[reaction: see text] Syntheses of variously modified ligands for the dinuclear zinc catalysts for the asymmetric aldol and nitroaldol (Henry) reactions are reported. Catalytic enantioselective nitroaldol reactions promoted by these modified ligands led to efficient syntheses of the beta-receptor agonists (-)-denopamine and (-)-arbutamine.

New asymmetric methods to generate the cyclopropane motif have attracted widespread attention from the synthetic community owing to their ubiquitous presence in a diverse range of natural products and their crucial role in the mode of action of many therapeutic agents.[1] Furthermore, the rigid structure and strain-driven reactivity make them attractive intermediates in complex molecule synthesis.[2] Because of these important properties and the need for efficient methods for their stereoselective formation, the synthesis of cyclopropane-containing molecules has become a platform for the development of new asymmetric catalytic processes.[3] Notably, in the last few years numerous metal-catalyzed and organocatalytic intermolecular cyclopropanation reactions have been reported that enable the generation of discrete three-membered ring systems with high diastereo-and enantioselectivity.[4] In contrast, there are few corresponding catalytic asymmetric intramolecular reactions. Although recently a number of catalytic diastereoselective intramolecular cyclopropanation processes have been reported, [5] only methods that exploit the metal-catalyzed decomposition of adiazo-carbonyl compounds lead to a general enantioselective assembly of [n.1.0]-bicycloalkane frameworks.[6] The development of a new catalytic enantioselective intramolecular cyclopropanation method would be a valuable tool for the synthetic chemist and would further aid the quest for novel

No abstract

Development of a convergent synthesis of omarigliptin (MK-3102) suitable for commercial manufacture is described. The target molecule is assembled through a diastereoselective reductive amination of a highly functionalized pyranone with a mesylated pyrazole followed by deprotection of a Boc group. The synthesis of the pyranone relies on three Ru-catalyzed reactions, 1) a DKR reduction of a rac-α-aminoketone to set the two contiguous stereogenic centers, 2) a cycloisomerization of a bis-homopropargylic alcohol to a dihydropyran, and finally 3) a Ru-catalyzed oxidation of a pyranol to the desired pyranone. A regioselective synthesis of an N-Boc-1-mesyl pyrazole fragment was achieved via a base promoted mesyl group isomerisation to afford 30:1 selectivity. A highlight of the endgame process development is telescoping a Boc deprotection and reductive amination followed by direct crystallization of the penultimate from the reaction mixture. This avoids handling of an unstable, mutagenic 1-mesylpyrazole BSA salt used in the earlier multi-kilogram deliveries, and improved the overall diastereoselectivity and efficiency of the route.

Allylic amides and their derivatives represent a versatile class of nitrogen-containing building blocks, the bifunctional nature of which has enabled a diverse array of transformations and established them as strategically important molecules in chemical synthesis. [1,2] Particularly useful are reactions where an electrophile activates the carbon-carbon double bond towards attack of the pendant oxygen atom of the amide carbonyl group to form either a five or sixmembered ring heterocycle, depending on the mode of cyclization (Scheme 1 a). [3] Most of these reactions are triggered by heteroatom electrophiles, often activated by a catalyst, and result in the formation of a carbon-oxygen and a carbon-heteroatom bond. It is, however, surprising that the related electrophilic carbofunctionalization process is rare. One possible reason for this is the lack of suitable carbon electrophiles that can activate the carbon-carbon double bond of the allylic amide. The development of Pd-catalyzed oxyarylation and aminoarylation reactions, in particular by Wolfe and co-workers, [4] as well as related Pd, [5] Cu, [6] and Aucatalyzed [7] processes have provided an alternative approach to related alkene difunctionalization [8] and can be applied to derivatives of the generic allylic amine framework. Despite these advances, the development of novel methods that catalytically generate carbon electrophiles capable of activating alkenes to nucleophilic attack remains a challenge; the solution to this challenge would be of significant use in complex molecule synthesis.As part of an overarching program aimed at the exploitation of high oxidation state metal species we, [9] and others, [10] have established that the combination of copper catalysts and diaryliodonium salts gives rise to a high oxidation state Cu III / aryl [11] intermediate that displays reactivity of an aromatic electrophile (Scheme 1 b). We reasoned that this distinct catalytic activation strategy could be used to generate the aromatic electrophile equivalent that would be needed to affect an intramolecular oxyarylation of allylic amides, thus complementing the corresponding heteroatom electrophile triggered cyclizations that have become a mainstay in synthesis.We selected aryl-substituted allylic amides with which to test our copper-catalyzed oxyarylation strategy as the products would generate a broadly useful class of diarylated amino alcohols. Furthermore, we noted that some aryl-substituted allylic amides have been utilized in other electrophile triggered cyclization reactions. For example, treatment with acid induces an intramolecular hydration-type reaction to form the 6-membered-ring oxazine product (Scheme 1 c). [13] Similarly, treatment with bromine gives rise to a bromocyclization, again forming the oxazine product, although this is dependent on the geometry of the starting alkene and the electronic nature of the aromatic ring. [14,15] To the best of our knowledge, there are no examples of such a catalytic electrophilic carbofunctionalization of this class of ...