John S. Snaith

Changing the local coordination environment in mono- and bi- nuclear lanthanide complexes through “click” chemistry

Alkyne appended lanthanide complexes derived from DO3A undergo copper catalysed cycloaddition reactions with azides to form triazole appended complexes: coordination of one of the triazole nitrogen atoms to the metal centre changes the local coordination environment and the spectroscopic properties of the complex.

Synthesis and biological evaluation of novel thiocolchicine–podophyllotoxin conjugates

The synthesis and biological evaluation of 9 dimeric compounds obtained by condensation of thiocolchicine and/or podophyllotoxin with 6 different dicarboxylic acids is described. In particular, tubulin assembly assay and immunofluorescence analysis results are reported. The biological data highlighted three compounds as being more active than the others, having a marked ability to inhibit the polymerization of tubulin in vitro and causing significant disruption to the microtubule network in vivo. The spacer unit was found to have a significant effect on biological activity, reinforcing the importance of the design of conjugate compounds to create new biologically active molecules in which the spacer could be useful to improve the solubility and to modulate the efficacy of well known anticancer drugs.

Stereoselective synthesis of 2,4,5-trisubstituted piperidines by carbonyl ene and Prins cyclisations

An approach to 2,4,5-trisubstituted piperidines is reported, in which the key step is the Prins or carbonyl ene cyclisation of aldehydes of the type 1. Prins cyclisation catalysed by concentrated hydrochloric acid in CH(2)Cl(2) at -78 degrees C afforded good yields of two of the four possible diastereomeric piperidines, with the 4,5-cis product 7 predominating in a diastereomeric ratio of up to 94:6. The diastereoselectivity of the cyclisation decreased as the 2-substituent increased in size, becoming unselective for very bulky 2-substituents. In contrast, cyclisation catalysed by MeAlCl(2) in CH(2)Cl(2) or CHCl(3) at temperatures of between 20-60 degrees C, favoured the 4,5-trans diastereomer 8, in a diastereomeric ratio of up to 99:1. The low-temperature cyclisations catalysed by HCl proceed under kinetic control via a mechanism involving the development of significant carbocationic character, in which the 4,5-cis cation is more stable than the 4,5-trans cation as a result of overlap with the neighbouring oxygen. The cyclisations catalysed by MeAlCl(2) proceed under thermodynamic control, affording the product in which both the 4- and 5-substituents are equatorial.

Photolabile benzoin and furoin esters of a biologically active peptide

Abstract Benzoin and furoin esters of N-carbobenzyloxyglycylphenylalanine were prepared and photolyzed under a variety of conditions. The photochemistry of peptide-derived benzoin esters is more efficient than that of furoin esters and is appropriate for the photolytic initiation of biochemical processes. Methodology to assess the enantiomeric purity of the resulting free peptide was developed and used to monitor the protection-deprotection chemistry. Synthesis based on alkylation of the cesium salt of the peptide proved more effective than DCCI-mediated chemistry on stereochemical grounds.

Tris(trimethylsilyl)silane: an unprecedented enhancement in the diastereoselectivity of radical cyclisations to give 2,4-disubstituted piperidines

Cyclisation of bromides 4a-f mediated by tributyltin hydride affords predominantly the trans piperidines 5a-f with modest diastereomeric ratios, while cyclisation with tris(trimethylsilyl)silane affords the same products with diastereomeric ratios of up to 99 : 1.

Stereoselective Synthesis of 2,4,5-Trisubstituted Piperidines via Radical Cyclization

A novel approach to 2,4,5-trisubstituted piperidines is reported, involving the 6-exo cyclization of stabilized radicals onto α,β-unsaturated esters. Only two of the four possible diastereoisomers are observed, with diastereomeric ratios ranging from 3:2 to 40:1 when the radical stabilizing group is vinyl or phenyl. Cyclization of a (triethylsilyl)vinyl-stabilized radical gives the corresponding piperidine radical as a single diastereoisomer that may either be trapped by tributyltin hydride to afford the 2,4,5-trisubstituted piperidine or undergo a second 5-endo cyclization onto the (triethylsilyl)vinyl substituent to produce the 3,5,7-trisubstituted octahydro[2]pyrindene as a single diastereoisomer.

Synthesis and photolysis studies of carboxylic esters of 2-hydroxy-1,2,2-triphenylethanone: a novel tandem photocyclisation

Carboxylic esters of 2-hydroxy-1,2,2-triphenylethanone can be prepared in good yield by reaction between 2-chloro-1,2,2-triphenylethanone and a carboxylic acid in the presence of silver carbonate and silver tetrafluoroborate. Irradiation of the ester with a medium pressure mercury lamp results in a rapid and quantitative photolysis to afford the carboxylic acid and benzo[b]phenanthro[9,10-d]furan.

α-Carboxy-6-nitroveratryl: A Photolabile Protecting Group for Carboxylic Acids

The synthesis of a new photolabile protecting group for carboxylic acids, alpha-carboxy-6-nitroveratryl (alphaCNV), is described. Bromide 3, prepared in four steps from 3,4-dimethoxyphenylacetic acid, was used to alkylate carboxylic acids under mild conditions in good yield. Palladium-catalyzed deallylation afforded the acids 4a-h, which underwent rapid and quantitative photolysis at wavelengths longer than 300 nm to liberate the carboxylic acid in good to quantitative yield. The rate of photolysis and quantum yield were determined to be 325 s(-1) and 0.17.

Photorelease of tyrosine from α-carboxy-6-nitroveratryl (αCNV) derivatives

The synthesis of photolabile tyrosine derivatives protected on the phenolic oxygen by the α-carboxy-6-nitroveratryl (αCNV) protecting group is described. The compounds undergo rapid photolysis at wavelengths longer than 300 nm to liberate the corresponding phenol in excellent yield (quantum yield for the deprotection of tyrosine = 0.19). Further protection of caged tyrosine is possible, yielding N-Fmoc protected derivatives suitable for direct incorporation of caged tyrosine in solid-phase peptide synthesis.