Stereochemical scrambling

The oxygen rebound mechanism was supported by experimental evidence including (1) high kinetic isotope effects, (2) partial positional or stereochemical scrambling, and (3) allylic rearrangements. For instance, in the presence of [Fe(TPP)Cl] and PhIO, dx-stilbene was stereospecihcally epoxidized. In addition, it was found that cis-stilbene was 15 times more reactive than trans-stilbene in competitive epoxidations. (see Figure 7.20). " ... 

Metal-catalyzed allylic substitution reactions have been a mainstay of synthetic chemistry because of their ability to proceed irreversibly and with high selectivity [42]. It is also feasible, however, to produce analogous systems that are completely reversible and nonselective, or ideally situated for use in DCC. These are essentially metal-catalyzed transesterification reactions, with the added feature of potentially providing stereochemical scrambling (and selection) as well as constitutional variation. An early example of this was provided in 2000 by Kaiser and Sanders [43]. In the absence of a template, reaction of diallyl diacetate 22 with a dicarboxylic acid in the presence of catalytic Pd(0) produced a negligible amount of the cycfized compound 23 (Fig. 1.9). However, when templated with 1,3-bis(4-pyridyl) benzene, yield of the cyclic structure increased to roughly 10%, independent of the dicarboxylic acid used. 

Loss of stereospecificity, however, has also been reported in the addition of amines. The use of homogeneous Pd° catalysts in the addition of dimethylamine to a cyclohexenyl acetate led to substantial stereochemical scrambling (equation 186). Employment of polymer-bound Pd° catalysts, however, gave complete stereospecificity via ligand addition.398 The epimerization noted in this reaction is apparently due to acetate attack at the metal center, which is prohibited by steric congestion of the metal in the polymer matrix (equation 187).398... 

For a closely related example of stereochemical scrambling reported in the synthesis of the Strychnos alkaloid mossambine, see Kuehne, M. E., Wang, T. S., Seraphin, D., J. Org. Chem. 1996,61,7873. 

Moreno-Manas, M. Morral, L. Pleixats, R. Palladium(0)-catalyzed allylation of highly acidic and nonnucleophilic anilines. The origin of stereochemical scrambling when using allyliccarbonates./. Org. Chem. 1998, 63, 6160-6166. 

Remarkably, alkene stereochemistry in allylic chlorides is completely retained in the Pd-catalyzed coupling with alkenyl-Al (equations 495 and 196) °° and aryl-Sn reagents (equation 203), ° whereas stereochemical scrambling is also encountered in some cases (equation 204). ° Retention of alkene stereochemistry is also observed in the Cu-catalyzed Grignard coupling of allylic acetates (equation 205).2f ... 

Usually, the alkylation does not occur in a stereospecific fashion. Although treatment of endo-9-bromobicyclo[6.1.0]nona-2,4,6-triene with butyllithium at — 60°C followed by iodomethane at the same temperature gave exclusively e /o-9-methylbicyclo[6.1.0]nona-2,4,6-triene (endo-S), the corresponding exo-isomer gave a 1 1 mixture of endo-S and exo-5. Halocyclopropanes, in general, suffer stereochemical scrambling when alkylcyclopropanes are prepared by alkylation of a nucleophilic cyclopropyl species, but exceptions are known ... 

Exclusive oxetan (30a—e) formation has been observed in the photochemical addition of olefins to the cyclopentene-l,3-diones (31a,b).18 The regioselectivity of the addition was established as 4.26 1 for the formation of the oxetans (30b) and (30c) by the addition of isobutene to dione (31a) and 3.55 1 for the formation of (30d) and (30e) from the addition of the same olefin to dione (31b). This addition follows the now well-established path in oxetan formation involving addition of the nir excited state of the ketone to the olefin to afford preferentially the more stable biradical intermediate. The fact that a triplet state was involved in the addition was demonstrated by the stereochemical scrambling encountered in the addition of either cis- or /ra/w-but-2- , when four oxetans were obtained. 

Cycloadditions. An intramolecular [2+3]-cycloaddition involving a methylene-cyclopropane unit and a conjugated ester proceeds without stereochemical scrambling. A formal Diels-Alder reaction to rapidly build up the skeleton of rebeccamycin is reported. 

The origin of the 3.3.0 diene would appear to be a 1,3-shift in the bisallylic biradical which forms the 3.2.1 diene (Scheme 9.55). However, this biradical species must be formed with rotation around the CHD group to give the stereochemical scrambling observed. 

Careful experiments using deuterated substrate 55 by Kakinuma and Eguchi revealed that (1) the Perrier carbocyclization of 55 involved no retro-aldol process and was thus an irreversible reaction and (2) the overall cyclization reaction was nonstereoselective with respect to the C-6 methylene site fScheme 12.15). Based on the results of complete stereochemical scrambling at C-6 in cyclized product 57, Kakinuma and Eguchi proposed the presence of radical intermediate 56. They also suggested that the cyclization might be a radical process, although this model could not explain the stereoselectivity at C-5. 

Resonance Raman measurements indicate that the S atoms in [Cu(15S5)] migrate rapidly between apical and equatorial positions [192]. Presumably the strain evident in the ring pushes this complex well up the potential curve toward the transition state for rearrangement, and thereby facilitates this stereochemical scrambling. 

Tj -allylpalladium complex as a possible reason for stereochemical scrambling. a hypothesis firmly reinforced by Backvall and co-workers much later." " ... 

If the mechanism is stepwise, it should lead to stereochemical scrambling of the groups originally attached to the dienophile (Rg. 12.60). 

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