BIOPYRR · New Methodology for the Synthesis of Bioactive Pyrrolidines and Pyrrolidinones

New Methodology for the Synthesis of Bioactive Pyrrolidines and Pyrrolidinones

Investigations focused on 5-endo and 5-exo cyclisations of alkynyl amino malonates for the synthesis of nitrogen containing heterocycles. The aim of the project was the development of transition metal catalysed methodologies to generate highly functionalised pyrrolidines and pyrrolidinones as synthetic building blocks for natural product synthesis. The methodologies were then applied in the construction of the pyrrolidine core of the oxazolomycins and related natural products. First a palladium catalysed cyclisation/coupling reaction of butynyl amino malonates was developed which is suitable for the generation of various highly substituted exo-alkylidene pyrrolidines and pyrrolidinones. The reaction is high yielding and one stereoisomer of the olefin is obtained exclusively. Additionally the same starting materials were used successfully in a zinc catalysed Conia-ene reaction which leads to differentially functionalised products. The complementary reaction selectively delivers the E-isomer in high yield. As a catalytic process employing a non-toxic and inexpensive metal catalyst this approach is both economically attractive end environmentally benign. Both the palladium and the zinc based method can be used to synthesise piperidines by means of a 6-exo cyclisation, as well as further heterocycles (tetrahydrofurans) which was demonstrated for a small subset of substrates. Beside the catalytic methods a manganese(III)-promoted radical cyclisation was also investigated which delivers Conia-ene type products in a complementary fashion (Z-isomer) to the zinc catalysed reaction from the same starting materials. During the investigation of the zinc catalysed 5-exo cyclisation the analogous 5-endo cyclisation of propargylic amino malonates was serendipitiously discovered which can be utilized to generate useful pyrroline or pyrrolinone building blocks. Comparable 5-endo cyclisations of substituted malonates are only sparsely documented in the scientific literature prompting us to investigate the reaction in more detail for the formation of nitrogen containing cycles, for the synthesis of carbocycles and dihydrofurans. The reliable and efficient reaction uses an inexpensive and non-toxic catalyst and can be used to generate various cyclic products in excellent yield. With the methodologies in hand we attempted the synthesis of the pyrrolidinone core of oxazolomycin A. The zinc catalysed reaction as well as the manganese promoted method were most suitable for our approach. Following optimisation of the reaction conditions the cyclisations efficiently generated the desired pyrrolidines which can be converted to the appropriately functionalised core motifs in a few steps. We are now in an excellent position to synthesise the lactone-pyrrolidinone core of the oxazolomycins and submit these highly functionalised small molecules for antibiotic and anticancer testing. In summary, we have developed highly efficient catalytic and non-catalytic methodologies for the synthesis of highly functionalised nitrogen- and oxygen-containing heterocycles as well as carbocycles by 5-endo and 5-exo cyclisation reactions. These products, especially the nitrogen containing pyrrolidines and pyrrolidinones are valuable building blocks in synthetic, medicinal and pharmaceutical chemistry. A vast number of natural products and biologically active compounds contain such core structures emphasizing the need for efficient synthetic access. Work in our group is ongoing using these efficient reactions towards the synthesis of further natural product scaffolds (e. g. oxazolomycins, omuralide) which will allow biological testing to commence. See attachment for report with chemical schemes.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз