Necine base

Bale and Crout 25 a) have carried out feeding experiments with arginine and ornithine labelled with different isotopes ( H and C). They found that ornithine is a slightly more efficient precursor than arginine for retronecine biosynthesis. 

Direct evidence for the involvement of a symmetrical dimeric intermediate in retronecine biosynthesis was obtained by Khan and Robins (755). They fed [1-ammu- N l- C]-putrescine to S, isatideus plants. The n.m.r. spectrum of the retronecine hydrochloride obtained showed enrichment factors of 0.4—0.5% for the signals at C-3, C-5, C-8, and C-9. In addition, the presence of species was evident from the presence of 

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The strategy based on tandem cycloaddition leads to a short and efficient asymmetric synthesis of the pyrrolizidine necine base (-)-hastanecine, as shown in Scheme 8.32.163 Pyrrolizidine alkaloids have a long history for attracting the interest of synthetic chemists because of their physiological properties. The method of Denmark shown in this scheme is very simple and applied to synthesis of various alkaloids. The Lewis acid-promoted [4+2] cycloaddition between 2-acyloxy nitroalkene and chiral vinyl ether gives a nitronate that... 

Scheme 11.14 The synthesis of building block 44 in the total synthesis of (+)-heliotridine, a necine base present in a large diversity of pyrrolizidine alkaloids [69], a)78 22 mixture of diastereomers.

Highly efficient and stereoselective addition of tertiary amines to electron-deficient alkenes is used by Pete et al. for the synthesis of necine bases [26,27], The photoinduced electron transfer of tertiary amines like Af-methylpyrrolidine to aromatic ketone sensitizers yield regiospecifically only one of the possible radical species which then adds diastereospecifically to (5I )-5-menthyloxy-2-(5//)-furanone as an electron-poor alkene. For the synthesis of pyrrazolidine alkaloids in approximately 30% overall yield, the group uses a second PET step for the oxidative demethylation of the pyrrolidine. The resulting secondary amine react spontaneously to the lactam by intramolecular aminolysis of the lactone (Scheme 20) [26,27]. 

We have extended our work on a new synthesis of the antiprotozoal antibiotic anisomycin to the necine bases of the pyrrolizidine alkaloids, in particular retronecine and crotanecine. The key intermediate, (2R,3S,4R)-2-(alkoxy-carbonylmethyl)-3,4—isopropylidenedioxypyrrolidine, has been prepared by three distinct routes from D-ribose and g-erythrose, using reactions of high stereoselectivity. 

The Geissman-Waiss lactone (7)( ) is a well-known precursor of (+)- retronecine ( ) ( -y-), one of the most common necine bases... 

The Lewis acid-promoted tandem inter[4 + 2]/intra[3 + 2]-cycloaddition of the (fumaroyloxy)nitroalkene (124) with the chiral /i-silylvinyl ether (125) is the key step in the total synthesis of (+)-crotanecine (126), the necine base of a number of pyrrolizidine alkaloids (Scheme 46).237 The tandem inter[4 + 2]/intra[3 + 2]-cycload-ditions of nitroalkenes (127) with dipolarophiles attached to the /f-carbon of a vinyl ether (128) provides a method of asymmetric synthesis of highly functionalized aminocyclopentanes (129) (Scheme 47).238 trans-2-( 1 -Methyl-phenylethyl)cyclohex-anol has been developed as a new auxiliary in tandem 4 + 2/3 + 2-cycloadditions of nitroalkenes.239 The scope and limitations of the bridged mode tandem inter-[4 + 2]/intra[3 + 2]-cycloadditions involving simple penta-1,4-dienes are described in detail.240 A tandem intermolecular/intramolecular Diels-Alder cycloaddition was successfiilly used to synthesize a B/C cA-fused taxane nucleus (130) in 50% overall... 

Tufariello has reviewed his strategy for the synthesis of alkaloids (including necine bases) using the 1,3-dipolar cycloaddition of nitrones to alkenes.5 This work began with the synthesis of ( )-supinidine (7) from 1-pyrroline 1-oxide (see these Reports, Vol. 2, Ch. 4). A related approach has been used by Iwashita et al. in their synthesis of ( )-isoretronecanol (5).6 The stereochemistry of the exo-product (8), formed by regiospecific 1,3-dipolar cycloaddition of 1-pyrroline 1-oxide to dihydrofuran (Scheme 2), was confirmed by its conversion into... 

