Reconfigurable system for automated optimization of diverse chemical reactions.

Chemical synthesis generally requires labor-intensive, sometimes tedious trial-and-error optimization of reaction conditions. Here, we describe a plug-and-play, continuous-flow chemical synthesis system that mitigates this challenge with an integrated combination of hardware, software, and analytics. The system software controls the user-selected reagents and unit operations (reactors and separators), processes reaction analytics (high-performance liquid chromatography, mass spectrometry, vibrational spectroscopy), and conducts automated optimizations. The capabilities of this system are demonstrated in high-yielding implementations of C-C and C-N cross-coupling, olefination, reductive amination, nucleophilic aromatic substitution (SNAr), photoredox catalysis, and a multistep sequence. The graphical user interface enables users to initiate optimizations, monitor progress remotely, and analyze results. Subsequent users of an optimized procedure need only download an electronic file, comparable to a smartphone application, to implement the protocol on their own apparatus.

Phase Separation Macrocyclization in a Complex Pharmaceutical Setting: Application toward the Synthesis of Vaniprevir.

A phase separation/continuous flow strategy employing an oxidative Glaser-Hay coupling of alkynes has been applied toward the synthesis of the macrocyclic core of complex pharmaceutical vaniprevir. The phase separation/continuous flow strategy afforded similar yields at 100-500 times the concentration and at shorter reaction times than common slow addition/high dilution techniques. In addition, dendritic PEG cosolvents were employed in the phase separation strategy for the first time and shown to allow productive macrocyclization at concentrations up to 200 mM.

Minimizing E-factor in the continuous-flow synthesis of diazepam and atropine.

Minimizing the waste stream associated with the synthesis of active pharmaceutical ingredients (APIs) and commodity chemicals is of high interest within the chemical industry from an economic and environmental perspective. In exploring solutions to this area, we herein report a highly optimized and environmentally conscious continuous-flow synthesis of two APIs identified as essential medicines by the World Health Organization, namely diazepam and atropine. Notably, these approaches significantly reduced the E-factor of previously published routes through the combination of continuous-flow chemistry techniques, computational calculations and solvent minimization. The E-factor associated with the synthesis of atropine was reduced by 94-fold (about two orders of magnitude), from 2245 to 24, while the E-factor for the synthesis of diazepam was reduced by 4-fold, from 36 to 9.

Advanced strategies for efficient macrocyclic Cu(I)-catalyzed cycloaddition of azides.

An advanced strategy for efficient macrocyclic Cu(I)-catalyzed cycloaddition is described. The key features include employing azide-iodoalkyne cycloadditions (CuAiAC), low catalyst loadings, relatively high concentrations (30 mM → 300 mM), and application to continuous flow. The remarkably efficient new tool affords a variety of macrocyclic skeletons having either different alkyl, aryl, or amino acid spacers in high yields (70-97%). The macrocyclic CuAiAC process affords macrocycles having an iodotriazole moiety that can be further functionalized using standard Pd-catalyzed cross-couplings.

Cu(I)-catalyzed macrocyclic Sonogashira-type cross-coupling.

A macrocyclic Cu-catalyzed Sonogashira-type cross-coupling reaction has been developed that employs an operationally simple CuCl/phen/Cs2CO3 catalyst system. Macrocyclizations can be performed at relatively high concentrations without the need for slow addition techniques and form macrocycles with various ring sizes and functional groups. The optimized protocol was employed in the synthesis of (S)-zearalane, demonstrating applicability toward the synthesis of a macrocycle with known biological activity.

Studies on difficult intramolecular hydroaminations in the context of four syntheses of alkaloid natural products.

Examples of intramolecular alkene hydroaminations forming six-membered ring systems are rare, especially for systems in which the double bond is disubstituted. Such cyclizations have important synthetic relevance. Herein we report a systematic study of these cyclizations using recently developed Cope-type hydroamination methodologies. Difficult intramolecular alkene hydroaminations were used as key steps in syntheses of 2-epi-pumiliotoxin C, coniine, N-norreticuline and desbromoarborescidine A. This effort required the development of optimized hydroamination conditions to improve the efficiency of the cyclizations. Collectively, our results show that Cope-type cyclizations can be achieved on a variety of challenging substrates and proceed under similar conditions for both N-H and N-substituted hydroxylamines.

Synthesis, crystal structure and photophysical properties of pyrene-helicene hybrids.

Synthesis of helically chiral aromatics resulting from fusion of pyrene and [4]- or [5]helicene has been accomplished using photoredox catalysis employing a Cu-based sensitizer as the key step. Photocyclisation experiments for the synthesis of the target compounds were carried out in batch and using continuous flow strategies. The solid-state structures, UV/Vis absorption spectra and fluorescence spectra of the pyrene-helicene hybrids were investigated and compared to that of the parent [5]helicene to discern the effects of merging a pyrene moiety within a helicene skeleton. The studies demonstrated that pyrene-helicene hybrids adopt co-planar or stacked arrangements in the solid state, in contrast to the solid-state structure of the parent [5]helicene. The UV/Vis and fluorescence spectra of the pyrene-helicene hybrids exhibited strong red-shifts when compared to the parent [5]helicene. DFT calculations suggest that the strategy of extending the π surface in the y axis of the helicenes increased their HOMO levels while also decreasing their LUMO levels, resulting in significantly reduced band gaps.

