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The Development of a Novel Tin-Free Radical Methodology and its Application to the Asymmetric Total Synthesis of (+)-Ineleganolide

Final Report Summary - RADICALS 2009 (The Development of a Novel Tin-Free Radical Methodology and its Application to the Asymmetric Total Synthesis of (+)-Ineleganolide.)


Executive Summary:

The project RADICALS 2009 has been based on synthetic chemistry methodology and has explored the generation and reactivity of a specific chemical function called cyclopropylketones.

Historically, the generation of cyclopropylketones has proved difficult to achieve, and, as a result, new methods are continuously sought-after. Making available this functional group is important because it serves as a standpoint to access many other key chemical structures which can lead to the synthesis of biologically active substances (such as beneficial pharmaceutical drugs). These, in turn, are crucial in the development of a society.

A few years ago, our group discovered that this chemical function could conveniently be introduced from another class of compounds named xanthatesg by using a special type of chemical technology called the Radical Transfer of Xanthates. At Ecole Polytechnique, we have been developing this technology for almost two decades. Its operational simplicity; the absence of heavy metals; and, more importantly, its convergent nature, allows the intermolecular (or intramolecular) assembling of large and often complex chemical entities in one single step. The efficient increment of chemical complexity is one of the major goals of modern chemical synthesis and the Radical Transfer of Xanthates technology represents a powerful synthetic methodology that achieves this precisely. In addition, non-toxic and low-cost materials are usually employed rendering it a highly attractive option for both industrial and academic laboratories.

At the beginning of the project we already knew that it was possible to introduce this specific functional group by using xanthates, but we didn’t know the scope and the limitations for this transformation. One major problem appeared to be a detrimental side-reaction in which a molecule of carbon monoxide was lost during the reaction conditions (decarbonylation process). We began by studying systematically the nature of this reaction. Thus, we synthesized different substrates containing the cyclopropane function with variations on the nature of the substituent on the cyclopropane ring and observing their reactivity in the Radical Transfer of Xanthates.

(I) Aromatic substitution on the cyclopropane ring

The decarbonylation process appeared to be a significant issue. Different parameters of the reaction were consequently explored. Lowering the temperature of the reactions did decrease the ratio of the decarbonylated product vs. carbonylated; however, longer time reaction were also required along with the appearance of several side products hence lower yields of the desired product were obtained. The reactions were found irreproducible and the mixtures obtained difficult to separate by chromatography. The products obtained were nevertheless induced to cyclise to provide and interesting class of compounds called tetralones.

(II) Nitrogen-substituents on the cyclopropane ring

Although decarbonylation in this type of substrate was not observed, reactions were found to be irreproducible and/or very sensitive to the reaction scale and olefinic partner. Synthetic applications were unsuccessful and this approach was not considered further.

(III) Oxygen-substituents on the cyclopropane:

Studies of this class of substrates were abandoned due to difficulties encountered while the synthesis of the required starting materials.

(IV) Carbon substituents on the cyclopropane

After some initial difficulties we eventually synthesized a reagent able to introduce the desired functionality into a large number of compounds without the undesired decarbonylation process in good yield. This compound can be used as a modular reagent to access this important chemical function reliably. Its preparation is simple and only requires standard purification techniques; therefore, it can be obtained in large quantities easily.

Applications of more complex advanced structures included 2-pyrrolines and 2-dihydrofurans. These compounds have traditionally been prepared as advanced precursors of complex targets (such as natural products and/or pharmaceuticals) and this method provides an efficient route to access both these families of heterocycles.

Conclusions

The project has explored different aspects of an important chemical function and several goals of the proposed project have been achieved successfully. The major success of this project is the development of a new reagent that should prove useful to introduce the cyclopropyl ketone functionality to many different chemical systems. Academic as well as industrial laboratories could find these results very useful in the elaboration of complex targets for the benefits of the society. Finally, the products obtained, have been manipulated in several ways to produce important intermediates in the synthesis of substances with biological properties.