Vito Capriati

Anatomy of Long-Lasting Love Affairs with Lithium Carbenoids: Past and Present Status and Future Prospects

After a long adolescence, the chemistry of lithium carbenoids has currently been entering its maturity bringing a dowry of a more in-depth and less empirical knowledge of the structure and configurational stability of such double-faced intermediates; this, thanks in particular to the synergistic and harmonic cooperation between calculations and the most modern NMR techniques now at our disposal. Such knowledge has stimulated the development of fruitful stereoselective applications in the field of organic synthesis, providing in addition a rationale to observed selectivities. Such aspects together with the role played by aggregation and solvation on the structure-reactivity relationship are highlighted throughout this Minireview with selected examples extracted from recent literature.

α-Substituted α-Lithiated Oxiranes: Useful Reactive Intermediates

Epoxides, strained three-membered ring heterocycles, are among the most versatile intermediates in organic chemistry. The paramount interest for this type of heterocyclic system is amply justified by the great number of biologically significant molecules that contain this motif within their structures and its large use as synthetic building block. A number of important advances have been achieved in the chemistry of epoxides over the last years. Reviews and books have been published to summarize such achievements. Undoubtedly, one of the most fascinating aspects of the chemistry of epoxides is concerned with their behavior toward bases or nucleophilic reagents. Depending on the ring substituents, treatment of an epoxide with a base/nucleophile may cause mainly three different events: (a) cleavage of the strained heterocyclic ring (path a); (b) abstraction of a -proton to give an allylic alcohol in a process that is called -elimination (path b); (c) removal of an R-proton to generate an R-metallated epoxide (oxiranyl anion) (path c) (Scheme 1). This review will focus on generation, reactivity, and synthetic applications of R-metallated oxiranes with special attention addressed to R-lithiated oxiranes. R-Lithiated oxiranes (LO) and their chemistry have driven the interest of several research groups after the pioneering * To whom correspondence should be addressed. Phone: +39.080.54427492251. Fax: +39.080.5442539. E-mail: florio@farmchim.uniba.it. Saverio Florio received his “Laurea” in Chemistry at the University of Bari (Italy) and started his academic career there, first as Assistant Professor (1969) and then as Associate Professor of Organic Chemistry (1982). In 1986, he was appointed Full Professor of Organic Chemistry at the University of Lecce. In 1990 he moved to the University of Bari on the chair of organic chemistry. He has been the Director of Dipartimento Farmaco Chimico of the University of Bari from 1993 to 1997 and, at present, is Director of “Consorzio Interuniversitario sulle Metodologie e Processi Innovativi di Sintesi” (CINMPIS) since its institution in 1994. He has been member and vice president of the Division of Organic Chemistry of the Italian Chemical Society from 1993 to 1997. Since 1997 to 2001 he acted as the President of the same division and from December 2007 he is vice president of the Italian Chemical Society. He has been component of national committees for the evaluation of associate and full professors of organic chemistry in national competitions. At present, Prof. Florio is a member of the Board of consulting editors of Tetrahedron and Tetrahedron Letters, a member of the Scientific Advisory Board of the Ischia IASOC School, and a member of the “Academy of Science and Arts of Salsburg”. His research interests are concerned with the synthesis and reactivity of heterocyclic compounds, in particular metallated epoxides and aziridines, asymmetric synthesis, organometallic chemistry, spectroscopic and computational investigation of organic lithiated species. Prof. Florio has supervised many dozens of undergraduate and PhD students and published more than 180 papers on important international scientific journals and acts as referee for international journals. He has been awarded with “Ziegler-Natta Lecture” (Deutscher Chemiker) in 2005 and with the “Angelo Mangini Gold Medal” of the Division of Organic Chemistry of the Italian Chemical Society in 2007. Chem. Rev. 2008, 108, 1918–1942 1918

Direct observation of a lithiated oxirane: a synergistic study using spectroscopic, crystallographic, and theoretical methods on the structure and stereodynamics of lithiated ortho-trifluoromethyl styrene oxide

α-Lithiated epoxides, long considered “fleeting” intermediates in the reactions of epoxides with strong bases, have nowadays proven to be key synthons for asymmetric synthesis. In this study, the solution and the solid state structure of an α-lithiated aryloxirane, namely α-lithiated ortho-trifluoromethyl styrene oxide (1-Li), were determined. Single crystal X-ray diffraction analysis of 1-Li performed at 100 K applying the X-TEMP-2 device revealed a self-assembled heterochiral dimeric structure with a rare central six-membered (O–Li–C)2 planar core, which is unprecedented in Li/oxygen carbenoids. Multinuclear magnetic resonance (1H, 13C, 19F, 7Li) studies suggested that 1-Li exists in THF solution as a mixture of two interconverting diastereomeric dimeric aggregates, each one featuring a single σ-contact between lithium and a carbon atom. Line shape analysis provided activation parameters for both the dynamic interconversion of the two dimers and the enantiomerisation of 1-Li, which proved to be mostly entropy controlled. The structural assignment in solution was supported by density functional theory computations through the investigation of conformers of monomeric and dimeric complexes of 1-Li featuring different degrees of specific solvation. A mechanism based on the equilibration of six-membered homo- and heterochiral dimers was proposed to explain the configurational instability exhibited by 1-Li in THF.

