The present dissertation covers the total synthesis of viridiofungin triesters and studies toward the total synthesis of xeniolide F. In both cases, sigmatropic rearrangements of α-allyloxy substituted α,β-unsaturated esters are employed: for the viridiofungin ester synthesis a [2,3]-Wittig rearrangement and for the xeniolide F synthesis a catalytic asymmetric Claisen rearrangement CAC. For both rearrangement reactions the historical development, main characteristic and important variations are discussed. The viridiofungin triester synthesis represents a convergent and highly flexible route toward these natural products. The [2,3]-Wittig rearrangement allowed the diastereoselective synthesis of the polar head group with two adjacent stereogenic centers. The E-configured double bond was formed by a Julia-Kocienski olefination. During the studies toward the total synthesis of xeniolide F a new, diastereoselective strategy for the generation of allyl vinyl ethers with E-configured vinyl ether double bond was established employing rhodium catalyzed OH-insertion and an E-selective Horner-Wadsworth-Emmons olefination. Under the conditions of the catalytic asymmetric Claisen rearrangement (CAC) this highly substituted allyl vinyl ether rearranged diastero- and enantioselectively to the corresponding a-keto ester. This example clearly illustrates the high potential of the CAC as synthetic tool for natural product synthesis. / In der vorliegenden Arbeit wird die Totalsynthese von Tirestern der Viridiofungine A, A2 und A4 sowie die Synthese eines Schlüsselintermediates für die Totalsynthese von Xeniolid F dargestellt. In beiden Fällen wird ausgehend von einem α-allyloxysubstituierten α,β-ungesättigten Ester eine Umlagerungsreaktion als Schlüsselschritt eingesetzt: im Falle der Viridiofunginester eine diastereoselektive [2,3]-Wittig-Umlagerung, bei den Arbeiten zur Totalsynthese von Xeniolid F eine diastero- und enantioselektive, katalytische Claisenumlagerung. Für beide Umlagerungsreaktionen werden ausführlich die theoretischen Hintergründe sowie die historische Entwicklung und wichtige Varianten besprochen. Mit der Viridiofungintriestersynthese wird eine konvergente und bezüglich der lipophilen Seitenkette sehr flexible Syntheseroute vorgestellt. Die [2,3]-Wittig-Umlagerung konnte dabei erfolgreich für die diastereoselektive Synthese der hochsubstituierten, polaren Kopfgruppe der Viridiofunginester mit zwei benachbarten stereogenen Zentren (davon eines quartär) eingesetzt werden. Zur Bildung der E-konfigurierten Doppelbindung wurde die Julia-Kocienskie-Olefinierung ausgenutzt. Bei den Arbeiten zur Totalsynthese von Xeniolid F wurde eine neuartige Strategie zur diastereoselektiven Synthese eines Allylvinylethers mit E-konfigurierter Vinyletherdoppelbindung eingesetzt. Die Horner-Wadsworth-Emmons-Olefinierung (HWE-Olefinierung) generierte dabei E-selektiv die Vinyletherdoppelbindung. Das für die HWE-Olefinierung benötigte Phosphonat wurde durch rhodiumkatalysierte OH-Insertion aus einem Allylalkohol und einem Diazaphosphonoacetat hergestellt. Der hochsubstituierte Allylvinylether wurde unter den Bedingungen der katalytisch asymmetrischen Claisenumlagerung umgesetzt und führte mit exzellenter Diastereo- und Enantioselektivität zum entsprechenden α-Ketoester. Anhand dieses Beispiels konnte das Potential der katalytisch asymmetrischen Claisenumlagerung zum Aufbau von hochfunktionalisierten Bausteinen für die Naturstoffsynthese verdeutlicht werden.

The present dissertation covers the total synthesis of viridiofungin triesters and studies toward the total synthesis of xeniolide F. In both cases, sigmatropic rearrangements of α-allyloxy substituted α,β-unsaturated esters are employed: for the viridiofungin ester synthesis a [2,3]-Wittig rearrangement and for the xeniolide F synthesis a catalytic asymmetric Claisen rearrangement CAC. For both rearrangement reactions the historical development, main characteristic and important variations are discussed. The viridiofungin triester synthesis represents a convergent and highly flexible route toward these natural products. The [2,3]-Wittig rearrangement allowed the diastereoselective synthesis of the polar head group with two adjacent stereogenic centers. The E-configured double bond was formed by a Julia-Kocienski olefination. During the studies toward the total synthesis of xeniolide F a new, diastereoselective strategy for the generation of allyl vinyl ethers with E-configured vinyl ether double bond was established employing rhodium catalyzed OH-insertion and an E-selective Horner-Wadsworth-Emmons olefination. Under the conditions of the catalytic asymmetric Claisen rearrangement (CAC) this highly substituted allyl vinyl ether rearranged diastero- and enantioselectively to the corresponding a-keto ester. This example clearly illustrates the high potential of the CAC as synthetic tool for natural product synthesis. / In der vorliegenden Arbeit wird die Totalsynthese von Tirestern der Viridiofungine A, A2 und A4 sowie die Synthese eines Schlüsselintermediates für die Totalsynthese von Xeniolid F dargestellt. In beiden Fällen wird ausgehend von einem α-allyloxysubstituierten α,β-ungesättigten Ester eine Umlagerungsreaktion als Schlüsselschritt eingesetzt: im Falle der Viridiofunginester eine diastereoselektive [2,3]-Wittig-Umlagerung, bei den Arbeiten zur Totalsynthese von Xeniolid F eine diastero- und enantioselektive, katalytische Claisenumlagerung. Für beide Umlagerungsreaktionen werden ausführlich die theoretischen Hintergründe sowie die historische Entwicklung und wichtige Varianten besprochen. Mit der Viridiofungintriestersynthese wird eine konvergente und bezüglich der lipophilen Seitenkette sehr flexible Syntheseroute vorgestellt. Die [2,3]-Wittig-Umlagerung konnte dabei erfolgreich für die diastereoselektive Synthese der hochsubstituierten, polaren Kopfgruppe der Viridiofunginester mit zwei benachbarten stereogenen Zentren (davon eines quartär) eingesetzt werden. Zur Bildung der E-konfigurierten Doppelbindung wurde die Julia-Kocienskie-Olefinierung ausgenutzt. Bei den Arbeiten zur Totalsynthese von Xeniolid F wurde eine neuartige Strategie zur diastereoselektiven Synthese eines Allylvinylethers mit E-konfigurierter Vinyletherdoppelbindung eingesetzt. Die Horner-Wadsworth-Emmons-Olefinierung (HWE-Olefinierung) generierte dabei E-selektiv die Vinyletherdoppelbindung. Das für die HWE-Olefinierung benötigte Phosphonat wurde durch rhodiumkatalysierte OH-Insertion aus einem Allylalkohol und einem Diazaphosphonoacetat hergestellt. Der hochsubstituierte Allylvinylether wurde unter den Bedingungen der katalytisch asymmetrischen Claisenumlagerung umgesetzt und führte mit exzellenter Diastereo- und Enantioselektivität zum entsprechenden α-Ketoester. Anhand dieses Beispiels konnte das Potential der katalytisch asymmetrischen Claisenumlagerung zum Aufbau von hochfunktionalisierten Bausteinen für die Naturstoffsynthese verdeutlicht werden.

