Enantioselectivity external

The most successful of the Lewis acid catalysts are oxazaborolidines prepared from chiral amino alcohols and boranes. These compounds lead to enantioselective reduction of acetophenone by an external reductant, usually diborane. The chiral environment established in the complex leads to facial selectivity. The most widely known example of these reagents is derived from the amino acid proline. Several other examples of this type of reagent have been developed, and these will be discussed more completely in Section 5.2 of part B. 

It may be concluded from die different examples sliown here tiiat die enantio-selective copper-catalyzed allylic substitution reaction needs ftirdier improvemetiL High enantioselectivities can be obtained if diirality is present in tiie leaving group of die substrate, but widi external diiral ligands, enantioselectivities in excess of 9096 ee have only been obtained in one system, limited to die introduction of die sterically hindered neopeatyl group. 

Addition of a chiral carrier can improve the enantioselective transport through the membrane by preferentially forming a complex with one enantiomer. Typically, chiral selectors such as cyclodextrins (e.g. (4)) and crown ethers (e.g. (5) [21]) are applied. Due to the apolar character of the inner surface and the hydrophilic external surface of cyclodextrins, these molecules are able to transport apolar compounds through an aqueous phase to an organic phase, whereas the opposite mechanism is valid for crown ethers. 

In one case, the insertion of the whole chiral hgand into a Co-exchanged zeohte by subhmation was described [24], Only small ligands, such as li and 2i, can be efficiently introduced into the micropores of the Y zeohte, whereas the bulkier Jacobsen s hgand la only remains on the external surface of the sohd. Unfortunately, these occluded (salen)Co complexes led to very low enantioselectivities (up to 8% ee) in the reduction of acetophenone with NaBH4. 

ORMOSIL are chemical sponges they adsorb and concentrate reactants at their surface, thereby enhancing reaction rates and sensitivity (in sensing applications). ORMOSIL-imprinted materials with a suitable chiral template such as a surfactant or a protein selectively adsorb (and detect) external reactants. A remarkable example is provided by thin materials that are generally enantioselective, namely where the chirally imprinted cavities can discriminate between enantiomers of molecules not used in the imprinting process, and completely different from the imprinting ones. 

In the enantioselective synthesis, the asymmetry (i.e., the stereoselectivity) is induced by the external chiral catalyst, while the diastereoselective synthesis does not require a chiral catalyst. The stereogenic center already present in the molecule is able to induce stereoselectivity, assuming that the synthesis starts with a single enantiomer. For instance, imagine that an a,/ -substituted product is formed, and that the reactant already contains a stereogenic carbon at a. If the reaction of (aS) leads, e.g., largely to (aS, / R) and hardly to the (aS, /IS) diastereomer (i.e., stereoisomers that are not mirror-images of each other), the reaction is diastereoselective (Scheme 14.2). 

Recent developments have impressively enlarged the scope of Pauson-Khand reactions. Besides the elaboration of strategies for the enantioselective synthesis of cyclopentenones, it is often possible to perform PKR efficiently with a catalytic amount of a late transition metal complex. In general, different transition metal sources, e.g., Co, Rh, Ir, and Ti, can be applied in these reactions. Actual achievements demonstrate the possibility of replacing external carbon monoxide by transfer carbonylations. This procedure will surely encourage synthetic chemists to use the potential of the PKR more often in organic synthesis. However, apart from academic research, industrial applications of this methodology are still awaited. 

Finally, another possibility is to design enantioselective syntheses by using external chiral auxiliaries either in catalytic or in stoichiometric quantities [21], Since these strategies are nowadays of great interest in organic synthesis, we will consider here some of the most recent results achieved in enantioselective aldol condensations, as well as in the asymmetric epoxidation and hydroxylation of olefmic double bonds. 

It is worthwhile emphasising that the abovementioned syntheses using chiral auxiliaries covalently bound to the substrate bearing the prochiral center prior to the creation of the new asymmetric centre mean converting the problem of enantiofacial recognition into a problem of diastereofacial selectivity i.e. the pair of enantiomers 41 and 42 are actually obtained from hydrolysis of two different diastereomers 39 and 40. In fact, "direct enantioselectivity" can only be attained by using an external chiral catalyst,23 as shown in Figure 9.1 [26]. 

Absolute asymmetric synthesis refers to the situation in which an asymmetric induction occurs in the absence of an externally imposed source of chirality [5]. Such reactions are invariably carried out in the crystalline state, where the asymmetric influence governing the enantioselectivity derives from the spontaneous crystallization of an achiral compound in a chiral space group. This phenomenon, which is analogous to the spontaneous crystallization of racemates as... 

