Harnessing non-covalent interactions to exert control over regioselectivity and site-selectivity in catalytic reactions

Abstract

Asymmetric catalysis has been revolutionised by the realisation that attractive non-covalent interactions such as hydrogen bonds and ion pairs can act as powerful controllers of enantioselectivity when incorporated into appropriate small molecule chiral scaffolds. Given these tremendous advances it is surprising that there are still a relatively limited number of examples of non-covalent interactions being harnessed for control of regioselectivity or site-selectivity in catalysis, two other fundamental selectivity aspects facing the synthetic chemist. This perspective examines the progress that has been made in this area thus far using non-covalent interactions in conjunction with transition metal catalysis as well as in the context of purely organic catalysts. We hope this will highlight the great potential in this approach for designing selective catalytic reactions.

Fig. 1. (a) Proposed mode of reaction for para-chlorination of anisole bound inside α-cyclodextrin (CD). (b) Rationalisation of selectivity in para-selective formylation of phenol catalysed by β-cyclodextrin. (c) The same for carboxylation.

Fig. 2. (a) ortho-Selective borylation of N-Boc anilines. (b) Schematic of proposed transition state for reaction together with results of theoretical predictions and calculations of N–H and O–H bond distances in the TS. (c) ortho-Selective borylation of anilines by in situ formation of N-BPin derivative. (b) Reprinted with permission from ref. 35. Copyright 2012 American Chemical Society.

Fig. 3. (a) The optimal bifunctional bipyridine ligand bearing a hydrogen bond-donor urea, together with the catalyst–substrate complex thought responsible for meta-selective borylation. (b) A selection of substrates, highlighting meta:para selectivity for both the optimal bifunctional ligand and standard borylation ligand dtbpy.

Fig. 4. (a) Optimal ligand design bearing anionic sulfonate group together with working hypothesis for ion-pair directed borylation. (b) Selection of substrates, highlighting meta:para selectivity for both the anionic ligand B and dtbpy.

Fig. 5. (a) An octahedral cage and square-pyramidal bowl assembled from cis end-capped Pd(ii) ions and triazine-cored tridentate ligands. (b) Divergent regioselectivity obtained in the presence of the cage and bowl structures in the Diels–Alder reaction of anthracenes with phthalimides. (a) Reprinted with permission from ref. 41. Copyright 2006 The American Association for the Advancement of Science.

Fig. 6. (a) trans-Selective hydrostannation of propargylic alkynes using ruthenium chloride complex B as opposed to cationic variant A. (b) High regioselectivity is also observed in other unsymmetrical alkynes bearing protic functionality, with selectivity reversal in the case of an ester. (c) Selected experiments conducted to probe the role of hydrogen bonding in the observed regioselectivity. (d) Hypothesis for origin of regioselectivity (left), plus application of this hypothesis to explain observed regioselectivity in two previously reported ruthenium catalysed reactions. (c) and (d) Reprinted with permission from ref. 45. Copyright 2015 American Chemical Society.

Fig. 7. (a) Evaluation of ligands for the hydroformylation of β,γ-unsaturated carboxylic acids and original hypothesis for control of regioselectivity. (b) Calculated transition state for reaction which involves interactions between two bifunctional ligands and the substrate. (b) Reprinted with permission from ref. 53. Copyright 2010 Wiley.

Fig. 8. (a) Highly regioselective hydroformylation of a range of unsaturated alkene chain lengths, except for n = 1, using ligand A compared to using PPh₃. (b) Active complex for hydroformylation as determined by mechanistic studies and DFT calculations. (c) Illustration of high regioselectivities achievable on internal alkenes of variable chain lengths. (d) A phosphite-based DIMPhos ligand is able to invert the standard regioselectivity for hydroformylation of 2-carboxylvinylarenes.

Fig. 9. Reversal of regioselectivity observed in Baeyer–Villiger oxidation of particular cyclic ketones using catalyst A when compared with mCPBA.

Fig. 10. (a) Structure of manganese porphyrin catalysts developed for steroid functionalisation. (b) Outline of design principle used, involving binding groups on the steroid substrate to interact with cyclodextrin units on the porphyrin catalyst. (c) Selective oxidation at C-6 followed by installation of a further binding group then selective oxidation at C-9.

Fig. 11. (a) Outline of catalyst structure (only one half of μ-oxo dimer shown for clarity) with components highlighted, in a hydrogen bonded complex with ibuprofen. (b) Results for oxidation of ibuprofen using catalyst depicted in (a) as well as a control variant without the binding site portion. (c) Outcome of oxidation of a mixture of cis and trans 4-methylcyclohexyl acetic acid using the same two catalysts.

Fig. 12. (a) Structures of two peptides identified to give complementary site-selectivity for epoxidation of farnesol. (b) Site-selectivity for farnesol epoxidation using peptides A and B. (c) One of several plausible models advanced to account for site-selective epoxidation of the 6,7 alkene of farnesol using peptide B. Reprinted with permission from ref. 78. Copyright 2014 American Chemical Society.

Fig. 13. (a) Proposed model for highly site-selective C-4 acylation of glucopyranoside primarily via catalyst interaction with C-6 hydroxyl. (b) Details of site selectivity comparing catalyst A and DMAP as well as the effect of methylating the C-6 hydroxyl. (c) Total synthesis of multifidoside B through selective final step acylation in the presence of two primary hydroxyl groups.

Fig. 14. (a) Structure of aminoglycoside targets with blue and red arrows indicating sites of functionalisation after treatment with the aptamer and then either a succinimide ester (blue) or isocyanate (red). (b) Neomycin B bound to one of the RNA aptamers employed in the study, with the two accessible amines. Reprinted with permission from ref. 83. Copyright 2012 Nature Publishing Group.

Fig. 15. (a) Selective acetylation of the C-4 hydroxyl of a partially protected glucosamine using pentamer peptide A, a catalyst discovered though combinatorial screening. (b) Results of studies to differentiate the three secondary hydroxyls of antibiotic erythromycin A.

Fig. 16. (a) Crystal structure of teicoplanin complexed with a DAla–DAla peptide. (b–d) Extrapolation of this binding mode to incorporate phosphoryl delivery from histidine in different positions in order to access each sugar, as initial hypothesis for rational design of peptide catalysts. (e) Selective phosphorylation of teicoplanin by catalysts 1, 2 and 3. Also shown are sites of bromination with NBP, both uncatalysed (purple) and using catalyst 4. Reprinted with permission from ref. 86. Copyright 2013 American Chemical Society.

Holly J. Davis

Robert J. Phipps