Of lupinine

Confirmation of Karrer s formula has been provided by the investigation of special reactions of lupinine and lupininic acid and by syntheses of norlupinane and j3-lupinane. 

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]... 

The primary hydroxymethyl group of lupinine 6 was studied with regard to the addition of acetylene in basic systems to give the vinylated product 111 (Equation 7). As compared with aliphatic amino alcohols, the vinylation of lupinine required more drastic conditions <2004RCB242>. 

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>. 

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. 

Lupinus luteus L., Lupinus hispanicus L., Lupinus hirsutus L. They have also been found in Anabasis aphyla. In absolute configuration, lupinine is in its (—)-form, which is non-stable thermally, and is easily epimerized to epilupinine, which is a stable (+)- form of lupinine . The melting point of (—)-lupinine is 70-71 °C, of mixed (+ and —)-lupinine 63-64°C, and of (+)-lupinine (synthetic)... 

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). 

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 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). 

The second method122 uses a polar aprotic medium, such as DMF or N-methylpyrrol idone, a strong base, such as CsOH or KH, and r-BuOOH to facilitate nucleophilic attack at silicon sometimes, the presence of fluoride ion is advantageous. This protocol also cleaves sterically hindered alkoxysilanes. It provided a key step (equation 32) in a total synthesis123 of ( )-lupinine. 

Lupinine-Cytisine Group.—An X-ray analysis of (-)-lupinine hydrochloride and of (+)-epilupinine shows that bond lengths and angles are similar to those of lupinine (cf. Vol. 10, p. 68).16 Aminobenzoate esters of lupinine were prepared by transesterification reactions.17... 

New esters of lupinine have been prepared14 and the mass spectra of lupinine alkyl and aryl esters have been studied.15 Pyrolysis of lupinine methiodide yields... 

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. 

Until fairly recently only the absolute configuration of (— )-lupinine (VI) was known and its correlation with the quinolizidine bases had not been achieved. Two recent publications (8, 9) have reported such correlations for a number of alkaloids. The oxidation of (— )-anagyrine (IX) with permanganate gave the 17-oxolactam (X) upon ozonization it was converted to the dilactam (XI) which on hydrolysis to the intermediate XII followed by decarboxylation and lithium aluminum hydride... 

In accord with theory it was found that C-atoms 2, 6, 10, and 11 of lupinine (VI) each contained one quarter of the radioactivity administered as cadaverine (1 to Lupinus luteus L. as a result of degrada-... 

The tosylate of epilupinine (XIV) is thermally stable, whereas that of lupinine (XVIII) is quarternized, the structure of the resulting salt (XIX)... 

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

BCnight and co-workers approached the synthesis of the unnatural ( + )-enantiomer of lupinine (ent-344) by first resolving racemic 2-(piperidin-2-yl)-ethanol with (+ )-camphorsulfonic acid (357,358). The (i -( + )-enantiomer 362 was then converted into the substituted acetic ester 363, the enolate of which was stereoselectively allylated to give 364 and 365 in isolated yields of 71% and 12%, respectively (Scheme 45). The major isomer 364 was readily hydroborated and cyclized to the bicyclic ester 366, reduction of which completed the first reported synthesis of (+ )-lupinine (ent-344). The optical rotation was measured as +19.5° (c 1, EtOH), which compared favorably with the rotation of natural (- )-lupinine (-21°) recorded under similar conditions (359). It was also hoped that epimeriza-tion of 366 would give the thermodynamically more stable compound 377 in which the ester group is equatorial, after which reduction would provide access to (- )-epilupinine (ent-331). However, the product obtained after these transformations was optically inactive, which indicated that epimerization was accompanied by racemization, probably through base-induced retro-Michael reaction followed by Michael recyclization. 

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

B. Bicyclic Alkaloids.—Full details of the syntheses of lupinine and epilupinine, first reportedin 1960, have now been published this paper also includes the synthesis of sparteine. 

The isomerisation of ( —)-lupinine (5) to (+)-epilupinine (6) has long been known to be possible by chemical methods, e.g. by refluxing natural (-)-lupinine in benzene with metallic sodium, but the yields are low and not consistently reproducible. A preferred method, which consistently gives yields of 20— 25 %, involves the photochemical isomerisation of lupinine in the presence of acetophenone as sensitiser. ... 

In a reaction related to the transformation ((226)-> (228)), acid-promoted cyclization of the hydroxylactam (229) afforded a 7 3 mixture of the quinolizidines (230) and (231), easily transformed into the alkaloids myrtine and epimyrtine (Scheme 44) <92TL73). Related hydroxylactams bearing bromoalkynyl substituents can also give similar cyclizations. For example, treatment of compound (232) with trifluoroacetic acid and methanol afforded a 45 55 mixture of the quinolizidines (233) and (234), precursors of lupinine and epilupinine (Equation (22)) <92TL3633>. 

The use of imines as dienophilic components in [4 - - 2] cycloaddition reactions is well known <79H(12)949,82T3087). For example, a Diels-Alder reaction between the tetrahydropyridine (263) and ethyl 2,4-pentadienoate was the key step in Bohlmann s synthesis of lupinine (Scheme 54) <67CB2742>. Similar methodology has been applied to the preparation of a variety of areno[a]quinolizidin-2-ones (264) <85TL1277> (Equation (29)). 

Enamines have been used extensively in synthesis. 26.277 example is the synthesis of lupinine (529)... 

Lupin alkaloids can be classified into seven structural groups according to the carbon skeleton and the oxidative states (Fig. 1). The alkaloids of lupinine- and... 

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