A’-Piperideines

A -Piperideine — see Pyridine, 2,3,4,5-tetrahydro-A -Piperideine — see Pyridine, 1,2,3,4-tetrahydro-A -Piperideine — see I ridine, 1,2,3,6-tetrahydro-Piperideines — see Pyridines, tetrahydro-Piperidine, 1-acryIoyI-polymers, 1, 284 Piperidine, JV-acyl-... 

A -Pyrroline has been prepared in low yield by oxidation of proline with sodium hypochlorite (71), persulfate (102), and periodate (103). A -Pyrroline and A -piperideine are products of enzymic oxidation via deamination of putrescine and cadaverine or ornithine and lysine, respectively (104,105). This process plays an important part in metabolism and in the biosynthesis of various heterocyclic compounds, especially of alkaloids. 

A -Piperideine-N-oxide was obtained along with a dimeric product by oxidation of N-hydroxypiperidines with mercuric acetate or potassium ferricyanide (107-109). 2l -Pyrroline-N-oxide is formed by oxidation of N-ethylpyrrolidine with hydrogen peroxide with simultaneous formation of ethylene (110). 

Heterocyclic enamines A -pyrroline and A -piperideine are the precursors of compounds containing the pyrrolidine or piperidine rings in the molecule. Such compounds and their N-methylated analogs are believed to originate from arginine and lysine (291) by metabolic conversion. Under cellular conditions the proper reaction with an active methylene compound proceeds via an aldehyde ammonia, which is in equilibrium with other possible tautomeric forms. It is necessary to admit the involvement of the corresponding a-ketoacid (12,292) instead of an enamine. The a-ketoacid constitutes an intermediate state in the degradation of an amino acid to an aldehyde. a-Ketoacids or suitably substituted aromatic compounds may function as components in active methylene reactions (Scheme 17). 

The simplest compounds, -pyrroline and -piperideine,donotexistin the monomeric form. Schdpf et al. (29S) described two geometric isomers of J -piperideine trimer and called them a- and -tripiperideines (182). An equilibrium exists between A -piperideine and both trimers which, therefore, react as typical aldehyde ammonia. The trimer rearranges at pH 9-10 in an almost quantitative yield to isotripiperideine (183) which, in turn, is in equilibrium with tetrahydroanabasine (184) and -piperideine. 

The last isomer, the so-called aldotripiperideine (185), is obtained by the action of acid catalysts on a-tripiperideine at its boiling point (298,299), or in aqueous solution at pH 9.2 and 100°C. Further aldol reaction between tetrahydroanabasine and A -piperideine obviously occurs. Hydrogenolysis of this compound gives dihydroaldotripiperideine (186) which is convertible into matridine (187), a reduction product of the alkaloid matrine. 

Condensation of -pyrroline with pyrrole readily affords 2-(2-pyrro-lidyl)pyrrole (82). The dimerizations of some derivatives of A -piperideine, e.g., zl -pyrroiine and -piperideine-2-carboxylic acids, take a similar course (301). 

An enzyme that catalyzes the reduction of A -piperidein-2-carboxylate to piperidine-2-car-boxylate (r-pipecolate) in the catabolism of o-lysine by Pseudomonas putida ATCC12633 is an NADPH-dependent representative of a large family of reductases that are distributed among bacteria and archaea (Muramatsu et al. 2005). It also catalyzes the reduction of A -pyrrolidine-2-carboxylate to L-proline. 

Muramatsu H, H Mihara, R Kakutani, M Yasuda, M Ueda, T Kurihara, N Esaki (2005) The putative malate/lactate dehydrogenase from Pseudomonas putida is an NADPH-dependent A -piperideine-2-carboxylate/ALpyrroline-2-carboxylate reductase involved in the catabolism of L-lysine and D-proline. J Biol Chem 280 5329-5335. 

