Piperidine alkaloid

The simple piperidine alkaloid coniine from poison hemlock is not derived from lysine, but originates by an animation process and is discussed on page 381. 

Claisen reaction chain extension reduction/dehydration reactions 

The piperic acid portion is derived from a cinnamoyl-CoA precursor, with chain extension using acetate/malonate (compare flavonoids, page 149), and combines as its CoA ester with piperidine. 

Piperidine Alkaloids.—There is now a wealth of detail on the incorporation of lysine into the piperidine nucleus of alkaloids such as sedamine (20), anabasine 

One way in which the unsymmetrical incorporation of lysine could be explained was by invoking mono-N-methyl derivatives as adduced analogously 

Schiitte, in Biosynthese der Alkaloide , ed. K. Mothes and H. R. Schiitte, VEB Deutscher Verlag der Wissenschaften, Berlin, 1969, p. 324. 

The validity of the above scheme was further explored with cadaverine samples chirally labelled with tritium at C-1. (The samples were obtained by decarboxylation of L-lysine mediated by L-lysinedecarboxylase from Bacillus cadaveris. The absolute configuration of the two materials is unknown and they were accordingly named [L4- H]- and [15- H]-cadaverine.) The labelling pattern of the derived N-methylpelletierine (22) was in accord with stereospecific oxidative deamination to A -piperideine (30) and in agreement with the proposed model. Both cadaverine samples afforded iV-methylpelletierine (22) with a label at C-6 but only [l/4- H]cadaverine labelled C-2. (The puzzling loss of 25% of the tritium from non-chirally labelled [l- C,l- H]cadaverine on incorporation into N-methylpelletierine is now explained in terms of this model, the tritium loss being exactly as predicted. It seems that subsequent elaboration of N-methylpelletierine (22) to pseudopelletierine (24) is accompanied by preferential tritium retention at C-6 by a primary isotope effect. ) 

In a notable piece of research it was shown that the L-isomer of lysine was much preferred for anabasine biosynthesis whereas the D-isomer was preferentially utilized for L-pipecolic acid biosynthesis in N. glauca. In a more rigorous study this was confirmed for sedamine (20), JV-methylpelletierine (22), N-methyl-allosedridine (25) (in two Sedm species), and anabasine (in N. glauca) and also for 

Piperine (1-piperoylpiperidine), alkaloid from piper nigrum L., belonged to the group of 

GLASS CAPILLARY GC ANALYSIS WITH COLD ON-COLUMN INJECTION OF PIPERINE2 A = pure piperine and B = pepper extract. Internal standard (1) tetrahydropiperine, and piperine (2). Column 25 m x 0.5 m I.D. HTS-OV-1 column, 250°C isothermal. 

Moll3 gas chromatographed some Conium alkaloids and a number of other piperidine bases. 

A good separation was obtained on a packed column of 30 % polyethylene glycol 4000 on silica gel impregnated with 20 % potassium hydroxide. Potassium hydroxide was used to reduce adsorption to the solid support. The results are given in Table 6.1. 

EXPERIMENTAL CONDITIONS USED FOR GAS CHROMATOGRAPHY OF PIPERIDINE ALKALOIDS 

The a is L-lysine, as in the case of piperidine, but the f3 is different. The /3 is a-aminoadipic acid 6-semialdehyde. The q is L-pipecolic acid, which is synthesized in plants from piperideine-6-carboxylic acid. In the case of many other organisms, the obligatory intermedia (q ) is derived from the /3. The p retains one ring structure. The indolizidine nucleus will be formed only in the synthesis of the x- The deep structmal change occms when p is transformed by a chain of reactions the formation of CoA ester (CoAe), the Claisen reaction with acetyl or malonyl CoA (Cra/mCoA) and the ring closme process (by amide or imine) to 1-indolizidinone, which is the x- The second obligatory intermedia ( k ) only has the indolizidine nucleus. 

The X is transformed by hydroxylation to A, which is castanospermine. The A is a typical sub-way product. The main pathway is transformed to the x by hydroxylation and the ring fusion to another A, which is swansonine. 

Both alkaloids (castanospermine and swansonine) have the ahility to inhihit glycosidase enzymes (GE), the activity of which is necessary in glycoprotein biosynthesis. 

Lysine and the Piperidine Alkaloids.—The amino-acid lysine serves as the precursor of a piperidine ring in the biosynthesis of a large number of alkaloids. Several alkaloid families are under active investigation and because the attack on this problem is taking place on several fronts, progress is difficult to follow. 

Therefore, a brief outline of the salient features of past work is desirable to help to put current results in perspective. 

