Reaction epimerization

The reduction of (32) with NaBH4 also induced the retro-aldol reaction which would give the syn-compound (33) and finally an epimerization reaction j ould convert (33) to the anti-compound (34)... 

Dihydrocorynantheine was obtained via similar steps from normal cyanoacetic ester 319 (172). Stereoselective transformation of the alio cyanoacetic ester 315 to the normal stereoisomer 319 was achieved by utilizing a unique epimerization reaction of the corresponding quinolizidine-enamine system (174). Oxidation of alio cyanoacetic ester 315 with lead tetraacetate in acetic acid medium, followed by treatment with base, yielded the cis-disubstituted enamine 317, which slowly isomerized to the trans isomer 318. It has been proved that this reversible eipmerization process occurs at C-15. The ratio of trans/cis enamines (318/317) is about 9 1. The sodium borohydride reduction of 318 furnished the desired cyanoacetic ester derivative 319 with normal stereo arrangement. The details of the C-15 epimerization mechanism are discussed by B rczai-Beke etal. (174). 

Fig. 7.13. HO -Catalyzed ring opening of pilocarpine (7.76) and isopilocarpine (7.77) to pilocarpic acid and isopilocarpic acid, respectively, and proton-catalyzed lactonization of the two acids to the respective lactone. Note that pilocarpine and isopilocarpine interconvert by a base-catalyzed reaction of epimerization (Reaction a).

Tetracyclines commonly comprise a plethora of related substances and degradation products, resulting from dehydration and epimerization reactions, and separating all of these constituents has proven to be quite a challenge. The necessity of adding ethylenediamine... 

During this epimerization process, it was found that the reactivity in the 4-position was however much higher than in the 2-position. At room temperature, the epimerizatiou reaction in the 4-position occurred instantaneously, completed withiu teu to tweuty minutes, whereas in the 2-position the epimerization reaction proceeded very slowly under these conditions. This result incited us to make use of the reactivity difference between the different positions to develop a new method, stepwise inversion of the hydroxyl groups amounting to a double serial inversion protocol, by which carbohydrate structures where one position is a hydroxyl group and the other positions were protected with ester groups could be obtained. 

The Suter-Flory model was successfully used to interpret the results of the epimerization reaction carried out on propylene oligomers (204) and on polypropylene itself (106, 205). In both cases a slight prevalence of the r dyad over the m (52/48) is observed. The epimerized polypropylene has a microstmcmre almost coincident with a Bernoulli distribution and represents the polymer sample closest to an ideal atactic polymer so far obtained. 

The central event in an epimerization reaction is the removal of a proton from the chiral a-carbon of an amino acid residue. This event generates an enolate with a trigonal planar carbon atom. Replacement of the proton on the face opposite from which it was abstracted results in the inversion of the configuration of the a-carbon. In theory, this event can occur at any stage of peptide synthesis. In practice, however, epimerization is observed almost exclusively during the amide-bond-formation step. This discussion will be confined to that type of epimerization. 

Epimerization reactions of D-glucose and D-mannose catalysed by various transition metals (Cu, Ni, Co etc.) modified with the ligands 113 (Table 6).272... 

ABSTRACT The acid-catalysed epimerization reaction of bioactive indole alkaloids and their derivatives is reviewed. The three mechanisms, which have been proposed for the (J-carboline-type indole alkaloids, are discussed. Through recent developments, evidence for all three mechanisms has been obtained, which shows the complexity of the epimerization reaction. The epimerization seems to depend on structural features and reaction conditions making it difficult to define one universal mechanism. On the other hand, the isomerization mechanism of oxindole alkaloids has been widely accepted. The acid-catalysed epimerization reaction provides a powerful tool in selectively manipulating the stereochemistry at the epimeric centre and it can also have a marked effect on the pharmacology of any epimerizable compound. Therefore, examples of this reaction in die total synthesis of indole alkaloids are given and pharmacological activities of some C-3 epimeric diastereomers are compared. Finally, literature examples of acid-catalysed epimerization reactions are presented. 

