"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.
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