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.     

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.     

Novel dual methylation of cytidines in the RNA of mammals

RNA modifications play critical roles in regulating a variety of physiological processes. Methylation is the most prevalent modification occurring in RNA. Three isomeric cytidine methylation modifications have been reported in RNA, including 3-methylcytidine (m³C), N4-methylcytidine (m⁴C), and 5-methylcytidine (m⁵C), in mammals. Aside from the single methylation on the nucleobase of cytidines, dual methylation modifications occurring in both the 2′ hydroxyl of ribose and the nucleobase of cytidines also have been reported, including N4,2′-O-dimethylcytidine (m⁴Cm) and 5,2′-O-dimethylcytidine (m⁵Cm). m⁴Cm has been found in the 16S rRNA of E. coli, while m⁵Cm has been found in the tRNA of terminal thermophilic archaea and mammals. However, unlike m⁴Cm and m⁵Cm, the presumed dual methylation of 3,2′-O-dimethylcytidine (m³Cm) has never been discovered in living organisms. Thus, the presence of m³Cm in RNA remains an open question. In the current study, we synthesized m³Cm and established a liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) method to determine the dimethylation of cytidines, m³Cm, m⁴Cm and m⁵Cm. Under optimized analytical conditions, m³Cm, m⁴Cm and m⁵Cm can be clearly distinguished. Using the method, we discovered the existence of m³Cm in the RNA of mammals. The identified m³Cm is a novel modification that hasn''t been reported in the three-domain system, including archaea, bacteria, and eukaryotes. We confirmed that m³Cm mainly existed in the small RNA (<200 nt) of mammals. In addition, we identified, for the first time, the presence of m⁴Cm in the 18S rRNA of mammalian cells. The stable isotope tracing monitored by mass spectrometry demonstrated that S-adenosyl-l-methionine was a methyl donor for all three dimethylations of cytidines in RNA. The discovery of m³Cm broadens the diversity of RNA modifications in living organisms. In addition, the discovery of m³Cm and m⁴Cm in mammals opens new directions in understanding RNA modification-mediated RNA processing and gene expression regulation.

We synthesized 3,2′-O-dimethylcytidine (m³Cm) and determined the dimethylation of cytidines in mammals by mass spectrometry analysis. We discovered m³Cm in small RNA and N4,2′-O-dimethylcytidine (m⁴Cm) in 18S rRNA of mammals.     

The crystal engineering of radiation-sensitive diacetylene cocrystals and salts

In this work we develop photoreactive cocrystals/salts of a commercially-important diacetylene, 10,12-pentacosadiynoic acid (PCDA, 1) and report the first X-ray crystal structures of PCDA based systems. The topochemical reactivity of the system is modified depending on the coformer used and correlates with the structural parameters. Crystallisation of 1 with 4,4′-azopyridine (2), 4,4′-bipyridyl (3), and trans-1,2-bis(4-pyridyl)ethylene (4) results in unreactive 2 : 1 cocrystals or a salt in the case of 4,4′-bipiperidine (5). However, salt formation with morpholine (6), diethylamine (7), and n-butylamine (8), results in highly photoreactive salts 12·7 and 1·8 whose reactivity can be explained using topochemical criteria. The salt 1·6 is also highly photoreactive and is compared to a model morpholinium butanoate salt. Resonance Raman spectroscopy reveals structural details of the photopolymer including its conformational disorder in comparison to less photoactive alkali metal salts and the extent of solid state conversion can be monitored by CP-MAS NMR spectroscopy. We also report an unusual catalysis in which amine evaporation from photopolymerised PCDA ammonium salts effectively acts as a catalyst for polymerisation of PCDA itself. The new photoreactive salts exhibit more reactivity but decreased conjugation compared to the commercial lithium salt and are of considerable practical potential in terms of tunable colours and greater range in UV, X-ray, and γ-ray dosimetry applications.

In this work we develop photoreactive cocrystals/salts of a commercially-important diacetylene, 10,12-pentacosadiynoic acid (PCDA, 1) and report the first X-ray crystal structures of PCDA based systems.     

