Upper-Rim Monofunctionalisation in the Synthesis of Triazole- and Disulfide-Linked Multicalix[4]- and -[6]arenes.

Covalently linked multiple calixarenes are valued in supramolecular chemistry. This work reports an easy and versatile synthetic route to covalently linked double and triple calix[4]arene and calix[6]arenes by a novel DMF-controlled selective alkylation of a convenient and readily available upper-rim dimethylaminomethyl-substituted tetrahydroxy and hexahydroxy calix[4]arene and -[6]arenes. Synthetic routes to upper-rim functionalised redox active disulfide-linked double-, tetra- and peptidohybrid-calixarenes employing either redox chemistry (CH2 SH) or thiolates (CH2 S- ) are also opened up from the same key starting material.

Gaining Insight Into Reactivity Differences Between Malonic Acid Half Thioesters (MAHT) and Malonic Acid Half Oxyesters (MAHO).

An efficient two-step synthesis of structurally and functionally diverse thiophenol- and (cyclo)alkyl-derived malonic acid half thioesters (MAHTs) and phenol-derived malonic acid half oxyesters (MAHOs) has been achieved using cheap, readily available and easily handled starting materials. The synthesis of the MAHTs and MAHOs (the majority of which have not been previously reported) is readily scalable to afford gram quantities of product. In a hydrogen→deuterium exchange, an interesting stereoelectronic effect was observed when different aryl groups were incorporated. Significant changes in the rates of hydrogen→deuterium exchange and levels of isotope incorporation were observed. By way of example, using [2 H]methanol and 4-bromophenol-derived MAHO afforded only 14 % [2 H]-incorporation (9 min, k=31) whereas the corresponding 4-bromothiophenol-derived MAHT afforded 97 % [2 H]-incorporation (9 min, k=208). In a benchmark procedure and comprehensive DFT study, 54 ester and thioester configurations and conformations were characterized. In the MAHT series, a sulfur-containing molecular orbital provides a path for increased delocalisation of electron density into the enol that is unavailable in MAHOs. This facilitates keto-enol tautomerisation and consequently enhances the rate and percentage of hydrogen→deuterium exchange.

Chiral Brønsted Acid-Catalyzed Asymmetric Synthesis of N-Aryl-cis-aziridine Carboxylate Esters.

We report a multi-component asymmetric Brønsted acid-catalyzed aza-Darzens reaction which is not limited to specific aromatic or heterocyclic aldehydes. Incorporating alkyl diazoacetates and, important for high ee's, ortho-tert-butoxyaniline our optimized reaction (i.e. solvent, temperature and catalyst study) affords excellent yields (61-98 %) and mostly >90 % optically active cis-aziridines. (+)-Chloramphenicol was generated in 4 steps from commercial starting materials. A tentative mechanism is outlined.

Efficient syntheses of climate relevant isoprene nitrates and (1R,5S)-(-)-myrtenol nitrate.

Here we report the chemoselective synthesis of several important, climate relevant isoprene nitrates using silver nitrate to mediate a 'halide for nitrate' substitution. Employing readily available starting materials, reagents and Horner-Wadsworth-Emmons chemistry the synthesis of easily separable, synthetically versatile 'key building blocks' (E)- and (Z)-3-methyl-4-chlorobut-2-en-1-ol as well as (E)- and (Z)-1-((2-methyl-4-bromobut-2-enyloxy)methyl)-4-methoxybenzene has been achieved using cheap, 'off the shelf' materials. Exploiting their reactivity we have studied their ability to undergo an 'allylic halide for allylic nitrate' substitution reaction which we demonstrate generates (E)- and (Z)-3-methyl-4-hydroxybut-2-enyl nitrate, and (E)- and (Z)-2-methyl-4-hydroxybut-2-enyl nitrates ('isoprene nitrates') in 66-80% overall yields. Using NOESY experiments the elucidation of the carbon-carbon double bond configuration within the purified isoprene nitrates has been established. Further exemplifying our 'halide for nitrate' substitution chemistry we outline the straightforward transformation of (1R,2S)-(-)-myrtenol bromide into the previously unknown monoterpene nitrate (1R,2S)-(-)-myrtenol nitrate.

