Christian Marazano

Stereocontrolled Alkylation of Chiral Pyridinium Salt Toward a Short Enantioselective Access to 2‐Alkyl‐ and 2,6‐Dialkyl‐1,2,5,6‐Tetrahydropyridines

Treatment of salts 1a-b with Grignard reagents gives, after reduction of the resulting unstable dihydropyridines 7, the tetrahydropyridines 8a-c, with modest selectivities but in very few steps and under practical conditions. Higher stereo- and regioselectivities are obtained with salt 1c which gives the tetrahydropyridines 15a-e. In addition, the dihydropyridine intermediates 11b cyclize to give the new oxazolidine derivatives 12a-e, which turn out to be good precursors of the 2,6-trans-disubstituted tetrahydropyridines 21a-e. Selective syntheses of (−)-lupetidin, (+)-solenopsin, and indolizidines (−)-5 and (−)-6 are presented as representative examples of applications.

Synthesis of chiral isoquinuclidines and determination of their absolute configuration

Abstract A route to 1,2-dihydropyridines N1-substituted with chiral auxiliaries has been developed starting from commercially available chiral amines. Cycloaddition between these dihydropyridines and methyl acrylate gave, in moderate d.e., isoquinuclidines of good enantiomeric purity whose absolute configuration has been established.

Stereoselective cycloaddition of N-glycopyranosyl 1,2-dihydropyridines with methyl acrylate.

Stereoselective cycloaddition of N-glycopyranosyl 1,2-dihydropyridines (2)–(4) with methyl acrylate allowed asymmetric synthesis of isoquinuclidines (−)-(1) (84% e.e.) or (+)-(1) (72% e.e.).

3-Alkyl 1,6-dihydropyridines from 3-alkyl 5,6-dihydro-pyridinium salts. Implications in the biosynthesis of some macrocyclic marine alkaloids

Abstract Additions of salts 1 and dihydropyridines 2 in an intramolecular manner have been invoked in the biosynthesis of some macrocyclic alkaloids such as manzamines, sarain A and halicyclamine A, recently isolated from sponges. We report conditions for the deprotonation of easily accessible salts 1 , giving a regioselective entry to 3-alkyl 1,6-dihydropyridines 2 . Also, we show that species 1 and 2 can be generated from a common intermediate such as 9 . Dihydropyridines 2 are unstable at high temperatures giving isomeric 1,2- and 1,4-dihydropyridines, but were conveniently trapped by dienophiles to give synthetically useful isoquinuclidines such as 18 or 20 .

Further Insight from Model Experiments into a Possible Scenario Concerning the Origin of Manzamine Alkaloids

The common source of this new class of alkaloids and the structural similarities of these compounds suggest the existence of a unique biosynthetic pathway, in a particularly striking example of “nature diversity-oriented synthesis”. The biosynthetic pathway is unknown to date; however, in 1992, Baldwin and Whitehead put forward the hypothesis that dihydropyridinium salts 1 formed through the condensation of aminoaldehydes with acrolein may serve as key intermediates(Scheme 2). This hypothesis was tested experimentally and, remarkably, provided access to keramaphidin B. However, the efficiency of this kind of strategy was limited as a result of a competing dihydropyridine redox process. Furthermore, the model proposed by Baldwin and Whitehead did not permit access to the manzamine skeleton. Studies towards the synthesis of cyclostellettamines led us to propose an alternate scenario based upon the chemistry of aminopentadienal species 2, which could be formed from malonaldehyde instead of acrolein. This modification of the initial proposal is summarized in Scheme 2. Experimental studies revealed that only regioisomers of aminopentadienals 2 were available (isomers 14, see Scheme 5), but that these regioisomers do add to salts 1 to deliver the AB ring system of halicyclamine A (via analogues of 3), whereas the condensation of aminopentadienoic esters enabled the synthesis of analogues of the AB ring system of manzamine A (via analogues of 4). Herein, we report further results related to the chemistry depicted in Scheme 2. We describe a new method based on the original proposal of Baldwin and Whitehead for the preparation of salts 1, as well as a Chichibabin-like process for the formation of a common intermediate, which, depending on the reaction conditions, rearranges to give a ring system equivalent to the AB ring system of 3 or the AB ring system of 4. To our knowledge, the condensation of an unsaturated aldehyde, such as acrolein, with aldehydes and amines to give dihydropyridinium salts 1 has no equivalent in the literature. However, as acrolein can be viewed as the aldol-condensation product of acetaldehyde and formaldehyde, the reaction could be considered to be related to the Chichibabin synthesis of pyridines. Indeed, this multicomponent procedure, known as early as the beginning of the 20th century, involves the condensation of three equivalents of an aldehyde with ammonia at high temperature to give 2,3,5-trisubstituted pyridines (Scheme 3, R=H). If R is an alkyl group, the reaction produces the corresponding pyridinium salts. In fact, the intermediates of this reaction are believed to be dihydropyridinium salts 7, or even dihydropyridines 8, which are oxidized spontaneously under the rather harsh and acidic reaction conditions. The initial main drawbacks of this process were the necessary use of the same aldehyde, which does not allow variation of the R groups, and the difficulty in stopping the reaction at the dihydropyridinium stage. The selective synthesis of salts 1 by the route proposed in Scheme 2 could thus be viewed as a useful modified Chichibabin synthesis of six-membered nitrogen heterocycles. After some unsuccessful attempts, we have now found a sequence that mimics this process (Scheme 4). The Strecker Scheme 1. Some natural products representative of the manzamine family of alkaloids.

