Borane-catalyzed selective dihydrosilylation of terminal alkynes: reaction development and mechanistic insight

Here, we describe simple B(C₆F₅)₃-catalyzed mono- and dihydrosilylation reactions of terminal alkynes by using a silane-tuned chemoselectivity strategy, affording vinylsilanes and unsymmetrical geminal bis(silanes). This strategy is applicable to the dihydrosilylation of both aliphatic and aryl terminal alkynes with different silane combinations. Gram-scale synthesis and conducting the reaction without the exclusion of air and moisture demonstrate the practicality of this methodology. The synthetic utility of the resulting products was further highlighted by the structural diversification of geminal bis(silanes) through transforming the secondary silane into other silyl groups. Comprehensive theoretical calculations combined with kinetical isotope labeling studies have shown that a prominent kinetic differentiation between the hydrosilylation of alkynes and vinylsilane is responsible for the chemoselective construction of unsymmetrical 1,1-bis(silanes).

A B(C₆F₅)₃/silane-based system enables the chemoselective dihydrosilylation of terminal alkynes. Using a combination of different types of hydrosilanes, a series of unsymmetrical or symmetrical 1,1-bis(silanes) could be constructed.     

Enantioselective [1,2]-Stevens rearrangement of thiosulfonates to construct dithio-substituted quaternary carbon centers

An enantioselective [1,2] Stevens rearrangement was realized by using chiral guanidine and copper(i) complexes. Bis-sulfuration of α-diazocarbonyl compounds was developed through using thiosulfonates as the sulfenylating agent. It was undoubtedly an atom-economic process providing an efficient route to access novel chiral dithioketal derivatives, affording the corresponding products in good yields (up to 90% yield) and enantioselectivities (up to 96 : 4 er). A novel catalytic cycle was proposed to rationalize the reaction process and enantiocontrol.

An asymmetric [1,2] Stevens rearrangement was realized via chiral guanidine and copper(i) complexes. A series of novel chiral dithioketal derivatives were obtained with good yields (up to 90% yield) and enantioselectivities (up to 96 : 4 er).     

Enantioselective one-carbon expansion of aromatic rings by simultaneous formation and chromoselective irradiation of a transient coloured enolate

Enantioenriched seven-membered carbocycles are motifs in many molecules of structural and biological interest. We report a simple, practical, transition metal-free and mechanistically unusual method for the enantioselective synthesis of substituted cycloheptatrienes. By forming a coloured enolate with an appropriate absorption band and selectively irradiating in situ, we to initiate a tandem, asymmetric anionic and photochemical ring expansion of readily accessible N-benzylbenzamides. The cascade of reactions leading to the products entails enantioselective benzylic deprotonation with a chiral lithium amide, dearomatizing cyclization of the resulting configurationally defined organolithium to give an extended amide enolate, and photochemically induced formal [1,7]-sigmatropic rearrangement and 6π-electrocyclic ring-opening – the latter all evidently being stereospecific – to deliver enantioenriched cycloheptatrienes with embedded benzylic stereocentres.

Irradiation of a mixture of aromatic amide and chiral base leads to a tandem reaction sequence in which dearomatization forms a chromophore capable of photochemical rearrangement leading to overall asymmetric expansion of the aromatic ring.     

Three-component carboacylation of alkenes via cooperative nickelaphotoredox catalysis

Various commercially available acyl chlorides, aldehydes, and alkanes were exploited for versatile three-component 1,2-carboacylations of alkenes to forge two vicinal C–C bonds through the cooperative action of nickel and sodium decatungstate catalysis. A wealth of ketones with high levels of structural complexity was rapidly obtained via direct functionalization of C(sp²)/C(sp³)–H bonds in a modular manner. Furthermore, a regioselective late-stage modification of natural products showcased the practical utility of the strategy, generally featuring high resource economy and ample substrate scope.

Various commercially available acyl chlorides, aldehydes, and alkanes were exploited for versatile three-component 1,2-carboacylations of alkenes to forge two vicinal C–C bonds through the cooperative action of nickel and sodium decatungstate catalysis.     

