2- -1-piperideine structure

The piperideine derivatives have not been studied as extensively as the analogous pyrrolines (151,152). The imino structure has been established, for example, for the alkaloid y-coniceine (146) (46). The great influence of conjugation on the structure is seen with l-(a-picolyl)-6,7-methylenedioxy-3,4-dihydroisoquinoline (47), possessing an enamine structure, whereas the analogous 1-methyl derivative (48) possesses an imine structure according to infrared spectra (152,153). 

Tertiary pyrrolines (49, = 1) and piperideines (49, = 2) (if R = H and the enamine can exist in the monomeric form or if R = aryl) evidently possess an endocyclic -double bond (79,155,156). The stretching frequency of the double bond can be lowered to 1620-1635 cm by conjugation with an aromatic substituent. The double bond of an analogous compound with aliphatic substituents in position 2 may occupy either the endo or the exo position. Lukes and co-workers (157) have shown that the majority of the five-membered-ring compounds, traditionally formulated with the double bond in a position, possess the structure of 2-alkylidene derivatives (50) with an exocyclic double bond, infrared absorption at 1627 cm . Only the 1,2-dimethyl derivative (51) is actually a J -pyrroline, absorbing at 1632 cm . For comparison, l,3,3-trimethyl-2-methylene pyrrolidine (52) with an unambiguous exocyclic double bond has been prepared (54). 

Physicochemical investigations of enamines and their salts have shown that the addition of a proton occurs almost exclusively at the /3-carbon atom of the enamine grouping. This means that salts of pyrrolines (82), piperideines (83), and enamines of 1-azabicycloalkanes (84) possess immon-ium structures. 

The addition of ethyl acrylate to 1,2-dimethyl- -piperideine 163), l-methyl-2-ethyl-zJ -piperideine 164), and 1,2-dimethyl- -pyrrolidine 216,217) occurs, yielding both possible enamine structures (138 and 139, n=I,2). 

Isotripiperideine and a-tripiperideine structures differ from each other in a new C—C bond formed in is otripiperideine by an aldol reaction (296, 297). In aqueous media at pH 2-13, two molecules of -piperideine yield tetrahydroanabasine (297). 

The study above does not account for the extra six carbons acquired in the conversion of piperideine (8, 10 carbons) to phlegmarine (9, 16 carbons). It was initially proposed that the carbons were incorporated via pelletierine (12), which was incorporated twice into lycopodine resulting in two symmetrical halves of the alkaloid (Scheme 6.2). However, when 14C-labeled pelletierine (12, label at C2) was fed to the plant, degradation studies of lycopodine revealed that only one half consisted of the 14C label from pelletierine (the half containing C9-C16) [10]. The other half does not result from pelletierine 12 but must be something similar in structure since it does contain the piperideine unit (8) resulting from lysine. It was of interest then to determine the exact source of the three-carbon propionate unit in pelletierine (12). 

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

ring structure. The indolizidine nucleus will be formed only in the synthesis of the x- The deep structmal change occms when

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 simple non-aromatic pyridines discussed in this Section are represented by nine structures (l)-(9). These are the fully saturated piperidine (1), the tetrahydropyridines (2)-(4) and the dihydropyridines (5)-(9). In this section (2), (3) and (4) will be referred to as A5-, A2- and A1-piperideine as well as 1,2,3,6-, 1,2,3,4- and 2,3,4,5-tetrahydropyridine. The former designation is rather archaic but less cumbersome and it has also been used by other authors of the review literature in this area (74HC(14-Sl)i). The latter designation is used by Chemical Abstracts. 

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. 

Addition of hypobromous acid to l-methyl-4-phenyl-3-piperideine hydrobromide (127) was accomplished by the action of bromine in aqueous sodium bromide. Treatment of the resulting l-methyl-3-bromo-4-phenyl-4-piperidinol hydrobromide (128) with 10% aqueous sodium hydroxide gave l-methyl-4-phenyl-3,4-epoxypiperidine (129).114 (Compound 128 was formerly given the erroneous structure of l-methyl-5-bromo-4-phenyl-3-piperideine hydrobromide.7)... 

The structure of a 3-piperideine derivative was proposed tentatively for some further naturally occurring substances or their transformation products, e.g., pseudoconiceine173 (179), tropidine174 (180), and ecgonidine methyl ester175-177 (181 or 182). 

The well-known piperidine alkaloid anabasine, found in Anabasis aphylla L. (Chenopodiaceae) and Nicotiana glauca Graeb. (Solanaceae), is thought to be synthesized in plants through dimerization of A1-piperideine (followed by oxidation).243 A terpyridine nicotelline (173) was found in tobacco leaf,244andits structure was proved by synthesis.245... 

DL-[2- C]Lysine [as (1)] and [2- C]-A -piperideine [as (2)] afforded securinine (3) in which the label was confined essentially to the asterisked carbon atom. Further, [i 5-6- H 6- C]-DL-lysine [as (1)] gave securinine without loss of tritium. Consequently C-6 of lysine does not undergo oxidation in the course of securinine biosynthesis and so the e-amino-group of (1) must be retained whilst the a-amino-group and carboxy-function are lost. The combined results are consistent with the hypothetical route to securinine shown in Scheme 1. This pathway will now gain more validity if alkaloids with structures similar to those of the proposed intermediates can be found in Securinega or related plants. 