Exploiting aggregation to achieve phase separation in macrocyclization.

The aggregation properties of poly(ethylene glycol) (PEG) can be exploited in organic synthesis to control dilution effects. Through the use of solvent mixtures containing PEG(400) /MeOH, macrocyclization by Glaser-Hay coupling can be conducted at high concentrations. The origin of the selectivity has been studied by using surface tension measurements, UV spectroscopy, and chemical tagging and demonstrates the dependence of the yield and selectivity on the aggregation of PEG(400) and its ability to preferentially solubilize organic substrates, resulting in a phase separation from the catalyst system.

Microwave accelerated Glaser-Hay macrocyclizations at high concentrations.

Efficient macrocyclization can be conducted at high concentrations employing microwave irradiation and a phase separation strategy. The rate of the Glaser-Hay macrocyclization is accelerated using microwave irradiation and reaction times decreased from 48 h to 1-6 h, depending on the nature of the substrate. Macrocyclization concentrations could be increased up to 0.1 M compared to traditional concentrations (0.2 mM).

Phase separation as a strategy toward controlling dilution effects in macrocyclic Glaser-Hay couplings.

Macrocycles are abundant in numerous chemical applications, however the traditional strategy for the preparation of these compounds remains cumbersome and environmentally damaging; involving tedious reaction set-ups and extremely dilute reaction media. The development of a macrocyclization strategy conducted at high concentrations is described which exploits phase separation of the catalyst and substrate, as a strategy to control dilution effects. Sequestering a copper catalyst in a highly polar and/or hydrophilic phase can be achieved using a hydrophilic ligand, T-PEG(1900), a PEGylated TMEDA derivative. Similarly, phase separation is possible when suitable copper complexes are soluble in PEG(400), a green and efficient solvent which can be utilized in biphasic mixtures for promoting macrocyclization at high concentrations. The latter phase separation technique can be exploited for the synthesis of a wide range of industrially relevant macrocycles with varying ring sizes and functional groups.

The tandem Cope-type hydroamination/[2,3]-rearrangement sequence: a strategy to favor the formation of intermolecular hydroamination products and enable difficult cyclizations.

The tandem hydroamination/Meisenheimer rearrangement sequence was developed to address the issue of unfavorable reaction thermodynamics for intermolecular reactions of alkenes and to improve the scope of Cope-type hydroaminations. This tandem sequence allows intermolecular reactions of N-alkyl-N-methallylhydroxyl-amines to be energetically more favorable: the N-oxide intermediate formed via Cope-type hydroamination, which can revert to the starting materials via a Cope elimination, can form a more stable neutral product via a [2,3]-Meisenheimer rearrangement. This tandem sequence also leads to increased efficiency in intramolecular systems as illustrated by syntheses of two alkaloids (coniine and norreticuline) featuring difficult hydroamination key steps.

Intermolecular cope-type hydroamination of alkenes and alkynes using hydroxylamines.

The development of the Cope-type hydroamination as a method for the metal- and acid-free intermolecular hydroamination of hydroxylamines with alkenes and alkynes is described. Aqueous hydroxylamine reacts efficiently with alkynes in a Markovnikov fashion to give oximes and with strained alkenes to give N-alkylhydroxylamines, while unstrained alkenes are more challenging. N-Alkylhydroxylamines also display similar reactivity with strained alkenes and give modest to good yields with vinylarenes. Electron-rich vinylarenes lead to branched products while electron-deficient vinylarenes give linear products. A beneficial additive effect is observed with sodium cyanoborohydride, the extent of which is dependent on the structure of the hydroxylamine. The reaction conditions are found to be compatible with common protecting groups, free OH and NH bonds, as well as bromoarenes. Both experimental and theoretical results suggest the proton transfer step of the N-oxide intermediate is of vital importance in the intermolecular reactions of alkenes. Details are disclosed concerning optimization, reaction scope, limitations, and theoretical analysis by DFT, which includes a detailed molecular orbital description for the concerted hydroamination process and an exhaustive set of calculated potential energy surfaces for the reactions of various alkenes, alkynes, and hydroxylamines.

A rare ligand bridged ferromagnetically coupled MnIV3 complex with a ground spin state of S = 9/2.

An exclusively chelating ligand bridged high-valent [MnIV3] complex has been synthesized, in which all Mn(IV) ions are ferromagnetically-coupled to exhibit an S(T) = 9/2 spin ground state.