Nannocystin A is a novel 21-membered macrolactone isolated from myxobacterium Nanocystis sp. It is a potent elongation factor 1 inhibitor and inhibits cancer cell line growth at nanomolar concentrations. In this work, a concise asymmetric total synthesis of nannocystin A has been developed, which features Sharpless epoxidation, Stille coupling, and final macrolactamization.

The first formal [3 + 2] cycloaddition reaction of in situ generated azaoxyallyl cation with cyclic ketones has been developed using mild reaction conditions. A variety of spiro-4-oxazolidinones was obtained in excellent yields (up to 99%). The high efficiency of this process, coupled with the operational simplicity, makes it an attractive method for the synthesis of spiro-4-oxazolidinones.

Kanamienamide is a novel enol ether containing enamide with a single digit micromolar inhibitory activity against cancer cell lines. An efficient and convergent total synthesis of kanamienamide has been developed for the first time, which features a Cu-mediated amide coupling with vinyl iodide at the late stage. Other key transformations include Evans asymmetric alkylation, CBS asymmetric reduction, ring-closing metathesis reaction, and Stork–Zhao–Wittig olefination. This strategy is amenable for facile analogue preparation and SAR studies.

A method for intramolecular sp2 C–H oxidative arylation of unactivated cyclic olefins has been developed to access spiro-dihydroquinoline and octahydrophenanthrene derivatives in a straightforward and efficient manner. Bearing picolinamide as a directing group, the alkenyl anilines cyclized to afford spiro-dihydroquinolines in moderate to excellent yields via direct oxidative arylation, while the alkenyl benzylamines furnished the octahydrophenanthrene derivatives in moderate yields via sequential oxidative arylation and double acetoxylation.

An unprecedented catalytic asymmetric method for the [3+2] cycloaddition of isocyanoacetates with α-thioacrylates/α-phthalimidoacrylates has been developed with excellent enantioselectivities. The generated pyrrolines could be readily further reduced to an array of structurally various and biologically important pyrrolidine derivatives. α-Tosyloxyacrylate with isocyanoacetates as well as tosylmethylisocyanide could be used to produce 2,4-disubstituted pyrroles.

Transition-metal-free inverse electron-demand aza Diels–Alder and domino [4+2]/[2+2] cycloaddition reaction of arynes and N-sulfonyl ketimines has been demonstrated. This novel, mild, and efficient protocol allows rapid access to isothiazole dioxide-fused dihydroquinoline or dihydrocyclobutaquinoline derivatives selectively by simply varying the equivalents of aryne precursors. The application of this method has been amply illustrated in the synthesis of 2,4-diarylquinolines.

An effective method for the synthesis of multi-substituted β-keto thioethers via Stevens rearrangement of simple β-keto thioethers with arynes has been developed. In these reactions, successive C–S/C–H/C–C bonds were formed in one pot under mild and transition-metal free conditions to afford multi-substituted β-keto thioethers in moderate to good yields.

A method for the oxidative arylacetoxylation of alkenes has been developed to synthesize indole and indoline derivatives from readily accessible substrates. The cinnamyl tethered anilines with picolinamide as a directing group provided 3-substituted indoles via intramolecular oxidative arylacetoxylation, and the 2-methyl substituted cinnamyl anilines furnished indoline derivatives with 3-position quaternary stereocenters in good to excellent yields via sequential intramolecular oxidative arylacetoxylation, hydrolysis and oxidation steps.

The first enantioselective formal [3 + 2] cycloaddition of α-unsubstituted isocyanoacetates with protecting-group-free methyleneindolinones was developed. A variety of optically enriched 3,3′-pyrrolidinyl spirooxindoles were obtained in excellent yields, and diastereo- and enantioselectivities (up to 99% yield, >20 : 1 dr, 99% ee) with low catalyst loading under mild reaction conditions.

