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

Acceptor-substituted lithio compounds LiACR1R2, in which the acceptor A is an RC(0), NC, RSO2, RS(O)NR, RSO, RS, O2N, or RC(NNR2) group, have long played an important role in organic synthesis. Their significance has grown still further in the last fifteen years, as one has increasingly learnt to employ them successfully in chemo-, regio-, diastereo-and enantioselective reactions. Remarkably, little if anything was known of the structures of these compounds. It is therefore not surprising that interest in the structures of this class of compounds has greatly increased in recent years. In the following review, we shall summarize recent research into the structures of the lithio compounds of sulfones, sulfoximides, sulfoxides, thioethers and 1,3-dithianes, nitriles, nitro compounds, and hydrazones. Crystal structure determinations from recent years are central to this study. They are supplemented by solution studies and by calculations of structures. Structural similarities and differences between the individual states of aggregation are pointed out wherever possible, as is also the relationship between structure and reactivity.

The Structure of Lithium Compounds of Sulfones, Sulfoximides, Sulfoxides, Thioethers and 1,3-Dithianes, Nitriles, Nitro Compounds and Hydrazones

Role of Organolithium Aggregates and Mixed Aggregates in Organolithium Mechanisms

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

Carbon−Carbon Bond-Forming Reductive Elimination from Arylpalladium Complexes Containing Functionalized Alkyl Groups. Influence of Ligand Steric and Electronic Properties on Structure, Stability, and Reactivity

Treatment of 2-carbomethoxycyclohexanone dimethylhydrazone with lithium diisopropylamide as a hydrocarbon solution afforded the corresponding lithiated hydrazone as a tetrahydrofuran solvate 1. An X-ray crystallographic structure determination showed 1 to be dimeric in the solid state. Solution molecular weight and spectroscopic studies in aromatic hydrocarbon solvents uncovered a dissociative process involving either monomer-dimer equilibrium or solvent dissociation. Treatment of cyclohexanone phenylimine with lithium diisopropylamide in hydrocarbon solution afforded the corresponding lithiated derivative as the diisopropylamine solvate 2. An X-ray crystallographic structure determination showed 2 to exist as a dimer with significant disorder in the cyclohexenyl and phenyl moieties. Lithium-xrbon contacts of the q3-azaallyl type were not observed. 6Li and \"C NMR studies showed 2 to exist as a 2:l mixture of two rapidly equilibrating forms. By titration of the corresponding solvent-free anion (2sobcnt.frce) with diisopropylamine, the two species were shown to be bis-solvated dimers in close analogy to the solid-state structure. The structures are discussed in light of the stereochemistry of imine alkylation and the syn effect of lithiated imines. We became interested in the mechanism of the alkylations of metalated Schiff s bases (azaallyilithiums).l~* Although on first inspection the C=N-R moiety and C=O ketone carbonyl group appear to be interchangeable, studies by Corey, Enders, Fraser, and others uncovered some notable differences in the alkylation stere~selectivities.~~~ For example, metalated Schiffs bases derived from conformationally anchored cyclohexanones exhibit axial (1) Collum, D. B.; Kahne, D.; Gut, S. A,; Dehe, R. T.; Mohamadi, F.; Wanat, R. A,; Clardy, J.; Van Duyne, G. J . Am. Chem. Soc. 1985,106,4865. (2) Wanat, R. A,; Collum, D. B. J . Am. Chem. Soc. 1985, 107, 2078. (3) Reviews of the chemistry of metalated Schiffs bases: (a) Hickmott, P. W. Tetrahedron 1982, 38, 1975. (b) Enders, D. In Currenf Trends in Organic Synthesis; Nozaki, H., Ed.; Pergamon: New York, 1983. (c) Whitesell, J. K.; Whitesell, M. A. Synthesis 1983, 517. (d) Fraser, R. R. In Comprehensive Carbanion Chemistry; Elsevior: New York, 1980. (4) The nitroso derivatives of 4-terr-butylpiperidines exhibit high alkylation stereoselectivities that seem to imply a close mechanistic relationship to lithiated Schiffs base alkylations (cf. ref 3d). alkylation selectivities of a significantly greater magnitude than those of the corresponding ketone enolates (eq l).5 In the specific case of dimethylhydrazone alkylation, the axial selectivities are sensitive to substituents on the carbanionic carbon. Cyanoand (methy1thio)-substituted lithiated hydrazones alkylate with high axial selectivities. However, the corresponding carbomethoxysubstituted derivative exhibits a lower selectivity more characteristic of ketone enolates. Equally intriguing is the propensity of the 3and 6-substituted lithiated cyclohexanone dimethylhydrazones to alkylate from the more hindered face.' ( 5 ) Huff, B. J. L.; Tuller, F. N.; Caine, D. J. Org. Chem. 1969, 34, 3070. House, H. 0.; Umen, M. J. J. Org. Chem. 1973, 38, 1000. Howe, R.; McQuillin, F. J. J. Chem. SOC. 1958, 1194. Kuwajima, 1.; Nakamura, E. J . Am. Chem. SOC. 1975, 97, 3257. Djerassi, C.; Osiecki, J.; Eisenbraun, E. J. J. Am. Chem. Soc. 1%1,83,4433. House, H. 0.; Tefertiller, B. A,; Olmstead, H. D. J. Org. Chem. 1968,33,935. Kuehne, M. E. J . Org. Chem. 1970,35, 171. Kuwajima, I.; Nakamura, E.; Shimizu, M. J . Am. Chem. Soc. 1982,204, 1025. 0002-7863/86/1508-3415$01.50/0

Solid-state and solution studies of lithiated 2-carbomethoxycyclohexanone dimethylhydrazone and lithiated cyclohexanone phenylimine

Substituent effects on the alkylations of the dimethylhydrazones of 2,4- and 2,6-disubstituted cyclohexanones are reported. High axial selectivities are observed in the alkylations of cyano-substituted metalated hydrazones, but not with alkoxycarbonyl-substituted cases. Hydrazones of 2-substituted cyclohexanones appear to alkylate axially out of a conformer with the 2-substituent pseudoaxially disposed. The possible origins of the stereoselectivities are addressed in light of an X-ray crystal structure of lithiated cyclohexanone dimethylhydrazone.

Substituent effects on the stereochemistry of substituted cyclohexanone dimethylhydrazone alkylations. An x-ray crystal structure of lithiated cyclohexanone dimethylhydrazone

On montre que les stereoselectivites des alkylations d'hydrazones ne derivent pas des effets d'agregation des anions mais de l'alkylation stereoselective de derives monomeres du lithium bis-solvates

On the origin of the stereoselectivity of hydrazone alkylations. Investigation of aggregation effects and solution kinetics

Substituent effects on the stereochemistry of substituted cyclohexanone dimethylhydrazone alkylations. an x-ray crystal structure of lithiated cyclohexanone dimethylhydrazone

Approaches to the synthesis and detection of a transient palladium(0) alkylidene

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