NEW SYNTHETIC ROUTES TO BRIDGEHEAD N-HETEROCYCLES

Research Plan

1.Introduction

The pyrrolizidine-, indolizidine-, and quinolizidine-alkaloids (izidines) found in diverse species of the biosphere (fungi, arthropoda, amphibia, plants) exhibit versatile biological activities. Some of them are defending compounds of arthropoda, while others are very toxic, like alkyl-indolizidines isolated from the skin secretions of neotropical frogs. As potential therapeutic agents against HIV, the polyhydroxy indolizidine alkaloids have received considerable interest, while some simple hydroxy-formyl-pyrrolizidines isolated from certain types of moth act as pheromones. Their comprehensive study is stimulated not only by their extreme biological and ecotoxicological properties, but the minute concentration of numerous representatives of these alkaloids in living organisms (e.g. some indolizidine toxins of Dendrobates species). For this reason, the thorough chemical and physiological investigation of these compounds encounters serious difficulties or even it is often impossible. Therefore, the research of this field became lively in the last few years indicated by the rapidly growing number of related scientific publications. In our planned project we wish to focus on the synthesis and structure elucidation of above mentioned type of compounds.

2.Preliminary Research

Recently numerous experiments were performed on 5-, 6-, and 7-membered heterocyclic enamines containing an electronwithdrawing group in beta-position. These double nucleophiles react with electrophiles in versatile [3+2] or [3+3] cyclization reactions. Thus, we have prepared new indolizidine derivatives from different enamines with dicarbonyl compounds and some new products from the [3+3] cyclizations of -nitroenamines and -enaminonitriles with ,-unsaturated carboxylic acid chlorides (Fig. 1).

Figure 1.
New saturated pyrrolo-pyrimidines and pyrrolo-pyrazines were synthesized from 2-nitromethylene-pyrrolidine. Additionally, some simple aminomethylated derivatives of Mannich type were prepared. The nitro compounds were reduced into diastereomeric amines, which were separated and characterized structurally (Fig. 2).

Figure 2.

Recent papers published by our research team in area of the present project:

1) Pilipecz, M. V.; Mucsi, Z.; Nemes, P.; Scheiber, P.: Chemistry of Nitroenamines. Synthesis of Pyrrolizine Derivatives; Heterocycles, 2007, 71 (9), 1919-1928.
2) Pilipecz, M. V.; Varga, T. R.; Mucsi, Z.; Scheiber, P.; Nemes, P.: [3+3] Cyclization reactions of -nitroenamines and β-enaminonitriles with alfa,beta-unsaturated carboxylic acid chlorides; Tetrahedron, 2008, 64, 5545-5550
3) Scheiber, P.; Tóth, G.; Pilipecz, M. V.; Varga, T. R.; Nemes, P.: Chemistry of Nitroenamines. Part 2: Synthesis of Saturated Pyrrolo-Pyrimidines and – Pyrazines; Heterocycles, 2011, 83, 2001-2010
4) Pilipecz, M.V.; Varga, T.R.; Scheiber, P.; Mucsi, Z.; Fàvre-Mourgues, A.; Boros, S.; Balázs, L.; Tóth, G.; Nemes, P.: Reductive transformations of unsaturated azabicyclic nitrolactams; Tetrahedron 2012, 68, 5547-5553

3.Objectives and expected results of the research plan

The aim of the project is

-to develop new and efficient methods for synthesis of new indolizidine, and benzo- indolizidine derivatives in few steps and acceptable yields using simple and easily available starting materials,
-where the primary products can be converted into natural molecules or new analogues which can draw attention for pharmacological investigations, and
-to exploit the inherent synthetic potential of previously successfully employed intermediates, i.e. mainly ?push-pull? alkenes (enamines with an electronwithdrawing group in -position), and to synthesize a broad spectrum of new heterocyclic compounds.

The expected results of our planned project can contribute to the chemistry of natural products and provide new substances for the pharmaceutical research.

4.Detailed research plan

4.1.Multicomponent reactions of push-pull alkenes

Multicomponent reactions (MCRs) are one-pot reactions employing more than two starting materials, for example, 3, 4, …, 7, where most of the atoms of the starting materials are incorporated in the final product. They are atom economic, for example, the majority if not all of the atoms of the starting materials are incorporated in the product; they are efficient, for example, they efficiently yield the product since the product is formed in one-step instead of multiple sequential steps; they are convergent, for example, several starting materials combine in one reaction to form the product; they exhibit a very high bond-forming-index (BFI), for example, several non-hydrogen atom bonds are formed in one synthetic transformation. Therefore MCRs are often a useful alternative to sequential multistep synthesis. We are going to employ three component reaction of push-pull alkenes to synthetise versatile indolizine-, and kinolizine derivates. Furthermore, these unsaturated compounds can be reduced to indolizidines and kinolizidines (Fig. 3).

Figure 3.

The above detailed research plan is directed toward novel synthetic methods, new compounds or preparations of natural products, therefore it can be regarded as a completely basic research. In case of its successful completion, the results can significantly enrich of the chemistry of polycyclic N-heterocycles. These methods might be valuable tools in the synthesis of novel, pharmacologically active compounds and natural products, as well.