Diverse saturated heterocycles from a hydroacylation/conjugate addition cascade

Rhodium-catalyzed hydroacylation using alkynes substituted with pendant nucleophiles, delivers linear α,β-unsaturated enone intermediates with excellent regioselectivity. These adducts are used to construct a broad range of diversely substituted, saturated O-, N- and S-heterocycles in a one-pot process. Judicious choice of cyclisation conditions enabled isolation of O-heterocycles with high levels of diastereoselectivity. A variety of derivatisation reactions are also performed, generating functionalised hydroacylation products. This sequence serves as a general approach for the synthesis of fully saturated heterocycles.

We demonstrate a one-pot hydroacylation/intramolecular conjugate-addition sequence to access a series of complex stereodefined heterocycles. Subsequent diversification of products is achieved, furnishing functionalized sp³-rich fragments.     

Direct access to tetrasubstituted cyclopentenyl scaffolds through a diastereoselective isocyanide-based multicomponent reaction

An efficient strategy combining the stereocontrol of organocatalysis with the diversity-generating character of multicomponent reactions is described to produce structurally unique, tetrasubstituted cyclopentenyl frameworks. An asymmetric Michael addition–hemiacetalization between α-cyanoketones and α,β-unsaturated aliphatic aldehydes was performed for constructing cyclic hemiacetals, which were next employed as chiral bifunctional substrates in a new diastereoselective intramolecular isocyanide-based multicomponent reaction. This approach furnished a diversity of structurally complex compounds – including peptidomimetics and natural product hybrids in high stereoselectivity (up to >99% ee and up to >99 : 1 dr) and in moderate to high yields.

Simple and available reagents are combined in this new three-component isocyanide-based multicomponent reaction providing an interesting and straightforward way to prepare complex and highly functionalized cyclopentenyl rings.     

Rapid one-pot iterative diselenide–selenoester ligation using a novel coumarin-based photolabile protecting group

The development of an iterative one-pot peptide ligation strategy is described that capitalises on the rapid and efficient nature of the diselenide–selenoester ligation reaction, together with photodeselenisation chemistry. This ligation strategy hinged on the development of a novel photolabile protecting group for the side chain of selenocysteine, namely the 7-diethylamino-3-methyl coumarin (DEAMC) moiety. Deprotection of this DEAMC group can be effected in a mild, reagent-free manner using visible light (λ = 450 nm) without deleterious deselenisation of selenocysteine residues, thus enabling a subsequent ligation reaction without purification. The use of this DEAMC-protected selenocysteine in iterative DSL chemistry is highlighted through the efficient one-pot syntheses of 60- and 80-residue fragments of mucin-1 as well as apolipoprotein CIII in just 2–4 hours.

A method for the rapid one-pot iterative assembly of proteins via diselenide–selenoester ligation (DSL) chemistry is described that capitalises on a novel coumarin-based photolabile protecting group for selenocysteine.     

Rhodium-catalyzed intermolecular hydroacylation of 1-alkynes: Effect of phosphines and MK-10 on the reaction selectivity

The use of bulky ligands in the rhodium-catalyzed reaction of aldehydes 7 (R¹ = Ph) and 18 with 1-octyne increased the selectivity for ketones 13 and 20, to the detriment of ketones 12 and 19. Bulky phosphines reduced the hydroacylation reaction rate, leading to competition from the addition of the benzoic acid co-catalyst to the alkynes. This competing reaction can be suppressed by using the clay Montmorillonite K 10 (MK-10) as the co-catalyst instead of benzoic acid.     

Chemo- and regio-divergent access to fluorinated 1-alkyl and 1-acyl triazenes from alkynyl triazenes

The 1,1,2,2-tetrafluoroethylene unit is prevalent in bioactive molecules and functional materials. Despite being in principle a straightforward strategy to access this motif, the direct tetrafluorination of alkynes involves very hazardous or inconvenient reagents. Therefore, safer and convenient alternatives are sought after. We developed a mild and operationally simple perfluorination method converting 1-alkynyl triazenes into 1,1,2,2-tetrafluoro alkyl triazenes, employing cheap and readily accessible reagents. Moreover, a judicious tuning of the reaction conditions enables access to α-difluoro triazenyl ketones. Complementary, electrophilic fluorination of alkynyl triazenes gives rise to the regioisomeric α-difluoro acyl triazenes. These three chemo- and regio-divergent protocols enable access to elusive fluorinated 1-alkyl and 1-acyl triazenes, thus expanding the chemical space for these unusual entities. Furthermore, several reaction intermediates and side products revealed insights on the reaction pathways that may be useful for further fluorination chemistry of alkynes.

