Aromatic natural products biomimetic synthesis

In nature, the intramolecular condensation of a 1,3-dicarbonyl moiety with a keto group in polyketides is an important step in the biosynthesis of aromatic compounds. Biomimetic transformations of this type have been intensively investigated by Harris. (For a discussion, see Chapter 1.5, this volume.) In the following, the synthesis of some natural products and biologically active compounds using the Knoevenagel reaction will be described. 

In 2005, the group of Nicolaou reported the total synthesis of the biomimetic (-l-)-rugulosin (15) by employing an impressive one-pot, seven-step cascade sequence (Scheme 13.2) [3]. Following the biosynthetic proposals of Shibata and the preliminary experimental results of Nicolaou, a major obstacle to the synthesis of the natural product was the presence of p-alkoxy ketone moieties in both the monomeric ketone 7 and the dimeric intermediates, as these alkoxy groups were very prone to elimination and subsequent aromatization of the resulting cyclohexenone ring. Nicolaou... 

The first biomimetic synthesis of morphine was described by Sir Derek Barton (Imperial College in London). Barton showed that oxidation of reticuline (31) with potassium ferricyanide gave salutaridine (32) in 0.015% yield. Since salutaridine had been converted to morphine, this constituted a synthesis of the target alkaloid. How does one isolate a product in 0.015% yield. Not easily. In this case, the isotope dilution method was used to establish yield. Reticuline was prepared in radioactive hot form (tritiation in the aromatic ring). The oxidation reaction was run and a known amount of cold salutaridine was added to the reaction mixture. The salutaridine was then isolated and purified to a constant level of radioactivity. The amount of hot salutaridine derived from reticuline was calculated based on the radioactivity that had been incorporated, and the percentage yield of salutaridine (from reticuline) was thus determined. The details are given on Morphine-6. The bottom line is that this demonstrated the feasability of this route to morphine, but it did not provide a practical route to the natural product. 

The mew-substituted porphyrins, though not naturally occurring, are widely preferred candidates in various fields such as biomimetic models, materials chemistry, photodynamic therapy, catalysis, electron transfer, etc. [180]. The synthesis of these derivatives is much simpler compared to their -substituted counterparts. Rothenmund et al. prepared the first mew-tetramethyl porphyrin derivative by the condensation of acetaldehyde and pyrrole [181]. A side-product chlorin , a porphyrin-related macrocycle, which is largely, but not completely aromatic in nature, is usually formed in this reaction. However, chlorins can be easily oxidized to form the corresponding porphyrins. Alder et al. developed a new method in the 1960s to synthesize tetraphenyl derivatives by the condensation reaction of benzaldehyde and pyrrole in the presence of acidic solvents under refluxing... 

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