Synthetic Methodology

why alkylamines?

Alkylamines are ubiquitous motifs in medicines, pre-clinical candidates, biological probes, agrochemicals & functional materials. Amine functionality has the potential to bind to proteins due to its capacity to form donor/acceptor hydrogen bonds. Furthermore, upon protonation, the solubility and the bioavailability of the dugs containing amine motifs can be enhanced. Accordingly, alkylamines appear in approx. 35% of pharmaceuticals and around 60% contain a tertiary alkylamine. Therefore, the need to access alkylamine scaffolds drives the continued development of general methods for their synthesis. Despite their importance, amine synthesis is still dominated by two methods: N-alkylation and carbonyl reductive amination. The increasing demand for ‘sp3-rich’ molecules in drug-discovery continues to drive development of practical catalytic methods to synthesize complex saturated alkylamines. In particular, processes that transform diverse, readily-available feedstocks into structurally diverse sp3-rich architectures provides a strategic advantage in complex alkylamine synthesis.

Aliphatic Amines by Pd(II)-Catalysed C–H Activation

 

Our group has established and driven the field of directed palladium(II) catalysed C(sp3)–H activation on free(NH) alkylamines, with several important contributions to our name.

Have a look at our most recent paper >

Catalytic C–H Activation in Aliphatic Amines

PREMISE

We showed that a number of factors can be used to leverage the strong directing effect of free(NH) alkylamine motif to drive C(sp3)–H activation at a variety of positions along saturated substitutents in these important molecules. We show that the steric properties of the amine could be used to destabilise the catalytically inactive bis-amine-Pd(II) complexes facilitating the formation of mono-amine Pd(II) complexes empirically required for C–H activation.

our work

A number of transformations have been developed using this activation mode, with previously unknown b-C(sp3)–H activation as well as gamma-C(sp3)–H activation enabling a number of distinct new reactions. Mechanistic and computational work identified that a crucial hydrogen bond exists between the Pd(II)-ligated N–H and the carbonyl of an acetate ligand, which organises the mono-amine Pd(II) complex in such a way as to promote C–H activation. Indeed, based on this hypothesis, we were also able to affect catalytic enantioselective C–H activation in alkylamines.

In a complementary system, we also discovered a new activation mode that utilises CO to affect b-C(sp3)–H activation in a vast array of structurally diverse secondary alkylamines. 

Guided by mechanistic studies and computation, we elucidated a novel pathway wherein b-C(sp3)–H takes place via an Pd-carboxamide species and ultimately leads to a general and practical process for the synthesis of beta-lactams. Moreover, the reaction is also amenable to methylene b-C(sp3)–H activation to form substituted beta-lactams. With over 150 examples of this C–H carbonylation, this process can be benchmarked as one of the most general and robust Pd-catalyst C(sp3)–H activation reaction that has been reported.

Outlook

Our current efforts are focussed on the design of ligands for Pd(II)-catalysts that help to facilitate the substrate unbiased C–H activation and expansion of the activation platform through the Pd(II)/Pd(0) and Pd(II)/Pd(IV) manifolds to facilitate a wider range of transformations. We are also engaged in the development of previously unknown g-C(sp3)–H activation reactions on tertiary alkylamines. 

Aliphatic Amines by Visible-Light Photochemistry

 

Following up on our interest in aliphatic amine synthesis, our group has recently started to expand our synthetic expertise into the areas of visible-light photoredox catalysis and general photochemistry.

Have a look at our most recent paper >

Catalytic Regiospecific alpha-Amino Radical Formation

PREMISE

The last 10 years have seen a remarkable advance on the area of visible-light photoredox catalysis and associated photochemistry. Recently, we became interested in harnessing new photocatalytic activation modes that would exploit the reactivity of iminium ions for the synthesis of complex tertiary alkylamines.

Our Initial Work

We have developed a multicomponent reductive photocatalytic technology that combines readily-available dialkylamines, carbonyls and alkenes to build architecturally complex and functionally diverse tertiary alkylamines in a single step.