Three mild and operationally simple fluorination protocols convert 1-alkynyl triazenes either into attractive 1,1,2,2-tetrafluoro alkyl triazenes, α-difluoro α-triazenyl ketones or α-difluoro acyl triazenes.     

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).     

Kinetic trapping of a cobalt(ii) metallocage using a carbazole-containing expanded carbaporphyrinoid ligand

The meso-unsubstituted expanded porphyrinoid 3, incorporating two carbazole moieties, acts as an effective ligand for Co(ii) and permits the isolation and X-ray diffraction-based characterization of a 6 : 3 metal-to-ligand metallocage complex that converts spontaneously to the constituent 2 : 1 metal-to-ligand metalloring species in chloroform solution. The discrete metalloring is formed directly when the Co(ii) complex is crystallized from supersaturated solutions, whereas crystallization from more dilute solutions favors the metallocage. Studies with two other test cations, Pd(ii) and Zn(ii), revealed exclusive formation of the monomeric metalloring complexes with no evidence of higher order species being formed. Structural, electrochemical and UV-vis-NIR absorption spectral studies provide support for the conclusion that the Pd(ii) complex is less distorted and more effectively conjugated than its Co(ii) and Zn(ii) congeners, an inference further supported by TD-DFT calculations. The findings reported here underscore how expanded porphyrins can support coordination modes, including bimetallic complexes and self-assembled cage structures, that are not necessarily easy to access using more traditional ligand systems.

Carbazole containing expanded carbaporphyrinoid ligand supports the formation of 2 : 1 metal-to-ligand complexes with Pd, Co, and Zn. Solid-state studies also revealed formation of a 6 : 3 metal-to-ligand metallocage in the case of Co complexation.     

Tandem sequential catalytic enantioselective synthesis of highly-functionalised tetrahydroindolizine derivatives

An isothiourea-catalysed enantioselective synthesis of novel tetrahydroindolizine derivatives is reported through a one-pot tandem sequential process. The application of 2-(pyrrol-1-yl)acetic acid in combination with either a trifluoromethyl enone or an α-keto-β,γ-unsaturated ester in an enantioselective Michael addition–lactonisation process, followed by in situ ring-opening and cyclisation, led to a range of 24 tetrahydroindolizine derivatives containing three stereocentres in up to >95 : 5 dr and >99 : 1 er.

The isothiourea-catalysed enantioselective synthesis of tetrahydroindolizine derivatives containing three stereocentres is reported through a one-pot tandem sequential process.     

Illuminating anti-hydrozirconation: controlled geometric isomerization of an organometallic species

A general strategy to enable the formal anti-hydrozirconation of arylacetylenes is reported that merges cis-hydrometallation using the Schwartz Reagent (Cp₂ZrHCl) with a subsequent light-mediated geometric isomerization at λ = 400 nm. Mechanistic delineation of the contra-thermodynamic isomerization step indicates that a minor reaction product functions as an efficient in situ generated photocatalyst. Coupling of the E-vinyl zirconium species with an alkyne unit generates a conjugated diene: this has been leveraged as a selective energy transfer catalyst to enable E → Z isomerization of an organometallic species. Through an Umpolung metal–halogen exchange process (Cl, Br, I), synthetically useful vinyl halides can be generated (up to Z : E = 90 : 10). This enabling platform provides a strategy to access nucleophilic and electrophilic alkene fragments in both geometric forms from simple arylacetylenes.

A general strategy to enable the formal anti-hydrozirconation of arylacetylenes is reported that merges cis-hydrometallation using the Schwartz Reagent (Cp₂ZrHCl) with a subsequent light-mediated geometric isomerization at λ = 400 nm.

The venerable Schwartz reagent (Cp₂ZrHCl) is totemic in the field of hydrometallation,¹ where reactivity is dominated by syn-selective M–H addition across the π-bond.^2,3 This mechanistic foundation can be leveraged to generate well-defined organometallic coupling partners that are amenable to stereospecific functionalization. Utilizing terminal alkynes as readily available precursors,⁴ hydrozirconation constitutes a powerful strategy to generate E-configured vinyl nucleophiles that, through metal–halogen exchange, can be converted to vinyl electrophiles in a formal Umpolung process.⁵ Whilst this provides a versatile platform to access the electronic antipodes of the E-isomer, the mechanistic course of addition renders access to the corresponding Z-isomer conspicuously challenging. To reconcile the synthetic importance of this transformation with the intrinsic challenges associated with anti-hydrometallation and metallometallation,⁶ it was envisaged that a platform to facilitate geometric isomerization⁷ would be of value. Moreover, coupling this to a metal–halogen exchange would provide a simple Umpolung matrix to access both stereo-isomers from a common alkyne precursor (Fig. 1).Open in a separate windowFig. 1The stereochemical course of alkyne hydrometallation using the Schwartz reagent and an Umpolung platform to generate both stereo-isomers from a common alkyne precursor.Confidence in this conceptual blueprint stemmed from a report by Erker and co-workers, in which irradiating the vinyl zirconium species derived from phenyl acetylene (0.5 M in benzene) with a mercury lamp (Philips HPK 125 and Pyrex filter) induced geometric isomerization.⁸ Whilst Hg lamps present challenges in terms of safety, temperature regulation, cost and wavelength specificity, advances in LED technology mitigate all of these points. Therefore, a process of reaction development was initiated to generalize the anti-hydrozirconation of arylacetylenes. Crucial to the success of this venture was identifying the light-based activation mode that facilitates alkene isomerization. Specifically, it was necessary to determine whether this process was enabled by direct irradiation of the vinyl zirconium species, or if the E → Z directionality results from a subsequent selective energy transfer process involving a facilitator. Several accounts of the incipient vinyl zirconium species reacting with a second alkyne unit to generate a conjugated diene have been disclosed.^9,10 It was therefore posited that the minor by-product diene may be a crucial determinant in driving this isomerization (Fig. 2).Open in a separate windowFig. 2A working hypothesis for the light-mediated anti-hydrozirconation via selective energy transfer catalysis.To advance this working hypothesis and generalize the formal anti-hydrozirconation process, the reaction of Cp₂ZrHCl with 1-bromo-4-ethynylbenzene (A-1) in CH₂Cl₂ was investigated (‡ for full details). This generates a versatile electrophile for downstream synthetic applications. Gratifyingly, after only 15 minutes, a Z : E-composition of 50 : 50 was reached (entry 1) and, following treatment with NBS, the desired vinyl bromide (Z)-1 was obtained in 76% yield (isomeric mixture) over the two steps. Further increasing the irradiation by 15 minute increments (entries 2–4) revealed that the optimum reaction time for the isomerization is 45 minutes (74%, Z : E = 73 : 27, entry 3). Extending the reaction time to 60 minutes (entry 4, 54%) did not lead to an improvement in selectivity and this was further confirmed by irradiating the reaction mixture for 90 minutes (entry 5). In both cases, a notable drop in yield was observed and therefore the remainder of the study was performed using the conditions described in entry 3. Next, the influence of the irradiation wavelength on the isomerization process was examined (entries 6–11). From a starting wavelength of λ = 369 nm, which gave a Z : E-ratio of 27 : 73 (entry 6), a steady improvement was observed by increasing the wavelength to λ = 374 nm (Z : E = 44 : 56, entry 7) and λ = 383 nm (Z : E = 53 : 47, entry 8). The selectivity reached a plateau at λ = 400 nm, with higher wavelengths proving to be detrimental (Z : E = 60 : 40 at λ = 414 nm, entry 9; Z : E = 26 : 74 at λ = 435 nm, entry 10). It is interesting to note that at λ = 520 nm, Z-1 was not detected by ¹H NMR (entry 11).Reaction optimization^a

Direct growth of crystalline triazine-based graphdiyne using surface-assisted deprotection–polymerisation

Graphdiyne polymers have interesting electronic properties due to their π-conjugated structure and modular composition. Most of the known synthetic pathways for graphdiyne polymers yield amorphous solids because the irreversible formation of carbon–carbon bonds proceeds under kinetic control and because of defects introduced by the inherent chemical lability of terminal alkyne bonds in the monomers. Here, we present a one-pot surface-assisted deprotection/polymerisation protocol for the synthesis of crystalline graphdiynes over a copper surface starting with stable trimethylsilylated alkyne monomers. In comparison to conventional polymerisation protocols, our method yields large-area crystalline thin graphdiyne films and, at the same time, minimises detrimental effects on the monomers like oxidation or cyclotrimerisation side reactions typically associated with terminal alkynes. A detailed study of the reaction mechanism reveals that the deprotection and polymerisation of the monomer is promoted by Cu(ii) oxide/hydroxide species on the as-received copper surface. These findings pave the way for the scalable synthesis of crystalline graphdiyne-based materials as cohesive thin films.

We present a one-pot deprotection/polymerisation protocol for the synthesis of crystalline graphdiynes on top of a copper surface starting with stable trimethylsilylated alkyne monomers.      

Stereoretentive and regioselective selenium-catalyzed intermolecular propargylic C–H amination of alkynes

Herein we report an intermolecular propargylic C–H amination of alkynes. This reaction is operationally convenient and requires no transition metal catalysts or additives. Terminal, silyl, and internal alkynes bearing a wide range of functional groups can be aminated in high yields. The regioselectivity of amination for unsymmetrical internal alkynes is strongly influenced by substitution pattern (tertiary > secondary > primary) and by relatively remote heteroatomic substituents. We demonstrate that amination of alkynes bearing α-stereocenters occurs with retention of configuration at the newly-formed C–N bond. Competition experiments between alkynes, kinetic isotope effects, and DFT calculations are performed to confirm the mechanistic hypothesis that initial ene reaction of a selenium bis(imide) species is the rate- and product-determining step. This ene reaction has a transition state that results in substantial partial positive charge development at the carbon atom closer to the amination position. Inductive and/or hyperconjugative stabilization or destabilization of this positive charge explains the observed regioselectivities.

Selenium catalysis enables a general intermolecular propargylic C–H amination of alkynes. The concerted mechanism gives rise to high regioselectivity for the more electron-rich end of the alkyne and retention of the C–H propargylic stereocenter.     

Visible-light mediated carbonyl trifluoromethylative amination as a practical method for the synthesis of β-trifluoromethyl tertiary alkylamines

We report the development of an operationally straigtforward, visible-light-mediated multicomponent strategy for the construction of β-trifluoromethylated tertiary alkylamines from feedstock aldehydes, secondary amines and a convenient source of trifluoromethyl iodide. The new process does not require a photocatalyst, is metal-free, displays a broad functional group tolerance and offers rapid, one-pot access to trifluoromethylated drug-like compounds that will be of interest in medicinal chemistry.

An operationally straightforward, visible-light-mediated multicomponent strategy for the construction of β-trifluoromethylated tertiary alkylamines from aldehydes, secondary amines and a convenient source of trifluoromethyl iodide is reported.     

Asymmetric synthesis of dibenzo[b,d]azepines by Cu-catalyzed reductive or borylative cyclization

A copper-catalyzed asymmetric intramolecular reductive cyclization for the synthesis of dibenzo[b,d]azepines is described. Use of 2′-vinyl-biaryl-2-imines as substrates and in situ formed [Cu^I/(Ph-BPE)] as the catalyst enables the synthesis of 7-membered bridged biarylamines containing both central and axial stereogenic elements in high yields (up to 98%) and with excellent diastereo- and enantioselectivities (>20 : 1 d.r., up to 99% ee). Moreover, the same catalyst was found to facilitate a related borylative cyclization to afford versatile boronic ester derivatives. Both reactions proceed under mild conditions (rt) and are applicable to a variety of substituted aromatic and heterocyclic derivatives.

Dibenzo[b,d]azepines featuring axially chiral 7-member-bridged biaryls have been prepared by asymmetric reductive or borylative cyclizations using copper catalysis.     

Catalytic enantioselective synthesis of 1,4-dihydropyridines via the addition of C(1)-ammonium enolates to pyridinium salts

The regio- and stereoselective addition of C(1)-ammonium enolates – generated in situ from aryl esters and the isothiourea catalyst (R)-BTM – to pyridinium salts bearing an electron withdrawing substituent in the 3-position allows the synthesis of a range of enantioenriched 1,4-dihydropyridines. This represents the first organocatalytic approach to pyridine dearomatisation using pronucleophiles at the carboxylic acid oxidation level. Optimisation studies revealed a significant solvent dependency upon product enantioselectivity, with only toluene providing significant asymmetric induction. Using DABCO as a base also proved beneficial for product enantioselectivity, while investigations into the nature of the counterion showed that co-ordinating bromide or chloride substrates led to higher product er than the corresponding tetrafluoroborate or hexafluorophosphate. The scope and limitations of this process are developed, with enantioselective addition to 3-cyano- or 3-sulfonylpyridinium salts giving the corresponding 1,4-dihydropyridines (15 examples, up to 95 : 5 dr and 98 : 2 er).

The regio- and stereoselective addition of C(1)-ammonium enolates – generated in situ from aryl esters and the isothiourea catalyst (R)-BTM – to pyridinium salts allows the synthesis of a range of enantioenriched 1,4-dihydropyridines.     

Catalytic asymmetric hydrometallation of cyclobutenes with salicylaldehydes

Chiral, substituted cyclobutanes are common motifs in bioactive compounds and intermediates in organic synthesis but few asymmetric routes for their synthesis are known. Herein we report the Rh-catalyzed asymmetric hydrometallation of a range of meso-cyclobutenes with salicylaldehydes. The ortho-phenolic group promotes hydroacylation and can be used as a handle for subsequent transformations. The reaction proceeds via asymmetric hydrometallation of the weakly activated cyclobutene, followed by a C–C bond forming reductive elimination. A prochiral, spirocyclic cyclobutene undergoes a highly regioselective hydroacylation. This report will likely inspire the development of other asymmetric addition reactions to cyclobutenes via hydrometallation pathways.

Chiral, substituted cyclobutanes are common motifs in bioactive compounds and intermediates in organic synthesis but few asymmetric routes for their synthesis are known.     

Organocatalytic enantioselective SN1-type dehydrative nucleophilic substitution: access to bis(indolyl)methanes bearing quaternary carbon stereocenters

A highly general and straightforward approach to access chiral bis(indolyl)methanes (BIMs) bearing quaternary stereocenters has been realized via enantioconvergent dehydrative nucleophilic substitution. A broad range of 3,3′-, 3,2′- and 3,1′-BIMs were obtained under mild conditions with excellent efficiency and enantioselectivity (80 examples, up to 98% yield and >99 : 1 er). By utilizing racemic 3-indolyl tertiary alcohols as precursors of alkyl electrophiles and indoles as C–H nucleophiles, this organocatalytic strategy avoids pre-activation of substrates and produces water as the only by-product. Mechanistic studies suggest a formal S_N1-type pathway enabled by chiral phosphoric acid catalysis. The practicability of the obtained enantioenriched BIMs was further demonstrated by versatile transformation and high antimicrobial activities (3al, MIC: 1 μg mL⁻¹).

A highly general and straightforward approach to access chiral bis(indolyl)methanes (BIMs) bearing quaternary stereocenters has been realized via enantioconvergent dehydrative nucleophilic substitution.     

