Atropisomeric Properties of N-Acyl/N-Sulfonyl 5H-Dibenzo[b,d]azepin-7(6H)-ones.

Takuya Namba,Tetsuta Oshitari,Hidetsugu Tabata,Mayuno Hotta,Hideyo Takahashi,Hideaki Natsugari,Kosho Makino

doi:10.1021/acs.joc.1c00594

Takuya Namba, Tetsuta Oshitari + Show 5 more

Open Access

https://doi.org/10.1021/acs.joc.1c00594

Copy DOI

Abstract

The stereochemistry of N-acyl/N-sulfonyl 5H-dibenzo[b,d]azepin-7(6H)-ones (I, II) was examined in detail by freezing the conformation with a methyl group at the C-4 of dibenzoazepine. Because the two axes (axis 1, axis 2) move together concertedly, I and II exist only as a pair of enantiomers [(a1R, a2R) and (a1S, a2S)], which was confirmed by X-ray analysis of IIBc. It was elucidated that the amide derivatives I exist in equilibrium with the E/Z-amide (100:2–100:34), which means that the exocyclic bond (axis 3) is not in concert with the endocyclic axes (axis 1, axis 2). For the preparation of 5H-dibenzo[b,d]azepin-7(6H)-one, the intramolecular Friedel–Crafts acylation of N-(1,1′)-biphenyl-2-yl-glycine derivatives was revisited. It was revealed that the electron-withdrawing property of the amino-protective group was a key to the success of seven-membered cyclization.

Highlights

We have been interested in the conformational analysis of benzo-fused seven-membered-ring nitrogen heterocycles, which are found as the scaffolds of many drugs.[1]
According to the procedure reported in a previous paper,[4] the corresponding acid chlorides, prepared from N-(1,1′)biphenyl-2-yl-glycine using thionyl chloride, were treated with anhydrous aluminum chloride
Improvement of the Friedel−Crafts acylation of N(1,1′)-biphenyl-2-yl-glycine derivatives[17] was achieved by the introduction of the amino-protective groups with electronwithdrawing properties. 1H NMR revealed that N-acyl 5H

Summary

Introduction

We have been interested in the conformational analysis of benzo-fused seven-membered-ring nitrogen heterocycles, which are found as the scaffolds of many drugs.[1] Our continuing interest in the relationship between axial chirality and biological activity[2,3] prompted us to examine the N-acyl/ N-sulfonyl 5H-dibenzo[b,d]azepin-7(6H)-ones (I, II) (Figure 1), which were reported to have immunosuppressive effects by inhibiting the potassium channel (Kv1.3, IK-1) of T cells.[4] The Ca2+-dependent potassium channel IK-1 and the voltage-gated potassium channel Kv1.3 in human T cells play a pivotal role during cell proliferation. It was shown that the electron-withdrawing effect of the N-substituent of the amino acids affects the yield of cyclized compounds

Methods

Results

Conclusion