Therefore, cadaverine (84), because of its symmetry, cannot serve as an intermediate between lysine and the alkaloids. Other significant findings are that the nitrogen on C-6 of lysine is retained in anabasine54 and that both hydrogens on 

Bentley, in Biogenesis of Antibiotic Substances ed. Z. Vanek and Z. Hostalik, Publishing house of the Czechoslovak Academy of Sciences, Prague, 1965, p. 241. 

It will be interesting to see if the hydrogen at C(2) of lysine is retained in the biosynthesis of the other alkaloids of this family, such as anabasine (86) and pelletierine (89), where the nitrogen atom is not methylated. It is significant that the pipecolic acid (88) produced along with the sedamine in this experiment, was devoid of tritium. Therefore, the pathway a could be in operation for this natural product and it may be the normal route for some of the alkaloids also. 

Dioscorine 6.8) is, like anatabine, exceptional in that the piperidine ring (heavy bonding) also derives from nicotinic acid 6.4) the remaining atoms derive from acetate (acetoacetate) [see (. 9)] [5]. 

Pinidine 6.15) [8], with a structure similar to that of coniine 6.14), also derives by simple linear combination of acetate units C-2, C-4, C-6, and G-9 were labelled by [l- G]acetate. One of the acetate carboxy groups is lost during biosynthesis (from C-1 or C-10). Non-radioactive sodium acetate fed at the same time as diethyl [l- C]malonate diluted radioactivity from C-2 which must therefore be part of the starter acetate unit (see Chapter 3), i.e. the carboxy group is lost from C-10. This, in the light of coniine biosynthesis, leads to 6.16), and possibly decanoic acid, as intermediates 

The pathways deduced for coniine 6.14) and pinidine 6.15) on the one hand, and anatabine 6.7) and dioscorine 6.8) on the other, are exceptional. That deduced for iV-methylpelletierine 6.19) can be considered much more typical of piperidine alkaloids because the piperidine ring originates from lysine 6.17). Two other alkaloids, anabasine 6.20) and sedamine 6.21) have similar origins and much of the evidence for the three alkaloids is interlocking so they are best discussed together. 

The results of extensive experiments with variously labelled samples of lysine closely define the way in which this amino acid is assimilated into the alkaloids. Thus C-2 and C-6 of the precursor become C-2 and C-6, respectively, in 6.19) [9], 6.21) [10, 11], and 6.20) [12]. Although cadaverine 6.26) is also an alkaloid precursor it cannot be an intermediate following lysine because any label at C-2 or C-6 of the amino acid would become spread over both C-1 and C-5 of the symmetrical diamine 6.26) a single lysine label would thus be spread over both C-2 and C-6 of the alkaloids. 

Tritium at C-2 and C-6 of lysine is retained on formation of sedamine 6.21) [10, 11]. These results, supported by those with [ N]-labelled samples of lysine, indicate that alkaloid formation involves retention of the C-6 amino-group and loss of the one at C-2. Loss of the C-6 amino group would require oxidation of C-6 and tritium loss, but removal of the other amino-group is not expected, necessarily, to result in tritium loss from C-2. The reaction may be one of deaminative decarboxylation (see below) leading to 

Reagents i, 0HCCH=CHC02Et, BuLi ii, OHCCH CHCOaEt, BuLi, Lil iii, ClCOzEt, piperidine 

Two new alkaloids of the carpaine group, dehydrocarpaine-I and -II, have been isolated from papaya leaves (Carica papaya L.). They have been formulated as (33) and (34) respectively, on spectral evidence and on the basis of their easy hydrogenation to carpaine.  

Total stereospecific syntheses of (+)-azimic (35) and (+)-carpamic acids (36), which are the hydroxy-acids in the macrocyclic dilactone structures of azimine and carpaine respectively, have been described, starting from (+)-glucose.  

Decahydroqninoline Alkaloids.—Full details of two earlier briefly reported total syntheses of ( )-pumiliotoxin-C have been disclosed. A third total synthesis 

Inubushi, Chem. Pharm. Bull., 1978,26, 2442. 

Although amino-acids have been administered to plants on occasions legion in number, rarely has attention been paid to the question of whether there is any selectivity for the D- or L-amino-acid in alkaloid biosynthesis. An exception appears in work on the Amaryllidaceae alkaloids where it was shown that d- and L-tyrosine were equally well utilized in lycorine biosynthesis. The question has now been answered in Nicotiana glauca for the biosynthesis of anabasine (118) and pipecolic acid (113) from lysine. Pipecolic acid was found to be derived preferentially from the D-isomer ( 48 times better), in accord with a similar preference in intact rats and corn seedlings, whereas L-lysine was the more effective precursor ( 30 times) for anabasine. 

