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Crosslinking is a valuable route to creating new polymeric materials and normally involves introduction of a cross linker or some form of secondary processing. Here we report the discovery and analysis of a self-crosslinking sustainable terpene derived monomer, α-pinene methacrylate (αPMA). This monomer undergoes crosslinking during free radical homopolymerisation and with comonomers e.g. methyl methacrylate (MMA). αPMA does not appear to contain any obvious functionality that would induce crosslinking such as vinyl bonds, but we postulate that it may undergo a fortuitous abstraction of a hydrogen atom from the pendant group. A combined computational (DFT) and experimental approach has been applied to investigate this. Further, we used DFT analysis to predict the behaviour of a related monomer, beta-pinene methacrylate (βPMA). To the best of our knowledge this is the first-time that self-crosslinking has been observed in free radical polymerisation of methacrylates via chain transfer through hydrogen abstraction from a pendant group. We have exploited this crosslinking to generate new, renewable poly high internal phase emulsions (polyHIPEs) that could rival those derived from fossil-based styrene- polyHIPEs and we have done this in a process which does not require any additional cross-linking agent.

A simple and efficient stereoselective total syntheses of two natural products (+)-monomorine I and (+)-indolizidine 195B in high yields starting from a readily available alcohol is described. The key step in this synthetic route exploits the judicious use of solvent to enable a closed or open transition state in a nucleophilic addition of Grignard reagent to sulfinimine, giving selective access to two distinct diastereomers required for the formation of the two target natural products.

Terpenes are ideal candidates for sustainable polymer feedstocks, due to their natural abundance and availability from existing waste streams. Previously, we have shown that a range of terpene(meth)acrylate monomers can be synthesised from the most commonly available terpenes (α-pinene, β-pinenene and limonene) and that these readily undergo radical polymerisation. We now report the synthesis of well-defined polymers and precise di- and multiblock copolymer architectures by use of RAFT control. A very wide range of Tg values are observed for the terpene (meth)acrylate homopolymers, from −3 °C for poly(limonene acrylate), up to +168 °C for poly(α-pinene methacrylate), and we exploit these to create renewably-sourced hard–soft block copolymers. We also report the synthesis of difunctional poly(α- and β-pinene methacrylate) macro-RAFT agents and the preparation of ABA triblock copolymers. Promising adhesive properties are observed for a triblock copolymer comprised of poly(α-pinene methacrylate) and poly(butyl acrylate) blocks. A range of fully terpene-based triblock copolymers containing poly(limonene acrylate) soft blocks are also reported.

A versatile method for the synthesis of enantioenriched N-H sulfoximines is reported. The approach stems from the organomagnesium-mediated ring opening of novel cyclic sulfonimidate templates. The reactions proceed in high yield and with excellent stereofidelity with alkyl, aryl, and heteroaryl Grignard reagents. The chiral auxiliary is readily removed from the resultant sulfoximines via an unusual oxidative debenzylation protocol that utilizes molecular oxygen as the terminal oxidant. This provides a general strategy for the synthesis of highly enantioenriched N-H sulfoximines.

This review article explores the synthesis of the organosulfur(VI) species named sulfonimidates, focusing on their synthesis from sulfur(II), sulfur(IV) and sulfur(VI) reagents, and investigates their recent resurgeance in interest as intermediates to access other important organosulfur compounds. Sulfonimidates have been utilized as precursors for polymers, sulfoximine and sulfonimidamide drug candidates and as alkyl transfer reagents.

Biosynthesis of (1R,4aS,7S,7aR)-nepetalactol (1) and (4aS,7S,7aR)-nepetalactone (2) in plants involves iridoid synthase (ISY), an atypical reductive cyclase that catalyses the reduction of 8-oxogeranial into the reactive enol of (S)-8-oxocitronellal, and cyclization of this enol intermediate, either non-enzymatically or by a nepetalactol-related short chain dehydrogenase enzyme (NEPS) that yields the nepetalactols. In this study, we investigated the biosynthesis in vivo of 1 and 2 in the pea aphid, Acyrthosiphon pisum, using a library of isotopically-labelled monoterpenoids as molecular probes. Topical application of deuterium-labelled probes synthesized from geraniol and nerol resulted in production of 2 H4 -lactol 1 and 2 H4 -lactone 2. However, deuterium incorporation was not evident using labelled probes synthesized from (S)-citronellol. These results suggest that iridoid biosynthesis in animals, specifically aphids, may follow a broadly similar route to that characterised for plants.

