Reserpine conformation

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 relationship between 20 and reserpine (1) is close like reserpine, intermediate 20 possesses the linear chain of all five rings and all six stereocenters. With the exception of the 3,4,5-tri-methoxybenzoate grouping, 20 differs from reserpine (1) in one very important respect the orientation of the ring C methine hydrogen at C-3 in 20 with respect to the molecular plane is opposite to that found in reserpine. Intermediate 20 is a reserpate stereoisomer, epimeric at position 3, and its identity was secured by comparison of its infrared spectrum with that of a sample of (-)-methyl-O-acetyl-isoreserpate, a derivative of reserpine itself.9 Intermediate 20 is produced by the addition of hydride to the more accessible convex face of 19, and it rests comfortably in a conformation that allows all of the large groups attached to the D/E ring skeleton to be equatorially disposed. 

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. 

After opening the lactone ring with NaOMe, rings and substituents take up the original conformations. Esterification of the free OH group gives finally reserpine (9). 

The opening of the epoxide in the cij-decalin 24 by acetic acid leads exclusively to the hydroxyacetate 25 (through a kinetically controlled rrani-diaxial opening) rather than to the wanted diastereomer 26 (c/ the stereochemistry of the "southern" part of reserpine). To obtain the correct diastereomer the epoxy-lactone 22 is first formed (Scheme 8.6). Thus the conformation of the cij-decalin system, and therefore that of the substituents, is reversed. The kinetic tran -diaxial opening of the epoxide occurs in a regio- and stereoselective manner to afford compound 28 in which the substituents have the correct position and configuration (a-OH, P-OAc),... 

Reserpine (1) epimerizes to isoreserpine (2) with great ease to give a ratio of 15 85 [18]. Hence, isoreserpine is the more stable epimer. The empiric result can be verified by stereochemical and conformational analysis. In reserpine (1) the conformational equilibrium is shifted to... 

The acid-catalysed epimerization reaction often contributes to the change of conformation that alters the sterical shape of a compound. This may have a severe effect on pharmacological properties as with reserpine (1) and isoreserpine (2). The same seems to apply to the C-3 epimers yohimbine (78) and pseudoyohimbine (79). Yohimbine (78) blocks ai-receptors, whereas pseudoyohimbine (79) has little affinity for this... 

Darchen F, Scherman D, Henry JP (1989) Reserpine binding to chromaffin granules suggests the existence of two conformations of the monoamine transporter. Biochemistry 28 1692-1697. 

Much of the chemistry of reserpine and its congeners becomes clear and compelling if the conformational mobility of the CDE rings of its 3-epialloyohimbane nucleus is remembered (134). It was the gradual realization of this property and how to take advantage of it that led to the very elegant experiments which established the complete relative stereochemistry of the reserpine molecule (135, 136). Not unexpectedly, it is found that reserpine under normal conditions prefers the cis-trans-cis CDE conformation (137, 138), but this does not prevent it from assuming the trans-trans-cis shape to make possible the formation of reserpic acid lactone (125) and the quaternary salt III (136). 

Fio. 1. A stereodiagram showing the structure and conformation of reserpine (6), one of the first crystal-structure determinations without the presence of a heavy atom. The ellipsoids represent the thermal motions of the atoms, drawn at the 50% probability level. 

Cope substrates derived from bicyclo[2.2.2]oct-5-en-2-ones with an fWo vinyl group undergo Cope rearrangements via boatlike transition state conformations to yield cw-fused decalins, as exemplified by the rearrangement of 1107S. Product 4 is used in the synthesis of lucidu-line 1075,1076, and 6 in the synthesis of reserpine 1077 1078. 

The n.m.r. spectrum of reserpine in the presence of the europium shift reagent is interpreted" in terms of a boat-shaped conformation of ring c. 

Kasturi (1963) has presented some infrared data concerning alkaloids. Among the compounds were quinozilidine alkaloids, methyl neoreserpate, 3-epialloyo-himbone, and 3-epialloyohimbine (conformational data). Other compounds mentioned were the tobacco alkaloid myosmine the substances histisine, angustifoline, recanescine, and reserpine other Rauwolfia alkaloids some Vinca alkaloids and powellane. Neuss (1959) has also supplied data on indole and dihydroindole alkaloids. 

The plan revolves around the notion that the indole should kinetioally add to an iminium ion such that carbon-carbon bond and lone-pair are developed with an anf/ -periplanar reiationship. This can occur in two ways. If the C-ring is born as a chair (with the requisite anti-periplanar relationship), the resulting product is reserpine. If the C-ring is born as a boat, the result is isoreserpine. Although isoreserpine is more stable than reserpine, the presumed conformations in which they would be born would favor reserpine over isoreserpine. This assumes that product partitioning is controlled by kinetics (is not reversible). The "key intermediate" also deals nicely with regiochemical issues. Three syntheses of the key intermediate were described. We will examine only one of these. 

One of these compounds (8b) was considerably more potent than amitriptyline in preventing reserpine-lnduced ptosis in mice and rats. Other phenothlazines with antidepressive actions Included 8c, the 1-chloro-analog of chlorpromazine, which produced imlpramine-like actions in mice and rats, and the azaphenothiazine-lO-thiolcarboxylate which induced antidepresslve-llke symptoms (mydriasis, Increased sensitivity to touch) in mice. The antidepressive effects of phenothiazine derivatives with 1- or oc-substituents may be associated with the steric influence of these groups in interfering with attainment of a nearly flat conformation by the tricyclic system. ... 

Three aspects of their chemistry are important 1. The stereochemistry at C-3 its determination and control. 2. The chemistry of ring E (of the substituents in the case of the seco alkaloids). 3. The determination of the configuration and conformation of the ring systems. The solution to these problems was greatly accelerated in the years following 1952 because of the discovery and commercial importance of the antihypertensive drug, reserpine, a derivative of 3-epialloyohimbane (see Chart 5.3). 

Woodward designed a clever solution to obtain the desired C(3)-epimer. He reasoned that if 25 could be locked into conformation 25A in which the E-ring substituents are axially disposed, epimerization at C-3 under equilibrating conditions would furnish the reserpine 3) -H stereochemistry since it would alleviate the strain engendered by the axial bulky indole moiety. In the event, Woodward converted 25 to lactone 26 which enforces the E-ring triaxial conformation. As predicted, when exposed to pivalic acid in refluxing xylenes, 26 cleanly epimerized to produce epimer 27 having the desired ster-... 

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