Determining the Diastereoselectivity of the Formation of Dipeptidonucleotides by NMR Spectroscopy

Proteins are composed of l -amino acids, but nucleic acids and most oligosaccharides contain d -sugars as building blocks. It is interesting to ask whether this is a coincidence or a consequence of the functional interplay of these biomolecules. One reaction that provides an opportunity to study this interplay is the formation of phosphoramidate-linked peptido RNA from amino acids and ribonucleotides in aqueous condensation buffer. Here we report how the diastereoselectivity of the first peptide coupling of the peptido RNA pathway can be determined in situ by NMR spectroscopy. When a racemic mixture of an amino acid ester was allowed to react with an 5′-aminoacidyl nucleotide, diastereomeric ratios of up to 72 : 28 of the resulting dipeptido nucleotides were found by integration of ³¹P- or ¹H-NMR peaks. The highest diastereomeric excess was found for the homochiral coupling product d -Ser-d -Trp, phosphoramidate-linked to adenosine 5′-monophosphate with its d -ribose ring. When control reactions with an N-acetyl amino acid and valine methyl ester were run in organic solvent, the diastereoselectivity was found to be lower, with diastereomeric ratios≤62 : 38. The results from the exploratory study thus indicate that the ribonucleotide residue not only facilitates the coupling of lipophilic amino acids in aqueous medium but also the formation of a homochiral dipeptide. The methodology described here may be used to search for other stereoselective reactions that shed light on the origin of homochirality.     

Modification of amyloid-beta peptide aggregation via photoactivation of strained Ru(ii) polypyridyl complexes

Alzheimer''s disease (AD) is a chronic neurodegenerative disorder characterized by progressive and irreversible damage to the brain. One of the hallmarks of the disease is the presence of both soluble and insoluble aggregates of the amyloid beta (Aβ) peptide in the brain, and these aggregates are considered central to disease progression. Thus, the development of small molecules capable of modulating Aβ peptide aggregation may provide critical insight into the pathophysiology of AD. In this work we investigate how photoactivation of three distorted Ru(ii) polypyridyl complexes (Ru1–3) alters the aggregation profile of the Aβ peptide. Photoactivation of Ru1–3 results in the loss of a 6,6′-dimethyl-2,2′-bipyridyl (6,6′-dmb) ligand, affording cis-exchangeable coordination sites for binding to the Aβ peptide. Both Ru1 and Ru2 contain an extended planar imidazo[4,5-f][1,10]phenanthroline ligand, as compared to a 2,2′-bipyridine ligand for Ru3, and we show that the presence of the phenanthroline ligand promotes covalent binding to Aβ peptide His residues, and in addition, leads to a pronounced effect on peptide aggregation immediately after photoactivation. Interestingly, all three complexes resulted in a similar aggregate size distribution at 24 h, forming insoluble amorphous aggregates as compared to significant fibril formation for peptide alone. Photoactivation of Ru1–3 in the presence of pre-formed Aβ_1–42 fibrils results in a change to amorphous aggregate morphology, with Ru1 and Ru2 forming large amorphous aggregates immediately after activation. Our results show that photoactivation of Ru1–3 in the presence of either monomeric or fibrillar Aβ_1–42 results in the formation of large amorphous aggregates as a common endpoint, with Ru complexes incorporating the extended phenanthroline ligand accelerating this process and thereby limiting the formation of oligomeric species in the initial stages of the aggregation process that are reported to show considerable toxicity.

Photoactivation of a series of Ru(ii) polypyridyl complexes leads to ligand exchange and modulation of amyloid-beta peptide aggregation of relevance to Alzheimer''s disease.     

Single-site binding of pyrene to poly(ester-imide)s incorporating long spacer-units: prediction of NMR resonance-patterns from a fractal model

Co-polycondensation of the diimide-based diols N,N′-bis(2-hydroxyethyl)hexafluoroisopropylidene-diphthalimide, (HFDI), and N,N′-bis(2-hydroxy-ethyl)naphthalene-1,4,5,8-tetracarboxylic-diimide, (NDI), with aliphatic diacyl chlorides ClOC(CH₂)_xCOCl (x = 5 to 8) affords linear copoly(ester-imide)s. Such copolymers interact with pyrene via supramolecular binding of the polycyclic aromatic at NDI residues. This interaction results in upfield complexation shifts and sequence-related splittings of the NDI ¹H NMR resonances, but gives a very different final resonance-pattern from the copolymer where x = 2. Computational modelling of the polymer with x = 5 suggests that each pyrene molecule binds to just a single NDI residue rather than by intercalation between a pair of NDI''s at a tight chain-fold, as was found for x = 2. The new single-site binding model enables the pattern of ¹H NMR resonances for copolymers with longer spacers (x = 5 to 8) to be reproduced and assigned by simulation from sequence-specific shielding factors based on a type of fractal known as the last-fraction Cantor set. As this type of fractal also enables an understanding of pairwise binding systems, it evidently provides a general numerical framework for supramolecular sequence-analysis in binary copolymers.

Nine ¹H NMR resonances assignable to specific copoly(ester-imide) sequences identified from a fractal model result from 1 : 1 supramolecular binding of pyrene to NDI residues.     

