Bayesian Optimization of Computer-Proposed Multistep Synthetic Routes on an Automated Robotic Flow Platform

Computer-aided synthesis planning (CASP) tools can propose retrosynthetic pathways and forward reaction conditions for the synthesis of organic compounds, but the limited availability of context-specific data currently necessitates experimental development to fully specify process details. We plan and optimize a CASP-proposed and human-refined multistep synthesis route toward an exemplary small molecule, sonidegib, on a modular, robotic flow synthesis platform with integrated process analytical technology (PAT) for data-rich experimentation. Human insights address catalyst deactivation and improve yield by strategic choices of order of addition. Multi-objective Bayesian optimization identifies optimal values for categorical and continuous process variables in the multistep route involving 3 reactions (including heterogeneous hydrogenation) and 1 separation. The platform’s modularity, robotic reconfigurability, and flexibility for convergent synthesis are shown to be essential for allowing variation of downstream residence time in multistep flow processes and controlling the order of addition to minimize undesired reactivity. Overall, the work demonstrates how automation, machine learning, and robotics enhance manual experimentation through assistance with idea generation, experimental design, execution, and optimization.

Design of dynamic trajectories for efficient and data-rich exploration of flow reaction design spaces

Batch and continuous reactors both enable exploration of a chemical design space. The former rely on transient experiments, thus experiencing a wide variety of operating conditions over time, whereas the latter are usually operated at steady state and are representative of only one set of conditions. Operating a continuous reactor under dynamic conditions allows more efficient exploration of the underlying reaction space for extraction of kinetics and optimization of performance. We present a methodology to efficiently explore a design space using a tubular flow reactor installed on an automatic platform (equipped with FTIR and HPLC analysis) operated in a transient regime using sinusoidal variations of the parameters. This data-dense method proves to be quicker with respect to steady-state operations because of the larger amount of information collected during a single experiment. A computational analysis provides a simple criterion for the design of dynamic experiments in order for them to be representative of steady-state conditions. The methodology is applied experimentally to the synthesis of a pharmaceutical intermediate via an esterification reaction in the presence of base. In the experiments, up to three parameters (reaction time, base equivalents, and temperature) are changed simultaneously. Proper design of the trajectories in the design space allows verification of the consistency of the results by exploiting the self-crossings within each trajectory and crossings between different trajectories. The experiments further validate the developed criterion for dynamic operations.

Asymmetric Faradaic Systems for Selective Electrochemical Separations

Ion-selective electrochemical systems are promising for liquid phase separations, particularly for water purification and environmental remediation, as wel as in chemical production operations. Redoxmaterials offer an attractive platform for these separations based on their remarkable ion selectivity. Water splitting, a primary parasitic reaction in aqueous-phase processes, severely limits the performance of such electrochemical processes through significant lowering of current efficiencies and harmful changes in water chemistry. We demonstrate that an asymmetric Faradaic cell with redox-functionalization of both the cathode and the anode can suppress water reduction and enhance ion separation, especially targeting organic micropollutants with current efficiencies of up to 96% towards selective ion-binding A number of organometallic redox-cathodes with electron-transfer properties matching those of a ferrocene-functionalized anode, and with potential cation selectivity, were used in the asymmetric cell, with cobalt polymers being particularly effective towards aromatic cation adsorption. We demonstrate the viability and superior performance of dual-functionalized asymmetric electrochemical cells beyond their use in energy storage systems; they can be considered as a next-generation technology for aqueous-phase separations, and we anticipate their broad applicability in other processes, including electrocatalysis and sensing.

Anion-Selective Redox-Electrodes: Electrochemically-Mediated Separation with Heterogeneous Organometallic Interfaces

Redox species have been explored extensively for catalysis, energy storage, and molecular recognition. It is shown that nanostructured pseudocapacitive electrodes functionalized with ferrocene-based redox polymers are an attractive platform for the selective sorptive separation of dilute organic anions from strong aqueous and organic electrolyte solutions, and subsequent release of the sorbed ions to a stripping phase through electrochemical control of the specific binding processes. A remarkable degree of selectivity is shown for carboxylates (–COO–), sulfonates (–SO3−), and phosphonates (–PO3−2) over inorganic anions such as PF6− and ClO4− (separation factor >140 in aqueous and >3000 in organic systems), and between carboxylates with various substituents, based on differences in electronic structure and density of the adsorbates, beyond size, and charge. Our organometallic redox electrodes are a promising platform for targeting aqueous and organic systems requiring high separation factors and fast throughput, such as in the recovery of value-added products from organic synthesis and isolation of dilute yet highly toxic organic contaminants. The combination of spectroscopic experiments and quantum chemistry sheds light on a selective binding mechanism based on redox-enhanced hydrogen bonding between the cyclopentadienyl ligand and the carboxylate functional group, with broader implications for molecular design, supramolecular recognition, and metallocene catalysis.

