Periodic Reporting for period 2 - HALOBORYLATION (Electrophilic-induced asymmetric boronate rearrangements via CAPT catalysis. A novel approach towards the formal trifunctionalization of alkenes.)
Reporting period: 2018-11-01 to 2019-10-31
The significance of enantiomerically pure compounds in the pharmaceutical industry–around 50% of the marketed drugs possess at least one stereocenter-has motivated vast scientific efforts towards the development of stereoselective methodologies for their preparation, especially after FDA’s policy for the development of stereoisomeric drugs in 1992. This paradigmatic shift from racemates to single-enantiomer drugs has brought asymmetric synthesis into the mainstream of the drug discovery process.
The handedness associated with organizing the transition state in a catalytic process, such that only a single enantiomer of a chiral product is produced, is the key to asymmetric catalysis. Since the first reports from Knowles in the 60s, chemists have made significant inroads in the synthesis of optically active molecules using synthetic chiral catalysts. The success of asymmetric catalysis can largely be attributed to the development of structurally diverse catalysts with tunable stereoelectronic properties, as well as the discovery of distinct activation modes for harnessing multiple functionalities. Nevertheless, genuine de novo design of catalysts for novel asymmetric transformations is not commonplace.
The overarching goal of our research stands on the establishment of new foundations for novel constructions and mode of operation of chiral catalysts, which have the potential to make the chemical community think in a different light, opening up a previously inaccessible reaction space to build enantioenriched molecules. In this regard, enzymatic catalysis in Nature represents a paragon of what we strive to achieve as synthetic chemists, comprising the factors of substrate organization and activation, transition state stabilization and product release all in one highly efficient package. Despite this, the vast majority of synthetic catalysts behave as stereochemically rigid scaffolds, ignoring the evidence of other models presented to us by the natural world; the reorganization event, whereby the enzyme and the ligand mold together via mutual induced-fit shifting of their conformational ensemble has been largely overlooked. We have found evidence of an analogous induced-fit mechanism in a double axially chiral phosphoric acid that adapts its conformation, akin to the active pocket of an enzyme, to catalyze the first highly enantioselective allenoate-Claisen rearrangement.
The handedness associated with organizing the transition state in a catalytic process, such that only a single enantiomer of a chiral product is produced, is the key to asymmetric catalysis. Since the first reports from Knowles in the 60s, chemists have made significant inroads in the synthesis of optically active molecules using synthetic chiral catalysts. The success of asymmetric catalysis can largely be attributed to the development of structurally diverse catalysts with tunable stereoelectronic properties, as well as the discovery of distinct activation modes for harnessing multiple functionalities. Nevertheless, genuine de novo design of catalysts for novel asymmetric transformations is not commonplace.
The overarching goal of our research stands on the establishment of new foundations for novel constructions and mode of operation of chiral catalysts, which have the potential to make the chemical community think in a different light, opening up a previously inaccessible reaction space to build enantioenriched molecules. In this regard, enzymatic catalysis in Nature represents a paragon of what we strive to achieve as synthetic chemists, comprising the factors of substrate organization and activation, transition state stabilization and product release all in one highly efficient package. Despite this, the vast majority of synthetic catalysts behave as stereochemically rigid scaffolds, ignoring the evidence of other models presented to us by the natural world; the reorganization event, whereby the enzyme and the ligand mold together via mutual induced-fit shifting of their conformational ensemble has been largely overlooked. We have found evidence of an analogous induced-fit mechanism in a double axially chiral phosphoric acid that adapts its conformation, akin to the active pocket of an enzyme, to catalyze the first highly enantioselective allenoate-Claisen rearrangement.
In 2003 MacMillan reported a method for the diastereoselective preparation of 4,5-disubstituted-enamino esters, the allenoate-Claisen rearrangement. In this transformation, a Lewis acid-activated allenoate reacts with a tertiary allylamine to form an allyl-vinylammonium intermediate with the appropriate charge orientation to further participate in a [3,3]-sigmatropic rearrangement. However, a highly enantioselective version still remains elusive, mirroring a limitation observed for most Claisen rearrangements. This challenge has been commonly addressed through the use of chiral Lewis acidic metal complexes; however, in the present scenario such a strategy would place the necessary chiral information far from the bond reorganization event. As an alternative approach, the cationic nature of the ammonium intermediate opens an opportunity for chiral counterion catalysis. We envisioned that, in a non-polar media, a chiral anion could potentially intercept this intermediate via ion-pairing. This interaction would place the ‘ligand’ in close proximity to the active site of the catalyst, resulting in a chiral environment more likely to render the process stereoselective.
