Although continuous flow technology can facilitate the scale-up of photochemical processes it is not yet routinely implemented on production scale in the fine chemical industries. This can be attributed to additional challenges compared to thermal processes, mostly in the homogeneous irradiation of the flow reactor. Here, we detail the process of bringing a previously developed photochemical benzylic bromination, utilizing in situ bromine generation, from lab to pilot scale. The process setup is discussed in detail, alongside a comprehensive risk assessment and discussion of problems encountered in the investigation of key reaction parameters. Ultimately, an assay yield of 88% was obtained in 22 s irradiated residence time, resulting in a productivity of 4.1 kg h–1 (space-time yield = 82 kg L–1 h–1) representing a 14-fold scale-up versus the lab-scale process.

The stereochemical role of the phosphoramidite ligand in the asymmetric conjugate addition of alkylzirconium species to cyclic enones has been established through experimental and computational studies. Systematic, synthetic variation of the modular ligand established that the configuration of the binaphthol backbone is responsible for absolute stereocontrol, whereas modulation of the amido substituents leads to dramatic variations in the level of asymmetric induction. Chiral amido substituents are not required for enantioselectivity, leading to the discovery of a new family of easily synthesized phosphoramidites based on achiral amines that deliver equal levels of selectivity to Feringa's ligand. A linear correlation between the length of the aromatic amido groups and experimentally determined enantioselectivity was uncovered for this class of ligand, which, following an optimisation, leading to the highly selective ligands (up to 94% ee) with naphthyl rather than phenyl groups. An electronic effect of sterically similar aromatic substituents was investigated through NMR and DFT studies, showing that electron rich aryl groups allow better Cu-coordination. An interaction between the metal center and an aromatic group is responsible for this enhanced affinity and leads to a more tightly-coordinated transition structure leading to the major enantiomer. These studies illustrate the use of parametric quantitative structure-selectivity relationships to generate mechanistic models for asymmetric induction and catalyst structures that may be further probed by experiment and computation. This integrated approach leads to the rational modification of chiral ligands to achieve enhanced levels of selectivity.

Catalytic asymmetric conjugate addition reactions with organometallic reagents are powerful reactions in synthetic chemistry. Procedures that use non-stabilized carbanions have been developed extensively, but these suffer from a number of limitations that prevent their use in many situations. Here, we report that alkylmetal species generated in situ from alkenes can be used in highly enantioselective 1,4-addition initiated by a copper catalyst. Using alkenes as starting materials is desirable because they are readily available and have favourable properties when compared to pre-made organometallics. High levels of enantioselectivity are observed at room temperature in a range of solvents, and the reaction tolerates functional groups that are not compatible with comparable methods-a necessary prerequisite for efficient and protecting-group-free strategies for synthesis.

Alkenes are among the most readily available organic molecules, and are feedstocks for the preparation of many commodity chemicals. [1] Using alkenes as starting materials in synthesis is practical because they are inexpensive and easy to handle. We recently reported [2] that alkenes can be used as the equivalents to premade alkyl metal species in coppercatalyzed asymmetric conjugate additions (ACA). [3] In these reactions hydrometalation (HM) of terminal alkenes with the Schwartz reagent [4] generates alkylzirconocenes, [5] which undergo asymmetric 1,4-additions catalyzed by complex A (Scheme 1). These processes are currently limited to the formation of tertiary centers from ACA to unsubstituted cyclic enones. [2] Herein we report that this approach can be used to form quaternary centers. Scheme 1. Hydrometalation/asymmetric conjugate addition of alkenes. Cp = cyclopentadienyl, Tf = trifluoromethanesulfonyl, TMS = trimethylsilyl.

The expedient enantioselective synthesis of 5 bisabolane sesquiterpenes has been achieved using a common, one-pot lithiation-borylation reaction of secondary benzylic carbamates and either protodeboronation or oxidation to give the natural products in fewer than 5 steps, with high yield and >94 : 6 er.

Catalytic asymmetric conjugate addition reactions of alkylzirconium species to acyclic enones are reported. The alkylzirconium nucleophiles are generated in situ by hydrozirconation of alkenes with the Schwartz reagent. The reaction proceeds under mild and convenient conditions. A variety of functionalized nucleophiles can be used, and the method tolerates some variation in enone scope. The method uses a new chiral nonracemic phosphoramidite ligand in a complex with copper triflate.

Copper catalysis allows alkyl zirconium species, generated in situ from alkenes, to undergo conjugate addition reactions. A hydrometallation-catalytic asymmetric 1,4-addition was used to synthesize either enantiomer of a natural product in one step from commercially available materials. Hydrometallation-addition sequences applied to steroids containing a cross-conjugated dienone or 1,6-acceptor give highly functionalized products.

Carrying out photoredox direct arylation couplings between aryl halides and aryls in water solution of surfactants enables unprecedented selectivity with respect to the competing dehalogenation process, thanks to the partition...