Reserpine Woodward

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. 

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... 

In the post-World War II years, synthesis attained a different level of sophistication partly as a result of the confluence of five stimuli (1) the formulation of detailed electronic mechanisms for the fundamental organic reactions, (2) the introduction of conformational analysis of organic structures and transition states based on stereochemical principles, (3) the development of spectroscopic and other physical methods for structural analysis, (4) the use of chromatographic methods of analysis and separation, and (5) the discovery and application of new selective chemical reagents. As a result, the period 1945 to 1960 encompassed the synthesis of such complex molecules as vitamin A (O. Isler, 1949), cortisone (R. Woodward, R. Robinson, 1951), strychnine (R. Woodward, 1954), cedrol (G. Stork, 1955), morphine (M. Gates, 1956), reserpine (R. Woodward, 1956), penicillin V (J. Sheehan, 1957), colchicine (A. Eschenmoser, 1959), and chlorophyll (R. Woodward, 1960) (page 5). ... 

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

Gomez, A.M., L6pez, J.C., Fraser-Reid, B. (1994) Serial Radical Cyclization ofPyranose-Derived Dienes in the StereocontroUed Synthesis of Densely Functionalized Cyclohexanes. A Route to Woodward s Reserpine Precursor. Journal of Organic Chemistry, 59, 4048M 050. 

Mehta, G. Reddy, D.S. (2000) A Formal Synthesis of Reserpine Hydrindane Approach to the Woodward s Ring-E Precursor. Journal of the Chemical Society Perkin Transactions J, 1399-1404. 

Reserpine (R. B. Woodward) a clinically used antipypertensive agent. 

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 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... 

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. 

In the synthesis of reserpine by Woodward (see Scheme 8.5) the stereochemical control of the five chiral centres follows a more elaborated route, but equally efficient and elegant. 

Woodward then moved across town in Cambridge to devote a year of postgraduate study at Harvard University. At the end of that year, he accepted an appointment to the Harvard chemistry faculty, a post he held for most of the rest of his life. One of his great interests at Harvard was the synthesis of large, complex molecules, the first of which was quinine in 1944. He followed that work with the elucidation of other molecular structures and the development of synthetic methods for each. Included among these molecules were penicillin (1945), patulin (1948), cholesterol and cortisone (1951), oxytetracycline (1952), strychnine (1954), lysergic acid (1954), reserpine (1956), chlorophyll (1960), colchicine (1963), cephalosporin C (1965), and vitamin (1971). 

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]. 

Scheme (11). The final stages of Woodward s reserpine synthesis.

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... 

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... 

An ingenious new method for the preparation of Woodward s intermediate (97) by Pearlman70 constitutes another formal synthesis of reserpine. The essence of this new approach is an adaptation of the de Mayo reaction which allows the introduction of vicinal aldehyde and acetic ester functions on to a double-bond (Scheme 13). An internal [2tt + 27r] photocyclization of the diene (98) gave the tetracyclic cyclobutane derivative (99), which was converted into the ester (100) by standard procedures. Methanolysis of the acetate function with concomitant retro-aldol fission completed the introduction of the vicinal aldehyde and acetic ester functions obvious manipulation then gave the desired intermediate (97). 

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 -... 

The trisubstituted benzene 14 was used by Woodward as a starting material for his synthesis of the natural product reserpine.5 It too has to be made. We shall not add the MeO group but buy anisole (methoxybenzene) as starting material. Both nitrogens will be added by nitration but in which order ... 

Fraser-Reid and co-workers have examined serial radical cyclization of pyranose-derivatives [95AJC333] in the stereocontrolled synthesis of Woodward s reserpine precursor [95JOC3859]. Treatment of the bromosilane 188 under reductive conditions resulted in a 5-exo followed by a 6-exo cyclization. The intermediate radical eliminates phenylsulfinyl radical to provide the alkene 189 as the product. The intermediate has been converted to the reserpine precursor 190. The temporary silicon method has been utilized for the synthesis of brassinolide side chain [95SL850]. 

The Diels-Alder condensation of p-benzoquinone with vinylacrylic acid gives a cis decalin adduct (XXXIV), which is a prerequisite for the desired DE ring junction of the reserpine molecule. This cis configuration is preserved by proper choice of reagents, and in only one single instance has a transformation into a trans decalin been reported (186). In his modified route, Woodward has used methyl acrylate instead of the free acid, and others have used the corresponding ethyl or isopropyl esters (187, 186). 

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