Helix-mediated over 1 nm-range chirality recognition by ligand-to-ligand interactions of dinuclear helicates

Long-range chirality recognition between the two chiral guest ligands can be tuned based on the helix distances (d_Ln–Ln = 11.5 and 14.0 Å) of bis-diketonate bridged dinuclear lanthanide complexes (2Th and 3Th, respectively) used as mediators. Both 2Th and 3Th form one-dimensional (1D) helical structures upon terminal binding of two chiral guest co-ligands (L^R or L^S). Long-range chiral self-recognition is achieved in self-assembly of 2Th with L^R and L^S to preferentially form homochiral assemblies, 2Th-L^R·L^R and 2Th-L^S·L^S, whereas there is no direct molecular interaction between the two guest ligands at the terminal edges. X-ray crystal structure analysis and density functional theory studies reveal that long-range chiral recognition is achieved by terminal ligand-to-ligand interactions between the bis-diketonate ligands and chiral guest co-ligands. Conversely, in self-assembly of 3Th with a longer helix length, statistical binding of L^R and L^S occurs, forming heterochiral (3Th-L^R·L^S) and homochiral (3Th-L^R·L^R and 3Th-L^S·L^S) assemblies in an almost 1 : 1 ratio. When phenyl side arms of the chiral guest co-ligands are replaced by isopropyl groups (L′^R and L′^S), chiral self-recognition is also achieved in the self-assembly process of 3Th with the longer helix length to generate homochiral (3Th-L′^R·L′^R and 3Th-L′^S·L′^S) assemblies as the favored products. Thus, subtle modification of the chiral guests is capable of achieving over 1.4 nm-range chirality recognition.

Long-range chirality recognition between the two chiral guest ligands can be tuned based on the helix distances (d_Ln–Ln = 11.5 and 14.0 Å) of bis-diketonate bridged dinuclear lanthanide complexes (2Th and 3Th, respectively).     

Use of a cyclo-P4 building block – a way to networks of host–guest assemblies

Despite the proven ability to form supramolecular assemblies via coordination to copper halides, organometallic building blocks based on four-membered cyclo-P₄ ligands find only very rare application in supramolecular chemistry. To date, only three types of supramolecular aggregates were obtained based on the polyphosphorus end-deck complexes Cp^RTa(CO)₂(η⁴-P₄) (1a: Cp^R = Cp′′; 1b: Cp^R = Cp′′′), with none of them, however, possessing a guest-accessible void. To achieve this target, the use of silver salts of the weakly coordinating anion SbF₆⁻ was investigated as to their self-assembly in the absence and in the presence of the template molecule P₃Se₄. The two-component self-assembly of the building block 1a and the coinage-metal salt AgSbF₆ leads to the formation of 1D or 3D coordination polymers. However, when the template-driven self-assembly was attempted in the presence of an aliphatic dinitrile, the unprecedented barrel-like supramolecular host–guest assembly P₃Se₄@[{(Cp′′Ta(CO)₂(η⁴-P₄))Ag}₈]⁸⁺ of 2.49 nm in size was formed. Moreover, cyclo-P₄-based supramolecules are connected in a 2D coordination network by dinitrile linkers. The obtained compounds were characterised by mass-spectrometry, ¹H and ³¹P NMR spectroscopy and X-ray structure analysis.

A one-pot self-assembly template-controlled reaction is reported to result in a 2D coordination network of first host-guest assemblies P₃Se₄@[{(Cp′′Ta(CO)₂(η⁴-P₄))Ag}₈]⁸⁺ of 2.49 nm in size based on an organometallic complex with a cyclo-P₄ end-deck.     

A covalent organic cage compound acting as a supramolecular shadow mask for the regioselective functionalization of C60

A trigonal-bipyramidal covalent organic cage compound serves as an efficient host to form stable 1 : 1-complexes with C₆₀ and C₇₀. Fullerene encapsulation has been comprehensively studied by NMR and UV/Vis spectroscopy, mass spectrometry as well as single-crystal X-ray diffraction. Exohedral functionalization of encapsulated C₆₀via threefold Prato reaction revealed high selectivity for the symmetry-matched all-trans-3 addition pattern.

The taming of the Prato reaction: a covalent organic cage compound serves as a supramolecular template for the regioselective functionalization of C₆₀.     

