Gilles Dujardin

N-Benzyl Aspartate Nitrones: Unprecedented Single-Step Synthesis and [3 + 2] Cycloaddition Reactions with Alkenes

N-benzyl aspartate nitrones 2, prepared by addition of N-benzylhydroxylamine to dialkyl acetylenedicarboxylates 1, underwent [3 + 2] thermal cycloaddition with a wide range of alkenes to afford isoxazolidines 4 bearing a polyfunctionalized quaternary center. Under these uncatalyzed conditions, the trans stereocontrol observed with vinyl ethers is higher than that obtained with all acyclic activated nitrones reported to date. The first asymmetric access to a type-4 pure adduct was achieved starting from the chiral aspartate nitrone derived from (S)-alpha-methylbenzylhydroxylamine.

Isoxazolidine: A Privileged Scaffold for Organic and Medicinal Chemistry

The isoxazolidine ring represents one of the privileged structures in medicinal chemistry, and there have been an increasing number of studies on isoxazolidine and isoxazolidine-containing compounds. Optimization of the 1,3-dipolar cycloaddition (1,3-DC), original methods including electrophilic or palladium-mediated cyclization of unsaturated hydroxylamine, has been developed to obtain isoxazolidines. Novel reactions involving the isoxazolidine ring have been highlighted to accomplish total synthesis or to obtain bioactive compounds, one of the most significant examples being probably the thermic ring contraction applied to the total synthesis of (±)-Gelsemoxonine. The unique isoxazolidine scaffold also exhibits an impressive potential as a mimic of nucleosides, carbohydrates, PNA, amino acids, and steroid analogs. This review aims to be a comprehensive and general summary of the different isoxazolidine syntheses, their use as starting building blocks for the preparation of natural compounds, and their main biological activities.

The first semi-synthesis of enantiopure homoharringtonine via anhydrohomoharringtonine from a preformed chiral acyl moiety☆☆☆

Abstract (2′ R ,3 S ,4 S ,5 R )-(−)-Homoharringtonine 2 was synthesized by direct esterification of cephalotaxine, using the activatedforms of suitably substituted tetrahydropyrancarboxylic acids as sterically compact chiral side-chain precursors, followed by selective ring opening of the resulting (2′ R ,3 S ,4 S ,5 R )-(−)-anhydrohomoharringtonine 6 . Both enantiomers of the anhydro acyl moiety were prepared either by asymmetric α-hydroxyalkylation of the suitably substituted ethylenic α-ketoester 7 followed by acidic cyclisation, or by resolving the corresponding racemic mixture via formation of diastereomers with (−)-quinine. Racemic cephalotaxine, as well as both its enantiomers, were prepared from natural -partially racemized- (−)-cephalotaxine 1 .

Access to α-Substituted Amino Acid Derivatives via 1,3-Dipolar Cycloaddition of α-Amino Ester Derived Nitrones

Amino acid derived nitrones were conveniently synthesized in good-to-excellent yields by condensation of alpha-ketoesters with N-benzylhydroxylamine. The cycloaddition reactions of these nitrones with different alkenes were investigated under thermal solvent-free conditions. Considering conversions, yields, and selectivities, alkyl vinyl ethers have proven to be valuable partners to achieve this transformation, which creates a tetrafunctionalized stereogenic quaternary center. From the adducts derived from vinyl ethers, a three-step access to highly functionalized alpha-substituted amino acid derivatives is described.

Hetero-Diels-Alder reactions of cyclic ketone derived enamide. A new and efficient concept for the asymmetric Robinson annulation.

Chiral enamides, easily prepared in one step from a cyclic ketone and an oxazolidinone, are successfully employed in high-yielding, endo, and facially selective Hetero-Diels-Alder reactions involving activated oxadienes and Sievers reagent as catalyst. From the resulting bicyclic heteroadducts, a novel and efficient asymmetric modification for the Robinson annulation of cyclic monoketones is described.

1,3-Dipolar Cycloadditions of Nitrones to Heterosubstituted Alkenes. Part 1: Oxa and Aza-substituted Alkenes

Introduction ..........................................................................................389 I. Reactions with Oxa-substituted Alkenes.............................................391 1. Nitrones Activated by Electron-withdrawing Groups ..............................391 a) Thermal Conditions.......................................................................392 i. Acyclic Nitrones .....................................................................392 ii. Cyclic Nitrones ......................................................................395 b) Brønsted Acid-catalyzed Conditions ...............................................397 c) Lewis Acid-catalyzed Conditions ....................................................397 i. Europium(III) Catalyst ...........................................................397 ii. Copper(II) and Zinc(II) Catalysts ............................................398 2. C-Aryl-substituted Nitrones...................................................................399 a) Thermal Conditions.......................................................................399 b) Lewis Acid-catalyzed Conditions ....................................................399 i. TMSOTf-promoted Reactions ..................................................399 ii. Boron(III) Catalyst .................................................................400 iii. Aluminium(III) Catalyst ..........................................................401 c) Brønsted Acid-catalyzed Conditions ...................................................403 3. Other Nitrones .....................................................................................404 a) Thermal Conditions.......................................................................404 i. Acyclic Nitrones .....................................................................404 ii. Cyclic Nitrones ......................................................................408 b) Lewis Acid-catalyzed Conditions ....................................................410 i. Titanium(IV) Catalyst .............................................................410 ii. Aluminium(III) Catalyst ..........................................................410 iii. Trimethylsilyl Trifluoromethanesulfonate ..................................411 iv. Boron Catalyst .......................................................................411 II. Reaction with Aza-substituted Alkenes...............................................412 1. Enamines as Dipolarophile ...................................................................412 2. Enamides as Dipolarophiles ..................................................................413