The transient-chelating-group-controlled stereoselective Rh(i)-catalyzed silylative aminocarbonylation of 2-alkynylanilines: access to (Z)-3-(silylmethylene)indolin-2-ones

A new method involving mild acryl transient-chelating-group-controlled stereoselective Rh(i)-catalyzed silylative aminocarbonylation of 2-alkynylanilines with CO and silanes is presented for producing (Z)-3-(silylmethylene)indolin-2-ones. Upon using an acryl transient chelating group, 2-alkynylanilines undergo an unprecedented alkyne cis-silylrhodation followed by aminocarbonylation to assemble (Z)-3-(silylmethylene)indolin-2-ones. Mechanistic studies show that acryl transient chelating effects result in the key alkyne cis-silylrhodation process.

Transient-chelating-group-controlled stereoselective rhodium(I)-catalyzed silylative aminocarbonylation of 2- alkynylanilines with CO and silanes toward (Z)-3-(silylmethylene)indolin-2-ones is presented.     

The mechanism of oxidative addition of Pd(0) to Si–H bonds: electronic effects,reaction mechanism,and hydrosilylation

The oxidative addition of Pd to Si–H bonds is a crucial step in a variety of catalytic applications, and many aspects of this reaction are poorly understood. One important yet underexplored aspect is the electronic effect of silane substituents on reactivity. Herein we describe a systematic investigation of the formation of silyl palladium hydride complexes as a function of silane identity, focusing on electronic influence of the silanes. Using [(μ-dcpe)Pd]₂ (dcpe = dicyclohexyl(phosphino)ethane) and tertiary silanes, data show that equilibrium strongly favours products formed from electron-deficient silanes, and is fully dynamic with respect to both temperature and product distribution. A notable kinetic isotope effect (KIE) of 1.21 is observed with H/DSiPhMe₂ at 233 K, and the reaction is shown to be 0.5^th order in [(μ-dcpe)Pd]₂ and 1^st order in silane. Formed complexes exhibit temperature-dependent intramolecular H/Si ligand exchange on the NMR timescale, allowing determination of the energetic barrier to reversible oxidative addition. Taken together, these results give unique insight into the individual steps of oxidative addition and suggest the initial formation of a σ-complex intermediate to be rate-limiting. The insight gained from these mechanistic studies was applied to hydrosilylation of alkynes, which shows parallel trends in the effect of the silanes'' substituents. Importantly, this work highlights the relevance of in-depth mechanistic studies of fundamental steps to catalysis.

Mechanistic studies reveal the rate law, an H/D KIE, and that the silane’s electronics impact the thermodynamic and kinetic energetics of the oxidative addition reaction. These electronic effects are relevant in the hydrosilylation of alkynes.     

Radical boron migration of allylboronic esters

A photocatalyzed 1,3-boron shift of allylboronic esters is reported. The boron atom migration through the allylic carbon skeleton proceeds via consecutive 1,2-boron migrations and Smiles-type rearrangement to furnish a variety of terminally functionalized alkyl boronates. Several types of migrating variations of heteronuclei radicals and dearomatization processes are also tolerated, allowing for further elaboration of highly functionalized boron-containing frameworks.

A photocatalyzed 1,3-boron shift of allylboronic esters is reported. The atom-switch acrobatics proceeds via cascade 1,2-boron migrations and Smiles type rearrangement to furnish a variety of terminally functionalized alkyl boronates.     

NHC and visible light-mediated photoredox co-catalyzed 1,4-sulfonylacylation of 1,3-enynes for tetrasubstituted allenyl ketones

The modulation of selectivity of highly reactive carbon radical cross-coupling for the construction of C–C bonds represents a challenging task in organic chemistry. N-Heterocyclic carbene (NHC) catalyzed radical transformations have opened a new avenue for acyl radical cross-coupling chemistry. With this method, highly selective cross-coupling of an acyl radical with an alkyl radical for efficient construction of C–C bonds was successfully realized. However, the cross-coupling reaction of acyl radicals with vinyl radicals has been much less investigated. We herein describe NHC and visible light-mediated photoredox co-catalyzed radical 1,4-sulfonylacylation of 1,3-enynes, providing structurally diversified valuable tetrasubstituted allenyl ketones. Mechanistic studies indicated that ketyl radicals are formed from aroyl fluorides via the oxidative quenching of the photocatalyst excited state, allenyl radicals are generated from chemo-specific sulfonyl radical addition to the 1,3-enynes, and finally, the key allenyl and ketyl radical cross-coupling provides tetrasubstituted allenyl ketones.

Unprecedented NHC and photocatalysis co-catalyzed radical 1,4-sulfonylacylation of 1,3-enynes has been realized, providing structurally diversified tetrasubstituted allenyl ketones via allenyl and ketyl radical cross-coupling.     

