Synthesis of -coniine

Scheme 8 Synthesis of (+)-coniine-HCl via enantioselective aminodiene hydroamination/ cyclization...

Schiff (135) reported a synthesis of coniine involving the action of alcoholic ammonia on butyraldehyde, but it was later shown that the resulting tertiary amine was not identical with coniine. The first synthesis of coniine and the first sjm thesis of an alkaloid is that of Laden burg (136) who condensed 2-methylpyridine with paraldehyde at 250° and reduced the resulting 2-allylpyridine (XCVIII) with sodium in ethanol, thereby obtaining an inactive base (XCIX) very similar to coniine in properties. The... 

An ingenious synthesis of coniine has been obtained by an adaptation of the Diels-Alder type of reaction thus the reaction of pyridine with methyl acetylene dicarboxylate in ether gives rise to methyl quinolizine-1 2 3 4-tetracarboxylate (CII), m.p. 187-188°, and this, on oxidation either... 

Reactions in plants are of course catalyzed by enzymes, but the reactions are simply those allowed by organic chemical principles. Familiar processes such as methylation, oxidation, reduction, decarboxylation, aldol condensations, and so on, are frequently involved. In many cases it is difficult to determine the exact sequence of events, but the broad outlines of the biosynthesis of many alkaloids have been elucidated. To take a simple case for illustration of a biosynthetic pathway, the synthesis of coniine in the hemlock tree will be presented. Coniine (3.6) is the poison in hemlock that was used to kill Socrates. As found in Scheme 3.5, the amino acid lysine is the precursor of coniine. The use of radioactive isotopic labels is invaluable in proving such pathways. 

SCHEME 2439. Total synthesis of coniine using ARCM. 

Although [Mo]-II was the only effective chiral catalyst available in the early 2000s,molybdenum-based catalysts prepared from easy-to-handle precursors by in situ methods have led to a significantly efficient asymmetric catalyst. For example, [Mo]-III (5mol%) exerted the efficiency on the ARCM reaction of 151 (83% yield, 87% ee) in an enantioselective synthesis of coniine (153, Scheme 24.39), a poisonous alkaloid found in poison hemlock and the yellow pitcher plant. [Mo]-II can be considered as a first-choice catalyst for the ARCM reaction as a result of its commercial availability, and it has been used in recent synthesis of natural product. 

Synthesis of (+)-Coniine (+)-Coniine is obtained from hemlock seeds and is known for its toxic properties. Various synthetic routes have been designed for the synthesis of this alkaloid, and asymmetric... 

This was a key step in the first synthesis of coniine. How would the product be converted to coniine ... 

Total Synthesis of Coniine through Enantioselective RCM with Substrates Bearing a Tertiary Amine... 

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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