John Tsanaktsidis

Highly efficient dehydration of carbohydrates to 5-(chloromethyl)furfural (CMF), 5-(hydroxymethyl)furfural (HMF) and levulinic acid by biphasic continuous flow processing

Using a continuous flow reactor, the dehydration of D-fructose and other carbohydrates to 5-(chloromethyl)furfural (1) is achieved in reaction times as short as 60 s. The biphasic flow process allows for high-yielding multigram scale production of CMF (1) which is obtained with excellent purity after a simple extractive work-up. Efficient conversion of D-fructose into 5-(hydroxymethyl)furfural (2) and levulinic acid (6) is also demonstrated using flow reactor techniques.

The scope for synthesis of macro-RAFT agents by sequential insertion of single monomer units

The scope for synthesis of new macro-RAFT agents (Z–C(S)S–(M)–R) by sequential insertion of monomers (M) ‘one at a time’ into an initial RAFT agent (Z–C(S)S–R) has been explored. The process is illustrated with the preparation of a styrene-N-isopropylacrylamide (NIPAM) co-dimer macro-RAFT agent [(CH3)3C(CN)–CH2CH(Ph)–CH2CH(CONHiPr)–SC(S)–S-alkyl] by successive single unit monomer insertions into a cyanoisopropyl trithiocarbonate. Critical factors for success are a high transfer constant for the RAFT agent and a high rate of addition of the radical (R·) to monomer relative to further propagation. With these conditions satisfied, the rate of reaction is largely determined by the rate of R· adding to monomer. Initiator-derived by-products (Z–C(S)S–(M)–I) become an issue when R· is different from the initiator-derived radical (I·).

Reducing the Cost, Smell, and Toxicity of the Barton Reductive Decarboxylation: Chloroform as the Hydrogen Atom Source

When used as solvent, chloroform was found to act as a hydrogen atom donor in Barton reductive decarboxylation reactions. Chloroform offers a substantial practical advantage over pre-existing hydrogen atom donors.

RAFT‐Derived Polymer–Drug Conjugates: Poly(hydroxypropyl methacrylamide) (HPMA)–7‐Ethyl‐10‐hydroxycamptothecin (SN‐38) Conjugates

A series of well‐defined polymer–drug conjugates were prepared in order to modify the physical properties of a known cytotoxic drug, 7‐ethyl‐10‐hydroxycamptothecin (SN‐38), the active metabolite of irinotecan (CPT‐11). Reversible addition–fragmentation chain transfer (RAFT) polymerisation was used to covalently and site‐specifically append a defined N‐(2‐hydroxypropyl)methacrylamide (HPMA) polymer to SN‐38 using a graft‐from process. These poly‐HPMA–SN‐38 conjugates displayed excellent aqueous solubility and stability, whilst retaining the cytotoxic activity of the parent SN‐38. In vitro co‐culture assays containing both cancer and noncancer cell lines demonstrated the specificity of RAFT‐derived poly‐HPMA–SN‐38 conjugates for cancerous cells. The concept of post‐optimisation modification of small‐molecule drugs through a graft‐from polymer conjugation method is introduced.

Validating Eaton's Hypothesis: Cubane as a Benzene Bioisostere

Pharmaceutical and agrochemical discovery programs are under considerable pressure to meet increasing global demand and thus require constant innovation. Classical hydrocarbon scaffolds have long assisted in bringing new molecules to the market place, but an obvious omission is that of the Platonic solid cubane. Eaton, however, suggested that this molecule has the potential to act as a benzene bioisostere. Herein, we report the validation of Eatons hypothesis with cubane derivatives of five molecules that are used clinically or as agrochemicals. Two cubane analogues showed increased bioactivity compared to their benzene counterparts whereas two further analogues displayed equal bioactivity, and the fifth one demonstrated only partial efficacy. Ramifications from this study are best realized by reflecting on the number of bioactive molecules that contain a benzene ring. Substitution with the cubane scaffold where possible could revitalize these systems, and thus expedite much needed lead candidate identification.