•Dual temperature/oxidation-responsive polymer was synthesized with defined structure.•The aggregates prepared with the amphiphilic polymer demonstrated dual responsiveness towards the stimuli.•The prepared micellar dispersion showed tuneable LCST from 33.5 to 41.1 °C.This work reports a facile method to prepare dually responsive poly(propylene sulphide)-b-poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (PPS-P(NIPAm-co-DMAA)) block copolymers which can respond to both oxidative and thermal stimuli. These novel dually responsive materials formed micellar structure in water and exhibited sensitive responsiveness to both oxidants and temperature. The lower critical solution temperature (LCST) can be tuned from 33 to 41 °C. The mechanism of the oxidation-responsiveness and the phase transformation behaviours of the materials under different temperatures were discussed, elucidating the potential of PPS-P(NIPAm-co-DMAA) as highly promising biomedical materials for advanced drug delivery.

The object of this study was to develop a thermally and reactive oxygen species-responsive nanocarrier system for cancer therapy.PPS-PNIPAm block copolymer was designed and synthesised using a combination of living anionic ring-opening polymerization and atom transfer radical polymerization. The synthesized polymer formed micellar aggregates in water and demonstrated dual responsiveness towards temperature and oxidants. Using doxorubicin (DOX) as a model drug, encapsulation and in vitro release of the drug molecules in PPS-PNIPAm nanocarriers confirmed the responsive release properties of such system. Cell uptake of the DOX loaded micelles was investigated with human breast cancer cell line (MCF-7). The results showed Dox-loaded micelles were able to be taken by the cells and mainly reside in the cytoplasma. In the stimulated cells with an elevated level of ROS, more released DOX was observed around the nuclei. In the cytotoxicity experiments, the Dox-loaded micelles demonstrated comparable efficacy to free DOX at higher concentrations, especially on ROS stimulated cells.These results demonstrated that PPS-PNIPAm nanocarriers possess the capability to respond two typical stimuli in inflammatory cells: temperature and oxidants and can be used in anticancer drug delivery.

A novel “one-pot” aryne transformation is described that affords various 4-quinolone derivatives without recourse to transition-metal catalysis. Arynes react with aza-Morita–Baylis–Hillman (AMBH) adducts through a cascade sequence involving an insertion/cyclization/ene reaction process to afford 4-quinolones in high yields with a broad substrate scope under mild reaction conditions. Essentially, an umpolung of reactivity at the β carbon of α,β-unsaturated ketone has been achieved by an inverse electron demand aryne–ene reaction to provide a C-arylated product.

A formal cycloaddition reaction for the synthesis of biologically and pharmaceutically important carbazolequinones via the annulation of aminoquinones with arynes has been developed. This practical and metal-free cascade reaction proceeds through successive C–C/C–N bond formations. Moreover, this novel method has been utilized for the concise synthesis of bioactive murrayaquinone A and koeniginequinone B and their analogues.

The concise total syntheses of the potent HIV inhibitors aetheramides A and B (IC50 values of 15 and 18 nM), as well as three pairs of their stereoisomers, were achieved, which allowed the complete stereochemical assignment of aetheramides for the first time. With a longest linear sequence of 15 steps, the convergent, fully stereocontrolled route provided aetheramides A and B in 5.3% and 3.6% yields, respectively. The synthetic strategy features efficient Stille coupling for macrocyclization, asymmetric aldol reactions to establish the ambiguous stereochemistries at C-17 and C-26, and implementation of mild conditions to avoid the epimerization of the sensitive polyketide moiety and the migration of the labile lactone.

The insertion of arynes into P–O bonds for the preparation of o-hydroxy-substituted arylphosphine oxides, -phosphinates, and -phosphonates is described. This novel reaction leads to the simultaneous formation of C–P and C–O bonds in one step with good yields and regioselectivities under mild and transition-metal-free conditions. The easy follow-up transformations of the resulting o-hydroxyl group extend these reactions to the facile construction of other ortho-substituted arylphosphorus compounds.

