Periodic Reporting for period 2 - ECHO-GRACADE (Enantioselective C-H Oxidation Guided by Rational Catalyst Design)
Reporting period: 2022-07-01 to 2023-12-31
The most important advances in organic synthesis originate from reactions that differ in a fundamental manner from traditional synthetic methodologies, and open novel paths to assemble organic molecules. Traditionally, organic synthesis has been based on the manipulation of functional groups, while C-H bonds were considered inert and disregarded in synthetic planning. Instead, modern organic chemistry recognizes C-H bonds as functional groups, thus providing points for chemical elaboration, and considers the presence of non-equivalent C-H bonds in a molecule as an opportunity for building product diversity from a common precursor. Following this reasoning, a plethora of methods have been described for functionalizing C-H bonds in a regio-selective manner. However, stereoselective C-H functionalization reactions remains an unsolved problem, accessible to limited reagents. This limitation is important because biological systems are inherently chiral, and chirality is a key factor in their interaction with organic compounds, with pharmaceuticals being the most obvious example. Chemo- and enantioselective oxidation of non-activated aliphatic C-H bonds is one of the reactions with the greatest potential to change organic synthesis because it transforms relatively inert aliphatic C-H groups, ubiquitous in organic molecules, into alcohols and carbonyl moieties, which are recognized as the most versatile functionalities in contemporary organic synthesis. Furthermore, since most organic compounds with biological relevance are chiral-oxygenated hydrocarbon scaffolds, asymmetric oxidations are recognized as particularly valuable reactions.
Despite its huge potential in organic synthesis, non-enzymatic enantioselective C-H oxidation of aliphatic sites remains inaccessible and has never been incorporated in synthesis. The huge potential of aliphatic C-H oxidation reactions has fuelled extensive exploration of novel methods over the last decade, where the challenge posed by the relatively inert nature of the aliphatic C-H bond has been addressed by using photo-, electro-chemically or
thermally-generated radical and radical–like reagents. These reagents cleave the C-H bond via a hydrogen atom transfer (HAT) process to form a substrate radical. Two main limitations exist; firstly, in the absence of directing groups, siteselectivity is dictated and limited by the innate relative HAT reactivity of the different C-H bonds in the substrate, irrespective of the reagent. A second long-standing limitation is that strong aliphatic C-H bonds are not accessible in the presence of conventional functional groups, such as alcohols, amines, ethers or amides, which strongly activate the adjacent C-H bonds towards oxidation. Chemo-selectivity is thus a problem that imposes the use of protecting-deprotecting sequences. Progress has been made to address these aspects only to a limited extent.
However, the most challenging and as yet insurmountable problems with existing methodologies are encountered for realizing enantioselective C-H oxidations. the first place, reagents that are both chiral and capable of oxygenating strong aliphatic C-H bonds via mechanisms potentially susceptible to inducing enantioselectivity are unknown. In addition, the more facile overoxidation of secondary alcohols with respect to the C-H precursor usually eliminates chirality. Unsurprisingly, examples of enantioselective aliphatic C-H oxidation with non-enzymatic systems are rare and limited to weak C-H bonds (benzylic, allylic and adjacent to heteroatom) most commonly with low substrate conversion to avoid oxidation of the first formed alcohol. Enantioselective oxidation of non-activated aliphatic C-H bonds is nowadays only possible with enzymes, and their elaboration via direct evolution (mutations) of the active site. Realizing the potential of the reaction, the topic has experienced a revolution in recent years, and paradigmatic examples of its use in the straightforward preparation of natural products have been described. However, C-H oxidations are a particularly complex class of reactions where enzymatic methods perform far from satisfactorily because of the need of expensive co-factors and limited enzyme stability. In this scenario, highly enantioselective C-H oxidation methods based on small molecule catalysts will provide an extraordinarily useful tool for synthetic planning, orthogonal to existing methods.
Considering these premises, the current project targets the design and development of chiral C-H oxidation catalysts in order to set enantioselective aliphatic C-H oxidation as a reliable tool in organic synthesis. This will be demonstrated by proof-of-principle realization of four classes of chiral aliphatic CH oxidation reactions; a) desymmetrization of cyclic substrates via enantioselective C-H oxidation, b) lactonization via an initial enantioselective C-H hydroxylation, c) atropoenantioselective C-H oxidation of biaryls and d) site- and enantioselective desymmetrizations of primary alkyl amines guided by remote supramolecular recognition. Of note, with the single exception of an initial report from the PI team, none of the four chiral reactions has previously been described with non-enzymatic methodologies.