The presence of some enamine, at equilibrium, is demonstrated by the conversion of piperideine into a dimer, indeed, the ability of these two systems to serve as both imines and enamines in such condensations is at the basis of their roles in alkaloid biosynthesis. Formed in nature by the oxidative deamination and decarboxylation of ornithine and lysine, they become incorporated into alkaloid structures by condensation with other precursor units. Hygrine is a simple example in which the pyrroline has condensed with ace-toacetate, or its equivalent. 

The IR spectrum confirmed an indolic NH and a carbomethoxy group. In the 270 MHz (182) NMR spectrum all 20 protons were observed and many of the key aspects of the structure were obvious in particular, the indolic nucleus, a part structure 335 for the piperideine ring and ethyl side chain, and the unit 336 for the C-17 methylene were evident. These elements in the structure were substantiated by the CMR spectrum, which indicated two nonaromatic, noncarbonyl quaternary carbons as singlets at... 

The two trimeric forms of A -piperideine (2,3,4,5-tetrahydropyridine) have been obtained in excellent yield from l-formyl-2-methoxypiperidine. The reaction of A -piperideine (108) with electron-deficient alkenes gives dimeric products (109) that are notable for their AT-alkylated structures (Scheme 42)." ... 

Hemscheidt and Spenser conducted feeding experiments and found that Lycopodium alkaloids are secondary metabolites of lysine (3) [18] (Scheme 1). The decarboxylation of lysine (3) yields cadaverine (4), which consists of five carbons, and this, in turn, is converted into A -piperideine (5). The condensation of A -piperideine (5) with 3-oxoglutaric acid (6) produces 4-(2-piperidyl)acetoacetic acid (7) and this is converted into pelletierine (8) after a decarboxylation reaction. The biosynthetic process from this point to structurally complex Lycopodium alkaloids, such as lycopodine (1) and huperzine A (2), is deduced from the structures of the isolated alkaloids. The condensation of pelletierine (8) with 4-(2-piperidyl)... 

Most remarkable for proving that structural relationships are not always what they seem are anatabine [(34) p. 11] and dioscorine (8). Inspection and experience with other piperidine alkaloids leads one to expect a biosynthesis for the piperidine ring [heavy bonding in (8)] from lysine via A -piperideine (3). However, in both cases it turns out that this ring derives from nicotinic acid [the exceptional derivation of the piperidine nuclei of coniine and pinidine (9) from acetate has been known for some time ]. 

The structural development of quinolizidine alkaloids is presented in Figure 2.34. The a (L-lysine) provides the basic components of the quinolizidine nucleus and skeleton. The p is cadaverine and is synthesized in the same way as piperidine alkaloids (by the activity of PLP). The transformation from p to q) also occurs through the activity of diamine oxidase (DAO). The 9 is A -piperideine, which develops by the Schiff-base formation, the... 

Coniine possesses a similar chemical structure to that of pelletierine (Section 4.2), isolated from the stem bark and root bark of Punka granatum. Thus Robinson [3] estimated coniine to be derived biosynthetically from a lysine moiety and a C4 unit as in the case of pelletierine, and as shown in the following figure. However, when [2- " C]lysine or its metabolites, [l,5- C2]cadaverine or [6- " C]-A -piperideine, were fed to hemlock,none of the alkaloids isolated from this plant were labeled. 

The biosynthesis of the structurally complex alkaloids of the primitive club moss Lycopodium species), e.g. lycopodine 6.43) and cernuine 6.44), has been analysed simply in terms of a pathway which involves the dimerization of two pelletierine units (Scheme 6.11). Substance is given to this hypothesis by the appropriate incorporations of acetate, lysine 6.17), and A -piperideine 6.18) into lycopodine 6.43) and cernuine 6.44). Significantly, these precursors were incorporated equally into both putative pelletierine (CgN) units [27]. 

Study lycopodine biosynthesis and is formed from lycopodine precursors. Unlabelled pelletierine, when fed with radioactive cadaverine or A -piperideine, very efficiently diluted activity in the one CgN unit (heavy bonding) of lycopodine 6.43) for which it is a precursor. It follows that pelletierine is a normal intermediate in the biosynthesis of lycopodine (and cernuine), but unlike the other precursors tested is involved in the biosynthesis of only one unit. The equal labelling of both CsN units by A -piperideine 6.18) (and lysine) requires that the second CgN unit must be closely related to pelletierine 6.42) significant differences in structure would be associated with differing pathways and hence unequal incorporation of label into the two CgN units. The results argue thus for the pelletierine-dimer hypothesis, but in modified form. It is not easy, however, to propose modifications to the pathway which will fit the results. Hypotheses surrounding 6.45) and 6.46) as intermediates have not been supported by subsequent experimentation. So the puzzle remains. One possibility not so far examined is 6.47), potentially an intermediate in the condensation of 6.18) with acetoacetate (cf Scheme 6.7). 

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