Alkaloids deserpidine

Mariano et al. developed alkyne carbonester Claisen rearrangements as key steps in alkaloid syntheses. A convincing application of such a process was published in 1990 describing the total synthesis of the RauwoHia alkaloid Deserpidine 223 [34]. Isoquinuclidene 217 was synthesized in several steps starting from a dihydropyri-... 

The previously known reserpine-type alkaloids (3) are shown below. They are reserpine (109), deserpidine (110), rescinnamine (111), veneserpine (112), pseudoreserpine (113), raunescine (114), rescidine (115), raugustine (116), and isoraunescine (117). It should be mentioned that all reserpine-type alkaloids are trisubstituted at ring E and that the substituents at C-16, C-17, and C-18 are all in equatorial positions on the epiallo yohimbane ring system existing predominantly... 

Certain steps of Woodward s synthesis of reserpine have been modified by French (235, 236) and Czech (237-243) research groups. Deserpidine (110) has also been synthesized by the use of key building block 462 (240-242). Some approaches aiming toward the preparation of similar ring-E products have appeared (244-249) however, no alkaloid total synthesis was reported during the two decades following Woodward s work. 

After an interval of more than 20 years, a second synthesis of ( )-deserpidine and the achievement of some stereoisomers of ( )-raunescine (114) have been reported by Szdntay and co-workers (250,255). The basic idea of this linear total synthesis was similar to that utilized by them for the synthesis of yohimbine alkaloids. First, tetracyclic key intermediate 467 was prepared (253), in which the methoxy substituent of the side chain, on the one hand, represents the future C-18—O bond of the end product and will, on the other hand, control the regioselectivity of the Dieckmann ring closure. 

In 1918 the traditional Indian remedy rauwolfia was reported to be useful in the treatment of hypertension. Reexamination of this material led to the isolation of reserpine (28 R1 = Me, R2 = 3,4,5-trimethoxybenzoyl) which was shown in 1952 to have hypotensive and tranquilizing effects. Other alkaloids such as deserpidine (28 R1 = H, R2 = 3,4,5-trimethoxybenzoyl) and rescinnamine (28 R1 = Me, R2 = 3,4,5-trimethoxycinnamoyl) were later isolated. They are useful when alternative, more potent drugs are not well tolerated. 

Deserpidine (Harmonyl) is an alkaloid from Rauwolfia root. 

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. 

Reserpine. which is the major active constituent of Rauwol-fia, was isolated in 1952 and is a much weaker base than the alkaloids just mentioned. Reserpinuid alkaloids are yo-himbinc-like ba.ses that have an additional functional group on C-18. Only three naturally occurring alkaloids possess reserpine-like activity strong enough for use in treating hypertension re.serpine. deserpidine. and rescinnamine. 

In the rootbark of R. serpentina more than 50 indole alkaloids occnr. Only font have a hypotensive effect reserpine, rescinnamine, deserpidine and serpentine. 

According to their mode of action the Rauvolfia-alkaloids can be divided into two gronps the centrally acting reserpine, rescinnamine, and deserpidine and the peripherally acting yohimbine, raubasine and ajmaline. The blood pressure lowering effect is dne to an inhibition of the sympathomimetic effects in the autonomic nervous system and has a long latency and duration. The effect is dne to depletion of the serotonin and... 

The use of reserpine, rescinnamine, and deserpidine as mild antihypertensives, mostly in combinations, has become a standard treatment of today. The search for additional antihypertensive plant alkaloids which set in after the discovery of reserpine has not yielded any great results. Some extracts or crystalline material... 

Yohimbine alkaloids possess a characteristic pentacyclic indole skeleton. Representative members of the family include the rauwolfia (reserpine and deserpidine) and the yohimbines. A wide range of medicinal properties has been associated with these compounds and extensive studies have been carried out on the synthesis of the yohimbine alkaloids, including enantioselective syntheses [13,14]. In our approach, we view the acetylenic sulfoxide as a two-carbon synthon for the C3-C14 segment of the pentacyclic system (see 27). The chirali-... 

The pharmacological properties of deserpidine are similar to those of reserpine, causing sedation and tranquilization. Toxic effects from high doses include drowsiness, depression, nansea, diarrhea, abdominal cramps, and hypotension. It is less toxic than reserpine. However, the poisoning effects may be greater than those of other Rauwolfia alkaloids, such as rescinnamine. An oral LD50 value in mice is 500 mg/kg. 

