Reserpine oxidation

Kertesz, V., and Van Berkel, G. J. (2004). Investigation of reserpine oxidation using on-line electrochemistry/electrospray mass spectrometry. Poster presented at 52nd ASMS Conference on Mass Spectrometry and Allied Topics, Nashville, TN. 

The indole alkaloids of the yohimbine-reserpine series exist in four configurations normal (74), alio (75), pseudo (76), and epiallo (77). The results of the mercuric acetate oxidation of the indole alkaloids are in general... 

A new multistep synthesis of ( )-reserpine (109) has been published by Wender et al. (258). The key building block of the synthesis is cw-hexahydroiso-quinoline derivative 510, prepared by the extension of the previously elaborated (259) Diels-Alder addition-Cope rearrangement sequence. Further manipulation of 510 gave 2,3-secoreserpinediol derivative 512, which already possesses the required stereochemistry in ring E. Oxidative cyclization of 512 yielded 3-isoreserpinediol (513), which was transformed by the use of simple reaction... 

Oxidation of reserpine (109) with iodosobenzene diacetate in alcoholic medium (284) afforded in a single step the corresponding 7-alkoxyindolenine derivatives... 

A new convergent total synthesis of reserpine (109) has been developed by Martin and co-workers (399). In the first phase of the synthesis they constructed the trisubstituted cis-decahydroisoquinoline 549 as the key intermediate by utilizing a number of stereoselective reaction steps as shown in Scheme C. N-Alkyla-tion with 6-methoxytryptophyl bromide and subsequent oxidative cyclization of 547 resulted in reserpine (109) and 3-epireserpine (514). 

Other analyses done on serum samples include the use of RPC for the determination of cannabinoids (555) in post mortem analyses of fatally injured drivers (556). Reserpine was analyzed by ion-pairing subsequent to oxidation to a fluorophore (557). 

C. Amphetamine is an indirectly acting adrenomimetic amine that depends on the release of norepinephrine from noradrenergic nerves for its action. Tlius, its effect depends on neuronal uptake (blocked by cocaine) to displace norepinephrine from the vesicles and the availability of norepinephrine (depleted by reserpine). The substitution on the a-carbon atom blocks oxidation by monoamine oxidase. With no substitution on its benzene ring, amphetamine resists metabolism by COMT. 

The oxidation probably involves a mercurated complex through the electron pair on nitrogen followed by a concerted removal of a proton from the a-carbon and then cleavage of the mercury-nitrogen bond. The suggestion that a trans elimination occurs is reinforced by the evidence that yohimbine can be hydrogenated by mercuric acetate, whereas reserpine methyl reserpate, deserpine, or pseudoyohimbine does not react [122]. 

The oxidation of primary and secondary alcohols by stable organic nitroxyl radicals has been reviewed.111 The kinetics of reactions of alkanes and arenes with peroxynitrous acid suggest the participation of the same active oxidizing species in both gas and aqueous phase HOONO or its decomposition product OONO. 112 The oxidation of the alkaloids reserpine and rescinnamine by nitric acid has been studied.113... 

Fraser-Reid s stereocontrolled synthesis of the Woodward reserpine precursor 195 relied upon a tandem 5-exol6-exo radical cyclization of pyranose-derived dienes [76-77]. As outlined in Scheme 36, a,P-unsaturated ester 188 was prepared by free radical coupling of iodide 187 with a tin acrylate. After hydrolysis of 188 (MeONa, MeOH, 100%) to give primary alcohol 189, the silicon tethered diene 190 was installed by silylation. Treatment of 190 with n-BujSnH led to the desired cage molecule 192 in high yield via a 5-exo-trig cyclization to intermediate 191 followed by a 6-exo cyclization. Tamao oxidation of tricycle 192 led to diol... 

Indoles are very important in medicinal chemistry. The indole moiety is electron-rich so it is very easily oxidized. One example of severe cleavage of the indole ring is the oxidation of tryptophan to V-formylkynurenine. An example of milder oxidation of indoles is reserpine degradation. Reserpine, an indole alkaloid, spontaneously decomposes in chloroform solution to give oxygenated products (58) (Fig. 11). Reserpine 7-hydroperoxide (XIV) was isolated in the reaction mixture this is the key intermediate in the oxidative pathways of many indoles (59). 

In contrast to the oxidative reactions discussed above, the only reported biotransformations of reserpine (21) and rescinnamine (23) (42-44) appear to involve hydrolytic processes. Reserpine is readily metabolized by liver homogenates from the mouse (43), rat, guinea pig, dog, and cat (44) to yield methyl reserpate (22) and 3,4,5-trimethoxybenzoic acid in yields of up to 70% (43). The use of reserpine labeled with tritium in the 2 and 6 positions of the trimethoxybenzoate residue indicated that no significant metabolism of reserpine by another route occurred before hydrolysis, reserpine and 3,4,5-trimethoxybenzoic acid being the only detectable radioactive components of the incubation mixture at the conclusion of the reaction (44). An... 

In common with other indole derivatives, reserpine is susceptible to decomposition by light and oxidation, so it must be stabilized. Modifying the trimethoxyphenyl portion of the molecule gives other antihypertensive drugs with various potency and rapidity of action. 

A new synthesis of reserpine (Scheme 19)60 makes use of a very neat synthesis of cw-hydroisoquinoline derivatives, e.g. (Ill), by means of a Diels- Alder /Cope rearrangement sequence. Manipulation of (111) by unexceptional methods then gives (112), which possesses the required stereochemistry in ring E. Oxidative cyclization of (112) affords 3-isoreserpinediol (113) but, unfortunately, some inside isomer, originating from the cyclization of C-2 with C-21, is also obtained. The synthesis also loses some elegance in the multi-stage conversion of 3-isoreserpinediol into 3-isoreserpine (114), since, in the Swem oxidation of the C-16 aldehyde cyanhydrin by means of DMSO with oxalyl chloride as activator, the over-oxidized products (115) and (116) were obtained. However, reduction of (115) gave 3-isoreserpine (114), which has previously been converted into reserpine by four different methods. 

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. 

At an early date it was already recognized that the ketone (IX) derived from an oxidation of the C-18 carbinol function of methyl reserpate could be of considerable utility for further transformation of the reserpine pentacyclic ring system, but early attempts at the preparation of the desired compound by conventional oxidation, e.g., by Oppenauer s method, AAchlorosuceinimide, sodium dichromate, or chromic oxide in pyridine, were unsuccessful with both methyl reserpate and methyl 18-epireserpate. The ketone was finally obtained by heating methyl reserpate p-bromobenzene sulfonate with dimethyl sulfoxide in the presence of triethylamine (162), a method successfully used for simpler compounds (163). Subsequently, it was found that this oxidation could also be realized with other benzene sulfonate esters of methyl reserpate and 18-epireserpate. That the stereochemistry of the molecule was unaffected was proved by sodium borohydride reduction of the ketone, which gave equal amounts of methyl reserpate and its 18-epimer. This and other simple reactions of the ketone are sketched in Chart III, and additional observations will be given. 

For example, yohimbine containing an a-oriented axial hydrogen at C3 can be dehydrogenated by mercuric acetate, whereas reserpine or pseudoyohimbine with /1-oriented hydrogen does not react305,309-312. Sparteine (83) is oxidized to a mixture of isomers A5,11-didehydrosparteine (84) and A5-dehydrosparteine (85). The other two stereoisomers of sparteine, i.e. a-isosparteine (86) and jS-isosparteine (87) dehydrogenate to 84290,313-315. 

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