Practical prediction model of the clinical response to programmed death-ligand 1 inhibitors in advanced gastric cancer

The identification of predictive biomarkers or models is necessary for the selection of patients who might benefit the most from immunotherapy. Seven histological features (signet ring cell [SRC], fibrous stroma, myxoid stroma, tumor-infiltrating lymphocytes [TILs], necrosis, tertiary lymphoid follicles, and ulceration) detected in surgically resected tissues (N = 44) were used to train a model. The presence of SRC became an optimal decision parameter for pathology alone (AUC = 0.78). Analysis of differentially expressed genes (DEGs) for the prediction of genomic markers showed that C-X-C motif chemokine ligand 11 (CXCL11) was high in responders (P < 0.001). Immunohistochemistry (IHC) was performed to verify its potential as a biomarker. IHC revealed that the expression of CXCL11 was associated with responsiveness (P = 0.003). The response prediction model was trained by integrating the results of the analysis of pathological factors and RNA sequencing (RNA-seq). When trained with the C5.0 decision tree model, the categorical level of the expression of CXCL11, a single variable, was shown to be the best model (AUC = 0.812). The AUC of the model trained with the random forest was 0.944. Survival analysis revealed that the C5.0-trained model (log-rank P = 0.01 for progression-free survival [PFS]; log-rank P = 0.012 for overall survival [OS]) and the random forest-trained model (log-rank P < 0.001 for PFS; log-rank P = 0.001 for OS) predicted prognosis more accurately than the PD-L1 test (log-rank P = 0.031 for PFS; log-rank P = 0.107 for OS).Subject terms: Predictive markers, Predictive markers, Translational research, Predictive medicine     

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.     

The simplest Diels–Alder reactions are not endo-selective

There is a widespread perception that the high level of endo selectivity witnessed in many Diels–Alder reactions is an intrinsic feature of the transformation. In contrast to expectations based upon this existing belief, the first experimental Diels–Alder reactions of a novel, deuterium-labeled 1,3-butadiene with commonly used mono-substituted alkenic dienophiles (acrolein, methyl vinyl ketone, acrylic acid, methyl acrylate, acrylamide and acrylonitrile) reveal kinetic endo : exo ratios close to 1 : 1. Maleonitrile, butenolide, α-methylene γ-butyrolactone, and N-methylmaleimide behave differently, as does methyl vinyl ketone under Lewis acid catalysis. CBS-QB3 calculations incorporating solvent and temperature parameters give endo : exo product ratios that are in near quantitative agreement with these and earlier experimental findings. This work challenges the preconception of innate endo-selectivity by providing the first experimental evidence that the simplest Diels–Alder reactions are not endo-selective. Trends in behaviour are traced to steric and electronic effects in Diels–Alder transition structures, giving new insights into these fundamental processes.

Cycloadditions of deuterium-labeled 1,3-butadiene with monosubstituted alkenic dienophiles challenge the widespread assumption of endo-selectivity in prototypical Diels–Alder reactions.     

Difluorination of α-(bromomethyl)styrenes via I(I)/I(III) catalysis: facile access to electrophilic linchpins for drug discovery

Simple α-(bromomethyl)styrenes can be processed to a variety of 1,1-difluorinated electrophilic building blocks via I(I)/I(III) catalysis. This inexpensive main group catalysis strategy employs p-TolI as an effective organocatalyst when combined with Selectfluor® and simple amine·HF complexes. Modulating Brønsted acidity enables simultaneous geminal and vicinal difluorination to occur, thereby providing a platform to generate multiply fluorinated scaffolds for further downstream derivatization. The method facilitates access to a tetrafluorinated API candidate for the treatment of amyotrophic lateral sclerosis. Preliminary validation of an enantioselective process is disclosed to access α-phenyl-β-difluoro-γ-bromo/chloro esters.

Simple α-(bromomethyl)styrenes can be processed to a variety of 1,1-difluorinated electrophilic building blocks via I(I)/I(III) catalysis.