Recent advances in the synthesis of new glycopeptide antibiotics.

The vancomycin family of glycopeptide antibiotics has been inspiring research in the field of synthetic chemistry since the 1980s. Recent studies have moved away from the focus of total synthesis into new territory: the design and evaluation of novel compounds based on the natural products which exhibit improved antibacterial activity. Modern approaches to drug synthesis draw together investigations into the nature of the binding environment, and innovative synthetic methodologies which provide solutions to the challenging structural features and stereochemistry associated with this intriguing class of compounds. New analogues, derivatives and dimers of the natural products, as well as recent successes in the total synthesis of the complestatins are described in this tutorial review, covering literature from the last decade.

Do commercially available metal salts mediate calixarene formation via hydrogen-bonded dimers?

In this article we report the first example of a Lewis acid promoted, one-pot, Brønsted acid free, high-yielding synthesis of the calixarene macrocycle from the "monomer" p-tert-butylphenol. We report that when a commercially available metal salt (Lewis acid) is incorporated within the calixarene-forming reaction, a certain amount of control over the size of the calixarenes produced can be gained. Although a detailed mechanistic rationale on how the macrocycle is assembled is unclear, what is evident from this work is that the metal cation, the counteranion, and the oxidation state of the salt employed are all important contributors to the outcome of the reaction process. Indeed, evidence to date suggests that a subtle "symbiotic" relationship exists between the metal cation, its oxidation state, and the anion that allows the efficient transformation of the "monomeric" p-tert-butylphenol into linear oligomers and, ultimately, into macrocyclic calixarenes. Athough the metal salt mediated process described herein is efficient and high-yielding, what is also fundamentally important is that a comprehensive mechanistic understanding of how the calixarenes are assembled be accrued. Searching for possible indicators or clues, we propose that oligomeric methylene-linked phenolic entities are initially formed and that these, we tentatively suggest, generate metal and/or anion hydrogen-bonded supramolecular intermediates. It is possible that the preorganization of the linear polyphenolic oligomers allows the formation of hydrogen-bonded structures which, critically, result in the formation of supramolecular assemblies that are subsequently "stitched" together, generating the p-tert-butylcalix[n]arenes (n = 4-9) in excellent yields. Substantiating the possibility that hydrogen-bonded entities are generated (and that these subsequently afford metal-templated assemblies), we make reference to a seldom cited 1962 Nature publication that reported the propensity of polyphenolic linear oligomers to form "well-defined intramolecularly hydrogen-bonded conformations".

Synthesis of C-propargylic esters of N-protected amino acids and peptides.

Recent years have seen a huge surge of interest in the application of alkyne-derived motifs for so-called "click" chemistry. Given the critical importance of amino acids in organic synthesis as well as their myriad of applications in "click" chemistry it is interesting to note that the synthesis of C-propargyl derived amino acid esters has not been particularly well served. We report a convenient, straightforward, and high-yielding synthesis of structurally diverse C-propargyl-derived N-protected amino acid esters.

Upper rim appended hybrid calixarenes via click chemistry.

We report the application of "click" chemistry for the synthesis of hybrid calixarenes appended on the upper rim with carbohydrate and N,C-protected alpha-amino acids. The chemoselective N- or C-deprotection of the alpha-amino acids and their subsequent transformation into dipeptides is described. The first example of a chemo-enzymatic synthesis on upper rim derived calix[4]arenes using trans-sialidase affords sialylated lactose calix[4]arenes. Our innovative chemo-enzymatic process paves the way for further applications.

An expedient one-pot synthesis of para-tert-butylcalix[8]- and [9]arene.

We report the first efficient synthesis of para-tert-butylcalix[8]arene and -[9]arene via an exceptionally straightforward innovative protocol that takes place at ambient temperature, employing readily available tin(IV) chloride and s-trioxane.

Alpha-amino acid Tröger base derivatives, possible conformationally restricted scaffolds?

The first synthesis of innovative alpha-amino acid conjugates of Tröger base is reported; their potential application as conformationally restricted scaffolds is proposed and has been investigated using high level ab initio calculations.