1,3-Dipolar Cycloadditions of Nitrones to Hetero-substituted Alkenes Part 2: Sila-, Thia-, Phospha- and Halo-substituted Alkenes

Introduction .....................................................................................3 I. Reactions with Sila-substituted Alkenes ............................................3 1. Vinyltrimethylsilane as Dipolarophile ....................................................... 3 2. α-Substituted Vinyltrimethylsilanes as Dipolarophiles ............................... 8 3. β-Substituted Vinyltrimethylsilanes as Dipolarophiles ............................... 9 4. Vinylalkoxysilanes as Dipolarophiles .......................................................10 II. Reactions with Thia-substituted Alkenes ......................................... 13 1. Vinyl Sulfides and Ketene Dithioacetals as Dipolarophiles ........................13 2. Vinyl Sulfoxides as Dipolarophiles ..........................................................15 3. Vinyl Sulfones as Dipolarophiles .............................................................20 a) Phenyl Vinyl Sulfone towards Acyclic Nitrones ......................................20 b) Phenyl Vinyl Sulfone towards Cyclic Nitrones........................................22 c) Substituted Acyclic Vinyl Sulfones.........................................................24 d) Cyclic Vinyl Sulfones...........................................................................28 4. Vinyl Sulfonates as Dipolarophiles ..........................................................30 III. Reactions with Phospha-substituted Alkenes ................................... 32 1. Vinylphosphines and Vinylphosphonium Salts as Dipolarophiles ..............32 2. Vinylphosphine Oxides, Chalcogenides and Vinylphosphinates as Dipolarophiles....................................................................................34 a) Achiral Phosphine Derivatives .............................................................34 b) Chiral Phosphine Derivatives ..............................................................38 3. Vinylphosphonates as Dipolarophiles ......................................................44 a) Unsubstituted Vinylphosphonates Towards Acyclic Nitrones....................44 b) αand β-Substituted Vinylphosphonates Towards Acyclic Nitrones..........46 c) Vinylphosphonates Towards Cyclic Nitrones ..........................................47 IV. Reactions with Halo-substituted Alkenes......................................... 48 1. Fluoro-substituted Alkenes .....................................................................48 a) Terminal Polyfluoroalkenes: 1,1-Difluoroolefins as Dipolarophiles ..........48 b) Internal Perfluoroalkenes as Dipolarophiles ..........................................49

1,3-Dipolar Cycloaddition of N-Substituted Dipolarophiles and Nitrones: Highly Efficient Solvent-Free Reaction

New isoxazolidines were synthesized in good to excellent yields by 1,3-dipolar cycloaddition of N-vinylamide dipolarophiles and nitrones. Strikingly, solvent-free conditions gave high conversion and yields, shortened reaction time, and minimized degradation products. N-Vinyloxazolidin-2-one and its analogues used in these cycloaddition reactions were conveniently prepared in excellent yields by a modified version of Buchwalds one-step copper-catalyzed vinylation using vinyl bromide. From the adducts, a two-step access to various unsymmetric aspartate derivatives was also described.

Efficient mercury-free preparation of vinyl and isopropenyl ethers of chiral secondary alcohols and α-hydroxyesters

Abstract Mixed acetals 2a-h and 5a-d , readily deriving from the α-chiral alcohols 1a-h and ethyl vinyl ether or isopropenyl methyl ether, underwent selective elimination of primary alcohol upon treatment with triethylamine and trimethylsilyl trifluoromethanesulfonate, and thus afforded good to high yields of the chiral enol ethers 3a-h and 6a-d , respectively.

Synthèse asymétrique et configuration absolue de dihydropyranes substitués, par hétérocycloaddition intermoléculaire d'éthers vinyliques chiraux

Abstract The alkyl vinyl ethers 2b–8b (deriving from the alcohols 2a–8a) smoothly reacted with methyl E-benzylidenepyruvate 10 in the presence of catalytic amounts of Eu(fod)3 or Yb(fod)3 in refluxing hexane, thus leading to the dihydropyran endo adducts 13–19 in high yields (80–95%). The endo -cycloadducts 13–17 were obtained with diastereofacial selectivities (ds) ranging from 76/24 to 87.5/12.5. Asymmetric induction was found to culminate with the vinyl ether (−)-7b deriving from n -butyl (R)-(⊃-mandelate: the best ds (92.5/7.5) was obtained for the corresponding adduct 18 after 6 days at room temperature. The absolute configurations of the major isomers of the dihydropyrans 16–18, 20 and 21 were established by oxydative degradation to optically active α-phenylsuccinic acid derivatives.