In the presence of substoichiometric Pd(OAc)(2), carboxylic acids undergo highly regio- and stereoselective additions to ynamides to provide α-acyloxyenamides.

A Baeyer−Villiger monooxygenase enzyme has been used to manufacture a chiral sulfoxide drug intermediate on a kilogram scale. This paper describes the evolution of the biocatalytic manufacturing process from the initial enzyme screen, development of a kilo lab process, to further optimization for plant scale manufacture. Efficient gas−liquid mass transfer of oxygen is key to obtaining a high yield.

AZD6738 is currently being tested in multiple phase I/II trials for the treatment of cancer. Its structure, comprising a pyrimidine core decorated with a chiral morpholine, a cyclopropyl sulfoximine, and an azaindole, make it a challenging molecule to synthesize on a large scale. We describe the evolution of the chemical processes, following the manufacture of AZD6738 from the initial scale-up through to multikilos on plant scale. During this evolution, we developed a biocatalytic process to install the sulfoxide with high enantioselectivity, followed by introduction of the cyclopropyl group first in batch, then in a continuous flow plate reactor, and finally through a series of continuous stirred tank reactors. The final plant scale process to form AZD6738 was operated on 46 kg scale with an overall yield of 18%. We discuss the impurities formed throughout the process and highlight the limitations of this route for further scale-up.

Antipodal relationship: A convergent synthetic pathway leading to 4‐hydroxy‐2‐pyridinones was involved in the synthesis of apiosporamide (1) and YM‐215343 (2). Both have an antipodal relationship to the natural metabolites, whose relative and absolute configurations have been established. Activated β‐alanine enolate equivalents derived from β‐lactams were the key to the synthesis.

The development of a continuous flow sulfoxide imidation protocol for a pharmaceutically relevant target molecule is described. Sulfoxide imidation is a key-step in the preparation of certain ATR kinase inhibitors. Reactions with NaN 3 or TMSN 3 and concentrated sulfuric acid under literature conditions provided slow reactions and poor selectivities. In contrast, reactions employing fuming sulfuric acid afforded the target sulfoximine with a selectivity of ~90% after a reaction time of only 10 to 15 min at 50 °C.The imidation reaction using TMSN 3 as reagent was successfully performed in a flow reactor utilizing CH 2 Cl 2 /H 2 SO 4 biphasic conditions. The mixture was subsequently quenched in-line with H 2 O. Phase separation, neutralization and re-extraction with an organic solvent furnished the product in excellent purity and good yields, albeit with loss of chirality.