Acid catalysed epimerization

Results of a study of acid-catalysed epimerization of indolo [2,3-a]quinolizidine derivatives support a mechanism involving nitrogen lone pairs in an eliminative ring opening-ring closure. ... 

ACID-CATALYSED EPIMERIZATION OF BIOACTIVE INDOLE ALKALOIDS AND THEIR DERIVATIVES... 

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. 

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

The canonical forms displayed above show a similarity with Mechanism 3, namely, the positive charge at Nb. Proof of the involvement of Mechanism 3 was therefore sought. When 36 was refluxed in a Zn/TFA solution for 3.5 h the secolactam 38, Fig. (9), was obtained in 22% yield. Compound 38 indicates that Mechanism 3 is active in the acid-catalysed epimerization of such lactams, a finding in accordance with the previously reported result that C-12b methyl substituted lactams epimerized under acidic conditions (see above). 

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

Woodward and co-workers [11] in the 1950s, constitutes one of the most classical acid-catalysed epimerizations in indole alkaloid chemistry. After the key intermediate 43 had been prepared, it was reacted with 6-methoxytryptamine (42) in benzene, Scheme (11). 

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... 

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. ...

Ring-opening of Epoxides. Diversity of results from the reaction of HF with some steroidal epoxy-ketones seems to stem from a critical dependence of reaction path on solvent.A 4, 5) -epoxy-3-ketone (76) reacted with HF in anhydrous chloroform to give the 5a-fluoro-4a-alcohol (78), probably resulting from acid-catalysed epimerization of an initially formed 5a-fluoro-4) -alcohol (77), the... 

Full details have been given of the the synthesis of (+)-hydantocidin and 5-epi-hydantocidin from D-fructose carried out in Terashima s laboratory (see Vol. 27, p. 339-340). The same group has also described a one-step synthesis of 5-epi-hydantocidin from D-isoascorbic acid and urea, by heating them together at 130 °C with no solvent, although the yield was very low. Studies on the acid-catalysed epimerization of hydantocidin to the 5-cpi-compound were also reported, with the epimer being preferred at equilibrium. ... 

The acid catalysed epimerization of the C-21 group of leucotylin (482), to give isoleucotylin (483) in addition to leucotylidiene (484) has been reported 342) (Scheme 65). Methyl leucotylate is known to react in a similar manner 343, 341). 

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