In these systems, after the crystal chirality induced the chirality of asymmetric carbon in external organic compound, the subsequent asymmetric autocatalysis gives the greater amount of enantiomerically amplified product. These results clearly demonstrate that the crystal chirality of achiral organic compound is responsible for the enantioselective addition of /-Pr2Zn to pyrimidine-5-carbalde-hyde Ic. 

Terada expanded the phospha-Michael reaction to include diphenyl-phosphites [128]. A novel binaphthol-derived guanidine catalyst promoted the addition in high yields and enantioselectivities (Scheme 73). Functionalizing the external nitrogen with a diphenylmethine moeity enhanced selectivities for a large scope of nitro-olefm derivatives. 

Astonishingly enough, enantioenriched lithiated cyclooctene oxides 142, originating from (—)-sparteine-mediated lithiation of 124 by i-BuLi/(—)-sparteine (11), could be trapped by external electrophiles, resulting in substituted epoxides 143 (equation 31) ° . Again, the use of i-PrLi furnished better enantioselectivities (approx. 90 10). Lithiated epoxides, derived from tetrahydrofurans and A-Boc-pyrrolidines, undergo an interesting elimination reaction . ... 

This chapter deals mainly with the 1,3-dipolar cycloaddition reactions of three 1,3-dipoles azomethine ylides, nitrile oxides, and nitrones. These three have been relatively well investigated, and examples of external reagent-mediated stereocontrolled cycloadditions of other 1,3-dipoles are quite limited. Both nitrile oxides and nitrones are 1,3-dipoles whose cycloaddition reactions with alkene dipolarophiles produce 2-isoxazolines and isoxazolidines, their dihydro derivatives. These two heterocycles have long been used as intermediates in a variety of synthetic applications because their rich functionality. When subjected to reductive cleavage of the N—O bonds of these heterocycles, for example, important building blocks such as p-hydroxy ketones (aldols), a,p-unsaturated ketones, y-amino alcohols, and so on are produced (7-12). Stereocontrolled and/or enantiocontrolled cycloadditions of nitrones are the most widely developed (6,13). Examples of enantioselective Lewis acid catalyzed 1,3-dipolar cycloadditions are summarized by J0rgensen in Chapter 12 of this book, and will not be discussed further here. 

Control of reaction selectivities with external reagents has been quite difficult. Unsolved problems remaining in the held of nitrile oxide cycloadditions are (a) Nitrile oxide cycloadditions to 1,2-disubstituted alkenes are sluggish, the dipoles undergoing facile dimerization to furoxans in most cases (b) the reactions of nitrile oxides with 1,2-disubstituted alkenes nonregioselective (c) stereo- and regiocontrol of this reaction by use of external reagents are not yet well developed and (d) there are few examples of catalysis by Lewis acids known, as is true for catalyzed enantioselective reactions. 

Substituted cyclohexanones, bearing a methyl, isopropyl, tert-butyl or phenyl group, give, on deprotonation with various chiral lithium amides in the presence of chlorotrimethylsilane (internal quench), the corresponding chiral enol ethers with moderate to apparently high enantioselec-tivity and in good yield (see Table 2)13,14,24> 29 36,37,55. Similar enantioselectivities are obtained with the external quench " technique when deprotonation is carried out in the presence of added lithium chloride (see Table 2, entries 5, 10, and 30)593. 

The enantioselectivity of the two-step process (deprotonation and trapping of the enolate) is considerably higher in the case of internal quenching with chlorotrimethylsilane as shown by the results of the external quenching of the lithium enolate with acetic anhydride (Table 4)20. 

Seebach and Naef1961 generated chiral enolates with asymmetric induction from a-heterosubstituted carboxylic acids. Reactions of these enolates with alkyl halides were found to be highly diastereoselective. Thus, the overall enantioselective a-alkyla-tion of chiral, non-racemic a-heterosubstituted carboxylic acids was realized. No external chiral auxiliary was necessary in order to produce the a-alkylated target molecules. Thus, (S)-proline was refluxed in a pentane solution of pivalaldehyde in the presence of an acid catalyst, with azeotropic removal of water. (197) was isolated as a single diastereomer by distillation. The enolate generated from (197) was allylated and produced (198) with ad.s. value >98 %. The substitution (197) ->(198) probably takes place with retention of configuration 196>. 

The cyclopropanation of alkenes using external stoichiometric chiral additives can be divided according to their general mechanistic scheme into two classes. The enantios-elective cyclopropanation of allylic alcohols, in which a pre-association between the corresponding zinc alkoxide and the zinc reagent probably takes place, constitutes the first class. The second class involves the enantioselective cyclopropanation of unfunctionalized alkenes. The latter implies that there will be no association between the reagent and the alkene through alkoxide formation. 

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