The development of a continuous flow process for the multistep synthesis of α-halo ketones starting from N-protected amino acids is described. The obtained α-halo ketones are chiral building blocks for the synthesis of HIV protease inhibitors, such as atazanavir and darunavir. The synthesis starts with the formation of a mixed anhydride in a first tubular reactor. The anhydride is subsequently combined with anhydrous diazomethane in a tube-in-tube reactor. The tube-in-tube reactor consists of an inner tube, made from a gas-permeable, hydrophobic material, enclosed in a thick-walled, impermeable outer tube. Diazomethane is generated in the inner tube in an aqueous medium, and anhydrous diazomethane subsequently diffuses through the permeable membrane into the outer chamber. The α-diazo ketone is produced from the mixed anhydride and diazomethane in the outer chamber, and the resulting diazo ketone is finally converted to the halo ketone with anhydrous ethereal hydrogen halide. This method eliminates the need to store, transport, or handle diazomethane and produces α-halo ketone building blocks in a multistep system without racemization in excellent yields. A fully continuous process allowed the synthesis of 1.84 g of α-chloro ketone from the respective N-protected amino acid within ~4.5 h (87% yield).

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A configurationally simple and robust semibatch apparatus for the in situ on-demand generation of anhydrous solutions of diazomethane (CH2N2) avoiding distillation methods is presented. Diazomethane is produced by base-mediated decomposition of commercially available Diazald within a semipermeable Teflon AF-2400 tubing and subsequently selectively separated from the tubing into a solvent- and substrate-filled flask (tube-in-flask reactor). Reactions with CH2N2 can therefore be performed directly in the flask without dangerous and labor-intensive purification operations or exposure of the operator to CH2N2. The reactor has been employed for the methylation of carboxylic acids, the synthesis of α-chloro ketones and pyrazoles, and palladium-catalyzed cyclopropanation reactions on laboratory scale. The implementation of in-line FTIR technology allowed monitoring of the CH2N2 generation and its consumption. In addition, larger scales (1.8 g diazomethane per hour) could be obtained via parallelization (numbering up) by simply wrapping several membrane tubings into the flask.

A new method for the preparation of α,β-unsaturated diazoketones from aldehydes and a Horner-Wadsworth-Emmons reagent is reported. The method was applied to the short synthesis of two substituted pyrrolidines.

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A versatile and concise approach for the stereoselective synthesis of mono-, di-, and trihydroxylated indolizidines is presented in four to six steps from Cbz-prolinal and a diazophosphonate. The key steps involved a Wolff rearrangement, followed by a stereoselective dihydroxylation/epoxidation reaction, from an α,β-unsaturated diazoketone. The strategy also permits extension to the synthesis of many natural hydroxylated indolizidine alkaloids as demonstrated in the formal synthesis of pumiliotoxin 251D.

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The coupling between cyclic and acyclic α-amino acid derivatives and methyl acrylate, mediated by samarium diiodide, is described. The method constitutes a powerful tool to construct indolizidine, quinolizidine, and piperidine systems in a straightforward two-step fashion. The formal synthesis of (-)-pumiliotoxin 251D and (±)-epiquinamide is achieved after two or three steps from these amino acid derivatives.