© 2020 Elsevier Ltd In this work we aimed to achieve a totally sustainable Ring Opening Polymerisation (ROP) process, by harmonising the use of naturally occurring or derivable initiators and the green solvent 2-Methyltetrahydrofuran (2-MeTHF). First, a library of novel monoterpene-alcohols and existing terpenoids was used to provide renewably sourced initiators for a metal-free ROP synthetic step. A number of these initiators are derived from waste materials, further improving their sustainability. Secondly, we selected lactide (LA) as a monomer, because not only is it derived from biomass, but its resultant polymers are biocompatible and biodegradable. Interestingly, these new polymers self-assembled in water producing well defined, biocompatible nanoparticles (NPs) via direct nanoprecipitation without the use of additional stabilisers. We have highlighted a novel and promising (ROP) approach to produce biodegradable, amphiphilic ester-based macromolecules, based on lactide and terpenes (as initiators) in a green solvent, 2-MeTHF thus reducing solvent toxicity in an efficient, simple and sustainable new synthesis. The monoterpenes may provide a highly functionalisable and bio-renewable toolbox for a new generation of ROP initiators.

Unprotected tertiary sulfonimidamides have been prepared in good to excellent yields in a one‐pot transformation from tertiary sulfinamides through NH transfer. The reaction is mediated by commercially available (diacetoxyiodo)benzene and ammonium carbamate in methanol under convenient conditions. A wide range of functional groups are tolerated and initial results indicate that the NH transfer is stereospecific. A small molecule X‐ray analysis of NH sulfonimidamide 2 a and its behavior in selected in vitro assays in comparison to the matched sulfonamide are also reported. This new reaction provides a safe, short and efficient approach to sulfonimidamides, which have been the subject of recent, growing interest in the life sciences.

A simple and efficient asymmetric synthesis of novel sp3 -rich pyrrolidine chemical scaffolds over five steps starting from simple ketones is described. Key steps involve the use of tert-butanesulfinamide as a chiral auxiliary to perform an asymmetric Tsuji-Trost allylation, with subsequent cross-metathesis with an acrylate ester and reduction of the sulfinimine/cyclisation of the resulting amine giving the pyrrolidine scaffolds in high yields and diastereoselectivites. By removing the chiral auxiliary and functionalising the ester group, the resulting scaffold core can be further derivatised.

A diastereoselective mono-allylation reaction at the α-position of symmetric cyclic ketones by using tert-butanesulfinamide as a chiral auxiliary is explored. Excellent yields and high diastereomeric ratios were achieved under palladium(0) catalysis in the presence of a readily available achiral phosphine ligand.

International audience; A bis-epoxide monomer was synthesised in two steps from (R)-carvone, a terpenoid renewable feedstock derived from spearmint oil, and used to prepare β-aminoalcohol oligomers in polyaddition reactions with bis-amines without requiring solvent or catalyst. A sub-set of the resultant materials were readily water soluble and were investigated for antifungal activity in combination with the fungicide iodopropynyl-butylcarbamate (IPBC) or the antifungal drug amphotericin B. The oligo-(β-aminoalcohol)s alone were inactive against Trichoderma virens and Candida albicans but in combination with IPBC and amphotericin B demonstrated synergistic growth-inhibition of both fungi. Quantitative analysis showed that the presence of the terpene-based oligomers decreased the minimum inhibitory concentration (MIC) of IPBC by up to 64-fold and of amphotericin B by 8-fold. The efficacy of the combined formulation was further demonstrated with agar disk diffusion assays, which revealed that IPBC and amphotericin B reduced the growth of the fungi, as shown by zones of inhibition, to a greater extent when in the presence of the oligo-(β-aminoalcohol)s. These data suggest potential future use of these renewable feedstock derived oligomers in antifungal material and related biomedical applications.

