Alberto Brandi

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.

(1S,2S,7R,8aS)- and (1S,2S,7S,8aS)-trihydroxyoctahydroindolizine: Two new glycosidase inhibitors by nitrone cycloaddition strategy

Abstract The two new epimeric (1 S ,2 S ,7 R ,8a S )- and (1 S ,2 S ,7 S ,8a S )-1,2,7-trihydroxyoctahydroindolizines 4 and 5 have been synthesized via methylenecyclopropane-nitrone cycloaddition-rearrangement methodology employing an enantiomerically pure l -tartaric acid derived nitrone 7b . Highly stereoselective reductions of the intermediate indolizidinone 10b and final deprotection furnished the two title indolizidinetriols 4 and 5 , the inhibiting abilities of which toward 24 commercially available glycosidases were tested. Both 4 and 5 are good competitive inhibitors of amyloglucosidases with K i values of ca. 6 and 75 μM, respectively. Compared with (+)-lentiginosine 3, 4 and 5 are less powerful inhibitors but, in contrast to 3 , the (7 R )-hydroxy analogue 4 possesses a weak inhibiting activity toward α- l -fucosidase from bovine epididymis. A model to rationalize the structure-activity relationship of (+)-lentiginosine and the two new 7-hydroxylentiginosines toward glucoamylases is proposed on the basis of their structural comparison with known inhibitors and with the natural enzymes substrate amylose.

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.

Cycloadditions onto methylene- and alkylidenecyclopropane derivatives

Alkylidenecyclopropanes are a peculiar class of olefinic compounds characterized by a high ring strain, but at the same time a sufficient stability to permit their use in organic synthesis. The strain associated with the structure of these compounds is in general responsible for the good reactivity of the carbon-carbon double bond, even in sterically encumbered substrates. The key role of these compounds in organic synthesis resides in the exclusive, and by far the most useful, possibility of the introduction of a cyclopropyl ring in a more complex molecule through reactions onto the exocyclic double bond. For this reason the investigations on the synthesis and reactivity of these compounds has exploded in the last decade. This article will deal with all the reactions which involve the exocyclic double bond of alkylidenecyclopropanes in cycloaddition processes. Albeit most of the reactions are true pericyclic cycloaddition processes, also those reactions which lead to cycles by stepwise processes will be reported with comments on the mechanism.

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.

Stereodivergent Approach to Enantiopure Hydroxyindolizidines Through 1,3‐Dipolar Cycloaddition of 3‐Hydroxypyrroline N‐Oxide Derivatives

The (3S)-3-alkoxypyrroline N-oxides 7 and 27 were easily prepared from L-malic acid and used as starting materials for enantiospecific syntheses of stereodifferentiated polyhydroxyindolizidines. Selection of the appropriate modality (inter- or intramolecular) for 1,3-dipolar cycloaddition of the cyclic nitrone with 5-hydroxypentenoic acid derivatives gave access to either [1,8a]-trans- or -cis-hydroxyindolizidines 31 and 24, respectively, through elaboration of the primary cycloadducts. Moreover, the choice of the esterification conditions (Ph3P/DEAD or DIC/DMAP) used in linking the nitrone and the dipolarophile moieties in the intramolecular approach determined the absolute configuration of the final product, allowing the selective synthesis of both enantiomers, (−)-24 and (+)-24. This strategy required protection of the nitrone functionality to avoid racemization of the unprotected hydroxy nitrone during the introduction of the dipolarophile moiety. Protection/deprotection were achieved by cycloaddition/retro-cycloaddition reactions. The different propensity of some pyrrolo[1,2-b]isoxazolidines to undergo retro-cycloaddition with regeneration of the nitrone functionality was investigated both experimentally and by semiempirical and ab initio calculations on model compounds. The relative calculated activation energies were qualitatively in good agreement with the experimental observations. Fumaronitrile was found to be a convenient protecting reagent for the nitrone moiety and could be removed by retro-cycloaddition at lower temperatures than styrene and ethyl acrylate. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

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.