Stereochemistry reserpine synthesis

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... 

A new method, reported by Pearlman (262), for the preparation of Woodward s key building block also constitutes a new synthesis of reserpine as well as deserpidine. In the key step of the synthesis an internal (2ir + 2-tt] photocycliza-tion of dienone 518 gave cyclobutane derivative 519 with the established stereochemistry. Methanolysis and subsequent peracid treatment of 520 yielded lactone ester 521. Repeated methanolysis and retroaldol fission of the cyclobutane... 

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. 

In the original synthesis, there still remained three problems (a) conversion of the 3-iso compound into the 3-normal (b) replacement of the 18-0-acetate by a trimethoxybenzoyloxy group and (c) the resolution of the racemic alkaloid. The last two problems require no detailed comments, but the solution provided for the first led to the reserpine configuration, resulting in an unequivocal proof of the stereochemistry at C-3. The lactone of dCisoreserpic acid was prepared, and this, upon refluxing in pivalic acid, was converted into the thermodynamically... 

During the synthesis of the Woodward reserpine precursor (17 Scheme 4), Peailman used the protected acylacetal (13) to control the stereochemistry of an intramolecular photochemical cycloaddition to (14). The strategy for opening the cyclobutane ring employed the Baeyer-Villiger reaction to convert the 7-keto ester (15) to a 3-hydroxy ester (16), which underwent retroaldolization to (17). 

As a route to the c/5-hydroisoquinoline moiety of reserpine-type indole alkaloids, further additions to dihydropyridines have been investigated. Following successful [4 -I- 2] cycloaddition to acrolein, subsequent elaboration permitted selective generation of the required stereochemistry by Cope rearrangement (Scheme 4). Investigations aimed at the synthesis of Erythrina alkaloids have... 

In 1933, Chopra et al. found that a crystallized alkaloid isolated from the roots of this plant showed hypotensive activity [1]. Subsequently, reserpine, an alkaloid possessing sedative activity, was isolated and characterized in 1952 [2].The chemical structure,including stereochemistry, was determined subsequendy [3,4], and the first total synthesis of reserpine [5] was achieved by Woodward et al. 

The projected free radical cyclization proceeded as planned to give 172. Ozonolysis of the vinyl group, oxidation of the resulting aldehyde to an acid, and alkylation with diazomethane provided projected intermediate 162. Reduction of the lactone provided 173. Treatment of 173 with 6-methoxytryptamine and pivalic acid then provided a nearly equal mixture of lactams 174 (isoreserpine stereochemistry at Cg) and 175 (reserpine stereochemistry at C3). The correct C3 stereoisomer was moved forward to 176 (protection of the tertiary alcohol followed by reduction of the lactam). The silyl ethers were removed, the secondary ether was re-protected, and reaction with samarium iodide accomplished reduction of the a-hydroxy ester to provide 177. Removal of the TBS group and esterification of the alcohol completed the synthesis of reserpine. 

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. 

The route employed to prepare indanone 51 involved the cycloaddition-hydrolysis-aldol sequence shown in Scheme 3.9. Accordingly, condensation of cyclopentenone 52 with ynamine 53 (84) afforded the bicyclic enamine 54 which was converted to indanones 51 and 55 by hydrolytic cyclobutane ring opening followed by intramolecular aldol condensation. Interestingly, treatment of 54 with aqueous formic acid yielded indanone 51 which has stereochemistry complementary to that at C(15) and C(20) in reserpine. In contrast, hydrolysis of this substance with aqueous hydrochloric acid afforded the trans-fused indanone 55. Subsequent to this work, the Ficini group found that esterification of 51 followed by photochemically induced addition of methanol afforded adduct 56 which has four of the reserpine stereocenters in place (23). While no further work on this problem has been reported, these preliminary investigations demonstrate a novel use of [2 -h 2] photocycloaddition chemistry in potential approaches to yohimbane alkaloid synthesis. 

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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