Reserpine oxidation products

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 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... 

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). 

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. 

Lang et al. reported the use of a post-column air-segmented reactor to enable fluorimetric detection of reserpine. As oxidizing reagent sulfuric acid - sodium nitrite was used, which converted reserpine into 3,4-dehydroreserpine. The reaction product was detected by measuring emission above 470 nm after excitation at a wavelength of 395 nm. 

Oxidative cyclization of 135 occurred with little regioselectivity. Oxidation at C3 afforded isoreserpine analog 136, and a nearly equal amount of material derived from oxidation at C21 was obtained (so-called inside isomers). Based on earlier work, it is probable that the sequence of events leading to 136 involve oxidation of 135 to an iminium ion, cyclization via an electrophilic aromatic substitution reaction, oxidation of the resulting cyclized products to an iminium ion related to 105 (see Alkaloids-13) and finally, reduction (NaBH4) of that iminium ion to provide 136. Conversion of 136 to isoreserpine (140) was relatively straightforward. I will leave the details to you (see problems for guidance). Since isoreserpine had previously been converted to reserpine (see Wooward synthesis for example), this constituted a synthesis of 79. 

Reserpine is oniy siowiy oxidized to the corresponding iminium ion by Hg ". Therefore the reserpine (or a portion ofthe reserpine) represents a kinetic cyciization product. 

The Martin group used an oxidation-reduction sequence that was similar to that used by Wender. The reaction conditions, however, were slightly different and Zn-perchloric acid was used in the reduction step rather than sodium borohydride. The results differed from those obtained by Wender in that reserpine (79) was the major product and isoreserpine (140) the minor product. Inside isomers were also obtained due to lack of regioselectivity in the mercuric acetate oxidation. 

Nonetheless, electrochemical reactions of the analytes under study in an ES-MS experiment can and do take place, and these reactions can substantially alter the analytes such that the ions observed in the gas phase have a different mass and/or charge than the species originally in the solution (Table 3.3). Many fundamental smdies of the electrochemical processes in ES have made use of analytes that are relatively easy to oxidize/ reduce and have both stable oxidized and reduced forms that differ in mass, each of which can be detected in the gas phase by ES-MS. Some compounds of this type that we have used include various metalloporphyrins, aniline dimers, the dyes thionine and methylene blue, and the drug reserpine. >>>>>> The ability to observe both the starting material and the redox products with compounds of this type enhances the abUity to smdy the electrochemical reactions that occur. These same molecules and those others with similar redox character are potentially those that can be altered unexpectedly in an ES-MS experiment. 

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