These results tie in neatly with others obtained for the biosynthesis of sedamine (117), anabasine (118), and N-methylpelletierine (119) where, it was shown, the pathway differs from that which leads to pipecolic acid. In essence the results show that (117), (118), and (119) derive from lysine without loss of the hydrogens from C-2 and C-6, whereas the genesis of pipecolic acid (113) is with retention of the hydrogens from C-6 and loss of the one from C-2. Further, all these piperidine derivatives arise from lysine without the intermediacy of a symmetrical intermediate. The results may be summarized in terms of the 

in Biogenesis of Natural Compounds , ed. P. Bernfeld, Pergamon, Oxford, 2nd edn., 1967, p. 968. 

8-Phenyl-lobelol-I, which differs from sedamine (117) only in the configuration at C-8, occurs together with lobeline (120) in Lobelia The 

The tetrahydroanabasine skeleton is found in the Adenocarpus alkaloids adenocarpine (122) and santiaguine (123). Adenocarpine is known to incorporate the A -piperideine dimer (124) with efficiency lending credence to the view that the tetrahydroanabasine alkaloids may arise from two molecules of lysine rather than one, as is found for anabasine in Nicotiana  

Reagents i, LiN(CHMe2)2 ii. Ph3P=CHMe, iii, BuLi iv, HCHO v, LiMe, p-MeC6H4S02CI, LiCl vi, Lil, CuCN vii, UN  

CH2OTHP viii, ix, Cr03-py2 NaCN—AcOH—Mn02, 

MeOH xi, o-dichlorobenzene, reflux xii, Lil, lutidine xiii, m-ClC5H4C03H xiv, Cr03 xv, SnCl2 HQ, EtOH xvi, Me03SF xvii, NaBH3CN. 

The crystal structures and absolute stereochemistry of tecomanine (21) and alkaloid-C (22), occurring in Tecoma starts, have been settled by X-ray diffraction analysis of their respective methoperchlorate and methiodide salts. In the latter case the results reveal the position of the angular hydroxy-group, hitherto not known with certainty. 

Isopelletierine (23) undergoes a Mannich reaction with both m-methoxy- and m-hydroxy-benzaldehyde, to give respectively a mixture of the cis (24 R = Me) and trans (25 R = Me) quinolizidines, and exclusively the tran -quinolizidine (25 R = H). The ratio of stereoisomers in the former reaction varies widely with solvent used.  

Reagents i, Ag20, at 135 C for 5 hours ii, NH2OH, NaOAc, MeOH iii, MeS02Cl, EtjN, CH2CI2 iv, AlMe, PhMe, at -78°C, then NaF, H2O v, Bu 2AlH or LiAlH. vi, LiAlH, + AlMe  

Full details of a total synthesis of ( )-cassine, reported briefly 

A brief review of the chemistry and biology of ant venom alkaloids, some of which are piperidines, has been published,  

The venoms of four unstudied Solenopsis (fire ant) species contain the expected 2,6-dialkylpiperidines, and one, S. sp. A (Puerto 

In the pepper alkaloid group, several new amides have been isolated from Achillea spp. One of them, from A, biebersteinil Afan, is the piperideide(19)Others include (20) (from A. ly caonica Boiss, et Heldr.), and the hitherto structurally unencountered acetylenic amides (21) and (22) (from A. spinulifolia Fenzl ex 

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New synthetic methodology on the route to asymmetric piperidine alkaloids 99JHC1549. 

Hyperaspine (1), a perhydropyrido[l,2-c][l,3]oxazine alkaloid was isolated from the ladybird beetle H. campestris (01TL4621). 9-Epi-6-epipinidinol (90), a piperidine alkaloid, was prepared from a perhydropyrido[l,2-c][l,3]oxazin-l-one derivative (98T13505). Perhydropyrido[l,2-c][l,3]oxa-zin-l-ones were used to prepare 2,6-disubstituted piperidines (96CJC2434). 

As an application of this method1S, the preparation of enantiomerically pure piperidine alkaloids ( )-(i )-coniine (3 steps, 72% overall yield) and (-)-(2i ,6S)-dihydropinidine (6) from 5 is described. For related works, see refs 16, 19-29 and literature cited therein. 

Aliphatic nitriles (—CH2CH2CH2CH2CN) (m/z 82, 96, 110, 124, 138, 152, etc., suggest straight-chain nitriles) Benzoquinones Piperidine alkaloids Some fluoroalcohols... 

