The stereoselective reagent-controlled homologation of boronic esters is one of a small number of iteratable synthetic transformations that if automated could form the basis of a veritable molecule-making machine. Recently, α-stannyl triisopropylbenzoates and α-sulfinyl chlorides have emerged as useful building blocks for the iterative homologation of boronic esters. However, α-stannyl benzoates need to be prepared using stoichiometric amounts of the (+)- or (-)-enantiomer of the scarcely available and expensive diamine sparteine; also, these building blocks, together with the byproducts that are generated during homologation, are perceived as being toxic. On the other hand, α-sulfinyl chlorides are difficult to prepare with high levels of enantiopurity and are prone to undergo deleterious acid-base side-reactions under the reaction conditions for homologation, leading to low stereospecificity. Here, we show that the use of a hybrid of these two building blocks, namely, α-sulfinyl triisopropylbenzoates, largely overcomes the above drawbacks. Through either the sulfinylation of α-magnesiated benzoates with either enantiomer of Andersen's readily available menthol-derived sulfinate or the α-alkylation of enantiopure S-chiral α-sulfinyl benzoates, we have prepared a range of highly enantiopure mono- and disubstituted α-sulfinyl benzoates, some bearing sensitive functional groups. Barbier-type reaction conditions have been developed that allow these building blocks to be converted into lithium (t-BuLi) and magnesium (i-PrMgCl·LiCl) carbenoids in the presence of boronic esters, thus allowing efficient and highly stereospecific homologation. The use of magnesium carbenoids allows carbon chains to be grown with the incorporation of sensitive functional groups, such as alkyl/aryl halides, azides, and esters. The use of lithium carbenoids, which are less sensitive to steric hindrance, allows sterically encumbered carbon-carbon bonds to be forged. We have also shown that these building blocks can be used consecutively in three- and four-step iterative homologation processes, without intervening column chromatography, to give contiguously substituted carbon chains with very high levels of enantio- and diastereoselectivity.

Automation has fuelled dramatic advances in fields such as proteomics and genomics (e.g., in preparation of proteins and nucleic acids), 1,2 enabling non-experts to prepare, test and analyse complex biological molecules. However, the field of automated organic synthesis lags far behind, partly because of the complexity and variety of organic molecules. As a result, only a handful of relatively simple organic molecules, requiring a small number of synthetic steps, have been made in an automated fashion. Herein, we report an automated assembly-line synthesis that allows iterative, stereocontrolled formation of C(sp 3 )-C(sp 3 ) bonds with high stereochemical fidelity and reproducibility, enabling access to complex organic molecules even by non-synthesis experts. This was achieved on a commercially available robotic platform capable of handling air sensitive reactants and performing low temperature reactions, which enabled six sequenced one-carbon homologations of organoboron substrates to be performed iteratively without human intervention. Together with other automated functional group manipulations, this methodology has been exploited to rapidly build the core fragment of the natural product (+)-kalkitoxin, thus leading the way towards automated organic synthesis.

Alkenyl boronic esters are important reagents in organic synthesis.H erein, we report that these valuable products can be accessed by the homologation of boronic esters with lithiated epoxysilanes.A liphatic and electron-rich aromatic boronic esters provided vinylidene boronic esters in moderate to high yields,while electron-deficient aromatic and vinyl boronic esters were found to give the corresponding vinyl silane products.Through DFT calculations,this divergence in mechanistic pathway has been rationalized by considering the stabilization of negative charge in the CÀSi and CÀBb ond breaking transition states.T his vinylidene homologation was used in ashort six-step stereoselective synthesis of the proposed structure of machillene,h owever,s ynthetic and reported data were found to be inconsistent.

A screening method for the rapid identification of catalytic conditions for Pd-catalyzed C–N cross-coupling reactions is reported. The strategy evaluates mixtures of precatalysts, ligands, and bases to identify productive conditions that are subsequently optimized through two deconvolution steps, which uncover the active catalyst and identify the optimal solvent and base for the catalytic system. The efficacy of this approach was demonstrated through application to a previously reported reaction, whereby both the literature conditions and additional solutions were retrieved. The same approach to Ni-catalyzed C–N cross-coupling was investigated in parallel but was found to be less successful due to limited activity of the evaluated reagent combinations. Finally, the utility of this method was showcased by identifying effective conditions for the Pd-catalyzed cross-coupling of complex molecules, which not only revealed nonobvious solutions for the processes under evaluation but also resulted in the discovery of new chemical reactions.

We report on our successful efforts to advance the robustness of screening photochemical reactions run in batch by using commercially available, temperature-controlled multiwell reactors in combination with ChemBead technology for precise solid dosing of the photoredox catalysts. The utility of this experimental setup was validated for five reaction classes, which were selected based on their varying sensitivity toward oxygen, temperature, and degree of homogeneity. The advantages and potential issues associated with the use of ChemBeads in high-throughput experimentation (HTE) photochemistry have been critically assessed. The presented multiarray photochemical setup was then applied to improve the scope of an Ir/Ni-co-catalyzed C−N visible-light crosscoupling reaction between aryl halides and fluorinated amines, which had remained limited until now. The optimal combination of categorical variables, the functional group compatibility, and the required structural elements in both the nucleophile and the electrophile partner for successful reactions were pinpointed. The reproducibility and transferability of the results to a larger-scale batch platform (PHIL photoreactor) was confirmed with a scale-up factor of 100. Finally, some suggestions for further improvements for temperature-controlled multiwell photoreactors compatible with HTE setups were listed.

Automation has fuelled dramatic advances in fields such as proteomics and genomics (e.g., in preparation of proteins and nucleic acids),1,2 enabling non-experts to prepare, test and analyse complex biological molecules. However, the field of automated organic synthesis lags far behind, partly because of the complexity and variety of organic molecules. As a result, only a handful of relatively simple organic molecules, requiring a small number of synthetic steps, have been made in an automated fashion. Herein, we report an automated assembly-line synthesis that allows iterative, stereocontrolled formation of C(sp3)–C(sp3) bonds with high stereochemical fidelity and reproducibility, enabling access to complex organic molecules even by non-synthesis experts. This was achieved on a commercially available robotic platform capable of handling air sensitive reactants and performing low temperature reactions, which enabled six sequenced one-carbon homologations of organoboron substrates to be performed iteratively without human intervention. Together with other automated functional group manipulations, this methodology has been exploited to rapidly build the core fragment of the natural product (+)-kalkitoxin, thus leading the way towards automated organic synthesis.

Alkenyl boronic esters are important reagents in organic synthesis. Herein, we report that these valuable products can be accessed by the homologation of boronic esters with lithiated epoxysilanes. Aliphatic and electron‐rich aromatic boronic esters provided vinylidene boronic esters in moderate to high yields, while electron‐deficient aromatic and vinyl boronic esters were found to give the corresponding vinyl silane products. Through DFT calculations, this divergence in mechanistic pathway has been rationalized by considering the stabilization of negative charge in the C−Si and C−B bond breaking transition states. This vinylidene homologation was used in a short six‐step stereoselective synthesis of the proposed structure of machillene, however, synthetic and reported data were found to be inconsistent.

We report a Pd-catalyzed ring-opening/arylation/cyclization reaction sequence between 2-aminothiazoles and aryl (pseudo)­halides that provides modular access to isocytosine analogues. The scope of the reaction is broad with respect to both coupling partners and a robustness test demonstrated the functional group tolerance of the methodology. Visual kinetic analysis revealed that the product may inhibit catalyst turnover for some substrates.