The first Pd-catalyzed multisite-selective acetoxylation reactions are disclosed at an unactivated alkene sp2 C–H bond versus secondary allylic sp3 C–H bond in cyclic olefins via the modulation of directing groups. The different directing groups overcome the key challenge in differentiating C–H bonds and provide a new controlling approach for site-specific C–H activation. A wide variety of substrates are readily acetoxylated under operationally simple conditions. Mechanistic studies suggest that different Pd (IV) intermediates were involved in the multisite-selective acetoxylation reactions.

The transition-metal-free multicomponent coupling of arynes, anilines, and ethylglyoxylate, proceeding via an inverse electron-demand aza Diels–Alder cycloaddition and N-arylation, has been demonstrated. This protocol allows rapid access to N-aryl dihydrophenanthridine derivatives in moderate to high yields at room temperature from readily available starting materials. In addition, an unprecedented fluoride induced annulation of ethyl(arylimino)acetates led to the formation of highly functionalized oxoimidazolidine derivatives in good yields under mild conditions.

A highly efficient and versatile synthetic strategy has been developed for the synthesis of meta-, para-azabenzeno or azanaphthaleno phanes (II–IV) with varying ring sizes (12–25) through intramolecular Mitsunobu reaction from the corresponding Ns-arylamino alcohols. The reaction is compatible with olefin and ketone moieties in the backbone tether and has been applied in the synthesis of various simplified structural motifs of ansamycins.

•Calothrixin A and B have been synthesized via [3+2] formal cycloaddition.•Key step proceeds through C–C/C–N bond formation and subsequent oxidation.•Advantageous method to prepare ring-A modified calothrixins for SAR studies.Bioactive indolo[3,2-j]phenanthridine alkaloids, calothrixin A, B, and their analogues have been synthesized via formal cycloaddition of arynes and 2-aminophenanthridinedione as the key step, which proceeds through successive C–C/C–N bond formation and subsequent oxidation under transition-metal-free and mild conditions in the final stage of the synthesis.

A concise total synthesis of aetheramide A in an overall yield of 4.7% with a longest linear sequence of 15 steps is described. This synthetic strategy features macrocyclization via an intramolecular trapping of acylketene generated from dioxinone precursor, and stereoselective late-stage methylation of β-ketoamide. Aetheramide B could be synthesized via the ester migration of aetheramide A.

The synthesis of novel amphiphilic poly(propylene sulfide) (PPS) and poly(N-isopropylacrylamide) (PNIPAm) block copolymers is reported as a strategy to respond stimuli in inflammatory tissues. In addition to the formation of defined PPS-block-PNIPAm assemblies, the encapsulation of fluorescent dyes and the selective response to the heat and oxidants are studied. The synthesis of the dual responsive PPS-b-PNIPAm is carried out by combining a living anionic ring-opening and an atom transfer radical polymerization (ATRP) process. The resulting copolymers are self-assembled in water to form aggregated structures, which are characterized by dynamic light scattering (DLS) and scanning electronic microscopy (SEM). DLS measurements show that heat and oxidants cause a significant change to the hydrodynamic diameter of the particles. Fluorescent spectroscopy data confirms the liberation of the encapsulated dye, which indicates the decomposition of the particles and validates the concept of stimuli-triggered payload release. Finally, cytotoxicity assays confirm that the PPS-b-PNIPAm copolymer is biocompatible with A549 lung cancer cells.

An effective method for the synthesis of multi-substituted β-keto thioethers via Stevens rearrangement of simple β-keto thioethers with arynes has been developed. In these reactions, successive C–S/C–H/C–C bonds were formed in one pot under mild and transition-metal free conditions to afford multi-substituted β-keto thioethers in moderate to good yields.

The first enantioselective formal [3 + 2] cycloaddition of α-unsubstituted isocyanoacetates with protecting-group-free methyleneindolinones was developed. A variety of optically enriched 3,3′-pyrrolidinyl spirooxindoles were obtained in excellent yields, and diastereo- and enantioselectivities (up to 99% yield, >20:1 dr, 99% ee) with low catalyst loading under mild reaction conditions.