After some initial exploration, we found that, under basic conditions, BINOL-based phosphoric acids provided the product in 14% ee, confirming the feasibility of our hypothesis. We evaluated a variety of chiral phosphoric acids and doubly axially chiral phosphate produced a clear improvement respect to other backbone scaffolds. This catalyst architecture can be prepared from the homocoupling of two BINOL scaffolds, resulting in a structure containing two chiral axes, while retaining a configurationally flexible central axis. Further investigations on the ester and amine substitution afforded a moderate increase in selectivity. A small library of DAPs was then prepared and screened, revealing a more efficient catalyst. From these results, we initiated a multidimensional correlation analysis, in the hope of finding a selectivity model that would lead us to more rational catalyst design.
A univariate correlation was found for the cation-interaction energy between the catalysts and pyrrolidinium moiety on the intermediate. Based on this, a new designed catalyst was synthesized, being validated as a better catalyst. With this catalyst we explored the scope of the process. The reactions proceeded in good yields and stereoselectivity, especially considering the lack of alternative approaches.
Based on the correlation model, the intermediate interacts with the Na salt of the catalyst through both the pyrrolidinium interaction, as through the Na cation . Among converged structures, the pyrrolidinium interaction was only present in conformers of the catalyst with an opposite configuration of the central axis respect to the X-ray structure. Further computations confirmed a preference for conformers with a twisted-central axis and a low barrier for axis inversion, suggesting this is a dynamic catalyst.
A publication disclosing the above discussed results is under preparation and is expected to be published soon in a high impact-factor international journal. Furthermore, these results are going to be presented along next year in international conferences by the fellow and Prof. Toste. In agreement with the Open Access policy, all scientific results of this project will ultimately remain free.
After some initial exploration, we found that, under basic conditions, BINOL-based phosphoric acids provided the product in 14% ee, confirming the feasibility of our hypothesis. We evaluated a variety of chiral phosphoric acids and doubly axially chiral phosphate produced a clear improvement respect to other backbone scaffolds. This catalyst architecture can be prepared from the homocoupling of two BINOL scaffolds, resulting in a structure containing two chiral axes, while retaining a configurationally flexible central axis. Further investigations on the ester and amine substitution afforded a moderate increase in selectivity. A small library of DAPs was then prepared and screened, revealing a more efficient catalyst. From these results, we initiated a multidimensional correlation analysis, in the hope of finding a selectivity model that would lead us to more rational catalyst design.
A univariate correlation was found for the cation-interaction energy between the catalysts and pyrrolidinium moiety on the intermediate. Based on this, a new designed catalyst was synthesized, being validated as a better catalyst. With this catalyst we explored the scope of the process. The reactions proceeded in good yields and stereoselectivity, especially considering the lack of alternative approaches.
Based on the correlation model, the intermediate interacts with the Na salt of the catalyst through both the pyrrolidinium interaction, as through the Na cation . Among converged structures, the pyrrolidinium interaction was only present in conformers of the catalyst with an opposite configuration of the central axis respect to the X-ray structure. Further computations confirmed a preference for conformers with a twisted-central axis and a low barrier for axis inversion, suggesting this is a dynamic catalyst.
A publication disclosing the above discussed results is under preparation and is expected to be published soon in a high impact-factor international journal. Furthermore, these results are going to be presented along next year in international conferences by the fellow and Prof. Toste. In agreement with the Open Access policy, all scientific results of this project will ultimately remain free.
Originally, biochemists adopted the view of enzymes as rigid scaffolds whose selectivity and catalytic activity arose from the unbending fit of the substrate into the preformed active site, the same way a key fits a lock. Of course, enzymes are now recognized as dynamic entities that undergo conformational transitions to accommodate the substrate. Although the induced-fit model was postulated 60 years ago, most modern-day synthetic approaches to asymmetric catalysis continue to rely on fairly rigid catalysts, lacking the flexibility that would allow them to properly adapt to the corresponding transition-state dynamics.
We think that the underlying fundamental concept of the induced-fit principle is directly transferable to other catalyzed reactions, so we hope these results will further stimulate collective thinking on new approaches for stereocenter-forming reactions involving dynamic catalysts. Further exploration of this new type of dynamic catalysts in other asymmetric transformations is currently underway.
In asymmetric catalysis, we are still far to address selectivity in any reaction type. New advances can potentially emerge at this fascinating research frontier through both enzymology and studies of small molecules catalysis.
We think that the underlying fundamental concept of the induced-fit principle is directly transferable to other catalyzed reactions, so we hope these results will further stimulate collective thinking on new approaches for stereocenter-forming reactions involving dynamic catalysts. Further exploration of this new type of dynamic catalysts in other asymmetric transformations is currently underway.
In asymmetric catalysis, we are still far to address selectivity in any reaction type. New advances can potentially emerge at this fascinating research frontier through both enzymology and studies of small molecules catalysis.