Structural editing with fluorine enables geometric and electronic variation to be explored in functional small molecules whilst mitigating steric drawbacks.¹ This expansive approach to manipulate structure–function interplay continues to manifest itself in bio-organic and medicinal chemistry.² Of the plenum of fluorinated motifs commonly employed, the geminal difluoromethylene group³ has a venerable history.⁴ This is grounded in the structural as well as electronic ramifications of CH₂ → CF₂ substitution, as is evident from a comparison of propane and 2,2-difluoropropane (Fig. 1, upper). Salient features include localized charge inversion (C–H^δ+ to C–F^δ−) and a widening of the internal angle from 112° to 115.4°.⁵ Consequently, geminal difluoromethylene groups feature prominently in the drug discovery repertoire⁶ to mitigate oxidation and modulate physicochemical parameters. Catalysis-based routes to generate electrophilic linchpins that contain the geminal difluoromethylene unit have thus been intensively pursued, particularly in the realm of main group catalysis.^7–9 Motivated by the potential of this motif in contemporary medicinal chemistry, it was envisaged that an I(I)/I(III) catalysis platform could be leveraged to convert simple α-(bromomethyl)styrenes to gem-difluorinated linchpins: the primary C(sp³)–Br motif would facilitate downstream synthetic manipulations (Fig. 1, lower). To that end, p-TolI would function as a catalyst to generate p-TolIF₂in situ in the presence of an external oxidant¹⁰ and an amine·HF complex. Alkene activation (I) with subsequent bromonium ion formation (II)¹¹ would provide a pre-text for the first C–F bond forming process (III) with regeneration of the catalyst. A subsequent phenonium ion rearrangement¹²/fluorination sequence (III and IV) would furnish the geminal difluoromethylene group and liberate the desired electrophilic building block.Open in a separate windowFig. 1The geminal difluoromethylene group: bioisosterism, and catalysis-based access from α-(bromomethyl)styrenes via I(I)/I(III) catalysis.To validate this conceptual framework, a short process of reaction optimization (1a → 2a) was conducted to assess the influence of solvent, amine·HF ratio (Brønsted acidity)¹³ and catalyst loading (Table 1). Initial reactions were performed with p-TolI (20 mol%), Selectfluor® (1.5 equiv.) as an oxidant, and CHCl₃ as the reaction medium. Variation of the amine : HF ratio was conducted to explore the influence of Brønsted acidity on catalysis efficiency (entries 1–4). An optimal ratio of 1 : 6 was observed enabling the product 2a to be generated in >95% NMR-yield. Although reducing the catalyst loading to 10 and 5 mol% (entries 5 and 6, respectively) led to high levels of efficiency (79% yield with 5 mol%), the remainder of the study was performed with 20 mol% p-TolI. Notably, catalytic vicinal difluorination was not observed at any point during this optimization, in contrast with previous studies from our laboratory.^9d,i A solvent screen revealed the importance of chlorinated solvents (entries 7 and 8): in contrast, performing the reaction in ethyl trifluoroacetate (ETFA) and acetonitrile resulted in a reduction in yield (9 and 10). Finally, a control reaction in the absence of p-TolI confirmed that an I(I)/I(III) manifold was operational (entry 11). An expanded optimization table is provided in the ESI.^†Reaction optimization^a

Solvate sponge crystals of (DMF)3NaClO4: reversible pressure/temperature controlled juicing in a melt/press-castable sodium-ion conductor

A new type of crystalline solid, termed “solvate sponge crystal”, is presented, and the chemical basis of its properties are explained for a melt- and press-castable solid sodium ion conductor. X-ray crystallography and atomistic simulations reveal details of atomic interactions and clustering in (DMF)₃NaClO₄ and (DMF)₂NaClO₄ (DMF = N-N′-dimethylformamide). External pressure or heating results in reversible expulsion of liquid DMF from (DMF)₃NaClO₄ to generate (DMF)₂NaClO₄. The process reverses upon the release of pressure or cooling. Simulations reveal the mechanism of crystal “juicing,” as well as melting. In particular, cation–solvent clusters form a chain of octahedrally coordinated Na⁺–DMF networks, which have perchlorate ions present in a separate sublattice space in 3 : 1 stoichiometry. Upon heating and/or pressing, the Na⁺⋯DMF chains break and the replacement of a DMF molecule with a ClO₄⁻ anion per Na⁺ ion leads to the conversion of the 3 : 1 stoichiometry to a 2 : 1 stoichiometry. The simulations reveal the anisotropic nature of pressure induced stoichiometric conversion. The results provide molecular level understanding of a solvate sponge crystal with novel and desirable physical castability properties for device fabrication.

Stimuli-responsive “solvate-sponge”-(DMF)₃NaClO₄ exhibits linear chains of DMF–Na⁺ ions with ClO₄⁻ anions in the interstitial space. At increased pressure or temperature, DMF is expelled (reversibly), resulting in a new stoichiometry-(DMF)₂NaClO₄.     

Asymmetric hydrogenation of exocyclic γ,δ-unsaturated β-ketoesters to functionalized chiral allylic alcohols via dynamic kinetic resolution

An iridium catalyzed asymmetric hydrogenation of racemic exocyclic γ,δ-unsaturated β-ketoesters via dynamic kinetic resolution to functionalized chiral allylic alcohols was developed. With the chiral spiro iridium catalysts Ir-SpiroPAP, a series of racemic exocyclic γ,δ-unsaturated β-ketoesters bearing a five-, six-, or seven-membered ring were hydrogenated to the corresponding functionalized chiral allylic alcohols in high yields with good to excellent enantioselectivities (87 to >99% ee) and cis-selectivities (93 : 7 to >99 : 1). The origin of the excellent stereoselectivity was also rationalized by density functional theory calculations. Furthermore, this protocol could be performed on gram scale and at a lower catalyst loading (0.002 mol%) without the loss of reactivity and enantioselectivity, and has been successfully applied in the enantioselective synthesis of chiral carbocyclic δ-amino esters and the β-galactosidase inhibitor isogalactofagomine.

