Streamlined Synthesis of C(sp3)-Rich N-Heterospirocycles Enabled by Visible-Light-Mediated Photocatalysis

We report a general visible-light-mediated strategy that enables the construction of complex C(sp3)-rich N-heterospirocycles from feedstock aliphatic ketones and aldehydes with a broad selection of alkene-containing secondary amines. Key to the success of this approach was the utilization of a highly reducing Ir-photocatalyst and orchestration of the intrinsic reactivities of 1,4-cyclohexadiene and Hantzsch ester. This methodology provides streamlined access to complex C(sp3)-rich N-heterospirocycles displaying structural and functional features relevant to fragment-based lead identification programs.We are grateful to the Gates Cambridge Trust (N.J.F.) and Herchel Smith Scholarship Scheme (A.T.) for studentships, the EPSRC (EP/S020292/1 and EP/N031792/1), Ambitious Leader’s Program, Hokkaido University, Japan (Y.K.), and the Royal Society for a Wolfson Merit Award (M.J.G.). S.M.W. is a Fellow of the AstraZeneca Postdoctoral program. We are grateful to the EPSRC UK National Mass Spectrometry Facility at Swansea University for HRMS analysis

Streamlined Synthesis of C(sp3)-Rich N-Heterospirocycles Enabled by Visible-Light-Mediated Photocatalysis

We report a general visible-light-mediated strategy that enables the construction of complex C(sp3)-rich N-heterospirocycles from feedstock aliphatic ketones and aldehydes with a broad selection of alkene-containing secondary amines. Key to the success of this approach was the utilization of a highly reducing Ir-photocatalyst and orchestration of the intrinsic reactivities of 1,4-cyclohexadiene and Hantzsch ester. This methodology provides streamlined access to complex C(sp3)-rich N-heterospirocycles displaying structural and functional features relevant to fragment-based lead identification programs.We are grateful to the Gates Cambridge Trust (N.J.F.) and Herchel Smith Scholarship Scheme (A.T.) for studentships, the EPSRC (EP/S020292/1 and EP/N031792/1), Ambitious Leader’s Program, Hokkaido University, Japan (Y.K.), and the Royal Society for a Wolfson Merit Award (M.J.G.). S.M.W. is a Fellow of the AstraZeneca Postdoctoral program. We are grateful to the EPSRC UK National Mass Spectrometry Facility at Swansea University for HRMS analysis

Catalytic C(sp3)-H bond activation in tertiary alkylamines.

The development of robust catalytic methods to assemble tertiary alkylamines provides a continual challenge to chemical synthesis. In this regard, transformation of a traditionally unreactive C-H bond, proximal to the nitrogen atom, into a versatile chemical entity would be a powerful strategy for introducing functional complexity to tertiary alkylamines. A practical and selective metal-catalysed C(sp3)-H activation facilitated by the tertiary alkylamine functionality, however, remains an unsolved problem. Here, we report a Pd(II)-catalysed protocol that appends arene feedstocks to tertiary alkylamines via C(sp3)-H functionalization. A simple ligand for Pd(II) orchestrates the C-H activation step in favour of deleterious pathways. The reaction can use both simple and complex starting materials to produce a range of multifaceted γ-aryl tertiary alkylamines and can be rendered enantioselective. The enabling features of this transformation should be attractive to practitioners of synthetic and medicinal chemistry as well as in other areas that use biologically active alkylamines

Radical methods for the synthesis of aliphatic amines

The aliphatic amine motif is a ubiquitous and uniquely important functional group in pharmaceutical agents and the development of ever more efficient synthetic methods for their synthesis is a continuous challenge. This thesis details the development of three new radical reactions for the synthesis of aliphatic amines. Following an introduction to radical chemistry and a summary of previous advances in amine synthesis, chapter 2 will describe a general carbonyl alkylative amination reaction, a successful version of which has been sought for over 70 years. Facilitated by visible light and a silane reducing agent, the operationally straightforward reaction forms tertiary amines via the coupling of aldehydes and secondary amines with alkyl halides. Combining an efficient radical-chain mechanism with the structural and functional diversity of readily available starting materials, the carbonyl alkylative amination provides a flexible strategy for the streamlined synthesis of complex tertiary amines. In chapter 3, an improved carbonyl alkylative amination was sought by replacing the alkyl halide with a more abundant radical precursor. This led to the development of a new carbonyl alkylative amination reaction using tetrachloro N-hydroxyphthalimide esters, prepared from carboxylic acids, in conjunction with inexpensive and environmentally friendly zinc dust instead of the costly silane reducing agent. The use of a carboxylic acid derived nucleophile enabled a broader scope in both amine and nucleophile components and the full potential of this reaction is currently being developed. In chapter 4, a visible light-mediated direct synthesis of N-heterospirocycles is reported. A photocatalyst was employed to reduce an aliphatic iminium ion to the corresponding -amino radical, which was cyclized to afford polar, heteroatom-rich spirocycles. The reaction tolerated a range of polar functional groups and the resulting scaffolds were shown to occupy a promising yet less exploited area of chemical space, making the reaction relevant for fragment-based drug discovery.Gates Cambridge Foundatio

Catalytic C(sp3)-H bond activation in tertiary alkylamines.