Chloroform as a Hydrogen Atom Donor in Barton Reductive Decarboxylation Reactions

The utility of chloroform as both a solvent and a hydrogen atom donor in Barton reductive decarboxylation of a range of carboxylic acids was recently demonstrated (Ko, E. J. et al. Org. Lett. 2011, 13, 1944). In the present work, a combination of electronic structure calculations, direct dynamics calculations, and experimental studies was carried out to investigate how chloroform acts as a hydrogen atom donor in Barton reductive decarboxylations and to determine the scope of this process. The results from this study show that hydrogen atom transfer from chloroform occurs directly under kinetic control and is aided by a combination of polar effects and quantum mechanical tunneling. Chloroform acts as an effective hydrogen atom donor for primary, secondary, and tertiary alkyl radicals, although significant chlorination was also observed with unstrained tertiary carboxylic acids.

Continuous flow hydrogenations using novel catalytic static mixers inside a tubular reactor

This work describes a novel continuous flow reactor concept for organic synthesis using heterogeneous catalysts. The concept is based on static mixers coated with a catalytic metal layer, which can be inserted into standard stainless steel reactor tubing. The static mixers were prepared by 3D metal printing, allowing for maximum design flexibility and thus can be tailored to a large number of chemical synthesis applications. The nickel or platinum catalysts were deposited either by metal cold spraying or electrodeposition, which allows for potential scale up and mass production and these techniques are compatible with a range of different catalytic metals. The catalytic flow reactor was evaluated for a series of continuous flow hydrogenations of alkenes and carbonyls.

Dithiocarbamate RAFT agents with broad applicability – the 3,5-dimethyl-1H-pyrazole-1-carbodithioates

3,5-Dimethyl-1H-pyrazole-1-carbodithioates are shown to be extremely versatile dithiocarbamate RAFT agents with wide-spread applicability. The cyanomethyl and benzyl dithiocarbamates offer very low dispersities (Đ < 1.1) for polymers based on more activated monomers [MAMs: methyl acrylate (MA), N,N-dimethylacrylamide (DMA) and styrene (St)] and Đ < 1.3 in polymerization of vinyl acetate (VAc), a less activated monomer (LAM). The tertiary, 2-cyano-2-butyl dithiocarbamate, provides molar mass control and Đ < 1.5 in methyl methacrylate (MMA) polymerization. Lower dispersities can be obtained for MMA copolymers. End group fidelity was proved with the synthesis of block copolymers, poly(DMA)-block-poly(MA). With the ability to control polymerization of both MAMs and LAMs, the RAFT agents were also shown to be suitable for the synthesis of a poly(MAM)-block-poly(LAM), specifically poly(DMA)-block-poly(VAc). The RAFT agents are an appropriate replacement for trithiocarbonate RAFT agents in most circumstances and have the distinct advantage that the RAFT agents have low odour and the derived polymers do not develop odour on storage (i.e., no low molar mass thiols are generated).

Structure-activity relationships of N-substituted 4-(trifluoromethoxy)benzamidines with affinity for GluN2B-containing NMDA receptors.

GluN2B subtype-selective NMDA antagonists represent promising therapeutic targets for the symptomatic treatment of multiple CNS pathologies. A series of N-benzyl substituted benzamidines were synthesised and the benzyl ring was further replaced with various polycyclic moieties. Compounds were evaluated for activity at GluN2B containing NMDA receptors where analogues 9, 12, 16 and 18 were the most potent of the series, replacement of the benzyl ring with polycycles resulted in a complete loss of activity.

The Synthesis of a Cubane-Substituted Dipeptide

Amino acids and peptides bearing cyclic hydrocarbon side-chains are of interest in the development of a wide range of bioactive molecules. The preparation of an amino acid and a dipeptide derivative bearing an unfunctionalised cubane substituent is described. Attempts to prepare a cubylalanine derivative via the corresponding dehydroalanine were unsuccessful due to the high sensitivity of this vinyl cubane compound. Conversely, the addition of cubyllithium to a (RS)-glyoxylate sulfinimine led to an effective synthesis of a cubylglycine derivative and a cubane-substituted dipeptide in diastereomerically pure form.