An iridium catalyzed asymmetric hydrogenation of exocyclic γ,δ-unsaturated β-ketoesters via dynamic kinetic resolution was developed, providing efficient protocol for enantioselective synthesis of functionalized chiral allylic alcohols.     

Access to P-stereogenic compounds via desymmetrizing enantioselective bromination

A novel and efficient desymmetrizing asymmetric ortho-selective mono-bromination of bisphenol phosphine oxides under chiral squaramide catalysis was reported. Using this asymmetric ortho-bromination strategy, a wide range of chiral bisphenol phosphine oxides and bisphenol phosphinates were obtained with good to excellent yields (up to 92%) and enantioselectivities (up to 98.5 : 1.5 e.r.). The reaction could be scaled up, and the synthetic utility of the desired P-stereogenic compounds was proved by transformations and application in an asymmetric reaction.

A highly efficient desymmetrizing asymmetric bromination of bisphenol phosphine oxides was developed, providing a wide range of chiral bisphenol phosphine oxides and bisphenol phosphinates with high yields and enantioselectivities.

P-Stereogenic compounds are a class of privileged structures, which have been widely present in natural products, drugs and biologically active molecules (Fig. 1a).^1–4 In addition, they are also important chiral materials for the development of chiral catalysts and ligands (Fig. 1b), because the chirality of the phosphorus atom is closer to the catalytic center which can cause remarkable stereo-induction.^5,6 Thus, the development of efficient methods for the synthesis of P-stereogenic compounds with novel structures and functional groups is very meaningful.^5a Conventional syntheses of P-stereogenic compounds mainly depended on the resolution of diastereomeric mixtures and chiral-auxiliary-based approaches, in which stoichiometric amounts of chiral reagents are usually needed.⁷ By comparison, asymmetric catalytic strategies, including asymmetric desymmetric reactions of dialkynyl, dialkenyl, diaryl and bisphenol phosphine oxides,^8–14 (dynamic) kinetic resolution of tertiary phosphine oxides,¹⁵ and asymmetric reactions of secondary phosphine oxides,¹⁶ can effectively solve the above-mentioned problems and have been considered as the most direct and efficient synthesis methods for constructing P-chiral phosphine oxides (Fig. 1c). Among them, organocatalytic asymmetric desymmetrization methods have been sporadic, in which the reaction sites were mainly limited to the hydroxyl group of bisphenol phosphine oxides that hindered their further transformation.^8–11 It is worth mentioning that asymmetric desymmetrization methods, especially organocatalytic desymmetrization reactions, due to their unique advantages of mild reaction conditions and wide substrate scope, have become an important strategy for asymmetric synthesis. Accordingly, the development of efficient organocatalytic desymmetrization strategy for the synthesis of important functionalized P-stereogenic compounds which contain multiple conversion groups is very meaningful and highly desirable.Open in a separate windowFig. 1(a) Examples of natural products containing P-stereogenic centers. (b) P-Stereogenic compound type ligand and catalyst. (c) Typical P-stereogenic compounds'' synthetic strategies.On the other hand, asymmetric bromination has been demonstrated to be one of the most attractive approaches for chiral compound syntheses.¹⁷ Since the pioneering work on peptide catalyzed asymmetric bromination for the construction of biaryl atropisomers,^18a the reports on constructing axially biaryl atropisomers,¹⁸ C–N axially chiral compounds,¹⁹ atropisomeric benzamides,²⁰ axially chiral isoquinoline N-oxides,²¹ and axially chiral N-aryl quinoids²² by electrophilic aromatic bromination have been well developed (Scheme 1a). In comparison, the desymmetrization of phenol through asymmetric bromination to construct central chirality remains a daunting task. Miller discovered a series of tailor made peptide catalyzed enantioselective desymmetrizations of diarylmethylamide through ortho-bromination (Scheme 1b).²³ Recently, Yeung realized amino-urea catalyzed desymmetrizing asymmetric ortho-selective mono-bromination of phenol derivatives to fix a new class of potent privileged bisphenol catalyst cores with excellent yields and enantioselectivities (Scheme 1b).