The research described herein consists of two disparate areas of study. The first and largest portion describes the development of novel palladium-catalyzed C-C and C-N bond forming reactions. The second portion describes the development of the Reaction Predictor system and its application towards identification of reaction products and pathways.

Palladium-carbenes are important intermediates in many modern C-C and C-heteroatom bond forming reactions. Palladium-catalyzed carbenylative coupling reactions are analogous to carbonylative processes with carbon monoxide. Insertion of a cis X type ligand into the palladium-carbene can potentially generate a new stereogenic center, making these reactions worthy of study. Carbenylative insertions have been used to generate electrophilic η3- allylpalladium species which were trapped with nitrogen and carbon nucleophiles. This work describes the cyclization of η3-benzylpalladium species derived from palladium-catalyzed carbenylative insertion. This optimization and broad substrate scope of this reaction led to the synthesis of 1-arylindanes and 1-aryltetralins in high yields. Additionally, this reaction was used to prepare tetralone 2.30bl, a synthetic intermediate in the Curran synthesis of (±)-podophyllotoxin. The carbenylative cyclization also led us to pursue utilizing aliphatic N-tosylhydrazones as palladium-carbene precursors in other coupling reactions. It was realized that aliphatic N-tosylhydrazones with adjacent hydrogens can effectively participate in three-component palladium-catalyzed carbenylative cross-coupling reactions of vinyl iodides while avoiding β-hydride elimination.

Development of a palladium-catalyzed enantioselective carbene insertion into the N-H bond of aromatic heterocycles to obtain α-(N-indolyl)-α-arylesters and α-(N-carbazolyl)-α-arylesters, using α-diazo-α-arylacetates as palladium carbene precursors is also described. Aliphatic amines were also competent coupling partners in the reaction, affording biologically active piperdine derivatives in moderate yields. The reaction was applied towards the synthesis of a bioactive carbazole derivative in a concise manner.

In a separate project an inductive machine learning reaction prediction program called Reaction Predicator has been trained and applied towards identification of plausible reaction products in ESI spectra. The reaction predictor training set has been expanded by the addition of new reactions written in our lab. Over 800 transition metal based training reactions have been written. In addition, over 10,000 new complex training reactions have been written and added to the training set. The Reaction Predictor pathway search feature has been customized to match products to unknown m/z peaks in ESI spectra. Pathway search was applied towards unknown identification in palladium-catalyzed N-H insertion reactions.

Abstract of the Dissertation

CO2-Binding by a Bifunctional Guanidine and Bifunctional Alcohol

Employing Chelate Cooperativity

and

Palladium-Catalyzed Enantioselective Carbene Insertion into the N–H Bonds

of Aromatic Amine Heterocyclic and Non-Conjugated Amines

by

Stanley C. Hiew

Doctor of Philosophy

University of California, Irvine, 2019

Professor David L. Van Vranken, Chair

The research described herein consists of two distinct parts. The first part describes the development of a new solution phase system for binding CO2. CO2 capture and sequestration has been proposed as a tool for reducing global CO2 emissions and usually involves separating CO2 from a mixed stream of gasses, such as that encountered in the flue gas of fossil-fueled power plants. The cost of existing CO2 capture technologies has limited their widespread deployment, motivating the search for new reagents and materials that are cheaper, scalable, and more efficient.

The design, synthesis, and CO2-absorption properties of the new solution phase system will be discussed. The system employs a bifunctional guanidine and bifunctional alcohol pair to bind CO2 and uses the principle of chelate cooperativity to elicit unique thermodynamic behavior. The CO2-binding properties of the system were examined at the bulk scale using absorption isotherm measurements, and at the microscopic scale using 1H NMR spectroscopy. Molecular dynamics simulations are presented that provide insight about the intermolecular interaction and aggregation state of the system. Finally, a thermodynamic model is proposed that rationalizes the observed CO2 absorption isotherms.

The second section concerns the development of palladium-catalyzed carbene insertions into the N–H bonds of amines. Amine substrates for such insertion reactions have largely been confined to carbamates and anilines. This section will focus on expanding the substrate scope to include other types of amines. The section will begin by discussing enantioselective carbene insertion into aromatic heterocyclic amines, such as carbazoles and indoles. The reaction employs a palladium(II) catalyst and chiral PyBOX ligand to achieve up to 98% yield and 99% ee.

