlBr3/AIMe3) catalyses the Diels-Alder reaction of hindered silyloxydienes with substituted enones to produce highly substituted cyclohexenes.121 Chiral /V-enoyl sultams have been used as chiral auxiliaries in the asymmetric Diels-Alder reactions with cyclopentadiene.122... 

Asymmetric aldol reactions5 (11, 379-380). The lithium enolate of the N-propionyloxazolidinone (1) derived from L-valine reacts with aldehydes with low syn vs. anti-selectivity, but with fair diastereofacial selectivity attributable to chelation. Transmetallation of the lithium enolate with ClTi(0-i-Pr)3 (excess) provides a titanium enolate, which reacts with aldehydes to form mainly the syn-aldol resulting from chelation, the diastereomer of the aldol obtained from reactions of the boron enolate (11, 379-380). The reversal of stereocontrol is a result of chelation in the titanium reaction, which is not possible with boron enolates. This difference is of practical value, since it can result in products of different configuration from the same chiral auxiliary. 

Until now, only few attempts were made to control the absolute configuration of the chiral polycyclic products. When salicylic esters of type 77 (Sch. 14) possessing an asymmetric alcohol moiety as chiral auxiliary instead of the n-butyl group are irradiated, the corresponding products can be isolated with 17% ee [50]. Better results can be obtained with the additionally acylated substrates 79a-c (Sch. 15). Compounds 80a-c were isolated with diastereomeric excesses up to 90% [29,56]. These compounds were formed via [2+2] photocycloaddition yielding the intermediates X. A thermal rearrangement leads to 80a-c. Compounds 81a-c are produced in the same time via a further photochemical rearrangement but due to thermal reversibility of the last step, 80a-d could be isolated with yields up to 90% when the reaction was completed. 

Reactions that involve asymmetric synthesis are traditionally classified separately from other dia-stereoselective transformations of chiral substrates, even though there is little fundamental differoice between them. The degree of success realized in both categories depends on the ability of the chemist to distinguish between competing, diastereomeric transition states the critical objective is to maximize AAG - This classification system undoubtedly evolved since the chiral auxiliary used in asymmetric reactions, whether it is introduced as part of a catalyst or is covalently bound to the substrate, is not destined to be an integral structural component of subsequent transformation products, while the reverse situation obviously pertains in the more frequently encountered diastereoselective transformations of chiral substrates. Work that has been reported for asymmetric IMDA reactions is summarized in this section." ... 

Asymmetric induction from a removable chiral auxiliary has been demonstrated in a limited number of examples41. In the example shown here, the auxiliary 5-methyl-2-(l-phenyl-1-methylethyl)cyclohexanol4 44 imparts control at the 95 5 level with the Z-isomer and 15 85 in the reverse sense with the -isomcr. The trans orientation of substituents is favored even... 

When lactate is used as a chiral auxiliary, the proximity of the enolic hydroxyl group and the carboxyl of the lactate induces an interaction between the functional groups in the photodienol. Therefore, a surprising solvent effect, and even a reversal of the diastereoselectivity with the content of 2-propanol in water, was reported [53]. Except for lactate 8f in methanol and 2-propanol/water mixtures, it was possible to correlate the chirality of the new asymmetric center with the configuration of the lactyl chiral auxiliary. When (S)-lactyl derivatives were examined, models indicated that the S-configuration of the new chiral center can be deduced from a sterically easier approach of the carboxylate group at the re face of the a-carbon of the dienol. 

Enantioselective 2- -2 Photocycloadditions. When 2-l-2 photocycloadditions of prochiral enones and alkenes are carried out in chiral fluid solutions, asymmetric induction could be expected on the new asymmetric centers. Unfortunately, successful examples of such enantioselective syntheses of chiral cyclobutanes have not yet been reported. However, a formal enantioselective 2 -f 2 photocycloaddition can be represented by a three-step sequence, as shown in Scheme 25, where a functional group such as a carboxylic acid can be modified easily and reversibly by simple reaction with a chiral auxiliary. The photochemical reaction can then be carried out with chiral enones or alkenes. 

Not only do chiral hypervalent iodine reagents have the potential for such conversions, achiral iodanes in combination with chiral auxiliaries can also be used in asymmetric oxidative protocols. The Kita group performed the controlled oxidation of sulfides to sulfoxides using iodoxybenzene (PWO2) in a cationic reversed micellar system. High chemical yields and good stereoselectivities... 

Yb(OTf)3 was effective for asymmetric induction in hetero Diels-Alder reaction of thiabutadiene and electron-deficient olefin bearing chiral auxiliary [37]. 10 mol% of catalyst effected the reaction into giving cycloadduct in excellent Tc-facial selectivity, whereas selectivity was reversed with modest degree in the absence of the catalyst (Scheme 13.15). The reaction in which a coordinative solvent such as dimethylsulfoxide (DMSO) or dimethylformamide (DMF) displayed similar selectivity came from that of noncatalyzed reaction, suggesting well-organized coordination of substrates to Yb. 

Our studies on the adamantyl (10) and decalyl (1) systems are onlytwo of several examples of the successful application of the ionic chiral auxiliary approach to asymmetric induction in the Yang photocyclization reaction. Space does not permit a full exposition of our results in this area. The interested reader may wish to consult references 17, 25, 27, 31, 35, 38 and 44 for additional examples and further details. As a note of interest, reference 44 describes the use of anionic chiral auxiliaries in the Yang photocyclization of a cationic counterion in the crystalline state aU of our other studies have been of the reverse type. 

Recent developments in enantioselective protonation of enolates and enols have been reviewed, illustrating the reactions utility in asymmetric synthesis of carbonyl compounds with pharmaceutical or other industrial applications.150 Enolate protonation may require use of an auxiliary in stoichiometric amount, but it is typically readily recoverable. In contrast, the chiral reagent is not consumed in protonation of enols, so a catalytic quantity may suffice. Another variant is the protonation of a complex of the enolate and the auxiliary by an achiral proton source. Differentiation of these three possibilities may be difficult, due to reversible proton exchange reactions. 

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