Dirhodium Carboxylate Catalysts from 2-Fenchyloxy or 2-Menthyloxy Arylacetic Acids: Enantioselective C-H Insertion, Aromatic Addition and Oxonium Ylide Formation/Rearrangement.

A new class of dirhodium carboxylate catalysts have been designed and synthesized from 2-fenchyloxy or 2-menthyloxy arylacetic acids which display excellent enantioselectivity across a range of transformations of α-diazocarbonyl compounds. The catalysts were successfully applied to enantioselective C-H insertion reactions of aryldiazoacetates and α-diazo-ß-oxosulfones affording the respective products in up to 93 % ee with excellent trans diastereoselectivity in most cases. Furthermore, efficient desymmetrization in an intramolecular C-H insertion was achieved. In addition, these catalysts prove highly enantioselective for intramolecular aromatic addition with up to 88 % ee, and oxonium ylide formation and rearrangement with up to 74 % ee.

Exploiting Continuous Processing for Challenging Diazo Transfer and Telescoped Copper-Catalyzed Asymmetric Transformations.

Generation and use of triflyl azide in flow enables efficient synthesis of a range of α-diazocarbonyl compounds, including α-diazoketones, α-diazoamides, and an α-diazosulfonyl ester, via both Regitz-type diazo transfer and deacylative/debenzoylative diazo-transfer processes with excellent yields and offers versatility in the solvent employed, in addition to addressing the hazards associated with handling of this highly reactive sulfonyl azide. Telescoping the generation of triflyl azide and diazo-transfer process with highly enantioselective copper-mediated intramolecular aromatic addition and C-H insertion processes demonstrates that the reaction stream containing the α-diazocarbonyl compound can be obtained in sufficient purity to pass directly over the immobilized copper bis(oxazoline) catalyst without detrimentally impacting the catalyst enantioselectivity.

Copper-Mediated, Heterogeneous, Enantioselective Intramolecular Buchner Reactions of α-Diazoketones Using Continuous Flow Processing.

Enantioselective intramolecular Buchner reactions of α-diazoketones can be effected using heterogeneous copper-bis(oxazoline) catalysts in batch or using continuous flow processing in up to 83% ee. The catalyst can be reused up to 7 times without loss of activity. For α-diazoketones 3 and 4, the enantioselection achieved in flow with the immobilized catalyst was comparable with the standard homogeneous catalyzed process.

Taming tosyl azide: the development of a scalable continuous diazo transfer process.

Heat and shock sensitive tosyl azide was generated and used on demand in a telescoped diazo transfer process. Small quantities of tosyl azide were accessed in a 'one pot' batch procedure using shelf stable, readily available reagents. For large scale diazo transfer reactions tosyl azide was generated and used in a telescoped flow process, to mitigate the risks associated with handling potentially explosive reagents on scale. The in situ formed tosyl azide was used to rapidly perform diazo transfer to a range of acceptors, including ß-ketoesters, ß-ketoamides, malonate esters and ß-ketosulfones. An effective in-line quench of sulfonyl azides was also developed, whereby a sacrificial acceptor molecule ensured complete consumption of any residual hazardous diazo transfer reagent. The telescoped diazo transfer process with in-line quenching was used to safely prepare over 21 g of an α-diazocarbonyl in >98% purity without any column chromatography.