Reserpine epimerization

Acid-catalyzed C-3 epimerization of reserpine and other indolo[2,3-fl]quinolizi-dines 98H(48)1275. 

The relationship between 20 and reserpine (1) is close like reserpine, intermediate 20 possesses the linear chain of all five rings and all six stereocenters. With the exception of the 3,4,5-tri-methoxybenzoate grouping, 20 differs from reserpine (1) in one very important respect the orientation of the ring C methine hydrogen at C-3 in 20 with respect to the molecular plane is opposite to that found in reserpine. Intermediate 20 is a reserpate stereoisomer, epimeric at position 3, and its identity was secured by comparison of its infrared spectrum with that of a sample of (-)-methyl-O-acetyl-isoreserpate, a derivative of reserpine itself.9 Intermediate 20 is produced by the addition of hydride to the more accessible convex face of 19, and it rests comfortably in a conformation that allows all of the large groups attached to the D/E ring skeleton to be equatorially disposed. 

Some indolo[2..w/]c iiinolixidines undergo easy acid-catalyzed epimerization <1998H(50)243>. For instance, the alkaloid reserpine equilibrates to a mixture of starting material and its 3-epimer, isoreserpine, under acid or basic catalysis (Equation 6). A controlled epimerization of this type has been employed as the key step in a total synthesis of ( )-tacamonine <1998T157>. 

The normal indoloquinolizidines 20 and 21 resemble compounds such as reserpine (1). Considering the results of the deuterium experiments (see above), one could expect compounds 20 and 21 to epimerize under acidic conditions. And indeed, refluxing 20 or 21 in TFA overnight yielded an equilibrium ratio of 55 45 (21 20). 

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 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. 

In connection with the preparation of (+)- and (-)-tetrahydroharmine (compounds 39 and 40 in Fig. (10), respectively) the racemization of these compounds was studied by Chnsey and Brossi [34]. They demonstrated that, under acidic conditions, the pure enantiomers racemized with relative ease, and suggested that the racemization resembled epimerization of reserpine (1) and 1,3-disubstituted tetrahydro-P-carbolines. Therefore, the mechanism responsible for the racemization would be one of those mentioned above. 

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. 

Reserpine (1) epimerizes to isoreserpine (2) with great ease to give a ratio of 15 85 [18]. Hence, isoreserpine is the more stable epimer. The empiric result can be verified by stereochemical and conformational analysis. In reserpine (1) the conformational equilibrium is shifted to... 

In the course of the first total synthesis of reserpine (1), Woodward and co-workers [11] obtained an isoreserpine derivative instead of a reserpine derivative (see above). Thus, the problem arose of how to epimerize with good yield the more stable isoreserpine derivative to a reserpine... 

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... 

Epimerization of the API reserpine to 3-isoreserpine occurs readily in strong acid solution but has also been observed in solution using heat and... 

A brief, selective review of epimerizations in the isoquinoline and indole alkaloid series inevitably gives prominence to epimerizations at C-3 of tetrahydro-/3 -carbo-line derivatives, in particular of reserpine and reserpic acid lactone the epimerizations involved in Brown s synthesis33/ of Afa-methyl-tetrahydroalstonine and 3/3-H,20/3 -H-lVa-methyldihydrogeissoschizine, from ATb-benzyl-lVa-methylvincoside, are also discussed.69... 

Epimerization at C-3 to the extent of about 15% takes place when yohimbine is heated for prolonged times in acetic acid. The reverse epimerization is a practical one (8) and has been utilized in the analogous transformation of reserpine into isoreserpine (9). 

The major focus of this chapter is on the synthetic developments in the yohimbine area in the past dozen years. However, no discussion of this area would be complete without a presentation of the elegant and seminal Woodward (1958) synthesis of reserpine (2) (Scheme 3.3). The Woodward route began with a brilliant stereoselective elaboration of the stereochemically-and functionally-rich E-ring and was followed by incorporation of the tryp-tophyl unit and subsequent C-ring closure. The sequence concluded with a cleverly executed epimerization at C(3) to create the correct 3j8-H stereochemistry found in reserpine. 

Woodward designed a clever solution to obtain the desired C(3)-epimer. He reasoned that if 25 could be locked into conformation 25A in which the E-ring substituents are axially disposed, epimerization at C-3 under equilibrating conditions would furnish the reserpine 3) -H stereochemistry since it would alleviate the strain engendered by the axial bulky indole moiety. In the event, Woodward converted 25 to lactone 26 which enforces the E-ring triaxial conformation. As predicted, when exposed to pivalic acid in refluxing xylenes, 26 cleanly epimerized to produce epimer 27 having the desired ster-... 

As can be seen by reviewing the chemistry outlined above, a variety of cleverly devised strategies have been employed for the synthesis of the structurally complex yohimbine alkaloids. One elusive problem in many of these approaches has been the proper adjustment of the C(3) stereochemistry, particularly in approaches to reserpine (2) and deserpidine (3). It is well-known that epimerization at C(3) of the yohimbine skeleton 1 can occur under acidic conditions presumably via a mechanism involving cleavage of either the C(2)-C(3) or C(3)-N(4) bond to afford the respective iminium cation 532 or a-indolylcarbinyl cation 533. In this section, we will review investigations which focus on this epimerization process. 

Schiffl and Pindur have examined the C(3) epimerization of reserpine (2)... 

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