Articles dealing with the epimerization reaction are not easy to find. The term epimerization is often not mentioned in the abstract or title of an article and hence the discovery of a specific publication is sometimes pure coincidence. Furthermore, some authors use the term isomerization instead of epimerization, which naturally makes the search even more complicated. By definition, epimerization is the alteration of one asymmetric centre (the given compound has more than one asymmetric centre) but isomerization is the process whereby a compound is converted into an isomer [9]. Isomerization is therefore a more general term, resulting in an abundance of references and making it virtually impossible to track down all the publications of interest. We therefore apologize if we have omitted any crucial publications from this review. 

To test the necessity of aromatic n electrons in the epimerization reaction, indolo[2,3-a]quinolizidines with different substituents at C-10 were prepared [14]. Subjecting these compounds to epimerization conditions (TFA, 90°C, 60 min) gave the following results, Table 1. 

Another way to test the operation of Mechanism 1 is to subject C-l2b alkyl substituted indolo[2,3-a]quinolizidines to epimerization conditions. Should Mechanism 1 be operative, these compounds could not epimerize. Thus, C-l2b methyl substituted indoloquinolizidines 20 - 25 with different structural features were prepared by Lounasmaa and co-workers [22], Fig. (3). As well as testing Mechanism 1, they investigated the effect of different structural features on the epimerization reaction in general. 

Lactams 22 and 23 were also expected to epimerize, since prior results (see below) suggested that Mechanism 3 is active in the epimerization reaction of these compounds. Compounds 22 and 23 epimerized in de-aired TFA resulting in an equilibrium ratio of 65 35 (23 22). Winterfeldt and co-workers [23] have reported epimerization of similar compounds under acidic conditions. 

Mechanism 2, which constitutes a retro Pictet-Spengler type process, has long been held responsible for the acid-catalysed epimerization reaction... 

Although compound 27 was obtained in a much higher yield than was 26, Gaskell and Joule concluded that Mechanism 2 is active in the epimerization reaction of reserpine (1). They discredited Mechanism 3 because of the incapability of the metho salts 28 and 29 to epimerize. Instead, treatment of 28 and 29 with AcOH (140°C, 3 d) resulted in inversion of Nb to yield 30 and 31, respectively, Fig. (5). It was concluded that the inversion probably occurs via C-3 - Nb bond scission. 

In conjunction with their studies on electrophilic substitution in indoles, Jackson and co-workers [28] suggest that the initial protonation occurs at C-7 as in Mechanism 1, followed by hydride rearrangement of the indole P-hydrogen to the a-position. The epimerization reaction would then take place as depicted in Mechanism 2. Hence, Gaskell and Joule and Jackson et al. differ only in the matter of initial protonation. 

In 1989, Cook and co-workers [29] reinvestigated the epimerization reaction in connection with reserpine (1). One of their key observations, based on the results of Martin et al. [30] and of Sakai and Ogawa [31], is that Mechanism 2 cannot be primarily responsible for the epimerization reaction of reserpine (1). Both Martin and co-workers and Sakai and Ogawa report that the iminium species 32, Fig. (7), cyclizes under acidic conditions mainly to reserpine (1) and not to isoreserpine (2). If Mechanism 2 alone were responsible for epimerization, then isoreseipine (2), not 1 should be the main product. Mechanism 2 was accordingly discredited. 

Synthesis of Bioactive Indole Alkaloids and Their Derivatives by Utilizing the Acid-Catalysed Epimerization Reaction... 

Immediate sodium borohydride (NaBfLt) reduction gave lactam 44. Bischler-Napieralski cyclization of 44 followed by NaBfLt reduction yielded ( )-methyl-0-acetyl-isoreserpate (45). The correct stereochemistry at C-3 was obtained by first lactonizing compound 45 epimerization with pivalic acid then resulted in ( )-reserpic acid lactone (47). Treatment with base followed by acylation with TMBCI yielded racemic reserpine. The stereochemical considerations involved in the epimerization reaction will be discussed later. 

