Irma Panfil

Cycloaddition of nitrones and α,β-unsaturated sugar lactones

Abstract It was found that 1,3-cycloaddition of nitrones 1 – 3 to α,β-unsaturated sugar carbonyl compounds 4 – 8 proceeds regiospecifically to give mixtures of stereoisomers. Nitrones 1 – 3 entered compounds 4 – 8 in trans -relation to the existing ring substituent.

1,3-dipolar cycloaddition of nitrones to sugar enlactones

It was found that 1,3-dipolar cycloaddition of nitrones derived from formaldehyde and acetaldehyde to sugar enlactones proceeds regio- and stereospecifically to afford anti - endo adducts.

A Formal Synthesis of Ezetimibe via Cycloaddition/Rearrangement Cascade Reaction

A formal synthesis of a powerful cholesterol inhibitor, ezetymibe 1, is described. The crucial step of the synthesis is based on Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade reaction between terminal acetylene derived from acetonide of L-glyceraldehyde and suitable C,N-diarylnitrone. The adduct with (3R,4S) configuration at the azetidinone ring, obtained with high stereoselectivity, was subsequently subjected to deprotection of the diol side chain followed by glycolic cleavage and base-induced isomerization at the C3 carbon atom to afford the (3S,4S) aldehyde, which has been already transformed into ezetimibe by the Schering-Plough group.

An approach to carbapenems from α,β-unsaturated sugar lactones

Abstract Conjugate addition-rearrangement of N-substituted hydroxylamines to α,β-unsaturated D-lactones provides a short and effective route to 3-substituted isoxazolidin-5-ones. These compounds were converted into 4-substituted azetidin-2-ones via a two-step procedure involving hydrogenolysis of the NO bond followed by cyclization of the resulting β-amino acids. N-Benzyl-4-(3′-acetoxy-2′-tert-butyldimethylsiloxypropyl)azetidin-2-one ( 37 ) was transformed into known precursors of carbapenem antibiotics.

Synthesis of enantiomerically pure 2,3-disubstituted isoxazolidin-5-ones

Abstract Conjugate addition-rearrangement of N -substituted hydroxylamines to α,β-unsaturated sugar δ-lactones provides a short and effective route to title compounds.

Total Synthesis of Ezetimibe, a Cholesterol Absorption Inhibitor

Ezetimibe (1), a strong β-lactamic cholesterol absorption inhibitor, was synthesized from (R)-6-(4-fluorophenyl)-5,6-dihydro-2H-pyran-2-one 7. Independent pathways were analyzed in order to select the optimal one, which involved 1,3-dipolar cycloaddition with C-(4-benzyloxyphenyl)-N-(4-fluorophenyl)-nitrone (8), intramolecular nucleophilic displacement at the benzylic position of the lactone, cleavage of the N-O bond, elimination of a water molecule, hydrogenation of the double bond, rearrangement of the six-membered lactone ring into a β-lactam moiety, and final deprotection of the phenolic hydroxyl group. Highly stereoselective Sc(OTf)3-catalyzed 1,3-dipolar cycloaddition was the most crucial step of the synthesis. Owing to the rigid transition state of the cycloaddition, the absolute configuration of the starting lactone controlled the formation of other stereogenic centers of the final molecule 1.

Synthesis of (−)‐Isofagomine

Abstract 1,3‐Dipolar cycloaddition of N‐benzyl nitrone 2 to D‐threo δ‐lactone 15 proceeded with excellent stereoselectivity to provide only one adduct 16. Cycloadduct 16 was subsequently subjected to a sequence of reactions involving rearrangement to γ‐lactone, glycolic cleavage/reduction, protection of the terminal hydroxymethyl group, reduction of the lactone, desilylation/mesylation, and hydrogenolysis of the N‐O bond providing (−)‐isofagomine and its N‐substituted derivatives. The biologic activity of N‐substituted (−)‐isofagomines toward commercially available α‐ and β‐glucosidases, α‐D‐mannosidase, α‐L‐fucosidase, β‐D‐glucuronidase, and β‐D‐galactosidase was tested.

Reaction of α, β-unsaturated sugar lactones with formaldoxime

Abstract Unsaturated sugar δ-lactones react with a mixture of hydroxylamine and formaldehyde (formaldoxime) either via stepwise process to produce the 1-aza-3,9-dioxa-8-oxo-bicyclo(4.3.0)nonan derivative, or via 1,3-dipolar cycloaddition of the nitrone form affording the 8-aza-3,7-dioxa-2-oxo-bicyclo(4.3.0)nonan derivative.

Isoxazolidin-5-one analogs of β-lactam antibiotics

Abstract Isoxazolidin-5-ones, readily available via conjugate addition–rearrangement of hydroxylamine to α , β -unsaturated sugar 1,5-lactones, react with aldehydes and diethoxymethyl acetate to afford 2,4,5-trisubstituted 1-aza-3,9-dioxa-8-oxo-bicyclo[4.3.0]nonanes. 4,5-Disubstituted 1-aza-2-butoxycarbonyl-3,9-dioxa-8-oxo-bicyclo[4.3.0]nonanes undergo base-catalyzed rearrangement to 4,6-disubstituted butyl 2,3-dideoxy-3- N -oxamate- d -ribohexaldono-1,5-lactones. The configuration of representative compounds: (2 S ,4 R ,5 S ,6 S ) 5-acetoxy-4-acetoxymethyl-1-aza-3,9-dioxo-2-methyl-8-oxo-bicyclo[4.3.0]nonane and butyl 4,6-di- O -(tert-butyldimethylsilyl)-2,3-dideoxy-3- N -oxamate- d -ribohexaldono-1,5-lactone were proved by X-ray crystallography.

An Entry to the Optically Pure β-Lactam Skeleton Based on 1,3-Dipolar Cycloaddition of Nitrones to 4,6-Di-O-Acetyl-2,3-Dideoxy-D-Threo-Hex-2-Enono-1,5-Lactone

Abstract Saturated lactone 8, easily available by 1,3-dipolar cycloaddition of nitrone 4 to unsaturated lactone 7 was transformed into the β-lactam 22having a polyol side chain at the C-3 position of the azetidinone ring. The same sequence of reactions, when applied to 9 and 10 failed to give the respective β-lactams owing to the removal of the nitrogen atoms from those molecules.