Unusually robust: A remarkably temperature‐independent catalyst has been developed for the imino aldol reaction of imines derived from ortho‐aminophenols (see scheme). This catalyst is prepared from two equivalents of the VAPOL ligand and a zirconium tetraalkoxide. From a consideration of likely intermediates in the catalytic cycle it was deduced that a methyl substituent ortho to the phenol (R1) should enhance induction. This resulted in asymmetric inductions in excess of 98 % ee at room temperature as well as at 100°C. TMS=trimethylsilyl.

Process development of a six-stage synthesis of upadacitinib, a JAK1 inhibitor, is described. It is highlighted by an enantioselective and diastereoselective hydrogenation of a tetrasubstituted olefin to set the two pyrrolidine stereocenters. Preparation of the main fragments and strategies to link them together, optimization of the imidazole cyclization, and in-depth understanding of the formation of the urea moiety at the final stage are discussed.

The reactions of terminal alkenes in the presence of ketones or aldehydes with a variety of borane reagents have been investigated. It was found that the selective hydroboration of a terminal alkene in the presence of a ketone or an aldehyde is most efficient when dicyclohexylborane is used as the hydroborating agent. The hydroboration of olefinic ketones and olefinic aldehydes with dicyclohexylborane generates the corresponding hydroxyaldehydes and hydroxyketones in good yields after oxidation with sodium perborate. The hydroboration of alkynyl ketones and alkynyl aldehydes with dicyclohexylborane yields the corresponding olefinic carbonyl compounds after protonation, or dicarbonyl compounds after oxidation.Key words: hydroboration, reduction, dicyclohexylborane, hydroxyaldehyde, hydroxyketone.

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A five-step synthesis of a TRPV1 receptor antagonist 1 is described. The key step involves a novel palladium-catalyzed amidation reaction of 4-chloro-1-methylindazole 8 with the benzyl urea 9 to form the unsymmetrically substituted urea 1.