An efficient route to both cis- and frans-deethylebumamonines is a further example of the efficacy of the epimerization reaction [36]. These unnatural compounds are close derivatives of the well-known, pharmacologically important indole alkaloid, ebumamonine. For the synthesis of m-deethylebumamonine (3), Scheme (12), trans-ester 6 was epimerized in refluxing TFA to give a readily separable mixture of starting material and cis-ester 7 (ratio 22 78). 

Tangutorine (51), Fig. (11), an indole alkaloid recently isolated from the leaves of Nitraria tangutorum [37] constitutes an interesting synthetic target for pharmacological evaluation. The carbon framework of 51 was therefore prepared to investigate, for the first time, the conformational and stereochemical features of this ring system [38]. The epimerization reaction served as a tool in the studies. 

While working on the synthesis of dihydrocinchonamine, Sawa and Matsumura [54] clarified the correct configuration at the epimeric centre via the acid-catalysed epimerization reaction. They easily obtained both epimers of the skeleton by equilibrating methoxy-substituted dihydrocinchonamine 76 in HCl/EtOH, Scheme (20), thus providing a basis for structure determination. 

The acid-catalysed epimerization reaction often contributes to the change of conformation that alters the sterical shape of a compound. This may have a severe effect on pharmacological properties as with reserpine (1) and isoreserpine (2). The same seems to apply to the C-3 epimers yohimbine (78) and pseudoyohimbine (79). Yohimbine (78) blocks ai-receptors, whereas pseudoyohimbine (79) has little affinity for this... 

Obtaining the correct stereochemistry at an asymmetric centre is crucial in the total syntheses of natural products. Moreover, pharmacological properties are closely related to the correct stereochemistry. Thus, the epimerization reaction, which enables equilibration of C-3 epimers,... 

The mechanistic studies of the epimerization reaction still cause confusion. For the first time, direct evidence for Mechanism 1 has been presented based on the incapability of the C-12b methyl substituted vinylogous urethanes to epimerize. Further evidence for Mechanism 1 was provided by deuterium incorporation at the epimeric centre of various compounds (see above), a process most likely due to a mechanism analogous to Mechanism 1. The difference in epimerization rate and deuterium incorporation states merely that Mechanism 1 is not primarily responsible for the acid-catalysed epimerization reaction and hence does not completely discredit it. Evidence for all three mechanisms therefore now exists, revealing the complexity of the epimerization process. The results with p-carbolines and the trapping of 3,4-secoreserpine (27) and secolactam 38 provide strong evidence for Mechanism 3. Mechanism 2, which was earlier considered to be responsible for the epimerization reaction, has since been discredited. Nevertheless, the presence of 2,3-secoreserpine (26) in the trapping reaction remains undisputed and indicates that Mechanism 2 is active under the conditions employed. Thus, several mechanisms may be active simultaneously in the epimerization reaction, so further complicating the matter. 

Structural features, reaction conditions and acid strength also influence the acid-catalysed epimerization reaction. For example, Mechanism 1 requires protonation at C-7, which seems to occur under strongly acidic conditions. When a P-carboline derivative was treated with a weakly acidic solution (TFA-d, 2.9 equiv., rt), deuterium incorporation did not occur, whereas refluxing of a similar compound in a DCl/MeOH solution resulted in deuterium incorporation at the epimeric centre. Therefore, it is impossible to define one universal mechanism to explain the epimerization reaction for any given compound. On the contrary, each compound type must be separately investigated under different conditions. Clearly, then, the acid-catalysed epimerization reaction of indole alkaloids is a fruitful research area. 

Finally, we provide a list of literature examples of acid-catalysed epimerization reactions, Table 2, that can be used as a guideline in epimerizing similar compounds. We emphasize, however, that all data presented here are valid only under the conditions applied. 

Table 2. Examples of Acid-Catalysed Epimerization Reactions. ...

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