Catalytic Enantioselective Allene Cycloisomerisation Reactions for Alkaloid Total Synthesis

Project Information

CATRATS

Grant agreement ID: 751281

DOI

10.3030/751281

Project closed

EC signature date 14 March 2017

Start date 12 June 2017

End date 11 June 2019

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 183 454,80

EU contribution

€ 183 454,80

Coordinated by

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
United Kingdom

Periodic Reporting for period 1 - CATRATS (Catalytic Enantioselective Allene Cycloisomerisation Reactions for Alkaloid Total Synthesis)

Reporting period: 2017-06-12 to 2019-06-11

Summary of the context and overall objectives of the project

The morphan core is common to >300 natural products, some of which have very important biological properties that may benefit society. Synthetic access to such compounds is challenged by the fact that the morphan is inherently chiral and enantioseletive methods are needed. Catalysing such reactions requires the development of novel catalysts and catalytic systems. The aim of this project was to discover a new catalysed reaction that could access these desirable motifs from easily synthesised allene-linked substrates, and to explore the scope of the reaction with respect to all possible variations.

During the course of this project, we have developed a desymmetric intramolecular cyclization of N/O-tethered allenyl cyclohexanones by means of a dual catalytic system via concomitant activation of the cyclohexanone with chiral prolineamide and activation of the allene with copper catalyst is reported. This cyclization strategy provides a reliable solution to construct 4-vinyl-2-azabicyclo[3.3.1]nonan-6-ones the key precursors of leuconicine A and B. In addition, this cyclization strategy has been successfully expanded to the construction of 4-vinyl-2-oxabicyclo[3.3.1]nonan-6-ones with excellent diastereoselectivity and enantioselectivity.

Additionally, we discovered a new enantioselective insertion of diazo compounds into C-C bond of 1.3-dicarbonyl compounds. This reaction provides an efficient method for the construction of an all-carbon quaternary stereocenters, which could be of great interest. There is no sufficient time for me to finish this reaction, and the further research about this transformation is ongoing in our lab.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We prepared a series of N/O-tethered allenyl cyclohexanones from simply and commercially available chemicals. After scanning a diversity of organocatalysts, metal catalysts and other reaction parameters, the synthesis of morphan core has been destablished from allenyl cyclohexanones catalyzed by a dual catalyst system in one step, using a chiral prolineamide as organocatalyst and a proper copper salt as the metal catalyst, which has allowed us to obtain the initial core in good yield and excellent enantioselectivty.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

We have successfully developed a new enantioselective approach to multi-substituted morphan core and oxabicyclo[3.3.1]nonan-6-ones which could also be used in the synthesis of many alkaloids containing a morphan substructure. Beyond this, we can further synthesis some morphan contained alkaloids, test the bioactivities and collect full data for the medchemists.

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