Total synthesis and absolute configuration assignment of MRSA active garcinol and isogarcinol

A short total synthesis of (±)-garcinol and (±)-isogarcinol, two endo-type B PPAPs with reported activity against methiciline resistant Staphylococcus aureus (MRSA), is presented. The separation of framework-constructing from framework-decorating steps and the application of two highly regio- and stereoselective Pd-catalysed allylations, that is, the Pd-catalysed decarboxylative Tsuji-Trost allylation and the diastereoselective Pd-catalysed allyl-allyl cross-coupling, are key elements that allowed the total synthesis to be accomplished within 13 steps starting from acetylacetone. After separation of the enantiomers the absolute configurations of the four natural products (i.e., (-)-garcinol, (+)-guttiferone E (i.e., ent-garcinol), (-)-isogarcinol, and (+)-isoxanthochymol (i.e., ent-isogarcinol)) were assigned based on ECD spectroscopy.Fil: Socolsky, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Tucumán. Instituto de Quimica del Noroeste; Argentina. Universidad Nacional de Tucumán; ArgentinaFil: Plietker, Bernd . Universität Stuttgart. Institut für Organische Chemie; Alemani

Synthèse d'acylphloroglucinols polyisoprénylés

La première partie de ce travail concerne la synthèse des acylphloroglucinols polyisoprénylés (PPAPs).La construction du système bicyclo [3.3.1] nonane -2-4-9 trione des ces composés, a été envisagée à partir de deux stratégies différentes. La première correspond à une réaction d annélation a, a d un éther d énol silylé dérivé d une cyclohexanone avec le dichlorure de malonyle. Elle nous a permis d aboutir à la synthèse totale de la clusianone. De plus les produits secondaires isolés lors de cette réaction, seraient issus de réarrangements structuraux faisant intervenir des intermédiaires proches de ceux qui sont imaginés dans le scénario biogénétique de formation ds PPAPs. La seconde stratégie s inspire de l hypothèse biogénétique. Une méthode originale d alkylation du phloroglucinol en milieu aqueux a conduit aux composés triakylés gem-disubstitués qui, par réaction de C-benzolylation a permis la synthèse de benzoylphloroglucinols, précurseurs biogénétiques des PPAPs. Toutefois, les essais de cyclisation se sont avérés problématiques car seul un modèle très simplifié a pu être obtenu. La deuxième partie de ce manuscrit concerne la réactivité électrophile des aminopentadiènals impliquant des espèces diacylées de type N-acyliminium. Cette réactivité a été mise en valeur dans une réaction de type Pictet-Spengler, en série dopaminique et indolique. Une méthode originale de cyclisation par addition de Michael d un aminonitrile aliphatique sur un aldéhyde a,ß insaturé a aboutit à la synthèse formelle de l émétine, ainsi qu a celle d homologues d alcaloïdes.La dernière partie est un travail exploratoire portant sur la synthèse du cœur pentacyclique des manadomanzamines selon deux stratégies. La première correspond à une réaction de cycloaddition formelle entre deux unités provenant des aminopentadiènals, tandis que la deuxième correspond à un réarrangement issu de la réaction entre un sel de dihydropyridinium et un sel de glutaconaldéhyde.The topic of the first part of this work is the synthesis of polycyclic polyprenylated acylphloroglucinols (PPAPs). The building of the bicyclo [3.3.1] noname 2,4,9- trione system belonging to the compounds was envisaged according to two different strategies. The first one corresponds to an a,a -annelation reaction of a silylated enol ether derived from a cyclohexanone by malonyl dichloride. This allowed us to achieve the total synthesis of the clusianone. Moreover, the side products of this reaction would arise from structural rearrangements involving intermediates close to those imagined in the biogenetic scenario of the PPAPs formation. The second strategy is inspired by the biogenetic hypothesis . An original method for alkylation of phloroglucinol in aqueous medium led to trialky compounds having a gem-disubstitution which, by a reaction of c-benzolylation, led the synthesis of benzoylphloroglucinols, biogenetic precursors of bicyclononanetriones. However, cyclisation tries turned out to be problematic. In spite of our efforts, only a very simplified could be obtained. The second part of this manuscript concerns the electrophilic activation of aminopentadienals involving diacylated species of N-acyliminium type. This reactivity was highlighted in a Pictet-Spengler reaction, leading to dopamine and indole alkaloids. An original method of cyclization using a Michel addition of an aliphatic aminonitrile to a a,b-unsaturated aldehyde led to the formal synthesis of emetine, as well that of structural counterparts. The last part in an exploratory work concerning the synthesis of the pentacyclic core of manadomanzamines according to two strategies. The first one corresponds to a formal cycloaddition between two units coming from aminopentadienals, whereas the second corresponds to a rearrangement following a reaction between a dihydropyridinium salt and a glutaconaldehyde salt.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Enantio- and Diastereoselective Synthesis of <i>N</i>‑Acetyl Dihydrotetrafibricin Methyl Ester