Among Nature's creation, terpenoids are more versatile and exciting natural products. In a remarkable display of synthetic ingenuity and creativity, nature has endowed terpenes with a bewildering array of carbocyclic frameworks with unusual assemblage of rings and functionalities. This phenomenal structural diversity of terpenes makes them ideal targets for developing and testing new synthetic strategies for efficient articulation of carbocyclic frameworks. The thesis entitled “Ireland-Claisen Rearrangement Based Strategy to Sesquiterpenes Containing Vicinal Quaternary Carbon Atoms” demonstrates the utility of the Ireland ester Claisen rearrangement and RCM reactions for the synthesis of a variety of sesquiterpenes containing vicinal quaternary carbon atoms. The results are described in five different sections, viz., (a) Synthesis of herbertene-1,13-diol and α-herbertenol; (b) Total syntheses of herbertenolide, herberteneacetal, herbertene-1,14-diol and herbertene-1,15-diol; (c) First total synthesis of the spirobenzofuran isolated from Acremonium sp. HKI 0230; (d) Total synthesis of lagopodin A; and (e) Synthesis of Laurencenone C, α- and β-chamigrenes. Complete details of the experimental procedures and the spectroscopic data were provided in a different section. A brief introduction is provided wherever appropriate to keep the present work in proper perspective. The compounds are sequentially numbered (bold), references are marked sequentially as superscripts and listed in the last section of the thesis. All the spectra included in the thesis were obtained by xeroxing the original NMR spectra. To begin with a short and efficient synthesis of herbertene-1,13-diol and α-herbertenol has been achieved starting from 2-allyl-4-methylanisole. Ireland ester Claisen rearrangement of the dimethylallyl 2-arylpent-4-enoate, obtained from p-cresol in seven steps, followed by RCM reaction of the resultant diene generated 1-aryl-1,2,2-trimethylcyclopent-3-enecarbo-xylate, which on functional group transformations provided (±)-herbertene-1,13-diol and (±)-α-herbertenol. Ireland ester Claisen rearrangement of E-3-(2-methoxy-5-methylphenyl)but-2-en-1-yl 2-methylpent-4-enoate furnished a stereoisomeric mixture of the dieneesters, which on RCM reaction generated an epimeric mixture of 2-aryl-1,2-dimethylcyclopent-3-enecarboxylates. These esters were further elaborated into (±)-herbertene-1,14-diol, (±)-herbertene-1,15-diol and (±)-herberteneacetal via epi-herbertenolide and (±)-herbertenolide. First total synthesis of a spirobenzofuran isolated from Acremonium sp. HKI 0230 has been accomplished starting from 2,5-dimethoxy-4-methylphenylacetate, confirming the structure of the natural product. Ireland ester Claisen rearrangement of dimethylallyl 2-(2,5-dimethoxy-4-methylphenyl)pent-4-enoate followed by RCM reaction and demethylation furnished a lactone, cyclopentaspirobenzofuranone, which on further functional group transformations completed the first total synthesis of the spirobenzofuran. 1-(2,5-Dimethoxy-4-methylphenyl)-1,2-dimethylcyclopent-3-enecarboxylate, an intermediate in the synthesis of spirobenzofuran, has been further elaborated into 1-aryl-1,2,2-trimethylcyclopent-3-ene, which on functional group transformations transformed into (±)lagopodin A and (±)-enokipodins A and B. Efficient total syntheses of laurencenone C, α-chamigrene and β-chamigrenes have been accomplished employing an Ireland ester Claisen rearrangement and RCM reaction as key steps starting from the Diels-Alder adduct of isoprene and acrylic acid. Ireland ester Claisen rearrangement of dimethylallyl cyclohex-3-enecarboxylate generated methyl 1-(1',1'-dimethylallyl)cyclohex-3-enecarboxylate, which was further elaborated into 5,5,9-trimethyl-spiro[5.5]undeca-3,8-dien-1-ol employing an RCM reaction as the key step. The spirodienol on further functional group transformations generated (±)-laurencenone C, (±)-α-chamigrene and (±)-β-chamigrene.

Die Nitron-Cycloaddition an ein dearomatisiertes Phenol ermöglichte den leichten Aufbau des Phenanthrengerüstes von Codein in der gewünschten Konfiguration. Weitere Schritte führten mit kompletter Diastereoselektivität zu Allopseudocodein und nach Allylverschiebung durch Hydrolyse der Chlorcodide schließlich zu (±)-Codein.

Synthetic approaches towards linear fused carbon rings have been developed over the last decades due to their high interest as compounds with potential antibiotic activity and as organic electronics. The application of a novel iterative route towards linear fused carbon ring systems could provide a versatile new mode of access to complex substituted ring systems. Studies have previously demonstrated the use of an allylation-double Claisen-RCM sequence to build fused carbon rings (C). In this thesis we described our work to expand the use of this methodology by developing milder reaction conditions that could be applied to a wider range of compounds. This novel methodology was applied towards the synthesis of benzodifuran compounds (D). Our work was extended by developing, for the first time, a mixed Fries-Claisen rearrangement strategy which furnishes template (F), a key intermediate in the synthesis of pyranonaphthoquinones (G). Our work culminated in a new approach to the pyranonaphthoquinone natural products eleutherin (H) and isoeleutherin (I). [Figures missing from abstract].