Diastereoconvergent synthesis of anti-1,2-amino alcohols with N-containing quaternary stereocenters via selenium-catalyzed intermolecular C–H amination

We report a diastereoconvergent synthesis of anti-1,2-amino alcohols bearing N-containing quaternary stereocenters using an intermolecular direct C–H amination of homoallylic alcohol derivatives catalyzed by a phosphine selenide. Destruction of the allylic stereocenter during the selenium-catalyzed process allows selective formation of a single diastereomer of the product starting from any diastereomeric mixture of the starting homoallylic alcohol derivatives, eliminating the need for the often-challenging diastereoselective preparation of starting materials. Mechanistic studies show that the diastereoselectivity is controlled by a stereoelectronic effect (inside alkoxy effect) on the transition state of the final [2,3]-sigmatropic rearrangement, leading to the observed anti selectivity. The power of this protocol is further demonstrated on an extension to the synthesis of syn-1,4-amino alcohols from allylic alcohol derivatives, constituting a rare example of 1,4-stereoinduction.

We report a diastereoconvergent synthesis of anti-1,2-amino alcohols bearing N-containing quaternary stereocenters using an intermolecular direct C–H amination of homoallylic alcohol derivatives catalyzed by a phosphine selenide.     

Ligand-enabled oxidation of gold(i) complexes with o-quinones

Chelating P^P and hemilabile P^N ligands were found to trigger the oxidation of Au(i) complexes by o-benzoquinones. The ensuing Au(iii) catecholate complexes have been characterized by NMR spectroscopy, single crystal X-ray diffraction and X-ray absorption spectroscopy. They adopt tetracoordinate square-planar structures. Reactivity studies substantiate the reversibility of the transformation. In particular, the addition of competing ligands such as chloride and alkenes gives back Au(i) complexes with concomitant release of the o-quinone. DFT calculations provide insight about the structure and relative stability of the Au(i) o-quinone and Au(iii) catecholate forms, and shed light on the 2-electron transfer from gold to the o-quinone.

Chelating P^P and hemilabile P^N ligands were found to trigger the oxidation of Au(i) complexes by o-benzoquinones.     

Direct metal–carbon bonding in symmetric bis(C–H) agostic nickel(i) complexes

Agostic interactions are examples of σ-type interactions, typically resulting from interactions between C–H σ-bonds with empty transition metal d orbitals. Such interactions often reflect the first step in transition metal-catalysed C–H activation processes and thus are of critical importance in understanding and controlling σ bond activation chemistries. Herein, we report on the unusual electronic structure of linear electron-rich d⁹ Ni(i) complexes with symmetric bis(C–H) agostic interactions. A combination of Ni K edge and L edge XAS with supporting TD-DFT/DFT calculations reveals an unconventional covalent agostic interaction with limited contributions from the valence Ni 3d orbitals. The agostic interaction is driven via the empty Ni 4p orbitals. The surprisingly strong Ni 4p-derived agostic interaction is dominated by σ contributions with minor π contributions. The resulting ligand–metal donation occurs directly along the C–Ni bond axis, reflecting a novel mode of bis-agostic bonding.

Symmetric Ni(i) agostic complexes reveal an unusual mode of bonding that is dominated by direct carbon-to-metal charge transfer.     

Backbone-controlled LUMO energy induces intramolecular C–H activation in ortho-bis-9-borafluorene-substituted phenyl and o-carboranyl compounds leading to novel 9,10-diboraanthracene derivatives

The choice of backbone linker for two ortho-bis-(9-borafluorene)s has a great influence on the LUMO located at the boron centers and, therefore, the reactivity of the respective compounds. Herein, we report the room temperature rearrangement of 1,2-bis-(9-borafluorenyl)-ortho-carborane, C₂B₁₀H₁₀-1,2-[B(C₁₂H₈)]₂ ([2a]) featuring o-carborane as the inorganic three-dimensional backbone and the synthesis of 1,2-bis-(9-borafluorenyl)benzene, C₆H₄-1,2-[B(C₁₂H₈)]₂ (2b), its phenylene analog. DFT calculations on the transition state for the rearrangement support an intramolecular C–H bond activation process via an S_EAr-like mechanism in [2a], and predicted that the same rearrangement would take place in 2b, but at elevated temperatures, which indeed proved to be the case. The rearrangement gives access to 3a and 3b as dibora-benzo[a]fluoroanthene isomers, a form of diboron polycyclic aromatic hydrocarbon (PAH) that had yet to be explored. The isolated compounds 2b, 3a, and 3b were fully characterized by NMR, HRMS, cyclic voltammetry (CV), single-crystal X-ray diffraction analysis, and photophysical measurements, supported by DFT and TD-DFT calculations.

