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Michael addition of the carbanion of the dithian 7 (derived from O-benzyl vanillin) on butenolide, afforded the saturated lactone 8. Alkylation of the latter with the benzylic bromide 6, followed by regeneration of the carbonyl group gave the α,β-disubstituted lactone 10. Reduction of the ketonic carbonyl group of compound 10 using NaBH4, followed by treatment with CF3CO2H and catalytic hydrogenolysis afforded (d,l)α-conidendrin 1.

The biphenyl 16 (obtained from α-bromopiperonal and the aromatic iodide 14 by a modified Ullmann reaction) was cyclized by intramolecular hydroxyalkylation to the isomeric alcohols 17a and 17b . These were oxidized using Jones' reagent, to afford the enol 18a , together with the tautomeric β-ketolactone Decarboxylation of this mixture using barium hydroxide, followed by Jones' oxidation gave the isomeric γ-ketoacids 11a and 11b . These were converted to (±)-steganone 1 using Raphael's method, in an overall yield of ca 10% starting from 3, 4, 5-trimethoxybenzaldehyde, and in 20,7% yield, starting from the biphenyl 16 .

Michael addition of the carbanion of the dithian 8 on butenolide, followed by alkylation with the benzylic bromide 11 and regeneration of the ketonic carbonyl group, gave the α,β-disubstitued lactone 13 . Reduction of the ketonic carbonyl of the latter using NaBH4, followed by treatment with CF3CO2H and catalytic hydrogenolysis afforded (±)-α-conidendrin 1 . DIBAL reduction of O -dibenzyl (±)-α-conidendrin 15 and subsequent methylation of the intermediate lactol and catalytic hydrogenolysis, gave methyl 1-epi-(±)-α-conidendral 3a . This compound is an epimer of methyl α-conidendral described by Cambie as having also the structure 3a . Sodium methoxide treatment of 15 followed by catalytic hydrogenolysis yielded (±)-β-conidendrin 2 . Sodium methoxide treatment of 15 followed by DIBAL reduction, subsequent methylation of the intermediate lactol and catalytic hydrogenolysis afforded methyl (±)-β-conidendral 4 , whose diacetate was identical with the compound of natural origin.

all-cis-6-(5-Hydroxy-6-methylpiperidin-2-yl)hexanoic acid [(±)-azimic acid] has been obtained in five steps from ethyl 7-methyl-3-oxo-oct-6-enoate.

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.

Regioselective introduction of a benzoxy group, in the benzylic position of the β-benzyl-γ-butyrolactone (R)-(+)-8, was achieved by tretment with NBS followed with benzyl alcohol. α-Alkylation of the lithium enolate of the resulting intermediate 11, with O -benzylvanillyl bromide 5, gave the trans disubstituted lactone 13. Catalytic hydrogenolysis (PdC) of 13 selectively split the aryl benzyl ether linkage, thus giving the compound 14. Intramolecular Friedel-Crafts cyclisation of the latter, using the benzoxy group as the leaving group, was induced with BF3. Et2O and afforded high yields of (−)-α-conidendrin 2.

Resume The use of lithium hexamethyldisilylamide (LHDS) in α-hydroxyalkylatoin of β-(3,4-methylenedioxybenzyl)-γ-butyrolactone gives high yields of (±) podorhizol and (±) epi-podorhizol as 1:1 diastereoisomer mixture. Cyclisation of both alcohols using trifluoroacetic acid afforded only (±) isodeoxypodophyllotoxin, an “all-trans” diastereopisomer of deoxypodophyllotoxin.

Kinetically controlled intramolecular α-hydroxyalkylation of a suitable diphenyl aldehyde lactone gave a dibenzocyclooctenolactone having a cis lactone-ring junction, such as (±)-picrostegane and (±)-isopicrostegane. Subsequent transformations led to the known (±)-isostegane. The chemical properties, the physical data and biological activity of these three diastereoisomers were compared with those of(±)-stegane, a fourth diastereoisomer obtained by hydrogenolysis of synthetic (±)-steganacin.

1,7-Dibromoheptane was used to alkylate both ketoesters 2 and 4 successively. Hydrolysis and decarboxylation of the resulting intermediate afforded the ethylenic diketone (6). Ozonolysis of the double bond of 6 gave the diketonic aldehyde (8). Alkaline condensation of nitroethane on the aldehydic carbonyl of the latter, followed by hydrogenation using a Pd–Pt catalyst, afforded 3-r-hydroxy-6-c-(10-oxododecyl)-2-c-methylpiperidine [(±)-prosafrinine] (1a) and (±)-3-epiprosafrinine (1b). The structures of 1a, 1b, and some analogues were confirmed by 13C NMR studies.

