Stereo inversion

We ll see in the next chapter that alkyl halides react with nucleophiles to givi substitution products by a mechanism that involves inversion of stereo chemistry at carbon ... 

The chloroacetoxylation reaction is synthetically useful since the chloride can be substituted with either retention [Pd(0)-catalyzed reaction] or inversion (Sjv2 reaction) by a number of nucleophiles. In this way both the cis and trans isomers are accessible and have been prepared from a number of allylic acetates (Schemes 5 and 6). In a subsequent reaction the allylic acetate can be substituted by employing a copper- or palladium-catalyzed reaction. The latter reactions are stereo specific. 

C2 symmetry is a common feature in chiral bidentate ligands (119). If two identical enantiopure donor groups Y are connected by a tetrahedral bridging atom, any additional group Z at this atom will cause no additional stereo center but a prochiral center (Fig. 18a) (120). (S,S)- and (i2,i )-Trihydroxyglutaric acid are textbook examples for such compounds (120). Inversion of configuration at C3 in (S,S)-trihydroxyglutaric acid (Fig. 18b) yields the identical compound. 

In addition, a sample of (S)-hydroxyester of 85% e.e. was converted to the optically pure (R)-enantiomer under similar conditions. It is also possible to interconvert short chain 2-methyl-3-oxoalkanoates effecting an overall stereo-inversion of the C-2 centre. On prolonged exposure to G. candidum, syn (2R, 3S) ethyl 2-methyl-3-hydroxybutanoate 11 was converted, via the 3-oxoester 12, to the anti (2S,3S) compound 11 with an e.e. of 97% in around 23 h (Scheme 6). 

The enantioselective addition of the amino organolithium reagents consists of two stereo-controlled reactions, the asymmetric deprotonation (equation 14) and the following addition to electrophiles. The stereochemical course of the addition depends on the electrophile E. In the cases where heterocyclic enone or a,-unsaturated lactones are the electrophiles (entries 5-7), the addition proceeds with retention of configuration. In contrast, with the other electrophiles in Table 10 and trimethyltin chloride in equation 15, the addition proceeds with inversion of configuration. In the addition which proceeds with retention of configuration, a pre-complexation between the electrophiles and lithium may be involved (equation 16). 

Support-bound, enantiomerically pure alcohols can be converted into phosphonates by Mitsunobu esterification, which results in complete inversion at the stereo-genic center. This strategy has been used to prepare peptidyl phosphonates on solid phase. These are interesting transition-state analogs with potential utility as peptidase inhibitors (Figure 11.3 [12,13]) or tyrosine phosphatase inhibitors [14]. Serine or threonine derivatives can be converted into phosphonates by direct phosphonylation with an activated monoalkyl phosphonate [15] or by treatment with phosphonamidites RP(OR)NR2 in the presence of tetrazole followed by oxidation [16]. 

Several studies on the reactions and preparation of aziridines have been published. The ring opening of 2-substituted aziridines, accomplished by first converting them into aziridinium salts by reaction with a benzyl bromide and then attack of the bromide counter ion, gave only one bromide in a regio- and stereo-specific reaction.43 Since attack by the bromide ion of the aziridinium salt only occurred at the most substituted carbon with an inversion of stereochemistry, it was concluded the reaction occurred by an SN2 mechanism. This was supported by calculations at the MPWBlK/6-31+G(d) level of theory for reactions featuring two solvating acetonitrile molecules embedded in an acetonitrile matrix. 

Methylthiocyanate reacts with BF3 complexes of 3-aroylaziridines, yielding 4-aryl-5-aroyl-2-methylthio-2-imidazoazolines. During this reaction the three-membered ring opens in a regio- and stereo specific manner at the C(2) atom with inversion of the configuration [77]. 

Another example employed Mitsunobu reaction for the inversion reaction (Figure 10(b)).A single enantiomer of a (stereo)chemically labile allylic-homoallylic alcohol was obtained in 96% yield and 91% ee from the racemate through a lipase-catalyzed kinetic resolution coupled with in situ inversion under carefully controlled (Mitsunobu) conditions. Using this reaction, the algal fragrance component, (S)-dictyoprolene, was synthesized. 

