Coniine, synthesis

R = H), and coniine (12) were isolated (16) (Table 1). But, because the science was young and the materials complex, it was not until 1870 that the stmcture of the relatively simple base coniine (12) was estabUshed (17) and not until 1886 that the racemic material was synthesized (18). The correct stmcture for strychnine (13, R = H) was not confirmed by x-ray crystallography until 1956 (19) and the synthesis was completed in 1963 (20). 

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. ... 

Although less efficient (TOP = 0.04 h ), similar IH ofofy- and 5-allenic amines in the presence of AgNOj give 2-alkenylpyrrolidines and 2-alkenylpiperidines, respectively (5 [or 6]-Exo-Trig processes) [315]. These reactions have been applied to the synthesis of ( )-pinidine [316] and -) R) coniine [317]. 

A copper-catalyzed one-pot three-component atom-economical C-H functionalization process was used to form enantioenriched propargylamines. This protocol was also employed for the synthesis of the alkaloid (A)-(+)-coniine (Equation (196)).159 159a... 

Further applications include the synthesis of ( )-pinidine 132 (Scheme 15.41) [91] and the synthesis of (K)-(-)-coniine via an axial to central chirality transfer in the cydization of enantiomerically pure 133 to 134 [92]. 

As shown in Table I, this reaction sequence has wide generality and is readily applicable to the straightforward synthesis of various naturally occurring alkaloids such as coniine,9 pumiliotoxin C,11 1 and solenopsin A and B.11 Oxime sulfonates of either linear or cyclic structures may be used. Obviously, the regioselectivity of the reaction follows the general rule of... 

The chiral boron complex prepared in situ from chiral binaphthol and B(OPh)3 is utilized for the asymmetric aza-Diels-Alder reaction of Danishefsky s diene and imines [67] (Eq. 8A.43). Although the asymmetric reaction of prochiral imine affords products with up to 90% ee, the double asymmetric induction with chiral imine by using oc-benzylamine as a chiral auxiliary has achieved almost complete diastereoselectivity for both aliphatic and aromatic aldimines. This method has been successfully applied to the efficient asymmetric synthesis of anabasine and coniine of piperidine alkaloides. 

The simple piperidine alkaloid coniine (for selected asymmetric syntheses of coniine see [22, 81-85]) offered a preliminary test case for hybrid radical-ionic annulation in alkaloid synthesis. From butyraldehyde hydrazone and 4-chloro-iodobutane (Scheme 4), manganese-mediated photolysis afforded the acyclic adduct in 66% yield (dr 95 5) the cyclization did not occur in situ [69, 70]. Nevertheless, Finkelstein conditions afforded the piperidine, and reductive removal of the auxiliary afforded coniine in 34% overall yield for four steps. This reaction sequence enables a direct comparison between radical- and carbanion-based syntheses using the same retrosynthetic disconnection an alternative carbanion approach required nine to ten steps [81, 85]. The potential for improved efficiency through novel radical addition strategies becomes quite evident in such comparisons where multifunctional precursors are employed. 

This method was recently used in the synthesis of different natural products, like the ladybug defence alkaloid harmonine, a- and p-amino acetals and acids (eq 14), and both enantiomers of the hemlock alkaloid coniine, utilizing the nucleophilic 1,2-addition of organolithium and -lanthanoid reagents to SAMP/RAMP hydrazones. 

Diketones and their aldol-derived cyclohexenones are obtained from alkylation of l-benzyl-2,6-di-cyanopiperidine followed by hydrolysis. - This dicyano analog of (47) provides a new method for the synthesis of rra/u-2-mediyl-6-ui ecylpiperidine (solenopsin), a-propylpiperidine (coniine) and other 2,6- alkylpiperidine alkaloid. 

In a similar manner, the 2-cyano-6-oxazolopiperidine synthon is useful for the chiral synthesis of in-dolizidine (monomerine piperidine [(+)- and (-)-coniine and dihydropinidine] and quinolizidine alkaloids.2-Hydroxymethyl-1-amino-1-cyclopropanecarboxylic acid (-)-(2I )-hydroxy-(3S)-nonylamine and a-substituted phenylethylamines are obtained in optically active form from (-)-N-cyanomethyl-4-phenyloxazolidine. 

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