The backbone linker for two ortho-bis-(9-borafluorene)s influences the LUMO at the boron centers and the reactivity of the respective compounds.     

Temperature triggered alternating copolymerization of epoxides and lactones via pre-sequenced spiroorthoester intermediates

We report the alternating copolymerization of caprolactone and epoxide through the in situ formation of pre-sequenced spiroorthoester monomer. The reaction is catalyzed by the temperature triggered, bifunctional cationic indium complex (±)-[(NN_iO_tBu)In(CH₂SiMe₃)][B(C₆F₅)₄] (1). 1 can catalyze the coupling of epoxide and lactone to form spiroorthoester at 60 °C and its double ring-opening polymerization at 110 °C to form poly(ether-alt-ester). The post-polymerization modification and degradation of the poly(ether-alt-ester) are further investigated.

We report the alternating copolymerization of caprolactone and epoxide through the in situ formation of pre-sequenced spiroorthoester monomer.     

Me3SiSiMe2(OnBu): a disilane reagent for the synthesis of diverse silacycles via Brook- and retro-Brook-type rearrangement

Herein, a readily available disilane Me₃SiSiMe₂(OⁿBu) has been developed for the synthesis of diverse silacycles via Brook- and retro-Brook-type rearrangement. This protocol enables the incorporation of a silylene into different starting materials, including acrylamides, alkene-tethered 2-(2-iodophenyl)-1H-indoles, and 2-iodobiaryls, via the cleavage of Si–Si, Si–C, and Si–O bonds, leading to the formation of spirobenzosiloles, fused benzosiloles, and π-conjugated dibenzosiloles in moderate to good yields. Preliminary mechanistic studies indicate that this transformation is realized by successive palladium-catalyzed bis-silylation and Brook- and retro-Brook-type rearrangement of silane-tethered silanols.

A readily available disilane Me₃SiSiMe₂(OⁿBu) as a silylene source has been developed for the synthesis of diverse silacycles via Brook- and retro-Brook-type rearrangement.     

Phenanthroline-imine ligands for iron-catalyzed alkene hydrosilylation

Iron-catalyzed organic reactions have been attracting increasing research interest but still have serious limitations on activity, selectivity, functional group tolerance, and stability relative to those of precious metal catalysts. Progress in this area will require two key developments: new ligands that can impart new reactivity to iron catalysts and elucidation of the mechanisms of iron catalysis. Herein, we report the development of novel 2-imino-9-aryl-1,10-phenanthrolinyl iron complexes that catalyze both anti-Markovnikov hydrosilylation of terminal alkenes and 1,2-anti-Markovnikov hydrosilylation of various conjugated dienes. Specifically, we achieved the first examples of highly 1,2-anti-Markovnikov hydrosilylation reactions of aryl-substituted 1,3-dienes and 1,1-dialkyl 1,3-dienes with these newly developed iron catalysts. Mechanistic studies suggest that the reactions may involve an Fe(0)–Fe(ii) catalytic cycle and that the extremely crowded environment around the iron center hinders chelating coordination between the diene and the iron atom, thus driving migration of the hydride from the silane to the less-hindered, terminal end of the conjugated diene and ultimately leading to the observed 1,2-anti-Markovnikov selectivity. Our findings, which have expanded the types of iron catalysts available for hydrosilylation reactions and deepened our understanding of the mechanism of iron catalysis, may inspire the development of new iron catalysts and iron-catalyzed reactions.

Newly developed iron complexes bearing 2-imino-9-aryl-1,10-phenanthroline ligands were successfully used to catalyze hydrosilylation of terminal alkenes and conjugated dienes in high yields with excellent anti-Markovnikov selectivity.     

Phosphite mediated asymmetric N to C migration for the synthesis of chiral heterocycles from primary amines

A phosphite mediated stereoretentive C–H alkylation of N-alkylpyridinium salts derived from chiral primary amines was achieved. The reaction proceeds through the activation of the N-alkylpyridinium salt substrate with a nucleophilic phosphite catalyst, followed by a base mediated [1,2] aza-Wittig rearrangement and subsequent catalyst dissociation for an overall N to C-2 alkyl migration. The scope and degree of stereoretention were studied, and both experimental and theoretical investigations were performed to support an unprecedented aza-Wittig rearrangement–rearomatization sequence. A catalytic enantioselective version starting with racemic starting material and chiral phosphite catalyst was also established following our understanding of the stereoretentive process. This method provides efficient access to tertiary and quaternary stereogenic centers in pyridine systems, which are prevalent in drugs, bioactive natural products, chiral ligands, and catalysts.

