Tropane and related alkaloid skeletons via a radical [3+3]-annulation process

We report a mild and simple protocol for the synthesis of tropane and homotropane derivatives. The methodology provides these valuable bicyclic alkaloid skeletons in good yields and high levels of diastereoselectivity using visible-light photoredox catalysis.

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Tropane alkaloids are small natural products made of a bicyclic core bearing a nitrogen at the bridge position (Fig 1). They are ubiquitous in nature and are mostly found in Solanaceae plants such as the coca plant, from which the tropane alkaloid cocaine can be extracted, or the belladonna, which produces atropine. Scopolamine is for example a widely used pharmaceutical agent, and in general these structures are of interest for the pharmaceutical chemistry. Some patents refer to structurally related compounds – all bearing the bicyclic nitrogen core, with a variety of substituents on the alkane ring or at the nitrogen position.

Fig 1: Members of the tropane alkaloid family. The common bicyclic core is highlighted.

Historically, Robinson was the first to synthesize tropinone using a biomimetic approach based on an ionic [3+3]-annulation; the retrosynthesis traces back to 1,3-bis-iminium ions and 1,3-bis-enolate synthons. Inspired by this protocol, we envisioned that a 1,3-bis-α-amino radical donor and a 1,3-bis radical acceptor could be reacted in an unprecedented radical [3+3]-annulation (Fig 2).

Fig 2. Our proposed radical [3+3]-annulation compared to the Robinson biomimetic synthesis.

To implement this strategy, we chose cyclic tertiary N-arylamines as 1,3-bis radical donors and ester activated allylic traps as 1,3-bis radical acceptors (Fig 3). The methodology enables the synthesis of a variety of tropanes and homotropanes in good yields and good to excellent diastereoselectivity in favor of the alpha isomer. Importantly not only the aromatic moiety can be substituted, but as well the azabicyclic core structure.

Fig 3. Selected scope of the annulation reaction.

We have observed that during this [3+3]-annulation reaction, three different amines with very similar redox properties are present in solution at the same time: the starting aniline, the mono-allylated intermediate, and the bicyclic product (Fig 4). The success of this protocol relies on the fact that i) the starting aniline reacts only once with the radical trap, ii) the second radical formation is regioselective for the α' position, and iii) the bicyclic product does not react further. Additionally, the 6-endo-cyclization is fast enough to outcompete intermolecular processes. This unique selectivity has been rationalized using calculations (oxidation potentials and pKas) and electrochemical studies.

Fig 4. The amine species present in solution and their reactivity.

In conclusion, we present in this paper a new annulation strategy for the synthesis of bicyclic alkaloid skeletons. The reaction conditions are mild and enable to obtain N-arylated tropane and homotropane frameworks in good yields and good to excellent levels of diastereoselectivity starting from simple and readily available starting materials. The method complements nicely the classical Robinson synthesis by allowing to prepare directly the biologically relevant N-arylated skeletons and by introducing an ester group suitable for further derivatization towards applications in medicinal chemistry.

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Eloise Colson

PhD student, University of Bern