Lupine alkaloids synthesis

The cyclic ammonium ylide/[l,2]-shift approach has been successfully applied by West and Naidu to a key step in the total synthesis of (—)-epilupinine, one of the biologically active lupin alkaloids. Cu(acac)2-catalyzed diazo decomposition of enantiomeric pure diazoketone 160 in refluxing toluene generates a spiro ammonium ylide 161 and 162, which then undergoes [l,2]-shift to give rise to a quinolizidine skeleton as a mixture of diastereomers (95 5) (Scheme Major diastereomer 164 has enantiomeric purity of 75% ee. The partial retention of stereo-... 

Hypusine (Ne-(4-amino-2-hydroxybutyl)lysine)242 occurs in mammalian initiation factor 4D, which is utilized in protein synthesis (Chapter 29) and is formed by transfer of the 4-carbon butylamine group from spermidine to a lysine side chain followed by hydroxylation 280 2823 The lupine alkaloid lupinine283 is formed from two C5 units of cadaverine which arises by decarboxylation of lysine. Silaffins (pp. 178, 1381) also contain modified lysines. 

Comins, D.L., Zheng, X., and Goehring, R.R. (2002) Total synthesis of the putative structure ofthe lupin alkaloid plumerinine. Organic Letters, 4, 1611-1613. 

Alkaloid metabolism in lupine was proved by Wink and Hartmann to be associated with chloroplasts (34). A series of enzymes involved in the biosynthesis of lupine alkaloids were localized in chloroplasts isolated from leaves of Lupinus polyphylls and seedlings of L. albus by differential centrifugation. They proposed a pathway for the biosynthesis of lupanine via conversion of exogenous 17-oxosparteine to lupanine with intact chloroplasts. The biosynthetic pathway of lupinine was also studied by Wink and Hartmann (35). Two enzymes involved in the biosynthesis of alkaloids, namely, lysine decarboxylase and 17-oxosparteine synthetase, were found in the chloroplast stoma. The activities of the two enzymes were as low as one-thousandth that of diaminopimelate decarboxylase, an enzyme involved in the biosynthetic pathway from lysine to diaminopimelate. It was suggested that these differences are not caused by substrate availability (e,g., lysine concentration) as a critical factor in the synthesis of alkaloids. Feedback inhibition would play a major role in the regulation of amino acid biosynthesis but not in the control of alkaloid formation. 

During 1993, Daly and co-workers reviewed the alkaloids found in amphibians [5] and Takahata et al. focused on structural assignments and the synthesis of amphibian and polyhydroxylated indolizidines [6]. Wink reviewed the characterisation, natural distribution and biological activity of lupine alkaloids [7] and systematic updates on indolizidine and quinolizidine alkaloids are annually summarized by Michael [8-14]. 

A Sml2-promoted reductive deamination of methyl prolinate derivative 235 to a 5-aminoester, followed by spontaneous recyclization to lactam 236, was exploited in the synthesis of several lupine alkaloids (Scheme 69) <05JOC499>. 

Dimethoxycoumarin undergoes a two-photon (2 + 2)-dimerization when irradiated at 650 nm using a pulsed laser source. Two-photon irradiation has been used to regenerate the coumarin from the (2 -l- 2)-dimers. Comins and his co-workers described an approach to the synthesis of the lupin alkaloid (22). This is approached using intramolecular (2 + 2)-cycloaddition using a suitably sub-... 

Oxysparteine was also the intermediate which furnished conclusive proof of the ring structure of all the Cw lupin alkaloids. Clemo, Morgan, and Raper in 1936 (260) announced the synthesis, from non-alkaloid starting materials, of a compound with structure XCV and established the identity of this compound with the d/-oxysparteine obtained by alkaline ferricyanide oxidation of dZ-sparteine. The s3Tithesis of dZ-oxy-sparteine (XCV) was accomplished as outlined below. The Claisen condensation of ethyl 2-pyridylacetate (XCVI) with ethyl orthoformate... 

