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.

Structure and Reactivity of Lithium Enolates. From Pinacolone to Selective C‐Alkylations of Peptides. Difficulties and Opportunities Afforded by Complex Structures

The vinylogous aldol reaction: a valuable, yet understated carbon-carbon bond-forming maneuver.

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.

Struktur und Reaktivität von Lithiumenolaten, vom Pinakolon zur selektiven C‐Alkylierung von Peptiden – Schwierigkeiten und Möglichkeiten durch komplexe Strukturen

Ketene alkyltrialkylsilyl acetals: synthesis, pyrolysis and NMR studies

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.

Über die Wechselwirkung zwischen Lithium-enolaten und sekundären Aminen in Lösung und im Kristall

Metalated carboxylic acids. I. Alkylation

Metalated carboxylic acids. II. Monoalkylation of metalated toluic acids and dimethylbenzoic acids

Metalated carboxylic acids. III. Monoalkylation of alkylacetic acids. Possible alternative to the malonic ester synthesis for the preparation of dialkylacetic acids

Paul L. Creger

Papers

Metalated carboxylic acids. I. Alkylation

Metalated carboxylic acids. II. Monoalkylation of metalated toluic acids and dimethylbenzoic acids

Metalated carboxylic acids. III. Monoalkylation of alkylacetic acids. Possible alternative to the malonic ester synthesis for the preparation of dialkylacetic acids

Cinnolines. VI. The Structure of Neber's Lactam. A New Synthesis of 3-Cinnolinol1,2

Studies with the Amine Adducts of β-Benzoylacrylic Acid and its Methyl Ester1