Lupinine syntheses

Analogous reactions involving the more reactive iminium ions have also been observed. For example, a lupinine synthesis involved (203) as a reactive intermediate (60JA502). The decarboxylation of. the diacid was relatively nonstereospecific giving, after reduction, a mixture of ( )-lupinine and ( )-epilupinine. 

The acylation of enamines has been applied to the use of long-chain acid chlorides (388) and particularly to the elongation of fatty acids (389-391) and substituted aliphatic acids (392). The method has been used in the synthesis of the antineoplastic cycloheximide and related compounds (393-395) and in the acylation of steroids (396). Using an optically active chlorocarbonate, an asymmetric synthesis of lupinine could be achieved (397). 

Quinolizidine synthesis via intramolecular immonium ion based Diels-Alder reactions total synthesis of ( )-lupinine, ( )-epilupinine, ( )-criptopleurine and ( )-julandine [97]... 

An enantioselective synthesis of (—)-lupinine 6 was based on a similar reductive amination process. In this case, (k)-phcnylglycinol was used to obtain a chiral nonracemic oxazololactam which was cyclized after reduction of N-C and O-C bonds and subsequent hydrolysis of the masked aldehyde <2004T5433>. 

The intramolecular Pummerer reaction has been applied to the synthesis of simple quinolizidine alkaloids like lupinine <2000JOC2368>, and also to arenoquinolizine alkaloids. Thus, the 2-(2-piperidyl)indole 284 was converted to indolo[2,3- ]quinolizidine 287 following a protocol that has as the key step the regioselective cyclization onto the indole 3-position of a thionium ion generated by Pummerer reaction from the appropriately substituted compound... 

Another useful route to alkaloids involves the electrochemical oxidation of lactams (145) bearing functionality on nitrogen that can be used to intramolec-ularly capture an intermediate acyl im-minium ion (146). The concept is portrayed in Scheme 33 and is highlighted by the synthesis of alkaloids lupinine (150) and epilupinine (151) shown in Scheme 34 [60]. Thus, the electrooxidation of lactam (147) provided a 71% yield of ether (148). Subsequent treatment with titanium tetrachloride affected cyclization and afforded the [4.4.0] bicyclic adduct (149). Krapcho decarbomethoxylation followed by hydride reduction of both the... 

In 2008, Lhommet and co-workers, by extrapolation of a previously described polycyclic version [144], proposed the three-component condensation of acrolein, (5)-2-phenylglycinol, and various acyclic 1,3-dicarbonyls in toluene in the presence of 4 A molecular sieves for the preparation of chiral, bicyclic functionalized tetrahydropyridines (Scheme 50) [145]. These heterocycles may be used as chiral building blocks for the synthesis of alkaloids, as illustrated by the total enantiose-lective synthesis of (—)-lupinine in five steps and 29% overall yield. 

The lupinine, lupanine, sparteine and cytisine synthesis pathway... 

The synthesis pathway of quinolizidine alkaloids is based on lysine conversion by enzymatic activity to cadaverine in exactly the same way as in the case of piperidine alkaloids. Certainly, in the relatively rich literature which attempts to explain quinolizidine alkaloid synthesis °, there are different experimental variants of this conversion. According to new experimental data, the conversion is achieved by coenzyme PLP (pyridoxal phosphate) activity, when the lysine is CO2 reduced. From cadeverine, via the activity of the diamine oxidase, Schiff base formation and four minor reactions (Aldol-type reaction, hydrolysis of imine to aldehyde/amine, oxidative reaction and again Schiff base formation), the pathway is divided into two directions. The subway synthesizes (—)-lupinine by two reductive steps, and the main synthesis stream goes via the Schiff base formation and coupling to the compound substrate, from which again the synthetic pathway divides to form (+)-lupanine synthesis and (—)-sparteine synthesis. From (—)-sparteine, the route by conversion to (+)-cytisine synthesis is open (Figure 51). Cytisine is an alkaloid with the pyridone nucleus. 

This pathway clearly proves that the first quinolizidine alkaloid to be synthesized is (—) lupinine (two cycling alkaloids) and subsequently both (+)-lupanine and (-)-sparteine. This is a new approach to the synthesis of this type of alkaloids because in the older literature just four cycling alkaloids (lupanine and sparteine) were mentioned as the first synthesized molecules . In the cadaverine conversion, the participation of diamine oxidase is more reliable than the oxosparteine synthase mentioned by some older studies °. 

Figure 51. Diagram of the lupinine, sparteine, lupanine and cytisine synthesis pathway. Abbreviations PLP = coenzyme pyridoxal phosphate C = cleavage of C4 unit.