N-Alkylpyridinium salt of chiral amines undergoes phosphite mediated stereoretentive migrations to generate chiral alkylpyridines. The role of phosphite on reactivity and stereoselectivity were examined to achieve a catalytic asymmetric version.     

Highly selective addition of cyclosilanes to alkynes enabling new conjugated materials

Main group organometallic compounds can exhibit unusual optical properties arising from hybrid σ,π-conjugation. While linear silanes are extensively studied, the shortage of methods for the controlled synthesis of well-defined cyclic materials has precluded the study of cyclic conjugation. Herein we report that Ru-catalyzed addition of cyclosilanes to aryl acetylenes (hydrosilylation) proceeds with high chemoselectivity, regioselectivity, and diastereoselectivity, affording complex organosilanes that absorb visible light. We further show that the hydrosilylation products are useful building blocks towards novel conjugated polymers.

Hybrid σ,π-conjugated cyclosilanes were synthesized via highly selective hydrosilylation and have shown great potentials as building blocks to construct novel conjugated polymers with control of tacticity.     

Chelation-assisted C–C bond activation of biphenylene by gold(i) halides

A chelation-assisted oxidative addition of gold(i) into the C–C bond of biphenylene is reported here. The presence of a coordinating group (pyridine, phosphine) in the biphenylene unit enabled the use of readily available gold(i) halide precursors providing a new, straightforward entry towards cyclometalated (N^C^C)- and (P^C)-gold(iii) complexes. Our study, combining spectroscopic and crystallographic data with DFT calculations, showcases the importance of neighboring, weakly coordinating groups towards the successful activation of strained C–C bonds by gold.

Pyridine and phosphine directing groups promote the C–C activation of biphenylene by readily available gold(i) halides rendering a new entry to (N^C^C)- and (P^C)-gold(iii) species.

