Racemization-free synthesis of atropisomeric 1-phenylpyrrole based diamines using diphenylphosphoryl azide
Graphical abstract
Introduction
1-Phenylpyrrole backbone containing compounds are known as important building blocks for biologically active compounds.1, 2, 3, 4 Optically active 1-phenylpyrrole derivatives have also been used as chiral reagents5 and resolving agents.6 Recently, successful applications of 1-phenylpyrrole derived amino alcohols as highly efficient ligands in asymmetric transformations have been published.7, 8, 9, 10 An enantiopure amine can be prepared by resolution of the racemic mixture, although it is usually more convenient to synthesize the individual enantiomer from an enantiomerically pure key intermediate.11 The synthesis of the dicarboxylic acid intermediate of numerous enantiopure atropisomeric 1-phenylpyrrole derived amino alcohols was elaborated upon several years ago in our laboratory12 via o,α-dimetalated species.13 Thus, racemic 1-[2-carboxy-6-(trifluoromethyl)phenyl]-1H-pyrrole-2-carboxylic acid11 was prepared by dimetallation of 1-[2-(trifluoromethyl)phenyl]-1H-pyrrole with Schlosser’s base14 followed by dry ice addition. The single atropisomers of 1-[2-carboxy-6-(trifluoromethyl)phenyl]-1H-pyrrole-2-carboxylic acid were prepared via diastereomeric salt formation in pure form.6 However, the development of an efficient resolution for a new racemate is usually laborious. In the case of the widely used binaphthalene derived amino alcohol NOBIN, both methods (resolution and synthesis from optically active precursors) were published.15, 16 The synthetic method was used as the aromatic amine was prepared by Curtius reaction from enantiopure carboxylic acid and proved to be a highly stereoconvergent process.16 Other axially chiral aromatic amines were also synthesized using this method preserving the optical activities.17, 18 Diphenylphosphoryl azide (DPPA) is also a suitable reagent for modified Curtius reactions.18, 19, 20, 21, 22, 23, 24, 25 In addition, DPPA proved to be highly efficient for racemization-free peptide synthesis,26 azidation of alcohols,27 decarbonylation of aldehydes,28 and the synthesis of oxazoles29 and thiol esters30. Optically active amino alcohols are of great scientific interest;31, 32 the diamines and their derivatives are also widely used as excellent bifunctional ligands and organocatalysts.33, 34, 35, 36, 37 Moreover, recent advances in primary amine catalysed asymmetric transformations demonstrate the exceptional usefulness and versatility of primary amines in enantioselective synthesis.38 Therefore, the design and development of novel amine type chiral scaffolds is a major challenge in organic synthesis.
Herein, the first racemization-free synthesis of the primary amino group containing diamine-type axially chiral 1-phenylpyrroles is described. The comparison of the classical and the modified Curtius reactions is shown to demonstrate the functional sensitivity of the transformation. In addition, novel bifunctional primary/secondary and primary/tertiary diamines with an atropisomeric structural scaffold are presented.
Section snippets
Results and discussion
The atropisomeric biaryl type anilines (Ra)-3 were prepared from the readily available amido esters (Sa)-1 as shown in Scheme 1. The optically active amido esters (Sa)-1 were synthesized according to recently reported methods by our group.6, 11 After the selective hydrolysis of the ester group, we studied the transformation of the carboxylic acid function into an amino group by employing azide formation followed by Curtius rearrangement and hydrolysis (Scheme 1). Primary (Sa)-1a, secondary (Sa)-
Conclusions
On the basis of the experimental data we have concluded that the classical transformation of the free carboxylic acid function of optically active 1-(2-carboxy-6-trifluoromethylphenyl)-1H-pyrrole-2-carboxamides into an azide group via the acid chloride, or anhydride causes racemization because of the formation of a stereochemically labile tricyclic isoimidium cation intermediates. The structure of the intermediate is similar to the isoimidinium salts described in the literature.42 Each
General
All commercial starting materials were purchased from Sigma–Aldrich Kft. Hungary and Merck Kft. Hungary and were used without further purification. The reductions were carried out in Schlenk flasks under a dry nitrogen atmosphere. Solvents were typically freshly distilled or dried over molecular sieves. All reactions were monitored by thin-layer chromatography. TLC was carried out on Kieselgel 60 F254 (Merck) aluminium sheets (visualization of the products was made by exposing the plate to UV
Acknowledgements
The project was supported by the Hungarian Scientific Research Fund (OTKA K 104528) and it is connected to the New Széchenyi Development Plan (TÁMOP-4.2.1/B-09/1/KMR-2010-0002).
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