The dissertation describes Pd0-catalyzed formal 1,3-diaza-Claisen rearrangement and the design and development of cationic 1,3-diaza-Claisen rearrangement. Our previous work has shown that isocyanates react with azanorbornenes and azabicyclo[2.2.2]octenes under thermal conditions to afford zwitterionic intermediates that undergo a thermal 1,3-diaza-Claisen rearrangement to give both ureas and isoureas. However, some azanorbornenes and azabicyclooctenes failed to rearrange or proceeded in low yields. To address these challenging substrates for the thermal 1,3-diaza-Claisen rearrangement, we have developed a Pd0-catalyzed formal 1,3-diaza-Claisen rearrangement. Interestingly, under Pd0-catalyzed condition, both isocyanates with electron-withdrawing groups and isocyanates without electron-withdrawing groups react with azanorbornenes and azabicyclo[2.2.2]octenes to provide ureas as the only products in high yields. More importantly, the reactions that failed under thermal conditions were all successful under Pd0-catalysis. In addition to azanorbornenes and azabicyclo[2.2.2]octenes, other ring systems were also investigated. Pd0 catalysis has broadened the scope of tertiary allylic amines that react with isocyanates to afford 1,3-diaza-Claisen rearrangement products. In the presence of p-TsCl and NEt3, allylaminopropyl benzyl ureas were initially dehydrated to form protonated carbodiimides whose presence was confirmed by the infrared absorption frequency at 2100 cm-1 which is the characteristic band of -N=C=N-; then the in situ generated protonated carbodiimides were poised for further cationic 1,3-diaza-Claisen rearrangement to afford synthetically challenging guanidines. The effect of acid on the rearrangement was ascertained by the fact that no rearrangement product was observed by simply heating free base carbodiimide 3.10 in benzene at reflux. Other dehydration reagents, such as Tf2O, Ts2O, MsCl were also investigated, and none of them provide satisfactory results. A selection of allyamino benzyl ureas with different tether length, substituents, or in varied ring systems, were synthesized to explore the scope of this methodology. This methodology works best at allylaminopropyl benzyl ureas, and the substituents on the benzyl group does not seem to affect the reaction rate in a significant way.

La première partie décrit une approche synthétique de la macrolactine A, molécule naturelle à l'activité antibiotique. La stratégie de synthèse est basée sur deux réactions originales pour construire les systèmes diéniques. Une séquence réactionnelle Johnson- Claisen / isomérisation sur alumine a permis de construire le motif diénique (E)-8,(Z)-11. L'isomérisation d'une cétone propargylique en présence de triphénylphosphine a permis d'obtenir le diène (E)-16,(Z)-19. Les centres asymétriques C-13 et C-23 ont été construits grâce à deux réductions énantiosélectives de Noyori, tandis qu'une allylation asymétrique a permis de former le centre C-7. Le fragment C7-C24 a ainsi été synthétisé en 21 étapes. La deuxième partie de la thèse concerne le développement d'une nouvelle application pour le complexe NaAuCl4.2H2O en catalyse. Dix huit exemples de substitution nucléophile d'alcools propargyliques sont décrits. Ce projet a donné lieu à une collaboration avec une équipe américaine sur la synthèse et le réarrrangement sigmatropique de 6-vinylbicyclo[3.1.0]-hex-2-ènes.