Arctiid moths are also capable of synthesizing their own PAs from a necine base of plant origin and a necic acid synthesized from isoleucine in their own metabolism. Callimorphine, a PA not produced by plants, is synthesized by many arctiid moths and is sequestered as a defensive compound after re-esterification of retronecine of plant origin. Creatonotine, another insect PA, is produced by adults of C. transiens by esterifying ingested retroncine with a distinctive necic acid. These moths are unique in adding de novo-synthesized PAs to plant-derived alkaloids as part of their defensive arsenal. 

Bertrand, S., Hoffmann, N., and Pete, J.P. (2000) Highly efficient and stereoselective radical addition of tertiary amines to electron-deficient alkenes-application to the enantioselective synthesis of necine bases. European Journal of Organic Chemistry, 82, 2227—2238. 

The simple necine bases loline (18), norloline (19), and lolinine (20) have been identified previously from Lolium cuneatum Nevski.7 Further investigations on the seeds of this plant by Russian workers have established the presence of four new alkaloids. N-Formylnorloline (21),8 JV-methyl-loline (22), JV-acetylnorloline (23), and AT-formyl-loline (24)9 have been identified. In addition, a novel dimeric pyrrolizidine alkaloid, lolidine, containing chlorine, was isolated in trace amounts (7 mg from 10 kg of seeds). The structure (25) has been suggested for lolidine on the basis of spectral data.10... 

Figure 9.2. Metabolism of pyrrolizidine alkaloids (PAs) in Senecio vernalis. The substrates for alkaloid biosynthesis, putrescine and spermidine, are derived from primary metabolism. Homospermidine, synthesized by homospermidine synthase (HSS), is the first pathway specific intermediate. It is exclusively incorporated into the necine base moiety of senecionine A-oxide, the backbone structure of all PAs found in this Senecio species. During allocation from the roots as site of synthesis to the shoots, it is chemically modified to provide the species specific PA-pattem.

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. 

However, it has been shown that more than half the aminobutyl moiety of homospermidine comes directly from spermine, and the aminobutyl moiety of spermine is also incorporated directly into the necine base of pyrrolizidine alkaloids (Graser and Hartmann, 1997). 

These intramolecular ring-openings have been utilized in stereospecific syntheses of necine bases and mitosanes. ... 

Pyrrolizidine alkaloids ( )-trachelanthamidine (240) and ( )-supinidine (244) were synthesized, based on the Michael addition of an aziridine to an a,/J-unsaturated ester and subsequent ring opening of an aziridinium intermediate. Interest in these alkaloids stems from their biological activities. Treatment of ethyl 6-chloro-2-hexenoate (236) with excess aziridine at 0°C gave the pyrrolidine derivative 238 in one step, probably via the aziridinium salt 237 in 73% yield. The intramolecular cyclization of 238 with lithium diisopropylamide in tetrahydrofuran provided the thermodynamically more stable ester 239 as the sole product, (86%), which was then converted to ( )-trachelanthamidine (240) by reduction with lithium aluminum hydride. Since necine bases must contain a 1,2-didehydro system in their molecule to exhibit physiological activity, the following reactions were carried out to introduce a 1,2-didehydro system. Treatment of 238 with 2.4 equiv of lith-... 

Semisynthetic amides of retronamine (66), itself prepared from retronecine (65) in three steps, have been synthesized by coupling with the appropriate acid using AW -dicyclohexylcarbodi-imide. Several of the compounds prepared, notably the p hydroxy benzoyl-, cinnamoyl-, and benzoyl-retronamines, had marked hypotensive activity. The amides could not be crystallized and details of their characterization were not given. Atal and his co-workers have also prepared - a number of semisynthetic diesters of retronecine, heliotridine, and platynedne by esterification of the necine base with the appropriate acid chloride. Several of the compounds prepared had marked local anaesthetic activity. 

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