Next, carbene insertion into benzylic and aliphatic amines will be discussed. Historically, such substrates have proven extremely challenging owing to their tendency of coordinate and deactivate transition metal catalyst. We present a parallel slow addition procedure that permits high yields and moderate ees to be obtained for these types of substrates. The procedure involves simultaneous syringe pump addition of the amine substrate and supplemental palladium catalyst into a stirring solution of palladium catalyst and diazo substrate. This procedure was used to synthesize several morpholine, piperazine, and piperidine aminoester derivatives. Finally, a kinetic model is presented that provides insight into the relationship between amine addition rate, catalyst addition rate, and yield.

The research described in this work consists of two distinct fields of study. The first part of the work describes the design, synthesis, and testing of small molecule azole synergizers, while the second part describes work on computational and machine learning methods towards reaction prediction.

Five isoquinolones and phthalazinones were previously shown to increase the activity of fluconazole against Candida albicans. A dozen analogues were synthesized and one compound, 2.41, was shown to have activity at 1 nM against a susceptible strain of C. albicans. 2.41 was shown to be potent against resistant strains of C. albicans but lacked activity against a resistant strain of C. glabrata. Previously synthesized spiroindolinone azole synergizers were tested against resistant strains of C. albicans and C. glabrata in the presence of fluconazole. There was activity against both strains. Over fifty new spiroindolinones were synthesized and three, 3.61, 3.78, and 3.71, were found to have activity at or below 100 nM against both resistant strains.

Reaction Predictor was a system developed by the Baldi lab in the early 2010’s to use deep learning to predict reaction mechanisms. In collaboration with the Baldi lab, Reaction Predictor was improved in accuracy and performance through various ways including writing 1000’s of training reactions, modifying the architecture and features of the neural net, and using simple chemistry rules. Reaction Predictor was able to achieve a 80% top-5 recovery rate on a separate, challenging benchmark set of reactions drawn from modern organic chemistry literature. Using pathway search, Reaction Predictor was able to identify plausible products from organic synthesis reactions as well as drug degradation.

Methyl anion affinity has previously been shown to correlate linearly with electrophilicity only within specific sets of functional groups. Using a solvation model in the calculation of methyl anion affinity was shown to give a correlation with electrophilicity over a broad class of charged and uncharged electrophiles. Methyl cation affinity calculated with a solvation model was shown to correlate with nucleophilicity over a broad class of charged and uncharged nucleophiles. Using these correlations we were able to estimate the span of electrophilicity and nucleophilicity in the universe.

Throughout my time at UCI I have been involved in three projects: development of an asymmetric route to xantholipin B, asymmetric insertion of carbene groups into aliphatic N−H bonds, and developing a pedagogical training set for organic radical chemistry for prediction of reaction products and mechanistic pathways. In the Pronin group I optimized conditions for addition of a tri-n-butylstannylzinc reagent to a MOM-protected salicylaldehyde. In the Van Vranken group I synthesized and characterized a chiral guanidine catalyst useful for asymmetric catalysis. I then focused my efforts on the development of a prediction for prediction of step-wise organic reaction mechanisms based on machine learning. In order to improve the identification of electrophilic and nucleophilic atoms, I showed that easily calculated methyl ion affinities correlated with Mayr’s solution phase reactivity parameters, E and N•sN. I then helped to expand a training database of mechanistic radical reaction steps based on the SMIRKS formalism and test the system called Reaction Predictor once the training was complete.