Despite its huge potential in organic synthesis, non-enzymatic enantioselective C-H oxidation of aliphatic sites remains inaccessible and has never been incorporated in synthesis. The huge potential of aliphatic C-H oxidation reactions has fuelled extensive exploration of novel methods over the last decade, where the challenge posed by the relatively inert nature of the aliphatic C-H bond has been addressed by using photo-, electro-chemically or
thermally-generated radical and radical–like reagents. These reagents cleave the C-H bond via a hydrogen atom transfer (HAT) process to form a substrate radical. Two main limitations exist; firstly, in the absence of directing groups, siteselectivity is dictated and limited by the innate relative HAT reactivity of the different C-H bonds in the substrate, irrespective of the reagent. A second long-standing limitation is that strong aliphatic C-H bonds are not accessible in the presence of conventional functional groups, such as alcohols, amines, ethers or amides, which strongly activate the adjacent C-H bonds towards oxidation. Chemo-selectivity is thus a problem that imposes the use of protecting-deprotecting sequences. Progress has been made to address these aspects only to a limited extent.
However, the most challenging and as yet insurmountable problems with existing methodologies are encountered for realizing enantioselective C-H oxidations. the first place, reagents that are both chiral and capable of oxygenating strong aliphatic C-H bonds via mechanisms potentially susceptible to inducing enantioselectivity are unknown. In addition, the more facile overoxidation of secondary alcohols with respect to the C-H precursor usually eliminates chirality. Unsurprisingly, examples of enantioselective aliphatic C-H oxidation with non-enzymatic systems are rare and limited to weak C-H bonds (benzylic, allylic and adjacent to heteroatom) most commonly with low substrate conversion to avoid oxidation of the first formed alcohol. Enantioselective oxidation of non-activated aliphatic C-H bonds is nowadays only possible with enzymes, and their elaboration via direct evolution (mutations) of the active site. Realizing the potential of the reaction, the topic has experienced a revolution in recent years, and paradigmatic examples of its use in the straightforward preparation of natural products have been described. However, C-H oxidations are a particularly complex class of reactions where enzymatic methods perform far from satisfactorily because of the need of expensive co-factors and limited enzyme stability. In this scenario, highly enantioselective C-H oxidation methods based on small molecule catalysts will provide an extraordinarily useful tool for synthetic planning, orthogonal to existing methods.
Considering these premises, the current project targets the design and development of chiral C-H oxidation catalysts in order to set enantioselective aliphatic C-H oxidation as a reliable tool in organic synthesis. This will be demonstrated by proof-of-principle realization of four classes of chiral aliphatic CH oxidation reactions; a) desymmetrization of cyclic substrates via enantioselective C-H oxidation, b) lactonization via an initial enantioselective C-H hydroxylation, c) atropoenantioselective C-H oxidation of biaryls and d) site- and enantioselective desymmetrizations of primary alkyl amines guided by remote supramolecular recognition. Of note, with the single exception of an initial report from the PI team, none of the four chiral reactions has previously been described with non-enzymatic methodologies.
The project is organized in five working packages (WP’s). The first one (WP1) is devoted to catalyst design and evolution. The fourth following working packages (WP2-5) focus on a specific class of reactions where asymmetric C-H oxidation is applied and developed. The evolution of the project is planned in nine phases. The three first phases are scheduled for the current reporting period and the progress is detailed in the following lines;
• Phase 1 entails preparation of a training set of catalysts and model substrates to be employed in the first set of model reactions, corresponding to WP2-5, that will serve as the starting point for a multiparametric analysis in order to identify selectivity defining parameters. Catalysts initially planed for addressing WP's 2-4 have been prepared and characterized. Catalysts corresponding to WP5 are under development.
• Phases 2 and 3 entail performing the first set of catalytic model reactions on enantioselective C-H oxidation with the training set of catalysts, and consequently the elaboration of a matrix with selectivity parameters derived from catalyst and substrate chemical and 3D structure. Phase 3 has produced outstanding results in two of the working packages (WP2 and WP4). Specifically;
- WP2.1. A highly enantioselective hydroxylation of nonactivated tertiary C-H bonds has been accomplished. A manuscript detailing this work has been recently published.
- WP2.2. A highly enantioselective desymmetrization of polyol molecules via enantioselective C-H oxidation has been developed. A manuscript detailing this work is being written.
- WP2.3. A highly enantioselective desymmetrization of spyrocyclopropane cyclohexanes have been discovered. A manuscript detailing this work is being written
- WP2.4. A highly enantioselective oxidative desaturation of heterocyclic amines, and amino acid preparation via enantioselective oxidative deconstruction has been discovered. A manuscript is under preparation.
- WP4.1. Highly enantioselective lactonization of strong primary and secondary aliphatic C-H bonds has been accomplished. Two manuscripts have been recently published.
• Phase 4 entails building multiparametric models that identify key aspects that govern the enantioselectivity in the model reactions. This analysis has been performed so far for two asymmetric reactions and models have been extracted that are currently under validation (Phase 5).