²⁴ Despite this elegant work, there is no report on the synthesis of P-centered chiral compounds using the desymmetrizing asymmetric bromination strategy.Open in a separate windowScheme 1(a) Constructing axially chiral compounds by asymmetric bromination. (b) Known synthesis of central chiral compounds via asymmetric bromination. (c) This work: access to P-stereogenic compounds via desymmetrizing enantioselective bromination.Taking into account the above-mentioned consideration, we speculated that bisphenol phosphine oxides and bisphenol phosphinates are potential substrate candidates for desymmetrizing asymmetric bromination to construct P-stereogenic centers. The advantages of using bisphenol phosphine oxides and bisphenol phosphinates as substrates are shown in two aspects. First, the ortho-position of electron rich phenol is easy to take place electrophilic bromination reaction. Second, the corresponding bromination product structure contains abundant synthetic conversion groups, including bromine, hydroxyl group, alkoxy group and phosphoryl group. To achieve this goal, two challenges need to be overcome: (i) finding a suitable chiral catalyst for the desymmetrization process to induce enantiomeric control is troublesome, due to the remote distance between the prochiral phosphorus center and the enantiotopic site; (ii) selectively brominating one phenol to inhibit the formation of an achiral by-product is difficult. Herein, we report a chiral squaramide catalyzed asymmetric ortho-bromination strategy to construct a wide range of chiral bisphenol phosphine oxides and bisphenol phosphinates with good to excellent yields and enantioselectivities (Scheme 1c). It is worth mentioning that the obtained P-stereogenic compounds can be further transformed at multiple sites.Our initial investigation was carried out with bis(2-hydroxyphenyl)phosphine oxide 1a and N-bromosuccinimide (NBS) 2a as the model substrates, 10 mol% chiral amino-thiourea 4a as the catalyst, and toluene as the solvent, which were stirred at −78 °C for 12 h. As a result, the reaction gave the desired desymmetrization product 3a in 65% yield with 56 : 44 e.r. (Table 1, entry 1). Then, thiourea 4b was tested, in which a little better result was obtained (Table 1, entry 2). To our delight, using the chiral squaramides 4c–4f as the catalysts, the enantiomeric ratios of the desymmetrization products had been significantly improved (Table 1, entries 3–6). Especially, when chiral squaramide catalyst 4c was applied to this reaction, the enantiomeric ratio of 3a was increased to 95 : 5 (Table 1, entry 3). To further improve the yield and enantioselectivity, we next optimized the reaction conditions by varying reaction media and additives. As shown in Table 1, the reaction was affected by the solvent dramatically. Product 3a was obtained with low yield and enantioselectivity in DCM (Table 1, entry 7). Also, when Et₂O was used as the solvent, the yield and e.r. value of product 3a were all decreased (Table 1, entry 8). As a result, the initial used toluene was the optimal solvent. We also inspected the effect of different bromine sources, and found that the initially used NBS was the optimal one (Table 1, entries 3, 11 and 12). Fortunately, by adjusting the amount of bisphenol phosphine oxides to 1.5 equiv., the yield and the enantiomeric ratio of 3a were increased to 80% and 96.5 : 3.5, respectively (Table 1, entries 3, 13 and 14). Further increasing the amount of bisphenol phosphine oxides to 2.0 equiv. resulted in a reduced enantioselectivity (Table 1, entry 15).Optimization of the reaction conditions^a

Figure-eight thermal hysteresis of aminomethylenehelicene oligomers with terminal C16 alkyl groups during hetero-double-helix formation

1 : 1 mixtures of aminomethylenehelicene (P)-tetramer and (M)-pentamer with terminal C₁₆ alkyl groups in fluorobenzene showed structural changes between hetero-double-helices B and C and random-coils 2A. Figure-eight thermal hysteresis appeared when the solution was cooled and heated at a constant rate and involved the crossing of cooling and heating curves in Δε/temperature profiles. This unusual thermal hysteresis emerged in the intermediate state between counterclockwise and clockwise thermal hystereses. This phenomenon arose from the competition between self-catalytic reactions to form B and C from 2A. Significant effects of terminal C₁₆ alkyl groups on the thermodynamic and kinetic phenomena are also described.

1 : 1 mixtures of aminomethylenehelicene (P)-tetramer and (M)-pentamer with terminal C₁₆ alkyl groups in fluorobenzene showed structural changes between hetero-double-helices B and C and random-coils 2A.     

Asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B

The asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B was achieved in 6–7 steps using an easily accessible meso-cyclohexadienone derivative. The [6,6]-bicyclic decalin B–C ring and the all-carbon quaternary stereocenter at C-6 were prepared via a desymmetric intramolecular Michael reaction with up to 97% ee. The naphthalene diol D–E ring was constructed through a sequence of Ti(Oi-Pr)₄-promoted photoenolization/Diels–Alder, dehydration, and aromatization reactions. This asymmetric strategy provides a scalable route to prepare target molecules and their derivatives for further biological studies.

The asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B was achieved in 6–7 steps using an easily accessible meso-cyclohexadienone derivative.

Various halenaquinone-type natural products with promising biological activity have been isolated from marine sponges of the genus Xestospongia¹ from the Pacific Ocean. (+)-Halenaquinone (1),^2,3 (+)-xestoquinone (2), and (+)-adociaquinones A (3) and B (4)^4,5 bearing a naphtha[1,8-bc]furan core (Fig. 1) are the most typical representatives of this family. Naturally occurring (−)-xestosaprol N (5) and O (6)^6,7 have the same structure as 3 and 4 except for a furan ring, while a naphtha[1,8-bc]furan core can also be found in fungus-isolated furanosteroids (−)-viridin (7) and (+)-nodulisporiviridin E (8)^8,9 (Fig. 1). Halenaquinone (1) was first isolated from the tropical marine sponge Xestospongia exigua² and it shows antibiotic activity against Staphylococcus aureus and Bacillus subtilis. Xestoquinone (2) and adociaquinones A (3) and B (4) were firstly isolated, respectively, from the Okinawan marine sponge Xestospongia sp.^4a and the Truk Lagoon sponge Adocia sp.,^4b and they show cardiotonic,^4a,c cytotoxic,^4b,i antifungal,⁴ⁱ antimalarial,^4j and antitumor^4l activities. These compounds inhibit the activity of pp60v-src protein tyrosine kinase,^4d topoisomerases I^4e and II,^4f myosin Ca²⁺ ATPase,^4c,g and phosphatases Cdc25B, MKP-1, and MKP-3.^4h,kOpen in a separate windowFig. 1Structure of halenaquinone-type natural products and viridin-type furanosteroids.Owing to their diverse bioactivities, the synthesis of this family of natural compounds has been extensively studied, with published pathways making use of Diels–Alder,^{3a,d,e,5a–c,e,g} furan ring transfer,^5b Heck,^{3b,c,5f,7,9b,d} palladium-catalyzed polyene cyclization,^5d Pd-catalyzed oxidative cyclization,^3f and hydrogen atom transfer (HAT) radical cyclization^9c reactions. In this study, we report the asymmetric total synthesis of (+)-xestoquinone (2), (−)-xestoquinone (2′), and (+)-adociaquinones A (3) and B (4) (Fig. 1).The construction of the fused tetracyclic B–C–D–E skeleton and the all carbon quaternary stereocenter at C-6 is a major challenge towards the total synthesis of xestoquinone (2) and adociaquinones A (3) and B (4). Based on our retrosynthetic analysis (Scheme 1), the all-carbon quaternary carbon center at C-6 of cis-decalin 12 could first be prepared stereoselectively from the achiral aldehyde 13via an organocatalytic desymmetric intramolecular Michael reaction.^10,11 The tetracyclic framework 10 could then be formed via a Ti(Oi-Pr)₄-promoted photoenolization/Diels–Alder (PEDA) reaction^12–16 of 11 and enone 12. Acid-mediated cyclization of 10 followed by oxidation state adjustment could be subsequently applied to form the furan ring A of xestoquinone (2). Finally, based on the biosynthetic pathway of (+)-xestoquinone (2)^4b,5c and our previous studies,⁷ the heterocyclic ring F of adociaquinones A (3) and B (4) could be prepared from 2via a late-stage cyclization with hypotaurine (9).Open in a separate windowScheme 1Retrosynthetic analysis of (+)-xestoquinone and (+)-adociaquinones A and B.The catalytic enantioselective desymmetrization of meso compounds has been used as a powerful strategy to generate enantioenriched molecules bearing all-carbon quaternary stereocenters.^10,11 For instance, two types of asymmetric intramolecular Michael reactions were developed using a cysteine-derived chiral amine as an organocatalyst by Hayashi and co-workers,^11a,b while a desymmetrizing secondary amine-catalyzed asymmetric intramolecular Michael addition was later reported by Gaunt and co-workers to produce enantioenriched decalin structures.^11c Prompted by these pioneering studies and following the suggested retrosynthetic pathway (Scheme 1), we first screened conditions for organocatalytic desymmetric intramolecular Michael addition of meso-cyclohexadienone 13 (Table 1) in order to form the desired quaternary stereocenter at C-6. Compound 13 was easily prepared on a gram scale via a four-step process (see details in the ESI^†).Attempts of organocatalytic desymmetric intramolecular Michael addition^a