Among Nature’s creation, terpenoids are more versatile and exciting natural products. In a remarkable display of synthetic ingenuity and creativity, nature has endowed terpenes with a bewildering array of carbocyclic frameworks with unusual assemblage of rings and functionalities. This phenomenal structural diversity of terpenes make them ideal targets for developing and testing new synthetic strategies for efficient articulation of carbocyclic frameworks. The thesis entitled “Total synthesis of sesquiterpenes acorenols, chamigrenes, and laurokamurene B; and Enantiospecific synthesis of ABC-ring system of A-nor and abeo pentacyclic triterpenes” describes the studies directed towards the total synthesis of the sesquiterpenes mentioned in the title and exploratory studies towards triterpenoids. In each chapter of the thesis, the compounds are sequentially numbered (bold) and references are marked sequentially as superscripts and listed at the end of the chapter. All the spectra included in the thesis were obtained by xeroxing the original NMR spectra. The sesquiterpenes acorenols, containing an interesting spiro[4.5]decane carbon framework, was first isolated in 1970 by the research group of Tomita from the wood of Juniperus rigida. Recently, in 2003, Braun and coworkers reported the isolation of epi α- and epi β-acorenols along with α- and β-acorenols from the sandal wood oil Santalum spicatum. Total synthesis of all the four acorenols has been described in the first part of the first chapter of the thesis. Initially, a model study has been carried out for the spirocyclopentannulation of cyclohexanone employing a combination of Ireland ester Claisen rearrangement and ring closing metathesis reaction to furnish methyl 4-methylspiro[4.5]dec-3-en-1-carboxylate. The same methodology has been extended for the total synthesis of all the four acorenols starting from cyclohexane-1,4-dione via cis and trans isomers of methyl 4-methyl-8-methylene-spiro[4.5]dec-3-ene-1-carboxylate. Total synthesis of β-chamigrene, γ-chamigrene and laurencenone C, containing spiro[5.5]undecane carbon framework, has been described in the second part of the first chapter. As a model study, cyclohexanone has been transformed into 1,5,5-trimethylspiro-[5.5]undec-4-en-3-one employing a combination of Ireland ester Claisen rearrangement and intramolecular type-II carbonyl ene reactions. The methodology has been extended to chamigrenes starting from cyclohexane-1,4-dione via methyl 2-(1-isopropenyl-4-oxocyclo-hexyl)-2-methylpropanoate and 5,5-dimethyl-1,9-ismethylenespiro[5.5]undecan-3-ol. The marine sesquiterpenes laurokamurenes were first isolated in 2006 by Mao and Guo from Laurencia okamurai Yamada. First total synthesis of (±)-laurokamurene B has been described in the first part of the second chapter. To begin with Ireland ester Claisen rearrangement of but-2-enyl 2-methylpropionate furnished methyl 2,2,3-trimethylpent-4-enoate, which was then transformed into 4,5,5-trimethyl-3-(4-methylphenyl)hepta-1,6-dien-3-ol. RCM reaction followed by reductive deoxygeneation transformed 4,5,5-trimethyl-3-(4-methylphenyl)hepta-1,6-dien-3-ol into (±)-laurokamurene B. Subsequently, an enantioselective total synthesis of (+)-laurokamurene B has been accomplished. Stereoselective hydrogenation of methyl campholenoate furnished methyl 2-[(1S,3S)-2,2,3-trimethyl-cyclopent-1-yl]acetate, which was then transformed into (+)-laurokamurene B via degradation of the two carbon side chain and introduction of the aryl moiety, which established the absolute configuration of laurokamurenes. The third chapter deals with the enantiospecific generation of ABC-ring system of A-nor and abeo 4(3 → 2) tetra and pentacyclic triterpenes. To begin with (R)-carvone was identified as B-ring of ABC-ring system of A-nor and abeo tetra and pentacyclic triterpenes, as the absolute configuration at the C-5 position of the targets correlate to the stereo centre of carvone, and isopropenyl group can serve as the C-4 carbon of the targets along with the two gem-dimethyl groups. A lithium liquid ammonia mediated cyclisation of δ,ε-unsaturated esters was employed for the construction of the A ring and an RCM reaction was opted for the construction of the C ring. (R)-Carvone has been converted into 2-(1-ethoxyethoxy)-1,3,7,7-tetramethylbicyclo[4.3.0]non-3-en-8-ol via lithium liquid ammonia mediated cyclisation of methyl 2-(1-ethoxyethoxy)-6-isopropenyl-1,3-dimethylcyclohex-3-enyl]acetate, which was then transformed into 4-methoxymethoxy-2,5,5,9-tetramethyltricyclo[7.4.0.02,6]tridec-11-en-8-one via the RCM reaction of 3,4-bisallyl-8-methoxymethoxy-4,6,9,9-tetramethylbicyclo-[4.3.0]nonan-3-one. The strategy has been further extended to the synthesis of 4-methylene-2,5,5,9-tetramethyltricyclo[7.4.0.02,6]tridec-11-en-8-one, which contains the ABC ring system of abeo 4(3→2) tetra and pentacyclic triterpenes.