• Phase 6 will entail designing a new generation of catalysts guided from the models validated in Phase 5, which will be prepared in Phase 7.
• Phase 8 will entail testing and development of substrate scope for the new generation of catalysts.
• Phase 9 will focus in using the catalysts in relevant targets.
• Phase 1 entails preparation of a training set of catalysts and model substrates to be employed in the first set of model reactions, corresponding to WP2-5, that will serve as the starting point for a multiparametric analysis in order to identify selectivity defining parameters. Catalysts initially planed for addressing WP's 2-4 have been prepared and characterized. Catalysts corresponding to WP5 are under development.
• Phases 2 and 3 entail performing the first set of catalytic model reactions on enantioselective C-H oxidation with the training set of catalysts, and consequently the elaboration of a matrix with selectivity parameters derived from catalyst and substrate chemical and 3D structure. Phase 3 has produced outstanding results in two of the working packages (WP2 and WP4). Specifically;
- WP2.1. A highly enantioselective hydroxylation of nonactivated tertiary C-H bonds has been accomplished. A manuscript detailing this work has been recently published.
- WP2.2. A highly enantioselective desymmetrization of polyol molecules via enantioselective C-H oxidation has been developed. A manuscript detailing this work is being written.
- WP2.3. A highly enantioselective desymmetrization of spyrocyclopropane cyclohexanes have been discovered. A manuscript detailing this work is being written
- WP2.4. A highly enantioselective oxidative desaturation of heterocyclic amines, and amino acid preparation via enantioselective oxidative deconstruction has been discovered. A manuscript is under preparation.
- WP4.1. Highly enantioselective lactonization of strong primary and secondary aliphatic C-H bonds has been accomplished. Two manuscripts have been recently published.
• Phase 4 entails building multiparametric models that identify key aspects that govern the enantioselectivity in the model reactions. This analysis has been performed so far for two asymmetric reactions and models have been extracted that are currently under validation (Phase 5).
• Phase 6 will entail designing a new generation of catalysts guided from the models validated in Phase 5, which will be prepared in Phase 7.
• Phase 8 will entail testing and development of substrate scope for the new generation of catalysts.
• Phase 9 will focus in using the catalysts in relevant targets.
The selective oxidation of non-activated aliphatic C–H bonds is a very powerful and useful reaction because it transforms these poorly reactive bonds, ubiquitous in organic molecules, into chemically reactive C-O bonds, amenable for diverse chemical elaboration. Enantioselective C–H bond oxidations are particularly difficult because reagents that are both chiral and capable of oxidizing the inherently strong aliphatic C–H bonds (BDE > 95 Kcal.mol-1) are rare, and the facile overoxidation of the first formed secondary alcohol products, resulting from hydroxylation of a methylenic site, into ketone eliminates the chirality. As a consequence, enantioselective aliphatic C–H bond oxidation is only accessible via enzymatic methods and remains a non solved reaction in conventional organic synthesis. Enantioselective oxidation of non-ativated C-H bonds is currently being performed by enzymes, generally metalloenzymes that generate high valent iron oxo reactive species. State of the art non -enzymatic C-H oxidation methods operate in activated C-H bonds (adjacent to heteroatom, allyllic or benzylic) and generally require the use of large excess of substrate to minimize overoxidation reactions.
The ECHO-GRACADE project addresses the problem of C-H oxidation in order to convert the reaction in a powerful tool in organic synthesis. It does so by;
a) Developing new families of powerful but oxidatively robust chiral oxidation catalysts based on earth abundant metals, which generate reactive metal-oxo species that selectively attack aliphatic C-H bonds. The chiral nature of the catalysts convey them with the capability of introducing chirality in the C-H oxidation reaction.
b) Catalyst development, pursued via multiparametric analysis of four model reactions. Catalyst evolution will lead to catalysts to address the four classes of reactions, which have no current solution.
c) Developing four classes of general reactions that entail an initial C-H clavage by a metal-oxo species will be developed in highly enantiomeric form.
The ECHO-GRACADE project addresses the problem of C-H oxidation in order to convert the reaction in a powerful tool in organic synthesis. It does so by;
a) Developing new families of powerful but oxidatively robust chiral oxidation catalysts based on earth abundant metals, which generate reactive metal-oxo species that selectively attack aliphatic C-H bonds. The chiral nature of the catalysts convey them with the capability of introducing chirality in the C-H oxidation reaction.
b) Catalyst development, pursued via multiparametric analysis of four model reactions. Catalyst evolution will lead to catalysts to address the four classes of reactions, which have no current solution.
c) Developing four classes of general reactions that entail an initial C-H clavage by a metal-oxo species will be developed in highly enantiomeric form.