Holly J. Davis

Catalytic enantioselective Minisci-type addition to heteroarenes

Light and acid steer a radical addition So-called Minisci reactions have been used for decades in pharmaceutical and agrochemical synthesis to make carbon-carbon bonds. The reactions link carbon radicals to the carbon centers adjacent to nitrogen in pyridine rings. Proctor et al. devised a method to steer these reactions to just one of two possible mirror-image products. To make the radicals, they prepared derivatives of widely available amino acids and then activated them with an iridium photocatalyst. At the same time, a chiral phosphoric acid catalyst was used to activate the pyridine and bias the reaction geometry. Science, this issue p. 419 Pairing a photocatalyst with a chiral acid renders a widely used carbon-carbon bond-forming reaction asymmetric. Basic heteroarenes are a ubiquitous feature of pharmaceuticals and bioactive molecules, and Minisci-type additions of radical nucleophiles are a leading method for their elaboration. Despite many Minisci-type protocols that result in the formation of stereocenters, exerting control over the absolute stereochemistry at these centers remains an unmet challenge. We report a process for addition of prochiral radicals, generated from amino acid derivatives, to pyridines and quinolines. Our method offers excellent control of both enantioselectivity and regioselectivity. An enantiopure chiral Brønsted acid catalyst serves both to activate the substrate and induce asymmetry, while an iridium photocatalyst mediates the required electron transfer processes. We anticipate that this method will expedite access to enantioenriched small-molecule building blocks bearing versatile basic heterocycles.

Substrate Fragmentation for the Design of M. tuberculosis CYP121 Inhibitors

The cyclo‐dipeptide substrates of the essential M. tuberculosis (Mtb) enzyme CYP121 were deconstructed into their component fragments and screened against the enzyme. A number of hits were identified, one of which exhibited an unexpected inhibitor‐like binding mode. The inhibitory pharmacophore was elucidated, and fragment binding affinity was rapidly improved by synthetic elaboration guided by the structures of CYP121 substrates. The resulting inhibitors have low micromolar affinity, good predicted physicochemical properties and selectivity for CYP121 over other Mtb P450s. Spectroscopic characterisation of the inhibitors′ binding mode provides insight into the effect of weak nitrogen‐donor ligands on the P450 heme, an improved understanding of factors governing CYP121–ligand recognition and speculation into the biological role of the enzyme for Mtb.

Spirooxindoles as novel 3D-fragment scaffolds: Synthesis and screening against CYP121 from M. tuberculosis.

The search for new scaffolds to complement current HTS and fragment libraries is an active area of research. The development of novel strategies to synthesise compounds with 3D character in order to expand the diversity of a fragment library was explored. A range of substituted bicyclo[2,2,1]spirooxindoles were synthesised using a Diels-Alder [4+2] cycloaddition reaction. Both diastereoisomers were isolated from the reactions and these 3D fragment scaffolds were screened against the cytochrome P450 enzyme CYP121 from Mycobacterium tuberculosis. A number of hits were identified to bind to CYP121 and were shown to exhibit Type I binding interactions with the heme group.

Corrigendum: Substrate Fragmentation for the Design of M. tuberculosis CYP121 Inhibitors

a) On page 1927, left column, paragraph 1, the sentences that read “Deprotection of the a-amino group under anhydrous acidic conditions yielded the desired ligands 2, 3, and 5 as their hydrochloride salts, while compound 4 was retained as the Nacetyl protected ester. Both compounds 2 and 3, and the 1-N-methylated analogue 5, produced type II shifts of + 4.0–4.5 nm in the Soret lmax of the CYP121 optical spectrum. In contrast, the N-acetylated analogue 3 did not produce a significant change in the Soret (Dlmax<1 nm)” should instead read: