Enantio- and Diastereodivergent Cyclopropanation of Allenes by Directed Evolution of an Iridium-Containing Cytochrome.

Alkylidene cyclopropanes (ACPs) are valuable synthetic intermediates because of their constrained structure and opportunities for further diversification. Although routes to ACPs are known, preparations of ACPs with control of both the configuration of the cyclopropyl (R vs S) group and the geometry of the alkene (E vs Z) are unknown. We describe enzymatic cyclopropanation of allenes with ethyl diazoacetate (EDA) catalyzed by an iridium-containing cytochrome (Ir(Me)-CYP119) that controls both stereochemical elements. Two mutants of Ir(Me)-CYP119 identified by 6-codon (6c, VILAFG) saturation mutagenesis catalyze the formation of (E)-ACPs with -93% to >99% ee and >99:1 E/Z ratio with just three rounds of 96 mutants. By four additional rounds of mutagenesis, an enzyme variant was identified that forms (Z)-ACPs with up to 94% ee and a 28:72 E/Z ratio. Computational studies show that the orientation of the carbene unit dictated by the mutated positions accounts for the stereoselectivity.

Reversible Dihydrogen Activation and Catalytic H/D Exchange with Group 10 Heterometallic Complexes.

Reaction of a hexagonal planar palladium complex featuring a [PdMg3 H3 ] core with H2 is reversible and leads to the formation of a new [PdMg2 H4 ] tetrahydride species alongside an equivalent of a magnesium hydride co-product [MgH]. While the reversibility of this process prevented isolation of [PdMg2 H4 ], analogous [PtMg2 H4 ] and [PtZn2 H4 ] complexes could be isolated and characterised through independent syntheses. Computational analysis (DFT, AIM, NCIPlot) of the bonding in a series of heterometallic tetrahydride compounds (Ni-Pt; Mg and Zn) suggests that these complexes are best described as square planar with marginal metal-metal interactions; the strength of which increases slightly as group 10 is descended and increases from Mg to Zn. DFT calculations support a mechanism for H2 activation involving a ligand-assisted oxidative addition to Pd. These findings were exploited to develop a catalytic protocol for H/D exchange into magnesium hydride and zinc hydride bonds.

The Continuum Between Hexagonal Planar and Trigonal Planar Geometries.

New heterometallic hydride complexes that involve the addition of {Mg-H} and {Zn-H} bonds to group 10 transition metals (Pd, Pt) are reported. The side-on coordination of a single {Mg-H} to Pd forms a well-defined σ-complex. In contrast, addition of three {Mg-H} or {Zn-H} bonds to Pd or Pt results in the formation of planar complexes with subtly different geometries. We compare their structures through experiment (X-ray diffraction, neutron diffraction, multinuclear NMR), computational methods (DFT, QTAIM, NCIPlot), and theoretical analysis (MO diagram, Walsh diagram). These species can be described as snapshots along a continuum of bonding between ideal trigonal planar and hexagonal planar geometries.

Palladium-Catalysed C-H Bond Zincation of Arenes: Scope, Mechanism, and the Role of Heterometallic Intermediates.

Catalytic methods that transform C-H bonds into C-X bonds are of paramount importance in synthesis. A particular focus has been the generation of organoboranes, organosilanes and organostannanes from simple hydrocarbons (X=B, Si, Sn). Despite the importance of organozinc compounds (X=Zn), their synthesis by the catalytic functionalisation of C-H bonds remains unknown. Herein, we show that a palladium catalyst and zinc hydride reagent can be used to transform C-H bonds into C-Zn bonds. The new catalytic C-H zincation protocol has been applied to a variety of arenes-including fluoroarenes, heteroarenes, and benzene-with high chemo- and regioselectivity. A mechanistic study shows that heterometallic Pd-Zn complexes play a key role in catalysis. The conclusions of this work are twofold; the first is that valuable organozinc compounds are finally accessible by catalytic C-H functionalisation, the second is that heterometallic complexes are intimately involved in bond-making and bond-breaking steps of C-H functionalisation.

Reactions of an Aluminum(I) Reagent with 1,2-, 1,3-, and 1,5-Dienes: Dearomatization, Reversibility, and a Pericyclic Mechanism.

Addition of the aluminum(I) reagent [{(ArNCMe)2CH}Al] (Ar = 2,6-di-iso-propylphenyl) to a series of cyclic and acyclic 1,2-, 1,3-, and 1,5-dienes is reported. In the case of 1,3-dienes, the reaction occurs by a pericyclic reaction mechanism, specifically a cheletropic cycloaddition, to form aluminocyclopentene-containing products. This mechanism has been examined by stereochemical experiments and DFT calculations. The stereochemical experiments show that the (4 + 1) cycloaddition follows a suprafacial topology, while calculations support a concerted albeit asynchronous pathway in which the transition state demonstrates aromatic character. Remarkably, the substrate scope of the (4 + 1) cycloaddition includes styene, 1,1-diphenylethylene, and anthracene. In these cases, the diene motif is either in part, or entirely, contained within an aromatic ring and reactions occur with dearomatisation of the substrate and can be reversible. In the case of 1,2-cyclononadiene or 1,5-cyclooctadiene, complementary reactivity is observed; the orthogonal nature of the C═C π-bonds (1,2-diene) and the homoconjugated system (1,5-diene) both disfavor a (4 + 1) cycloaddition. Rather, reaction pathways are determined by an initial (2 + 1) cycloaddition to form an aluminocyclopropane intermediate which can in turn undergo insertion of a further C═C π-bond, leading to complex organometallic products that incorporate fused hydrocarbon rings.

Catalyst control of selectivity in the C-O bond alumination of biomass derived furans.

Non-catalysed and catalysed reactions of aluminium reagents with furans, dihydrofurans and dihydropyrans were investigated and lead to ring-expanded products due to the insertion of the aluminium reagent into a C-O bond of the heterocycle. Specifically, the reaction of [{(ArNCMe)2CH}Al] (Ar = 2,6-di-iso-propylphenyl, 1) with furans proceeded between 25 and 80 °C leading to dearomatised products due to the net transformation of a sp2 C-O bond into a sp2 C-Al bond. The kinetics of the reaction of 1 with furan were found to be 1st order with respect to 1 with activation parameters ΔH ‡ = +19.7 (±2.7) kcal mol-1, ΔS ‡ = -18.8 (±7.8) cal K-1 mol-1 and ΔG ‡ 298 K = +25.3 (±0.5) kcal mol-1 and a KIE of 1.0 ± 0.1. DFT calculations support a stepwise mechanism involving an initial (4 + 1) cycloaddition of 1 with furan to form a bicyclic intermediate that rearranges by an α-migration. The selectivity of ring-expansion is influenced by factors that weaken the sp2 C-O bond through population of the σ*-orbital. Inclusion of [Pd(PCy3)2] as a catalyst in these reactions results in expansion of the substrate scope to include 2,3-dihydrofurans and 3,4-dihydropyrans and improves selectivity. Under catalysed conditions, the C-O bond that breaks is that adjacent to the sp2C-H bond. The aluminium(iii) dihydride reagent [{(MesNCMe)2CH}AlH2] (Mes = 2,4,6-trimethylphenyl, 2) can also be used under catalytic conditions to effect a dehydrogenative ring-expansion of furans. Further mechanistic analysis shows that C-O bond functionalisation occurs via an initial C-H bond alumination. Kinetic products can be isolated that are derived from installation of the aluminium reagent at the 2-position of the heterocycle. C-H alumination occurs with a KIE of 4.8 ± 0.3 consistent with a turnover limiting step involving oxidative addition of the C-H bond to the palladium catalyst. Isomerisation of the kinetic C-H aluminated product to the thermodynamic C-O ring expansion product is an intramolecular process that is again catalysed by [Pd(PCy3)2]. DFT calculations suggest that the key C-O bond breaking step involves attack of an aluminium based metalloligand on the 2-palladated heterocycle. The new methodology has been applied to important platform chemicals from biomass.

The partial dehydrogenation of aluminium dihydrides.

