Simon B. Blakey

Enantioselective CH Amination Using Cationic Ruthenium(II)–pybox Catalysts†

C H bond amination has emerged as a powerful tool for the synthesis of complex nitrogen-containing molecules. Following the early discoveries by Breslow and Gellman, Du Bois and co-workers revolutionized this area of chemistry by developing protocols for practical, efficient, and predictable reactions for oxidative C H amination. Dirhodium(II) tetracarboxylate catalysts were shown to be particularly effective. Manganese– and ruthenium–porphyrin complexes, silver complexes, and preoxidized nitrogen sources have also been developed as catalysts to carry out this important reaction. Despite these recent advances, general methods for both enantioselective and intermolecular C H amination remain elusive. Although chiral dirhodium(II) complexes have been developed as catalysts for highly enantioselective metallocarbene reactions, their application to C H amination chemistry is yet to produce the same spectacular results. To date, the most effective protocol for asymmetric C H amination requires the combination of enantioenriched sulfoxamines as chiral auxiliaries and a chiral dirhodium(II) catalyst. To address the challenge of catalytic asymmetric C H amination, we chose to study ruthenium(II)–pybox (pybox= pyridine bisoxazoline) complexes (Scheme 1). Despite reports that show complex 1 exhibited limited reactivity and selectivity in C H amination reactions, we felt that the modular nature of the ligand, and the fact that the anionic ligands were independent of the chiral pybox ligand, offered us an opportunity which had not been possible by using either dirhodium(II)or porphyrin-based catalyst systems. Ruthenium(II)–pybox complexes 1–4 were readily prepared by using the method developed by Nishiyama et al. (Scheme 1). In our initial study, the challenging test substrate sulfamate ester 5 was treated with 1.1 equivalents of the oxidant bis(acetoxy)iodobenzene and 5 mol% catalyst 2 to give the desired product of C H insertion 6, albeit in modest yield and enantiomeric excess (Table 1, entries 1–3). Based on the study by Fiori and Du Bois, which demonstrates that rhodium-catalyzed C H amination involves formation of an electrophilic metallonitrene and a build up of positive charge on the carbon center during the insertion process, we rationalized that a cationic catalyst would be more reactive than its neutral analogue. Halide abstraction from the Scheme 1. Synthesis of ruthenium(II)–pybox complexes.

Total synthesis of diazonamide A

A total synthesis of the marine natural product diazonamide A (1) has been accomplished. This work features a highly stereoselective synthesis of the C(10) quaternary center and the central furanoindoline core enabled by an iminium-catalyzed alkylation-cyclization cascade. Additionally, a magnesium-mediated intramolecular macroaldolization and a palladium-catalyzed tandem borylation/annulation were developed to enable the closure of the two 12-membered macrocycles of diazonamide A. This synthesis involves 20 steps in its longest linear sequence and proceeds in 1.8% overall yield.

π-Nucleophile Traps for Metallonitrene/Alkyne Cascade Reactions: A Versatile Process for the Synthesis of α-Aminocyclopropanes and β-Aminostyrenes

The reaction of a sulfamate ester derived rhodium nitrenoid species with an alkyne produces a versatile intermediate, capable of cascading into a wide variety of secondary transformations. The nature of the intermediate has been probed by reactivity studies, and the synthetic utility of the cascade process, which facilitates the construction of complex heterocyclic structures from remarkably simple acyclic precursors, is highlighted.

Catalytic Metallonitrene/Alkyne Metathesis: A Powerful Cascade Process for the Synthesis of Nitrogen-Containing Molecules

A conceptually novel metallonitrene/alkyne metathesis cascade reaction has been developed for the construction of nitrogen-containing compounds from simple alkyne starting materials. Rhodium(II) tetracarboxylate salts are efficient catalysts for this reaction, in which an electrophilic rhodium nitrene is trapped by an alkyne, resulting in the formation of a new C-N bond and the generation of a reactive metallocarbene for cascade reaction. The reaction is tolerant of both alkyl and aryl substituents on the alkyne, and proceeds at room temperature in a variety of common solvents. The modular nature of the reaction allows for the rapid construction of congested bicyclic systems from remarkably simple alkyne starting materials.

Copper-Catalyzed Olefin Aminoacetoxylation

A new catalyst system for intramolecular olefin aminoacetoxylation is described. In contrast to previously reported palladium- and copper-catalyzed systems, the conditions outlined in this communication favor piperdine formation with terminal olefin substrates and induce cyclization with traditionally less reactive disubstituted olefins.

Rhodium catalyzed allene amination: diastereoselective synthesis of aminocyclopropanes via a 2-amidoallylcation intermediate.

The interaction of a sulfamate ester derived metallonitrene with an allene generates a versatile intermediate with 2-amidoallylcation-like reactivity, capable of rearranging to give highly substituted iminocyclopropanes or acting as a novel dipolar species engaging external dipolarophiles.

Studies in marine macrolide synthesis: stereocontrolled synthesis of a C21–C34 subunit of the aplyronines

Abstract The C21–C34 subunit 27 of the aplyronines, containing eight stereocentres and a terminal N -methyl- N -vinylformamide moiety, was prepared using the Horner–Wadsworth–Emmons coupling of β-ketophosphonate 5 with aldehyde 19 . The two stereotetrad sequences were constructed by chiral ketone aldol reactions, while the N -methyl- N -vinylformamide was introduced using a novel Wittig olefination.

Iridium(III)-bis(oxazolinyl)phenyl catalysts for enantioselective C–H functionalization

Recently, a small number of diverse iridium complexes have been shown to catalyze unusual atom transfer C–H functionalization reactions. To further our understanding and enhance the utility of iridium complexes for C–H functionalization, we report the design and synthesis of a family of iridium(III)-bis(oxazolinyl)phenyl complexes. The ability to tune the ligand environment around the metal in these systems is exploited to design complexes with the ability to catalyze the asymmetric insertion of donor/acceptor iridium carbenoids into activated C–H bonds. Low catalyst loadings (0.5 mol%) routinely lead to excellent reaction yields (51–99%) and enantioselectivities (83–99%). Density functional theory calculations provide compelling evidence that in these complexes the carbene binds to the iridium cis to the phenyl group of the bis(oxazolinyl)phenyl ligand. This finding is vital for understanding the observed stereochemical induction and is of particular significance in the field of enantioselective transition metal-catalysed atom transfer reactions utilizing oxazoline–X–oxazoline tridentate ligands, as previously employed stereochemical models for these ligand sets are based on the assumption that reactive ligands and Lewis bases bind trans to the central X ligand.

Rhodium catalyzed allene amidation: a facile entry into 2-amidoallylcations for unusual [3 + 3] annulation reactions

The interaction of a sulfamate ester derived metallonitrene with an allene generates a versatile intermediate with 2-amidoallylcation like reactivity. In this article we outline reactivity patterns for this novel dipolar species, demonstrating both [3 + 2] reactions with benzaldehyde, and unusual [3 + 3] annulation reactions with a variety of nitrones.

A C–H Functionalization Protocol for the Direct Synthesis of Benzobisthiazole Derivatives

Benzobisthiazole and thiazolothiazole derivatives are useful components in a variety of organic electronics devices resulting from their absorption, electroluminescence, and charge-transport properties. A convenient synthesis of these molecules via palladium/copper cocatalyzed C-H bond functionalization is described. Reaction conditions were optimized in a bromobenzene/benzobisthiazole system that allowed for the one-pot functionalization of both thioimidate positions of benzobisthiazole. The extension of this methodology to the synthesis of cruciform architectures and the functionalization of thiazolothiazole is also described.