Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - Leucophyl (Total Synthesis of Leucophyllidine)

Teaser

The search for potent chemotherapeutic agents with anticancer activity and issued from natural sources is still attracting a wide interest as drug-resistance tends to proliferate. Terpene indole alkaloids constitute a family of more than 3000 members, in which only a few...

Summary

The search for potent chemotherapeutic agents with anticancer activity and issued from natural sources is still attracting a wide interest as drug-resistance tends to proliferate. Terpene indole alkaloids constitute a family of more than 3000 members, in which only a few exhibit physiological effects on mammals. Vincristine and vinblastine, isolated from Catharanthus roseus, are the most well known, the former being used in the treatment of leukemia, while the latter was found active against Hodgkin’s disease. However, these alkaloids are rather expensive. For instance, 1 kg of vinblastine costs around a million dollars and the annual production in the world is 12 kg. It is interesting noticing that while vinca alkaloids are still the subject of numerous studies, there is not a similar interest for analogues. However, new biologically relevant dimeric alkaloids continue to be discovered that might be worth considering for future clinical applications. This is the case for Leucophyllidine, recently isolated from the stem-bark of Leuconotis griffithii, woody climbers found in Indonesia and Peninsular Malaysia. This alkaloid exhibits a promising in vitro cytotoxicity toward vincristine-resistant human KB cells with IC50 of less than 3 ug/mol. While the level of activity is not outstanding, the selectivity toward resistant cells is of considerable interest in the quest for more efficient and targetable antitumor agents. Leucophyllidine is thus a promising target, and possesses an unusual quinoline sub-structure that opens new perspectives for the discovery of potent drugs in cancer chemotherapy. Kam and co-workers who isolated Leucophyllidine suggested that this alkaloid could have arisen from biomimetic coupling between two natural products Eburnamine and Eucophylline. These different elements stimulated our interest for leucophyllidine, leading to the present research project.

The objective of the research program was thus three-fold, including :
- the development of the first asymmetric total synthesis of Eucophylline and Leucophyllidine,
- the design of new metal-free radical based methodologies using cyclopropenes,
- the identification of a possible biogenetic pathway for the synthesis of Leucophyllidine in the plant.
- and finally, in the endeavor of searching for more potent antitumor agents, the development of further biological testing of the final products and their intermediates.

Work performed

\"Our synthetic plan included the development of a new method to set up the all-carbon quaternary stereocenters found in eburnamine and eucophylline.

We have thus developed a multicomponent free radical carbocyanation addition onto substituted cyclopropenes that gives rise to tetrasubstituted cyclopropyl nitriles bearing the desired quaternary center in satisfying yields with moderate diastereocontrol. The structure of these cyclopropanes also allows subsequent base mediated ring opening, offering straightforward access to acyclic systems having functionalized all carbon quaternary stereocenters, which are important intermediates in the total synthesis of the natural products cited above.

During this study, a serendipitous discovery was made using a-bromoarylketones. These were shown to add stereospecifically onto cyclopropenes, furnishing the carbo-arylation product after cyclization and cyclopropane ring opening. Further elaborations of these naphthalenones bearing an all-carbon benzylic quaternary stereocenter, such as stereodivergent diesters, cyclopropane ring opening, oxa-Michael addition and tin-mediated cyclization\'s were realized.
These investigations led to the publication of two articles :
1. Organic Letters, 2016, 18, 6156 – 6159.
2. Organic Letters, 2017, 19, 3652 – 3655.

A poster presentation of this work was done at the 26th French-Japanese Symposium on Medicinal & Fine Chemistry in Strasbourg, France, September 17-20th 2017. Poster entitled “Stereocontrolled Access to All-Carbon Quaternary Stereocenters via Radical Addition to Cyclopropenes.”

Based on the free radical carbocyanation reaction, we were able to achieve the formal total synthesis of a bicyclic lactam, key-intermediate in the synthesis of Eucophylline.

As the free radical carbocyanation addition onto substituted cyclopropenes relied on the use of tin reagents, which have perceived toxicity, we parallely developed a \"\"tin-free\"\" approach using phenylboronic acids as tin surrogate. This work was completed by the joint efforts of a Japanese student and a master student from Bordeaux University. A publication is under preparation and will be submitted before mid 2018.

3. Eur. J. Org. Chem., 2018, under preparation.

Overall we have got success in achieving efficient methods, however we have faced difficulties in achieving the project goal within the span of research grant. Nevertheless, the progress made during these last 24 months have led the foundation for a successful access to the two key-fragments of Leucophyllidine, which total synthesis will hopefully succumbed in not too distant a future.




\"

Final results

\"Polysubstituted cyclopropanes are useful intermediates in organic synthesis, that have attracted a lot of interest due to their easy ring opening under acidic, basic or free-radical conditions. They are readily available in enantiopure form, and thus rapidly appeared as particularly attractive precursors for our natural targets. Recent progress in the stereocontrolled synthesis of cyclopropanes includes the functionalization of substituted cyclopropenes, also easily available in enantiopure form.

Although functionalization of cyclopropenes has attracted a great deal of interest, using organometallic reagents, little has been done using radical processes.

The work carried out during these 24 months has thus shown that radical addition of two carbon fragments across the cyclopropene π system, which had not been explored so far, is possible and can lead to valuable synthetic intermediates in only 2 steps starting from alkynes. This method gives rise to various tetrasubstituted cyclopropanes in diastereo and enantiopure form, which can then be opened under basic condtions to generate acyclic systems bearing all-carbon quaternary stereocenters as those present in alkaloids such as eucophylline and eburnamine.
This methodology opens a straightforward access to simple synthons, which may then be incorporated into pharmaceutically relevant targets. They may also serve as precursors of more complex molecular architectures including natural products of biological interest.
During this work, we have also faced some problems using tin chemistry, due to the percevied toxicity of these reagents. This led us to envision other modes of activation, including photocatalysis. We thus found that some free-radical additions onto cyclopropenes could be performed under visible-light activation in environmentally more acceptable solvents, using catalytic amount of a photocatalyst.
The access to useful cyclopropanes is now stereochemically controlled and can also be performed under \"\"green\"\" conditions. The tandem cyclopropene radical carbo-cyanation/cyclopropane ring opening provides a stereodivergent access to both enantiomers of acyclic systems having all-carbon quaternary stereocenters.
This methodology finally makes use of readily available enantioenriched cyclopropenes and leads to regioselectivity complementing that observed in carbometalation of cyclopropenes.\"

Website & more info

More info: http://ylandais-chemistry.info/.