Pseudo alkaloids

Amines are simple compounds derived from ammonia (NH3) in which one or more hydrogen atoms is replaced by carbon. Replacement of one, two or three hydrogen atoms results in primary, secondary and tertiary amines respectively. Amino acids and alkaloids are derived from amines however, in one group of alkaloids the only nitrogen atoms occur in the amino side group attached to a benzene ring—they are not heterocyclic. Hence alkaloidal amines are often regarded as pseudo alkaloids . The precursors for alkaloidal amines are aromatic amino acids—phenylalanine, tyrosine and tryptophan. 

There are now known a eonsiderable number of alkaloids containing two distinct woquinoline nuclei, such as emetine and its congeners (p. 394), and in the morphine sub-group, -morphine, dithebainone (p. 255), disinomenine and its pseudo-isomeride (p. 268). The most important collection of such alkaloids is the bisbenzylwoquinoline or biscoclaurine section of which the following two alkaloids, berbamine and oxyacanthine, are examples, but which is typically developed in the Menispermaceas. 

Pseudo ademno calima elegans. This toxic Brazilian plant was found to contain a laevorotatory alkaloid, mol. wt. 527, [a]i, — 20°. (Mello and Fernandes, Reu. soc. brasil. quim., 1940, 9, 155.)... 

Smilax pseudo-china (Tu-fu-ling). Among other products, probably alkaloids. (Liu and Kuo-Chen Chen, J. Chinese Chem. Soc., 1945, 12, 122 Chem. Abstr., 1946, 40, 3851.)... 

The indole alkaloids of the yohimbine-reserpine series exist in four configurations normal (74), alio (75), pseudo (76), and epiallo (77). The results of the mercuric acetate oxidation of the indole alkaloids are in general... 

Hantzsch 2 gave the name pseudo bases to those carbinols that gave salts with acids by the elimination of water and a simultaneous change of constitution. Such carbinols are common among the nitrogen heterocyclic compounds and the naturally occurring alkaloids e.g., berberine, sanguinarine, chelerythrine. 

Quaternization of harman (235) with ethyl bromoacetate, followed by cyclization of the pyridinium salt 236 with 1,2-cyclohexane-dione in refluxing ethanol yielded an ester which on hydrolysis gave the pseudo-cross-conjugated mesomeric betaine 237. Decarboxylation resulted in the formation of the alkaloid Sempervirine (238). The PCCMB 237 is isoconjugate with the 11/7-benzo[u]fluorene anion—an odd nonalternant hydrocarbon anion—and belongs to class 14 of heterocyclic mesomeric betaines (Scheme 78). 

Both quinine and dihydroquinine favored the required (S)-enantiomer. A small ee difference of the product might be due to inconsistent purity of the naturally obtained cinchona alkaloids. It was noted that quinidine (the pseudo-enantiomer of quinine) gave the (R)-enantiomer with a similar 55% ee. Since quinine was... 

Pseudo Series. Besides the previously known pseudoyohimbine (88), there is only one additional alkaloid found in Rauwolfia capuroni Mgf. (68) that belongs to the pseudo series, namely, 11-methoxypseudoyohimbine (89). 

Recently Isolated Yohimbine Alkaloids with Normal or Pseudo Skeletons and Their Primary Sources... 

Dihydrocorynantheol (21), first isolated from Aspidosperma marcgravianum (147), is the simplest corynanthe alkaloid. The members of this type of alkaloid have three stereo centers in the D ring of the indolo[2,3-a]quinolizine skeleton. This substitution pattern allows four possible relative arrangements for the C-3, C-15, and C-20 stereo centers, the names of which are normal, pseudo, alio, and epiallo, respectively. 

The utilization of the Robinson annellation method for the synthesis of cory-nanthe-type alkaloids has been thoroughly investigated by Kametani and coworkers (149-152). The tetracyclic ring system was efficiently formed via the Michael addition of dimethyl 3-methoxyallylidenemalonate (247) to the enamine derived from 3,4-dihydro-1 -methyl-(3-carboline (150). Alkylation of 248, followed by hydrolysis and decarboxylation, resulted in a mixture of stereosiomeric enamides 250 and 251. Hydrogenation of 250 afforded two lactams in a ratio of 2 1 in favor of the pseudo stereoisomer 253 over the normal isomer 252. On the other hand, catalytic reduction of 251 gave 254 as the sole product in nearly quantitative yield. Deprotection of 254, followed by lithium aluminum hydride reduction, yielded ( )-corynantheidol (255) with alio relative configuration of stereo centers at C-3, C-15 and C-20. Similar transformations of 252 and 253 lead to ( )-dihydrocorynantheol and ( )-hirsutinol (238), respectively, from which the latter is identical with ( )-3-epidihydrocorynantheol (149-151.). 

From lactams 266 and 267 the 18,19-didehydro alkaloid corynantheal (258) and its stereosiomers with pseudo and epiallo configurations have also been prepared in racemic form (154). 

Several inhibitors of AChE have been developed for use in treating Alzheimer s disease, which requires that the drugs readily enter the CNS. These inhibitors are structurally unrelated and vary in their mechanism of inhibition, although all are reversible inhibitors. Tacrine (Cognex) is a monoamine acridine. Donepezil (Aricept) is a piperidine derivative that is a relatively specific inhibitor of AChE in the brain, with little effect on pseudo-ChE in the periphery. Galanthamine (Reminyl) is a tertiary alkaloid and phenanthrene derivative extracted from daffodil bulbs that is a reversible competitive inhibitor of AChE it also acts on nicotinic receptors. 