Stereoselective synthesis of N-alkylaziridines from N-chloroamines.

We report the first racemic and stereoselective synthesis of cis- and trans-N-alkylaziridines viaN-chloroamines; using this methodology an N-3,4,5-trimethoxybenzylaziridine was synthesised and efficiently cleaved, affording the corresponding NH aziridine in high yield.

Expedient synthesis of substituted (S)-N-(alpha-methylbenzyl)aziridines.

We report for the first time that after O-acylation the conjugate addition products of (S)-N-(alpha-methylbenzyl)hydroxylamine undergo an efficient diastereoselective 3-exo-tet ring-closure reaction affording 2- and 2,3-disubstituted-N-alkylaziridines in good to excellent yields.

Malonic acid half oxyesters and thioesters: solvent-free synthesis and DFT analysis of their enols.

A much improved synthetic route to malonic acid half thioesters (MAHTs) and oxyesters (MAHOs), the easy incorporation of deuterium labeling expecially in MAHTs, and an unexpectedly large difference in enolization chemistry between MAHTs and MAHOs are reported. Density functional theory calculations explore the origins of this difference and identify an additional MAHT molecular orbital which increases delocalization between sulfur and the enol in both cisoid and transoid forms.

Mild reaction conditions for the terminal deuteration of alkynes.

Routinely employed syntheses of terminally deuterated alkynes often utilize strong bases (i.e., LDA, n-BuLi, or Grignard reagents) or low (i.e., -78 °C) or elevated (i.e., 56 °C) reaction temperatures; furthermore many of these procedures afford average yields and in some cases less than optimum deuterium incorporation. Herein we report the application of alternative extremely mild reaction conditions that readily afford quantitative yields of terminally deuterated alkynes in a matter of minutes with exceptional isotope incorporation at ambient temperature.

Calix[4]arene-based metal-organic frameworks: towards hierarchically porous materials.

An upper rim-functionalised calix[4]arene dicarboxylic acid (H(2)caldc) has been used to prepare four metal-organic frameworks, three of which have been structurally characterised and shown to form two- or three-dimensional network structures. Simulations suggest that such networks are likely to display interesting selectivity to guest molecules.

Hybrid calix[4]arenes via ionic hydrogenation and transition-metal-mediated processes.

We report the first application of ionic hydrogenation for the synthesis of upper-rim urea- or carbamate-derived hybrid calix[4]arenes. Subsequent metal-mediated transformations using 4-iodophenylurea calixarenes afforded structurally unique 1,3-di(biaryl)-, 1,3-di(biarylalkyne)-, or 1,3-(biaryl)(biarylalkyne)-derived hybrid calixarenes.

Organocatalytic aziridine synthesis using F+ salts.

This paper describes a unique application of the fluoronium cation (F+) as an organocatalyst for mediating the reaction between N-substituted imines and ethyl diazoacetate affording excellent yields of N-substituted aziridines.

Ferrocenium salts mediate para-tert-butylcalixarene synthesis.

Ferrocenium salts mediate high yielding one-pot and convergent syntheses of para-tert-butylcalixarenes in mild non-Lewis or Brønsted acidic reaction conditions; EPR indicates complex formation between the s-trioxane and the ferrocenium salt.

Expedient synthesis of substituted (diphenylphosphinoylmethyl)benzenes.

An efficient protocol for the synthesis of structurally diverse (diphenylphosphinoylmethyl)benzenes is described. The reaction employs readily available carboxylic acids, chlorodiphenylphosphine, and water as the reagents. A 97% reduction in the reaction times and substantially higher yields of products result, up to a 60% increase, if the reactions are performed under microwave irradiation. The first examples of transition-metal-catalyzed reactions applied to 4-bromo-1,3-bis(diphenylphosphinoylmethyl)benzene are also reported.

Acid-catalyzed synthesis of methylene-bridged (S)-tyrosine-phenol dimers.

The efficient synthesis of 2,2'-arylmethylene dimers from 3-hydroxymethyl or 3-methoxymethyl-5-halo-(S)-tyrosines and para-substituted phenols under acid-catalyzed reaction conditions using either conventional or microwave-assisted protocols is described.