Imine formation is an important reaction. It generates a C-N bond, and it is probably the most common way of forming heterocyclic rings containing nitrogen (see Section 11.10). Thns, cycliza-tion of 5-aminopentanal to A -piperideine is merely intramolecular imine formation. A further property of imines that is shared with carbonyl groups is their susceptibility to reduction via complex metal hydrides (see Section 7.5). This allows imines to be... 

Alkaloids with the piperidine nucleus, such as pelletierine (Punica grana-tum), lobelanine Lobelia inflata) and piperine Piper nigrum), have a typical biosynthesis pathway. It starts with L-lysine and continues via cadaverine (biogenic amine), A -piperideine and A -piperidinium cations and lobelanine, to be synthesized as lobeline. Piperine is synthesized from A -piperideine via piperidine (Figure 49). For the transformation from A -piperideine to A -piperideine cation, the residue from acetyl-CoA is needed, together with SAM activity in the transformation to lobelanine. Piperine is synthesized from piperidine through the formation of amide. 

The Diels-Alder reaction using the double bond of a A -piperideine as the dienophile is relatively rare. The potential of this reaction is illustrated by the synthesis of lupinine (242) <79H(12)949), where the quinolizidine ring was formally constructed by a Diels-Alder reaction involving A1-piperideine and the ester (240 Scheme 43). 

The double bond of A piperideines is known to participate in [2+2] cycloaddition reactions, particularly with electron rich ir-systems (Scheme 44) (70CB573). 

The pathway to sparteine and lupanine undoubtedly requires participation of another molecule of cadaverine or A piperideine. Experimental data are not clear-cut and Figure 6.25 merely indicates how incorporation of a further piperidine ring might be envisaged. Loss of one or other of the outermost rings and oxidation to a pyridone system offers a potential route to cytisine. 

A key stage in the biosynthesis of piperidine alkaloids is reached with the formation of A -piperideine. For the elaboration of diverse alkaloids, this intermediate undergoes condensation with a variety of nucleophiles, commonly a /3-keto-acid. (A similar situation is found for pyrrolidine alkaloid biosynthesis see, e.g., Scheme l).1,2 Existing evidence on Lythraceae alkaloid biosynthesis, taken up again below, indicated that condensation occurred in this case between A piperideine (17) and acetoacetic acid to give pelletierine (26), further elaboration yielding alkaloids like (22). In the event, however, labelled pelletierine was found not to be a precursor for (22) or (23).8 Negative evidence is always difficult to interpret, but is here made persuasive by the fact that other precursors that were fed concurrently were incorporated. Conclusive support for these results depended on others outlined below. 

The nature of the nucleophile which condenses with A piperideine (17) needs to be reconsidered. Very plausibly, this could be (18), which is formed as shown in Scheme 3 from phenylalanine (20) via cinnamic acid (19) and malonyl-CoA. A further unit of this type is found in alkaloids such as lythrumine (24). An outline biosynthetic route to Lythraceae alkaloids is given in Scheme 3.9... 

A -Piperideine (17) has been shown to be a precursor of quinolizidine alkaloids in whole plants (cf. Vol. 8, p. 3). However, neither it nor its self-condensation products could be detected as products in the enzymic reaction. [This conclusion is not completely unambiguous, albeit reasonably safe, because the products of the reaction of diamine oxidase, the first of which is (17), were simply compared with those of the alkaloid synthase reaction by g.l.c., and the products of the two reactions were found to be different].11 It seems likely at this stage that (17) is not normally implicated in quinolizidine biosynthesis but can be substituted for an enzyme-generated intermediate via its open form (32) (see Scheme 5). Since no intermediates earlier than (27) could be detected, it is suggested that biosynthesis in vitro and in vivo proceeds by a series of enzyme-linked intermediates (see Scheme 5), none of which is desorbed from the enzyme or enzyme-complex until (27) is liberated. However, in some plants, biosynthesis must stop with the liberation of a compound (31), having the lupinine skeleton... 

