Alkylation and oligomerization of the lithium enolate of 2-norbornenones. Stereochemical consequences of enolate aggregation
About: This article is published in Journal of Organic Chemistry.The article was published on 1986-10-01. It has received 20 citations till now. The article focuses on the topics: Lithium & Bicyclic molecule.
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TL;DR: The chemistry of lithium enolates is used to demonstrate that complex structures held together by noncovalent bonds (supramolecules) may dramatically influence the result of seemingly simple standard reactions of organic synthesis as mentioned in this paper.
Abstract: The chemistry of lithium enolates is used to demonstrate that complex structures held together by noncovalent bonds (“supramolecules”) may dramatically influence the result of seemingly simple standard reactions of organic synthesis. Detailed structural data have been obtained by crystallographic investigations of numerous Li enolates and analogous derivatives. The most remarkable features of these structures are aggregation to give dimers, tetramers, and higher oligomers, complexation of the metal centers by solvent molecules and chelating ligands, and hydrogen-bond formation of weak acids such as secondary amines with the anionoid part of the enolates. The presence in nonpolar solvents of the same supramolecules has been established by NMR-spectroscopic, by osmometric, and by calorimetric measurements. The structures and the order of magnitude of the interactions have also been reproduced by ab-initio calculations. Most importantly, supramolecules may be product-forming species in synthetic reactions of Li enolates. A knowledge of the complex structures of Li enolates also improves our understanding of their reactivity. Thus, simple procedures have been developed to avoid complications caused by secondary amines, formed concomitantly with Li enolates by the common methods. Mixtures of achiral Li enolates and chiral Li amides can give rise to enantioselective reactions. Solubilization by LiX is observed, especially of multiply lithiated compounds. This effect is exploited for alkylations of N-methylglycine (sarcosine) CH2 groups in open-chain oligopeptides. Thus, the cyclic undecapeptide cyclosporine, a potent immunosuppressant, is converted into a THF-soluble hexalithio derivative (without epimerization of stereogenic centers) and alkylated by a variety of electrophiles in the presence of either excess lithiumdiisopropyl amide or of up to 30 equivalents of lithium chloride. Depending on the nature of the LiX additive, a new stereogenic center of (R) or (S) configuration is created in the peptide chain by this process. A structure-activity correlation in the series of cyclosporine derivatives thus available is discussed.
695 citations
TL;DR: In this article, the authors show that the Reaktivitat von Li-Enolate is besser zu verstehen, wenn ihre komplexen Strukturen berucksichtigt werden.
Abstract: Am Beispiel der Li-Enolate last sich zeigen, das komplexe, durch nicht-kovalente Bindungen zusammengehaltene Gebilde („Ubermolekule”) das Ergebnis von scheinbar einfachen Standardreaktionen der organisch-chemischen Synthese beeinflussen konnen. Kristallographische Untersuchungen zahlreicher Li-Enolate und analoger Derivate ergaben eine Fulle detaillierter Strukturinformationen. Auffalligste Merkmale der Strukturen sind die Aggregation zu Dimeren, Tetrameren und zum Teil noch hoheren Oligomeren, die Komplexierung der Metallzentren mit Solvensmolekulen und Chelatbildnern sowie die Wasserstoff-bruckenbindung schwacher Sauren (z. B. sekundarer Amine) mit anionoiden Komponenten der Li-Enolate. Durch NMR-spektroskopische, osmometrische und calorimetrische Messungen ist die Anwesenheit derselben Ubermolekule in unpolaren Losungsmitteln (Kohlen-wasserstoffen und Ethern) wie in den Kristallen nachgewiesen worden. Mit ab-initio-Berechnungen wurden auser den Strukturen auch die Grosenordnung der Wechselwirkungen qualitativ reproduziert. Wichtig fur die Praxis der organischen Synthese mit Li-Enolaten ist schlieslich, das Ubermolekule auch produktbildende Spezies sein konnen. Die Reaktivitat von Li-Enolaten ist besser zu verstehen, wenn ihre komplexen Strukturen berucksichtigt werden. So kann der storende Einflus von sekundaren Aminen, den Nebenprodukten bei der ublichen Enolaterzeugung, durch Deprotonierung vermieden werden; in Mischungen aus achiralen Li-Enolaten und chiralen Li-Amiden finden enantioselektive Reaktionen statt; durch Zusatz von LiX werden die Eigenschaften von Li-Enolaten drastisch verandert; vor allem vielfach lithiierte Verbindungen konnen durch LiX auch solubilisiert werden. Offenkettige Oligopeptide lassen sich an der CH2-Gruppe von N-Methylglycin(Sarkosin)-Einheiten alkylieren. In Gegenwart von uberschussigem Lithiumdiisopropylamid oder von bis zu 30 Aquivalenten LiCl wird das cyclische Undecapeptid Cyclosporin, ein potentes Immunsuppressivum, uber ein in Tetrahydrofuran losliches Hexalithium-Derivat (ohne Epimerisierung stereogener Zentren) mit Elektrophilen umgesetzt. Dabei entsteht, je nach Art des LiX-Zusatzes, selektiv ein neues stereogenes Zentrum mit (R)- oder (S)-Konfiguration in der Peptidkette. Die so zuganglichen Abkommlinge des Cyclosporins sind Musterbeispiele fur das Studium von Struktur-Wirkungs-Beziehungen.
