Necine 7-hydroxylated

Structurally, the pyrrolizidine alkaloids are composed of a necine base (two fused five-membered rings with a nitrogen at one of the vertices) and one or more branched carboxylic acids attached as esters to one or two of the necine hydroxyl groups. The esterified branched mono-and di-carboxylic acids are unique to the pyrrolizidine alkaloids. The alkaloids are represented by three major structural groups saturated bases (i.e. platyphylline [29]), 1,2-unsaturated necines (i.e. senecionine [30]) and seco necines (i.e. (otosenine [31]). The N-oxides of these alkaloids frequently co-occur with the free alkaloids (Roitman and Panter, 1995). 

Fig. 13.16 HPLC-ESI-ion trap MS/MS spectra for peak 2 (top) and peak 4 (bottom) in the extract of Senecio ovatus (Figure 13.14). The differences in the fragmentation pattern support the extra hydroxylation of sarracine-N-oxide in the C-9 esterifying acid for peak2 ratherthan in the necine base to yield 2-hydroxysarracine-N-oxide (peak 4, Figure 13.14).

C-7 position will result in ions with the same m/z ratio, one of which wUl be protonated under the ESI conditions. The difference in molecular ion data between peak 4 and peaks 6 and 7 is consistent with an additional hydroxylation relative to sarracine-N-oxide and it is tentatively suggested that this extra hydroxylation is a result of hydration of the 1,2 olefinic center of triangularine-N-oxide to yield 2-hydroxysarracine-N-oxide. In support of this, the abundant presence of an ion at m/z 138 in the ESI-MS/MS spectra of peak 4, and its redox resin reduction product, can be rationalized as the 1,2-hydrated analog of the m/z 120 ion characteristically observed in the ESI-MS spectra of 1,2-dehydropyrrolizidine alkaloids [33]. In contrast to the proposed structure for peak 4, the MS/MS data for the minor, but isobaric, peak 2 clearly indicated the structural difference between the two (Figure 13.16) and suggested the extra hydroxylation of the C-9 esterifying add rather than in the necine base as with peak 4. 

The degradation of the Senecio alkaloids continues to be effected by saponification or hydrogenolysis. The use of alkali in the hydrolysis does not alter the necine moiety but it may cause a change in the geometrical configuration about an a,j8-oarbon-carbon double bond in the necic acid. Hydrogenolysis provides important information as to the location of the esterified hydroxyl on the necine, and subsequent conversions permit a decision as to which end of a dicarboxylic necic acid (in the cyclic diesters) is attached to the allylic or primary hydroxyl of the necine. 

Be this as it may, the problem of the position of the secondary hydroxyl in heliotridine was solved. Turning to further characterization of structure CXLIII for heliotridine, the necine was reduced with hydrogen and nickel to dihydroxyheliotridane (CXXXIII), mentioned in Section 3. Treatment of this compound with benzoyl chloride furnished monobenzoyldihydroxyheliotridane, CisHijNOg, m.p. 133-134°,... 

The alkaloids of this group all contain the necine bases with the C-7 hydroxyl trans to the C-8 hydrogen, that is, with the hydroxyl group in the fold of the molecule as if the macrocyclic diester necessitated this arrangement. The structures are coordinated according to the acid present and fall naturally into four groups (see Table IX). In this group also occurs the quaternary base otonecine. 

These results indicate that antifeedant PAs studied here are structure- and species-dependent. The PA-tolerant S. littoralis was deterred by all the unsaturated monoesters tested, and the secopyrrolizidinic diester otosenine (35). Therefore, esterification of the hydroxyl group at C-9 in the presence (37 and 38) or absence (39) of the C-7 hydroxylation and the C-l/C-2 insaturation of the necine base determined the antifeedant action on S. littoralis. Additionally, the antifeedant and postingestive effects of otosenine (35) indicate that the presence of an electrophyllic ketone group in C-8 at the necine base could play a role in determining such activity. 

The necic acids are those acids which are bound in ester combination with the hydroxyl group of the necines. Due to the wide divergencies in composition, properties, and structure, they will be treated individually in the order of increasing carbon content. 

Necines are classified into the following three categories by the number of hydroxyl groups attached (1) no other hydroxyl moieties, except a —CH2OH at the C-1 position, e.g., isoretronecanol and supinidine (2) a secondary alcohol is attached at the C-7 position, e.g., platynecine and retronecine and (3) an additional alcohol is attached at the C-2 or C-6 position, e.g., ros-marinecine and crotanecine.The alkaloids of the latter group are rare. 

The first step is the formation of the 1,2-double bond followed by a stereoselective hydroxylation at the C-7 converting the necine base moiety into either retronecine (7R) and heliotridine (7S) (Fig. 8). These structures may be further modified by introduction of a second necic acid (i.e., esterification at C-7) and additional modification of the necic acid moieties (i. e., hydroxylations, acetylations, etc.). The majority of the PAs of the lycopsamine type are monoesters or diesters of retronecine and heliotridine [3]. 

Neemes consist of a five-membered bicycfic ring system with a bridgehead nitrogen and - at least - a hydroxymethyl group at position 1 (Fig. 13.1). They can occur as saturated systems or possess a double bond in position 1,2. Most of the PAs show a further OH group at positimi 7. Further hydroxylation can take place at positions 6 and 2 in the case of saturated PAs a few molecules show hydroxylation at position 1 and in one case the (+) isomer of isoretronecanol (R3 = 6-H a-hydroxymethyl at position 1) is reported. Chiral carbons can be at positions 1 and 2 (saturated necines) and 6,7,8 (all necines). Mainly all PAs belong to the 8-a series (only two times the 8-B positimi is reported). In nature, the PAs mainly occur in their N-oxide form (water-soluble transport form). 

After oral uptake and absorption of the PAs (Scheme 13.3 la and Ib), a hydroxyl-group is introduced adjacent to the nitrogen atom in the necine (position 3 or 8) by the cytochrome P-450 monoxogenase enzyme complex in the liver (Scheme 13.3 Ila and Ilb). 

These hydroxyl PAs (OHPAs) are unstable and undergo a rapid dehydration to the dehydropyrroUzidine alkaloids (DHPAlk Scheme 13.3 III). This dehydration results in a second double bond in the necine followed by spontaneous rearrangement to an aromatic pyrrole system III. 

In the case of necine-diesters (as shown in la and Ib, Scheme 13.3), typical of Senecio species, the formation of the reactive carbonium ions is facilitated because the necic acid groups provide good leaving groups that facilitate rapid formation of the carbonium ions IV and VI in high yield. Where one of the hydroxy groups at C7 or Cl of the necine is not esterified, formation of the carbonium ions is not so spontaneous. In these cases, the carbonium ions are most readily formed after protonation of the hydroxyls and loss of H2O [90]. 

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