Metalated carboxylic acids. II. Monoalkylation of metalated toluic acids and dimethylbenzoic acids
01 Mar 1970-Journal of the American Chemical Society (American Chemical Society)-Vol. 92, Iss: 5, pp 1396-1397
About: This article is published in Journal of the American Chemical Society.The article was published on 1970-03-01. It has received 87 citations till now.
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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
TL;DR: In this article, it was shown that the freedom of rotation about a carbon carbon double bond is determined by the attached substituents, and the mechanism of this reaction has been established as intramolecular employing 18O.
193 citations
TL;DR: In this article, two X-ray crystal-structure analyses were undertaken to obtain detailed information about the geometry and bonding in such complexes, and they were interpreted using the structure correlation principle; the intermolecular interactions seen in these complexes are considered as points on the reaction coordinates of conversions between the species involved.
Abstract: On the Interaction between Lithium Enolates and Secondary Amines in Solution and in the Crystal
When lithium derivatives generated by lithium diisopropylamide (LDA) are quenched with a D+ source (large excess of ROD), there is frequently only partial deuterium incorporation (non-stoichiometric effect, Scheme 1). Experiments with tert-butyl 2-methylpropionate (1) and its deuterated derivative (2-D)-1 and LDA indicate that the lack of deuteration is not caused by an isotope effect (Scheme 2). A H-bonded complex between the amine (R2NH) and the Li-derivative was envisioned as being responsible for the observed effects. Some crystalline Li-enolate solvates with secondary amines were isolated, and gave rise to only partially deuterated products upon quenching with AcOD/CD3OD (Table 1). Enolates containing the Li-chelating diamine N,N,N′-trimethylethylenediamine (TriMEDA) turned out to be especially suitable for the isolation of single crystals. Thus, two X-ray crystal-structure analyses were undertaken to obtain detailed information about the geometry and bonding in such complexes. The structures of the dimeric N,N-dimethyl-propionamide lithium (Z)-enolate ([2 (Z)-4·2 TriMEDA]; R value 0,049, see Eqn. 2, Figs. 2, 4 and (5) and of the dimeric pinacolone lithium enolate ([2 6·2 TriMEDA]; R value 0,082, see Eqn. 3 and Figs. 3, and 6) were determined. In both centrosymmetric dimeric structures there is a Li-O-Li-O four-membered ring and a H-bridge between TriMEDA and the enolate moiety. In the case of the amide enolate (Z)-4·TriMEDA the bridge points from the amine N-atom to the pyramidalized, enamine-type N-atom of the enolate (N … N distance 3.173(1) A, H … N distance 2.21 (A). In the complex 6·TriMEDA of the ketone enolate there is a H-bridge pointing from the amine N-atom to the enolate double bond (N … Cterminal distance 3.45(1) A, H … Cterminal distance 2.62 A; see Table 3). The geometries of the TriMEDA-Li fragments in the two structures are compared with those of standard TMEDA-Li moieties (Table 2). The two structures are discussed and interpreted using the structure correlation principle; the intermolecular interactions seen in these complexes are considered as points on the reaction coordinates of conversions between the species involved. Thus, they resemble the approach of a secondary amine in the protonation of an enamine N-atom and of an enolate C-atom. At the same time, they represent the final stages of deprotonation of an enammonium ion and of a ketone. The NH … N bridge in 4 is in agreement with experimental observations and with calculations by Muller, indicating that enamines are kinetically protonated on the N-atom. From the pinacolone enolate structures which are now known, (a) possible transition states of deprotonation of carbonyl compounds by Li-amide bases (Figs. 7 and 8), (b) the hypothetical structure of a (i-Pr)2NH/ethyl tert-butyl ketone (E)-enolate (Fig. 8b and Fig. in Footnote 18), c) the approach of the two trigonal centers in an aldol-addition reaction, and the d) trajectory of electrophile attack on a double bond (Fig. 9) are deduced using simple molecular modeling without energy minimization. A comparison with and a discussion of the experimental and theoretical investigations about these same processes by Ireland, Corey, Dauben, Williard, and Houk are given. Finally, we believe that the H-bonding discovered in the crystal structures (Z)-4·TriMEDA and 6·TriMEDA is relevant to what Cram once called the ‘conducted-tour’ mechanism of base-catalyzed racemizations.
186 citations
TL;DR: The oxazoline ring system, first prepared in 1884, has only in the last five years been shown to possess considerable utility in the synthesis of a variety of functionalized organic compounds.
Abstract: The oxazoline ring system, first prepared in 1884, has only in the last five years been shown to possess considerable utility in the synthesis of a variety of functionalized organic compounds. By appropriate metalation of the 2-alkyl substituent it is possible to prepare a variety of homologated carboxylic acid derivatives, both chiral and achiral. Various other manipulations of the oxazoline ring lead to aldehydes, ketones, lactones, amino acids, thiiranes, and olefins. Due to the inertness of the oxazoline ring system to various reagents (RMgX, LiAlH4, CrO3, mild acid or alkali) it may be utilized as a protecting group for carboxylic acids during the transformations involving the above reagents. Two major new developments in oxazoline chemistry involve (a) the use of a chiral oxazoline as a reagent for asymmetric synthesis of chiral carboxylic acids, lactones, alcohol, thiiranes, and olefins and (b) a new mode of aromatic substitution in which the aryloxazolines act as nucleophilic or electrophilic reagents. This behavior has led to a variety of polysubstituted benzenes and biphenyls which would be inaccessible by classical routes. A variety of examples illustrating the utility of oxazolines indicated above are presented so that the reader may appreciate the vast potential of this simple ring system in synthesis.
142 citations