Activation of C–C bonds by transition metals is challenging given their inertness and ubiquitous presence alongside competing C–H bonds.¹ Both the intrinsic steric hindrance as well as the highly directional character of the p orbitals involved in the σ_C–C bond impose a high kinetic barrier for this type of processes.^2,3 Biphenylene, a stable antiaromatic system featuring two benzene rings connected via a four-membered cycle, has found widespread application in the study of C–C bond activation. Since the seminal report from Eisch et al. on the oxidative addition of a nickel(0) complex into the C–C bond of biphenylene,⁴ several other late transition metals have been successfully applied in this context.⁵ Interestingly, despite the general reluctance of gold(i) to undergo oxidative addition,⁶ its oxidative insertion into the C–C bond of biphenylene was demonstrated in two consecutive reports by the groups of Toste^7a and Bourissou,^7b respectively. The high energy barrier associated with the oxidation of gold could be overcome by the utilization of gold(i) precursors bearing ligands that exhibit either a strongly electron-donating character (e.g. IPr = [1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene])^7a or small bite angles (e.g. DPCb = diphosphino-carborane).^7b,8 In line with these two approaches, more sophisticated bidentate (N^C)- and (P^N)-ligated gold(i) complexes have also been shown to aid the activation of biphenylene at ambient temperature (Scheme 1a).^7c,dOpen in a separate windowScheme 1(a) Previous reports on oxidative addition of ligated gold(i) precursors onto biphenylene. (b) This work: pyridine- and phosphine-directed C–C bond activation of biphenylene by commercially available gold(i) halides.In this context, we hypothesized that the oxidative insertion of gold(i) into the C–C bond of biphenylene could be facilitated by the presence of a neighboring chelating group.⁹ This approach would not only circumvent the need for gold(i) precursors featuring strong σ-donor or highly tailored bidentate ligands but also offer a de novo entry towards interesting, less explored ligand templates. However, recent work by Breher and co-workers showcased the difficulty of achieving such a transformation.¹⁰Herein, we report the oxidative insertion of readily available gold(i) halide precursors into the C–C bond of biphenylene. The appendage of both pyridine and phosphine donors in close proximity to the σ_C–C bond bridging the two aromatic rings provides additional stabilization to the metal center and results in a de novo entry to cyclometalated (N^C^C)- and (P^C)gold(iii) complexes (Scheme 1b).Our study commenced with the preparation of 5-chloro-1-pyridino-biphenylene system 2via Pd-catalyzed Suzuki cross coupling reaction between 2-bromo-3-methylpyridine and 2-(5-chlorobiphenylen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1 (Scheme 2).¹¹ To our delight, the reaction of 2 with gold(i) iodide in toluene at 130 °C furnished complex κ³-(N^C^C)Au(iii)–I 3 in 60% yield.^12,13 Complex 3 was isolated as yellow plate-type crystals from the reaction mixture and its molecular structure was unambiguously assigned by NMR spectroscopy, high-resolution mass spectrometry (HR-MS) and crystallographic analysis. Complex 3 exhibits the expected square-planar geometry around the metal center, with a Au–I bond length of 2.6558(3) Å.¹⁴ The choice of a neutral weakly bound gold(i)-iodide precursor is key for a successful reaction outcome: similar reactions in the presence of [(NHC)AuCl + AgSbF₆] failed to deliver the desired biscyclometalation adducts, as reported by Breher et al. in ref. 10. The oxidative insertion of gold(i) iodide into the four-membered ring of pyridino-substituted biphenylene provides a novel and synthetically efficient entry to κ³-(N^C^C)gold(iii) halides. These species have recently found widespread application as precursors for the characterization of highly labile, catalytically relevant gold(iii) intermediates,^15a–d as well as for the preparation of highly efficient emitters in OLEDs.^15e–g Previous synthetic routes towards these attractive biscyclometalated gold(iii) systems involved microwave-assisted double C–H functionalization reactions that typically proceed with low to moderate yields.^15aOpen in a separate windowScheme 2Synthesis of complex 3via oxidative addition of Au(i) into the C–C bond of pyridine-substituted biphenylene. X-ray structures of complex 3 with atoms drawn using 50% probability ellipsoids. Hydrogen atoms have been omitted for clarity. Additional selected bond distances [Å]: N–Au = 2.126(2), C1–Au = 1.973(2), C2–Au = 2.025(2), Au–I = 2.6558(3) and bond angles [deg]: N–Au–I = 99.25(6), N–Au–C1 = 79.82(9), C1–Au–C2 = 81.2(1), C2–Au–I = 99.73(8). For experimental details, see ESI.^†Encouraged by the successful results obtained with the pyridine-substituted biphenylene and considering the prominent use of phosphines in gold chemistry,^6,16 we wondered whether the same reactivity would be observed for a P-containing system. To this end, both adamantyl- and tert-butyl-substituted phosphines were appended in C1 position of the biphenylene motif. Starting from 5-chlorobiphenylene-1-carbaldehyde 4, phosphine-substituted biphenylenes 5a and 5b could be accessed in 3 steps (aldehyde reduction to the corresponding alcohol, Appel reaction and nucleophilic displacement of the corresponding benzylic halide) in 64 and 57% overall yields, respectively.¹³ The reactions of 5a and 5b with commercially available gold(i) halides (Me₂SAuCl and AuI) furnished the corresponding mononuclear complexes 7a–b and 8a–b, respectively (Scheme 3).¹³ All these complexes were fully characterized and the structures of 7a, 7b and 8a were unambiguously characterized by X-ray diffraction analysis.¹³ Interestingly, the nature of the halide has a clear effect on the chemical shift of the phosphine ligand so that a Δδ of ca. 5 ppm can be observed in the ³¹P NMR spectra of 7a–b (Au–Cl) compared to 8a–b (Au–I), the latter being the more deshielded. The Au–X bond length is also impacted, with a longer Au–I distance (2.5608(1) Å for 8a) compared to that measured in the Au–Cl analogue (2.2941(7) Å for 7a) (Δd = 0.27 Å).¹³Open in a separate windowScheme 3Synthesis and reactivity of complexes 7a–b, 8a–b, 9 and 10. X-ray structure of complexes 11b, 12 and 14 with atoms drawn using 50% probability ellipsoids. Hydrogen atoms have been omitted for clarity. For experimental details and X-ray structures see ESI.^†Despite numerous attempts to promote the C–C activation in these complexes,^10,13 all reactions resulted in the formation of highly stable cationic species 11a–b and 12, which could be easily isolated from the reaction media. In the case of cationic mononuclear-gold(i) complexes 11, a ligand scrambling reaction in which the chloride ligand is replaced by a phosphine in the absence of a scavenger, a process previously described for gold(i) species, can be used to justify the reaction outcome.