The development of robust catalytic methods to assemble tertiary alkylamines provides a continual challenge to chemical synthesis. In this regard, transformation of a traditionally unreactive C-H bond, proximal to the nitrogen atom, into a versatile chemical entity would be a powerful strategy for introducing functional complexity to tertiary alkylamines. A practical and selective metal-catalysed C(sp3)-H activation facilitated by the tertiary alkylamine functionality, however, remains an unsolved problem. Here, we report a Pd(II)-catalysed protocol that appends arene feedstocks to tertiary alkylamines via C(sp3)-H functionalization. A simple ligand for Pd(II) orchestrates the C-H activation step in favour of deleterious pathways. The reaction can use both simple and complex starting materials to produce a range of multifaceted γ-aryl tertiary alkylamines and can be rendered enantioselective. The enabling features of this transformation should be attractive to practitioners of synthetic and medicinal chemistry as well as in other areas that use biologically active alkylamines

A general carbonyl alkylative amination for tertiary amine synthesis.

The ubiquity of tertiary alkylamines in pharmaceutical and agrochemical agents, natural products and small-molecule biological probes1,2 has stimulated efforts towards their streamlined synthesis3-9. Arguably the most robust method for the synthesis of tertiary alkylamines is carbonyl reductive amination3, which comprises two elementary steps: the condensation of a secondary alkylamine with an aliphatic aldehyde to form an all-alkyl-iminium ion, which is subsequently reduced by a hydride reagent. Direct strategies have been sought for a 'higher order' variant of this reaction via the coupling of an alkyl fragment with an alkyl-iminium ion that is generated in situ10-14. However, despite extensive efforts, the successful realization of a 'carbonyl alkylative amination' has not yet been achieved. Here we present a practical and general synthesis of tertiary alkylamines through the addition of alkyl radicals to all-alkyl-iminium ions. The process is facilitated by visible light and a silane reducing agent, which trigger a distinct radical initiation step to establish a chain process. This operationally straightforward, metal-free and modular transformation forms tertiary amines, without structural constraint, via the coupling of aldehydes and secondary amines with alkyl halides. The structural and functional diversity of these readily available precursors provides a versatile and flexible strategy for the streamlined synthesis of complex tertiary amines

Multicomponent Synthesis of α-Branched Amines via a Zinc-Mediated Carbonyl Alkylative Amination Reaction.

Publication status: PublishedMethods for the synthesis of α-branched alkylamines are important due to their ubiquity in biologically active molecules. Despite the development of many methods for amine preparation, C(sp3)-rich nitrogen-containing compounds continue to pose challenges for synthesis. While carbonyl reductive amination (CRA) between ketones and alkylamines is the cornerstone method for α-branched alkylamine synthesis, it is sometimes limited by the sterically demanding condensation step between dialkyl ketones and amines and the more restricted availability of ketones compared to aldehydes. We recently reported a "higher-order" variant of this transformation, carbonyl alkylative amination (CAA), which utilized a halogen atom transfer (XAT)-mediated radical mechanism, enabling the streamlined synthesis of complex α-branched alkylamines. Despite the efficacy of this visible-light-driven approach, it displayed scalability issues, and competitive reductive amination was a problem for certain substrate classes, limiting applicability. Here, we report a change in the reaction regime that expands the CAA platform through the realization of an extremely broad zinc-mediated CAA reaction. This new strategy enabled elimination of competitive CRA, simplified purification, and improved reaction scope. Furthermore, this new reaction harnessed carboxylic acid derivatives as alkyl donors and facilitated the synthesis of α-trialkyl tertiary amines, which cannot be accessed via CRA. This Zn-mediated CAA reaction can be carried out at a variety of scales, from a 10 μmol setup in microtiter plates enabling high-throughput experimentation, to the gram-scale synthesis of medicinally-relevant compounds. We believe that this transformation enables robust, efficient, and economical access to α-branched alkylamines and provides a viable alternative to the current benchmark methods