In the presence of /9-cyclodextrin, that binds to the R group of substituted epoxides, benzeneselenol reacts regio- and stereo-specifically to give an 80% yield of the j3-hydroxy selenide.42 Because the selenol only attacks the least substituted carbon with inversion of configuration, the reaction must occur by an SN2 mechanism. 

The presence of hydroxyl groups, both adjacent and remote from the epoxide group, have been found to control the regio- and stereo-specificity of the tetracyanoethylene-catalysed methanolysis of cyclohexane epoxides.44 Because the nucleophilic attack occurs at the carbon remote from the hydroxyl group with inversion of configuration, it was suggested the hydroxyl group participates in the reaction. 

A novel formal inverse-electron-demand hetero-Diels-Alder reaction between 2-aryl-a,/3-unsaturated aldehydes and ketones produces dihydropyran derivatives stereo-specifically.161 The inverse-electron-demand Diels-Alder reaction of 3,4-r-butylthio-phene 1-oxide with electron-rich dienophiles shows vyn-jr-face and endo selectivity.162 (g) The inverse-electron-demand Diels-Alder reaction of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate with a variety of dienophiles produces phthalazine-type dihydrodiol and diol epoxides which were synthesized as possible carcinogens.163... 

Whether you are dealing with enantiomerically pure or racemic compounds, once the first chiral centre (or centres) is in place, new chiral centres must be introduced. Stereo specific reactions give specific and predictable stereochemical outcomes because the mechanism of the reaction demands this. The formation of 17 from 16 had to give that enantiomer as the nucleophilic oxyanion had to approach the chiral centre from the back (inversion) as all Sn2 reactions must go with inversion. Starting with enantiomerically pure materials, each enantiomer of the tosylate 18 must react in an Sn2 reaction to give an inverted acetate. One enantiomer of 18 gives one enantiomer of 19 and the other enantiomer of 18 gives the other enantiomer of 19 by stereospecific inversion. 

A Ti(Oz -Pr)4-mediated kinetic spirocyclization (with C-l retention) for the stereocontrolled synthesis of spiroketals from glycal epoxides such as 485 has been reported (Scheme 87) <2006JA1792>. A complementary methanol-induced kinetic cyclization (with C-l inversion) allows for a synthetically systematic approach for accessing stereo-diversified spiroketals, for example, 486 and 487 from glycals (e.g., 484) <2005JA13796>. 

At carbon, most leaving groups are good in SN2 reactions these go with inversion. At carbon, most leaving groups are poor in SE2 reactions these go with retention. As for the SNi reaction, this is usually strongly assisted, e.g. in (129) and (130) by the formation of sulfur dioxide (Mackenzie, 1964 de la Mare, 1963). The stereo-... 

In recent years, even chemists have become concerned about terminology to be used for asymmetric syntheses and asymmetric reaction processes . Since catalysis by enzymes represents the ultimate in an asymmetric reaction, it is appropriate to consider briefly a new proposal. Izumi and Tai have proposed that the time has come to abandon the use of stereoselective and stereospecific [62], They point to two components in the transformation of a substrate to a product. The first resides in chemical structures (e.g., a double bond) rather than in a particular steric structure and the reaction is governed by the nature of the reagent or catalyst (whether the process proceeds with retention or inversion whether an addition is syn or anti). In the second component, the reagent or catalyst interacts topologically with the three-dimensional structure of the substrate. This is described as stereodifferentiation and results from the stereo-differentiating ability of the catalyst or reagent. 

These observations have led to the development of a trajectory-based model to rationalize die selectivity of the monooxygenase enzyme in Beauveria sulfurescens, and this may aUow the regio- and stereo-chonistry of transformations on new (related) substrates to be predicted. Also of some assistance in predicting the stereochemical outcome of the reactions is the study of the mechanism, and this has beoi investigated and diown, at least in some cases, to proceed with inversion of stereocheniistry. ... 

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