A highly diastereoselective synthesis of <i>N</i>-acetyl dihydrotetrafibricin methyl ester (<b>34</b>) is described. The synthesis features three enantioselective double allylboration reactions and an intramolecular hydrosilylation/Fleming–Tamao oxidation sequence to establish seven of the hydroxy-bearing stereocenters of <b>34</b>. Especially noteworthy is the fragment-assembly double allyboration reaction of <b>2</b> and <b>7</b> using reagent <b>3</b>, which provides the advanced intermediate <b>6</b> with >20:1 diastereoselectivity

Alpha,alpha'-annulation of 2,6-prenyl-substituted cyclohexanone derivatives with malonyl chloride: application to a short synthesis of (+/-)-clusianone. Formation and rearrangement of a biogenetic-like intermediate.

Conditions were found for the successful Effenberger alpha,alpha'-annulation of 3,3-dimethyl-2,4,6-triprenyl cyclohexanone silyl enol ethers with malonyl chloride to give the corresponding bicyclo[3.3.1]nonane-trione in 35% yield, this result allowing a short synthesis of (+/-)-clusianone. An isomeric rearranged bicyclo[3.3.1]nonane-trione was also isolated in 25% yield, and changing the Lewis acid resulted in formation of a lavandulyl-substituted phloroglucinol derivative in 38% yield. The mechanism of formation of these two last products mimics the biogenetic pathway to PPAPs. [reaction: see text]

(Diisopinocampheyl)borane-Mediated Reductive Aldol Reactions of Acrylate Esters: Enantioselective Synthesis of <i>Anti</i>-Aldols

The (diisopinocampheyl)borane promoted reductive aldol reaction of acrylate esters <b>4</b> is described. Isomerization of the kinetically formed <i>Z</i>(O)<i>-</i>enolborinate <b>5</b><i><b>Z</b></i> to the thermodynamic <i>E</i>(O)-enolborinate <b>5</b><i><b>E</b></i> via 1,3-boratropic shifts, followed by treatment with representative achiral aldehydes, leads to <i>anti</i>-α-methyl-β-hydroxy esters <b>9</b> or <b>10</b> with excellent diastereo- (up to ≥20:1 dr) and enantioselectivity (up to 87% ee). The results of double asymmetric reactions of <b>5</b><i><b>E</b></i> with several chiral aldehydes are also presented

Synthetic studies towards bridgehead diprenyl-substituted bicyclo[3.3.1]nonane-2,9-diones as models for polyprenylated acylphloroglucinol construction

The synthesis of bridgehead diprenylated bicyclo[3.3.1]-nonane-2,9-dione, based on a reductive rearrangement of an enol lactone, is presented. The same target could be reached by a one-step sequence involving Michael addition of 2,6-diprenylcyclohexanone onto acrolein and intramolecular aldol reaction. The first method could be extended to the formation of a compound with gem-dimethyl substituents adjacent to the bridgehead position, but the construction of a suitably substituted enol lactone, with a view to polyprenylated acylphloroglucinol elaboration, could not be achieved. © Wiley-VCH Verlag GmbH and Co. KGaA, 2007

(Diisopinocampheyl)borane-Mediated Reductive Aldol Reactions of Acrylate Esters: Enantioselective Synthesis of <i>Anti</i>-Aldols

The (diisopinocampheyl)borane promoted reductive aldol reaction of acrylate esters <b>4</b> is described. Isomerization of the kinetically formed <i>Z</i>(O)<i>-</i>enolborinate <b>5</b><i><b>Z</b></i> to the thermodynamic <i>E</i>(O)-enolborinate <b>5</b><i><b>E</b></i> via 1,3-boratropic shifts, followed by treatment with representative achiral aldehydes, leads to <i>anti</i>-α-methyl-β-hydroxy esters <b>9</b> or <b>10</b> with excellent diastereo- (up to ≥20:1 dr) and enantioselectivity (up to 87% ee). The results of double asymmetric reactions of <b>5</b><i><b>E</b></i> with several chiral aldehydes are also presented