The functionalisation of limonene has enabled the synthesis of two renewably-sourced monomers for the formation of terpene-derived polyesters. Three methods for the synthesis of the novel hydroxy-acid 6 are reported and their green-credentials scrutinised through comparison of their sustainability-metrics. Step-growth homo-polymerisation of 6 is demonstrated to yield a low molecular weight (2.6 kDa) novel polyester with 100% of its carbon content originating from the terpene starting material. The corresponding diol 2 is shown to act as a co-monomer with a renewable diacid. The resultant polyesters display impressive Mns of up to 30 kDa with Tgs between −6 and 24 °C. These materials have been shown to depolymerise under basic conditions for reclamation of the diol monomer 2.

The reaction of chiral (hetero)aryl benzyl sulfoxides with Grignard reagents affords enantiomerically pure diarylalkanes in up to 98 % yield and greater than 99.5 % enantiomeric excess. This ligand coupling reaction is tolerant to multiple substitution patterns and provides access to diverse areas of chemical space in three operationally simple steps from commercially available reagents. This strategy provides orthogonal access to electron-deficient heteroaromatic compounds, which are traditionally synthesized by transition metal catalyzed cross-couplings, and circumvents common issues associated with proto-demetalation and β-hydride elimination.

A novel rearrangement of 2-vinyl aziridine 2-carboxylates to unusual chiral cyclic sulfoximines is described herein. The method allows the synthesis of substituted cyclic sulfoximines in high yields with complete stereocontrol, displaying a wide substrate scope under mild conditions. Further development of a one-pot process directly from sulfinimines shows the synthetic applicability of this protocol, providing access to complex chiral sulfoximines in only two steps from commercially available aldehydes. A mechanistic hypothesis and synthetic application in the formal synthesis of trachelanthamidine by transformation of a cyclic sulfoximine into a pyrroline is also disclosed.

The first diastereoselective allylation reaction at the α-position of ketones by using tert-butanesulfinamide as a chiral auxiliary is explored. Excellent yields and high diastereomeric ratios were achieved under palladium catalysis in the presence of a readily available achiral phosphine ligand. The chiral auxiliary was removed in quantitative yield under the optimized conditions without any racemization.

The ever-increasing prevalence of sulfoximine derivatives in drug discovery programmes has brought about a renaissance in the development of methods for their synthesis. Sulfoximine synthesis via C-S bond formation however has been comparatively underexplored. Herein, we report that sulfonimidates constitute a versatile precursor for the synthesis of medicinally relevant sulfoximines.

An unprecedented set of structurally diverse sulfonimidamides (47 compounds) has been prepared by various N‐functionalization reactions of tertiary =NH sulfonimidamide 2 aa. These N‐functionalization reactions of model compound 2 aa include arylation, alkylation, trifluoromethylation, cyanation, sulfonylation, alkoxycarbonylation (carbamate formation) and aminocarbonylation (urea formation). Small molecule X‐ray analyses of selected N‐functionalized products are reported. To gain further insight into the properties of sulfonimidamides relevant to medicinal chemistry, a variety of structurally diverse reaction products were tested in selected in vitro assays. The described N‐functionalization reactions provide a short and efficient approach to structurally diverse sulfonimidamides which have been the subject of recent, growing interest in the life sciences.

A method for the continuous preparation of alcohols by hydroboration/oxidation of olefins using flow techniques is described. The process allows the isolation of up to 120 mmol h(-1) of the desired alcohol in a very rapid manner with good functional group tolerance. The flow setup can be modified to perform a continuous extraction of the desired alcohol from the biphasic mixture produced by the reaction.

The imminent depletion of resources derived from fossil fuels is a major concern for today’s society. 300 Mt of polymers are used every year in the form of plastics, most commonly derived from fossil fuels, hence the necessity to find new materials based on renewable resources. This review explores the utilisation of monoterpenes and terpenoids – a family of abundant and inexpensive natural products – as promising renewable monomers. Terpenes can be directly used in polymerisations or converted into bespoke monomers through organic transformations. The use of terpenes for the production of renewable plastics has been a prevalent topic of research for the past few decades. Early research focused on cationic polymerisation of terpenes by way of their alkene moieties; however, more recently terpenes are being functionalised to incorporate handles for a larger range of polymerisation techniques. Herein an assessment of the future prospects for the use of these small functional molecules to synthesise novel and valuable renewable materials is presented.

