Reserpine, natural product

Chen, RE. Huang, J. (2005) Reserpine A Challenge for Total Synthesis of Natural Products. Chemical Reviews, 105, 4671-4706. 

Varchi, G., Battaglia, A., Samori, C., Baldelli, E., Danieli, B., Fontana, G., Guerrini, A. and Bombardelli, E. 2005. Synthesis of deserpine from reserpine. Journal of Natural Products, 68 1629-1631. 

This is one of the most important reactions in all of organic synthesis, as it unites two moieties in a predictable stereochemical relationship, with the concomitant formation of two carbon-carbon bonds (Fig. 9.5) [37]. The reaction has been used in the synthesis of complex natural products, for example in an efficient synthesis of the antihypertensive drug reserpine [38], Such a reaction seems to be well worth studying. 

Fig. 9.5 The prototypical Diels-Alder reaction is that between 1,3-butadiene and ethene, to form cyclohexene. The Diels-Alder reaction has been used in the synthesis of complex natural products above, methyl 2,4-pentadienoate reacts with 1,4-benzoquinone to form an intermediate in the synthesis of the drug reserpine. In a one-pot reaction two carbon-carbon bonds are made and three chiral centers ( ) are created with the correct relative orientations (i.e. essentially one diastereomer is formed)...

The trisubstituted benzene 14 was used by Woodward as a starting material for his synthesis of the natural product reserpine.5 It too has to be made. We shall not add the MeO group but buy anisole (methoxybenzene) as starting material. Both nitrogens will be added by nitration but in which order ... 

Another fruitful means of identifying pharmacologically active natural products has been that of folk law remedies, many of which are plant products. Typical examples include alkaloids, such as atropine (from plants of the Solanaceae family, known to the ancient Greeks) and reserpine (from Rauwolfia serpentina, the snakeroot), which is popular in India as a herbal remedy for use as a tranquilizer or antihypertensive. Other chapters in the book relate to stigmines (based on phy-sostigmine, an anticholinesterase alkaloid from the Calabar bean in West Africa) that are used to treat Alzheimer s disease (Chapter 11-12), and opioid receptor ligands (based on morphine, the most important alkaloid of the opium poppy) for pain relief and as antitussives (Chapter 11-11). 

The occurrence of reserpine has been reported from all Rauwolfia species, with the exception of about half a dozen in which it is probably present in minute amounts. Renoxidine, the A-oxide of reserpine, has been isolated from R. vomitoria, R. serpentina, and R. canescens, and it may not be a natural product, since it could have been derived by autoxi-dation of the tertiary base which is abundant in these plants. If it was an artifact, the occurrence of other analogous A-oxides should have been noted, but so far the only other recognized case is raujemidine A-oxide, which is found along with the parent alkaloid, raujemidine (a minor base of R. canescens). In contrast to reserpine, deserpidine and rescinnamine are of restricted distribution, each being recognized so far in about ten species only. 

One of the most fascinating products containing multiple components is a combination of the natural product reserpine, hydralazine hydrochloride, and hydrochlorothiazide. This drug product is available in tablet form and contains 0.1 mg of reserpine USP, 25 mg of hydralazine hydrochloride, and 15 mg of hydrochlorothiazide (Fig. 6). Reserpine is an indole alkaloid derived from the dried root of Rauwolfia serpentina and is well known for its complex molecular architecture, the challenges faced during its total synthesis, and its profound effect on the central nervous system as an antihypertensive. Hydralazine is also an antihypertensive and hydrochlorothiazide has diuretic properties. The combination of these three very different molecular structures brings diversity to the analytical testing required. 

Pyrone-6-carboxylate 139 (Scheme 35) was shown to undergo an IMDA reaction to afford dihydrobenzofuranone 141, upon elimination of CO2 from the initially formed cycloadduct 140 <85CL151>. Analogously, the amide 142 produced 143, which was a key intermediate in syntheses of the natural products ( )-reserpine and ( )-yohimbine... 

Natural Product Sources. Approximately 70% of the drugs currently in human use originate from natural sources (3, 152). These include morphine, pilocarpine, phy-sostigmine, theophylline, cocaine, digoxin, salicylic acid, reserpine, and a host of antibiotics... 

When one considers the therapeutic impact of morphine, quinine, digitalis, ergot, atropine, cocaine, reserpine, and vincaleukoblastine, to name but a few, it is evident how great is the debt of medicine to plant-derived drugs even today. If one adds the synthetic derivatives and variants of plant-derived products, the role of natural products from plant sources has been most impressive. 

The class of indole alkaloids is so large that only a few of those that are physiologically active and pharmacologically important natural products can be mentioned here, e.g. strychnine, brucine (see p 462), yohimbine, reserpine, vincamine, ergotamine and lysergic acid. Some antibiotics are also derived from indole. 

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