Synthesis and evaluation of phorboid 20-homovanillates: discovery of a class of ligands binding to the vanilloid (capsaicin) receptor with different degrees of cooperativity.

A number of phorboid 20-homovanillates were prepared by condensation of phorbol 12,13-diesters and 12-dehydrophorbol 13-esters with Mem-homovanillic acid followed by removal of the protecting group with SnCl4 in THF. These compounds were evaluated for their ability to inhibit [3H]resiniferatoxin (RTX) binding to rat spinal cord membranes. Compounds bearing a lipophilic ester group on ring C were considerably active, but a surprising tolerance of the vanilloid receptor toward the location and the orientation of this ester group was disclosed. Unexpectedly, these ligands could also diminish, to a variable degree, the positive cooperativity which characterizes RTX binding to the vanilloid receptor. Phorbol 12-phenylacetate 13-acetate 20-homovanillate (PPAHV, 6a), a compound which abolished binding cooperativity, was further tested in a variety of in vivo assay used to characterize vanilloid-like activity. PPAHV showed only a marginal pungency and failed to induce a measurable hypothermia response at doses (up to 200 mg/kg) at which it effectively desensitized against neurogenic inflammation. These data suggest that the peculiar binding behavior of these ligands might be associated with a distinct spectrum of biological activity.

Soluble-polymer-supported synthesis of beta-lactams on a modified poly(ethylene glycol)

A modified poly(ethylene glycol) (PEG) has been developed for the soluble-polymer-supported synthesis of beta-lactams. The monomethylether of PEG (MeOPEG) with an average M(W) of 5000 was used as the support, a 4-(3-propyl)phenyl residue as the spacer, and a 4-oxyphenylamino group as the moiety with the reactive functionality. From this modified PEG representative aromatic, heteroaromatic, unsaturated, and aliphatic imines were obtained in high yields by different procedures. The polymer-supported imines were then employed to prepare several beta-lactams by enolate/imine condensation and ketene/imine cycloaddition. Examples of the control of the absolute stereochemistry during the azetidinone ring formation are also reported. The reactions carried out on the polymer-bound imines showed a remarkable similarity to those performed on nonimmobilized imines, both in terms of yields and stereoselectivities. Removal of the beta-lactams from the polymer has also been accomplished to directly deliver the N-unsubstituted azetidinones.

Stereoselective synthesis of new beta-lactams by cyclocondensation of 1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene with 4-formyl substituted azetidinones.

The BF3.OEt2 or LiClO4 catalyzed hetero Diels-Alder reaction of 1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene (Danishefsky's diene) with enantiomerically pure 4-formylazetidin-2-ones affords the corresponding cycloadducts in fair to good yields and in diastereoisomeric ratios of up to 98:2.

Structural characterisation of poly(amidoamine) networks via high-resolution magic angle spinning NMR.

A comprehensive structural characterisation of cross-linked insoluble poly(amidoamine) (PAA) networks was performed by high-resolution magic angle spinning (HRMAS) NMR spectroscopy. Model samples with 20%, 40% and 80% cross-linking degrees were prepared and the best conditions to obtain high-resolution spectra in the gel phase determined. Whereas the samples with 20% and 40% cross-linking degrees could be exhaustively resolved and described, the sample with 80% cross-linking degree could not be characterised by this technique owing to insufficient mobility of the polymer segments. Even with this limitation, the method developed in this study can be reasonably considered as a general one, which enables exhaustive characterisation of cross-linked PAA networks of biomedical interest.

Poly(ethylene glycol)-supported bisoxazolines as ligands for catalytic enantioselective synthesis.

Two chiral bisoxazolines (box) supported on a modified poly(ethylene glycol) (PEG) have been prepared by a reaction sequence that involved formation of the properly functionalized box and their attachment to the polymer matrix by means of a spacer and a linker. The solubility properties of PEG allowed use of the supported box as ligands in some catalytic asymmetric transformations carried out under homogeneous conditions and to recover the ligands as if bound to an insoluble support. When the supported box were employed in combination with Cu(II) salts in the Diels-Alder cycloaddition between cyclopentadiene and N-acryloyloxazolidinone, low levels of enantioselectivity were observed (up to 45% ee). Much better results were obtained in the cyclopropanation of styrenes carried out in the presence of CuOTf (up to 93% ee) and in the ene-reaction between alpha-methylstyrene or methylenecyclohexane and ethylglyoxalate (up to 95% ee). One of the ligands, readily recovered by precipitation and filtration, was recycled two times in the ene-reaction with marginal loss in the catalytic activity and very limited erosion of the enantioselectivity.

A short, stereoselective synthesis of (3R,4R)-4-acetoxy-3-[(R)-1'((t-butyldimethylsilyl)oxy)ethyl]-2-azetidin one, key intermediate for the preparation of carbapenem antibiotics.

A short stereoselective synthesis of the acetoxy azetidinone (1), an important precursor of several biologically active beta-lactam antibiotics, has been accomplished in seven steps and 32.8% overall yield from the easily available and inexpensive (R) ethyl 3-hydroxybutanoate.

A poly(ethylene glycol)-supported quaternary ammonium salt: An efficient, recoverable, and recyclable phase-transfer catalyst

A quaternary ammonium salt readily immobilized on a soluble poly(ethylene glycol) polymer support efficiently catalyzes different reactions carried out under phase-transfer catalysis conditions; the catalyst, easily recovered by precipitation and filtration, shows no appreciable loss of activity when recycled three times.