Timothy Hurst

Iridium-catalyzed C-H activation versus directed ortho metalation: complementary borylation of aromatics and heteroaromatics.

Systematic studies are presented demonstrating the complementarity of directed ortho metalation (DoM) and Ir-catalyzed strategies for the provision of borylated aromatics and their subsequent Suzuki-Miyaura coupling reactions. A new concept, the use of the TMS group, readily introduced by DoM, as a latent regiodirective moiety to overcome the otherwise problematic production of isomeric borylated product mixtures is presented. Additional electrophile-induced ipso-deborylation and DoM reactions of the Bpin products are described.

Copper‐Catalyzed Cross‐Coupling Interrupted by an Opportunistic Smiles Rearrangement: An Efficient Domino Approach to Dibenzoxazepinones

The construction of C O and C N bonds by palladiumand copper-mediated cross-coupling approaches has undergone a renaissance in the last decade. Although the utility of these coupling approaches to effect a single-bond construction event has now been established, the quest to improve efficiency has driven the further exploration of one-pot procedures for effecting multiple transformations, often by a domino approach. Success in this area has come from impressive examples of ligand control, finely tuned multicatalyst systems, and exploitation of established multicomponent reactions. Based on our previous experience with Ullmann couplings of 2-halobenzamides, combined with the established Goldberg N-arylation methods, 8] we envisaged that a copper-catalyzed one-pot annulation between 2-iodobenzamides 2 and 2-bromophenols 3 would allow access to dibenzoxazepinones 1 by selective C O and C N bond forming events (Scheme 1).

Copper-mediated construction of spirocyclic bis-oxindoles via a double C-H, Ar-H coupling process.

A double C-H, Ar-H coupling process for the conversion of bis-anilides into spirocyclic bis-oxindoles, enabling the concomitant formation of two all-carbon quaternary centers at oxindole 3-positions in a diastereoselective manner, is described. The optimum cyclization conditions utilize stoichiometric Cu(OAc)2·H2O/KOtBu in DMF at 110 °C and have been applied to prepare a range of structurally diverse bis-spirooxindoles in fair to good yields (28-77%); the method has also been extended to prepare bis-oxindoles linked by a functionalized acyclic carbon chain.

A Direct CH/ArH Coupling Approach to Oxindoles, Thio‐oxindoles, 3,4‐Dihydro‐1 H‐quinolin‐2‐ones, and 1,2,3,4‐Tetrahydroquinolines

A copper(II)-catalysed approach to oxindoles, thio-oxindoles, 3,4-dihydro-1H-quinolin-2-ones, and 1,2,3,4-tetrahydroquinolines via formal C-H, Ar-H coupling is described. In a new variant, copper(II) 2-ethylhexanoate has been identified as an inexpensive and efficient catalyst for this transformation, which utilises atmospheric oxygen as the re-oxidant.

Catabolism of the Last Two Steroid Rings in Mycobacterium tuberculosis and Other Bacteria

ABSTRACT Most mycolic acid-containing actinobacteria and some proteobacteria use steroids as growth substrates, but the catabolism of the last two steroid rings has yet to be elucidated. In Mycobacterium tuberculosis, this pathway includes virulence determinants and has been proposed to be encoded by the KstR2-regulated genes, which include a predicted coenzyme A (CoA) transferase gene (ipdAB) and an acyl-CoA reductase gene (ipdC). In the presence of cholesterol, ΔipdC and ΔipdAB mutants of either M. tuberculosis or Rhodococcus jostii strain RHA1 accumulated previously undescribed metabolites: 3aα-H-4α(carboxyl-CoA)-5-hydroxy-7aβ-methylhexahydro-1-indanone (5-OH HIC-CoA) and (R)-2-(2-carboxyethyl)-3-methyl-6-oxocyclohex-1-ene-1-carboxyl-CoA (COCHEA-CoA), respectively. A ΔfadE32 mutant of Mycobacterium smegmatis accumulated 4-methyl-5-oxo-octanedioic acid (MOODA). Incubation of synthetic 5-OH HIC-CoA with purified IpdF, IpdC, and enoyl-CoA hydratase 20 (EchA20), a crotonase superfamily member, yielded COCHEA-CoA and, upon further incubation with IpdAB and a CoA thiolase, yielded MOODA-CoA. Based on these studies, we propose a pathway for the final steps of steroid catabolism in which the 5-member ring is hydrolyzed by EchA20, followed by hydrolysis of the 6-member ring by IpdAB. Metabolites accumulated by ΔipdF and ΔechA20 mutants support the model. The conservation of these genes in known steroid-degrading bacteria suggests that the pathway is shared. This pathway further predicts that cholesterol catabolism yields four propionyl-CoAs, four acetyl-CoAs, one pyruvate, and one succinyl-CoA. Finally, a ΔipdAB M. tuberculosis mutant did not survive in macrophages and displayed severely depleted CoASH levels that correlated with a cholesterol-dependent toxicity. Our results together with the developed tools provide a basis for further elucidating bacterial steroid catabolism and virulence determinants in M. tuberculosis. IMPORTANCE Bacteria are the only known steroid degraders, but the pathway responsible for degrading the last two steroid rings has yet to be elucidated. In Mycobacterium tuberculosis, this pathway includes virulence determinants. Using a series of mutants in M. tuberculosis and related bacteria, we identified a number of novel CoA thioesters as pathway intermediates. Analysis of the metabolites combined with enzymological studies establishes how the last two steroid rings are hydrolytically opened by enzymes encoded by the KstR2 regulon. Our results provide experimental evidence for novel ring-degrading enzymes, significantly advance our understanding of bacterial steroid catabolism, and identify a previously uncharacterized cholesterol-dependent toxicity that may facilitate the development of novel tuberculosis therapeutics. Bacteria are the only known steroid degraders, but the pathway responsible for degrading the last two steroid rings has yet to be elucidated. In Mycobacterium tuberculosis, this pathway includes virulence determinants. Using a series of mutants in M. tuberculosis and related bacteria, we identified a number of novel CoA thioesters as pathway intermediates. Analysis of the metabolites combined with enzymological studies establishes how the last two steroid rings are hydrolytically opened by enzymes encoded by the KstR2 regulon. Our results provide experimental evidence for novel ring-degrading enzymes, significantly advance our understanding of bacterial steroid catabolism, and identify a previously uncharacterized cholesterol-dependent toxicity that may facilitate the development of novel tuberculosis therapeutics.

A Cu-Catalysed Radical Cross-Dehydrogenative Coupling Approach to Acridanes and Related Heterocycles

The synthesis of acridanes and related compounds through a Cu‐catalysed radical cross‐dehydrogenative coupling of simple 2‐[2‐(arylamino)aryl]malonates is reported. This method can be further streamlined to a one‐pot protocol involving the in situ fomation of the 2‐[2‐(arylamino)aryl]malonate by α‐arylation of diethyl malonate with 2‐bromodiarylamines under Pd catalysis, followed by Cu‐catalysed cyclisation.

Bacterial Catabolism of Biphenyls: Synthesis and Evaluation of Analogues

A series of alkylated 2,3‐dihydroxybiphenyls has been prepared on the gram scale by using an effective Directed ortho Metalation–Suzuki–Miyaura cross‐coupling strategy. These compounds have been used to investigate the substrate specificity of the meta‐cleavage dioxygenase BphC, a key enzyme in the microbial catabolism of biphenyl. Isolation and characterization of the meta‐cleavage products will allow further study of related processes, including the catabolism of lignin‐derived biphenyls.