¹⁷ The formation of dinuclear gold complex 12 can be ascribed to the combination of a strong aurophilic interaction between the two gold centers (Au–Au = 2.8874(4) Å) and the stabilizing η²-coordination of the metal center to the aromatic ring of biphenylene. Similar η²-coordinated gold(i) complexes have been reported but, to the best of our knowledge, only as mononuclear species.¹⁸Taking into consideration the observed geometry of complexes 7a–b in the solid state,¹³ the facile formation of stable cationic species 11 and 12 and the lack of reactivity of the gold(i) iodides 8a–b, we hypothesized that the free rotation around the C–P bond was probably restricted, placing the gold(i) center away from the biphenylene system and thus preventing the desired oxidative insertion reaction. To overcome this problem, we set out to elongate the arm bearing the phosphine unit with an additional methylene group, introduced via a Wittig reaction from compound 4 to yield ligand 6, prepared in 4 steps in 27% overall yield. Coordination with Me₂SAuCl and AuI resulted in gold(i) complexes 9 and 10, respectively (Scheme 3). The structure of 9 was unambiguously assigned by X-ray diffraction analysis and a similar environment around the metal center to that determined for complex 7a was observed for this complex.¹³With complexes 9 and 10 in hand, we explored their reactivity towards C–C activation of the four-membered ring of biphenylene.¹⁹ After chloride abstraction and upon heating at 100 °C for 5 hours, ring opening of the biphenylene system was observed for complex 9. Interestingly, formation of mono-cyclometalated adduct 13 was exclusively observed (the structure of 13 was confirmed by ¹H, ¹³C, ³¹P, ¹⁹F, ¹¹B and 2D NMR spectroscopy and HR-MS).¹³ The solvent appears to play a major role in this process, as performing the reaction in non-chlorinated solvents resulted in stable cationic complexes similar to 11.^13,20,21 The presence of adventitious water is likely responsible for the formation of the monocyclometalated (P^C)gold(iii) complex 13 as when the reaction was carried out in C₂H₄Cl₂ previously treated with D₂O, the corresponding deuterated adduct 13-d could be detected in the reaction media. These results showcase the difficulties associated with the biscyclometalation for P-based complexes as well as the labile nature of the expected biscyclometalated adducts. Interestingly though, these processes can be seen as a de novo entry towards relatively underexplored (P^C)gold(iii) species.²²The C–C activation was further confirmed by X-ray diffraction analysis of the phosphonium salt 14, which arise from the reductive elimination at the gold(iii) center in 13 upon exchange of the BF₄⁻ counter-anion with the weakly coordinating sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBAr^F).^13,23 The phosphorus atom is four-coordinate, with weak bonding observed to the distant counter-anion and a distorted tetrahedral geometry (C1–P–C2 = 95.05(17), C2–P–C3 = 112.1(1), C3–P–C4 = 116.6(1), C4–P–C1 = 107.4(2) deg). These results represent the third example in which the C(sp²)–P bond reductive elimination at gold(iii) has been reported.²⁴Further, it is important to note that, in contrast to the reactivity observed for the pyridine-substituted biphenylene, neither P-coordinated gold(i) iodo complexes 8a, 8b nor 10 reacted to give cyclometalated products despite prolonged heating, which highlights the need for highly reactive cationized gold(i) species to undergo oxidative addition when phosphine ligands are flanking the C–C bond.¹³To get a deeper understanding on the observed differences in reactivity for the N- vs. P-based directing groups, ground- and transition-state structures for the oxidative insertion of gold(i) halides in C1-substituted biphenylenes were computed by DFT calculations. The reactions of Py-substituted 2 with AuI to give 3 (I) and those of P-substituted 7a (II) and 9 (III) featuring the cationization of the gold(i) species were chosen as models for comparative purposes with the experimental conditions (Fig. 1 and S1–S10 in the ESI^†).^25–27 The computed activation energies for the three processes are in good agreement with the experimental data. The pyridine-substituted biphenylene I exhibits the lowest activation barrier for the oxidative insertion process (ΔG^‡ = 34.4 kcal mol⁻¹). The reaction on the phosphine-substituted derivatives II and III proved to be, after cationization of the corresponding gold(i) halide complexes (II-BF₄, III-BF₄) higher in energy (ΔG^‡ = 39.6 and 46.3 kcal mol⁻¹ respectively), although the obtained values do not rule out the feasibility of the C–C activation process. The transition state between I and I′ exhibits several interesting geometrical features: (a) the biphenylene is significantly bent, (b) the cleavage of the C–C bond is well advanced (d_C–C = 1.898 Å in TSIvs. d_C–C = 1.504 Å in I), and (c) the two C and the I atoms form a Y-shape around gold with minimal coordination from the pyridine (d_N–Au = 2.742 Å in TSIvs. d_N–Au = 2.093 Å in I and 2.157 Å in I′, respectively). The transition-state structures found for the P-based ligands (TSII and TSIII) also show an elongation of the C–C bond and display a bent biphenylene. However, much shorter P–Au distances (d_P–Au = 2.330 Å for TSII and 2.314 Å for TSIII) can be observed compared to the pyridine-based system, as expected due to the steric and electronic differences between these two coordinating groups. Analogously, longer C–Au distances were also found for the P-based systems (d_C1–Au = 2.152 Å for TSIvs. 2.235 Å and 2.204 Å for TSII and TSIII; d_C2–Au = 2.143 Å for TSIvs. 2.219 Å and 2.162 Å for TSII and TSIII), with a larger deviation of square planarity for Au in TSIII compared to TSII.^28,29 These results suggest that, provided the appropriate distance to the C–C bond is in place, the strong coordination of phosphorous to the gold(i) center does not prevent the C–C activation of biphenylene but other reactions (i.e. formation of diphosphine gold(i) cationic species, protodemetalation) can outcompete the expected biscyclometalation process. In contrast, a weaker donor such as pyridine offers a suitable balance bringing the gold in close proximity to the C–C bond and enables both the oxidative cleavage as well as the formation of the double metalation product.Open in a separate windowFig. 1Energy profile (ΔG and ΔG^‡ in kcal mol⁻¹), optimized structures, transition states computed at the IEFPCM (toluene/1,2-dichloroethane)-B3PW91/DEF2QZVPP(Au,I)/6-31++G(d,p)(other atoms) level of theory for the C–C activation of biphenylene with gold(i) iodide from I and gold(i) cationic from II and III. Computed structures of the transition states (TSI, TSII and TSIII) and table summarizing relevant distances.     