2-Lithiated-2-phenyloxetane: a new attractive synthon for the preparation of oxetane derivatives

A valuable and direct method to access 2-substituted-2-phenyloxetanes by electrophilic quenching of the corresponding 2-lithiated derivative has, for the first time, been described. 2-Lithiated-2-phenyloxetane was found to be configurationally unstable. Evidence is presented to show that electron-transfer processes are also operative in the coupling reactions with electrophiles.

Stereoselective organocatalysed reactions in deep eutectic solvents: highly tunable and biorenewable reaction media for sustainable organic synthesis

Three distinct stereoselective reactions, catalysed by using a chiral primary amine through different activation methods, have been successfully carried out for the first time in bio-based eutectic mixtures, thereby affording functionalised molecules in very high enantioselectivity. The use of these unconventional and biorenewable reaction media also provides opportunities for facilitating the recovery and the recycling of the chiral catalyst.

Exploiting the Lithiation‐Directing Ability of Oxetane for the Regioselective Preparation of Functionalized 2‐Aryloxetane Scaffolds under Mild Conditions

inde-pendently observed that the lithiation of an aromatic ringcouldbeachievedorthotoasubstituent,andhenceopenedupnew horizons for obtaining differently functionalized organo-lithium derivatives through what is today known as thedirected ortho metalation (DoM) reaction. Since then, andparticularly thanks to seminal contributions from the groupsof Hauser, Meyers, Gschwend, Beak, Snieckus, and others,

Lithiated Fluorinated Styrene Oxides: Configurational Stability, Synthetic Applications, and Mechanistic Insight

The configurational stability of some lithiated fluorinated styrene oxides has been investigated. Chemical studies have shown that in ethereal solvents alpha-lithiated ortho-, meta-, and para-fluorostyrene oxides (2-Li, alpha-5-Li, and alpha-6-Li) are all configurationally stable in the reaction time scale, whereas alpha-lithiated ortho-, meta-, and para-trifluoromethylstyrene oxides (9-Li, 13-Li, and 14-Li) are configurationally unstable. Optically active oxiranyllithiums 2-Li and 9-Li, could be stereospecifically generated and quenched with electrophiles. The corresponding derivatives were then successfully subjected to regiospecific ring-opening reactions with amines to give fluorinated beta-amino alcohols with a stereodefined quaternary carbinol center, which are useful synthons in medicinal chemistry. The barriers of inversion have been calculated (Eyring equation) for oxiranyllithiums 9-Li, 13-Li, and 14-Li by determining the enantiomeric ratios after electrophilic quenching on aging the enantioenriched organolithium for different times in THF; in the case of 9-Li, activation parameters have also been determined. Mechanisms that may be responsible of the racemization oxiranyllithiums 9-Li, 13-Li, and 14-Li undergo once generated are also discussed.

Regio- and stereoselective lithiation of 2,3-diphenylaziridines: a multinuclear NMR investigation.

The alpha-lithiation-trapping sequence of trans-N-alkyl-2,3-diphenylaziridines (s-BuLi or s-BuLi/TMEDA), taking place with a stereochemistry which dramatically depends on the solvent coordinating ability (inversion of configuration in THF and retention in toluene), has been carefully investigated. 1H,13C, and 7Li multinuclear NMR investigations at low temperature suggest that two differently configured lithiated aziridines (monomeric cis-1-Li in THF and dimeric trans-1-Li in toluene) are involved.

On the lithiation of oxazolinylaziridines

Abstract Lithiated N -sulfonyloxazolinylaziridines 6a and 7a , generated by deprotonation of the corresponding aziridines 6 and 7 with sec -BuLi/TMEDA at −98°C in THF, were found to be chemically and configurationally stable to be stereospecifically captured by electrophiles, while warming up to rt resulted in the formation of oxazolinylazirine 15 . In contrast, lithiation of N -phenyloxazolinylaziridines 8 and 9 led to oxazolinylenamine 18 . Tricyclic aziridines 10 and 11 resulted from an intramolecular addition of the aziridinyllithium 6a to the phenyl ring of the benzenesulfonyl group.

Synthesis of oxazolinyl aziridines

Abstract Aziridinyllithiums 4a and 4b , which are stable at low temperature, can be generated by deprotonation of 3a and 3b . Oxazolinyl aziridines 5a-j and 6a-b have been prepared by the reaction of oxazolinyl aziridinyllithiums 4a and 4b with electrophiles. Aziridines 6c and 6d were, instead, synthesized by a Darzens-like reaction from 2-(1-chloroethyl)-2-oxazoline 1b .