Nickel Catalysis: Synergy Between Method Development and Total Synthesis

Nickel(0) catalysts have proven to be powerful tools for multicomponent coupling reactions in our laboratories over the past 15 years. This interest was originally sparked by the ubiquity of allylic alcohol motifs in natural products, such as (−)-terpestacin, which we envisioned assembling by the coupling of two π components (alkyne and aldehyde) with concomitant reduction. Mechanistic investigations allowed us to elucidate several modes of controlling the regioselectivity and stereoselectivity in the oxidative cyclization, and these insights enabled us to leverage combinations of alkenes and phosphine ligands to direct regioselective outcomes. The initial success in developing the first intermolecular reductive alkyne−aldehyde coupling reaction launched a series of methodological investigations that rapidly expanded to include coupling reactions of alkynes with other electrophilic π components, such as imines and ketones, as well as electrophilic σ components, such as epoxides. Aziridines proved to be more challenging substrates for reductive coupling, but we were recently able to demonstrate that cross-coupling of aziridines and alkylzinc reagents is smoothly catalyzed by a zero-valent nickel/phenanthroline system. Moreover, the enantioselective alkyne−aldehyde coupling and the development of novel P-chiral ferrocenyl ligands enabled the total synthesis of (−)-terpestacin, amphidinolides T1 and T4, (−)-gloeosporone, and pumiliotoxins 209F and 251D

Development of a Multi-Step Synthesis and Workup Sequence for an Integrated, Continuous Manufacturing Process of a Pharmaceutical

The development and operation of the synthesis and workup steps of a fully integrated, continuous manufacturing plant for synthesizing aliskiren, a small molecule pharmaceutical, are presented. The plant started with advanced intermediates, two synthetic steps away from the final active pharmaceutical ingredient, and ended with finished tablets. The entire process was run on several occasions, with the data presented herein corresponding to a 240 h run at a nominal throughput of 41 g h−1 of aliskiren. The first reaction was performed solvent-free in a molten condition at a high temperature, achieving high yields (90%) and avoiding solid handling and a long residence time (due to higher concentrations compared to dilute conditions when run at lower temperatures in a solvent). The resulting stream was worked-up inline using liquid−liquid extraction with membrane-based separators that were scaled-up from microfluidic designs. The second reaction involved a Boc deprotection, using aqueous HCl that was rapidly quenched with aqueous NaOH using an inline pH measurement to control NaOH addition. The reaction maintained high yields (90−95%) under closed-loop control despite process disturbances.

Visible-Light Photoredox Catalysis in Flow

Photoredox catalysts have recently been used as powerful tools for synthetic chemists to exploit the energy gained by the absorption of low-energy light within the visible spectrum to initiate a variety of organic transformations.1 The development of methods based on the single-electron transfer properties of photoredox catalysts, particularly in the last several years, has represented a shift in models with respect to the way synthetic chemists consider both photochemistry and redox manipulations of organic molecules.2–4In addition, the advent of new technologies has enabled chemists to conduct reactions with greater efficiency than ever before. Among these new technologies is the development and wide implementation of flow reactors.5, 6 Conducting transformations in flow has many advantages compared to the more traditional batch reactions, in particular: a more predictable reaction scale-up, decreased safety hazards, and improved reproducibility. In addition, for photochemical transformations, the high surface-area-to-volume ratios typical of flow reactors allow for more efficient irradiation of a reaction mixture.7 Due to this feature, we reasoned that a mesofluidic photochemical flow reactor would be amenable to our group’s ongoing study of visible-light-induced organic transformations mediated by photoredox catalysts.

S.-L. Monodentate Chiral Ferrocenyl Ligands
Recent Advances in Organonickel Chemistry