Resume On decrit la synthese du t-propyl-6 piperidinol-3 (dl-pseudo-conhydrine) en 3 etapes a partir de reactions courantes. Ce schema reactionnel est analogue a celui propose recemment pour la biosynthese de la propyl-2 piperidine (coniine).

α-Hydroxyalkylation of β-(3,4-methylenedioxybenzyl)-γ-butyrolactone (1) with 3,4,5-trimethoxybenzaldehyde, using lithium hexamethyldisilylamide as a base, affords a 1 : 1 mixture of (±)-podorhizol (4) and (±)-epipodorhizol (5); Jones's oxidation of this mixture gives (±)-podorhizone (6) in 63% overall yield.

Acetessigester (I) liefert uber eine Umsetzung mit Allylbromid, Hydrolyse, Decarboxylierung und Behandlung mit Athylenglykol das Ketal (II), dessen Allylgruppierung uber eine Ozonolyse zum Aldehyd (III) abgebaut wurde, der auch bei der Oxidation des Carbinols (IV) entsteht.

Die Kondensation des Pentanals (I) mit Nitromethan gibt den Alkohol (II), der zum Keton (III) hydrolysiert wird.

Trimethylsilyl trifluoromethanesulfonate (TMSOTf) was conveniently used to promote the reaction involving N-alkenyloxazolidin-2-ones and activated nitrones, leading to new 4-substituted 5-azaisoxazolidines in good to excellent yields. This TMSOTf-promoted procedure expanded the scope of reaction of N-vinyloxazolidin-2-ones and nitrones in complementary way to the corresponding classical 1,3-dipolar cycloaddition. Some of these adducts could not be obtained under thermal activation.

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 Buchwald's one-step copper-catalyzed vinylation using vinyl bromide. From the adducts, a two-step access to various unsymmetric aspartate derivatives was also described.

α-Hydroxyalkylation of β-(3,4-methylenedioxybenzyl)-γ-butyrolactone (1) with 3,4,5-trimethoxybenzaldehyde, using lithium hexamethyldisilylamide as a base, affords a 1 : 1 mixture of (±)-podorhizol (4) and (±)-epipodorhizol (5); Jones's oxidation of this mixture gives (±)-podorhizone (6) in 63% overall yield.