The fission of the 2,3-bond in indole alkaloids, by means of formic acid and formamide, provides a route for the release of the d/e ring unit, and therefore a method for the interconversion of appropriate alkaloids. Thus, 2,3-seco-2,3-dihydroreserpine (127), prepared in this way from reserpine (126), reacts with trichloroethyl chloroformate to give mainly the urethane (128), reduction of which gives the d/e unit (129). Alkylation of (129) with tryptophyl bromide then gives 2,3-seco-2,3-dihydrodeserpidine (130), which one oxidation with mercuric acetate affords a low yield of deserpidine (131), together with a small amount of 3-wo-deserpidine (Scheme 19). "... 

The application of R. leads to a reduction in the levels of noradrenaline, dopamine, and serotonin in the synapses R. binds irreversibly to the transport system of noradrenaline (NA) so that the re-uptake of NA in the vesicles of the synapses is inhibited. Thus, transmission of stimuli is reduced, the blood pressure decreases with a concomitant central sedation. R. thus acts as a neuroleptic agent. The side effects of an overdose may include diarrhea, elevated secretion of saliva and gastric juices, depression, and Parkinson s disease. R. is suspected of being carcinogenic since in female patients an increased incidence of breast cancer seems to occur. The roots of R. serpentirm have been used in India for centuries as a sedative they also contain yohimbine. The first total synthesis was achieved by Woodward, for stereospecific synthesis, see Lit.. Deserpidine (11-demethoxyreserpine, canescine, recanescine, CsaHjgNjOg, Mr 578.64, cryst., mp. 228-230°C, [a]o-163° (pyridine) is also aRauvo/-fia alkaloid it exists in polymorphic forms and also lowers the blood pressure. 

It is a common knowledge that plants are useful sources of many valuable medicines. Among these medicines several indole alkaloids can be found, e.g. reserpine and deserpidine from Rauwolfia serpentina ajmalicine and yohimbine from Corynanthe yohimhe vinblastine and vincristine from Catharanthus roseus just to mention a few of them. 

With this new development in synthetic methodology, we have picked our target in yohimbine group of alkaloids including yohimbine, alloyohimbine, deserpidine, and reserpine, which are well known as clinically useful medicinals. 

Reserpine is found in the roots of Rauwolfia serpentina (Apocynaceae) along with the related alkaloids resicinnamine, deserpidine and ajmaltne. The main actions are hypotensive, sedative and tran-quillising. Ajmaline is of benefit for heart arrhythmias (Samuelsson 1992). 

The closely related alkaloids rescinnamine (XLV, R = 3,4,5-trimethoxy-cinnamyl Fig. 3) [982, 1030-1043] and deserpidine (11-desmethoxyreserpine) [982,1036-1039,1042,1044-1047] exhibit similar, though less potent, sedative and hypotensive properties to reserpine and they have seen clinical apphcation. In the synthetic compound methoserpidine the hypotensive properties are free from accompan5dng sedation provided only moderate doses are given [1048 to 1050], while the reserpic acid di-ester syrosingopine, exerts a mild h3 otensive effect with practically no accompanying sedation [1050-1057]. 

Members of the yohimbine alkaloid family possess a characteristic penta-cyclic indole skeleton 1. Representative compounds in this family include the Rauwolfia alkaloids, such as reserpine (2) and deserpidine (3), and the yohimbines (4-9). These compounds exhibit a wide range of medicinal properties (1,2). Reserpine, for example, has been used extensively in the treatment... 

By using this same Dieckmann cyclization strategy. Wenkert and his coworkers have accomplished a synthesis of raunescine (288) (Scheme 3.54) (58). Accordingly, ketoester 319 was benzylated to provide enol ether 325. Sequential reduction of the double bond and ketone of 325 by the protocol employed in the deserpidine synthetic route provided the C(18) alcohol 326. Acylation of the hydroxyl group and hydrogenolysis gave raunescine. Similar to the efforts of Szantay, Wenkert s investigations clearly demonstrate how Dieckmann cyclization chemistry can be applied to the synthesis of a variety of yohimbine alkaloids. 

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. 

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