This work focuses on the use of N-tosylhydrazones derived from α,β-unsaturated aldehydes – precursors to vinylcarbene ligands – in palladium-catalyzed carbenylative cross-coupling and carbenylative amination reactions. These carbenylative reactions were used to form η3-allylpalladium intermediates that generate stereogenic centers at the carbene center. An initial acyclic model system was used to intercept a well-known prochiral 1,3-diphenylallyl intermediate to probe the feasibility of enantioselectivity in a palladium-catalyzed carbenylative reaction as a proof of concept for asymmetric carbenylation. Following the proof of concept, the substrate scope was expanded to include aliphatic vinyl hydrazones in order to install prenyl functional groups. Conditions to form isoindolines and tetrahydroisoquinolines, present in many natural products, were developed by employing amine-tethered aryl iodides. The isoindoline model system established that kinetic 5-membered ring formation is preferred over thermodynamic 7-membered ring formation and that under our reaction conditions the cyclization is not reversible. Use of N-tosylhydrazones that generate unsymmetrical η3-allylpalladium intermediates that cannot racemize through η3-η1-η3 isomerization provided evidence consistent with migratory insertion as the step responsible for enantioselection in the catalytic cycle. Promising ees are demonstrated indicating that selection of the right chiral ligand and reaction conditions could lead to high levels of enantioselection. Finally, formation of 6-membered ring systems proved challenging in comparison to 5-membered and acyclic systems but provided beneficial information about N-tosylhydrazone decomposition rates and reactivity effects seen from ortho-substitution on the aryl iodide. These results provide new insights into the mechanism of asymmetric palladium-catalyzed carbenylative cross-coupling and carbenylative amination and provide a foundation for future method development.

In Chapter 1, an overview of the literature of palladium-catalyzed carbenylative coupling reaction was reviewed. Palladium alkylidene intermeditates derived from N-tosylhydrazones and diazo compounds were used in the carbenylative reactions with facile β-hydride elimination, which erased the stereogenic center formed during carbene insertion. The review also covered palladium-catalyzed carbenylative coupling reaction without β-hydride elimination.

In Chapter 2, a palladium-catalyzed three-component intermolecular carbenylative amination and alkylation reaction of vinyl iodides, N-tosylhydrazones and nucleophiles were successfully carried out to yield products resulting from nucleophilic attack on the least hindered side of the η3-allylpalladium complexes. With the optimized reaction conditions, a variety of N-tosylhydrazones and nucleophiles were explored. The reaction works well with cyclic secondary amines and stabilized enolates and moderately with primary amines. A variety of alkyl N-tosylhydrazones have been demonstrated to work with the reaction conditions as well. Good yields were obtained under conditions that minimized the palladium-catalyzed ionization of allylic amines and addition of metalated hydrazones to η3-allylpalladium complexes.

In Chapter 3, vinyl iodides, carbon or nitrogen based nucleophiles and trimethylsilyldiazomethane (TMSD) were utilized to form vinylsilanes via palladium-catalyzed carbenylative cross-coupling reactions. These vinylsilanes were then subjected to iododesilylation conditions to generate new vinyl iodides capable of undergoing a second palladium-catalyzed cross-coupling reaction. This two-step process could be used iteratively to form new C-C and C-N bonds that quickly increased molecular complexity.

This body of work revolves around two themes: palladium-catalyzed construction of new carbon–nitrogen (C–N) bonds in an enantioselective fashion, and the total synthesis of naturally occurring indano[2,1-c] chromans of biological interest. The development of new methods to synthesize complex molecules in an efficient and stereocontrolled manner is an essential goal. Transition metal catalysis has broadened the types of disconnections and connections available to synthetic chemists. Palladium carbene intermediates provide a new point of disconnection that has gained popularity. Not only do palladium carbene intermediates generate new carbon–carbon and carbon–heteroatom bonds, but they do so while providing an avenue for chiral control. Many biologically active compounds, such as RYDAPT®, contain aromatic heterocycles attached to chiral centers through a C–N bond. Methods to generate these types of linkages from achiral fragments with control of stereochemistry are invaluable. This work describes a method to access chiral C–N bonds between achiral α-aryl-α-diazocarbonyl compounds and achiral aromatic heterocycles containing N–H bonds.

Naturally occurring indano[2,1-c]chromans, such as (±)-brazilin, (±)-pestalachloride C, and (±)-pestalachloride D, are of analytical or biological importance. The second part of this work describes the synthesis of these three biologically active indano[2,1-c]chromans. (±)-Brazilin, a highly oxygen sensitive species, has been studied for its pharmacological activity since the discovery of its structural framework. Prior syntheses of (±)-brazilin that have utilized a common strategy: an intramolecular Friedel-Crafts-type acylation of an aromatic ring. The total synthesis described in this work takes advantage of palladium-catalyzed carbene insertion reaction to provide the core structure of (±)-brazilin through a non-obvious bond-disconnection. The carbene insertion approach was less efficient when applied to the synthesis of the highly functionalized indano[2,1-c]chroman core of (±)-pestalachloride C and (±)-pestalachloride D which occur in nature as racemates. These compounds exhibit interesting biological activity because pestalachloride C exhibits teratogenic activity whereas pestalachloride D does not. A biomimetic synthesis of these two compounds was developed which seems to support the Knoevenagel/hetero-Diels–Alder cascade reaction proposed for the biosynthesis. This concise synthesis facilitates construction of chemical analogues with higher potency.