Synthesis of macrocyclic or linear pyridinium oligomers from 3-substituted pyridines. Model synthetic studies toward macrocyclic marine alkaloids

Abstract Refluxing of 3-substituted pyridine 6 in acetonitrile resulted in the formation of a series of oligomers 8 , which with an average value of n=14, were found to possess cytotoxicity comparable with those of natural toxins 1 extracted from sponges. By contrast, refluxing of 6 in the presence of potassium iodide afforded the bispyridinium macrocycle 7 in fairly good yield. The macrocyclic compound 7 , whose structure was established by X-ray analysis, afforded in four steps an intermediate 13 which proved to be a stable precursor of bis 5,6-dihydropyridinium salt 12 or unstable bis 1,6-dihydropyridine 14 . These compounds are expected to be suitable models for studying intramolecular additions of species 4 which are considered to be key intermediates in the biosynthesis of a number of recently discovered macrocyclic pyridine alkaloids.

1,4-Dihydropyridines from Dithionite Reduction of Pyridinium Salts without Electron-Withdrawing Groups as Substituents

Abstract Conditions have been established for the sodium dithionite (Na2S2O4) reduction of pyridinium salts 1 lacking electron-withdrawing substituents to their corresponding 1,4-dihydropyridines (1,4-DHPs) 2, a reaction which was previously reported to fail. The importance of hydrophobic effects for this reduction to take place could be recognized from the results obtained. The present procedure offers a very convenient route to a number of 1,4-DHPs 2, in particular, a series of chiral derivatives such as 5 and 9.

One-pot formation of piperidine- and pyrrolidine-substituted pyridinium salts via addition of 5-alkylaminopenta-2,4-dienals to N-acyliminium ions: application to the synthesis of (±)-nicotine and analogs.

Addition of 5-alkylaminopenta-2,4-dienals onto N-acyliminium ions, generated in situ from α-hydroxycarbamates derived from pyrrolidine or piperidine, in the presence of zinc triflate, followed by dehydrative cyclization, allowed the formation of pyridinium salts substituted at their 3-position by a five- or six-membered nitrogen heterocycle. Subsequent N-dealkylation of the pyridinium moiety and deprotection of the secondary amine or reduction of the carbamate function led to (±)-nicotine and analogs.

Reaction of aldimine anions with vinamidinium chloride: three-component access to 3-alkylpyridines and 3-alkylpyridinium salts and access to 2-alkyl glutaconaldehyde derivatives.

N-tert-Butylimino derivatives of aldehydes were deprotonated with LDA and reacted with vinamidinium chloride to give 2-alkylaminopentadienimine derivatives, which were isolated as their corresponding hydrochloride in 68-81% yield. Reaction of these derivatives with ammonium acetate or salts of primary amines, in n-butanol at 80 degrees C, afforded the corresponding 3-alkylpyridines or 3-alkylpyridinium salts in high yield. Alkaline hydrolysis of 2-alkylaminopentadieneimine derivatives allowed a practical accesss to potassium salts of 2-alkylglutaconaldehyde.

Model studies towards a biomimetic synthesis of keramaphidin B and halicyclamine A

Abstract As a model for condensation reactions of macrocycles of type 1 , which are possibly implicated in the biosynthesis of a number of new alkaloids recently extracted from sponges, we now report that treatment of dihydropyridinium salt 13 with triethylamine in dichloromethane gave, after reduction with sodium borohydride, adducts 15 and 16 in 25% and 7% isolated yields, respectively. The structures of these adducts are identical to the core structures of keramaphidin B, a biogenetic precursor of manzamines, and halicyclamine A.