In order to address the current downturn in the drug discovery pipeline, initiatives are being undertaken to synthesise screening libraries of sp3-rich, low molecular weight compounds. As part of the European Lead Factory initiative, the synthesis and derivatisation of a simple hexahydrooxazolo[5,4-c]pyridin-2(1H)-one bicyclic carbamate has been achieved. The synthetic route employed involved a telescoped hetero-Diels-Alder/[2,3]-sigmatropic rearrangement/cyclisation sequence to deliver the desired core scaffold containing two points for further diversification. When applied, this synthesis was found to be robust and scalable which allowed the production of a 155 compound library.

We present new acrylic monomers derived directly from abundant naturally available terpenes via a facile, green and catalytic approach. These monomers can be polymerised to create new polymers with a wide range of mechanical properties that positions them ideally for application across the commodity and specialty plastics landscape; from packaging, cosmetic and medical, through to composites and coatings. We demonstrate their utility through formation of novel renewable polymer coatings.

Both two-directional synthesis and tandem reactions are able to form several bonds in a single transformation, making them excellent reaction types to build molecular complexity. Over the past decade, we have had an ongoing interest in combining these two strategies in order to give access to complex molecular building blocks suitable for the synthesis of natural products in as efficient and concise a manner as possible. To date, we have successfully applied this strategy for the concise syntheses of anatoxin a, homoanatoxin, histrionicotoxin, alkaloid 223B and hippodamine (Figure 1), among others.1 Herein we report our investigations into the reaction of these keto dienoates with a range of primary amines, yielding azabicyclic structures pertinent to the synthesis of a range of frog alkaloids (e.g., alkaloid 275B2 and gephyrotoxin3) and the antitumour compounds, the lepadins.4

One-pot five-component reactions of oxathiazolidine-S-oxides with mesitylmagnesium bromide, lithium bis(trimethylsilyl)amide, aldehydes and Grignard reagents afford chiral nonracemic amines or sulfinamides in good yields and high stereoselectivities.

A stable, simple to synthesise and versatile chiral alde- hyde building-block has been developed, its reactivity in Wittig, Horner-Wadsworth-Emmons and Grignard reactions investigated, and its use is demonstrated in a highly efficient synthesis of an in- termediate in Dixon's synthesis of nakadomarin A.

Syntheses of the potent neurotoxins and biochemical probes anatoxin-a and homoanatoxin and several analogues by a combined two-directional synthesis―tandem reaction strategy are presented. Key steps include an oxidative desymmetrisation and a tandem Michael―intramolecular Mannich cyclisation.

A direct multi-component coupling of (2S,4R,5S)-N-tosyl-4-methyl-5-phenyl-1,2,3-oxathiozolidine-2-oxide with mesityl magnesium bromide, LHMDS and a range of aldehydes produces chiral sulfinimines in essentially optically pure form in an operationally simple single pot procedure.

The application of a tandem condensation/cyclisation/[3+2]-cycloaddition/elimination reaction gives an sp(3)-rich tricyclic pyrazoline scaffold with two ethyl esters in a single step from a simple linear starting material. The successive hydrolysis and cyclisation (with Boc anhydride) of these 3-dimensional architectures, generates unprecedented 16-membered macrocyclic bisanhydrides (characterised by XRD). Selective amidations could then be achieved by ring opening with a primary amine followed by HATU-promoted amide coupling to yield an sp(3)-rich natural product-like library.

A tandem oxime formation/Michael addition/1,4-prototopic shift/[3+2]-cycloaddition of an acyclic symmetrical precursor results in a tricyclic isooxazolidine which then undergoes a further fragmentation/lactamisation cascade to generate a non-symmetrical tricyclic a-ketolactam as a single diastereomer.

The aza-Darzens reaction of substituted 2-bromoesters with chiral tert-butane- and mesitylsulfinimines provides a rapid access to a range of highly substituted aziridines in good yields and excellent levels of stereoselectivity. The synthetic potential of this protocol is further enhanced by the successful removal of the sulfinyl motif, yielding simple access to chiral N–H aziridines in just three steps from commercial aldehyde precursors.

