Alcide Perboni

Discovery of a Selective S1P1 Receptor Agonist Efficacious at Low Oral Dose and Devoid of Effects on Heart Rate.

Gilenya (fingolimod, FTY720) was recently approved by the U.S. FDA for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). It is a potent agonist of four of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors (S1P1 and S1P3-5). It has been postulated that fingolimods efficacy is due to S1P1 agonism, while its cardiovascular side effects (transient bradycardia and hypertension) are due to S1P3 agonism. We have discovered a series of selective S1P1 agonists, which includes 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]propanoate, 20, a potent, S1P3-sparing, orally active S1P1 agonist. Compound 20 is as efficacious as fingolimod in a collagen-induced arthritis model and shows excellent pharmacokinetic properties preclinically. Importantly, the selectivity of 20 against S1P3 is responsible for an absence of cardiovascular signal in telemetered rats, even at high dose levels.

Highly stereocontrolled synthesis of a novel tribactam by reaction of an ester enolate with a N-trimethylsilylimine

Abstract The azetidinone 14 , a key intermediate in the synthesis of novel tribactam antibiotics ( e.g. 2 ) was obtained via condensation of an ester enolate with a N -trimethylsilylimine.

The preparation of heterobiaryl phosphonates via the Stille coupling reaction

Abstract The Stille cross-coupling reaction between various heteroarylstannanes and substituted bromo-benzylphosphonates was used to prepare heterobiaryl phosphonates in moderate to good yields.

Access to pyrrolo-pyridines by gold-catalyzed hydroarylation of pyrroles tethered to terminal alkynes.

Summary In a simple procedure, the intramolecular hydroarylation of N-propargyl-pyrrole-2-carboxamides was accomplished with the aid of gold(III) catalysis. The reaction led to differently substituted pyrrolo[2,3-c]pyridine and pyrrolo[3,2-c]pyridine derivatives arising either from direct cyclization or from a formal rearrangement of the carboxamide group. Terminal alkynes are essential to achieve bicyclic pyrrolo-fused pyridinones by a 6-exo-dig process, while the presence of a phenyl group at the C–C triple bond promotes the 7-endo-dig cyclization giving pyrrolo-azepines.

Synthesis and antibacterial activity of 4- and 8-methoxy trinems

Abstract The synthesis of all the isomers of 8-methoxy-(9 S ,10 S ,12 R )-10-(1-hydroxyethyl)-11-oxo-1-azatricyclo-[7.2.0.0 3,8 ]-undec-2-ene-carboxylates 2 and 4-methoxy-(9 R ,10 S ,12 R )-10-(1-hydroxyethyl)-11-oxo-1-azatricyclo-[7.2.0.0 3,8 ]-undec-2-ene-carboxylates 3 is described. The biological data obtained indicated that the (4 S ,8 S )-4-methoxy derivative ( 3b ) is the best compound in terms of microbiological activity, breadth of spectrum of action and stability to hydrolytic enzymes, namely β-lactamases.

Synthesis of a novel fluoro-tribactam utilising an N-fluorosulfonimide in the key step

Abstract The electrophilic reagent N -fluorobenzenesulfonimide (NFSI) was used in the synthesis of the α-fluoro ketone 7, a key intermediate for the synthesis of the β-lactam 13 . This highly reactive fluorinated tribactam 13 was rapidly hydrolysed in aqueous solution.

Highly stereocontrolled synthesis of enantiomeric 4-methoxy trinems via resolution of scalemic enol phosphates

Abstract Stereocontrolled syntheses of 4-methoxy trinem 2 and its enantiomer 3 were achieved using the ester enolate N -trimethylsilylimine approach. The key step was the resolution of racemic enolphosphates derived from ephedrine.

Carbon–carbon bond formation at the C-4 position of an azetidin-2-one ring by intermolecular radical coupling reactions: a route to tribactams

The β-lactam 4 was linked to the enones 8–10 using a radical reaction mediated by tri-n-butyltin hydride to give the 2,6-disubstituted cyclohexanones 11–16, respectively: 13 was converted into the protected tribactam 18 in two steps.

SYNTHESIS OF ESTERS OF THE POTENT ANTI-BACTERIAL TRINEMS AND ANALOGUES

Coupling the silyl enol ether 5 and the β-lactam 9(R = Me3Si) affords the ketones 13a–d. Compounds 13a, 13c and 13d are converted into the tricyclic lactams 16–20, 23–25. (Chemoenzymatic synthesis of optically pure silyl enol ether 5 gave access to homochiral lactams 23–25.) In addition the ketoazetidinones 13 are protected as the 1,3-oxazanes 30. A hydroxyethyl moiety is introduced into these oxazanes at C-11 with the desired stereochemistry using the Bouffard methodology, to afford the alcohols 32. Formation of the corresponding nitrobenzyl carbonate, deprotection and oxidation furnishes the ketones 35a and 35b, which are subsequently converted into the trinems 41a and 41b, respectively.

The synthesis of 4-aminocarbonylmethoxy trinems

Abstract The synthesis of 4-aminocarbonylmethoxy trinems was accomplished through Lewis acid catalysed opening of an epoxide intermediate with allyl glycolate, followed by deallylation, activation of the free acid via the 2-pyridyl thiolester and reaction with a series of trimethylsilylamines. An alternative route involving a rhodium-catalysed diazoacetate insertion was also successfully exploited.