Our mechanistic proposal for photocatalytic olefin-hydroaminoalkylation begins with visible-light excitation of Ir(ppy)3 to the long-lived photoexcited *Ir(III) species. While this species may be sufficiently reducing [Ir(IV)/*Ir(III), Ered = –1.73 V vs. SCE in acetonitrile] to undergo SET to the alkyl-iminium ion, we recognized that *Ir(III)ppy3 is efficiently quenched by Hantzsch ester 4a [*Ir(III)/Ir(II), Ered = +0.31 V vs. SCE in acetonitrile] leading to [Ir(II)ppy3]– and the corresponding Hantzsch ester-radical cation. Importantly, [Ir(II)ppy3]– is sufficiently reducing [Ir(III)/Ir(II), Ered = –2.19 V vs. SCE in acetonitrile] to undergo SET with the full range of alkyl-iminium ions, leading to the key alpha-amino radical. We identified the enamine as the predominant species in the 1H NMR of the reaction mixture, which we believe is an off-cycle precursor to the iminium ion; the acid maintains a low concentration of iminium by protonation of the enamine. The alpha-amino radical engages a polarity-matched acrylate, creating a carbon-carbon bond and an alpha-ester radical. Given the propensity for mono-substituted alpha-ester radicals to undergo oligomerization, we anticipated that an intramolecular 1,5-HAT to the benzylic position may act as a kinetic trap to form a stabilized benzylic radical. Finally, we expected that the Hantzsch ester or its radical cation would participate in a HAT reaction with the benzylic radical, to form the amine product. A reaction using deuterium-labelled Hantzsch ester confirmed our hypothesis; deuterium was incorporated exclusively at the benzylic position of the amine, showing that 1,5-HAT occurred prior to interception with Hantzsch ester. This theory was further corroborated using deuterium-labelled dibenzylamine, wherein a deuterium was transferred to the position adjacent to the ester in the product amine. Our current thinking is based on the fact that the alpha-aminobenzyl radical can undergo oxidation [Ered = –0.9 V vs. SCE in acetonitrile] to the iminium, which is accessible to a range of oxidants, such as *Ir(III). Notably, selective reduction of benzaldiminium ion (over the initially formed iminium) can be accounted for by its inability to form a stable off-cycle enamine intermediate. The reduction could proceed by a 2-electron process with Hantzsch ester or photocatalytic SET and HAT. Interestingly, a pathway whereby the iminium is translated into a new iminium species represents an overall mechanism that can be described as a 'redox-relay' of iminium ions, which, to the best of our knowledge, has not been previously reported.

This olefin-hydroaminoalkylation process sequences a visible-light-mediated reduction of in-situ generated iminium ions, selectively furnishing previously inaccessible alkyl-substituted alpha-amino radicals, which engage alkenes and lead to C(sp3)–C(sp3) bond formation. The operationally straightforward reaction exhibits broad functional group tolerance, facilitates the synthesis of drug-like amines not readily accessible by other methods and is amenable to late-stage functionalization applications, making it of interest in pharmaceutical research and other areas. Over 60 examples, including different aldehydes, ketones, amines, and alkene acceptors are compatible with the process.  

Application to spirocycles

Growing evidence suggests that an increasing number of aromatic rings in lead compounds can result in greater attrition rates amongst pharmaceutical candidates due to poor solubility, bioavailability and pharmacokinetics. However, libraries of lead-like structures often comprise compounds with predominantly C(sp2)-rich scaffolds. Consequently, the assessment of structurally distinct libraries of C(sp3)-rich small molecules displaying diverse polar functionality could help to identify new lead candidates in fragment-based screening approaches that may exhibit enhanced physical and biological properties. In considering the design of novel C(sp3)-rich small molecules for fragment-based approaches, it is noticeable that conformationally restricted scaffolds show highly reproducible results in in silico screening programmes; the well-defined spatial orientation of molecular features in a candidate compound often leads to increased binding affinities. One approach towards limiting structural flexibility within C(sp3)-rich small molecules is through the introduction of a spirocycle. In comparison to aromatic scaffolds, fine-tuning the structural and functional features in these frameworks offers an alternative means through which to probe interactions with target binding sites by variation of ring size, adjusting electronic properties and manipulating substituent effects. As a result, spirocyclic motifs displaying polar functionality are emerging in pharmaceutical agents and lead compounds.

We developed a streamlined strategy for the synthesis of complex C(sp3)-rich N-heterospirocycles from readily available secondary amines and ketones enabled by visible-light photocatalysis. Key to the success of this strategy was the utilization of a highly reducing Ir-photocatalyst and orchestrating the intrinsic reactivities of 1,4-cyclohexadiene and Hantzsch ester, which facilitated controlled generation and fate of the radical intermediates present in the reaction. Under optimized conditions, the process combines a range of feedstock aliphatic ketones and aldehydes with alkene-containing secondary amines to forge complex C(sp3)-rich N-heterospirocycles displaying structural, functional and physical features that are likely to be attractive in fragment-based lead identification programs. 