Similar correlations exist between the stereochemistry of yohimbines and related indole alkaloids and the appearance of bands in the 2800-2600 cm 1 region of their IR spectra.130 All compounds possessing an a-hydrogen at C-3, i.e., normal (82) and alio (83) compounds, show two or more distinct and characteristic peaks of medium intensity on the low wave-number side of 2800 cm 1 in addition to the normal C—H stretching bands. Those compounds having a jff-orientation of the C-3 hydrogen, i.e., pseudo (84) and epiallo (85) compounds such as / -yohimbine, ( + )-epialloyohimbane, and 3-isoajmalicine, exhibit only shoulders on the low wave-number side of the main C—H band. 

Tetrahydroisoquinoline-l-carboxylic acids have been anodically decarboxylated in MeOH-NaOMe on a graphite felt anode, giving 3,4-di-hydroisoquinolines (50-90%)417 This may be an example of a pseudo-Kolbe reaction in support of Hahn s theory of the biosynthesis of isoquinoline alkaloids by providing a laboratory analogy for the crucial decarboxylation step. 

Hirsutine (85) is a corynantheine-type indole alkaloid with a C/D cis ring juncture (pseudo stereochemistry). This compound has recently been found to exhibit highly potent inhibition of the replication of the strains of influenza A (subtype H3N2) [63]. The EC50 of hirsutine was 11- to 20-fold more potent than that of the clinically used ribavirin. Exploration of the important structural features of this molecule revealed that the stereochemistry at C-3 (.R) and C-20 (R) as well as the presence of the Nb lone pair were essential for the anti-influenza A activity. Thus, the C-3 epimer, dihydrocorynantheine (86) (normal stereochemistry), was much less active than hirsutine (85). 

Two species had been reported in earlier literature as alkaloid-positive, blit Actinidia argula, A. chinensis, Saurauia oldharnii, A. pseudo-rubi/ormis, Saurauia spp. (5), and S. villosa gave negative tests in the present study. 

Scstjuiierpenoid alkaloids are found in some members of the family, stachydrine and many pseudo- or protoalkaloids in others. 

In particular, it is not only the cinchona alkaloids that are suitable chiral sources for asymmetric organocatalysis [6], but also the corresponding ammonium salts. Indeed, the latter are particularly useful for chiral PTCs because (1) both pseudo enantiomers of the starting amines are inexpensive and available commercially (2) various quaternary ammonium salts can be easily prepared by the use of alkyl halides in a single step and (3) the olefin and hydroxyl functions are beneficial for further modification of the catalyst. In this chapter, the details of recent progress on asymmetric phase-transfer catalysis are described, with special focus on cinchona-derived ammonium salts, except for asymmetric alkylation in a-amino acid synthesis. 

The four major stereochemical types of yohimbine alkaloids are illustrated by yohimbine (normal) [368], pseudoyohimbine (pseudo) [369], cr-yohimbine (alio) [370], and 3-ep/-a-yohimbine (epiallo) [371]. Of particular diagnostic importance are the C(3), C(6), and C(15) shifts... 

The, 3C NMR spectra of roxburghine B, C, D, and E are summarized in [498]—[501 ]. (302) The, 3C shift assignments are aided by data on the ajmalicinoid alkaloids (Sections XII.D). Thus roxburghine D and E are related to 3-iso-19-epi-ajmalicine (pseudo series) and roxburghine C to ajmalicine (normal series). The angular methyl group in roxburghine E is... 

A similar approach was reported by Lygo and co-workers who applied comparable anthracenylmethyl-based ammonium salts of type 26 in combination with 50% aqueous potassium hydroxide as a basic system at room temperature [26, 27a], Under these conditions the required O-alkylation at the alkaloid catalyst s hydroxyl group occurs in situ. The enantioselective alkylation reactions proceeded with somewhat lower enantioselectivity (up to 91% ee) compared with the results obtained with the Corey catalyst 25. The overall yields of esters of type 27 (obtained after imine hydrolysis) were in the range 40 to 86% [26]. A selected example is shown in Scheme 3.7. Because the pseudo-enantiomeric catalyst pairs 25 and 26 led to opposite enantiomers with comparable enantioselectivity, this procedure enables convenient access to both enantiomers. Recently, the Lygo group reported an in situ-preparation of the alkaloid-based phase transfer catalyst [27b] as well as the application of a new, highly effective phase-transfer catalyst derived from a-methyl-naphthylamine, which was found by screening of a catalyst library [27c],... 

It was mentioned at the beginning of this chapter that alkaloids were among the first catalysts to be used for asymmetric hydrocyanation of aldehydes. More recent work by Tian and Deng has shown that the pseudo-enantiomeric alkaloid derivatives 5/6 and 7/8 catalyze the asymmetric addition of ethyl cyanoformate to aliphatic ketones (Scheme 6.6) [50]. It is believed that the catalytic cycle is initiated by the alkaloid tertiary amine reacting with ethyl cyanoformate to form a chiral cyanide/acylammonium ion pair, followed by addition of cyanide to the ketone and acylation of the resulting cyanoalkoxide. Potentially, the latter reaction step occurs with dynamic kinetic resolution of the cyano alkoxide intermediate... 

Phase-transfer catalysis has been widely been used for asymmetric epoxidation of enones [100]. This catalytic reaction was pioneered by Wynberg et al., who used mainly the chiral and pseudo-enantiomeric quaternary ammonium salts 66 and 67, derived from the cinchona alkaloids quinine and quinidine, respectively [101-105],... 

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