Lupinine (2) is easily epimerized to epilupinine (33), a compound occurring in nature and also formed by synthesis (82-87). The synthesis of optically active natural lupinine and epilupinine was accomplished in 1967 (S5). Optically active... 

Nakai 124-126). UV and IR spectra of 78 and 81-83 are characteristic of lupinine alkaloids of the cytisine series containing an a-pyridine ring. MS fragmentation patterns are similar to those of cytisine alkaloids. The structures of these alkaloids were confirmed by synthesis from cytisine by reaction with HCOOH (81), (CHjCO) (78), C2H5Br (82), or CH2=CH—COCH3 (83). 

Pummerer reaction conditions was followed by cycUzation to isomilnchnone 292 and hence to cycloadduct 293, which loses water to form a-pyridone 294. Subsequent manipulation involving deoxygenation and debenzylation completed the synthesis. In similar fashion, the azaanthraquinone alkaloid dielsiquinone was synthesized for the first time. Also, the quinolizidine alkaloids ( )-lupinine and ( )-anagyrine, and the ergot alkaloid ( )-costaclavine were synthesized using this Pummerer cyclization-cycloaddition cascade of imidosulfoxides and isomiinch-nones. 

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). 

Tufariello and Tegeler18 have described a high-yield synthesis of the quinoliz-idine (11) by cycloaddition of nitrone (9) and the a/3-unsaturated ester (10) and then reduction (Scheme 1). The ester (10) was prepared conveniently from but-3-en-l-ol by ozonolysis of the tetrahydropyranyl ether followed by a Wittig reaction on the resultant aldehyde. The quinolizidine (11) was converted into lupinine (12) by a conventional procedure. 

In the synthesis of lupinine125 optically active quinolizidine esters have been reduced by sodium borohydride in methanol to the corresponding saturated systems, which furnished ( + ) and (— )-lupinine by treatment with lithium aluminum hydride (Scheme 94). 

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. 

The synthesis of alkaloids lupinine (106) and epilupinine (107) (Scheme 10) nicely illustrates the methodology [25]. Thus, electrochemical oxidation of lactam 103 (constant current, 50 mA Pt/Pt, Et4NC104) in methanol at room temperature afforded a 71% yield of ether 104 after the passage of 2.8F/mol. Subsequent treatment with titanium tetrachloride affected cyclization to the [4.4.0] bicyclic adduct 105. Krapcho decarbomethox-ylation followed by hydride reduction of both the amide and ester units of the resulting epimeric esters provided the natural products 106 and 107. 

A mixture of lupinine and epilupinine is obtainable by the following series of reactions. The betaine XXVI on cyclic hydrogenation and subsequent decarboxylation with 20 % hydrochloric acid gives a mixture of epimeric lupininic acids (XXIX). The dicarboxylic ester XXVIII is also obtained by the mercuric acetate dehydrogenation of the piperidine derivative XXX and by the alkylation of monomeric piperideine with a y-bromopropylmalonic ester. The last route is presumably a first Mannich condensation followed by an alkylation. Hydrolysis of the malonic esters, decarboxylation (XXIV), esterification, and reduction with lithium aluminum hydride complete the synthesis of a mixture which consists of 80% dZ-epilupinine and 20% dMupinine. Thermal... 

A simple synthesis of the lupininic acids has been reported as follows 43) ethyl a-pyridylacetate and an acrylic ester or acrylic nitrile undergo a simple Michael addition and hydrogenation of the product generates an epimeric mixture (7 3 or 1 4, respectively) of epilupininic and lupininic acids. 

Another synthesis under physiological conditions has been reported (36). The piperidinoquinolizidine (LIII), obtainable from epilupinine via bromolupinine, cyclizes when dehydrogenated with mercuric acetate to a mixture of LIV and LV which on reduction with sodium borohydride gives a separable mixture of sparteine and allomatrine. The epimeric piperidinoquinolizidine obtainable from lupinine gives a mixture of fl -isosparteine (LVIII) and allomatridine (LVI). The dehydrogenation... 

Lupinine Group.—A new lupinine ester (1) obtained from seedhngs of Lupinus luteus contained traces of the c -isomer, which could be obtained from the trans-derivative by irradiation. The structure of the alkaloid was established by hydrolysis and by synthesis from (-)-lupanine and trans-4-acetoxycinnamyl chloride. ... 

A new synthesis of lupinine (2) starts with 2-thiopiperidine (Scheme 1). ... 

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