Lupininic acid

Schdpf and Thoma found that lupininic acid yielded a methyl ester (b.p. 120-2°/10 mm.) which had [aj — 19-4° to 5-8° in different batches. The f-ester furnished a gummy picrate, [a]J, ° — 41-8°, and on hydrolysis by hydrochloric acid gave a crystalline lupininic acid hydrochloride, m.p. 275°, — 13T°, identical with that described by Willstatter and Fourneau, whilst the d-ester, or ester of f-rotation below — 19-4°, furnished a crystalline picrate, m.p. 185°, [a]j, -f- 61-8°, from which pure d-epi-ester,-b.p. 126°/11 mm., [aJi, 54-8°, was prepared, this in turn yielding amorphous d-lupininie acid hydrochloride. The f-ester is convertible into ... 

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. 

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. 

The results obtained with the anhydrolupinines and lupinanes indicated that there were two asymmetric centers in the lupinine molecule. The same conclusion was reached in studies on the isomerization of lupininic acid (XXIV) esters. Natural lupinine is levorotatory. Methyl lupininate (XXV) made by Schopf and Thoma (121) according to the directions of Willstatter and Fourneau (118) was obtained which varied from [a]n — 19.4° to -f 5.8° (methanol) in different batches. The most levorotatory sample of ester, methyl ( —)lupininate, formed a noncrystalline picrate, the rotation of which was useful for identification... 

The compound of oxidation state intermediate between that of lupinine and lupininic acid, namely, lupinal, C10H17NO, m.p. 93-96°, has been obtained by Zaboev (72) through the use of chromic anhydride in acetic acid. It appears that the first use of natural lupinine itself as a synthetic tool dates from the work of Bartholomaus and Schaumann, described in two patents (150, 151). Products were characterized which resulted from the condensation of chloro- or bromo-lupinane (derived from lupinine (124, 125)) with ammonia, aniline, methylamine, dimethyl-amine, and piperidine (150). The product resulting from chlorolupinane and piperidine was also described by Clemo and Paper (126). Compounds of possible therapeutic interest were made by the condensation of a halolupinane with 8-amino-2-methylquinoline, 4-amino-2-methyl-quinoline, and by the combination of methylaminolupinane with 4-chloro-... 

Karrer s lupinine formula (XI), lupininic acid is represented by (XX), anhydrolupinine by (XXI) and norlupinane, which has also been named octahydropyridocoline, octahydroquinolizine, quinolizidine and 1-azadicyclo-[0, 4, 4]-decane, by (XXII). 

The nature of the base, CmHijN, varies. When produced from pure Mupinine, m.p. 68-9°, it furnishes on oxidation only 3-methylpyridine-2-carboxylic acid (XV) and pyridine-2 3-dicarboxylic acid. If, however, lupinine, m.p. 63-3°, is used, the resulting pyridine base on oxidation furnishes in addition 2-n-butylpyridine-6-carboxylic acid (XVI) and 6-methylpyridine-2-carboxylic acid (XVII). The conclusion is drawn that lupinine, m.p. 63-3°, is a mixture of 1-lupinine (XI) with aZlolupinine (XII), each of these components furnishing its own lupinane (XIII and XIV), and that these two lupinanes contribute to the final degradation product, the tertiary pyridine base, CioHuN, the two isomerides 2-w-Ijutyl-3-inethylpyridine (XVIII) and 2-w-butyl-6-raethylpyridine (XIX) respectively. These interrelationships are shown by the following scheme —... 

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). 

Alkaloids 36-41 were isolated from Lupinus luteus L. seedlings. They are considered to be lupinine esters with 4-hydroxycinnamic acids (94-100). The structures of these new alkaloids were elucidated on the basis of H NMR, MS, and chemical and enzymatic transformations. All these alkaloids were obtained from lupinine and hydroxycinnamic acid by two enzymatic systems (96-97) ligase catalyzed formation of the CoA-thioester, and transferase catalyzed lupinine ester formation from the CoA-thioester. 

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 lactam 143 was treated with m-chloroperbenzoic acid, followed by treatment with acid anhydride to yield the aldehyde 144. Catalytic hydrogenation of unsaturated aldehyde 144 gave saturated aldehyde 145, and reduction of 145 with lithium aluminum hydride provided racemic lupinine 4 and racemic epilupinine 139. 

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. 

A new photometric determination of volatile bases in tobacco and tobacco smoke in terms of nicotine, which compares quantitatively with mass spectral and g.c. methods, has been developed.27 A colorimetric method for the estimation of nicotine alkaloids in tobacco by reaction with cyanogen bromide and 4,4 -di-aminostilbene-2,2 -disulphonic acid has also been reported.28 Dilute sulphuric acid extraction of nicotine and anabasine from autopsy tissue appears to be a more efficient method than extraction with acidified ethanol, aqueous oxalic acid, and steam distillation.29 Thin-layer chromatography has been effective in the analysis of nicotine and other alkaloids and drugs.30 Two reports on the isolation of anabasine from anabasine-lupinine mixtures have appeared.31 The P a values of some nicotine-type compounds have been determined.32... 

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