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

Abstract

Tropanes and related bicyclic alkaloids are highly attractive compounds possessing a broad biological activity. Here we report a mild and simple protocol for the synthesis of N-arylated 8-azabicyclo[3.2.1]octane and 9-azabicyclo[3.3.1]nonane derivatives. It provides these valuable bicyclic alkaloid skeletons in good yields and high levels of diastereoselectivity from simple and readily available starting materials using visible-light photoredox catalysis. These bicyclic aniline derivatives are hardly accessible via the classical Robinson tropane synthesis and represent a particularly attractive scaffold for medicinal chemistry. This unprecedented annulation process takes advantage of the unique reactivity of ethyl 2-(acetoxymethyl)acrylate as a 1,3-bis radical acceptor and of cyclic N,N-dialkylanilines as radical 1,3-bis radical donors. The success of this process relies on efficient electron transfer processes and highly selective deprotonation of aminium radical cations leading to the key α-amino radical intermediates.

Fig. 1. Tropanes and homotropanes.

Selected examples of tropane and homotropane alkaloids as well as N-arylated tropane derivatives of biological interest.

Fig. 2. Retrosynthetic analysis.

Retrosynthetic analysis of tropane alkaloids according to their biosynthesis and to Robinson synthesis (a) as a source of inspiration for a radical retrosynthetic analysis (b). New C–C bonds are indicated in red, radical donor as red dot and radical acceptor as red circle.

Fig. 3. Oxidation of trimethylamine.

One- vs. two-electron pathways. Desired radical process indicated in red.

Fig. 4. Photoredox catalyzed α-functionalization of tertiary amines.

Selected leading contributions in the field (a–e) and proposed annulation strategy (f). New C–C bonds are indicated in red (radical process) and in blue (ionic process).

Fig. 5. Cyclization of the mono-allylated pyrrolidine 2a.

Influence of acid additives on the cyclization step. New C–C bonds is indicated in red.

Fig. 6. Tropane skeletons via radical annulation.

Scope of the N-aryl moiety. New C–C bonds are indicated in red. X-ray crystal structure of 3a (ellipsoids drawn at 50% probability).

Fig. 7. Annulation reaction of N-phenyl-2-methylpyrrolidine.

New C–C are indicated in red. The reaction involves the regioselective activation of 2,5-disubstituted pyrrolidine to form preferentially R2f over R2f’.

Fig. 8. Homotropane [3.3.1] and extended tropane [4.3.1] skeletons.

New C–C bonds are indicated in red. Products are drawn in their major conformations attributed from ¹H-NMR spectra analysis. X-ray crystal structures of α-8g, ellipsoids drawn at 50% probability (oxygen and nitrogen atom are represented in red and blue, respectively).

Fig. 9. 2,3-Disubsituted [4.4.1]-homotropane.

Diastereoselective preparation of a 2,3-disubsituted [4.4.1]-homotropane. New C–C are indicated in red. X-Ray crystal structure of E-9 and 1, ellipsoids drawn at 50% probability.

Fig. 10. N-Dearylation.

Dearylation of (a) the N-MeOPh derivative 3c and 8e, and (b) the N-p-pinBPh derivative 8j.

Fig. 11. Epimerization.

Base promoted thermodynamic epimerization of tropane and homotropane derivatives.

Fig. 12. Mechanism.

Possible mechanism for the [3 + 3] radical annulation and analysis of (a) the regioselectivity of radical formation, (b) the selective formation of bicyclic radicals, and (c) the equilibrium between the different radical cations formed during the reaction. New C–C bonds are indicated in red. Redox potentials and pK_as are indicated in blue. Radical cations are labeled in green.

Fig. 13. Electrochemical study.

Cyclic voltammograms of N-p-methoxyphenylamines 1d and 3d (1 mM) in the absence (a and c) and in the presence of cesium pivalate (1.2 mM) (b and d). Voltammograms were recorded at 100 mV/s in acetonitrile containing [Bu₄N][PF₆] (0.1 M) as a supporting electrolyte. pK_as are indicated in red. Voltammogram traces are depicted in blue.

Fig. 14. Double annulation process.

Synthesis of a homotropane skeleton via a double [3 + 3] annulation reaction. C–C Bonds formed during the first annulation process are indicated in red, C–C Bonds formed during the second annulation process are indicated in blue.