In addition to these factors, the mechanisms for product accumulation and storage are of prime importance, but little studied (James, 1950 Matile, 1978, 1984 Wink, 1987). In general, there are few data concerning the site of storage of secondary compounds within the plant. As observed above, storage at a particular site does not necessarily imply that the compound was synthesized there. For example, lupine alkaloids are accumulated in epidermal cells (which lack chloroplasts) but synthesized in mesophyll cells. The alkaloids are transported to the epidermis via the phloem. Accumulation depends on the season and developmental stage of the plant (James, 1950 Mothes, 1955). Sites of synthesis and accumulation often are separated in cells by compart-mentation. Lipophilic compounds tend to be accumulated in membranes, vesicles, dead cells, or extracellular sites. Hydrophilic compounds tend to be stored in an aqueous environment, typically the vacuole (Matile, 1978, 1984 Wink, 1987). 

Figure 2.2. Schematic illustration of the pathways for alkaloid synthesis in a bitter (wild type) form (1) of lupines and in two different sweet mutants (2 and 3). The pathways are depicted as two parallel lines since in a plant usually two sets of genes are operating. The x indicates the blocked reaction in the sweet form. In the Fi generation of the cross between 2 and 3, i.e., 4, the biosynthetic pathway is regained, and the resulting plant is bitter. In crosses involving a bitter form and a sweet form the Fi generation is always bitter (5 and 6). In 7 there is a double recessive homozygote, and when these plants are crossed with either 2 or 3 only sweet plants are produced (Nowacki, 1966). Courtesy of the journal.

The starting material for the synthesis of the lupin alkaloids is the amino acid lysine, which is first decarboxylated to give its biogenic amine cadaverine. Two units of cadaverine are then joined via a still hypothetical intermediate to give lupinin. Addition of another cadaverine unit to lupinin gives sparteine, which then can be oxidized to lupanin and, further, to hydroxylupanin. The C skeleton of the quinolizidine alkaloids is derived entirely from lysine. We shall now consider two further groups of alkaloids, the nicotiana alkaloids and the tropane alkaloids, which derive only a part of their C skeleton from the aliphatic amino acids ornithine or lysine. 

Heteroatom nucleophiles were described less often. Ye and coworkers published a phospha-Michael addition catalysed by prolinol silyl ether catalyst. Another method for constructing a new C-N bond is the aza-Michael addition, that is the addition of nitrogen-based nucleophiles to a,(3-unsaturated aldehydes. Several groups published these type of reactions using diatylprolinol silyl ether as catalyst. " Fustero and coworkers used this reaction as a key step in the synthesis of biologically active chiral heterocycles. Recently, the authors showed the synthesis of quinolizidine alkaloids, such as (-l-)-myrtine, (-)-lupine and (-l-)-epiquinamide. Vicario applied 5-mercaptotetrazoles as nucleophiles towards a range of unsaturated aldehydes. The reaction proceeded via the iminium activation. The... 

Many alkaloids have been isolated from the lupin family. A neat synthesis (Scheme 19) of one of the simpler examples, lupinine (126), starts from tet-rahydroanabasine (123), obtained easily from dehydropiperidine (3,4,5,6-tetrahydropyridine) (122) (1996JOC5581). A clever aspect of this synthesis is the use of the ortho-qainone 125 as a selective oxidant to convert a primary amine (124) into an aldehyde. 

The effect of phosphorus is less spectacular. However, it is the reverse of that of potassium. With an increase of fertilization the level of alkaloids in the lupines rises both in percentage and in total amount (Ermakov et aL, 1935 Mironenko, 1965, 1975). Gentry et al. (1969) found that phosphorus and potassium added together greatly reduced perloline biosynthesis in tall fescue (Festuca arundinacea), whereas nitrogen increased perloline synthesis. Perloline and total alkaloid content were reduced as the plant approached maturity. The addition of phosphate either alone or together with nitrate had no significant effect on the perloline level (Bennett, 1963). 

Quinolizidines.—The quinolizidine nucleus is widespread in Nature and occurs in the lupin and other alkaloids. Earlier syntheses of these alkaloids suffered from poor stereospecificity of reactions, particularly in the reduction of quinolizinium salts to the reduced ring system. This problem has now been overcome and a total synthesis of ( )-deoxynupharidine achieved (Scheme 70). The reduction results in products with the correct configurations at C-4, C-7, and C-10, but the opposite... 

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