Arnaud Martel

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.

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.

Enantioselective Ruthenium-Catalyzed 1,3-Dipolar Cycloadditions between C-Carboalkoxy Ketonitrones and Methacrolein: Solvent Effect on Reaction Selectivity and Its Rational

A catalytic 1,3-dipolar cycloaddition between carboalkoxy ketonitrones and methacrolein under the effect of chiral ruthenium Lewis acid (R,R-1) was developed with high regio-, diastereo-, and enantiocontrol. The diastereochemical outcome of the cycloaddition reaction is marked by a significant solvent effect, and a divergent endo or exo control can be tuned by an appropriate choice of both the solvent and the N- and O-substituents of the ketonitrone. A rationale of the solvent effect, based on the computational study of the interactions between the methacrolein-Ru complex and its counteranion (SbF6(-)), is proposed to explain the selectivities obtained.

Asymmetric synthesis of α,α-disubstituted amino acids by cycloaddition of (E)-ketonitrones with vinyl ethers.

Original acyclic (E)-α,α-dialkylketonitrones bearing a chiral auxiliary on their nitrogen atom were synthesized and successfully employed for the asymmetric synthesis of α,α-disubstituted amino acids using regio- and stereocontrolled 1,3-dipolar cycloaddition reactions with vinyl ethers. N-Glycosyl chiral auxiliaries were found to provide excellent exo- and π-facial stereocontrol. The obtained enantiopure cycloadducts were selectively transformed into functional α,α-disubstituted amino acids and related β-peptides through the highly regioselective opening of an intermediate quaternary anhydride.

Low temperature syntheses of thioketals from enol ethers and carbonyl compounds

A dithioacetalisation procedure at low temperature using TMSOTf as the promoter is described. This method proved highly efficient for unprecedented transprotection of ketone enol ethers and was successfully applied to polyfunctional sensitive substrates.

Eu(fod)3 and SnCl4-catalyzed heterocycloadditions of O-silyl enol ethers deriving from cyclic ketones

Abstract O-t -Butyldimethylsilyl enol ethers deriving from simple cyclic ketones acted as efficient dienophiles in the Lewis acid-catalyzed heterocycloadditions with methyl benzylidenepyruvate 1 . Good selectivities were observed with cyclohexanone derivatives. Using Eu(fod) 3 , the dienophile 2b led to the expected endo adduct 3b (93–97%). When using SnCl 4 , the major product (89–95%) was found to be the “abnormal” adduct 5b with a trans ring junction.