Synthesis of N-acetylmannosamine-6-phosphate derivatives to investigate the mechanism of N-acetylmannosamine-6-phosphate 2-epimerase.

The synthesis of analogues of natural enzyme substrates can be used to help deduce enzymatic mechanisms. N-Acetylmannosamine-6-phosphate 2-epimerase is an enzyme in the bacterial sialic acid catabolic pathway. To investigate whether the mechanism of this enzyme involves a re-protonation mechanism by the same neighbouring lysine that performed the deprotonation or a unique substrate-assisted proton displacement mechanism involving the substrate C5 hydroxyl, the syntheses of two analogues of the natural substrate, N-acetylmannosamine-6-phosphate, are described. In these novel analogues, the C5 hydroxyl has been replaced with a proton and a methyl ether respectively. As recently reported, Staphylococcus aureus N-acetylmannosamine-6-phosphate 2-epimerase was co-crystallized with these two compounds. The 5-deoxy variant bound to the enzyme active site in a different orientation to the natural substrate, while the 5-methoxy variant did not bind, adding to the evidence that this enzyme uses a substrate-assisted proton displacement mechanism. This mechanistic information may help in the design of potential antibacterial drug candidates.

Synthesis and properties of photoswitchable diphosphines and gold(I) complexes derived from azobenzenes.

Diphosphines displaying azobenzene scaffolds and the corresponding bis-gold chloride complexes have been prepared and fully characterized by photophysical, spectroscopic and X-ray diffraction studies. DFT calculations provide complementary information on their electronic, structural and spectroscopic properties. Comparative investigations have been carried out on compounds featuring phosphorus functions in the meta- and para-positions, respectively, with respect to the azo functions, as well as on diphosphines with an ortho-tetrafluoro substituted azobenzene core. The effects of the substitution patterns on structural and spectroscopic properties are discussed.

On the ozonolysis of unsaturated tosylhydrazones as a direct approach to diazocarbonyl compounds.

The scope and limitations are described of reacting unsaturated tosylhydrazones with O3 followed by Et3N for the generation of 1,4- and 1,5-diazocarbonyl systems. Tosylhydrazones, from tosylhydrazide condensation with readily available δ- and ε-unsaturated α-ketoesters, led in the former case to a 2-pyrazoline whereas the latter cases led to α-diazo-ε-ketoesters, although a terminal alkene produced a tetrahydropyridazinol. Using the ozonolysis-Et3N strategy, tosylhydrazones from cyclic enones give 2,5- and 2,6-diazoketones with aldehyde or ester functionality at the 1-position; the α-diazoaldehydes prefer the s-trans conformation, with a rotation barrier of 74 kJ mol-1 at 25 °C determined by NMR. This one-pot ozonolysis/Bamford-Stevens chemistry demonstrates both the tolerance of tosylhydrazones to ozone, and the subsequently added amine playing a dual role to directly transform the intermediate tosylhydrazone ozonides into products containing reactive diazo and ketone functionalities; such adducts are of particular value as precursors to cyclic carbonyl ylides for 1,3-dipolar cycloadditions.

Enediynes bearing polyfluoroaryl sulfoxide as new antiproliferative agents with dual targeting of microtubules and DNA.

A novel series of enediynes possessing pentafluorophenylsulfoxide have been developed. The innovative compounds possess antiproliferative activity against a broad panel of human cancer cells originating from breast, blood, lung, kidney, colon, prostate, pancreas or skin with IC50 ranging from 0.6 to 3.4 µM. The antiproliferative activity of enediynes in darkness is associated to their ability to compromise microtubule network. In addition, exposure to UV leads to double-stranded DNA cleavage caused by the newly synthesized molecules reducing further their IC50 in nanomolar range against human tumor cells, including chemo-resistant pancreatic cancer cells. Taken together, the examined data demonstrate that enediynes possessing pentafluorosulfoxide are promising molecules in the cancer therapy.

Noncovalent Interactions of π Systems with Sulfur: The Atomic Chameleon of Molecular Recognition.

The relative strength of noncovalent interactions between a thioether sulfur atom and various π systems in designed top pan molecular balances was determined by NMR spectroscopy. Compared to its oxygen counterpart, the sulfur atom displays a remarkable ability to interact with almost equal facility over the entire range of π systems studied, with the simple alkene emerging as the most powerful partner. With the exception of the O⋅⋅⋅heteroarene interaction, all noncovalent interactions of sulfur with π systems are favoured over oxygen.

Synthesis of (-)-6,7-Dideoxysqualestatin H5 by Carbonyl Ylide Cycloaddition-Rearrangement and Cross-electrophile Coupling.

An asymmetric synthesis of (-)-6,7-dideoxysqualestatin H5 is reported. Key features of the synthesis include the following: (1) highly diastereoselective n-alkylation of a tartrate acetonide enolate and subsequent oxidation-hydrolysis to provide an asymmetric entry to a ß-hydroxy-α-ketoester motif; (2) facilitation of Rh(II)-catalyzed cyclic carbonyl ylide formation-cycloaddition by co-generation of keto and diazo functionality through ozonolysis of an unsaturated hydrazone; and (3) stereoretentive Ni-catalyzed Csp3-Csp2 cross-electrophile coupling between tricarboxylate core and unsaturated side chain to complete the natural product.

Noncovalent Lone Pair⋠⋠⋠(No-π!)-Heteroarene Interactions: The Janus-Faced Hydroxy Group.

A comparative study using NMR spectroscopy and designed top-pan molecular balances demonstrates that the noncovalent interaction of a hydroxy group with π-deficient pyrazine and quinoxaline units involves a lone pair-heteroarene interaction which is much stronger and solvent independent when measured relative to the classical π-facial hydrogen bond to a benzene ring. Alkyl fluorides also prefer the heteroarene rings over the benzene ring. The attractive interaction between a quinoxaline and a terminal alkyne is also stronger than the intramolecular hydrogen bond to an arene.

Double transfer of chirality in organocopper-mediated bis(alkylating) cycloisomerization of enediynes.

An original synthesis of chiral benzofulvenes triggered by organocopper reagents is reported. These enantiopure products are available through a highly chemo-, regio-, diastereo-, and enantioselective bis(alkylating) cycloisomerization process. A double chirality transfer (central-to-axial-to-central) is observed.

Disubstituted Z-allylic esters by Wittig-Schlosser reaction using methylenetriphenylphosphorane.

ß-Lithiooxyphosphonium ylides, generated in situ from aldehydes and methylenetriphenylphosphorane, react with halomethyl esters to form disubstituted allylic esters in good yields and with high Z-selectivity.

Convergent synthesis of trisubstituted Z-allylic esters by Wittig-Schlosser reaction.

ß-Lithiooxyphosphonium ylides, generated in situ from aldehydes and Wittig reagents, react readily with halomethyl esters to form trisubstituted Z-allylic esters. The methodology was applied to a total synthesis of the geranylgeraniol-derived diterpene (6S,7R,Z)-7-hydroxy-2-((E)-6-hydroxy-4-methylhex-4-enylidene)-6,10-dimethylundec-9-enyl acetate (12).