An organophotocatalytic late-stage N-CH3 oxidation of trialkylamines to N-formamides with O2 in continuous flow.

We report an organophotocatalytic, N-CH3-selective oxidation of trialkylamines in continuous flow. Based on the 9,10-dicyanoanthracene (DCA) core, a new catalyst (DCAS) was designed with solubilizing groups for flow processing. This allowed O2 to be harnessed as a sustainable oxidant for late-stage photocatalytic N-CH3 oxidations of complex natural products and active pharmaceutical ingredients bearing functional groups not tolerated by previous methods. The organophotocatalytic gas-liquid flow process affords cleaner reactions than in batch mode, in short residence times of 13.5 min and productivities of up to 0.65 g per day. Spectroscopic and computational mechanistic studies showed that catalyst derivatization not only enhanced solubility of the new catalyst compared to poorly-soluble DCA, but profoundly diverted the photocatalytic mechanism from singlet electron transfer (SET) reductive quenching with amines toward energy transfer (EnT) with O2.

A synthesis-enabled relative stereochemical assignment of the C1-C28 region of hemicalide.

Through synthesising both candidate diastereomers of a model C1-C28 fragment of the potent cytotoxic marine polyketide hemicalide, an assignment of the relative configuration between the C1-C15 and C16-C26 regions has been achieved. By detailed NMR comparisons with the natural product, the relative stereochemistry between these two 1,6-related stereoclusters is elucidated as 13,18-syn rather than the previously proposed 13,18-anti relationship. A flexible and modular strategy using an advanced C1-C28 ketone fragment 22 is outlined to elucidate the remaining stereochemical features and achieve a total synthesis.

Toward the stereochemical assignment and synthesis of hemicalide: DP4f GIAO-NMR analysis and synthesis of a reassigned C16-C28 subunit.

Using the DP4f GIAO-NMR method, the stereochemistry of hemicalide was computationally analysed, resulting in a reassignment at C18 as supported by improved NMR shift correlations with a model C13-C25 fragment 23. An advanced C16-C28 subunit 6 of this potent anticancer agent was then synthesised with the revised 18,19-syn relationship.