Enantioselective Route to 5-Methyl- and 5,7-Dimethyl-6,7-dihydro-5H-dibenz[c,e]azepine: Secondary Amines with Switchable Axial Chirality

Abstract

(-)-5-Methyl-6,7-dihydro-5H-dibenz[c,e]azepine 4, a new secondary amine featuring an axis-center stereochemical relay, was prepared enantioselectively from 2'-acetylbiphenyl-2-carboxylic acid, using (R)-2-phenylglycinol as an auxiliary for the control of both elements of chirality. The biaryl axis in 4 preferentially adopts the aS-configuration, with the methyl substituent pseudoequatorial, but conversion into the corresponding N-Boc derivative locks the axis into the aR-configuration, as predicted on the basis of molecular mechanics calculations.

Biocatalytic Routes to Enantiomerically Enriched Dibenz[c,e]azepines

“…Preparative‐scale reactions with 1 a were successfully performed with Asp RedAm and IR91 to isolate the enantiomers of 2 a in high conversion, yield, and enantioselectivity, thus demonstrating the synthetic utility of this biocatalytic approach (Scheme ). Product NMR spectra were identical to those previously reported, thus confirming the predominant conformers as ( R ,a S )‐ 2 a and ( S ,a R )‐ 2 a , respectively. The conformers obtained are the result of thermodynamic equilibration (86:14 major/minor at 298 K) .…”

“…Product NMR spectra were identical to those previously reported, thus confirming the predominant conformers as ( R ,a S )‐ 2 a and ( S ,a R )‐ 2 a , respectively. The conformers obtained are the result of thermodynamic equilibration (86:14 major/minor at 298 K) . As the conformers of 1 a can interconvert rapidly, it is possible the enzymes can carry out a dynamic process in which a single conformer of the imine is converted into the major product conformer (Scheme , Path A) .…”

“…Therefore, setting the C‐centred chirality during the synthesis of these compounds also establishes the preferred biaryl conformation. If the substituent at either C5 or C7 is perturbed from a pseudoequatorial to a pseudoaxial position, for example after N‐derivatisation, a resulting switch in axial conformation occurs by this centre‐axis relay effect (Figure b) …”

“…Enantiomerically pure dibenz[ c , e ]azepines have previously been synthesised by employing chiral‐pool starting materials, chiral‐auxiliary methodologies, and chiral‐transition‐metal catalysis for synthetic routes identified by traditional disconnection strategies. To identify new and potentially more‐efficient routes to these compounds, we sought to apply the principles, while at the same time expand the scope, of biocatalytic retrosynthesis …”

Di(1‐naphthyl) methanol ester of carboxylic acids for absolute stereochemical determination

“…Over the past 4 decades, chiroptical spectroscopy, and in particular circular dichroism (CD), has played a pivotal role in the absolute stereochemical determination of organic molecules . Numerous strategies have been devised to address this important issue; nonetheless, it is clear that a unified solution to the problem is not forthcoming.…”