Efficient access to molecular complexity and diversity is important for the development of small-molecule screening libraries designed to identify highly specific modulators of disease relevant macromolecular interactions. We envisioned the use of iteratively synthesized bis-vinyl ether substrates for cascade-type transformations to gain rapid access to several different classes of stereochemically rich, linear or polycyclic scaffolds. To evaluate their utility in this context, mechanistic investigations were undertaken to understand the chemical reactivity of bis-vinyl ethers in radical cyclization reactions and [3,3]-sigmatropic rearrangements. Radical cyclization across bis-vinyl ethers proceeded through an apparent 6-endo-trig/5-exo-trig ring closure to afford functionalized hexahydro-2H-furo[3,4-b]pyrans in good yield, with high diastereoselectivity and excellent regiocontrol. Combination of two electron-withdrawing substituents on the bis-vinyl ether backbone resulted in the trapping of a 5-exo-trig/β-scission product, prompting us to investigate the mechanism for cyclization. Formation of the hexahydrofuropyrans was found to be the result of a 5-exo-trig/3-exo-trig/retro-3-exo-trig pathway to afford a “formal” 6-endo pyranosyl radical that could participate in a second 5-exo-trig cyclization to secure the two ring system. From this earlier study, we found certain combinations of substituents on the bis-vinyl ether backbone increased the propensity for these substrates to undergo Claisen rearrangement at remarkably low temperatures. Kinetic investigations of the substituent effects influencing bis-vinyl ether stability found that electron-releasing substituents on the γ-allyloxy fragment increased the rate of rearrangement as a result of stabilization of a cationic allyl fragment in the transition state. Thermochemical data derived from the earlier kinetic investigations also indicated that the Claisen rearrangement of bis-vinyl ether substrates occured through a dissociative mechanism, characterised by an ΔS‡ of +2.3 cal K-1 mol-1. A palladium-catalyzed auxiliary-controlled diastereoselective Claisen rearrangement of bis-vinyl ethers to access aldol-type products is currently under development. Preliminary results indicate that a modest degree of diastereoselectivity can be achieved in this reaction, provided that the steric burden at the stereogenic element is close enough to the pericyclic framework to exert an influence on facial selectivity. / Graduate

Les cyclopropanes sont rencontrés dans de nombreux produits naturels ou synthétiques bioactifs. Les travaux exposés dans ce manuscrit portent sur le développement de réarrangements sigmatropiques [3,3] impliquant des dérivés de cyclopropénylcarbinols pour accéder à des alkylidènecyclopropanes fonctionnalisés, précurseurs de cyclopropanes diversement substitués. Le réarrangement des cyanates de cyclopropénylcarbinyle a permis d'obtenir des dérivés N-acylés d'alkylidène(aminocyclopropanes). Une méthode efficace et stéréosélective, impliquant le réarrangement d'Ireland-Claisen des glycolates et glycinates de cyclopropénylcarbinyle, a également été mise au point pour synthétiser des alkylidènecyclopropanes possédant un motif α-hydroxy ou α-amino acide. Le champ d'application de ce réarrangement a été étendu avec succès à des gem-difluorocyclopropènes. L'hydrogénation diastéréosélective des alkylidènecyclopropanes diversement substitués issus de ces rérrangements sigmatropiques a ensuite permis d'obtenir des cyclopropanes fonctionnalisés. / The cyclopropane ring is ubiquitous in natural and biologically active compounds. [3,3]-Sigmatropic rearrangements of cyclopropenylcarbinol derivatives have been developed to access functionalized alkylidenecyclopropanes, which are useful precursors of diversely substituted cyclopropanes. We have shown that the rearrangement of cyclopropenylcarbinyl cyanates could be accomplished under mild conditions to obtain N-acyl alkylidene(aminocyclopropanes). The Ireland–Claisen rearrangement of glycolates or glycinates derived from secondary cyclopropenylcarbinols has been developed as an efficient and stereoselective method for the synthesis of alkylidenecyclopropanes possessing an α-hydroxy or α-amino acid moiety. The scope of this transformation was successfully extended to gem-difluorocyclopropenes. The alkylidenecyclopropanes resulting from these latter sigmatropic rearrangements are valuable precursors of substituted cyclopropanes by diastereoselective hydrogenation of the exocyclic olefin.