The reactions of a series of ß-diketiminate stabilised aluminium dihydrides with ruthenium bis(phosphine), palladium bis(phosphine) and palladium cyclopentadienyl complexes is reported. In the case of ruthenium, alane coordination occurs with no evidence for hydrogen loss resulting in the formation of ruthenium complexes with a pseudo-octahedral geometry and cis-relation of phosphine ligands. These new ruthenium complexes have been characterised by multinuclear and variable temperature NMR spectroscopy, IR spectroscopy and single crystal X-ray diffraction. In the case of palladium, a series of structural snapshots of alane dehydrogenation have been isolated and crystallographically characterised. Variation of the palladium precursor and ligand on aluminium allows kinetic control over reactivity and isolation of intermetallic complexes that contain new Pd-Al and Pd-Pd interactions. These complexes differ by the ratio of H : Al (2 : 1, 1.5 : 1 and 1 : 1) with lower hydride content species forming with dihydrogen loss. A combination of X-ray and neutron diffraction studies have been used to interrogate the structures and provide confidence in the assignment of the number and position of hydride ligands. 27Al MAS NMR spectroscopy and calculations (DFT, QTAIM) have been used to gain an understanding of the dehydrogenation processes. The latter provide evidence for dehydrogenation being accompanied by metal-metal bond formation and an increased negative charge on Al due to the covalency of the new metal-metal bonds. To the best of our knowledge, we present the first structural information for intermediate species in alane dehydrogenation including a rare neutron diffraction study of a palladium-aluminium hydride complex. Furthermore, as part of these studies we have obtained the first SS 27Al NMR data on an aluminium(i) complex. Our findings are relevant to hydrogen storage, materials chemistry and catalysis.

A hexagonal planar transition-metal complex.

Transition-metal complexes are widely used in the physical and biological sciences. They have essential roles in catalysis, synthesis, materials science, photophysics and bioinorganic chemistry. Our understanding of transition-metal complexes originates from Alfred Werner's realization that their three-dimensional shape influences their properties and reactivity1, and the intrinsic link between shape and electronic structure is now firmly underpinned by molecular-orbital theory2-5. Despite more than a century of advances in this field, the geometries of transition-metal complexes remain limited to a few well-understood examples. The archetypal geometries of six-coordinate transition metals are octahedral and trigonal prismatic, and although deviations from ideal bond angles and bond lengths are frequent6, alternative parent geometries are extremely rare7. The hexagonal planar coordination environment is known, but it is restricted to condensed metallic phases8, the hexagonal pores of coordination polymers9, or clusters that contain more than one transition metal in close proximity10,11. Such a geometry had been considered12,13 for [Ni(PtBu)6]; however, an analysis of the molecular orbitals suggested that this complex is best described as a 16-electron species with a trigonal planar geometry14. Here we report the isolation and structural characterization of a simple coordination complex in which six ligands form bonds with a central transition metal in a hexagonal planar arrangement. The structure contains a central palladium atom surrounded by three hydride and three magnesium-based ligands. This finding has the potential to introduce additional design principles for transition-metal complexes, with implications for several scientific fields.

Unravelling nucleophilic aromatic substitution pathways with bimetallic nucleophiles.

The reaction of a metal complex containing a polar Fe-Mg bond with 2-(pentafluorophenyl)pyridine leads to selective C-F bond activation. A stepwise SNAr mechanism involving attack of the bimetallic nucleophile on the electron-deficient aromatic ring has been identified by DFT calculations. Despite the long and rich history of metal anions in organic synthesis, this is the first time the SNAr mechanism has been elucidated in detail for metal-based nucleophiles.

Palladium-catalysed magnesiation of benzene.

In the presence of a catalytic quantity of [Pd(PCy3)2], a reagent containing a Mg-Mg bond effects the C-H functionalisation of benzene resulting in a 100% atom efficient transformation to generate an unprecedented aryl magnesium hydride.

Room temperature catalytic carbon-hydrogen bond alumination of unactivated arenes: mechanism and selectivity.

We report the first catalytic methods for the transformation of C-H bonds of unactivated arenes into C-Al bonds. The catalytic reactions occur at 25 °C (benzene, toluene and xylenes) with palladium loadings as low as 0.1 mol%. Remarkably, the C-H activation of toluene and xylenes proceeds with ortho- and meta-selectivity. This selectivity is highly unusual and complementary to both Friedel-Crafts and the majority of C-H borylation methods. Through a detailed mechanistic analysis (Eyring analysis, KIE, DFT, QTAIM) we show that unusual Pd-Al intermetallic complexes are on the catalytic cycle and that the selectivity is determined by weak attractive dispersion forces in the transition state for C-H bond breaking.

Total Synthesis of ( R)-Sarkomycin Methyl Ester via Regioselective Intermolecular Pauson-Khand Reaction and Iridium-Catalyzed Asymmetric Isomerization.

A new five-step enantioselective synthesis of ( R)-sarkomycin methyl ester is described. The cyclopentane scaffold was built by a regioselective intermolecular Pauson-Khand reaction. Enantioselectivity was introduced by a novel Ir-catalyzed isomerization reaction. The last steps involved a catalytic hydrogenation of the exocylic double bond, followed by the deprotection and elimination of the amino group. This route is the shortest enantioselective synthesis of this antibiotic reported to date.