Catalysis-Enabled Access to Cryptic Geldanamycin Oxides.

Catalytic, selective modifications of natural products can be a fertile platform for not only unveiling new natural product analogues with altered biological activity, but also for revealing new reactivity and selectivity hierarchies for embedded functional groups in complex environments. Motivated by these intersecting aims, we report site- and stereoselective oxidation reactions of geldanamycin facilitated by aspartyl-peptide catalysts. Through the isolation and characterization of four new geldanamycin oxides, we discovered a synergistic effect between lead peptide-based catalysts and geldanamycin, resulting in an unexpected reaction pathway. Curiously, our discoveries would likely not have been possible absent the attractive noncovalent interactions intrinsic to both the catalysts and the natural product. The result is a set of new "meta" catalytic reactions that deliver both unknown and previously incompletely characterized geldanamycin analogues. Enabled by the catalytic, site-selective epoxidation of geldanamycin, biological assays were carried out to document the bioactivities of the new compounds.

Enantioselective fluorination of homoallylic alcohols enabled by the tuning of non-covalent interactions.

The study of the enantioselective fluorination of homoallylic alcohols via chiral anion phase transfer (CAPT) catalysis using an in situ generated directing group is described. Multivariate correlation analysis, including designer π-interaction derived parameters, revealed key structural features affecting the selectivity at the transition state (TS). Interpretation of the parameters found in the model equation highlights the key differences as well as similarities for the reaction of homoallylic and allylic substrates. A similar T-shaped π-interaction was found to occur between the substrate and the catalyst. The tuning of this crucial interaction by identification of the best combination of phosphoric acid catalyst and boronic acid directing group allowed for the development of a methodology to access γ-fluoroalkenols in typically high enantioselectivities (up to 96% ee).

Mechanistic Investigations of the Pd(0)-Catalyzed Enantioselective 1,1-Diarylation of Benzyl Acrylates.

A mechanistic study of the Pd-catalyzed enantioselective 1,1-diarylation of benzyl acrylates that is facilitated by a chiral anion phase transfer (CAPT) process is presented. Kinetic analysis, labeling, competition, and nonlinear effect experiments confirm the hypothesized general mechanism and reveal the role of the phosphate counterion in the CAPT catalysis. The phosphate was found to be involved in the phase transfer step and in the stereoinduction process, as expected, but also in the unproductive reaction that provides the traditional Heck byproduct. Multivariate correlations revealed the CAPT catalyst's structural features, affecting the production of this undesired byproduct, as well as weak interactions responsible for enantioselectivity. Such putative interactions include π-stacking and a CH···O electrostatic attraction between the substrate benzyl moiety and the phosphate. Analysis of the computed density functional theory transition structures for the stereodetermining step of the reaction supports the multivariate model obtained. The presented work provides the first comprehensive study of the combined use of CAPT and transition metal catalysis, setting the foundation for future applications.

Parametrization of Non-covalent Interactions for Transition State Interrogation Applied to Asymmetric Catalysis.

The use of computed interaction energies and distances as parameters in multivariate correlations is introduced for postulating non-covalent interactions. This new class of descriptors affords multivariate correlations for two diverse catalytic systems with unique non-covalent interactions at the heart of each process. The presented methodology is validated by directly connecting the non-covalent interactions defined through empirical data set analyses to the computationally derived transition states.

Exploiting non-covalent π interactions for catalyst design.

Molecular recognition, binding and catalysis are often mediated by non-covalent interactions involving aromatic functional groups. Although the relative complexity of these so-called π interactions has made them challenging to study, theory and modelling have now reached the stage at which we can explain their physical origins and obtain reliable insight into their effects on molecular binding and chemical transformations. This offers opportunities for the rational manipulation of these complex non-covalent interactions and their direct incorporation into the design of small-molecule catalysts and enzymes.

Development and Analysis of a Pd(0)-Catalyzed Enantioselective 1,1-Diarylation of Acrylates Enabled by Chiral Anion Phase Transfer.

