Chemoselective Strategy for the Direct Formation of Tetrahydro-2,5-methanobenzo[ c]azepines or Azetotetrahydroisoquinolines via Regio- and Stereoselective Reactions.

Ervin Kovács,Balázs Huszka,Ferenc Faigl,Miklós Nyerges,Zoltán Mucsi,Tamás Gáti

doi:10.1021/acs.joc.9b00798

Ervin Kovács, Balázs Huszka + Show 4 more

Open Access

https://doi.org/10.1021/acs.joc.9b00798

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Abstract

The present study reports regio- and highly diastereoselective preparative methods for the synthesis of versatile alkaloid-type compounds from oxiranylmethyl tetrahydroisoquinolines. 2,5-Methanobenzo[ c]azepines or azetidine-fused heterocycles were synthesized in tandem reactions depending on the absence or presence of a BF3 co-reagent. A high functional group tolerance has also been demonstrated. DFT calculations with an explicit solvent model confirmed the proposed reaction mechanisms and the role of kinetic controls on the stereochemical outcome of the reported new methods.

Highlights

The pyrrolidine- and azetidine-fused 1,2,3,4-tetrahydroisoquinolines are among the most frequently used heterocycles in medicinal chemistry due to the wide range of physiological activities displayed in their drug representatives
A novel, highly stereo- and diastereoselective method has been developed for preparation of pyrrolidine- and azetidine-fused 1,2,3,4-tetrahydroisoquinolines (7a−i, 8a,b, 9aj, and 10a,b) by using strong alkali amide-type bases
Quantum-chemical investigations of the mechanism are in accordance with the experimental findings and shed light on the details of the novel intramolecular reactions

Summary

■ INTRODUCTION

The pyrrolidine- and azetidine-fused 1,2,3,4-tetrahydroisoquinolines are among the most frequently used heterocycles in medicinal chemistry due to the wide range of physiological activities displayed in their drug representatives. The construction of the 2,5-methanotetrahydro-2H-2benzazepine skeleton (2) has been achieved through only three main strategies:[27] Pictet−Spengler reaction[11,28−31] or a ring closure of the pyrrolidine derivative,[10,32] an intramolecular [3 + 2]-cycloaddition,[13,14] and via intramolecular Nalkylation.[12] Other special examples have been reported like lactamization.[33]. Clean metalation of N-alkyltetrahydroisoquinolines could be accomplished in the C4 position with butyllithium.[34−41] Almena has reported a fast β-elimination from the C4-lithiated N-methy-tetrahydroisoquinoline during metal-. This side reaction may be responsible for the lower yields of such metalation electrophile addition reaction sequences. (1) and pyrrolidine-fused (2) heterocycles from oxiranylmethyl group substituted tetrahydroisoquinoline derivatives, along with the results of quantum chemical calculations, for the confirmation of the proposed reaction mechanism

■ RESULTS AND DISCUSSION

■ CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES