Catalytic asymmetric synthesis of 3,2′-pyrrolinyl spirooxindoles via conjugate addition/Schmidt-type rearrangement of vinyl azides and (E)-alkenyloxindoles

A catalytic asymmetric conjugate addition/Schmidt-type rearrangement of vinyl azides and (E)-alkenyloxindoles was realized. It afforded a variety of optically active 3,2′-pyrrolinyl spirooxindoles with high yields (up to 98%), and excellent diastereo- and enantioselectivities (up to 98% ee, >19 : 1 dr), even at the gram-scale in the presence of a chiral N,N′-dioxide–nickel(ii) complex. In addition, a possible catalytic cycle and transition state model were proposed to rationalize the stereoselectivity.

Lewis acid catalyzed asymmetric synthesis of 3,2′-pyrrolinyl spirooxindole skeletons via conjugate addition/Schmidt-type rearrangement of vinyl azides and (E)-alkenyloxindoles.     

Regio- and diastereoselective reactions of chiral secondary alkylcopper reagents with propargylic phosphates: preparation of chiral allenes

The diastereoselective S_N2′-substitution of secondary alkylcopper reagents with propargylic phosphates enables the preparation of stereodefined alkylallenes. By using enantiomerically enriched alkylcopper reagents and enantioenriched propargylic phosphates as electrophiles anti-S_N2′-substitutions were performend leading to α-chiral allenes in good yields with excellent regioselectivity and retention of configuration. DFT-calculations were performed to rationalize the structure of these alkylcopper reagents in various solvents, emphasizing their configurational stability in THF.

The diastereoselective S_N2′-substitution of secondary alkylcopper reagents with propargylic phosphates enables the preparation of stereodefined alkylallenes.     

Meeting key synthetic challenges in amanitin synthesis with a new cytotoxic analog: 5′-hydroxy-6′-deoxy-amanitin

Appreciating the need to access synthetic analogs of amanitin, here we report the synthesis of 5′-hydroxy-6′-deoxy-amanitin, a novel, rationally-designed bioactive analog and constitutional isomer of α-amanitin, that is anticipated to be used as a payload for antibody drug conjugates. In completing this synthesis, we meet the challenge of diastereoselective sulfoxidation by presenting two high-yielding and diastereoselective sulfoxidation approaches to afford the more toxic (R)-sulfoxide.

Elucidating a highly diastereoselective sulfoxidation of S-deoxy-amanitin to afford α-amanitin and a more synthetically accessible analog of near-native toxicity.     

Total synthesis of (+)-spiroindimicin A and congeners unveils their antiparasitic activity

The spiroindimicins are a unique class of chlorinated indole alkaloids characterized by three heteroaromatic rings structured around a congested spirocyclic stereocenter. Here, we report the first total synthesis of (+)-spiroindimicin A, which bears a challenging C-3′/C-5′′-linked spiroindolenine. We detail our initial efforts to effect a biomimetic oxidative spirocyclization from its proposed natural precursor, lynamicin D, and describe how these studies shaped our final abiotic 9-step solution to this complex alkaloid built around a key Pd-catalyzed asymmetric spirocyclization. Scalable access to spiroindimicins A, H, and their congeners has enabled discovery of their activity against several parasites relevant to human health, providing potential starting points for new therapeutics for the neglected tropical diseases leishmaniasis and African sleeping sickness.

Spiroindimicins A and H have been synthesized for the first time via a key palladium-catalyzed spirocyclization. Access to these alkaloids and several congeners has allowed the discovery of their antiparasitic properties.     

A chiral cobalt(ii) complex catalyzed enantioselective aza-Piancatelli rearrangement/Diels–Alder cascade reaction

A chiral N,N′-dioxide/cobalt(ii) complex catalyzed highly diastereoselective and enantioselective tandem aza-Piancatelli rearrangement/intramolecular Diels–Alder reaction has been disclosed. Various valuable hexahydro-2a,5-epoxycyclopenta[cd]isoindoles bearing six contiguous stereocenters have been obtained in good yields with excellent diastereo- and enantio-selectivities from a wide range of both readily available 2-furylcarbinols and N-(furan-2-ylmethyl)anilines.

An asymmetric aza-Piancatelli rearrangement/Diels–Alder cascade reaction between 2-furylcarbinols and N-(furan-2-ylmethyl)anilines was realized by using a chiral N,N′-dioxide/cobalt(ii) complex catalyst.     

Reactivity of cyano- and isothiocyanatoborylenes: metal coordination,one-electron oxidation and boron-centred Brønsted basicity

Doubly base-stabilised cyano- and isothiocyanatoborylenes of the form LL′BY (L = CAAC = cyclic alkyl(amino)carbene; L′ = NHC = N-heterocyclic carbene; Y = CN, NCS) coordinate to group 6 carbonyl complexes via the terminal donor of the pseudohalide substituent and undergo facile and fully reversible one-electron oxidation to the corresponding boryl radical cations [LL′BY]˙⁺. Furthermore, calculations show that the borylenes have very similar proton affinities, both to each other and to NHC superbases. However, while the protonation of LL′B(CN) with PhSH yielding [LL′BH(CN)⁺][PhS⁻] is fully reversible, that of LL′B(NCS) is rendered irreversible by a subsequent B-to-C_CAAC hydrogen shift and nucleophilic attack of PhS⁻ at boron.

Borylenes of the form (CAAC)(NHC)BY (Y = CN, NCS; CAAC = cyclic alkyl(amino)carbene; NHC = N-heterocyclic carbene) coordinate to group 6 carbonyl complexes via Y, and show reversible boron-centered Brønsted basicity and one-electron oxidation.     

Total synthesis of dimeric Securinega alkaloids (−)-flueggenines D and I

We describe the total synthesis of (−)-flueggenines D and I. This features the first total synthesis of dimeric Securinega alkaloids with a C(α)–C(δ′) connectivity between two monomeric units. The key dimerization was enabled by a sequence that involves Stille reaction and conjugate reduction. The high chemofidelity of the Stille reaction enabled us to assemble two structurally complex fragments that could not be connected by other methods. Stereochemical flexibility and controllability at the δ′-junction of the dimeric intermediate render our synthetic strategy broadly applicable to the synthesis of other high-order Securinega alkaloids.

The first total synthesis of dimeric securinega alkaloids (−)-flueggenines D and I was completed by a dimerization strategy that involves Stille reaction and stereoselective conjugate reduction.     

Acyclic diaminocarbene-based Thiele,Chichibabin, and Müller hydrocarbons

Thiele, Chichibabin and Müller hydrocarbons are considered as classical Kekulé diradicaloids. Herein we report the synthesis and characterization of acyclic diaminocarbene (ADC)-based Thiele, Chichibabin, and Müller hydrocarbons. The calculated singlet–triplet energy gaps are ΔE_S–T = −27.96, −3.70, −0.37 kcal mol⁻¹, respectively, and gradually decrease with the increasing length of the π-conjugated spacer (p-phenylene vs. p,p′-biphenylene vs. p,p′′-terphenylene) between the two ADC-scaffolds. In agreement with the calculations, we also experimentally observed the enhancement of paramagnetic diradical character as a function of the length of the π-conjugated spacer. ADC-based Thiele''s hydrocarbon is EPR silent and exhibits very well resolved NMR spectra, whereas ADC-based Müller''s hydrocarbon displays EPR signals and featureless NMR spectra at room temperature. The spacer also has a strong influence on the UV-Vis-NIR spectra of these compounds. Considering that our methodology is modular, these results provide a convenient platform for the synthesis of an electronically modified new class of carbon-centered Kekulé diradicaloids.

We report the synthesis of acyclic diaminocarbene (ADC)-scaffold based Thiele, Chichibabin, and Müller hydrocarbons. Studies support that the singlet-triplet energy gap depends on the π-conjugated spacer between the ADC scaffolds.     

2′-O-Trifluoromethylated RNA – a powerful modification for RNA chemistry and NMR spectroscopy

New RNA modifications are needed to advance our toolbox for targeted manipulation of RNA. In particular, the development of high-performance reporter groups facilitating spectroscopic analysis of RNA structure and dynamics, and of RNA–ligand interactions has attracted considerable interest. To this end, fluorine labeling in conjunction with ¹⁹F-NMR spectroscopy has emerged as a powerful strategy. Appropriate probes for RNA previously focused on single fluorine atoms attached to the 5-position of pyrimidine nucleobases or at the ribose 2′-position. To increase NMR sensitivity, trifluoromethyl labeling approaches have been developed, with the ribose 2′-SCF₃ modification being the most prominent one. A major drawback of the 2′-SCF₃ group, however, is its strong impact on RNA base pairing stability. Interestingly, RNA containing the structurally related 2′-OCF₃ modification has not yet been reported. Therefore, we set out to overcome the synthetic challenges toward 2′-OCF₃ labeled RNA and to investigate the impact of this modification. We present the syntheses of 2′-OCF₃ adenosine and cytidine phosphoramidites and their incorporation into oligoribonucleotides by solid-phase synthesis. Importantly, it turns out that the 2′-OCF₃ group has only a slight destabilizing effect when located in double helical regions which is consistent with the preferential C3′-endo conformation of the 2′-OCF₃ ribose as reflected in the ³J (H1′–H2′) coupling constants. Furthermore, we demonstrate the exceptionally high sensitivity of the new label in ¹⁹F-NMR analysis of RNA structure equilibria and of RNA–small molecule interactions. The study is complemented by a crystal structure at 0.9 Å resolution of a 27 nt hairpin RNA containing a single 2′-OCF₃ group that well integrates into the minor groove. The new label carries high potential to outcompete currently applied fluorine labels for nucleic acid NMR spectroscopy because of its significantly advanced performance.

The new 2′-OCF₃ label for nucleic acid NMR spectroscopy carries high potential to outcompete currently applied fluorine labels because of significantly advanced performance.     

Transition-metal-mediated reduction and reversible double-cyclization of cyanuric triazide to an asymmetric bitetrazolate involving cleavage of the six-membered aromatic ring

Cyanuric triazide reacts with several transition metal precursors, extruding one equivalent of N₂ and reducing the putative diazidotriazeneylnitrene species by two electrons, which rearranges to N-(1′H-[1,5′-bitetrazol]-5-yl)methanediiminate (biTzI²⁻) dianionic ligand, which ligates the metal and dimerizes, and is isolated from pyridine as [M(biTzI)]₂Py₆ (M = Mn, Fe, Zn, Cu, Ni). Reagent scope, product analysis, and quantum chemical calculations were combined to elucidate the mechanism of formation as a two-electron reduction preceding ligand rearrangement.

Cyanuric triazide reacts with transition metal precursors, extruding N₂ and reducing the ligand by two electrons, which breaks an aromatic ring and rearranges to a bitetrazolylmethanediiminate (biTzI²⁻) ligand, forming two new aromatic rings.     

Catalytic enantioselective synthesis of macrodiolides and their application in chiral recognition

New types of C₂-symmetric chiral macrodiolides are readily obtained via chiral N,N′-dioxide-scandium(iii) complex-promoted asymmetric tandem Friedel–Crafts alkylation/intermolecular macrolactonization of ortho-quinone methides with C3-substituted indoles. This protocol provides an array of enantioenriched macrodiolides with 16, 18 or 20-membered rings in moderate to good yields with high diastereoselectivities and excellent enantioselectivities through adjusting the length of the tether at the C3 position of indoles. Density functional theory calculations indicate that the formation of macrocycles is more favorable than that of 9-membered-ring lactones in terms of kinetics and thermodynamics. The potential utility of these intriguing chiral macrodiolide molecules is demonstrated in the enantiomeric recognition of aminols and chemical recognition of metal ions.

An asymmetric tandem Friedel–Crafts alkylation/intermolecular macrolactonization of ortho-quinone methides with C3-substituted indoles was achieved by using a chiral N,N′-dioxide-scandium(iii) complex.     

Templates direct the sequence-specific anchoring of the C-terminus of peptido RNAs

When amino acids and ribonucleotides react in aqueous condensation buffer, they form peptido RNA with a phosphoramidate bond between the N-terminus of the peptide and the 5′-terminal phosphate of a ribonucleotide. If peptido RNA was the product of spontaneous reactions of amino acids and nucleotides, there must have been a transition to peptidyl tRNAs, where the C-terminus of the peptide is ester-linked to the 2′,3′-terminus of an oligonucleotide. Here we report how short peptido RNAs react with the 3′-terminus of oligodeoxynucleotides, templated by RNA strands. In our model system, the rate and yield of the anchoring of the C-terminus of the dipeptido dinucleotides to an amino group was found to depend on the sequence of the peptide, the 5′-terminal nucleotide of the dinucleotide and the RNA template. In all cases tested, highest yields were found for dinucleotides hybridizing next to the primer terminus. For the most reactive species, GlyPro-AA, anchoring yields ranged from 8–99%, depending on the template. When LeuLeu-AA, PhePhe-AA and GlyGly-AA were allowed to compete for anchoring on 3′-UUC-5′ as templating sequence, they gave a product ratio of 1 : 2 : 6, and this selectivity was almost independent of the terminal base of the primer. Our results show the control that a simple duplex context has over the covalent anchoring of peptido RNAs at a position known from peptidyl tRNAs. Processes of this type may have bridged the gap between untemplated condensation reactions and the highly specific processes of ribosomal protein synthesis.

The C-terminus of dipeptido dinucleotides reacts with the 3′-terminus of a primer strand in template directed fashion with a strong dependence on the structures of peptide and template.     

Asymmetric synthesis of γ-chiral borylalkanes via sequential reduction/hydroboration using a single copper catalyst

The synthesis of γ-chiral borylalkanes through copper-catalyzed enantioselective S_N2′-reduction of γ,γ-disubstituted allylic substrates and subsequent hydroboration was reported. A copper–DTBM-Segphos catalyst produced a range of γ-chiral alkylboronates from easily accessible allylic acetate or benzoate with high enantioselectivities up to 99% ee. Furthermore, selective organic transformations of the resulting γ-chiral alkylboronates generated the corresponding γ-chiral alcohol, arene and amine compounds.

Copper-catalyzed reductive hydroboration of γ,γ-disubstituted allylic substrates enables preparation of γ-chiral alkylboron compounds in a one-pot cascade manner.     

Asymmetric synthesis of dihydro-1,3-dioxepines by Rh(ii)/Sm(iii) relay catalytic three-component tandem [4 + 3]-cycloaddition

Heterocycles have been widely used in organic synthesis, agrochemical, pharmaceutical and materials science industries. Catalytic three-component ylide formation/cycloaddition enables the assembly of complex heterocycles from simple starting materials in a highly efficient manner. However, asymmetric versions remain a yet-unsolved task. Here, we present a new bimetallic catalytic system for tackling this challenge. A combined system of Rh(ii) salt and chiral N,N′-dioxide–Sm(iii) complex was established for promoting the unprecedented tandem carbonyl ylide formation/asymmetric [4 + 3]-cycloaddition of aldehydes and α-diazoacetates with β,γ-unsaturated α-ketoesters smoothly, affording various chiral 4,5-dihydro-1,3-dioxepines in up to 97% yield, with 99% ee. The utility of the current method was demonstrated by conversion of products to optically active multi-substituted tetrahydrofuran derivatives. A possible reaction mechanism was provided to elucidate the origin of chiral induction based on experimental studies and X-ray structures of catalysts and products.

Catalytic asymmetric tandem carbonyl ylide formation/[4 + 3]-cycloaddition of β,γ-unsaturated α-ketoesters, aldehydes and α-diazoacetates was achieved by using a bimetallic rhodium(ii)/chiral N,N′-dioxide–Sm(iii) complex catalyst.     

Design and enhanced gene silencing activity of spherical 2′-fluoroarabinose nucleic acids (FANA-SNAs)

Drug delivery vectors for nucleic acid therapeutics (NATs) face significant barriers for translation into the clinic. Spherical nucleic acids (SNAs) – nanoparticles with an exterior shell made up of DNA strands and a hydrophobic interior – have recently shown great potential as vehicles to improve the biodistribution and efficacy of NATs. To date, SNA design has not taken advantage of the powerful chemical modifications available to NATs. Here, we modify SNAs with 2′-deoxy-2′-fluoro-d-arabinonucleic acid (FANA-SNA), and show increased stability, enhanced gene silencing potency and unaided uptake (gymnosis) as compared to free FANA. By varying the spacer region between the nucleic acid strand and the attached hydrophobic polymer, we show that a cleavable DNA based spacer is essential for maximum activity. This design feature will be important when implementing functionalized nucleic acids into nanostructures for gene silencing. The modularity of the FANA-SNA was demonstrated by silencing two different targets. Transfection-free delivery was superior for the modified SNA compared to the free FANA oligonucleotide.

Optimizing FANA modified spherical nucleic acids (FANA-SNAs) for highly efficient delivery of nucleic acid therapeutics.     

A 2,2′-diphosphinotolane as a versatile precursor for the synthesis of P-ylidic mesoionic carbenes via reversible C–P bond formation

A metal-templated synthetic route to cyclic (aryl)(ylidic) mesoionic carbenes (CArY-MICs) featuring an endocyclic P-ylide is presented. This approach, which requires metal templates with two cis-positioned open coordination sites, is based on the controlled cyclisation of a P,P′-diisopropyl-substituted 2,2′-diphosphinotolane (1) and leads to chelate complexes coordinated by a phosphine donor and the CArY-MIC carbon atom. The C–P bond formation involved in the former partial cyclisation of 1 proceeds under mild conditions and was shown to be applicable all over the d-block. In the presence of a third fac-positioned open coordination site, the P–C bond formation was found to be reversible, as shown for a series of molybdenum complexes. DFT modelling studies are in line with an interpretation of the target compounds as CArY-MICs.

A metal-templated synthesis of cyclic (aryl)(ylidic)mesoionic carbene complexes (CArY-MICs) is presented. In the case of molybdenum carbonyls, the crucial P–C bond formation, which occurs during CArY-MIC formation, was found to be reversible.     

Visible light driven generation and alkyne insertion reactions of stable bis-cyclometalated Pt(iv) hydrides

Hydride complexes resulting from the oxidative addition of C–H bonds are intermediates in hydrocarbon activation and functionalization reactions. The discovery of metal systems that enable their direct formation through photoexcitation with visible light could lead to advantageous synthetic methodologies. In this study, easily accessible dimers [Pt₂(μ-Cl)₂(C^N)₂] (C^N = cyclometalated 2-arylpyridine) are demonstrated as a very convenient source of Pt(C^N) subunits, which promote photooxidative C–H addition reactions with different 2-arylpyridines (N′^C′H) upon irradiation with blue light. The resulting [PtH(Cl)(C^N)(C′^N′)] complexes are the first isolable Pt(iv) hydrides arising from a cyclometalation reaction. A transcyclometalation process involving three photochemical steps is elucidated, which occurs when the C^N ligand is a monocyclometalated 2,6-diarylpyridine, and a detailed analysis of the photoreactivity associated with the Pt(C^N) moiety is provided. Alkyne insertions into the Pt–H bond of a photogenerated Pt(iv) hydride are also reported as a demonstration of the ability of this class of compounds to undergo subsequent organometallic reactions.

The photochemical generation of isolable bis-cyclometalated Pt(iv) hydrides via photooxidative C–H addition reactions is demonstrated from easily accessible Pt(ii) precursors using visible light.     

Pt(ii)-coordinated tricomponent self-assemblies of tetrapyridyl porphyrin and dicarboxylate ligands: are they 3D prisms or 2D bow-ties?

Thermodynamically favored simultaneous coordination of Pt(ii) corners with aza- and carboxylate ligands yields tricomponent coordination complexes with sophisticated structures and functions, which require careful structural characterization to paint accurate depiction of their structure–function relationships. Previous reports claimed that heteroleptic coordination of cis-(Et₃P)₂Pt^II with tetrapyridyl porphyrins (M′TPP, M′ = Zn or H₂) and dicarboxylate ligands (XDC) yielded 3D tetragonal prisms containing two horizontal M′TPP faces and four vertical XDC pillars connected by eight Pt(ii) corners, even though such structures were not supported by their ¹H NMR data. Through extensive X-ray crystallographic and NMR studies, herein, we demonstrate that self-assembly of cis-(Et₃P)₂Pt^II, M′TPP, and four different XDC linkers having varied lengths and rigidities actually yields bow-tie (⋈)-shaped 2D [{cis-(Et₃P)₂Pt}₄(M′TPP) (XDC)₂]⁴⁺ complexes featuring a M′TPP core and two parallel XDC linkers connected by four heteroleptic Pt^II corners instead of 3D prisms. This happened because (i) irrespective of their length (∼7–11 Å) and rigidity, the XDC linkers intramolecularly bridged two adjacent pyridyl-N atoms of a M′TPP core via Pt^II corners instead of connecting two cofacial M′TPP ligands and (ii) bow-tie complexes are entropically favored over prisms. The electron-rich ZnTPP core of a representative bow-tie complex selectively formed a charge-transfer complex with highly π-acidic 1,4,5,8,9,12-hexaazatriphenylene-2,3,6,7,10,11-heaxacarbonitrile but not with a π-donor such as pyrene. Thus, this work not only produced novel M′TPP-based bow-tie complexes and demonstrated their selective π-acid recognition capability, but also underscored the importance of proper structural characterization of supramolecular assemblies to ensure accurate depiction of their structure–property relationships.

Thermodynamically favored heteroleptic coordination of Pt(ii) corners with tetrapyridyl porphyrins and dicarboxylate ligands produces 2D bow-tie shaped complexes instead of previously mischaracterized 3D tetragonal prisms.     

New atomically precise M1Ag21 (M = Au/Ag) nanoclusters as excellent oxygen reduction reaction catalysts

By introducing 1,1′-bis-(diphenylphosphino)ferrocene (dppf) as an activating ligand, two novel nanoclusters, M1Ag21 (M = Au/Ag), have been controllably synthesized and structurally characterized. The atomically precise structures of the M1Ag21 nanoclusters were determined by SCXC and further confirmed by ESI-TOF-MS, TGA, XPS, DPV, and FT-IR measurements. The M1Ag21 nanoclusters supported on activated carbon (C) are exploited as efficient oxygen reduction reaction (ORR) catalysts in alkaline solutions. Density functional theory (DFT) calculations verify that the catalytic activities of the two cluster-based systems originate from the significant ensemble synergy effect between the M₁₃ kernel and dppf ligand in M1Ag21. This work sheds lights on the preparation of cluster-based electrocatalysts and other catalysts that are activated and modified by peripheral ligands.

The presence of 1,1′-bis-(diphenylphosphino)ferrocene ligands and ensemble effects in novel nanoclusters M₁Ag₂₁(dppf)₃(SAdm)₁₂ (M = Au/Ag) provide excellent ORR performances.