This dissertation will focus on four main areas: The first aspect to be discussed will be reaction of allyl 2-diazo-2-phenylacetates with trimethylsilyl thioethers in the presence of rhodium(II) catalysts. These conditions generate α-allyl-α-thio silyl esters which undergo a spontaneous Ireland–Claisen rearrangement. Competing side-reactions, substrate scope and application will be explored. The second aspect to be discussed will be metal-catalyzed halogen insertion into α-diazocarbonyl compounds. Attempts to optimize the reaction and efforts to obtain asymmetric induction will be explored. The third aspect to be discussed will be rhodium(II)-catalyzed carbene transfer from trimethylsilyldiazomethane to arylmethyl thioethers, generating sulfonium ylides that undergo [2,3]-sigmatropic rearrangement, punching quaternary centers into aromatic rings. Substrate scope and competing side-reactions will be discussed. The final aspect to be discussed will be rhodium(II)-catalyzed carbene transfer from trimethylsilyldiazomethane to allylic thioesters, generating S-acyl allylsulfonium ylides that undergo [2,3]-sigmatropic rearrangement. This is the first report of an S-acyl Doyle-Kirmse reaction.

ABSTRACT OF THE DISSERTATION

Design, Synthesis and Study of Potent Small Molecule Antifungal Synergizers

and

Palladium-Carbene Mediated C–C and C¬–N Bond Formations

By

Ilandari Dewage Udara Anulal Premachandra

Doctor of Philosophy in Chemistry

University of California, Irvine, 2016

Professor David L Van Vranken, Chair

The doctoral studies described herein include two distinct aspects. One involves the design, synthesis and study of small molecule antifungal synergizers and the other consists of novel palladium-catalyzed C–C and C¬–N bond formations.

Spiroindolinones and dihydroisoquinolines were previously reported to enhance the antifungal effect of Candida albicans. A different diastereomer of a lead spiroindolinone, CID 6584729 was synthesized and shown to have synergy with fluconazole against C. albicans. Various other analogues of spiroindolinones and dihydroisoquinolines were designed, synthesized and studied. Many of the compounds were shown to enhance the antifungal activity of fluconazole against C. albicans, some with exquisite potency. One spirocyclic compound, which we have named synazo-1 and one dihydroisoquinoline analogue, compound 3-19 were shown to enhance fluconazole activity against several resistant clinical isolates with low EC50 values. Both of these compounds exhibit true synergy with fluconazole, with FIC indices below 0.5 in both susceptible and resistant strains. Synazo-1 and compound 3-19 also exhibited low intrinsic cytotoxicity in mammalian cells.

In a separate project, vinyl iodide were shown to be useful precursors in palladium-catalyzed transformations to gain access to η3-allylpalladium intermediates that resist β-hydride elimination and to generate cyclodimerization and cyclopropanation adducts in synthetically useful yields.

Most palladium-catalyzed reactions involving insertion of alkylidenes with α-hydrogens undergo β-hydride elimination from alkylpalladium(II) intermediates to form alkenes. Vinyl iodides were utilized to generate η3-allylpalladium intermediates and preserve the sp3 center adjacent to the carbene. Acyclic stereocontrol (syn/anti) for carbenylative amination and alkylation reactions was found to be low, suggesting lack of control in the migratory insertion step. Highly hindered carbene precursors inexplicably led to formation of Z-alkenes with high levels of stereocontrol.

Vinyl iodides were shown to undergo palladium-catalyzed dimerizations and cyclization to generate pyrrolidine and piperidine dimers connected by a trans-ethylene bridge. The dimerization generates the skeleton of the alkaloid, hyalbidone in a single step. A crossover experiment is consistent with a Michael-type addition to vinylpalladium cation to generate Pd(0) alkylidene intermediate. A palladium-catalyzed intramolecular aminocyclopropanation of norbornenes with vinyl halides was shown to generate cycolpropylcarbinyl adducts in good yields. Stabilized enolate nucleophiles were also employed in these transformations.