The photoredox strategy offers an intuitive retrosynthetic disconnection for difficult-to-access C(sp3)-rich N-heterospirocyclic scaffolds that may be of interest to practitioners of both synthetic and medicinal chemistry. 

 

High-Oxidation State Enantioselective Copper Catalysis

 

Pd-catalyzed cross coupling is one of the most important advances in synthetic chemistry. Central to its success is the versatility of the Pd(II) oxidation state, a key intermediate with a d8 electron configuration. Our PI Matthew Gaunt questioned how its reactivity would be affected by changing the metal to Cu but maintaining a configuration isoelectronic to Pd(II) in order to unlock underexplored organometallic reactivity of Cu(III), allowing the design of previously unknown transformations. Since then, our group has accumulated several publications based on this concept.

Have a look at our most recent paper >

High-Oxidation State Copper Catalysis with Aryliodonium Salts

C–H arylation with iodonium salts

Our PI Matthew Gaunt recognized that organo-Cu(III) species are isoelectronic but, likely, more electrophilic than Pd(II) as a result of the higher oxidation state. A report from 1953 led him to speculate that Cu salts decomposed a class of unusual oxidants (diaryliodonium salts) through a putative electrophilic organo-Cu(III) species. He speculated that harnessing this apparently simple activation mode may lead to a broad synthetic platform for catalytic activation of aromatic electrophiles, which would enable new bond-forming reactions with organic nucleophiles. The basic reactivity for this Cu-catalysed arylation platform (CCAP) was first realized through a site-selective arylation of indoles. Based on this seminal contribution our group has published >20 publications in top-ranked journals and our work has established a field of synthesis research that now comprises >200 papers & has now become a general strategy for arylation (for an independent review, see: Synthesis 201749, 1905). We reported C–H arylation methodologies for indoles (C2 or C3), anisoles (para), anilines (para) & a ground-breaking meta-selective arylation strategy.

Of particular significance is our 2009 Science publication on meta-selective arylation. The rules for electrophilic aromatic substitution dictate that electron-donating groups direct reaction to ortho/para positions; this guideline has stood ‘as law’ for over 100 years. Using the CCAP, we uncovered a class of electron-rich arenes that underwent arylation at the meta position – opposite to traditional reactivity patterns. This first-in-class transformation is general across a range of aromatic coupling partners & it is controlled by a unique interaction between a carbonyl group in the arene and the Cu(III)-aryl species. This reaction has changed thinking in aromatic chemistry and paved the way for many meta-selective reactions using metal catalysts.

Alkene & alkyne arylation

Alkenes & alkynes are among the most important hydrocarbon feedstocks. Our group showed that the CCAP enabled alkene arylation to synthetically versatile products that are not accessible by other means. We determined that the arylation pathway is distinct from carbopalladation-based reactions, and developed a number of alkene arylations to form carbocycles, heterocycles and polyols, all molecules that display structural features common to many biologically active molecules. Our group also showed that CCAP could reverse classical alkyne reactivity via an electrophilic carbometallation, and exploited a mechanistic peculiarity of Cu(III) species to add a versatile 4th substituent across the alkyne to form tetrasubstitued alkenes, a long-standing challenge in synthesis. Further application of the CCAP led to novel alkyne functionalization strategies to make pharmaceuticals and synthetic intermediates. The first example of a stereospecific carbocationic C–H functionalization process using this activation mode was also uncovered.

enantioselective arylation

By deploying chiral ligands on Cu catalysts, our group adapted the CCAP to an enantioselective process. Enol-silanes underwent arylation with excellent yield & enantioselectivity, contributing to early examples of catalytic enantioselective enolate arylation. We also reported the first example of a catalytic enantioselective oxyarylation of alkenes to form aliphatic heterocycles, & an arylative semi-pinacol reaction to form spirocyclic ketones. Enantioselective arylation of simple alkenes by this method is a powerful strategy for formation of versatile non-racemic small molecules. They also discovered the catalytic enantioselective arylation at phosphorous to form tertiary phosphine oxides, precursors to chiral-at-P phosphine ligands.

© 2019 The Gaunt Group

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