Robert Dhal

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.

Syntheses totales et etudes de lignanes biologiquement actifs—I : Application de la reaction d'ullmann a la synthese de biaryles precurseurs de lignanes bisbenzocyclooctadienes☆

Abstract Several biaryls bearing various substituents on both rings were synthesized in a preparative fashion, and in yields up to 88% by a technical improvement on the classical Ullmann reaction. All these biaryls bear reactive functional groups (i.e. formyl, methoxycarbonyl, dimethoxycarbonylpropyl and butanolidylmethyl) in both the o and o′ positions. The biaryls 9, 13, 21 and 26–33 are plausible synthons for bisbenzocyclooctadiene lignans such as schizandrin and steganacin.

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.

New agents of biaryl oxidative coupling in fluoro acid medium. VI. Application to the synthesis of phenolic bisbenzocyclooctadiene lignans

Abstract A systematic study of redox couples in fluoro acid medium has been carried out for the oxidative coupling of bisbenzocyclooctadiene lignan precursors. Tl2O3 and Re2O7 were found to be the more efficient reagents with precursors possessing methylenedioxy substituents for the former and only methoxy groups for the latter. Finally, oxidative coupling of a phenolic dibenzylbutane led to a mixture of two BBCODs, resulting from para and ortho coupling to the phenolic group.

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

Synthesis of non-phenolic bisbenzocyclooctadiene lignan lactones and aporphinic alkaloids, by oxidative coupling with new agents in fluoro acid medium. IV.☆

Abstract A systematic study of oxidants used in fluoro acid medium allowed us to increase notably the number of efficient reagents for the non-phenolic oxidative coupling of lignan and alkaloid precursors. If dibenzylbutanolide had no methylenedioxyle group, Re 2 O 7 and RuO 2 .2H 2 O were the most efficient. With a methylenedioxyle group, best results were obtained with Tl 2 O 3 , Mn(OAc) 3 .2H 2 O and Ce(OH) 4 . Finally, aporphines were obtained with good yields with Ce(OH) 4 , RuO 2 .2H 2 O and Fe(OH)(OAc) 2 .

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

Total syntheses of (−)-trachelogenin, (−)-nortrachelogenin and (+)-wikstromol

Abstract The title compounds were obtained by α-hydroxylation of the corresponding α,β-dibenzyl-γ-butyrolactones (lignans of synthetic origin), and were correlated to (±)-methyltrachelogenin 9 whose relative structure was definitely established by X-ray cristallography. (-)-Trachelogenin 1 and (-)-nortrachelogenin 12 thus have the (8S,8′S) absolute configuration, whereas (+)-nortrachelogenin 20 (or wikstromol) has the (8R,8′R) absolute configuration.

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.