A unified strategy to prostaglandins: chemoenzymatic total synthesis of cloprostenol,bimatoprost, PGF2α, fluprostenol,and travoprost guided by biocatalytic retrosynthesis

Development of efficient and stereoselective synthesis of prostaglandins (PGs) is of utmost importance, owing to their valuable medicinal applications and unique chemical structures. We report here a unified synthesis of PGs cloprostenol, bimatoprost, PGF_2α, fluprostenol, and travoprost from the readily available dichloro-containing bicyclic ketone 6a guided by biocatalytic retrosynthesis, in 11–12 steps with 3.8–8.4% overall yields. An unprecedented Baeyer–Villiger monooxygenase (BVMO)-catalyzed stereoselective oxidation of 6a (99% ee), and a ketoreductase (KRED)-catalyzed diastereoselective reduction of enones 12 (87 : 13 to 99 : 1 dr) were utilized in combination for the first time to set the critical stereochemical configurations under mild conditions. Another key transformation was the copper(ii)-catalyzed regioselective p-phenylbenzoylation of the secondary alcohol of diol 10 (9.3 : 1 rr). This study not only provides an alternative route to the highly stereoselective synthesis of PGs, but also showcases the usefulness and great potential of biocatalysis in construction of complex molecules.

We report a unified chemoenzymatic asymmetric synthesis of five prostaglandins, featuring two enzymatic redox transformations and a copper(ii)-catalyzed regioselective p-phenylbenzoylation.     

Electrochemical oxidative N–H/P–H cross-coupling with H2 evolution towards the synthesis of tertiary phosphines

Tertiary phosphines(iii) find widespread use in many aspects of synthetic organic chemistry. Herein, we developed a facile and novel electrochemical oxidative N–H/P–H cross-coupling method, leading to a series of expected tertiary phosphines(iii) under mild conditions with excellent yields. It is worth noting that this electrochemical protocol features very good reaction selectivity, where only a 1 : 1 ratio of amine and phosphine was required in the reaction. Moreover, this electrochemical protocol proved to be practical and scalable. Mechanistic insights suggested that the P radical was involved in this reaction.

A facile and novel electrochemical oxidative N–H/P–H cross-coupling method for obtaining tertiary phosphines(iii) was developed.     

Multicomponent formation route to a new class of oxygen-based 1,3-dipoles and the modular synthesis of furans

A new class of phosphorus-containing 1,3-dipoles can be generated by the multicomponent reaction of aldehydes, acid chlorides and the phosphonite PhP(catechyl). These 1,3-dipoles are formally cyclic tautomers of simple Wittig-type ylides, where the angle strain and moderate nucleophilicity in the catechyl-phosphonite favor their cyclization and also direct 1,3-dipolar cycloaddition to afford single regioisomers of substituted products. Coupling the generation of the dipoles with 1,3-dipolar cycloaddition offers a unique, modular route to furans from combinations of available aldehydes, acid chlorides and alkynes with independent control of all four substituents.

A new class of phosphorus-containing 1,3-dipoles has been developed, which, when coupled with cycloaddition, offers modular synthesis of furans with independent control of all four substituents.     

Efficient access to materials-oriented aromatic alkynes via the mechanochemical Sonogashira coupling of solid aryl halides with large polycyclic conjugated systems

Sonogashira coupling represents an indispensable tool for the preparation of organic materials that contain C(sp)–C(sp²) bonds. Improving the efficiency and generality of this methodology has long been an important research subject in materials science. Here, we show that a high-temperature ball-milling technique enables the highly efficient palladium-catalyzed Sonogashira coupling of solid aryl halides that bear large polyaromatic structures including sparingly soluble substrates and unactivated aryl chlorides. In fact, this new protocol provides various materials-oriented polyaromatic alkynes in excellent yield within short reaction times in the absence of bulk reaction solvents. Notably, we synthesized a new luminescent material via the mechanochemical Sonogashira coupling of poorly soluble Vat Red 1 in a much higher yield compared to those obtained using solution-based conditions. The utility of this method was further demonstrated by the rapid synthesis of a fluorescent metal–organic framework (MOF) precursor via two sequential mechanochemical Sonogashira cross-coupling reactions. The present study illustrates the great potential of Sonogashira coupling using ball milling for the preparation of materials-oriented alkynes and for the discovery of novel functional materials.

Using a high-temperature ball-milling technique, a practical mechanochemical protocol for the Sonogashira cross-coupling of polyaromatic halides was achieved, which provides efficient access to materials-oriented aromatic alkynes.