Protecting group free glycosylation: one-pot stereocontrolled access to 1,2-trans glycosides and (1→6)-linked disaccharides of 2-acetamido sugars

Unprotected 2-acetamido sugars may be directly converted into their oxazolines using 2-chloro-1,3-dimethylimidazolinium chloride (DMC), and a suitable base, in aqueous solution. Freeze drying and acid catalysed reaction with an alcohol as solvent produces the corresponding 1,2-trans-glycosides in good yield. Alternatively, dissolution in an aprotic solvent system and acidic activation in the presence of an excess of an unprotected glycoside as a glycosyl acceptor, results in the stereoselective formation of the corresponding 1,2-trans linked disaccharides without any protecting group manipulations. Reactions using aryl glycosides as acceptors are completely regioselective, producing only the (1→6)-linked disaccharides.

Un-protected 2-acetamido sugars are stereoselectively converted into 1,2-trans glycosides and (1→6)-linked disaccharides without any protecting groups. Reaction proceeds via intermediate oxazolines which react with acceptors under acid catalysis.     

Enzymology of standalone elongating ketosynthases

The β-ketoacyl-acyl carrier protein synthase, or ketosynthase (KS), catalyses carbon–carbon bond formation in fatty acid and polyketide biosynthesis via a decarboxylative Claisen-like condensation. In prokaryotes, standalone elongating KSs interact with the acyl carrier protein (ACP) which shuttles substrates to each partner enzyme in the elongation cycle for catalysis. Despite ongoing research for more than 50 years since KS was first identified in E. coli, the complex mechanism of KSs continues to be unravelled, including recent understanding of gating motifs, KS–ACP interactions, substrate recognition and delivery, and roles in unsaturated fatty acid biosynthesis. In this review, we summarize the latest studies, primarily conducted through structural biology and molecular probe design, that shed light on the emerging enzymology of standalone elongating KSs.

Ketosynthases (KSs) accept substrates from the acyl carrier protein (ACP) to catalyse carbon–carbon bond formation in fatty acid and polyketide biosynthesis. In this review, we delineate the enzymology of standalone elongating ketosynthases with a focus on the enzyme gates.