Enantioselective 1,1-diarylation of terminal alkenes enabled by the combination of Pd catalysis with a chiral anion phase transfer (CAPT) strategy is reported herein. The reaction of substituted benzyl acrylates with aryldiazonium salts and arylboronic acids gave the corresponding 3,3-diarylpropanoates in moderate to good yields with high enantioselectivies (up to 98:2 er). Substituents on the benzyl acrylate and CAPT catalyst significantly affect the enantioselectivity, and multidimensional parametrization identified correlations suggesting structural origins for the high stereocontrol.

Palladium-Catalyzed Enantioselective Redox-Relay Heck Arylation of 1,1-Disubstituted Homoallylic Alcohols.

An enantioselective redox-relay oxidative Heck arylation of 1,1-disubstituted alkenes to construct ß-stereocenters was developed using a new pyridyl-oxazoline ligand. Various 1,2-diaryl carbonyl compounds were readily obtained in moderate yield and good to excellent enantioselectivity. Additionally, analysis of the reaction outcomes using multidimensional correlations revealed that enantioselectivity is tied to specific electronic features of the 1,1-disubstituted alkenol and the extent of polarizability of the ligand.

Relative reactivity of alkenyl alcohols in the palladium-catalyzed redox-relay Heck reaction.

The relative rates of alkenyl alcohols in the Pd-catalyzed redox-relay Heck reaction were measured in order to examine the effect of their steric and electronic properties on the rate-determining step. Competition experiments between an allylic alkenyl alcohol and two substrates with differing chain lengths revealed that the allylic alcohol reacts 3-4 times faster in either case. Competition between di- and trisubstituted alkenyl alcohols provided an interesting scenario, in which the disubstituted alkene was consumed first followed by reaction of the trisubstituted alkene. Consistent with this observation, the transition structures for the migratory insertion of the aryl group into the di- and trisubstituted alkenes were calculated with a lower barrier for the former. An internal competition between a substrate containing two alcohols with differing chain lengths demonstrated the catalyst's preference for migrating towards the closest alcohol. Additionally, it was observed that increasing the electron density in the arene boronic acid promotes a faster reaction, which correlates with Hammett σp values to give a ρ of -0.87.

Investigating the nature of palladium chain-walking in the enantioselective redox-relay Heck reaction of alkenyl alcohols.

The mechanism of the redox-relay Heck reaction was investigated using deuterium-labeled substrates. Results support a pathway through a low energy palladium-alkyl intermediate that immediately precedes product formation, ruling out a tautomerization mechanism. DFT calculations of the relevant transition structures at the M06/LAN2DZ+f/6-31+G* level of theory show that the former pathway is favored by 5.8 kcal/mol. Palladium chain-walking toward the alcohol, following successive ß-hydride eliminations and migratory insertions, is also supported in this study. The stereochemistry of deuterium labels is determined, lending support that the catalyst remains bound to the substrate during the relay process and that both cis- and trans-alkenes form from ß-hydride elimination.

Mechanism, reactivity, and selectivity in palladium-catalyzed redox-relay Heck arylations of alkenyl alcohols.

The enantioselective Pd-catalyzed redox-relay Heck arylation of acyclic alkenyl alcohols allows access to various useful chiral building blocks from simple olefinic substrates. Mechanistically, after the initial migratory insertion, a succession of ß-hydride elimination and migratory insertion steps yields a saturated carbonyl product instead of the more general Heck product, an unsaturated alcohol. Here, we investigate the reaction mechanism, including the relay function, yielding the final carbonyl group transformation. M06 calculations predict a ΔΔG(‡) of 1 kcal/mol for the site selectivity and 2.5 kcal/mol for the enantioselectivity, in quantitative agreement with experimental results. The site selectivity is controlled by a remote electronic effect, where the developing polarization of the alkene in the migratory insertion transition state is stabilized by the C-O dipole of the alcohol moiety. The enantioselectivity is controlled by steric repulsion between the oxazoline substituent and the alcohol-bearing alkene substituent. The relay efficiency is due to an unusually smooth potential energy surface without high barriers, where the hydroxyalkyl-palladium species acts as a thermodynamic sink, driving the reaction toward the carbonyl product. Computational predictions of the relative reactivity and selectivity of the double bond isomers are validated experimentally.