The attempted stereoselective synthesis of chiral 2,2′-biindoline
Graphical abstract
Introduction
Chiral biamine compounds are commonly used as ligands in stereoselective metal-catalysed reactions, including Michael additions, biaryl couplings and asymmetric dihydroxylations to name just a few.1 We are interested in chiral ligand designs based on helix sense discrimination and ligand types of appeal include biphosphines, biarsines, biamines and helical ligands that possess a mixture of heteroatoms. Our general target structures are encapsulated by 2 (Fig. 1) where the helix is defined by two stereogenic atoms, flanked by metal co-ordinating heteroatoms, thus forming an arc of helicity. The helical groove depth and degree of twist could be modulated by a range of substituents ‘R’, including the presence of fused rings. Importantly, an appropriate synthetic strategy towards these structures should not only be highly stereoselective, but should allow articulation to produce different ring sizes, fused-ring structures and a range of substituted ligands stereoselectively, and in an efficient manner.
The importance of the indoline structure has long been recognised with reference to its place in natural product chemistry, drug design and development and in industry as a key element in catalysts. Despite this illustrious history, there has been surprisingly little investigation into the 2,2′-biindoline structure 42—even more surprising is the lack of any reporting of the stereoselective synthesis of 4 or related compounds that contain 4 as a substructure. In this paper, we report the first attempted stereoselective synthesis of the parent 2,2′-biindoline 4 starting from achiral substrates and utilising Sharpless asymmetric dihydroxylation as the key reaction for the introduction of the chiral elements.
Section snippets
Results
We, and others, have previously reported a self-metathesis—dihydroxylation strategy for the stereoselective synthesis of 2,2′-bipyrrolidine3 and 2,2′-bistetrahydrofuran.4 Here we utilise the same strategy (Fig. 1), starting with the protection of 2-allylaniline20 to produce 6 in 88% yield (Scheme 1).5 Olefin metathesis of 6 using Grubbs II catalyst in CH2Cl2 at reflux yielded the dimer 7 (61%) as a 92:8 mixture of the E/Z isomers—a single recrystallisation from hexanes increased the ratio to E/Z
Conclusion
We have shown that the metathesis—dihydroxylation strategy can be extended from the synthesis of 2,2′-bipyrrolidines to the synthesis of 2,2′-biindolines, however, it is not a valid stereoselective synthesis with poor ee returns during the dihydroxylation reactions. We suggested that the steric intrusion of the two aromatic ortho substituents are responsible and that it is sufficiently general to say that the Sharpless AD reactions are not suitable conditions for any allylic bis(di-ortho
General procedures
Reagents and solvents were purchased reagent grade and used without further purification unless otherwise stated. THF and Et2O were distilled from sodium/benzophenone and CH2Cl2 was distilled from CaH2. All reactions were performed in standard oven-dried glassware under a nitrogen atmosphere unless otherwise stated. UV irradiation was carried out with a 500 W Iwasaki Electric Lamp at 250–400 nm. Melting points were determined using a Gallenkamp (Griffin) melting point apparatus. Temperatures are
Acknowledgements
Financial support from UoW small grants schemes is gratefully acknowledged. MJG and SMW thank the Australian Research Council for PhD scholarships.
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