RRM of enantiopure cyclopentene 382, induced by commercially available catalyst C, was the key step in Blechert s total synthesis of the bis-piperidine alkaloid (+)-astrophylline (384) [159]. Exposure of metathesis precursor 382 to only 1 mol% C provided within 2 h bicycle 383 in 82% yield (Scheme 75). 

Blechert s synthesis of the piperidine alkaloid (-)-halosaline (387) by Ru-catalyzed RRM is outlined in Scheme 76 [160]. In the presence of 5 mol% of catalyst A, the ring rearrangement of metathesis precursor 385 proceeded cleanly with formation of both heterocyclic rings in 386. In situ deprotection of the cyclic silyl ether in 386, followed by selective reduction and removal of the to-syl group led to 387. 

The utility of strained disubstituted cycloheptenes in alkaloid syntheses is highlighted by Blechert s total syntheses of the bis-pyrrolidine alkaloid (+)-dihydrocuscohydrine (390) [161],thebis-piperidine alkaloid (-)-anaferin (in the form of its dihydrochloride 393) [162], and indolizine 167B (397) [163] (Scheme 77). 

Felpin, F.X., Girard, S., Vo-Thanh, G., Robins, R.f, ViUieras, L, Lebreton, L (2001) Efficient Enantiomeric Synthesis of PyrroUdine and Piperidine Alkaloids from Tobacco. Journal of Organic Chemistry, 66, 6305-6312. 

An excellent example of a RCM/ROM domino process is shown in the total synthesis of the piperidine alkaloid (-)-halosaline (6/3-19) by Blechert and coworkers (Scheme 6/3.3) [231]. The key step is the reaction of the enantiopure cyclopentene derivative 6/3-17 to give 6/3-18 with 5 mol% of the catalyst 6/3-13. Further transformations of 6/3-18 led to the natural product 6/3-19. 

Besides piperidine alkaloids, a total of 19 pyrrolidines have been found in the secretions of thief ants and fire ants of the genera Solenopsis and Monomorium. Among these, compounds 80-84 are simple pyrrolidines with two saturated linear all-carbon side chains only in Solenopsis latinode is there a secondary amine (82) and its methylated analog (85). One or two terminal unsaturations are present in compounds 86-91, which all possess a (hex-l-en)-6-yl chain and a 5-, 7-, or 9-carbon saturated chain. Compounds 93, 94, 96, 97, and 98 are the A-l-pyrrolines corresponding to pyrrolidines 80, 82, 90 (93 and 96 corresponding to 80, 94 to 82, and 97 and 98 to 90). 

The chemistry of pepper has long been studied and the pungent principle of black pepper—a piperidine alkaloid, piperine 134—was isolated as early as 1877 (201). Its synthesis from the acid and piperidine was accomplished in 1882. (202). The corresponding pyrrolidine alkaloid trichostachyne (135) was isolated some 100 years later from several Piper species (see below). The cooccurence of piperidine and pyrrolidine alkaloids is a common feature of the chemistry of pepper. In many cases, the crude alkaloid extract is first cleaved with acids or bases and then each alkaloid is reconstituted by selective amidation. For the sake of unity, this chapter will be limited to comments on pyrrolidines, even in cases where they are minor alkaloids. 

The total syntheses of these pepper alkaloids are not those of pyrrolidines but rather syntheses of their acid parts. Thus dihydrowisanidine (137) has been prepared by a series of reactions, the key step of which is the formation of the carbon-carbon double bond by a Wittig-Homer reaction (217, 218). Schemes 41 and 42 summarize two syntheses of okolasine from sesamolmethyl ether (279) of course, routes to okolasine also yield the corresponding piperidine alkaloid wisanine. Molybdenum-catalyzed elimination of allylic acetate (149) yielded (E,E)-diene ester 150 en route to trichonine (220) worthy of note is the use of an aluminum amide in the preparation of amide 143 from ester 150 (Scheme 43). 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

Figure 2.2 Three piperidine alkaloid teratogens from Conium maculatum (poison-hemlock) (a) coniine, (b) y-coniceine, and (c) A-methyl coniine, with accompanying LD50 as determined in a mouse bioassay.

Nicotiana species and certain lupine species also contain potent toxic and teratogenic piperidine alkaloids (Figure 2.4). All teratogenic piperidine alkaloids have specific structural characteristics that are responsible for induction of birth defects. Their molecular structures include a piperidine ring, with a side chain of at least three carbons or larger attached adjacent to... 

In addition to lupines, poison-hemlock and Nicotiana spp., other plant species of the genera Genista, Prosopis, Lobelia, Cytisus, Sophora, Pinus, Punica, Duboisia, Sedum, Withania, Carica, Hydrangea, Dichroa, Cassia, Ammondendron, Liparia, and Colidium contain potentially toxic and teratogenic piperidine alkaloids. Many plant species or varieties from these genera may be included in animal and human diets (Keeler and Crowe, 1984). 

