Diastereomers stereoselective reaction

The stereoselective reactions in Scheme 2.10 include one example that is completely stereoselective (entry 3), one that is highly stereoselective (entry 6), and others in which the stereoselectivity is modest to low (entries 1,2,4, 5, and 7). The addition of formic acid to norbomene (entry 3) produces only the exo ester. Reduction of 4-r-butylcyclohexanone (entry 6) is typical of the reduction of unhindered cyclohexanones in that the major diastereomer produced has an equatorial hydroxyl group. Certain other reducing agents, particularly sterically bulky ones, exhibit the opposite stereoselectivity and favor the formation of the diastereomer having an axial hydroxyl groi. The alkylation of 4-t-butylpiperidine with benzyl chloride (entry 7) provides only a slight excess of one diastereomer over the other. 

Most asymmetric induction processes with chiral auxiliaries involve a stereo-differentiating reaction that affords one diastereomer as the primary product. To obtain the desired enantiomer, the chiral auxiliary must be removed. Highly dia-stereoselective reactions between organocopper reagents and allylic substrates with... 

In recent work, Chmielewski and co-workers (174) reported the highly stereoselective reaction of ene-lactones with chiral pyrrolidine nitrone (141) to afford tricyclic adducts (Scheme 1.31). A 1 1 mixture of ene-lactone 142 and nitrone 141 provided adduct 143 with an uncharacterized isomer (97 3) (91%) whUe homo-chiral D-glycero (138) gave the adduct 144 as a single diastereomer (88%). A 2 1 mixture of racemic 138 and nitrone 141 afforded a 91 1 mixture of the two possible adducts, representing an effective kinetic resolution of the racemic lactone. 

The description of a stereoselective reaction primarily requires characterization of enantiomeric and/or diastereomeric products by their configuration (not their stereochemistry , see Introduction). Problems have not arisen with enantiomers but difficulties (see enumerations in refs 1 and 2) are. or perhaps were, apparent for diastereomers, a focal point having been acyclic compounds, in particular aldol addition products. These are pertinent examples to illustrate the problems and their various solutions very well ... 

The description of stereoselective reactions in which one new stereogenic unit is created, i.e., where a pair of enantio- or diastereomers can result, is straightforward. However, there are now numerous examples known of stereoselective reactions in which two or more stereogenic units are generated in the bond-forming step. Accordingly, more than two stereoisomers are formed. In principle, stating the ratio of the stereoisomeric products would suffice for the description of the outcome of such a reaction. However, mechanistic rationalization and prediction of the results are vastly simplified when subsets of the stereoisomers and their relative ratios are considered. Here the terms simple and induced diastereoselectivity play an important practical role. 

The terms stereoselective and stereospecific properly refer only to reactions in which diastereomerically different materials may be formed or destroyed during the course of the reaction. Stereoselective reactions are all those in which one diastereomer (or one enantiomeric pair of diastereomers) is formed or destroyed... 

The matched double stereoselective reaction between the chiral C-phenyl A -( 1-phenylethyl) nitrone and the chiral silyl ketene acetals 558 in acetonitrile/dichloromethane at 20 °C under zinc iodide-catalyzed conditions resulted in only the single diastereomer 559 in 98% yield. Exposure of 559 to acid afforded the isoxazolidinone 560 in 74% yield, together with the chiral auxiliary (li ,2 S )-2-phenylcyclohexanol (Scheme 135) <1997JOC6672>. 

The reactant, too, exists as diastereomers a pair of geometric isomers. If we start with, say, ci5-2-butene, which of the stereoisomeric products do we get A mixture of all of them No. cw-2-Butene yields only racemic 2,3-dibromobutane none of the meso compound is obtained. A reaction that yields predominantly one stereoisomer (or one pair of enantiomers) of several diastereomeric possibilities is called a stereoselective reaction. 

P, P] Seebach and Brock reported the dichlorodiisopropoxytitanium-mediated addition of the trimethylsilyl enol ether of cyclohexanone to /3-nitrostyrenes (83). The initial products generated are nitronic esters 39.1-39.3. Separation followed by fluoride-induced desilylation of these intermediates yields the corresponding syn and anti nitroketones. The results of this study are summarized in Scheme 39 and Table 12. Anti isomers are obtained in moderate diastereomeric excess. Moreover, the method is complementary to the additions of similar substrates by way of their lithium enolates (2) or enamines (vide supra), which provide the syn diastereomers. Further reactions of the intermediate nitronic esters were briefly explored. For example, addition of aldehydes and activated olefins provides stereoselectively the products from nitroaldol and [3 + 2] cycloadditions. 

