Lupinanes

A number of other syntheses of coniine have been effected, of which that of Diels and Alder is of special interest. The initial adduct of pyridine and methyl acetylenedicarboxylate, viz., tetraraethylquinolizine-1 2 3 4-tetracarboxylate (IX) on oxidation with dilute nitric acid is converted into methyl indolizinetricarboxylate (X). This, on hydrolysis and decarboxylation, furnishes indolizine, the octahydro-derivative (XI) of which, also known as octahydropyrrocoline, is converted by the cyanogen bromide method (as applied by Winterfeld and Holschneider to lupinane, p. 123) successively into the broraocyanoamide (XII), cyanoaraide (XIII) and dZ-coniine (XIV). A synthesis of the alkaloid, starting from indolizine (pyrrocoline) is described by Ochiai and Tsuda. ... 

The same authors have investigated the degradation of lupinane (XIII), cf. (XIV), by the cyanogen bromide process, the steps and products being as follows —... 

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 —... 

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. 

In 1931 Winterfeld and Kneuer, as a result of their observation that jS-lupinane can be obtained from lupanine, and the formation of 2-methyl-pyrrolidine by the oxidation of sparteine, combined these two features in a partial formula (II) for lupanine, which could be developed in various ways depending on the mode of attachment of the methylpyrrolidine residue. In view, however, of Ing s demonstration of the relationship of anagyrine, CJ5H20ON2, to Z-lupanine, CJ5H24ON2, and d-sparteine, C15H28N2, it was elearly neeessary to consider formul for lupanine derivable from the two alternati-ves, which Ing had proposed for anagyrine and which are shown below as (III) and (IV) with the formul for lupanine derived from them (V) by Ing and (VI) by Clemo and Raper. Sparteine would be represented by (V) or (VI) with the change CO CH2. 

The lupinane group has not attracted chemists as a primary material for modification in the hope of developing substances of possible therapeutic interest. Liberalli found lupanine was inactive in avian malaria and Clemo and Swan state that this is also the case for ll-(e-diethylamino- -pentyl)aminolupinane. Lupinine -aminobenzoate has been investigated in Russia and shown to possess marked local anaesthetic action. ... 

The reaction is particularly useful for investigation of the structure of alkaloids. For example, in the study of lupinene, lupinane (1) was cleaved by reaction with cyanogen bromide in boiling benzene to a product shown to be (2) by degradation to quinolinic acid (3). ... 

The structure of lupinine (II) was confirmed by Winterfeld and Holschneider (120) by means of a cyanogen bromide degradation of lupinane (XV) to l-cyano-2-(o)-bromobutyl)-3-methylpiperidine (XVI). Lupinane (XV) was obtained from pure lupinine by sulfuric acid degrada-... 

Willstatter and Foumeau (118) and found that their product was optically inactive. The loss of activity may have been inherent in the method of dehydration. A product could have been produced which would equilibrate between XXI and the structure XXIa, in which the second asymmetric carbon would also be destroyed. Hydrogenation of anhydrolupinine (121) over palladium on calcium carbonate according to the method of Bartholomaus and Schaumann (122) gave two isomeric, optically inactive lupinanes (XV), C10H19N, separated by the fractional crystallization of their picrates from methanol a-lupinane picrate, m.p. 187° j8-lupinane picrate, m.p. 163°. Karrer and Vogt (123) were able... 

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... 

A closer approach to the synthesis of lupinine was made by Winter-feld and Holschneider (144, 145) in their synthesis of /3-lupinane (see... 

LI by reaction with y-ethoxypropylmagnesium bromide. Reduction to the piperidyl carbinol LII was followed by treatment with hydriodic acid. The base produced, CxoHuN, formed a picrate, m.p. 163 , and an aurichloride, m.p. 142-143 . The melting points were undepressed when the derivatives were mixed with the corresponding derivatives of inactive /3-lupinane (XV) obtained from natural lupinine (120). The total synthesis of lupinine itself was achieved somewhat later by Clemo, Morgan, and Raper (146, 147). 

The synthesis of dl-lupinine was also accomplished by Winterfeld and von Cosel (149) by a process similar to that which had been employed in the earlier synthesis of lupinane (144, 145) (see LI —> LII XV), but... 

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-... 

Two isomeric picrates, m.p. 187° and 195°, were isolated by means of their differential solubility in ethanol, corresponding to the two racemates expected for aZlo-lupinane. In the synthesis of 4-methylquinolizidine by Boekelheide and Rothchild (141), the only picrate obtained for characterization of the base, CioHi9N, melted at 191-195°. 

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