This thesis work is dealing with development of new methodologies in the field of 1,3-dipolar cycloaddition and focused on two main aspects :• Reactivity study of N-alkenyloxazolidin-2-ones as new aza-substituted dipolarophiles in an inverse 1,3-dipolar cycloaddition involving nitrones.• Use of original aspartic nitrones in cycloaddition involving different alkenes to afford a masked form of α-substituted aspartates by a functional chain.The first chapter describes the one-step synthesis of N-alkenyloxazolidin-2-ones using two modified literature methods : (i) copper-catalyzed N-vinylation using alkenyl bromides (ii) condensation of aldehyde. These simple, general, high-yield and straightforward methods provide a wide range of N-alkenyloxazolidin-2-ones.The second chapter demonstrates the high reactivity of N-alkenyloxazolidin-2-ones toward a variety of nitrones under thermal (with or without solvent) and TMSOTf-mediated conditions. Original diversely substituted 5-aza-isoxazolidines have been obtained in high yields. In contrast, the low stereoselectivities could be explained by Z−E isomerization of activated nitrones and by conformational flexibility of N-alkenyloxazolidin-2-ones. This limitation has been resolved by using the geometry-fixed chiral Tamura's nitrone : the trans-β adducts were obtained with excellent selectivities.The third chapter deals with the transformation of adducts derived from N-benzyl-α-carbonyloxyethylnitrone into carboxy-differentiated aspartates derivatives. This sequence consists in two steps : (i) isoxazolidine ring-opening via N-quaternization (ii) chemoselective attack of a heteronucleophile on amide function. The carboxy-differentiated aspartates were obtained in high yields, with high enantiomeric excess in non-racemic series, and a high degree of functional diversity at the ω position (ester, amide, acid).In the fourth chapter, the study is extended to the 1,3-dipolar cycloaddition between original β,β-difluorinated N-vinyloxazolidin-2-ones and N-benzyl-α-carbonyloxyethylnitrone. The 4,4-difluoro-5-aza-isoxazolidines were obtained in high yields despite low reactivity, and with low stereoselectivity probably due to a non-concerted mechanism.The last chapter illustrates an original access to α,α-disubstituted α-amino acids via 1,3-dipolar cycloaddition involving new aspartic nitrones of a unique E-configuration. This type of nitrones − easily prepared by simple addition of an N-benzylhydroxylamine to the corresponding acetylenedicarboxylate – reacts with alkenes of different electronic natures to afford a set of original isoxazolidines in excellent yields and regioselectivities under thermal cycloaddition. In the case of alkyl vinyl ethers, high trans selectivities were observed. Asymmetric versions have been tried with chiral nitrones or chiral alkyl vinyl ethers, resulting in excellent yields and good to excellent trans selectivities. Starting from these adducts, a first successful asymmetric access to α,α-disubstituted α-amino acids derivatives was achieved in three steps. The diversification of this methodology has been exemplified by using a carboxy-differentiated aspartic nitrone.; Lors de ces travaux de thèse, nous nous sommes intéressés à de nouveaux développements méthodologiques en cycloaddition 1,3-dipolaire de nitrones suivant deux axes principaux :• l'étude de la réactivité des N-alcényloxazolidin-2-ones en tant que nouveaux dipolarophiles aza-substitués en cycloaddition 1,3-dipolaire à demande inverse vis-à-vis de nitrones.• la mise en jeu de nitrones aspartiques originales en cycloaddition vis-à-vis de différents alcènes pour fournir des précurseurs d'aspartates α-substitués par une chaîne fonctionnelle.Dans un premier temps, nous avons mis au point deux méthodes inspirées de celles de la littérature en partant d'une oxazolidin-2-ones pour synthétiser les N-alcényloxazolidin-2-ones: (i) vinylation cupro-catalysée utilisant un bromure d'alcényle, (ii) condensation avec un aldéhyde. Ces méthodes simples, générales, directes et à hauts rendements nous ont permis d'accéder aux N-alcényloxazolidin-2-ones de structure diverse.Ces N-alcényloxazolidin-2-ones ont montré une grande réactivité en tant que dipolarophile vis-à-vis de diverses nitrones dans différentes conditions : thermiques (avec/sans solvant) et promues par TMSOTf. Les 5-aza-isoxazolidines diversement substituées originales ont été obtenues avec des rendements élevés mais de faibles stéréosélectivités. Cette limitation − due à l'instabilité configurationnelle des nitrones activées et à la flexibilité conformationnelle des N-alcényloxazolidin-2-ones − a été résolue par utilisation de la nitrone chirale à géométrie fixe de Tamura : les adduits trans-β sont obtenus avec d'excellents sélectivitésLa tranformation des adduits issus de la N-benzyl-α-carbonyloxyéthylnitrone en dérivés aspartates carboxy-différenciés a été ensuite étudiée par une séquence en deux étapes (i) ouverture du cycle isoxazolidinique en aspartimide via N-quaternarisation par benzylation (ii) attaque chimiosélective d'un hétéronucléophile sur la fonction amide. Les aspartates carboxy-différenciés ont été obtenus avec de bons rendements, des excès énantiomériques élevés en version non-racémique, et un grand degré de diversité fontionnelle en ω (ester, amide, acide).L'étude a été étendu à la cycloaddition 1,3-dipolaire des N-vinyloxazolidin-2-ones β,β-difluorées originales avec la N-benzyl-α-carbonyloxyéthylnitrone : les 4,4-difluoro-5-aza-isoxazolidines sont obtenues avec de bons rendements malgré une faible stéréosélectivité probablement due à un mécanisme non-concerté.Notre étude a été complétée par l'accès à des dérivés d'α-aminoacides α,α-disubstitués via cycloaddition 1,3-dipolaire mettant en jeu de nouvelles nitrones aspartiques d'une stablilité configurationnelle inédite. Ce type de nitrones − préparé facilement par addition d'une N-benzylhydroxylamine sur un acétylènedicarboxylate – a montré une grande réactivité vis-à-vis d'une large gamme d'alcènes de différents natures électroniques. Les adduits issus des éthers vinyliques ont été obtenus avec de hauts sélectivités trans. L'extension asymétrique utilisant soit un éther vinylique chiral , soit une nitrone chirale a été effectuée et a permis l'obtention facile des adduits diastéréomériquement enrichis. A partie de ces adduits, un premier accès réussi aux dérivés aminoacides α,α-disubstitués a été réalisé en trois étapes. La diversification de cette méthodologie a été effectuée en utilisant une nitrone aspartique carboxy-différenciée.