274 citations
263 citations
TL;DR: In this paper, direct acid-catalysed condensation of substituted anilines with acetylacetone was found to give convenient access to β-enamineimines, which were conveniently metallated using BunLi.
Abstract: Direct acid-catalysed condensation of substituted anilines with acetylacetone was found to give convenient access to β-enamineimines [2-Pri-C6H4NCMeCHCMeNH-2-Pri-C6H4] and [2-MeO-C6H4NCMeCHCMeNH-2-MeO-C6H4], whereas TiCl4-mediated condensation was required to produce [2,6-Pri2-C6H3NHC(CF3)CHC(CF3)N-2,6-Pri2-C6H3], which was crystallographically characterized. All are conveniently metallated using BunLi. The structures of monomer [2-Pri-C6H4NCMeCHCMeN-2-Pri-C6H4·Li(thf)2], and dimer [{ 2-MeO-C6H4NCMeCHCMeN-2-MeO-C6H4·Li}2] are reported. The structure of the dimeric product of aldol addition of adamantan-2-one to [2-Pri-C6H4NCMeCHCMeN-2-Pri-C6H4·Li.], the lithium scorpionate [{(C10H14OLi)CH(CMeN-2-Pri-C6H4)2}2], is also reported. It undergoes retro-aldol dissociation upon dissolution in non-co-ordinating solvents. The efficient synthesis of α-C,C′ dialkylated ‘true’
β-diimines by repeat lithiation/alkylation of di- and mono-ortho-isopropylanilino diketiminates is also reported. The differing reactivity of the monomers and dimer with electrophiles, and its relation to the structures of the intermediates, are discussed.
71 citations
01 Jan 1991
TL;DR: In this paper, structural characterizations of carbanions of alkali and alkaline earth cations have been examined with the overall goal of collating this new information especially as it pertains to increasing our knowledge and control over the reactivity of these most useful and important synthetic reagents.
Abstract: In this chapter the focus is primarily on the recent structural work concerning carbanions of alkali and alkaline earth cations that are widely utilized in synthetic organic chemistry. In this context the year 1981 is significant because the first detailed X-ray diffraction analyses of two lithium enolates of simple ketones, i.e. 3,3-dimethyl-2-butanone and cyclopentanone, were published.1 Since 1981 a number of detailed X-ray diffraction analyses of synthetically useful enolate anions of alkali and alkaline earth cations have been described. Within this chapter, many recent structural characterizations will be examined with the overall goal of collating this new information especially as it pertains to increasing our knowledge and control over the reactivity of these most useful and important synthetic reagents. The chapter is organized by functional group because this classification is quite natural to synthetic chemists. The examples chosen have come to my attention while thinking about the role of these species in synthetic reactions. It is neither practical nor feasible to include in this chapter an exhaustive review of all structural characterizations of carbanions of alkali and alkaline earth cations.2 Should the complete list of all such structures be required, a comprehensive search of the Cambridge Structural Database (CSD) is recommended.3 Throughout this chapter structural references are given to six letter CSD reference codes as follows, (XXXXXX). These refcodes will assist in obtaining crystallographic coordinates directly from the CSD.
34 citations