Franca M. Cordero

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.

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.

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.

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.

The novel proapoptotic activity of nonnatural enantiomer of Lentiginosine

D-(-)-Lentiginosine [(-)-4], the nonnatural enantiomer of the iminosugar indolizidine alkaloid L-(+)-lentiginosine, acts as apoptosis inducer on tumor cells of different origin, in contrast to its natural enantiomer. Although D-(-)-4 exhibited a proapoptotic activity towards tumor cells at level lower than the chemotherapeutic agent, SN38, it was less proapoptotic towards normal cells and less cytotoxic. Apoptosis induced by D-(-)-4 was caspase-dependent, as shown by the increased expression and activity of caspase-3 and -8 in treated cells, and by inhibition following treatment with the pan caspase inhibitor, ZVAD-FMK. This study highlighted how a natural iminosugar alkaloid and its synthetic enantiomer, which were simply known for their inhibition against a fungal glucoamylase, could behave in a complete different way when tested towards cell growth and death of cells of different origin.

A new synthesis of (2S)-4-oxopipecolic acid by thermal rearrangement of enantiopure spirocyclopropaneisoxazolidine

Abstract A novel synthesis of (2S)-4-oxo-pipecolic acid is reported. The synthetic route employs as a key step the diastereoselective cycloaddition of the N-glycosylnitrone 7 to methylenecyclopropane followed by thermal rearrangement of the spirocyclopropaneisoxazolidine 8a . Stereoselective reduction of the N-BOC methyl ester of 4-oxopipecolic acid by L-selectride ® gives the protected cis-4-hydroxy-pipecolic acid 14 .

The isoxazoline-5-spirocyclopropane route to (±)-Pumiliotoxin C

Abstract A new total synthesis of (±)-Pumiliotoxin C has been achieved by the key thermal rearrangement of an appropriate 5-spirocyclopropane isoxazoline.

The regioselectivity of nitrone and nitrile oxide cycloadditions to alkylidenecyclopropanes

Abstract The 1,3-dipolar cycloaddition of nitrile oxides and a nitrone to alkylidencyclopropanes 1–5 ,used as model for methylenecyclopropanes substituted with aryl group ( 1 ), electron-releasing groups ( 2 and 3 ) and electron-attracting groups ( 4 and 5 ) is reported. The cycloaddition to alkylidenecyclopropanes 1–3 gives prevalently or exclusively adducts bearing the cyclopropane ring on the C4 position of the isoxazoline (isoxazol idine) ring, whereas methoxycarbonyl substituted methylenecyclopropanes 4 and 5 give adducts with the opposite regiochemistry. The high regioselectivity observed in the case of dialkyl substituted methylenecyclopropanes raises the question of the role played by the cyclopropylidene ring in these cycloadditions. A FMO approach based both on semiempirical and ab initio calculations is unable to explain this “cyclopropylidene effect”.