It is apparent from the preceding chapter that the analysis of enantiomers (by whatever means) addresses only part of the problem often, a stereoselective reaction produces a mixture of diastereomers, and polarimetry is an inappropriate technique. Thus, asymmetric synthesis requires the means for the analysis of both enantiomeric and diastereomeric mixtures. Ultimately, the ratio of isomers and the cofifiguration of each new stereocenter should be determined. 

While the majority of examples of substrate control deal with cyclic sterocontrol, there are a few examples where diasteroselectivity is induced in an acylic system.27 A notable example of this was demonstrated during the synthesis of a fragment of tubulysin, by Wipf and co-workers.28 Utilizing a Davis reagent in their synthesis of an a-hydroxy-y-amino acid, the enolate of the y-amino acid derivative 42 was reacted with 1 to form the a-hydroxy derivative 43 as a single diastereomer in good yield. The stereoselective reaction has precedence in literature and likely involves a highly chelated dianionic species.29... 

Aside from the well-documented ability of the Luche reduction to provide stereocontrol in cyclic systems, acyclic stereocontrol is also viable through this process.39-41 A notable example of this was demonstrated in the synthesis of (+)-cannabisativine, a unique natural product found in the common marijuana plant.42 This synthesis necessitated a stereoselective Luche reduction to produce the diol 36 as a single diastereomer. The reaction proceeded in 96% yield and with 95% de. The pronounced diastereoselectivity can be attributed to Cram s rule, in which the hydride ion is delivered from the least sterically hindered side of the intermediate 34. Reduction via the chelated intermediate 35 would also account for the observed stereochemical outcome. 

A stereoselective reaction is one in which at least one product/transition state can, in principle, form in two or more stereomeric forms, and, one of the stereomeric forms predominates over the other (e.g. one enantiomer over its counterpart, and/or one diastereomer over another). 

In Figure 18.4 (p. 106), transformations 15-20 constitute stereoaselective transformations, since there is convergence towards (one or more) products which are devoid of stereogenic elements. Transformations 21 and 22 are nonstereoselective the former transformation leads to a racemate - 102/103 = 104/105), while the latter one gives two nonequimeric racemates - 108/110 and 109/111. In Figure 18.5 (p. 108), we depict transformations 23-26 which are stereoselective. In each of transformations 23 (112+113 114(=117)+115(=116)) and 26(127+128 129(=132)+130(=131)), one obtains two chiral diastereomers in the case of 25 (121+122—>123(=125)+124(=126)), the product mixture consists of two achiral diastereomers. Stereoselectivity is also possible in transformation 24 (118—+119+120), if syn elimination of a-b occurs concurrently with anti elimination. It should be noted that any one of these reactions would be considered nonstereoselective, if the component diastereomers were to form in accidentally equal amounts ... 

Steteoselecdve teacdon (Sections 5.10B, 8.21C, and 12.3D) In reactions where chirality centers are altered or created, a stereoselective reaction produces a preponderance of one stereoisomer. Furthermore, a stereoselective reaction can be either enantiose-lective, in which case the reaction produces a preponderance of one enantiomer, or diastereoselective, in which case the reaction produces a preponderance of one diastereomer. 

Another example of a stereoselective reaction is the previously discussed reduction of (R)-3-chloro-2-butanone (see Figure 6.7). In this case the two products are diastereomers, and the reaction is referred to as diastereoselective. This reaction is also stereospecific, in that (S)-3-chloro-2-butanone will give a different ratio of products with the same reducing agent. If the two products are enantiomers [as in the reduction of 2-butanone (Figure 6.7)], the reaction is enantioselective if one enantiomer is formed preferentially. 

Meyers has demonstrated that chiral oxazolines derived from valine or rert-leucine are also effective auxiliaries for asymmetric additions to naphthalene. These chiral oxazolines (39 and 40) are more readily available than the methoxymethyl substituted compounds (3) described above but provide comparable yields and stereoselectivities in the tandem alkylation reactions. For example, addition of -butyllithium to naphthyl oxazoline 39 followed by treatment of the resulting anion with iodomethane afforded 41 in 99% yield as a 99 1 mixture of diastereomers. The identical transformation of valine derived substrate 40 led to a 97% yield of 42 with 94% de. As described above, sequential treatment of the oxazoline products 41 and 42 with MeOTf, NaBKi and aqueous oxalic acid afforded aldehydes 43 in > 98% ee and 90% ee, respectively. These experiments demonstrate that a chelating (methoxymethyl) group is not necessary for reactions to proceed with high asymmetric induction. 

At the other extreme of the stereoselectivity spectrum of the Bucherer-Bergs reaction, the steric bias is sometimes not powerful enough to exert any selectivity at all, as exemplified by the conversion of 37 — 38. " Amino acid 38 was produced as a 1 1 mixture of two diastereomers. 

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