Reserpine total synthesis

The Woodward total synthesis of reserpine is an inspirational accomplishment that will, no doubt, remain a classic in the history of total synthesis.10... 

Pearlman, B.A. (1979) A Total Synthesis of Reserpine. Journal of the American Chemical Society, 101, 6404-6408. 

Hanessian, S., Pan, J., CarneU, A., Bouchard, H., Lesage, L. (1997) Total Synthesis of (—)-Reserpine Using the Chiron Approach. Journal of Organic Chemistry, 62, 465-473. 

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

Some indolo[2..w/]c iiinolixidines undergo easy acid-catalyzed epimerization <1998H(50)243>. For instance, the alkaloid reserpine equilibrates to a mixture of starting material and its 3-epimer, isoreserpine, under acid or basic catalysis (Equation 6). A controlled epimerization of this type has been employed as the key step in a total synthesis of ( )-tacamonine <1998T157>. 

In total syntheses where a homogeneously catalyzed transfer hydrogenation is applied, almost exclusively aluminum(III) isopropoxide is utilized as the catalyst. At an early stage in the total synthesis of (-)-reserpine (65) by Woodward [106], an intermediate with two ketone groups and two C-C double bonds is formed (66) by a Diels-Alder reaction of para-benzoquinone (67) and vinylacry-late (68). The two ketone groups were reduced with aluminum(III) isopropoxide... 

The first total synthesis of (-)-reserpine (109) was published in 1956 and 1958 by Woodward and co-workers (233, 234). Although this ingenious work has already been reviewed in The Alkaloids (3), it is worthwhile to present the reaction sequence to recapitulate this convergent approach. 

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. 

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). 

The importance of conformational analysis is made evident, for instance, in the total synthesis of reserpine (9) in which Woodward [6] introduced conformational stereochemical control, in two versions thermodynamic control and kinetic control. 

Dihydropyridines have also been starting points for stereospecific syntheses of hydro-phenanthridines and isoquinolines. Interest exists in these compounds because of the occurrence of this structural feature in alkaloids. For example, isoquinuclidine (263), derived from JV-alkoxycarbonyl-l,2-dihydropyridine, undergoes a Cope rearrangement to give the isoquinoline derivative (264) (80JA6157). Further chemical transformations of (264) provided a formal total synthesis of reserpine (Scheme 50). 

In 1955, Wenkert and Liu [10] proposed a mechanism for the acid-catalysed C-3 equilibration of alio- and epialloyohimbane (Mechanism 3). Three years later, in 1958, two other mechanisms (Mechanisms 1 and 2) were introduced by Woodward and co-workers in connection with the first total synthesis of reserpine (1) [11]. 

Reserpine (1) with its remarkable pharmacological properties remains an attractive synthetic target. The first total synthesis of reserpine (1), by... 

In the course of the first total synthesis of reserpine (1), Woodward and co-workers [11] obtained an isoreserpine derivative instead of a reserpine derivative (see above). Thus, the problem arose of how to epimerize with good yield the more stable isoreserpine derivative to a reserpine... 

In the total synthesis of reserpine, Woodward and collaborators (10) have reported that the quaternary iminium salt J8 was reduced with aqueous metha-nolic sodium borohydride to methyl 0-acetyl isoreserpate 09). This is the anticipated product whether the stereochemical sense of the reaction is subject to steric or thermodynamic control as pointed out by Woodward. It is also the expected one on the basis of stereoelectronic control. 

The structure (facing page) was confirmed by the total synthesis of Reserpine (1-3). 

The total synthesis of reserpine was achieved by Woodward et al. (1-3) in 1956. The remarkable Woodward s synthesis of reserpine is summarised as follows -... 

Cycloadditions. This reagent serves as a formyl acetic ester equivalent in [2 + 2] cycloadditions with alkenes. The addition provides a new method for vicinal attachment of carboxaldehyde and acetic ester appendages to double bonds (e.g., 2->5). An intramolecular version of this reaction was used in a total synthesis of reserpine. ... 

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. 

In the total synthesis of reserpine, Woodward and co-workers selectively oxidized the double bond of 15 that is on the exposed convex face of the molecule. Attack from the concave side of 15 is hindered.14... 

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