Fodor, G.B. and Colasanti, B. (1985). The pyridine and piperidine alkaloids chemistry and pharmacology, in Pelletier S., Ed., Alkaloids chemical and biological perspectives, Vol. 3, John Wiley and Sons, New York, pp. 3-91. 

Keeler, R.F. and Panter, K.E. (1989). Piperidine alkaloid composition and relation to crooked calf disease-inducing potential of Lupinus formosus. Teratology, 40, 423-432. 

Panter, K.E., Bunch, T.D., Keeler, R.F., Sisson, D.V. and Callan, R.J. (1990). Multiple congenital contractures (MCC). and cleft palate induced in goats by ingestion of piperidine alkaloid-containing plants Reduction in fetal movement as the probable cause, Clin. Toxicol., 28, 69-83. 

Panter, K.E., Gardner, D.R. and Molyneux, R.J. (1998a). Teratogenic and fetotoxic effects of two piperidine alkaloid-containing lupines L. formosus and L. arbustus) in cows, J. Nat. Toxins, 1, 131-140. 

The reactions depicted in Scheme 39 were already conducted in view of a potential use in the synthesis of pyrrolidinols and piperidinols. The structural feature of a 2-arylmethyl-3-hydroxysubstitution is not only found in preussin but also in anisomycin (152) [87] or in the piperidine alkaloid FR 901483 (153) [88] (Fig. 5). 

A new piperidine alkaloid Adalinine 352 was prepared in racemic form, using a rearrangement as a key step (equation 134). Enolate chemistry allowed double a-alkylation of cyclopentanone, producing 350 after oxime formation. Rearrangement provided a clear conversion into the lactam 351, easily converted to racemic Adalinine 352. 

During the synthesis of 436, Muraoka and colleagues produced the diazobi-cyclo[4.3.1]decane 435 via the classical ring expansion (equation 184). Huisgen-White rearrangement of the cyclic lactam leads to 436, a key synthetic intermediate for piperidine alkaloids. 

M. Yagi, T. Kouno, Y. Aoyagi, and H. Murai, The structure of moranoline, a piperidine alkaloid from Morns species, Nippon Nogei Kagaku Kaishi, 50 (1976) 571-572. 

L-lysine Piperidine alkaloids Piperidine Anaferine Lohelanine Lohehne A-methyl pelletierine Pelletierine Piperidine Piperine Pseudopelletierine Sedamine... 

L-methionine L-phenylalanine Phenylalanine-derived alkaloids Piperidine alkaloids Quinolizidine alkaloids Indolizidine alkaloids True alkaloids... 

Alkaloid biosynthesis needs the substrate. Substrates are derivatives of the secondary metabolism building blocks the acetyl coenzyme A (acetyl-CoA), shikimic acid, mevalonic acid and 1-deoxyxylulose 5-phosphate (Figure 21). The synthesis of alkaloids starts from the acetate, shikimate, mevalonate and deoxyxylulose pathways. The acetyl coenzyme A pathway (acetate pathway) is the source of some alkaloids and their precursors (e.g., piperidine alkaloids or anthraniUc acid as aromatized CoA ester (antraniloyl-CoA)). Shikimic acid is a product of the glycolytic and pentose phosphate pathways, a construction facilitated by parts of phosphoenolpyruvate and erythrose 4-phosphate (Figure 21). The shikimic acid pathway is the source of such alkaloids as quinazoline, quinoline and acridine. 

The synthesis pathway of quinolizidine alkaloids is based on lysine conversion by enzymatic activity to cadaverine in exactly the same way as in the case of piperidine alkaloids. Certainly, in the relatively rich literature which attempts to explain quinolizidine alkaloid synthesis °, there are different experimental variants of this conversion. According to new experimental data, the conversion is achieved by coenzyme PLP (pyridoxal phosphate) activity, when the lysine is CO2 reduced. From cadeverine, via the activity of the diamine oxidase, Schiff base formation and four minor reactions (Aldol-type reaction, hydrolysis of imine to aldehyde/amine, oxidative reaction and again Schiff base formation), the pathway is divided into two directions. The subway synthesizes (—)-lupinine by two reductive steps, and the main synthesis stream goes via the Schiff base formation and coupling to the compound substrate, from which again the synthetic pathway divides to form (+)-lupanine synthesis and (—)-sparteine synthesis. From (—)-sparteine, the route by conversion to (+)-cytisine synthesis is open (Figure 51). Cytisine is an alkaloid with the pyridone nucleus. 

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