The tobacco alkaloid anabasine (37) has been synthesized from 3-pyridyl-lithium (prepared from 3-bromopyridine and t-butyl-lithium) by reaction with A piperideine at —120 °C.46... 

Most of the work on the biosynthesis of Lythraceae alkaloids has been done by Spenser et al. (10, 84-87). First, the validity of the pelletierine hypothesis (c) of Ferris et al. (62) has been tested. The pelletierine (126) nucleus is generated from L-lysine (181) via cadaverine (182), and presumably A -piperideine (132) and its side chain originate from the acetate. Incorporation of radioactivity from 14C-labeled samples of these precursors to decodine (6) and decinine (2) in Decodon verticilatus has been investigated (85, 87). 

Decodine derived from [l-14C]cadaverine showed a distribution of label identical to that of the lysine-derived samples. Activity was equally divided between C-9 (j8-alanine) and C-5 (2-piperydylacetate minus -alanine). In decodine, into which AC - Cjpiperideine was incorporated, the label was confined to C-9. This was consistent with the established evidence that the double bond in A -piperideine does not migrate from one side of the nitrogen to the other (89, 90). 

In light of the present evidence the biogenesis of metacyclophane Ly-thraceae alkaloids required revision, since the only published proposal (9) was based on pelletierine. A new biogenetic scheme was proposed which invoked intermediacy of A piperideine and two C6-C4 units [derived from /i-kctoester (193)]. An intermediate disubstituted piperidine (194) would give rise to two types of metacyclophane alkaloids as a result of reduction and phenol coupling as well as Michael addition in the case of the quinoli-zidine bases (10). 

A situation analogous to that of the pyrroline derivatives also exists, according to spectroscopic data, with N-unsubstituted piperideine compounds. There is little experimental data because A 2-piperideines have not been studied as extensively as the analogous pyrrolines. The A structure has been established for some aliphatically substituted piperideines, e.g., J1(8)-hexahydropyrindene,12,13 J1(10)-octahydro-quinoline,13 and the alkaloid y-coniceine.14,15 According to conformational considerations, structures other than A piperideine could be expected more frequently in the piperideine series. The thia analog16 3 occurs in the amino form as shown by infrared spectral data and the estimation of active hydrogen. 

Dioscorine.—Labelling of C-5, C-.10, and C-12 of dioscorine (2) by [l-14C]acetic acid8 indicates that C-5, C-6, C-9, C-10, C-ll, C-12, and C-13 derive from acetate. This leaves a cyclic C5N unit unaccounted for, which, from the wealth of evidence on the biosynthesis of similar systems (see previous Reports), one expects will arise from the amino-acid lysine via A piperideine (1), an expectation not realized since neither compound is satisfactorily incorporated into dioscorine (2).8... 

The A piperideine trimer hypothesis is supported initially by the equal incorporation of lysine and cadaverine into all three alkaloid fragments13,14 but more significantly by the incorporation of three molecules of A piperideine (1) into lupanine (10) and by the manner of this incorporation label from C-6 appeared at C-2, C-15, and, by inference, C-10, whereas C-2 label appeared at C-17, C-ll, and, by inference, C-6, consistent with the hypothesis (see Scheme 3).19 Further, approximately a third of the label was located at each of the determined sites. 

Biosynthesis of piperidine alkaloids from lysine/cadaverine commonly occurs via A piperideine (31). Three molecules are utilized for the construction of lupanine (27), and an attractive biosynthetic route involving the all-trans-isomer of... 

The model scheme developed for the biosynthesis of lupanine from A piperideine and isotripiperideine33 has been adapted for the biosynthesis of matrine (32).35 At the moment, the two hypothetical pathways26,33,35 for the biosynthesis of quinolizidine alkaloids are manifestly different (cf. Vol. 11, p. 4 and Vol. 8, p. 3) one uses A piperideine (31) as an intermediate the other does not. Where the points of fundamental agreement between the two models lie, and which model is a more accurate picture of what is really happening, are questions that remain to be answered. 

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