Carbocations epimerization

The cyano-, carbomethoxy- and phenylsulfonyl-substituted cyclopropanes [54] (Cram and Ratajczak, 1968), [55] (Yankee and Cram, 1970a Yankee et al., 1973a) and [56] (Yankee and Cram, 1970b,c Howe etal., 1973 Yankee et al., 1973b) were epimerized or were solvolysed to give an open-chain methyl ether a carbocation-carbanion zwitterion was proposed as the intermediate. 

The mechanism of alkyl hydrogen exchange was not clarified, but a possible mechanism was postulated. Partial hydride abstraction by a Lewis acid site may have occured forming a carbocation-like species followed by exchange of a proton at a R-carbon. Such a mechanism predicts exchange to occur preferentially at methyl groups adjacent to the most stable carbocations (benzylic > 3° > 2° > 1°). This is consistent with the observed relative rates of epimerization of steranes during thermal maturation of sediments (83). 

Attempted iodocyclization with iodine in moist acetonitrile of ethyl 2-hydroxypent-4-enoate (59) to give the iodotetrahydrofuran (62) gave instead a 2 1 mixture (80%) of syn- and -lactones (60) and (61). Labelling studies with H2 0 indicated that the probable mechanism of the reaction involved initial attack of the ester group upon the iodonium ion (63) to yield a mixture of epimeric carbocations (64), which upon attack by water would yield the orthoesters (65), elimination of ethanol from which giving the epimeric y-lactones (60, 61). ... 

Due to the 18-CH3 —> 17-CH3 shift, a carbocation centered at C13 is formed, and further 14a-H elimination originates the A13-double bond. 16p-Epimers can be formed due to an acid-catalyzed retro-aldol equilibrium involving the 16-hydroxy-20-keto function of the rearranged steroid, under the reaction conditions employed, which is responsible for the epimerization at C16, as previously discussed by Herzog et al. [125, 126] and reviewed by Wendler (Scheme 34) [111]. 

The beneficial effect of fluorine atoms on hydrolytic stability has been demonstrated with synthetic prostaglandin (SC-46275). This compound possesses an antisecretory activity that protects the stomach mucous membrane. However, its clinical development was too problematic because of the instability of the tertiary allyl alcohol function in acidic media (epimerization, dehydration, etc). A fluorine atom has been introduced on the C-16 methyl to inhibit the formation of the allylic carbocation (Figure 4.39). The fluoroanalogue possesses the same biological activity but does not undergo any degradation or rearrangement, and it epimerizes only slowly. 

Evidence that this reduction proceeds mainly via an N-acyl iminium ion intermediate 120 was obtained by carrying out the triethylsilane reduction of 108 in deuterated trifluoroacetic acid (Scheme 49). As before, two C-4 epimeric protected kainoid analogues 121 and 122 were obtained, H NMR showing loss of the C-4 proton in both products accompanied by a simplification in the spin-spin coupling pattern of the C-5 protons.73 A close examination of the 2H NMR spectrum of each diastereoisomer did, however, reveal a trace of deuteration at C-5 indicating that a small percentage of the reduction also occurs via a benzylic carbocation intermediate 123 (Figure 12). 

These observations contrast with those of Shoppee and co-workers in a study of the epimeric 3-chloro-A -compounds which were believed to solvolyse via a single allylic carbocation. A re-examination of the solvolysis of the chloro-compounds appeared to confirm the intermediacy of two carbocations since the product ratios were very similar to those from the trifluoroacetates. Treatment of the trifluoroacetates with NaNs-HMPA resulted in substitution at C-3 with inversion of configuration. Reaction of the 17j8-trifluoroacetoxy-17a-vinyl compounds (7) and (8) under similar conditions gave the JB -17(20)-dehydro-21-azido-compounds (9). These reactions are not regarded as pure 5n2 processes since the compounds (7) and (8) may rearrange to compounds (10) in HMPA. Solvolysis of compounds (7) and (8) in MeOH-NaOAc gave product distributions... 

As discussed in Section 7.4, conformational control in deamination of open-chain amines is difficult to evaluate because the activation energies of conformational changes are often smaller than those of the steps in deamination reactions. Alicyclic amines are more suitable for such mechanistic investigations. In addition, the con-formers of such amines can be locked if they contain bulky substituents (tert-hvXyX) or if the amines are based on bi- and polycyclic hydrocarbons (decalinamines, cholestaneamines, norbornylamines, etc.). We shall therefore concentrate first on the deamination of the epimeric 4-( er butyl)cyclohexylamines. Then, we will discuss the structural problems of cyclic carbocations formed in deamination of norbor-nylamine, cyclopropylmethylamine, and cyclobutylamine, i. e., compounds that are at the center of interest in the debate on classical versus nonclassical carbocations. 

The NMR spectra -. To calculate the averaged shift of the C and C atoms for the rapid equilibration of epimeric 2-norbomyl cations Olah used an isopropyl ion as a secondary carbocation model. Kramer observes that the signal of the C atom in the tert-butyl cation spectmm is in a lower field than for an isopropyl cation. Kramer means that the positive charge on the secondary cation centre is lower than on the tertiary one this contradicts the fact that tertiary alkyl carbocations are more stable than secondarv ones. Hence he concludes that averaged shifts cannot be calculated from the NMR spectrum of the isopropyl cation since it is not a typical secondary carbocation. 

For a more convincing choice between structurally different carbocations study was made of the epimeric monofunctional dejivatives of polyfluorobenzocyclenes in which the splitting of the X-group must be followed by the formation of either different nonclassical ions S47 and 348 or the same classical ion 349 ... 

While the trifluoroacetolysis of the epimeric pairs of tosylates 369 and 370, 371 and 372 yields different reaction mixtures, the tosylates 371 and 372 interact quite differently with sodium azide in dimethylsulphoxide (i.e. with a strong nucleophile in a medium perfectly solvating carbocations) in this case only the k process is realized, the skeleton is retained and the configuration is inverted... 

In good accord with this assumption 5 ) are the data by Nisnevidi who compared the structure of stable secondary carbocations formed on solvolysis of epimeric esters and protonation of related olefine ... 

If additional chiral centers exist in the molecule and remain unchanged during this conversion, the pair of compounds with a mixture of R and S configurations at a single site would be related as diastereomers (more specifically, epimers) rather than enantiomers, so such a process would be described as an epimerization rather than a racemization. For example, sugars can undergo epimerization at the anomeric carbon via a resonance-stabilized carbocation intermediate. 

---