Stefano Cicchi

Novel Syntheses of Azetidines and Azetidinones

2.1.5. Electrophilic Attack on CdC 3994 2.1.6. NH Insertions in Diazo Compounds 3994 2.1.7. Pd Catalyzed Cyclizations 3994 2.2. Cyclizations by C-C Bond formation 3995 2.2.1. Nucleophilic Displacement of Halides 3995 2.2.2. Cyclizations Involving CdO Group 3995 2.3. Cycloadditions 3996 2.4. Ring Rearrangements 3997 2.4.1. Rearrangements of Four-Membered Rings 3997 2.4.2. Rearrangements of Larger Rings 3998 2.5. Reduction of Azetidin-2-ones 3998 2.6. Miscellaneous Syntheses 3999 2.7. Important Classes of Compounds 4000 2.7.1. Natural Products 4000 2.7.2. Azetidine Carboxylic Acids 4001 2.7.3. Exomethylene Azetidines 4002 2.7.4. Ligands for Metal-Catalyzed Reactions and Chiral Auxiliaries 4003

Stereocontrolled Cyclic Nitrone Cycloaddition Strategy for the Synthesis of Pyrrolizidine and Indolizidine Alkaloids

The synthesis of polyhydroxylated indolizidines and pyrrolizidines belonging to the class of iminosugars, endowed with a vast and assorted biological activity, can be achieved in a straightforward manner by a general strategy consisting of a highly stereoselective 1,3-dipolar cycloaddition of polyhydroxylated pyrroline-N-oxides followed by simple transformations of the isoxazolidine adducts. The strategy allows the complete control of the relative and absolute stereochemistry of the numerous stereogenic centers decorating these compounds.

1,3-Aminoalcohols by reductive cleavage of isoxazolidines with molybdenum hexacarbonyl

Abstract Isoxazolidines are reductively cleaved to 1,3-aminoalcohols by reacting with Mo(CO) 6 and water. Reaction conditions are simple, mild and selective giving good yields of highly functionalized products with complete retention of configuration of the stereocenters. The reduction fails when steric hindrance is experienced by the nitrogen atom.

Manganese dioxide oxidation of hydroxylamines to nitrones

Abstract Several structurally differentiated N,N-dialkylhydroxylamines were oxidised to the corresponding nitrones using MnO2. Manganese dioxide revealed an efficient and mild reagent for oxidation of hydroxylamines, showing a level of regioselectivity comparable to HgO. Its non-toxicity makes MnO2 the reagent of choice for replacing HgO in this oxidation.

Straightforward Access to Enantiomerically Pure, Highly Functionalized Pyrrolizidines by Cycloaddition of Maleic Acid Esters to Pyrroline N-Oxides Derived from Tartaric, Malic and Aspartic Acids − Synthesis of (−)-Hastanecine, 7-epi-Croalbinecine and (−)-Croalbinecine

The cycloaddition reactions of dimethyl maleate to three functionalized enantiopure pyrroline N-oxides and one related racemic nitrone are reported. The study of the diastereoselectivity in the cycloaddition has been carried out by ample variation of the substituents at both the dipole and dipolarophile counterparts. The major cycloadducts, derived from the preferred exo-anti transition states and formed with 62−90% diastereoselectivity, have been subjected to Mo(CO)6-induced reductive ring-opening to afford directly highly functionalized enantiopure pyrrolizinone derivatives, valuable as synthetic intermediates. Applications of this strategy to a straightforward formal synthesis of (−)-hastanecine and to the total synthesis of the novel 7-epi-croalbinecine and of (−)-croalbinecine are reported.

Synthesis of new enantiopure γ-aminoalcohols: their use as catalysts in the alkylation of benzaldehyde by diethylzinc

Abstract The straightforward synthesis of new enantiopure γ-aminoalcohols through 1,3-dipolar cycloadditon to a chiral cyclic nitrone derived from l -malic acid is described. Results of the application of these compounds as chiral catalysts in the alkylation of benzaldehyde with diethylzinc are also reported.

Synthesis of lentiginosine by stereoselective chiral nitrone cycloaddition and thermal rearrangement of strained spiroisoxazolidine

Abstract The total synthesis of Lentiginosine (3) is reported. The strategy is based on the 1,3-dipolar cycloaddition of a TBDPS protected 3,4-dihydroxypyrroline N-oxide to methylenecyclopropane followed by the thermal rearrangement of the resulting spirocyclopropaneisoxazolidine to give the functionalised indolizidine skeleton. The compound shows an [α]D value identical, but opposite in sign, with that reported for the natural isomer which has been assigned the same absolute configuration.

A comparative study of the stereoselective addition of trimethylsilyl cyanide and diethylaluminum cyanide to chiral cyclic nitrones

The mild cyanating agent trimethylsilyl cyanide adds with total stereoselectivity to α-alkoxy cyclic nitrones to afford the corresponding trans-hydroxyaminonitriles. The addition of Lewis acids to precomplexing the nitrones does not affect the stereoselectivity of these additions significantly. In all of the cases examined, excellent yields of diastereomerically homogeneous products were obtained. On the other hand, the use of diethylaluminum cyanide as cyanating agent leads to low diastereoselectivities. Both NMR studies and theoretical calculations show that whereas the addition of trimethylsilyl cyanide takes place through a concerted mechanism, in the addition of diethylaluminum cyanide, a complex is formed prior to the intramolecular delivery of the cyanide ion.

A Straightforward Route to Enantiopure Pyrrolizidines and Indolizidines by Cycloaddition to Pyrroline N-Oxides Derived from the Chiral Pool

Enantiomerically pure, five membered cyclic nitrones, easily obtained in large amounts from protected hydroxyacids and aminoacids such as D- and L-tartaric, L-malic, and L-aspartic acids, give cycloaddition reactions with a good diastereocontrol. The adducts of L-malic and L-aspartic acids derived from addition of nitrones to dimethyl maleate and g-crotonolactone were easily converted into enantiopure pyrrolizidinones, which can be transformed into polyhydroxypyrrolidines or polyhydroxypyrrolizidines, both interesting compounds as potential glycosidase inhibitors. The method is suitable for natural products synthesis as exemplified by a straightforward and convenient access to the pyrrolizidine alkaloid necine base (–)-hastanecine, as well as to indolizidine alkaloids, i.e. (+)- lentiginosine.

Self-sorting chiral organogels from a long chain carbamate of 1-benzyl-pyrrolidine-3,4-diol

(3S,4S)-1-benzylpyrrolidine-3,4-diyl bis(dodecylcarbamate), a pyrrolidine ring bearing two long carbon chains connected by carbamate functionalities, is the origin of stable gels in both polar and apolar solvents. Several experimental and theoretical techniques (cryo-TEM, AFM, DSC, circular dichroism (CD), molecular mechanics calculations and CD simulations) were used to describe the formation and the characteristics of the chiral supramolecular structures and fibers constituting the gel. The chirality at both supramolecular and microscopic level depends on the configuration of the stereogenic centers of the pyrrolidine unit. The gels formed by the two enantiomers of the gelator and their mixtures display enantiomeric discrimination resulting in a self-sorting process. In fact, separate fibers of opposite helicity are obtained, which suggests this class of compounds has strong potential for realizing functionalized chiral architectures.