A synthesis of the spirocyclic core structure of halichlorine, an inhibitor of the induced expression of VCAM-1 and the pinnaic acids, inhibitors of PLA 2 , is presented. A two-directional strategy is employed, in conjunction with a tandem oxime formation/Michael addition/cycloaddition to form the key azaspirocyclic skeleton in a very direct manner.

It has been a very active year in the arena of heterocyclic chemistry. Particular highlights include the use of N-bromosuccinimide to promote aziridination of alkenes by Chloramine-T, the first report of an aldehyde catalyst for the Oxone® mediated epoxidation of alkenes, asymmetric variants of the Kinugasa β-lactam synthesis reported by Tang and Fu, Gabrielle's comprehensive study of the 5-endo-dig cyclisation of aminoynenes to form tetrasubstituted pyrroles, Zard's report of an amidinyl radical approach to imidazolines and Woodward's direct synthesis of cyclic sulfates from alkenes.

The reaction of dimethylsulfonium methylide with a range of aromatic, heterocyclic and aliphatic tert-butylsulfinyl imines is presented. Aziridines were formed in 63-84% yield and 77-95% diastereomeric excess.

The thermolysis of S-aryl sulfinimines is shown to generate 1,2-disulfoxides and disulfides via initial Cope elimination, dimerisation of the produced sulfenic acid to a thiosulfinate, and subsequent disproportionation of the thiosulfinate.

Synthesis of a range of chiral non-racemic vinyl aziridines with varying substitutions on the alkene has been achieved by the reaction of ( S S )- tert -butylphenylsulfinimine with a range of ylides derived by deprotonation of substituted allyltetrahydrothiophenium salts. Yields of the substituted vinyl aziridines range from 0% to 90%, with trans:cis ratios between 1:1 and 0:100 and diastereomeric excesses of up to 99%.

Synthesis of a range of vinyl aziridines with varying substitution on the alkene has been achieved by the reaction of N-(di-methylsulfamoyl)phenylimine with a range ylides derived by deprotonation of substituted allyltetrahydrothiphenium salts. Yields of the substituted vinyl aziridines range from 57% to 77%.

Chiral amines are formed by the highly diastereoselective intramolecular addition of alkyl and aryl radicals onto chiral mesityl sulfinimines.

The cycloaddition of chiral tert-butanesulfinimines with trimethylenemethane is found to give facile access to methylene-pyrrolidines with good yields and diastereoselectivities. The full scope of the cycloaddition is explored, and a range of transformations of the formed methylenepyrrolidines to give a range of functionalized chiral pyrrolidines is presented.

A 6-step synthesis of the potent anthelmintic SB-201561 is described. The key stage of the synthesis is a novel Beckmann type oxime fragmentation to give a lactone, followed by a 2-step reassembly of the spirolcetal moiety.

A tandem bromonium ion-promoted cyclization of two pendant hydroxyl groups onto a central furan core provides a highly direct route to both the [5,5,5]- and the [6,5,6]-trioxadispiroketal ring systems.

One-pot five-component reactions of oxathiazolidine-S-oxides with mesitylmagnesium bromide, lithium bis(trimethylsilyl)amide, aldehydes and Grignard reagents afford chiral nonracemic amines or sulfinamides in good yields and high stereoselectivities.

A short and efficient synthesis of an advanced intermediate (1) in the Clive route to halichlorine has been achieved in 12 steps and 13.2% yield by a combined two-directional synthesis/tandem reaction strategy.

Stereoselective synthesis of 2,3-di- and 2,2′,3-tri-substituted aziridines in good yields and excellent diastereoselectivities are achieved through aza-Darzens reactions of a range of tert-butanesulfinyl aldimines and ketimines with ethyl bromoacetate.

Two oxathiozolidine-S-oxide templates have been developed and used in a four-component coupling protocol for the synthesis of a wide range of chiral sulfinimines in high enantiomeric excesses. The templates can be synthesized from cheap commodity chemicals in three steps in high yields. Furthermore the template is easily recovered in high yields for recycling.